Practice Guidelines Chest Physicians Evidence-Based

Transcription

Introduction to the Ninth Edition :
Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical
Practice Guidelines
Gordon H. Guyatt, Elie A. Akl, Mark Crowther, Holger J. Schünemann,
David D. Gutterman and Sandra Zelman Lewis
Chest 2012;141;48S-52S
DOI 10.1378/chest.11-2286
The online version of this article, along with updated information and
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Chest is the official journal of the American College of Chest
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ISSN:0012-3692
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© 2012 American College of Chest Physicians
CHEST
Supplement
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
Introduction to the Ninth Edition
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
Gordon H. Guyatt, MD, FCCP; Elie A. Akl, MD, PhD, MPH; Mark Crowther, MD;
Holger J. Schünemann, MD, PhD, FCCP; David D. Gutterman, MD, FCCP;
and Sandra Zelman Lewis, PhD
The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines differs substantially from the prior versions both in process and in content. In this introduction, we describe some of the differences and
the rationale for the changes.
CHEST 2012; 141(2)(Suppl):48S–52S
Abbreviations: ACCP 5 American College of Chest Physicians; AT6 5 Sixth ACCP Consensus Conference on
Antithrombotic Therapy; AT7 5 Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: EvidenceBased Guidelines; AT8 5 Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition); AT9 5 Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines; GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation
would like to begin by acknowledging the
Wecontributions
of the visionaries whose work on
past editions of these guidelines have allowed the
current panel to develop this edition using the changes
noted herein. First, James E. Dalen, respected clinician
Revision accepted August 31, 2011.
Affiliations: From the Department of Clinical Epidemiology
and Biostatistics (Drs Guyatt, Akl, and Schünemann) and Department of Medicine (Drs Guyatt, Crowther, and Schünemann),
McMaster University Faculty of Health Sciences, Hamilton, ON,
Canada; Departments of Medicine and Family Medicine (Dr Akl),
State University of New York, Buffalo, NY; Cardiovascular
Research Center (Dr Gutterman), Medical College of Wisconsin,
Milwaukee, WI; and Evidence-Based Clinical Practice Guidelines
and Clinical Standards (Dr Lewis), American College of Chest
Physicians, Northbrook, IL.
Funding/Support: The Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines received support from
the National Heart, Lung, and Blood Institute [R13 HL104758]
and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer,
Inc; Canyon Pharmaceuticals; and sanofi-aventis US.
Disclaimer: American College of Chest Physician guidelines
are intended for general information only, are not medical advice,
and do not replace professional medical care and physician
advice, which always should be sought for any medical condition.
The complete disclaimer for this guideline can be accessed at
http://chestjournal.chestpubs.org/content/141/2_suppl/1S
48S
and researcher, while President of the American
College of Chest Physicians (ACCP), had the foresight
not only to propose the original consensus conference
on the controversial issues of the indications for antithrombotics, antiplatelet agents, and thrombolytics
for the prevention and treatment of cardiovascular
disorders but also to invite Jack Hirsh, an extremely
productive scientist and leader in the field of thrombosis, to join him in leading this important project.
Drs Hirsh and Dalen brought a panel of leading
experts together for the first antithrombotic guideline1 in 1986. Dr Dalen was co-editor of the first six
guidelines from 1986 to 2001.
Dr Hirsh is, to an extraordinary extent, responsible
not only for creating the platform that has made Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Correspondence to: Gordon H. Guyatt, MD, FCCP, Department
of Clinical Epidemiology and Biostatistics, McMaster University,
Hamilton, ON, L8N 3Z5, Canada; e-mail: [email protected]
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.11-2286
Evidence-Based Clinical Practice Guidelines (AT9)
possible but also for the advances from Antithrombotic and Thrombolytic Therapy: American College
of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition) (AT8) to AT9. It was not
only the creation of an expert panel—a standard feature of specialty society clinical practice guidelines
from the outset—that made the antithrombotic
guidelines extremely successful. Dr Hirsh, an accomplished basic science researcher and a brilliant clinical trialist, deeply understood the value of what was
to become more than a decade later evidence-based
medicine. He recruited one of the world leaders
in the burgeoning field of clinical epidemiology,
David Sackett, to play a major role in the guidelines.
Drs Hirsh and Sackett developed and applied an
innovative system of rating the quality of evidence and
strength of recommendations that was at the time
unique to specialty guidelines. The combined impact
of the authoritative, carefully considered recommendations and explicit acknowledgment of the quality of
evidence and strength of recommendations immediately made these guidelines the reference standard
for antithrombotic therapy around the world.
Under Dr Hirsh’s leadership, the guidelines more
than kept pace with advances in the science of guideline methodology and continued to improve with
each iteration. Each new edition provided a model
incorporating not only the latest evidence regarding
antithrombotic therapy but also advances in specialty-based guidelines and therefore maintained preeminence in the field of thrombosis.
As Dr Hirsh was stepping down from the leadership of the guidelines in 2007, his insight led him to
question the reliance on expert opinion that provided
the basis for the first eight iterations of the antithrombotic guidelines. Reviewing his experience—and
in the process giving new life to an idea suggested
decades earlier but seldom applied2—Dr Hirsh concluded that the conflict of interest of leading experts
was highly problematic.3 Furthermore, the problem
arose not only from their financial but equally or perhaps more important, their intellectual conflict of
interest. This revelation and the changes in process
that Dr Hirsh suggested as a solution to the problem
had a profound impact on the leadership to whom he
was passing the torch. These changes underlie all the
innovations in AT9.
The New Process in AT9—Dealing
With Conflict of Interest
The solution that Dr Hirsh proposed was endorsed
by the ACCP leadership and implemented in AT9.
That solution is to give primary leadership and
www.chestpubs.org
Table 1—Major Innovations in AT9
1. Unconflicted methodologists as topic editors. Conflicted experts
did not participate in final process of making recommendations.
2. Many evidence profile and summary of finding tables.
3. New insights into evidence (asymptomatic thrombosis, aspirin).
4. Quantitative specification of values and preferences based on
systematic review of relevant evidence and formal preference
rating exercise.
5. Article addressing diagnosis of DVT.
AT9 5 Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines.
responsibility for each article not to a thrombosis
expert but to a methodologist who, in almost all cases,
also is a practicing physician without important conflicts of interest4,5 (Table 1). These editors of each
article had specific training in ACCP’s approach
to rating the quality of evidence and grading strength
of recommendations (see “Evidence Summaries”
section). Further, building on the work of prior guideline groups,6 the process stipulated that although
conflicted thrombosis experts could engage in discussion and even draft evidence summaries, they would
be excluded from the final decisions regarding quality of
evidence and direction and strength of recommendations. Intellectual conflicts received the same attention as financial conflicts. Readers of the guidelines
can find in the online data supplements to AT9 articles
a recommendation-by-recommendation accounting
of the intellectual and financial conflicts of each panel
member. The most important changes in AT9 content have flowed directly from this change in process.
Evidence Summaries
The Sixth ACCP Consensus Conference on Antithrombotic Therapy (AT6),7 published in 2001,
adopted an approach to rating quality of evidence
and strength of recommendations8 that presaged
that of the Grades of Recommendations, Assessment,
Development, and Evaluation (GRADE) working
group,9 itself adopted with minor modifications for
AT810 and for all ACCP guidelines.11 AT8, like AT6
and the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based
Guidelines (AT7),12 underwent thorough editing and
review of the quality of evidence, including in many
cases a careful assessment of single studies by topic
editors and the guideline executive committee.
Nevertheless, many of the topic editors did not have
methodologic training or, as was the case in AT8, specific training in the ACCP-GRADE approach. The
result was that in AT8, the ACCP-GRADE approach
often was not applied with optimal rigor, and authors
CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT
49S
produced very few of the summary tables that are the
hallmark end product of the GRADE process.
There are two types of such tables: evidence profiles and summary of findings. Evidence profiles summarize the quality of a body of evidence for each
relevant outcome and, when evidence comes from
randomized trials, include a presentation of reviewers’
assessment of risk of bias, precision, consistency,
directness, and publication bias.5 Readers of AT9 can
find the evidence profiles in the online data supplements. The text in the main AT9 articles includes
the more succinct summary of findings tables, which
include the overall quality assessment as well as
relative and absolute effect sizes for each outcome.
We did not succeed in the lofty goal of producing a
summary of findings table for each recommendation,
but readers will find these for most major and potentially controversial recommendations. Readers will
find . 10 such tables in most articles and . 20 in
some articles.
Producing these tables forces a rigor of thinking
achievable in few other ways. Creating a large number
of evidence profiles provides deep insight into the
ACCP-GRADE approach to assessing the quality of
evidence and strength of recommendations. Along
with recruitment of GRADE-expert topic editors,
production of evidence profiles and summary of findings tables is responsible for the increased methodologic rigor of AT9.
We also tried to apply a rigorous approach to
choosing the format of these tables, an issue that has
generated some controversy within the GRADE working group. Per Olav Vandvik, Holger Schünemann,
and Nancy Santesso led the group in a formal study
in which AT9 panelists expressed their view of the
optimal presentation of the tables.5 The results have
not only guided the presentation of evidence profiles
and summary of findings in AT9 but also provided
one of the recommended options for the GRADE
working group.
Reevaluation of Evidence
Relying on the perspective of unconflicted methodologists, rigorously applying the GRADE approach,
and excluding those with financial and intellectual
conflict of interests from bottom-line decisions
regarding the quality of evidence and strength of
recommendations led to reevaluations of previously
existing evidence (Table 1). For instance, application
of the ACCP-GRADE approach requires the distinction between patient-important and surrogate outcomes. The first eight editions of the antithrombotic
guidelines failed to fully recognize the implications
of a surrogate widely used in thrombosis prevention
50S
trials—asymptomatic, screening-detected thrombosis. Use of this surrogate creates major problems
in making the trade-off between patient-important
outcomes (thrombosis and serious bleeding). For
instance, if one knows that an intervention increases
serious bleeding by 20 events in 1,000 patients but
reduces asymptomatic thrombosis by 100 in 1,000,
what is the net benefit? Establishing net benefit in
outcomes important to patients requires knowing
the symptomatic DVT and symptomatic pulmonary embolism reduction represented by the reduction in 100 asymptomatic events. Dr Hirsh and
John Eikelboom led the prevention topic editors in
developing innovative approaches to dealing with
the problem of inferring the impact of thromboprophylaxis on symptomatic thrombosis from studies
that relied to a considerable extent on detection of
asymptomatic events.13 The available approaches,
although representing a step forward, all have limitations and highlight the need for studies that directly
measure symptomatic thrombosis without venographic or ultrasound surveillance.
As a result of a reevaluation led by Dr Eikelboom,
one consequence of the recognition that measurement of patient-important events in a naturalistic
clinical setting (as opposed to in the context of venographic or ultrasonographic screening for asymptomatic thrombosis) was a differing perspective on the
use of aspirin in thromboprophylaxis in orthopedic
surgery. The authors of AT8 had concluded that there
was high-quality evidence justifying a strong recommendation against aspirin as the sole agent for thromboprophylaxis in surgical patients. Authors of AT9
focused on results from a very large trial using concealed randomization and blinding and achieving
near-complete follow-up.14 After an exhaustive and
repeated discussion involving the authors of all the
prevention articles, and ultimately the entire panel,
AT9 authors concluded that the trial provides moderate-quality evidence supporting the use of aspirin,
which is now offered as an option for thromboprophylaxis in patients undergoing major orthopedic
procedures.15 AT9 authors concluded that there is
low-quality evidence supporting a weak recommendation of low-molecular-weight heparin over aspirin
in these patients.
The GRADE approach defines quality of evidence
as our level of confidence in estimates of diagnostic
or treatment effect to support a particular recommendation.16 In general, the changing perspectives
on evidence led to the conclusion that we often could
not be as confident in estimates of effect as previously
believed. Readers of AT9 will often find, therefore,
that some of the evidence previously rated as high
quality is now moderate, and evidence previously
rated as moderate quality is now low.
Values and Preferences
Serial iterations of AT9 dating back to AT6 have
gradually put increasing emphasis on patient values
and preferences. For the first time, the AT7 panel
made the assumptions about values and preferences
explicit. The AT9 panel has accelerated that process
by conducting a systematic review17 of the relevant
research of empirical investigations of values and preferences of patients regarding antithrombotic therapy.
Based on that review, AT9 panelists conducted a
value rating exercise that provided the basis for values
and preference judgments within AT9, judgments
that are summarized in the introductory section of
each article.13 The judgments are more explicit and
quantitative than any previous guideline. For example,
we estimated that on average, patients experience the
disutility of a GI bleed more or less equally to that of
VTE but only one-third of the disutility of a stroke.
Among the findings of the systematic review of
patient values and preferences regarding antithrombotic treatment are the heterogeneity of results
between studies and the wide variability in values and
preferences among patients. Because the core characteristic of a strong recommendation is the belief
that across the range of values and preferences, virtually all informed patients will make the same choice,
the wide variability in patient values and preferences
makes strong recommendations less likely.18
environment and to support efforts to make the
phrasing of recommendations more user friendly and
implementable.
A limitation of AT8 was the very inconsistent
approaches to assessing bleeding risk. Sam Schulman,
author of the bleeding risk article in AT8,19 took
responsibility for developing the AT9 approach to
bleeding and ensuring that it was consistently applied
across chapters.5
To address issues of economic efficiency, we
included “resource use consultants” on the AT9 article
panels charged with making recommendations. They
developed a transparent and systematic methodology
to address questions for which resource use might
change the direction or strength of recommendations.5
We made an intensive effort to remove duplication
between articles and to harmonize recommendations
between related articles. An important strategy was
to include topic editors and deputy editors as panelists from both articles when two had overlapping
issues.
Finally, for the first time, the antithrombotic guidelines have addressed issues of diagnosis. Shannon Bates
and Roman Jaeschke led a panel that took on the
challenging task of applying the newly developed
GRADE methodology for recommendations regarding
the diagnosis of DVT.20
Conclusion
Impact of Innovations on
the Recommendations
Readers of AT9 will find many weak recommendations replacing the strong recommendations of AT8.
One major reason for this change is the more critical
look at the evidence and the resulting inferences that
some evidence is lower quality than previously believed.
A second is the recognition of variability in values and
preferences. Third, in the small number of controversial
recommendations that came to a formal vote using
anonymous electronic voting, we required the endorsement of . 80% of panelists to make a strong recommendation. Finally, the exclusion of conflicted experts,
who often hold strong opinions about optimal management approaches, from final decisions regarding
quality of evidence and strength of recommendations
also may have contributed.
Building on the seminal work of Drs Hirsh and
Dalen and their colleagues over the 20-year history of
the ACCP antithrombotic guidelines, AT9 has made
a number of changes in process, resulting in differences in the approach to making recommendations
and their content. Past iterations of these guidelines
have celebrated new high-quality evidence and the
strong recommendations that such evidence warrants. The insights from AT9 include the persisting
limitations in evidence quality (particularly with
respect to the use of surrogate outcomes in prophylaxis trials) and the appropriateness of weak recommendations that reflect our lack of confidence in
effect estimates and the variability in patient values
and preferences. We believe that the objective, rigorous application of the science of guideline development will ultimately best serve our patients.
Other Innovations in AT9
Acknowledgments
For the first time, each panel included a frontline
clinician not involved in thrombosis research. The
goal of including these individuals was to ensure that
recommendations considered the full realities of clinical practice as viewed by those outside the research
Financial/nonfinancial disclosures: In summary, the authors
have reported to CHEST the following conflicts of interest:
Dr Crowther has served on various advisory boards, has assisted
in the preparation of educational materials, and has sat on data
safety and monitoring boards. His institution has received research
funds from the following companies: Leo Pharma A/S, Pfizer Inc,
Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals,
www.chestpubs.org
51S
Octapharm AG, CSL Behring, and Artisan Pharma. Personal total
compensation for these activities over the past 3 years totals less
than US $10,000. Dr Gutterman has had the following relationships that are entirely unrelated to the AT9 guidelines: ACCP
President, GlaxoSmithKline plc grant to study vasodilation in
adipose tissue, National Institutes of Health grant to study human
coronary dilation, and GE Healthcare consultation on a study
for ECG evaluation of chronic heart disease. Drs Guyatt and
Schünemann are co-chairs of the GRADE Working Group, and
Dr Akl is a member and prominent contributor to the GRADE
Working Group. Dr Lewis is a full-time employee of the ACCP.
Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot
recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline
panel members, including the chair, and members of the Health &
Science Policy Committee are blinded to the funding sources.
Further details on the Conflict of Interest Policy are available
online at http://chestnet.org.
Other contributions: The authors thank Rachel Gutterman, BA,
and Joe Ornelas, DC, for their assistance in managing this complex
project.
Endorsements: This guideline is endorsed by the American
Association for Clinical Chemistry, the American College of Clinical
Pharmacy, the American Society of Health-System Pharmacists,
the American Society of Hematology, and the International Society
of Thrombosis and Hematosis.
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5. Guyatt GH, Norris SL, Schulman S, et al. Methodology for
the development of antithrombotic therapy and prevention
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Physicians evidence-based clinical practice guidelines. Chest.
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6. Schünemann H, Osborne M, Moss J, et al. An official
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11. Guyatt G, Gutterman D, Baumann MH, et al. Grading
strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest
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outcome measurement in the prevention of thrombosis in
surgical and medical patients: antithrombotic therapy and
prevention of thrombosis, 9th ed: American College of Chest
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Introduction to the Ninth Edition : Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines
Gordon H. Guyatt, Elie A. Akl, Mark Crowther, Holger J. Schünemann, David
D. Gutterman and Sandra Zelman Lewis
Chest 2012;141; 48S-52S
DOI 10.1378/chest.11-2286
This information is current as of February 7, 2012
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Executive Summary : Antithrombotic
Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians
Gordon H. Guyatt, Elie A. Akl, Mark Crowther, David D. Gutterman,
Holger J. Schuünemann and for the American College of Chest
Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel
Chest 2012;141;7S-47S
DOI 10.1378/chest.1412S3
Supplemental material related to this article is available at:
http://chestjournal.chestpubs.org/content/suppl/2012/02/06/141.2_suppl.
7S.DC1.html
ISSN:0012-3692
CHEST
Supplement
Executive Summary
Gordon H. Guyatt, MD, FCCP; Elie A. Akl, MD, PhD, MPH; Mark Crowther, MD;
David D. Gutterman, MD, FCCP; Holger J. Schünemann, MD, PhD, FCCP; for the American
College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel*
CHEST 2012; 141(2)(Suppl):7S–47S
Abbreviations: ACS 5 acute coronary syndrome; AF 5 atrial
fibrillation; AIS 5 arterial ischemic stroke; APLA 5 antiphospolipid
antibodies; ASA 5 acetylsalicylic acid; AT9 5 Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice
Guidelines; BMS 5 bare-metal stent; CABG 5 coronary artery
bypass graft; CAD 5 coronary artery disease; CDT 5 catheterdirected thrombosis; CHADS2 5 congestive heart failure, hypertension, age !75 years, diabetes mellitus, prior stroke or transient
ischemic attack; CSVT 5 cerebral sinovenous thrombosis; CTPH 5
chronic thromboembolic pulmonary hypertension; CUS 5 compression ultrasound; CVAD 5 central venous access device;
DES 5 drug-eluting stent; GCS 5 graduated compression stockings;
HFS 5 hip fracture surgery; HIT 5 heparin-induced thrombocytopenia; HITT 5 heparin-induced thrombocytopenia complicated
by thrombosis; IA 5 intraarterial; ICH 5 intracerebral hemorrhage; IE 5 infective endocarditis; INR 5 international normalized
ratio; IPC 5 intermittent pneumatic compression; IPCD 5 intermittent pneumatic compression device; IVC 5 inferior vena cava;
LDUH 5 low-dose unfractionated heparin; LMWH 5 low-molecularweight heparin; LV 5 left ventricular; MBTS 5 modified BlalockTaussig shunt; MR 5 magnetic resonance; PAD 5 peripheral artery
disease; PCI 5 percutaneous coronary intervention; PE 5 pulmonary embolism; PFO 5 patent foramen ovale; PMBV 5 percutaneous mitral balloon valvotomy; PTS 5 postthrombotic syndrome;
PVT 5 prosthetic valve thrombosis; r-tPA 5 recombinant tissue plasminogen activator; RVT 5 renal vein thrombosis; SC 5 subcutaneous; TEE 5 transesophageal echocardiography; THA 5 total
hip arthroplasty; TIA 5 transient ischemic attack; TKA 5 total knee
arthroplasty; UAC 5 umbilical arterial catheter; UEDVT 5 upperextremity DVT; UFH 5 unfractionated heparin; US 5 ultrasound;
UVC 5 umbilical venous catheter; VAD 5 ventricular assist device;
VKA 5 vitamin K antagonist
iteration of the American College of
TheChesteighth
Physicians Antithrombotic Guidelines presented, in a paper version, a narrative evidence summary and rationale for the recommendations, a small
number of evidence profiles summarizing bodies of
www.chestpubs.org
evidence, and some articles with quite extensive
summary tables of primary studies. In total, this
represented 600 recommendations summarized in
968 pages of text. Many readers responded that the
result was too voluminous for their liking or practical use.
Cognizant of this feedback, we worked hard to
minimize the length of the text for the ninth iteration
of the guidelines Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice
Guidelines (AT9) without sacrificing key content. A
number of topic editors found our shortening edits
draconian, but we were determined to produce the
leanest product possible.
There were, however, a number of obstacles. In
what we believe is a key advance in AT9, we conducted a systematic review of what is known about
patients’ values and preferences regarding antithrombotic therapy and included the results as an article
in AT9. In another forward step, we recognized the
problems with asymptomatic thrombosis as a surrogate outcome, and devised strategies to estimate
reductions in symptomatic DVT and pulmonary
embolism with antithrombotic prophylaxis. We felt it
important to explain this innovation to users of AT9,
and this meant another article.
We included, for the first time, an article on diagnosis addressing patients with symptoms and signs
suggesting DVT. We increased the range of interventions we have covered, resulting in additional recommendations. Finally, we produced many summary
of findings tables, which offer extremely succinct and
informative presentations of best estimates of effect
and the confidence associated with those estimates.
If published in the same fashion as the Antithrombotic and Thrombolytic Therapy, 8th ed: American
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College of Chest Physicians Antithrombotic Guidelines, this would have resulted in a document
with . 850 pages of paper text, an unacceptable
length. Given this and with the advice of the journal,
we decided to adopt a highly focused print version
that includes only this executive summary and the
following articles:
• An introduction describing the major innovations
in AT9
• A methods article explaining how we developed the guidelines (a potential model for other
guideline groups interested in optimal rigor)
• Recommendations and grading from each article embedded in the table of contents of each
article
Those seeking the rationale for the recommendations, including the supporting evidence, should
access the online version of the guideline (http://
http://chestjournal.chestpubs.org/content/141/2_suppl)
that includes a narrative summaries and supporting summary of findings tables. The numbering indicated beside the recommendations in this summary
is aligned with the sections and tables found in the
full articles. Those interested in a deeper understanding of the evidence can turn to online data
supplements for each of the articles that include recommendations. There, they will find evidence profiles (expanded versions of the summary of findings
and Biostatistics (Drs Guyatt, Akl, and Schünemann) and Department of Medicine (Drs Guyatt, Crowther, and Schünemann),
McMaster University Faculty of Health Sciences, Hamilton,
ON, Canada; Departments of Medicine and Family Medicine
(Dr Akl), State University of New York, Buffalo, NY; Cardiovascular
Research Center (Dr Gutterman), Medical College of Wisconsin,
Milwaukee, WI.
*For complete panel list, see: http://chestjournal.chestpubs.org/
content/141/2_suppl/2S
and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer,
Disclaimer: American College of Chest Physician guidelines are
intended for general information only, are not medical advice,
and do not replace professional medical care and physician advice,
which always should be sought for any medical condition. The
complete disclaimer for this guideline can be accessed at http://
chestjournal.chestpubs.org/content/141/2_suppl/1S
DOI: 10.1378/chest.1412S3
tables) and some tables summarizing the methods
and results, and the risk of bias, associated with the
individual studies that contributed to the evidence
profiles and summary of findings tables.
The world of medical information is rapidly becoming a world of electronic storage and presentation
of primary studies, recommendations, and a wide
variety of other information of interest to health care
practitioners. Although our abbreviated paper copy
presentation represents a necessary response to a
challenging situation, it is also a harbinger of the
increasingly electronic world of medical information
into which future editions of guidelines are destined
to move.
Summary of Recommendations
Note on Shaded Text: Throughout this guideline,
shading is used within the summary of recommendations sections to indicate recommendations that are
newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy:
American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.
Evidence-Based Management of
Anticoagulant Therapy
For further details, see Holbrook et al.1
2.1 Loading Dose for Initiation of Vitamin K Antagonist
(VKA) Therapy
2.1. For patients sufficiently healthy to be
treated as outpatients, we suggest initiating VKA
therapy with warfarin 10 mg daily for the first
2 days followed by dosing based on international
normalized ratio (INR) measurements rather than
starting with the estimated maintenance dose
(Grade 2C).
2.2 Initial Dose Selection and Pharmacogenetic
Testing
2.2. For patients initiating VKA therapy, we
recommend against the routine use of pharmacogenetic testing for guiding doses of VKA
(Grade 1B).
2.3 Initiation Overlap for Heparin and VKA
2.3. For patients with acute VTE, we suggest
that VKA therapy be started on day 1 or 2
of low-molecular-weight heparin (LMWH) or
low-dose unfractionated heparin (UFH) therapy
rather than waiting for several days to start
(Grade 2C).
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Executive Summary
3.1 Monitoring Frequency for VKAs
3.8 VKA Drug Interactions to Avoid
3.1. For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing
frequency of up to 12 weeks rather than every
4 weeks (Grade 2B).
3.8. For patients taking VKAs, we suggest avoiding concomitant treatment with nonsteroidal
antiinflammatory drugs, including cyclooxygenase-2-selective nonsteroidal antiinflammatory
drugs, and certain antibiotics (see Table 8 in main
article1) (Grade 2C).
3.2 Management of the Single Out-of-Range INR
3.2. For patients taking VKAs with previously
stable therapeutic INRs who present with a
single out-of-range INR of " 0.5 below or above
therapeutic, we suggest continuing the current
dose and testing the INR within 1 to 2 weeks
(Grade 2C).
3.3 Bridging for Low INRs
3.3. For patients with stable therapeutic INRs
presenting with a single subtherapeutic INR
value, we suggest against routinely administering bridging with heparin (Grade 2C).
3.4 Vitamin K Supplementation
3.4. For patients taking VKAs, we suggest
against routine use of vitamin K supplementation (Grade 2C).
3.5 Anticoagulation Management Services for VKAs
3.5. (Best Practices Statement) We suggest that
health-care providers who manage oral anticoagulation therapy should do so in a systematic
and coordinated fashion, incorporating patient
education, systematic INR testing, tracking,
follow-up, and good patient communication of
results and dosing decisions.
3.6 Patient Self-Testing and Self-Management
3.6. For patients treated with VKAs who are
motivated and can demonstrate competency
in self-management strategies, including the
self-testing equipment, we suggest patient selfmanagement rather than usual outpatient INR
monitoring (Grade 2B). For all other patients,
we suggest monitoring that includes the safeguards in our best practice statement 3.5.
3.7 Dosing Decision Support
3.7. For dosing decisions during maintenance
VKA therapy, we suggest using validated decision support tools (paper nomograms or computerized dosing programs) rather than no
decision support (Grade 2C).
Remarks: Inexperienced prescribers may be more
likely to improve prescribing with use of decision support tools than experienced prescribers.
www.chestpubs.org
For patients taking VKAs, we suggest avoiding
concomitant treatment with antiplatelet agents
except in situations where benefit is known or is
highly likely to be greater than harm from
bleeding, such as patients with mechanical valves,
patients with acute coronary syndrome, or patients
with recent coronary stents or bypass surgery
(Grade 2C).
4.1 Optimal Therapeutic INR Range
4.1. For patients treated with VKAs, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) rather than a lower (INR , 2) or
higher (INR 3.0-5.0) range (Grade 1B).
4.2 Therapeutic Range for High-Risk Groups
4.2. For patients with antiphospholipid syndrome
with previous arterial or venous thromboembolism,
we suggest VKA therapy titrated to a moderateintensity INR range (INR 2.0-3.0) rather than
higher intensity (INR 3.0-4.5) (Grade 2B).
5.0 Discontinuation of Therapy
5.0. For patients eligible to discontinue treatment with VKA, we suggest abrupt discontinuation rather than gradual tapering of the dose to
discontinuation (Grade 2C).
6.1 Unfractionated Heparin (UFH) Dose Adjustment
by Weight
6.1. For patients starting IV UFH, we suggest
that the initial bolus and the initial rate of the
continuous infusion be weight adjusted (bolus
80 units/kg followed by 18 units/kg per h for VTE;
bolus 70 units/kg followed by 15 units/kg per h
for cardiac or stroke patients) or use of a fixed
dose (bolus 5,000 units followed by 1,000 units/h)
rather than alternative regimens (Grade 2C).
6.2 Dose Management of Subcutaneous (SC) UFH
6.2. For outpatients with VTE treated with SC
UFH, we suggest weight-adjusted dosing (first
dose 333 units/kg, then 250 units/kg) without monitoring rather than fixed or weightadjusted dosing with monitoring (Grade 2C).
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7.1 Therapeutic Dose of LMWH in Patients With
Decreased Renal Function
unfractionated heparin (LDUH) bid, LDUH
tid, or fondaparinux (Grade 1B).
7.1. For patients receiving therapeutic LMWH
who have severe renal insufficiency (calculated
creatinine clearance , 30 mL/min), we suggest
a reduction of the dose rather than using standard doses (Grade 2C).
Remarks: In choosing the specific anticoagulant drug
to be used for pharmacoprophylaxis, choices should
be based on patient preference, compliance, and ease
of administration (eg, daily vs bid vs tid dosing), as
well as on local factors affecting acquisition costs (eg,
prices of various pharmacologic agents in individual
hospital formularies).
8.1 Fondaparinux Dose Management by Weight
8.1. For patients with VTE and body weight
over 100 kg, we suggest that the treatment dose
of fondaparinux be increased from the usual
7.5 mg to 10 mg daily SC (Grade 2C).
9.1 Vitamin K for Patients Taking VKAs With High
INRs Without Bleeding
9.1.
(a) For patients taking VKAs with INRs between
4.5 and 10 and with no evidence of bleeding, we
suggest against the routine use of vitamin K
(Grade 2B).
(b) For patients taking VKAs with INRs . 10.0
and with no evidence of bleeding, we suggest
that oral vitamin K be administered (Grade 2C).
9.2 Clinical Prediction Rules for Bleeding While
Taking VKA
9.2. For patients initiating VKA therapy, we
suggest against the routine use of clinical prediction rules for bleeding as the sole criterion to
withhold VKA therapy (Grade 2C).
9.3 Treatment of Anticoagulant-Related Bleeding
9.3. For patients with VKA-associated major
bleeding, we suggest rapid reversal of anticoagulation with four-factor prothrombin complex
concentrate rather than with plasma. (Grade 2C).
We suggest the additional use of vitamin K 5 to
10 mg administered by slow IV injection rather
than reversal with coagulation factors alone
(Grade 2C).
Prevention of VTE in Nonsurgical Patients
2.4. For acutely ill hospitalized medical patients
at low risk of thrombosis, we recommend against
the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B).
2.7.1. For acutely ill hospitalized medical
patients who are bleeding or at high risk for
bleeding, we recommend against anticoagulant
thromboprophylaxis (Grade 1B).
2.7.2. For acutely ill hospitalized medical patients at
increased risk of thrombosis who are bleeding or
at high risk for major bleeding, we suggest the
optimal use of mechanical thromboprophylaxis
with graduated compression stockings (GCS)
(Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C), rather than no mechanical thromboprophylaxis. When bleeding risk
decreases, and if VTE risk persists, we suggest that pharmacologic thromboprophylaxis
be substituted for mechanical thromboprophylaxis (Grade 2B).
Remarks: Patients who are particularly averse to the
potential for skin complications, cost, and need for
clinical monitoring of GCS and IPC use are likely to
decline mechanical prophylaxis.
2.8. In acutely ill hospitalized medical patients
who receive an initial course of thromboprophylaxis, we suggest against extending the duration of thromboprophylaxis beyond the period
of patient immobilization or acute hospital stay
(Grade 2B).
3.0 Critically Ill Patients
3.2. In critically ill patients, we suggest against
routine ultrasound screening for DVT (Grade 2C).
2.0 Hospitalized Acutely Ill Medical Patients
3.4.3. For critically ill patients, we suggest using
LMWH or LDUH thromboprophylaxis over no
prophylaxis (Grade 2C).
2.3. For acutely ill hospitalized medical patients
at increased risk of thrombosis, we recommend
anticoagulant thromboprophylaxis with lowmolecular-weight heparin [LMWH], low-dose
3.4.4. For critically ill patients who are bleeding,
or are at high risk for major bleeding, we
suggest mechanical thromboprophylaxis with
GCS (Grade 2C) or IPC (Grade 2C) until the
For further details, see Kahn et al.2
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Executive Summary
bleeding risk decreases, rather than no mechanical thromboprophylaxis. When bleeding risk
decreases, we suggest that pharmacologic thromboprophylaxis be substituted for mechanical
thromboprophylaxis (Grade 2C).
4.0 Patients With Cancer in the Outpatient Setting
4.2.1. In outpatients with cancer who have no
additional risk factors for VTE, we suggest
against routine prophylaxis with LMWH or
LDUH (Grade 2B) and recommend against
the prophylactic use of VKAs (Grade 1B).
Remarks: Additional risk factors for venous thrombosis in cancer outpatients include previous venous
thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide.
4.2.2. In outpatients with solid tumors who have
additional risk factors for VTE and who are at
low risk of bleeding, we suggest prophylacticdose LMWH or LDUH over no prophylaxis
(Grade 2B).
Remarks: Additional risk factors for venous thrombosis in cancer outpatients include previous venous
thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide.
4.4. In outpatients with cancer and indwelling
central venous catheters, we suggest against
routine prophylaxis with LMWH or LDUH
(Grade 2B) and suggest against the prophylactic
use of VKAs (Grade 2C).
5.0 Chronically Immobilized Patients
5.1. In chronically immobilized persons residing
at home or at a nursing home, we suggest against
the routine use of thromboprophylaxis (Grade 2C).
6.0 Persons Traveling Long-Distance
6.1.1. For long-distance travelers at increased
risk of VTE (including previous VTE, recent
surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited
mobility, severe obesity, or known thrombophilic disorder), we suggest frequent ambulation, calf muscle exercise, or sitting in an aisle
seat if feasible (Grade 2C).
6.1.2. For long-distance travelers at increased
risk of VTE (including previous VTE, recent
surgery or trauma, active malignancy, pregnancy,
estrogen use, advanced age, limited mobility,
severe obesity, or known thrombophilic disorder), we suggest use of properly fitted, belowwww.chestpubs.org
knee GCS providing 15 to 30 mm Hg of pressure
at the ankle during travel (Grade 2C). For all
other long-distance travelers, we suggest against
the use of GCS (Grade 2C).
6.1.3. For long-distance travelers, we suggest
against the use of aspirin or anticoagulants to
prevent VTE (Grade 2C).
7.0 Persons With Asymptomatic Thrombophilia
7.1. In persons with asymptomatic thrombophilia (ie, without a previous history of VTE),
we recommend against the long-term daily use
of mechanical or pharmacologic thromboprophylaxis to prevent VTE (Grade 1C).
Prevention of VTE in Nonorthopedic
Surgical Patients
For further details, see Gould et al.3
3.6 Patients Undergoing General, GI, Urological,
Gynecologic, Bariatric, Vascular, Plastic, or Reconstructive Surgery
3.6.1. For general and abdominal-pelvic surgery patients at very low risk for VTE (, 0.5%;
Rogers score, , 7; Caprini score, 0), we recommend that no specific pharmacologic (Grade 1B)
or mechanical (Grade 2C) prophylaxis be used
other than early ambulation.
3.6.2. For general and abdominal-pelvic surgery patients at low risk for VTE (!1.5%; Rogers score, 7-10; Caprini score, 1-2), we suggest
mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no
prophylaxis (Grade 2C).
3.6.3. For general and abdominal-pelvic surgery patients at moderate risk for VTE (!3.0%;
Rogers score, . 10; Caprini score, 3-4) who are
not at high risk for major bleeding complications, we suggest LMWH (Grade 2B), LDUH
(Grade 2B), or mechanical prophylaxis, preferably with IPC (Grade 2C), over no prophylaxis.
Remarks: Three of the seven authors favored a strong
(Grade 1B) recommendation in favor of LMWH or
LDUH over no prophylaxis in this group.
3.6.4. For general and abdominal-pelvic surgery patients at moderate risk for VTE (3.0%;
Rogers score, . 10; Caprini score, 3-4) who are
at high risk for major bleeding complications
or those in whom the consequences of bleeding are thought to be particularly severe, we
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suggest mechanical prophylaxis, preferably with
IPC, over no prophylaxis (Grade 2C).
3.6.5. For general and abdominal-pelvic surgery patients at high risk for VTE (!6.0%;
Caprini score, ! 5) who are not at high risk for
major bleeding complications, we recommend
pharmacologic prophylaxis with LMWH (Grade
1B) or LDUH (Grade 1B) over no prophylaxis.
We suggest that mechanical prophylaxis with
elastic stockings or IPC should be added to pharmacologic prophylaxis (Grade 2C).
gest use of mechanical prophylaxis, preferably
with optimally applied IPC, over either no prophylaxis (Grade 2C) or pharmacologic prophylaxis (Grade 2C).
4.4.2. For cardiac surgery patients whose hospital course is prolonged by one or more nonhemorrhagic surgical complications, we suggest
adding pharmacologic prophylaxis with LDUH
or LMWH to mechanical prophylaxis (Grade 2C).
5.0 Patients Undergoing Thoracic Surgery
3.6.6. For high-VTE-risk patients undergoing
abdominal or pelvic surgery for cancer who are
not otherwise at high risk for major bleeding
complications, we recommend extended-duration
pharmacologic prophylaxis (4 weeks) with LMWH
over limited-duration prophylaxis (Grade 1B).
5.4.1. For thoracic surgery patients at moderate risk for VTE who are not at high risk for
perioperative bleeding, we suggest LDUH
(Grade 2B), LMWH (Grade 2B), or mechanical
prophylaxis with optimally applied IPC (Grade 2C)
over no prophylaxis.
Remarks: Patients who place a high value on minimizing out-of-pocket health-care costs might prefer
limited-duration over extended-duration prophylaxis
in settings where the cost of extended-duration prophylaxis is borne by the patient.
Remarks: Three of the seven authors favored a strong
(Grade 1B) recommendation in favor of LMWH or
LDUH over no prophylaxis in this group.
3.6.7. For high-VTE-risk general and abdominalpelvic surgery patients who are at high risk for
major bleeding complications or those in whom the
consequences of bleeding are thought to be
particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no
prophylaxis until the risk of bleeding diminishes
and pharmacologic prophylaxis may be initiated
(Grade 2C).
3.6.8. For general and abdominal-pelvic surgery patients at high risk for VTE (6%; Caprini
score, ! 5) in whom both LMWH and unfractionated heparin are contraindicated or unavailable and who are not at high risk for major
bleeding complications, we suggest low-dose
aspirin (Grade 2C), fondaparinux (Grade 2C), or
mechanical prophylaxis, preferably with IPC
(Grade 2C), over no prophylaxis.
3.6.9. For general and abdominal-pelvic surgery patients, we suggest that an inferior vena
cava (IVC) filter should not be used for primary
VTE prevention (Grade 2C).
3.6.10. For general and abdominal-pelvic surgery
patients, we suggest that periodic surveillance
with venous compression ultrasound should
not be performed (Grade 2C).
4.0 Patients Undergoing Cardiac Surgery
4.4.1. For cardiac surgery patients with an
uncomplicated postoperative course, we sug-
5.4.2. For thoracic surgery patients at high risk
for VTE who are not at high risk for perioperative bleeding, we suggest LDUH (Grade 1B) or
LMWH (Grade 1B) over no prophylaxis. In addition, we suggest that mechanical prophylaxis
with elastic stockings or IPC should be added to
pharmacologic prophylaxis (Grade 2C).
5.4.3. For thoracic surgery patients who are at
high risk for major bleeding, we suggest use of
mechanical prophylaxis, preferably with optimally applied IPC, over no prophylaxis until the
risk of bleeding diminishes and pharmacologic
prophylaxis may be initiated (Grade 2C).
6.0 Patients Undergoing Craniotomy
6.4.1. For craniotomy patients, we suggest that
mechanical prophylaxis, preferably with IPC,
be used over no prophylaxis (Grade 2C) or pharmacologic prophylaxis (Grade 2C).
6.4.2. For craniotomy patients at very high risk
for VTE (eg, those undergoing craniotomy for
malignant disease), we suggest adding pharmacologic prophylaxis to mechanical prophylaxis
once adequate hemostasis is established and the
risk of bleeding decreases (Grade 2C).
7.0 Patients Undergoing Spinal Surgery
7.4.1. For patients undergoing spinal surgery,
we suggest mechanical prophylaxis, preferably with IPC, over no prophylaxis (Grade 2C),
unfractionated heparin (Grade 2C), or LMWH
(Grade 2C).
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Executive Summary
7.4.2. For patients undergoing spinal surgery at
high risk for VTE (including those with malignant disease or those undergoing surgery with
a combined anterior-posterior approach), we
suggest adding pharmacologic prophylaxis to
mechanical prophylaxis once adequate hemostasis is established and the risk of bleeding
decreases (Grade 2C).
8.0 Patients With Major Trauma: Traumatic Brain
Injury, Acute Spinal Injury, and Traumatic Spine
Injury
8.4.1. For major trauma patients, we suggest
use of LDUH (Grade 2C), LMWH (Grade 2C), or
mechanical prophylaxis, preferably with IPC
(Grade 2C), over no prophylaxis.
8.4.2. For major trauma patients at high risk for
VTE (including those with acute spinal cord
injury, traumatic brain injury, and spinal surgery for trauma), we suggest adding mechanical prophylaxis to pharmacologic prophylaxis
(Grade 2C) when not contraindicated by lowerextremity injury.
8.4.3. For major trauma patients in whom
LMWH and LDUH are contraindicated, we suggest mechanical prophylaxis, preferably with
IPC, over no prophylaxis (Grade 2C) when not
contraindicated by lower-extremity injury. We
suggest adding pharmacologic prophylaxis with
either LMWH or LDUH when the risk of
bleeding diminishes or the contraindication to
heparin resolves (Grade 2C).
8.4.4. For major trauma patients, we suggest
that an IVC filter should not be used for primary VTE prevention (Grade 2C).
8.4.5. For major trauma patients, we suggest that
periodic surveillance with venous compression
ultrasound should not be performed (Grade 2C).
Prevention of VTE in Orthopedic
Surgery Patients
For further details, see Falck-Ytter et al.4
2.0 Patients Undergoing Major Orthopedic Surgery:
Total Hip Arthroplasty (THA), Total Knee Arthroplasty
(TKA), Hip Fracture Surgery (HFS)
2.1.1. In patients undergoing THA or TKA, we
recommend use of one of the following for a
minimum of 10 to 14 days rather than no antithrombotic prophylaxis: low-molecular-weight
heparin (LMWH), fondaparinux, apixaban, dabwww.chestpubs.org
igatran, rivaroxaban, low-dose unfractionated
heparin (LDUH), adjusted-dose VKA, aspirin
(all Grade 1B), or an intermittent pneumatic compression device (IPCD) (Grade 1C).
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpatients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. One panel member
believed strongly that aspirin alone should not be
included as an option.
2.1.2. In patients undergoing HFS, we recommend use of one of the following rather than no
antithrombotic prophylaxis for a minimum of
10 to 14 days: LMWH, fondaparinux, LDUH,
adjusted-dose VKA, aspirin (all Grade 1B), or an
IPCD (Grade 1C).
achieve 18 h of daily compliance. One panel member
believed strongly that aspirin alone should not be
included as an option.
2.2. For patients undergoing major orthopedic
surgery (THA, TKA, HFS) and receiving LMWH
as thromboprophylaxis, we recommend starting
either 12 h or more preoperatively or 12 h or more
postoperatively rather than within 4 h or less preoperatively or 4 h or less postoperatively (Grade 1B).
2.3.1. In patients undergoing THA or TKA,
irrespective of the concomitant use of an IPCD
or length of treatment, we suggest the use
of LMWH in preference to the other agents
we have recommended as alternatives: fondaparinux, apixaban, dabigatran, rivaroxaban,
LDUH (all Grade 2B), adjusted-dose VKA, or
aspirin (all Grade 2C).
Remarks: If started preoperatively, we suggest administering LMWH ! 12 h before surgery. Patients
who place a high value on avoiding the inconvenience
of daily injections with LMWH and a low value on
the limitations of alternative agents are likely to
choose an alternative agent. Limitations of alternative agents include the possibility of increased
bleeding (which may occur with fondaparinux, rivaroxaban, and VKA), possible decreased efficacy (LDUH,
VKA, aspirin, and IPCD alone), and lack of long-term
safety data (apixaban, dabigatran, and rivaroxaban).
Furthermore, patients who place a high value on
avoiding bleeding complications and a low value on
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its inconvenience are likely to choose an IPCD over
the drug options.
2.3.2. In patients undergoing HFS, irrespective
of the concomitant use of an IPCD or length of
treatment, we suggest the use of LMWH in preference to the other agents we have recommended
as alternatives: fondaparinux, LDUH (Grade 2B),
adjusted-dose VKA, or aspirin (all Grade 2C).
Remarks: For patients in whom surgery is likely to
be delayed, we suggest that LMWH be initiated
during the time between hospital admission and surgery but suggest administering LMWH at least 12 h
before surgery. Patients who place a high value on
avoiding the inconvenience of daily injections with
LMWH and a low value on the limitations of alternative agents are likely to choose an alternative agent.
Limitations of alternative agents include the possibility of increased bleeding (which may occur with
fondaparinux) or possible decreased efficacy (LDUH,
VKA, aspirin, and IPCD alone). Furthermore, patients
who place a high value on avoiding bleeding complications and a low value on its inconvenience are likely
to choose an IPCD over the drug options.
2.4. For patients undergoing major orthopedic
surgery, we suggest extending thromboprophylaxis in the outpatient period for up to 35 days
from the day of surgery rather than for only 10
to 14 days (Grade 2B).
2.5. In patients undergoing major orthopedic
surgery, we suggest using dual prophylaxis with
an antithrombotic agent and an IPCD during
the hospital stay (Grade 2C).
achieve 18 h of daily compliance. Patients who place
a high value on avoiding the undesirable consequences
associated with prophylaxis with both a pharmacologic
agent and an IPCD are likely to decline use of dual
prophylaxis.
surgery and increased risk of bleeding, we
suggest using an IPCD or no prophylaxis rather
than pharmacologic treatment (Grade 2C).
achieve 18 h of daily compliance. Patients who place
a high value on avoiding the discomfort and inconve-
nience of IPCD and a low value on avoiding a small
absolute increase in bleeding with pharmacologic
agents when only one bleeding risk factor is present
(in particular the continued use of antiplatelet agents)
are likely to choose pharmacologic thromboprophylaxis over IPCD.
surgery and who decline or are uncooperative
with injections or an IPCD, we recommend
using apixaban or dabigatran (alternatively
rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are unavailable) rather than
alternative forms of prophylaxis (all Grade 1B).
surgery, we suggest against using IVC filter
placement for primary prevention over no thromboprophylaxis in patients with an increased
bleeding risk or contraindications to both pharmacologic and mechanical thromboprophylaxis
(Grade 2C).
2.9. For asymptomatic patients following major
orthopedic surgery, we recommend against
Doppler (or duplex) ultrasound screening before
hospital discharge (Grade 1B).
3.0 Patients With Isolated Lower-Leg Injuries Distal
to the Knee
3.0. We suggest no prophylaxis rather than
pharmacologic thromboprophylaxis in patients
with isolated lower-leg injuries requiring leg
immobilization (Grade 2C).
4.0 Patients Undergoing Knee Arthroscopy
4.0. For patients undergoing knee arthroscopy
without a history of prior VTE, we suggest no
thromboprophylaxis rather than prophylaxis
(Grade 2B).
Perioperative Management of
Antithrombotic Therapy
For further details, see Douketis et al.5
2.1 Interruption of VKAs Before Surgery
2.1. In patients who require temporary interruption of a VKA before surgery, we recommend stopping VKAs approximately 5 days
before surgery instead of stopping VKAs a
shorter time before surgery (Grade 1C).
2.2 Resumption of VKAs After Surgery
2.2. In patients who require temporary interruption of a VKA before surgery, we recommend
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Executive Summary
resuming VKAs approximately 12 to 24 h after
surgery (evening of or next morning) and when
there is adequate hemostasis instead of later
resumption of VKAs (Grade 2C).
2.4 Bridging Anticoagulation During Interruption of
VKA Therapy
2.4. In patients with a mechanical heart valve,
atrial fibrillation, or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during interruption
of VKA therapy (Grade 2C).
Remarks: Patients who place a higher value on avoiding perioperative bleeding than on avoiding perioperative thromboembolism are likely to decline
heparin bridging.
In patients with a mechanical heart valve, atrial
fibrillation, or VTE at low risk for thromboembolism, we suggest no bridging instead of
bridging anticoagulation during interruption
In patients with a mechanical heart valve, atrial fibrillation, or VTE at moderate risk for thromboembolism, the bridging or no-bridging approach chosen is,
as in the higher- and lower-risk patients, based on an
assessment of individual patient- and surgery-related
factors.
2.5 Perioperative Management of VKA-Treated
Patients Who Require Minor Procedures
2.5. In patients who require a minor dental procedure, we suggest continuing VKAs with coadministration of an oral prohemostatic agent or
stopping VKAs 2 to 3 days before the procedure
instead of alternative strategies (Grade 2C). In
patients who require minor dermatologic procedures and are receiving VKA therapy, we suggest continuing VKAs around the time of the
procedure and optimizing local hemostasis
instead of other strategies (Grade 2C). In patients
who require cataract surgery and are receiving
VKA therapy, we suggest continuing VKAs
around the time of the surgery instead of other
strategies (Grade 2C).
3.4 Patients Undergoing a Minor Dental, Dermatologic,
or Ophthalmologic Procedure
3.4. In patients who are receiving acetylsalicylic acid (ASA) for the secondary prevention
of cardiovascular disease and are having minor
dental or dermatologic procedures or cataract
surgery, we suggest continuing ASA around the
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time of the procedure instead of stopping ASA
7 to 10 days before the procedure (Grade 2C).
3.5. In patients at moderate to high risk for
cardiovascular events who are receiving ASA
therapy and require noncardiac surgery, we
suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before
surgery (Grade 2C). In patients at low risk for
cardiovascular events who are receiving ASA
therapy, we suggest stopping ASA 7 to 10 days
before surgery instead of continuation of ASA
(Grade 2C).
3.6 Patients Undergoing Coronary Artery Bypass
Graft Surgery
3.6. In patients who are receiving ASA and
require coronary artery bypass graft (CABG)
surgery, we suggest continuing ASA around the
time of surgery instead of stopping ASA 7 to
10 days before surgery (Grade 2C). In patients
who are receiving dual antiplatelet drug therapy
and require CABG surgery, we suggest continuing ASA around the time of surgery and
stopping clopidogrel/prasugrel 5 days before
surgery instead of continuing dual antiplatelet
therapy around the time of surgery (Grade 2C).
3.7 Surgical Patients With Coronary Stents
3.7. In patients with a coronary stent who are
receiving dual antiplatelet therapy and require
surgery, we recommend deferring surgery for
at least 6 weeks after placement of a bare-metal
stent and for at least 6 months after placement
of a drug-eluting stent instead of undertaking
surgery within these time periods (Grade 1C). In
patients who require surgery within 6 weeks
of placement of a bare-metal stent or within
6 months of placement of a drug-eluting stent,
we suggest continuing dual antiplatelet therapy
around the time of surgery instead of stopping
dual antiplatelet therapy 7 to 10 days before
surgery (Grade 2C).
Remarks: Patients who are more concerned about
avoiding the unknown, but potentially large increase
in bleeding risk associated with the perioperative
continuation of dual antiplatelet therapy than avoiding the risk for coronary stent thrombosis are unlikely
to choose continuation of dual antiplatelet therapy.
4.2 Perioperative Use of IV UFH
4.2. In patients who are receiving bridging anticoagulation with therapeutic-dose IV UFH, we
suggest stopping UFH 4 to 6 h before surgery
instead of closer to surgery (Grade 2C).
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4.3 Preoperative Interruption of Therapeutic-Dose
Bridging LMWH
4.3. In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH,
we suggest administering the last preoperative
dose of LMWH approximately 24 h before surgery instead of 12 h before surgery (Grade 2C).
4.4 Postoperative Resumption of Therapeutic-Dose
Bridging LMWH
4.4. In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH
and are undergoing high-bleeding-risk surgery,
we suggest resuming therapeutic-dose LMWH
48 to 72 h after surgery instead of resuming
LMWH within 24 h after surgery (Grade 2C).
Diagnosis of DVT
For further details, see Bates et al.6
3.0 Diagnosis of Suspected First Lower Extremity
DVT
3.1. In patients with a suspected first lower
extremity DVT, we suggest that the choice of
diagnostic tests process should be guided by the
clinical assessment of pretest probability rather
than by performing the same diagnostic tests in
all patients (Grade 2B).
Remarks: In considering this recommendation, five
panelists voted for a strong recommendation and four
voted for a weak recommendation (one declined
to vote and two did not participate). According
to predetermined criteria, this resulted in weak
recommendation.
3.2. In patients with a low pretest probability
of first lower extremity DVT, we recommend
one of the following initial tests: (i) a moderately sensitive D-dimer, (ii) a highly sensitive
D-dimer, or (iii) compression ultrasound (CUS)
of the proximal veins rather than (i) no diagnostic testing (Grade 1B for all comparisons), (ii) venography (Grade 1B for all comparisons), or (iii)
whole-leg ultrasound (US) (Grade 2B for all comparisons). We suggest initial use of a moderately
sensitive (Grade 2C) or highly sensitive (Grade
2B) D-dimer rather than proximal CUS.
Remarks: The choice between a moderately sensitive
D-dimer test, a highly sensitive D-dimer test, or proximal CUS as the initial test will depend on local availability, access to testing, costs of testing, and the
probability of obtaining a negative D-dimer result if
DVT is not present. Initial testing with US would be
preferred if the patient has a comorbid condition associated with elevated D-dimer levels and is likely to have
a positive D-dimer result, even if DVT is absent. In
patients with suspected first lower extremity DVT in
whom US is impractical (eg, when leg casting or
excessive SC tissue or fluid prevent adequate assessment of compressibility) or nondiagnostic, we suggest CT scan venography or magnetic resonance
(MR) venography, or MR direct thrombus imaging
could be used as an alternative to venography.
If the D-dimer is negative, we recommend no
further testing over further investigation with
(i) proximal CUS, (ii) whole-leg US, or (iii) venography (Grade 1B for all comparisons). If the proximal CUS is negative, we recommend no further
testing compared with (i) repeat proximal CUS
after 1 week, (ii) whole-leg US, or (iii) venography (Grade 1B for all comparisons).
If the D-dimer is positive, we suggest further
testing with CUS of the proximal veins rather
than (i) whole-leg US (Grade 2C) or (ii) venography (Grade 1B). If CUS of the proximal veins is
positive, we suggest treating for DVT and performing no further testing over performing
confirmatory venography (Grade 2C).
Remarks: In circumstances when high-quality venography is available, patients who are not averse to the
discomfort of venography, are less concerned about
the complications of venography, and place a high
value on avoiding treatment of false-positive results
are likely to choose confirmatory venography if findings for DVT are less certain (eg, a short segment of
venous noncompressibility).
3.3. In patients with a moderate pretest probability of first lower extremity DVT, we recommend one of the following initial tests: (i) a highly
sensitive D-dimer or (ii) proximal CUS, or (iii)
whole-leg US rather than (i) no testing (Grade 1B
for all comparisons) or (ii) venography (Grade 1B for
all comparisons). We suggest initial use of a highly
sensitive D-dimer rather than US (Grade 2C).
Remarks: The choice between a highly sensitive
D-dimer test or US as the initial test will depend on
local availability, access to testing, costs of testing,
and the probability of obtaining a negative D-dimer
result if DVT is not present. Initial testing with US
may be preferred if the patient has a comorbid condition associated with elevated D-dimer levels and is
likely to have a positive D-dimer result even if DVT
is absent. Whole-leg US may be preferred in patients
unable to return for serial testing and those with
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Executive Summary
severe symptoms consistent with calf DVT. In patients
with suspected first lower extremity DVT in whom
US is impractical (eg, when leg casting or excessive
SC tissue or fluid prevent adequate assessment of
compressibility) or nondiagnostic, we suggest CT scan
venography, MR venography, or MR direct thrombus
imaging could be used as an alternative to venography.
If the highly sensitive D-dimer is negative, we
recommend no further testing over further
investigation with (i) proximal CUS, (ii) wholeleg US, or (iii) venography (Grade 1B for all
comparisons). If the highly sensitive D-dimer
is positive, we recommend proximal CUS or
whole-leg US rather than no testing (Grade 1B
for all comparisons) or venography (Grade 1B for
all comparisons).
If proximal CUS is chosen as the initial test and
is negative, we recommend (i) repeat proximal
CUS in 1 week or (ii) testing with a moderate or
highly sensitive D-dimer assay over no further
testing (Grade 1C) or venography (Grade 2B). In
patients with a negative proximal CUS but a
positive D-dimer, we recommend repeat proximal CUS in 1 week over no further testing
(Grade 1B) or venography (Grade 2B).
In patients with (i) negative serial proximal CUS
or (ii) a negative single proximal CUS and negative moderate or highly sensitive D-dimer, we
recommend no further testing rather than further testing with (i) whole-leg US or (ii) venography (Grade 1B for all comparisons).
If whole-leg US is negative, we recommend
no further testing over (i) repeat US in one
week, (ii) D-dimer testing, or (iii) venography
(Grade 1B for all comparisons). If proximal CUS
is positive, we recommend treating for DVT
rather than confirmatory venography (Grade 1B).
If isolated distal DVT is detected on wholeleg US, we suggest serial testing to rule out
proximal extension over treatment (Grade 2C).
Remarks: Patients with abnormal isolated distal US
findings on whole-leg US who place a high value on
avoiding the inconvenience of repeat testing and a
low value on avoiding treatment of false-positive
results are likely to choose treatment over repeat US.
Patients with severe symptoms and risk factors for
extension as outlined in Perioperative Management
of Antithrombotic Therapy. Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical
Practice Guidelines are more likely to benefit from
treatment over repeat US.
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3.4. In patients with a high pretest probability
of first lower extremity DVT, we recommend
either (i) proximal CUS or (ii) whole-leg US over
no testing (Grade 1B for all comparisons) or venography (Grade 1B for all comparisons).
Remarks: Whole-leg US may be preferred to proximal CUS in patients unable to return for serial testing and those with severe symptoms consistent with
calf DVT. In patients with extensive unexplained
leg swelling, if there is no DVT on proximal CUS or
whole-leg US and d-dimer testing has not been
performed or is positive, the iliac veins should be
imaged to exclude isolated iliac DVT. In patients with
suspected first lower extremity DVT in whom US is
impractical (eg, when leg casting or excessive SC
tissue or fluid prevent adequate assessment of compressibility) or nondiagnostic, we suggest CT scan
venography, MR venography, or MR direct thrombus
imaging could be used as an alternative to venography.
If proximal CUS or whole-leg US is positive for
DVT, we recommend treatment rather than
confirmatory venography (Grade 1B).
In patients with a negative proximal CUS, we
recommend additional testing with a highly
sensitive D-dimer or whole-leg US or repeat
proximal CUS in 1 week over no further
testing (Grade 1B for all comparisons) or venography (Grade 2B for all comparisons). We recommend that patients with a single negative
proximal CUS and positive D-dimer undergo
whole-leg US or repeat proximal CUS in 1 week
over no further testing (Grade 1B) or venography
(Grade 2B). In patients with negative serial proximal CUS, a negative single proximal CUS and
negative highly sensitive D-dimer, or a negative
whole-leg US, we recommend no further testing
over venography or additional US (Grade 1B for
negative serial proximal CUS and for negative single
proximal CUS and highly sensitive D-dimer; Grade
2B for negative whole-leg US).
We recommend that in patients with high pretest probability, moderately or highly sensitive
D-dimer assays should not be used as standalone tests to rule out DVT (Grade 1B).
3.5. If risk stratification is not performed in
patients with suspected first lower extremity
DVT, we recommend one of the following
initial tests: (i) proximal CUS or (ii) wholeleg US rather than (i) no testing (Grade 1B),
(ii) venography (Grade 1B), or D-dimer testing
(Grade 2B).
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Remarks: Whole-leg US may be preferred to proximal CUS in patients unable to return for serial
testing and those with severe symptoms consistent
with calf DVT or risk factors for extension of distal
DVT. In patients with suspected first lower extremity
DVT in whom US is impractical (eg, when leg casting or excessive SC tissue or fluid prevent adequate
assessment of compressibility) or nondiagnostic, we
suggest that CT scan venography, MR venography,
or MR direct thrombus imaging could be used as an
alternative to venography.
4.1 Venography in Patients With Suspected Recurrent DVT
We recommend that patients with a negative
proximal CUS undergo testing with a moderate- or high-sensitivity D-dimer, whole-leg
US, or repeat proximal CUS in 1 week over
no further testing (Grade 1B) or venography
(Grade 2B). In patients with a negative proximal CUS, we suggest D-dimer rather than
routine serial CUS (Grade 2B) or whole-leg US
(Grade 2C). We recommend that patients with
a single negative proximal CUS and positive
D-dimer undergo further testing with repeat
proximal CUS in 1 week or whole-leg US
rather than no further testing (Grade 1B for
both comparisons).
If the highly sensitive D-dimer is positive, we
recommend proximal CUS over venography, CT
venography, or MRI (Grade 1B for all comparisons).
We recommend that in patients with (i) negative serial proximal CUS, (ii) a negative D-dimer
following a negative initial proximal CUS, or (iii)
negative whole-leg US, no further testing be
performed rather than venography (Grade 1B).
If proximal US is positive for DVT, we recommend treatment rather than confirmatory venography (Grade 1B). If isolated distal DVT is
detected on whole-leg US, we suggest serial
testing to rule out proximal extension over treatment (Grade 2C).
Remarks: Patients with abnormal isolated distal US
findings on whole-leg US who place a high value on
avoiding the inconvenience of repeat testing and
a low value on avoiding treatment of false-positive
results are likely to choose treatment over repeat US.
Patients with severe symptoms and risk factors for
extension as outlined in “Perioperative Management
of Antithrombotic Therapy. Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical
Practice Guidelines” are more likely to benefit from
treatment over repeat US.
3.6. In patients with suspected first lower
extremity DVT, we recommend against the routine use of CT venography or MRI (Grade 1C).
4.1. In patients suspected of having recurrent
lower extremity DVT, we recommend initial
evaluation with proximal CUS or a highly sensitive D-dimer over venography, CT venography,
or MRI (all Grade 1B).
Remarks: Initial D-dimer testing with a high-sensitivity
assay is preferable if prior US is not available for
comparison.
In patients with suspected recurrent lower
extremity DVT in whom initial proximal CUS is
negative (normal or residual diameter increase
of , 2 mm), we suggest at least one further
proximal CUS (day 7 # 1) or testing with a moderately or highly sensitive D-dimer (followed by
repeat CUS [day 7 # 1] if positive) rather than
no further testing or venography (Grade 2B).
Remarks: In patients with an abnormal proximal CUS
at presentation that does not meet the criteria for the
diagnosis of recurrence, an additional proximal CUS
on day 2 # 1 in addition to that on (day 7 # 1) may be
preferred. Patients who place a high value on an
accurate diagnosis and a low value on avoiding the
inconvenience and potential side effects of a venography are likely to choose venography over missed
diagnosis (in the case of residual diameter increase
of , 2 mm).
We recommend that patients with suspected
recurrent lower extremity DVT and a negative
highly sensitive D-dimer or negative proximal
CUS and negative moderately or highly sensitive D-dimer or negative serial proximal CUS
undergo no further testing for suspected recurrent DVT rather than venography (Grade 1B).
If CUS of the proximal veins is positive, we recommend treating for DVT and performing no
further testing over performing confirmatory
venography (Grade 1B for the finding of a new noncompressible segment in the common femoral or
popliteal vein, Grade 2B for a ! 4-mm increase in
venous diameter during compression compared with
that in the same venous segment on a previous result).
Remarks: Patients with US abnormalities at presentation that do not include a new noncompressible
segment who place a high value on an accurate diagnosis and a low value on avoiding the inconvenience
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Executive Summary
and potential side effects of a venography are likely
to choose venography over treatment (in the case
of ! 4-mm increase in venous diameter).
4.2 Compression Ultrasonography in Patients With
Suspected Recurrent DVT
4.2. In patients with suspected recurrent lower
extremity DVT and abnormal but nondiagnostic
US results (eg, an increase in residual venous
diameter of , 4 but ! 2 mm), we recommend
further testing with venography, if available
(Grade 1B); serial proximal CUS (Grade 2B) or
testing with a moderately or highly sensitive
D-dimer with serial proximal CUS as above if
the test is positive (Grade 2B), as opposed to
other testing strategies or treatment.
4.3 Pretest Probability Assessment in Patients With
Suspected Recurrent DVT
4.3. In patients with suspected recurrent ipsilateral DVT and an abnormal US without a prior
result for comparison, we recommend further
testing with venography, if available (Grade 1B)
or a highly sensitive D-dimer (Grade 2B) over
serial proximal CUS. In patients with suspected
recurrent ipsilateral DVT and an abnormal US
without prior result for comparison and a negative highly sensitive D-dimer, we suggest no
further testing over venography (Grade 2C). In
patients with suspected recurrent ipsilateral
DVT and an abnormal US without prior result
for comparison and a positive highly sensitive
D-dimer, we suggest venography if available over
empirical treatment of recurrence (Grade 2C).
Remarks: Patients who place a high value on avoiding the inconvenience and potential side effects of
a venography are likely to choose treatment over
venography.
5.1 Venography in Pregnancy-Related DVT
5.1. In pregnant patients suspected of having
lower extremity DVT, we recommend initial
evaluation with proximal CUS over other initial
tests, including a whole-leg US (Grade 2C), moderately sensitive D-dimer (Grade 2C), highly
sensitive D-dimer (Grade 1B), or venography
(Grade 1B).
5.2 Compression Ultrasonography in PregnancyRelated DVT
5.2. In pregnant patients with suspected DVT in
whom initial proximal CUS is negative, we suggest further testing with either serial proximal
CUS (day 3 and day 7) (Grade 1B) or a sensitive
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D-dimer done at the time of presentation (Grade
2B) over no further testing for DVT. We recommend that patients with an initial negative
proximal CUS and a subsequent negative sensitive D-dimer or negative serial proximal CUS
undergo no further testing for DVT (Grade 1B)
and that patients with positive D-dimer have an
additional follow-up proximal CUS (day 3 and
day 7) rather than venography (Grade 1B) or
whole-leg US (Grade 2C).
5.3 Pretest Probability in Pregnancy-Related DVT
5.3. In pregnant patients with symptoms suggestive of isolated iliac vein thrombosis (swelling
of the entire leg, with or without flank, buttock,
or back pain) and no evidence of DVT on standard proximal CUS, we suggest further testing
with either Doppler US of the iliac vein (Grade
2C), venography (Grade 2C), or direct MRI
(Grade 2C), rather than standard serial CUS of
the proximal deep veins.
6.1 Ultrasonography in Patients With UpperExtremity DVT (UEDVT)
6.1. In patients suspected of having UEDVT, we
suggest initial evaluation with combined modality
US (compression with either Doppler or color
Doppler) over other initial tests, including highly
sensitive D-dimer or venography (Grade 2C).
6.2 Clinical Pretest Probability Assessment in Patients
With UEDVT
6.2. In patients with suspected UEDVT in whom
initial US is negative for thrombosis despite a
high clinical suspicion of DVT, we suggest further testing with a moderate or highly sensitive
D-dimer, serial US, or venographic-based imaging
(traditional, CT scan, or MRI), rather than no
further testing (Grade 2C).
In patients with suspected UEDVT and an initial negative combined-modality US and subsequent negative moderate or highly sensitive
D-dimer or CT or MRI, we recommend no further testing, rather than confirmatory venography (Grade 1C). We suggest that patients with
an initial combined negative modality US and
positive D-dimer or those with less than complete evaluation by US undergo venography
rather than no further testing, unless there is
an alternative explanation for their symptoms
(Grade 2B), in which case testing to evaluate for
the presence an alternative diagnosis should be
performed. We suggest that patients with a positive D-dimer or those with less than complete
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evaluation by US but an alternative explanation for their symptoms undergo confirmatory
testing and treatment of this alternative explanation rather than venography (Grade 2C).
Remarks: Further radiologic testing (serial US or
venographic-based imaging or CT/MR to seek an
alternative diagnosis) rather than d-dimer testing is
preferable in patients with comorbid conditions typically associated with elevated D-dimer levels.
Antithrombotic Therapy for VTE Disease
For further details, see Kearon et al.7
2.1 Initial Anticoagulation for Patients With Acute DVT
of the Leg
2.1. In patients with acute DVT of the leg treated
with VKA therapy, we recommend initial treatment with parenteral anticoagulation (LMWH,
fondaparinux, IV UFH, or SC UFH) over no
such initial treatment (Grade 1B).
Remarks: Patients at high risk for bleeding are more
likely to benefit from serial imaging. Patients who
place a high value on avoiding the inconvenience of
repeat imaging and a low value on the inconvenience
of treatment and on the potential for bleeding are
likely to choose initial anticoagulation over serial
imaging.
2.3.3. In patients with acute isolated distal DVT
of the leg who are managed with initial anticoagulation, we recommend using the same
approach as for patients with acute proximal
DVT (Grade 1B).
of the leg who are managed with serial imaging,
we recommend no anticoagulation if the thrombus does not extend (Grade 1B); we suggest anticoagulation if the thrombus extends but remains
confined to the distal veins (Grade 2C); we recommend anticoagulation if the thrombus
extends into the proximal veins (Grade 1B).
2.2 Parenteral Anticoagulation Prior to Receipt of the
Results of Diagnostic Work-up for VTE
2.4 Timing of Initiation of VKA and Associated
Duration of Parenteral Anticoagulant Therapy
2.2.1. In patients with a high clinical suspicion of
acute VTE, we suggest treatment with parenteral
anticoagulants compared with no treatment while
awaiting the results of diagnostic tests (Grade 2C).
2.4. In patients with acute DVT of the leg, we
recommend early initiation of VKA (eg, same
day as parenteral therapy is started) over
delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days
and until the international normalized ratio
(INR) is 2.0 or above for at least 24 h (Grade 1B).
2.2.2. In patients with an intermediate clinical
suspicion of acute VTE, we suggest treatment
with parenteral anticoagulants compared with
no treatment if the results of diagnostic tests
are expected to be delayed for more than 4 h
(Grade 2C).
2.2.3. In patients with a low clinical suspicion of
acute VTE, we suggest not treating with parenteral anticoagulants while awaiting the results
of diagnostic tests, provided test results are
expected within 24 h (Grade 2C).
2.3 Anticoagulation in Patients With Isolated Distal
DVT
of the leg and without severe symptoms or risk
factors for extension, we suggest serial imaging
of the deep veins for 2 weeks over initial anticoagulation (Grade 2C).
of the leg and severe symptoms or risk factors
for extension (see text), we suggest initial anticoagulation over serial imaging of the deep veins
(Grade 2C).
2.5 Choice of Initial Anticoagulant Regimen in
Patients With Proximal DVT
2.5.1. In patients with acute DVT of the leg, we
suggest LMWH or fondaparinux over IV UFH
(Grade 2C) and over SC UFH (Grade 2B for
LMWH; Grade 2C for fondaparinux).
Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice
between fondaparinux and LMWH. LMWH and
fondaparinux are retained in patients with renal
impairment, whereas this is not a concern with UFH.
2.5.2. In patients with acute DVT of the leg
treated with LMWH, we suggest once- over
twice-daily administration (Grade 2C).
Remarks: This recommendation only applies when
the approved once-daily regimen uses the same
daily dose as the twice-daily regimen (ie, the oncedaily injection contains double the dose of each
twice-daily injection). It also places value on avoiding
an extra injection per day.
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Executive Summary
2.7 At-Home vs In-Hospital Initial Treatment of Patients
With DVT
2.7. In patients with acute DVT of the leg and
whose home circumstances are adequate, we
recommend initial treatment at home over
treatment in hospital (Grade 1B).
Remarks: The recommendation is conditional on the
adequacy of home circumstances: well-maintained
living conditions, strong support from family or friends,
phone access, and ability to quickly return to the hospital if there is deterioration. It is also conditional on
the patient feeling well enough to be treated at home
(eg, does not have severe leg symptoms or comorbidity).
2.9 Catheter-Directed Thrombolysis for Patients With
Acute DVT
2.9. In patients with acute proximal DVT of the
leg, we suggest anticoagulant therapy alone over
catheter-directed thrombolysis (CDT) (Grade 2C).
Remarks: Patients who are most likely to benefit from
CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower
value to the initial complexity, cost, and risk of
bleeding with CDT, are likely to choose CDT over
anticoagulation alone.
2.10 Systemic Thrombolytic Therapy for Patients With
Acute DVT
2.10. In patients with acute proximal DVT of
the leg, we suggest anticoagulant therapy alone
over systemic thrombolysis (Grade 2C).
systemic thrombolytic therapy (see text), who do
not have access to CDT, and who attach a high value
to prevention of PTS, and a lower value to the initial
complexity, cost, and risk of bleeding with systemic
thrombolytic therapy, are likely to choose systemic
thrombolytic therapy over anticoagulation alone.
2.11 Operative Venous Thrombectomy for Acute DVT
operative venous thrombectomy (Grade 2C).
2.12 Anticoagulation in Patients Who Have Had Any
Method of Thrombus Removal Performed
2.12. In patients with acute DVT of the leg who
undergo thrombosis removal, we recommend
the same intensity and duration of anticoagulant therapy as in comparable patients who do
not undergo thrombosis removal (Grade 1B).
2.13 Vena Cava Filters for the Initial Treatment of
Patients With DVT
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recommend against the use of an IVC filter in
addition to anticoagulants (Grade 1B).
2.13.2. In patients with acute proximal DVT of the
leg and contraindication to anticoagulation, we
recommend the use of an IVC filter (Grade 1B).
2.13.3. In patients with acute proximal DVT of
the leg and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagulant therapy if their
risk of bleeding resolves (Grade 2B).
Remarks: We do not consider that a permanent
IVC filter, of itself, is an indication for extended
anticoagulation.
2.14 Early Ambulation of Patients With Acute DVT
suggest early ambulation over initial bed rest
(Grade 2C).
Remarks: If edema and pain are severe, ambulation
may need to be deferred. As per section 4.1, we suggest
the use of compression therapy in these patients.
3.0 Long-term Anticoagulation in Patients With Acute
DVT of the Leg
3.0. In patients with acute VTE who are treated
with anticoagulant therapy, we recommend longterm therapy (see section 3.1 for recommended
duration of therapy) over stopping anticoagulant therapy after about 1 week of initial therapy
(Grade 1B).
3.1 Duration of Long-term Anticoagulant Therapy
3.1.1. In patients with a proximal DVT of the leg
provoked by surgery, we recommend treatment
with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6 or
12 months) (Grade 1B), or (iii) extended therapy
(Grade 1B regardless of bleeding risk).
provoked by a nonsurgical transient risk factor,
we recommend treatment with anticoagulation
for 3 months over (i) treatment of a shorter
period (Grade 1B), (ii) treatment of a longer timelimited period (eg, 6 or 12 months) (Grade 1B),
and (iii) extended therapy if there is a high
bleeding risk (Grade 1B). We suggest treatment
with anticoagulation for 3 months over extended
therapy if there is a low or moderate bleeding
risk (Grade 2B).
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3.1.3. In patients with an isolated distal DVT
of the leg provoked by surgery or by a nonsurgical transient risk factor (see remark), we suggest treatment with anticoagulation for 3 months
over treatment of a shorter period (Grade 2C)
and recommend treatment with anticoagulation for 3 months over treatment of a longer timelimited period (eg, 6 or 12 months) (Grade 1B)
or extended therapy (Grade 1B regardless of
bleeding risk).
Remarks (3.1.3, 3.1.4, 3.1.4.3): Duration of treatment
of patients with isolated distal DVT refers to patients
in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not
all patients who are diagnosed with isolated distal
DVT will be given anticoagulants (see section 2.3). In
all patients who receive extended anticoagulant therapy,
the continuing use of treatment should be reassessed at
periodic intervals (eg, annually).
3.1.4. In patients with an unprovoked DVT of
the leg (isolated distal [see remark] or proximal),
for at least 3 months over treatment of a shorter
duration (Grade 1B). After 3 months of treatment,
patients with unprovoked DVT of the leg should
be evaluated for the risk-benefit ratio of extended
therapy.
3.2. In patients with DVT of the leg who are
treated with VKA, we recommend a therapeutic
INR range of 2.0 to 3.0 (target INR of 2.5) over
a lower (INR , 2) or higher (INR 3.0-5.0) range
for all treatment durations (Grade 1B).
3.1.4.1. In patients with a first VTE that is an
unprovoked proximal DVT of the leg and who
have a low or moderate bleeding risk, we suggest
extended anticoagulant therapy over 3 months
of therapy (Grade 2B).
3.3.1. In patients with DVT of the leg and no cancer, we suggest VKA therapy over LMWH for
long-term therapy (Grade 2C). For patients with
DVT and no cancer who are not treated with VKA
therapy, we suggest LMWH over dabigatran or
rivaroxaban for long-term therapy (Grade 2C).
have a high bleeding risk, we recommend
3 months of anticoagulant therapy over extended
therapy (Grade 1B).
unprovoked isolated distal DVT of the leg (see
remark), we suggest 3 months of anticoagulant
therapy over extended therapy in those with a low
or moderate bleeding risk (Grade 2B) and recommend 3 months of anticoagulant treatment
in those with a high bleeding risk (Grade 1B).
3.1.4.4. In patients with a second unprovoked
VTE, we recommend extended anticoagulant
therapy over 3 months of therapy in those who
have a low bleeding risk (Grade 1B), and we suggest extended anticoagulant therapy in those
with a moderate bleeding risk (Grade 2B).
VTE who have a high bleeding risk, we suggest 3 months of anticoagulant therapy over
extended therapy (Grade 2B).
3.1.5. In patients with DVT of the leg and active
cancer, if the risk of bleeding is not high, we
recommend extended anticoagulant therapy
over 3 months of therapy (Grade 1B), and if there
is a high bleeding risk, we suggest extended
anticoagulant therapy (Grade 2B).
3.2 Intensity of Anticoagulant Effect
3.3 Choice of Anticoagulant Regimen for Long-term
Therapy
3.3.2. In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade
2B). In patients with DVT and cancer who are
not treated with LMWH, we suggest VKA over
dabigatran or rivaroxaban for long-term therapy
(Grade 2B).
Remarks (3.3.1-3.3.2): Choice of treatment in patients
with and without cancer is sensitive to the individual
patient’s tolerance for daily injections, need for laboratory monitoring, and treatment costs. LMWH, rivaroxaban, and dabigatran are retained in patients with
renal impairment, whereas this is not a concern with
VKA. Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients,
may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these
guidelines were being prepared (October 2011),
postmarketing studies of safety were not available.
Given the paucity of currently available data and that
new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy
over dabigatran and rivaroxaban, and we have not
made any recommendations in favor of one of the
new agents over the other.
3.4 Choice of Anticoagulant Regimen for Extended
Therapy
3.4. In patients with DVT of the leg who receive
extended therapy, we suggest treatment with the
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Executive Summary
same anticoagulant chosen for the first 3 months
(Grade 2C).
3.5 Treatment of Patients With Asymptomatic DVT
of the Leg
3.5. In patients who are incidentally found to have
asymptomatic DVT of the leg, we suggest the same
initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 2B).
4.1 Compression Stockings and Bandages to Prevent
PTS
4.1. In patients with acute symptomatic DVT of
the leg, we suggest the use of compression stockings (Grade 2B).
Remarks: Compression stockings should be worn for
2 years, and we suggest beyond that if patients have
developed PTS and find the stockings helpful.
Patients who place a low value on preventing PTS or
a high value on avoiding the inconvenience and discomfort of stockings are likely to decline stockings.
4.2 Physical Treatment of Patients With PTS
4.2.1. In patients with PTS of the leg, we suggest a trial of compression stockings (Grade 2C).
4.2.2. In patients with severe PTS of the leg that
is not adequately relieved by compression stockings, we suggest a trial of an intermittent compression device (Grade 2B).
4.3 Pharmacologic Treatment of Patients With PTS
4.3. In patients with PTS of the leg, we suggest that
venoactive medications (eg, rutosides, defibrotide, and hidrosmin) not be used (Grade 2C).
Remarks: Patients who value the possibility of response
over the risk of side effects may choose to undertake a
therapeutic trial.
5.1 Initial Anticoagulation for Patients With Acute
Pulmonary Embolism (PE)
5.1. In patients with acute PE, we recommend
initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC
UFH) over no such initial treatment (Grade 1B).
5.2 Parenteral Anticoagulation Prior to Receipt of the
Results of Diagnostic Work-up for PE
5.2.1. In patients with a high clinical suspicion
of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic
tests (Grade 2C).
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suspicion of acute PE, we suggest treatment
(Grade 2C).
acute PE, we suggest not treating with parenteral anticoagulants while awaiting the results
early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation,
and continuation of parenteral anticoagulation
for a minimum of 5 days and until the INR is 2.0
or above for at least 24 h (Grade 1B).
5.4 Choice of Initial Parenteral Anticoagulant Regimen
in Patients With PE
5.4.1. In patients with acute PE, we suggest
LMWH or fondaparinux over IV UFH (Grade 2C
for LMWH; Grade 2B for fondaparinux) and over
SC UFH (Grade 2B for LMWH; Grade 2C for
fondaparinux).
Remarks: Local considerations such as cost, availability,
and familiarity of use dictate the choice between
fondaparinux and LMWH. LMWH and fondaparinux
are retained in patients with renal impairment,
whereas this is not a concern with UFH. In patients
with PE where there is concern about the adequacy
of SC absorption or in patients in whom thrombolytic
therapy is being considered or planned, initial treatment with IV UFH is preferred to use of SC therapies.
5.4.2. In patients with acute PE treated with
LMWH, we suggest once- over twice-daily administration (Grade 2C).
the approved once-daily regimen uses the same
daily dose as the twice-daily regimen (ie, the oncedaily injection contains double the dose of each
twice-daily injection). It also places value on avoiding
an extra injection per day.
5.5 Early vs Standard Discharge of Patients With
Acute PE
5.5. In patients with low-risk PE and whose
home circumstances are adequate, we suggest
early discharge over standard discharge (eg,
after first 5 days of treatment) (Grade 2B).
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Remarks: Patients who prefer the security of the hospital to the convenience and comfort of home are
likely to choose hospitalization over home treatment.
5.6 Systemic Thrombolytic Therapy for Patients With
PE
5.6.1.1. In patients with acute PE associated
with hypotension (eg, systolic BP , 90 mm Hg)
who do not have a high bleeding risk, we suggest systemically administered thrombolytic
therapy over no such therapy (Grade 2C).
5.6.1.2. In most patients with acute PE not associated with hypotension, we recommend against
systemically administered thrombolytic therapy
(Grade 1C).
5.6.1.3. In selected patients with acute PE not
associated with hypotension and with a low bleeding risk whose initial clinical presentation, or
clinical course after starting anticoagulant therapy, suggests a high risk of developing hypotension, we suggest administration of thrombolytic
therapy (Grade 2C).
5.6.2.1. In patients with acute PE, when a thrombolytic agent is used, we suggest short infusion
times (eg, a 2-h infusion) over prolonged infusion times (eg, a 24-h infusion) (Grade 2C).
5.6.2.2. In patients with acute PE when a thrombolytic agent is used, we suggest administration
through a peripheral vein over a pulmonary
artery catheter (Grade 2C).
5.7 Catheter-Based Thrombus Removal for the Initial
Treatment of Patients With PE
5.7. In patients with acute PE associated with
hypotension and who have (i) contraindications
to thrombolysis, (ii) failed thrombolysis, or (iii)
shock that is likely to cause death before systemic
thrombolysis can take effect (eg, within hours), if
appropriate expertise and resources are available, we suggest catheter-assisted thrombus
removal over no such intervention (Grade 2C).
5.8 Surgical Embolectomy for the Initial Treatment
of Patients With PE
hypotension, we suggest surgical pulmonary
embolectomy over no such intervention if they
have (i) contraindications to thrombolysis, (ii)
failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause
death before thrombolysis can take effect (eg,
within hours), provided surgical expertise and
resources are available (Grade 2C).
5.9. Vena Cava Filters for the Initial Treatment of
Patients With PE
5.9.1. In patients with acute PE who are treated
with anticoagulants, we recommend against the
use of an IVC filter (Grade 1B).
5.9.2. In patients with acute PE and contraindication to anticoagulation, we recommend the
5.9.3. In patients with acute PE and an IVC
filter inserted as an alternative to anticoagulation, we suggest a conventional course of
anticoagulant therapy if their risk of bleeding
resolves (Grade 2B).
anticoagulation.
6.0 Long-term Treatment of Patients With PE
6.1. In patients with PE provoked by surgery,
or (iii) extended therapy (Grade 1B regardless of
bleeding risk).
6.2. In patients with PE provoked by a nonsurgical transient risk factor, we recommend
treatment with anticoagulation for 3 months
over (i) treatment of a shorter period (Grade 1B),
(ii) treatment of a longer time-limited period
(eg, 6 or 12 months) (Grade 1B), and (iii) extended
therapy if there is a high bleeding risk (Grade
1B). We suggest treatment with anticoagulation
for 3 months over extended therapy if there is a
low or moderate bleeding risk (Grade 2B).
6.3. In patients with an unprovoked PE, we recommend treatment with anticoagulation for at
least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment,
patients with unprovoked PE should be evaluated
for the risk-benefit ratio of extended therapy.
6.3.1. In patients with a first VTE that is an
unprovoked PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy
(Grade 2B).
unprovoked PE and who have a high bleeding
risk, we recommend 3 months of anticoagulant
therapy over extended therapy (Grade 1B).
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Executive Summary
6.3.3. In patients with a second unprovoked
VTE who have a high bleeding risk, we suggest
3 months of therapy over extended therapy
(Grade 2B).
6.4. In patients with PE and active cancer, if
there is a low or moderate bleeding risk, we
recommend extended anticoagulant therapy
over 3 months of therapy (Grade 1B), and if there
is a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B).
Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment
should be reassessed at periodic intervals (eg, annually).
6.5. In patients with PE who are treated with
VKA, we recommend a therapeutic INR range
of 2.0 to 3.0 (target INR of 2.5) over a lower
(INR , 2) or higher (INR 3.0-5.0) range for all
treatment durations (Grade 1B).
6.6. In patients with PE and no cancer, we suggest VKA therapy over LMWH for long-term
therapy (Grade 2C). For patients with PE and no
cancer who are not treated with VKA therapy,
we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C).
6.7. In patients with PE and cancer, we suggest
LMWH over VKA therapy (Grade 2B). In patients
with PE and cancer who are not treated with
LMWH, we suggest VKA over dabigatran or
Remarks (6.6-6.7): Choice of treatment in patients
patient’s tolerance for daily injections, need for laboratory monitoring, and treatment costs. Treatment of
VTE with dabigatran or rivaroxaban, in addition to
being less burdensome to patients, may prove to be
associated with better clinical outcomes than VKA
and LMWH therapy. When these guidelines were
being prepared (October 2011), postmarketing studies
of safety were not available. Given the paucity of currently available data and that new data are rapidly
emerging, we give a weak recommendation in favor
of VKA and LMWH therapy over dabigatran and
rivaroxaban, and we have not made any recommendation in favor of one of the new agents over the other.
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6.8. In patients with PE who receive extended
therapy, we suggest treatment with the same
anticoagulant chosen for the first 3 months
(Grade 2C).
6.9. In patients who are incidentally found to
have asymptomatic PE, we suggest the same
initial and long-term anticoagulation as for
comparable patients with symptomatic PE
(Grade 2B).
7.1 Pulmonary Thromboendarterectomy, Anticoagulant
Therapy, and Vena Cava Filter for the Treatment of
Chronic Thromboembolic Pulmonary Hypertension
(CTPH)
7.1.1. In patients with CTPH, we recommend
extended anticoagulation over stopping therapy
(Grade 1B).
7.1.2. In selected patients with CTPH, such as
those with central disease under the care of
an experienced thromboendarterectomy team,
we suggest pulmonary thromboendarterectomy
over no pulmonary thromboendarterectomy
(Grade 2C).
8.1 Treatment of Patients With Superficial Vein
Thrombosis
8.1.1. In patients with superficial vein thrombosis of the lower limb of at least 5 cm in length,
we suggest the use of a prophylactic dose of
fondaparinux or LMWH for 45 days over no
anticoagulation (Grade 2B).
Remarks: Patients who place a high value on avoiding
the inconvenience or cost of anticoagulation and a
low value on avoiding infrequent symptomatic VTE
are likely to decline anticoagulation.
8.1.2. In patients with superficial vein thrombosis who are treated with anticoagulation, we
suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C).
9.1 Acute Anticoagulation for Patients With UEDVT
9.1.1. In patients with UEDVT that involves
the axillary or more proximal veins, we recommend acute treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH,
or SC UFH) over no such acute treatment
(Grade 1B).
9.1.2. In patients with acute UEDVT that
involves the axillary or more proximal veins, we
(Grade 2C) and over SC UFH (Grade 2B).
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9.2 Thrombolytic Therapy for the Initial Treatment
of Patients With UEDVT
suggest anticoagulant therapy alone over thrombolysis (Grade 2C).
9.4 Prevention of PTS of the Arm
9.4. In patients with acute symptomatic UEDVT,
we suggest against the use of compression
sleeves or venoactive medications (Grade 2C).
9.5 Treatment of Patients With PTS of the Arm
Remarks: Patients who (i) are most likely to benefit
from thrombolysis (see text); (ii) have access to CDT;
(iii) attach a high value to prevention of PTS; and (iv)
attach a lower value to the initial complexity, cost,
and risk of bleeding with thrombolytic therapy are
likely to choose thrombolytic therapy over anticoagulation alone.
9.5.1. In patients who have PTS of the arm, we
suggest a trial of compression bandages or
sleeves to reduce symptoms (Grade 2C).
9.2.2. In patients with UEDVT who undergo
thrombolysis, we recommend the same intensity and duration of anticoagulant therapy as in
similar patients who do not undergo thrombolysis (Grade 1B).
10.0 Patients With Splanchnic Vein Thrombosis
9.3 Long-term Anticoagulation for Patients With
UEDVT
9.3.1. In most patients with UEDVT that is associated with a central venous catheter, we suggest that the catheter not be removed if it is
functional and there is an ongoing need for the
catheter (Grade 2C).
the axillary or more proximal veins, we suggest
a minimum duration of anticoagulation of
3 months over a shorter period (Grade 2B).
Remarks: This recommendation also applies if the
UEDVT was associated with a central venous catheter that was removed shortly after diagnosis.
9.3.3. In patients who have UEDVT that is associated with a central venous catheter that is
removed, we recommend 3 months of anticoagulation over a longer duration of therapy in
patients with no cancer (Grade 1B), and we suggest this in patients with cancer (Grade 2C).
9.3.4. In patients who have UEDVT that is associated with a central venous catheter that is not
removed, we recommend that anticoagulation
is continued as long as the central venous catheter remains over stopping after 3 months of
treatment in patients with cancer (Grade 1C),
and we suggest this in patients with no cancer
(Grade 2C).
9.3.5. In patients who have UEDVT that is not
associated with a central venous catheter or with
cancer, we recommend 3 months of anticoagulation over a longer duration of therapy (Grade 1B).
9.5.2. In patients with PTS of the arm, we suggest against treatment with venoactive medications (Grade 2C).
10.1. In patients with symptomatic splanchnic
vein thrombosis (portal, mesenteric, and/or
splenic vein thromboses), we recommend anticoagulation over no anticoagulation (Grade 1B).
10.2. In patients with incidentally detected
splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we suggest no anticoagulation over anticoagulation
(Grade 2C).
11.0 Patients With Hepatic Vein Thrombosis
11.1. In patients with symptomatic hepatic vein
thrombosis, we suggest anticoagulation over no
anticoagulation (Grade 2C).
hepatic vein thrombosis, we suggest no anticoagulation over anticoagulation (Grade 2C).
Treatment and Prevention of
Heparin-Induced Thrombocytopenia
For further details, see Linkins et al.8
2.1 Platelet Count Monitoring Combined With the
4Ts Score for Patients Receiving Heparin/LMWH
2.1.1. For patients receiving heparin in whom
clinicians consider the risk of heparin-induced
thrombocytopenia (HIT) to be . 1%, we suggest
that platelet count monitoring be performed
every 2 or 3 days from day 4 to day 14 (or until
heparin is stopped, whichever occurs first)
(Grade 2C).
2.1.2. For patients receiving heparin in whom
clinicians consider the risk of HIT to be , 1%,
we suggest that platelet counts not be monitored (Grade 2C).
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Executive Summary
3.1 Discontinuation of Heparin or Initiation of VKAs
vs Treatment With Nonheparin Anticoagulants
3.1. In patients with HIT complicated by thrombosis
(HITT), we recommend the use of nonheparin
anticoagulants, in particular lepirudin, argatroban, and danaparoid, over the further use of
heparin or LMWH or initiation/continuation of
a VKA (Grade 1C).
3.2 Choice of Nonheparin Anticoagulants in Patients
With HITT
3.2.1. In patients with HITT who have normal
renal function, we suggest the use of argatroban
or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C).
Remarks: Other factors not covered by our analysis,
such as drug availability, cost, and ability to monitor the
anticoagulant effect, may influence the choice of agent.
3.2.2. In patients with HITT and renal insufficiency, we suggest the use of argatroban over
other nonheparin anticoagulants (Grade 2C).
3.3 Platelet Transfusions
3.3 In patients with HIT and severe thrombocytopenia, we suggest giving platelet transfusions
only if bleeding or during the performance
of an invasive procedure with a high risk of
bleeding (Grade 2C).
3.4 Starting VKAs Before Platelet Recovery
3.4.1. In patients with strongly suspected or
confirmed HIT, we recommend against starting
VKA until platelets have substantially recovered
(ie, usually to at least 150 3 109/L) over starting
VKA at a lower platelet count and that the VKA
be initially given in low doses (maximum, 5 mg
of warfarin or 6 mg phenprocoumon) over using
higher doses (Grade 1C).
3.4.2. We further suggest that if a VKA has already
been started when a patient is diagnosed with
HIT, vitamin K should be administered (Grade 2C).
and until the INR is within the target range over
shorter periods of overlap and that the INR be
rechecked after the anticoagulant effect of the
nonheparin anticoagulant has resolved (Grade 1C).
4.1 Discontinuation of Heparin or Initiation of VKAs
vs Treatment With Nonheparin Anticoagulants
4.1. In patients with isolated HIT (HIT without
thrombosis), we recommend the use of lepirudin
or argatroban or danaparoid over the further use
of heparin or LMWH or initiation/continuation
of a VKA (Grade 1C).
4.2 Choice of Nonheparin Anticoagulants in Patients
With Isolated HIT
4.2. In patients with isolated HIT (HIT without
thrombosis) who have normal renal function,
we suggest the use of argatroban or lepirudin
or danaparoid over other nonheparin anticoagulants (Grade 2C).
Remarks: Other factors such as drug availability, cost,
and ability to monitor the anticoagulant effect may
influence the choice of agent. The dosing considerations are the same as for patients with HITT (see
section 3.2). For a recommendation on choice of
nonheparin anticoagulants in the setting of renal
insufficiency, see Recommendation 3.2.2.
5.1 Patients Who Require Urgent Cardiac Surgery
5.1.1. In patients with acute HIT (thrombocytopenic, HIT antibody positive) or subacute HIT
(platelets recovered but still HIT antibody positive) who require urgent cardiac surgery, we
suggest the use of bivalirudin over other nonheparin anticoagulants and over heparin plus
antiplatelet agents (Grade 2C).
5.1.2. In patients with acute HIT who require
nonurgent cardiac surgery, we recommend
delaying the surgery (if possible) until HIT has
resolved and HIT antibodies are negative (see
section 6.1) (Grade 2C).
Remarks: We place a high value on the prevention
of venous limb gangrene and a low value on the cost
of the additional days of the parental nonheparin
anticoagulant.
Remarks: Other factors not covered by our analysis,
such as drug availability, cost, and ability to monitor
the anticoagulant effect may influence the choice of
agent. For recommendations for patients with a past
history of HIT (. 3 months previous) who require
cardiac surgery, see section 6.1.
3.5 Discontinuation of Thrombin Inhibitor After a
Minimum of 5 Days of Overlap With VKAs
5.2 Patients Who Require Urgent Percutaneous
Coronary Interventions
3.5. In patients with confirmed HIT, we recommend that that the VKA be overlapped with a nonheparin anticoagulant for a minimum of 5 days
5.2. In patients with acute HIT or subacute HIT
who require percutaneous coronary interventions, we suggest the use of bivalirudin (Grade 2B)
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or argatroban (Grade 2C) over other nonheparin
anticoagulants.
Remarks: Other factors, such as drug availability,
cost, and ability to monitor the anticoagulant effect,
may influence the choice of agent.
5.3 Patients Who Require Renal Replacement Therapy
5.3.1. In patients with acute or subacute HIT
who require renal replacement therapy, we
suggest the use of argatroban or danaparoid
over other nonheparin anticoagulants (Grade 2C).
Remarks: We acknowledge that the cost of argatroban
may be prohibitive at some clinical centers. We further suggest that if the prothrombotic state of HIT
appears to have resolved (as seen by normalization of
the platelet count), saline flushes during dialysis would
be a reasonable option. This suggestion is based on
the presumed pathogenesis of thrombosis in this
condition and not on the results of clinical trials.
5.3.2. In patients with a past history of HIT who
require ongoing renal replacement therapy
or catheter locking, we suggest the use of
regional citrate over the use of heparin or
LMWH (Grade 2C).
5.4 Pregnant Patients
5.4. In pregnant patients with acute or subacute
HIT, we suggest danaparoid over other nonheparin anticoagulants (Grade 2C). We suggest
the use of lepirudin or fondaparinux only if
danaparoid is not available (Grade 2C).
Remarks: Other factors, such as drug availability,
cost, and ability to monitor the anticoagulant effect,
may influence the choice of agent.
6.1 Patients With a History of HIT Who Require
Cardiac Surgery
6.1.1. In patients with a history of HIT in whom
heparin antibodies have been shown to be
absent who require cardiac surgery, we suggest
the use of heparin (short-term use only) over
nonheparin anticoagulants (Grade 2C).
6.1.2. In patients with a history of HIT in whom
heparin antibodies are still present who require
cardiac surgery, we suggest the use of nonheparin anticoagulants (see 5.1.1) over heparin or
LMWH (Grade 2C).
6.2 Patients Who Require PCI
6.2. In patients with a history of HIT in whom
heparin antibodies have been shown to be
absent who require cardiac catheterization or
percutaneous coronary interventions, the recommended treatment is the same as 5.2.
6.3 Patients Who Require Prophylaxis or Treatment
of Thrombosis
6.3. In patients with a past history of HIT who
have acute thrombosis (not related to HIT) and
normal renal function, we suggest the use of
fondaparinux at full therapeutic doses until
transition to a VKA can be achieved (Grade 2C).
Antithrombotic Therapy for
Atrial Fibrillation
For further details, see You et al.9
2.1 Patients With Nonrheumatic Atrial Fibrillation
(AF)
2.1.8. For patients with AF, including those with
paroxysmal AF, who are at low risk of stroke
(eg, CHADS2 [congestive heart failure, hypertension, age ! 75 years, diabetes mellitus, prior
stroke or transient ischemic attack] score 5 0),
we suggest no therapy rather than antithrombotic therapy (Grade 2B). For patients who do
choose antithrombotic therapy, we suggest aspirin (75 mg to 325 mg once daily) rather than
oral anticoagulation (Grade 2B) or combination
therapy with aspirin and clopidogrel (Grade 2B).
Remarks: Patients who place an exceptionally high
value on stroke reduction and a low value on avoiding
bleeding and the burden associated with antithrombotic therapy are likely to choose antithrombotic
therapy rather than no antithrombotic therapy. Other
factors that may influence the choices above are a
consideration of patient-specific bleeding risk and
the presence of additional risk factors for stroke,
including age 65 to 74 years and female gender, which
have been more consistently validated, and vascular
disease, which has been less well validated (see section 2.1.12). The presence of multiple non-CHADS2
risk factors for stroke may favor oral anticoagulation
therapy.
paroxysmal AF, who are at intermediate risk of
stroke (eg, CHADS2 score 5 1), we recommend
oral anticoagulation rather than no therapy
(Grade 1B). We suggest oral anticoagulation
rather than aspirin (75 mg to 325 mg once
daily) (Grade 2B) or combination therapy with
aspirin and clopidogrel (Grade 2B). For patients
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Executive Summary
who are unsuitable for or choose not to take an
oral anticoagulant (for reasons other than concerns about major bleeding), we suggest combination therapy with aspirin and clopidogrel
rather than aspirin (75 mg to 325 mg once daily)
(Grade 2B).
bleeding and the burden associated with anticoagulant therapy are likely to choose oral anticoagulation
rather than antiplatelet therapy. Other factors that
may influence the choice among antithrombotic
therapies are a consideration of bleeding risk and
the presence of additional risk factors for stroke,
including age 65 to 74 years and female gender,
which have been more consistently validated, and
vascular disease, which has been less well validated
(see section 2.1.12). The presence of multiple additional non-CHADS2 risk factors for stroke may favor
oral anticoagulation therapy.
paroxysmal AF, who are at high risk of stroke
(eg, CHADS2 score 5 2), we recommend oral anticoagulation rather than no therapy (Grade 1A),
aspirin (75 mg to 325 mg once daily) (Grade 1B),
or combination therapy with aspirin and clopidogrel (Grade 1B). For patients who are unsuitable
for or choose not to take an oral anticoagulant
(for reasons other than concerns about major
bleeding), we recommend combination therapy
with aspirin and clopidogrel rather than aspirin
(75 mg to 325 mg once daily) (Grade 1B).
2.1.11. For patients with AF, including those
with paroxysmal AF, for recommendations
in favor of oral anticoagulation (including
2.1.9, 2.1.10, and excluding 2.2, 3.1, 3.2, 3.3),
we suggest dabigatran 150 mg twice daily rather
than adjusted-dose VKA therapy (target INR
range, 2.0-3.0) (Grade 2B).
Remarks: Dabigatran is excreted primarily by the
kidney. It has not been studied and is contraindicated in patients with severe renal impairment (estimated creatinine clearance of 30 mL/min or less).
Clinicians should be aware that there is no antidote
for dabigatran.
2.2 Patients With AF and Mitral Stenosis
2.2. For patients with AF and mitral stenosis, we
recommend adjusted-dose VKA therapy (target
INR range, 2.0-3.0) rather than no therapy,
aspirin (75 mg to 325 mg once daily), or combination therapy with aspirin and clopidogrel (all
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Grade 1B). For patients with AF and mitral stenosis who are unsuitable for or choose not to
take adjusted-dose VKA therapy (for reasons
other than concerns about major bleeding), we
recommend combination therapy with aspirin
and clopidogrel rather than aspirin (75 mg to
325 mg once daily) alone (Grade 1B).
3.1 Patients With AF and Stable Coronary Artery
Disease
3.1. For patients with AF and stable coronary
artery disease (eg, no acute coronary syndrome
within the previous year) and who choose oral
anticoagulation, we suggest adjusted-dose VKA
therapy alone (target international normalized
ratio [INR] range, 2.0-3.0) rather than the combination of adjusted-dose VKA therapy and
aspirin (Grade 2C).
3.2 Patients With AF and Placement of an Intracoronary Stent
3.2. For patients with AF at high risk of stroke
(eg, CHADS2 score of 2 or greater) during the
first month after placement of a bare-metal
stent or the first 3 to 6 months after placement of a drug-eluting stent, we suggest triple
therapy (eg, VKA therapy, aspirin, and clopidogrel) rather than dual antiplatelet therapy
(eg, aspirin and clopidogrel) (Grade 2C). After
this initial period of triple therapy, we suggest
a VKA (INR 2.0-3.0) plus a single antiplatelet
drug rather than VKA alone (Grade 2C). At
12 months after intracoronary stent placement, antithrombotic therapy is suggested as
for patients with AF and stable coronary artery
disease (see section 3.1).
For patients with AF at low to intermediate risk
of stroke (eg, CHADS2 score of 0 or 1) during
the first 12 months after placement of an intracoronary stent (bare metal or drug eluting), we
suggest dual antiplatelet therapy rather than
triple therapy (Grade 2C). At 12 months after
intracoronary stent placement, antithrombotic
therapy is suggested as for patients with AF and
stable coronary artery disease (see section 3.1).
value on stroke reduction and a low value on avoiding bleeding and the burden associated with anticoagulant therapy are likely to choose triple therapy
rather than dual antiplatelet therapy. Other factors
that may influence this choice are a consideration of
bleeding risk and the presence of additional nonCHADS2 risk factors for stroke (see section 2.1.12).
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3.3 Patients With AF and ACS Who Do Not Undergo
Intracoronary Stent Placement
3.3. For patients with AF at intermediate to high
risk of stroke (eg, CHADS2 score of 1 or greater)
who experience an acute coronary syndrome
and do not undergo intracoronary stent placement, we suggest for the first 12 months, adjusted-dose VKA therapy (INR 2.0-3.0) plus single
antiplatelet therapy rather than dual antiplatelet therapy (eg, aspirin and clopidogrel) or
triple therapy (eg, warfarin, aspirin, and clopidogrel) (Grade 2C). After the first 12 months,
antithrombotic therapy is suggested as for
patients with AF and stable coronary artery
disease (see section 3.1).
For patients with AF at low risk of stroke (eg,
CHADS2 score of 0), we suggest dual antiplatelet therapy (eg, aspirin and clopidogrel) rather
than adjusted-dose VKA therapy (INR 2.0-3.0)
plus single antiplatelet therapy or triple therapy
(eg, warfarin, aspirin, and clopidogrel) (Grade
2C). After the first 12 months, antithrombotic
therapy is suggested as for patients with AF and
stable coronary artery disease (see section 3.1).
bleeding and the burden associated with anticoagulant therapy are likely to choose adjusted-dose VKA
therapy plus single antiplatelet therapy rather than
dual antiplatelet therapy. Other factors that may
influence this choice are a consideration of bleeding
risk and the presence of additional non-CHADS2 risk
factors for stroke (see section 2.1.12).
3.4 Patients With AF Managed by a Rhythm Control
Strategy
3.4. For patients with AF being managed with a
rhythm control strategy (pharmacologic or catheter ablation), we suggest that antithrombotic
therapy decisions follow the general risk-based
recommendations for patients with AF in section 2.1, regardless of the apparent persistence
of normal sinus rhythm (Grade 2C).
3.5 Patients With Atrial Flutter
3.5. For patients with atrial flutter, we suggest
that antithrombotic therapy decisions follow
the same risk-based recommendations as for
AF.
4.1 Patients Undergoing Elective Cardioversion of AF
4.1.1. For patients with AF of greater than
48 h or unknown duration undergoing elective
electrical or pharmacologic cardioversion,
we recommend therapeutic anticoagulation
(adjusted-dose VKA therapy, target INR range
2.0-3.0, low-molecular-weight heparin at full
venous thromboembolism treatment doses, or
dabigatran) for at least 3 weeks before cardioversion or a transesophageal echocardiography
(TEE)-guided approach with abbreviated anticoagulation before cardioversion rather than
no anticoagulation (Grade 1B). We recommend
therapeutic anticoagulation for at least 4 weeks
after successful cardioversion to sinus rhythm
rather than no anticoagulation, regardless of
the baseline risk of stroke (Grade 1B). Decisions
about anticoagulation beyond 4 weeks should
be made in accordance with our risk-based recommendations for long-term antithrombotic
therapy in section 2.1.
4.1.2. For patients with AF of documented
duration of 48 h or less undergoing elective
cardioversion (electrical or pharmacologic), we
suggest starting anticoagulation at presentation
(low-molecular-weight heparin or unfractionated heparin at full venous thromboembolism
treatment doses) and proceeding to cardioversion rather than delaying cardioversion
for 3 weeks of therapeutic anticoagulation or
a TEE-guided approach (Grade 2C). After successful cardioversion to sinus rhythm, we recommend therapeutic anticoagulation for at
least 4 weeks rather than no anticoagulation,
regardless of baseline stroke risk (Grade 2C).
Decisions about long-term anticoagulation
after cardioversion should be made in accordance with our risk-based recommendations
for long-term antithrombotic therapy in section 2.1.
4.2 Patients Undergoing Urgent Cardioversion for
Hemodynamically Unstable AF
4.2. For patients with AF and hemodynamic
instability undergoing urgent cardioversion
(electrical or pharmacologic), we suggest that
therapeutic-dose parenteral anticoagulation
be started before cardioversion, if possible
(Grade 2C), but that initiation of anticoagulation must not delay any emergency intervention
(Grade 2C). After successful cardioversion to
sinus rhythm, we suggest therapeutic anticoagulation for at least 4 weeks after successful
cardioversion to sinus rhythm rather than no
anticoagulation, regardless of baseline stroke
risk (Grade 2C). Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk-based recommendations
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Executive Summary
for long-term antithrombotic therapy in section 2.1.
4.3 Patients Undergoing Elective or Urgent
Cardioversion for Atrial Flutter
4.3. For patients with atrial flutter undergoing
elective or urgent pharmacologic or electrical
cardioversion, we suggest that the same
approach to thromboprophylaxis be used as
for patients with atrial fibrillation undergoing
cardioversion.
Antithrombotic and Thrombolytic
Therapy for Valvular Disease
For further details, see Whitlock et al.10
2.0 Patients With Rheumatic Mitral Valve Disease
2.0.1. In patients with rheumatic mitral valve
disease and normal sinus rhythm with a left
atrial diameter , 55 mm we suggest not using
antiplatelet or VKA therapy (Grade 2C).
2.0.2. In patients with rheumatic mitral valve
disease and normal sinus rhythm with a left
atrial diameter . 55 mm, we suggest VKA therapy (target INR, 2.5; range, 2.0-3.0) over no
VKA therapy or antiplatelet (Grade 2C).
2.0.3. For patients with rheumatic mitral valve
disease complicated by the presence of left
atrial thrombus, we recommend VKA therapy
(target INR, 2.5; range, 2.0-3.0) over no VKA
therapy (Grade 1A).
2.0.4. For patients with rheumatic mitral valve
disease complicated singly or in combination by
the presence of atrial fibrillation or previous
systemic embolism, we recommend VKA therapy
therapy (Grade 1A).
2.1 Patients With Rheumatic Mitral Valve Disease
Undergoing Percutaneous Mitral Balloon Valvotomy
(PMBV)
2.1.1. For patients being considered for PMBV
with preprocedural TEE showing left atrial
thrombus, we recommend postponement of
PMBV and that VKA therapy (target INR, 3.0;
range, 2.5-3.5) be administered until thrombus
resolution is documented by repeat TEE over
no VKA therapy (Grade 1A).
2.1.2. For patients being considered for PMBV
with preprocedural TEE showing left atrial
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thrombus, if the left atrial thrombus does not
resolve with VKA therapy, we recommend that
PMBV not be performed (Grade 1A).
6.2.1. In patients with asymptomatic patent
foramen ovale (PFO) or atrial septal aneurysm, we
suggest against antithrombotic therapy (Grade 2C).
6.2 Patients With PFO and Atrial Septal Aneurysm
6.2.2. In patients with cryptogenic stroke and
PFO or atrial septal aneurysm, we recommend aspirin (50-100 mg/d) over no aspirin
(Grade 1A).
PFO or atrial septal aneurysm, who experience
recurrent events despite aspirin therapy, we
suggest treatment with VKA therapy (target
INR, 2.5; range, 2.0-3.0) and consideration of
device closure over aspirin therapy (Grade 2C).
PFO, with evidence of DVT, we recommend
VKA therapy for 3 months (target INR, 2.5;
range, 2.0-3.0) (Grade 1B) and consideration of
device closure over no VKA therapy or aspirin
therapy (Grade 2C).
7.1 Role of Anticoagulants and Antiplatelet Agents in
Patients With Native Valve Endocarditis
7.1.1. In patients with infective endocarditis
(IE), we recommend against routine anticoagulant therapy, unless a separate indication exists
(Grade 1C).
7.1.2. In patients with IE, we recommend
against routine antiplatelet therapy, unless a
separate indication exists (Grade 1B).
7.2 Role of Anticoagulants in Patients With Prosthetic
Valve Endocarditis
7.2. In patients on VKA for a prosthetic valve
who develop IE, we suggest VKA be discontinued at the time of initial presentation until it
is clear that invasive procedures will not be
required and the patient has stabilized without
signs of CNS involvement. When the patient is
deemed stable without contraindications or neurologic complications, we suggest reinstitution
7.3 Patients With Nonbacterial Thrombotic Endocarditis
7.3. In patients with nonbacterial thrombotic
endocarditis and systemic or pulmonary emboli,
we suggest treatment with full-dose IV UFH or
SC LMWH over no anticoagulation (Grade 2C).
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8.2 Antithrombotic Therapy in the First 3 Months
After Surgery
3.0 (range, 2.5-3.5) over lower INR targets
(Grade 2C).
8.2.1. In patients with aortic bioprosthetic
valves, who are in sinus rhythm and have no
other indication for VKA therapy, we suggest
aspirin (50-100 mg/d) over VKA therapy in the
first 3 months (Grade 2C).
9.5 Intensity of VKA Therapy in Patients With Double
Mechanical Valve or With Additional Risk Factors
8.2.2. In patients with transcatheter aortic bioprosthetic valves, we suggest aspirin (50-100 mg/d)
plus clopidogrel (75 mg/d) over VKA therapy
and over no antiplatelet therapy in the first
3 months (Grade 2C).
8.2.3. In patients with a bioprosthetic valve in
the mitral position, we suggest VKA therapy
therapy for the first 3 months after valve insertion (Grade 2C).
8.3 Long-term Antithrombotic Therapy for Patients
With Bioprosthetic Valves
8.3. In patients with bioprosthetic valves in normal sinus rhythm, we suggest aspirin therapy
over no aspirin therapy after 3 months postoperative (Grade 2C).
9.5. In patients with mechanical heart valves in
both the aortic and mitral position, we suggest
target INR 3.0 (range 2.5-3.5) over target INR
2.5 (range 2.0-3.0) (Grade 2C).
9.6 Antiplaelet Agent in Addition to VKA Therapy for
Patients With Mechanical Aortic or Mitral Valve
Prostheses
9.6. In patients with a mechanical mitral or aortic valve at low risk of bleeding, we suggest adding over not adding an antiplatelet agent such
as low-dose aspirin (50-100 mg/d) to the VKA
therapy (Grade 1B).
Remarks: Caution should be used in patients at
increased bleeding risk, such as history of GI bleeding.
9.7 Antiplatelet Agent Therapy Instead of VKA Therapy
9.7. For patients with mechanical aortic or
mitral valves we recommend VKA over antiplatelet agents (Grade 1B).
9.1 Early Postoperative Bridging to Intermediate/
Long-term Therapy (Postoperative Day 0 to 5)
10.1 Antithrombotic Therapy After Mitral Valve
Repair
9.1. In patients with mechanical heart valves, we
suggest bridging with unfractionated heparin
(UFH, prophylactic dose) or LMWH (prophylactic or therapeutic dose) over IV therapeutic
UFH until stable on VKA therapy (Grade 2C).
10.1. In patients undergoing mitral valve repair
with a prosthetic band in normal sinus rhythm,
we suggest the use of antiplatelet therapy for
the first 3 months over VKA therapy (Grade 2C).
9.2 Long-term Antithrombotic Therapy for Patients
With Mechanical Valves
10.2. In patients undergoing aortic valve repair,
we suggest aspirin at 50 to 100 mg/d over VKA
therapy (Grade 2C).
9.2. In patients with mechanical heart valves,
we recommend VKA therapy over no VKA
therapy for long-term management (Grade 1B).
9.3 Intensity of VKA Therapy for Patients With
Mechanical Aortic Valve Prostheses
9.3.1. In patients with a mechanical aortic valve,
we suggest VKA therapy with a target of 2.5
(range, 2.0-3.0) over lower targets (Grade 2C).
9.3.2. In patients with a mechanical aortic
valve, we recommend VKA therapy with a target of 2.5 (range 2.0-3.0) over higher targets
(Grade 1B).
10.2 Patients Undergoing Aortic Valve Repair
11.1 Patients With Right-Sided Prosthetic Valve
Thrombosis
11.1. For patients with right-sided prosthetic
valve thrombosis (PVT), in the absence of contraindications we suggest administration of
fibrinolytic therapy over surgical intervention
(Grade 2C).
11.2 Patients With Left-Sided Prosthetic Valve
Thrombosis
9.4 Intensity of VKA Therapy for Patients With
Mechanical Mitral Valve Prostheses
11.2.1. For patients with left-sided PVT and large
thrombus area (! 0.8 cm2), we suggest early surgery over fibrinolytic therapy (Grade 2C). If contraindications to surgery exist, we suggest the
use of fibrinolytic therapy (Grade 2C).
9.4. In patients with a mechanical mitral valve,
we suggest VKA therapy with a target of
11.2.2. For patients with left-sided PVT and
small thrombus area (, 0.8 cm2), we suggest
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Executive Summary
administration of fibrinolytic therapy over
surgery. For very small, nonobstructive thrombus
we suggest IV UFH accompanied by serial Doppler echocardiography to document thrombus
resolution or improvement over other alternatives (Grade 2C).
Antithrombotic and Thrombolytic
Therapy for Ischemic Stroke
For further details, see Lansberg et al.11
2.1 IV Recombinant Tissue Plasminogen Activator
(r-tPA) for Patients With Acute Ischemic Stroke
2.1.1. In patients with acute ischemic stroke in
whom treatment can be initiated within 3 h of
symptom onset, we recommend IV r-tPA over
no IV r-tPA (Grade 1A).
whom treatment can be initiated within 4.5 but
not within 3 h of symptom onset, we suggest IV
r-tPA over no IV r-tPA (Grade 2C).
whom treatment cannot be initiated within 4.5 h
of symptom onset, we recommend against IV
r-tPA (Grade 1B).
2.2 Intraarterial Thrombolysis in Patients With
Acute Ischemic Stroke
2.2.1. In patients with acute ischemic stroke due
to proximal cerebral artery occlusions who do
not meet eligibility criteria for treatment with
IV r-tPA, we suggest intraarterial (IA) r-tPA
initiated within 6 h of symptom onset over no
IA r-tPA (Grade 2C).
2.2.2. In patients with acute ischemic stroke we
suggest IV r-tPA over the combination IV/IA
r-tPA (Grade 2C).
Remarks: Carefully selected patients who value the
uncertain benefits of combination IV/IA thrombolysis higher than the associated risks may choose
this intervention. Patients who prefer to avoid risk in
the setting of uncertain benefits are more likely to
choose IV r-tPA alone.
2.3 Mechanical Thrombectomy in Patients With
Acute Ischemic Stroke
2.3. In patients with acute ischemic stroke, we
suggest against the use of mechanical thrombectomy (Grade 2C).
Remarks: Carefully selected patients who value
the uncertain benefit of mechanical thrombectomy
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higher than the associated risks may choose this
intervention.
2.4 Aspirin in Patients With Acute Ischemic Stroke
2.4. In patients with acute ischemic stroke or
transient ischemic attack (TIA), we recommend
early (within 48 h) aspirin therapy at a dose of
160 to 325 mg over no aspirin therapy (Grade 1A).
2.5 Anticoagulation in Patients With Acute Ischemic
Stroke
2.5. In patients with acute ischemic stroke or
TIA, we recommend early (within 48 h) aspirin
therapy with an initial dose of 160 to 325 mg
over therapeutic parenteral anticoagulation
(Grade 1A).
3.1 VTE Prevention in Patients With Ischemic Stroke
3.1.1. In patients with acute ischemic stroke
and restricted mobility, we suggest prophylacticdose SC UFH or LMWH or intermittent pneumatic compression devices over no prophylaxis
(Grade 2B).
3.1.2. In patients with acute ischemic stroke and
restricted mobility, we suggest prophylactic-dose
LMWH over prophylactic-dose UFH (Grade 2B).
3.1.3. In patients with acute stroke and restricted
mobility, we suggest against elastic compression
stockings (Grade 2B).
Remarks: Pharmacologic and mechanical prophylaxis should be initiated as early as possible and should
be continued throughout the hospital stay or until
the patient has regained mobility. Mechanical devices
should be temporarily removed as often as needed
to allow for early mobilization and screening for
skin complications.
Combining pharmacologic therapy with intermittent
pneumatic compression devices may yield additional
benefit in prevention of VTEs compared with either
method used alone.
3.2 VTE Prevention in Patients With Hemorrhagic
Stroke
3.2.1. In patients with acute primary intracerebral hemorrhage and restricted mobility, we
suggest prophylactic-dose SC heparin (UFH or
LMWH) started between days 2 and 4 or intermittent pneumatic compression devices over
no prophylaxis (Grade 2C).
3.2.2. In patients with acute primary intracerebral hemorrhage and restricted mobility,
we suggest prophylactic-dose LMWH over
prophylactic-dose UFH (Grade 2B).
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3.2.3. In patients with primary intracerebral
hemorrhage and restricted mobility, we suggest
against elastic compression stockings (Grade 2B).
Remarks: Patients who prefer to avoid a theoretically increased risk of rebleeding with heparin
would favor mechanical prophylaxis with intermittent pneumatic compression devices over pharmacologic prophylaxis.
Combining pharmacologic therapy with intermittent pneumatic compression devices may yield additional benefit in prevention of VTEs compared with
either method used alone.
4.1 Antithrombotic Therapy for the Secondary
Prevention of Noncardioembolic Stroke
4.1.1. In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend
long-term treatment with aspirin (75-100 mg once
daily), clopidogrel (75 mg once daily), aspirin/
extended-release dipyridamole (25 mg/200 mg
bid), or cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants
(Grade 1B), the combination of clopidogrel plus
aspirin (Grade 1B), or triflusal (grade 2B).
4.1.2. Of the recommended antiplatelet regimens,
we suggest clopidogrel or aspirin/extendedrelease dipyridamole over aspirin (Grade 2B) or
cilostazol (Grade 2C).
Remarks: With long-term use (. 5 y), the benefit of
clopidogrel over aspirin in preventing major vascular
events may be offset by a reduction in cancer-related
mortality with regimens that contain aspirin.
4.2 Antithrombotic Therapy for the Secondary
Prevention of Cardioembolic Stroke
4.2.1. In patients with a history of ischemic
stroke or TIA and AF, including paroxysmal
AF, we recommend oral anticoagulation over
no antithrombotic therapy (Grade 1A), aspirin
(Grade 1B), or combination therapy with aspirin
and clopidogrel (Grade 1B).
stroke or TIA and atrial fibrillation, including
paroxysmal AF, we suggest oral anticoagulation
with dabigatran 150 mg bid over adjusted-dose
VKA therapy (target range, 2.0-3.0) (Grade 2B).
stroke or TIA and atrial fibrillation, including
paroxysmal AF, who are unsuitable for or choose
not to take an oral anticoagulant (for reasons
other than concerns about major bleeding), we
recommend combination therapy with aspirin
and clopidogrel over aspirin (Grade 1B).
Remarks: Patients should be treated (ie, bridged)
with aspirin until anticoagulation has reached a
therapeutic level.
Oral anticoagulation should generally be initiated
within 1 to 2 weeks after stroke onset. Earlier anticoagulation can be considered for patients at low
risk of bleeding complications (eg, those with a small
infarct burden and no evidence of hemorrhage on
brain imaging). Delaying anticoagulation should be
considered for patients at high risk of hemorrhagic
complications (eg, those with extensive infarct burden or evidence of significant hemorrhagic transformation on brain imaging).
Dabigatran is excreted primarily by the kidney. It has
not been studied and is contraindicated in patients
with severe renal impairment (estimated creatinine
clearance of 30 mL/min or less).
4.3 Antithrombotic Therapy for Stroke Prevention in
Patients With a History of Intracerebral Hemorrhage
(ICH)
4.3. In patients with a history of a symptomatic
primary ICH, we suggest against the long-term
use of antithrombotic therapy for the prevention of ischemic stroke (Grade 2C).
Remarks: Patients who might benefit from antithrombotic therapy are those at relatively low risk of recurrent ICH (eg, with deep hemorrhages) and relatively
high risk (. 7% per year) of thromboembolic events
(eg, with mechanical heart valves or CHADS2 (Congestive heart failure, Hypertension, Age . 75, Diabetes
mellitus, Stroke or TIA) score . 4 points).
5.1 Anticoagulation for Patients With Symptomatic
Cerebral Venous Sinus Thrombosis
5.1. In patients with cerebral venous sinus
thrombosis, we suggest anticoagulation over
no anticoagulant therapy during the acute and
chronic phases (Grade 2C).
Remarks: Patients with a history of ICH who might
benefit from antithrombotic therapy are those at relatively low risk of recurrent ICH (eg, with deep hemorrhages) and relatively high risk (. 7% per year) of
cardiac thromboembolic events (eg, with mechanical
heart valves or CHADS2 score . 4 points).
The Primary and Secondary Prevention
of Cardiovascular Disease
For further details, see Vandvik et al.12
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Executive Summary
2.0 Primary Prevention of Cardiovascular Disease
2.1. For persons aged 50 years or older without
symptomatic cardiovascular disease, we suggest
low-dose aspirin 75 to 100 mg daily over no
aspirin therapy (Grade 2B).
Remarks: Aspirin slightly reduces total mortality
regardless of cardiovascular risk profile if taken over
10 years. In people at moderate to high risk of cardiovascular events, the reduction in myocardial infarction (MI) is closely balanced with an increase in major
bleeds. Whatever their risk status, people who are
averse to taking medication over a prolonged time period
for very small benefits will be disinclined to use aspirin
for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI
bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin.
3.1 Choice of Long-term Antithrombotic Therapy in
Patients With Established Coronary Artery Disease (CAD)
3.1.1-3.1.5. For patients with established coronary
artery disease (CAD), defined as patients 1-year
post-acute coronary syndrome (ACS), with prior
revascularization, coronary stenoses . 50% by
coronary angiogram, and/or evidence for cardiac
ischemia on diagnostic testing, (including patients
after the first year post-ACS and/or with prior
coronary artery bypass graft [CABG] surgery):
• We recommend long-term single antiplatelet therapy with aspirin 75 to 100 mg daily
or clopidogrel 75 mg daily over no antiplatelet therapy (Grade 1A).
• We suggest single over dual antiplatelet therapy with aspirin plus clopidogrel (Grade 2B).
3.2 Choice of Antithrombotic Therapy Following ACS
3.2.1-3.2.5. For patients in the first year after an
ACS who have not undergone percutaneous
coronary intervention (PCI):
• We recommend dual antiplatelet therapy
(ticagrelor 90 mg twice daily plus low-dose
aspirin 75-100 mg daily or clopidogrel 75 mg
daily plus low-dose aspirin 75-100 mg daily)
over single antiplatelet therapy (Grade 1B).
• We suggest ticagrelor 90 mg daily plus lowdose aspirin over clopidogrel 75 mg daily
plus low-dose aspirin (Grade 2B).
For patients in the first year after an ACS who
have undergone PCI with stent placement:
• We recommend dual antiplatelet therapy
(ticagrelor 90 mg twice daily plus low-dose
aspirin 75-100 mg daily, clopidogrel 75 mg
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daily plus low-dose aspirin, or prasugrel
10 mg daily plus low-dose aspirin over
single antiplatelet therapy) (Grade 1B).
Remarks: Evidence suggests that prasugrel results in
no benefit net harm in patients with a body weight
of , 60 kg, age . 75 years, or with a previous stroke/
transient ischemic attack.
• We suggest ticagrelor 90 mg twice daily
plus low-dose aspirin over clopidogrel
75 mg daily plus low-dose aspirin (Grade 2B).
For patients with ACS who undergo PCI with
stent placement, we refer to sections 4.3.1 to
4.3.5 for recommendations concerning minimum
and prolonged duration of treatment.
3.2.6-3.2.7. For patients with anterior MI and left
ventricular (LV) thrombus, or at high risk for LV
thrombus (ejection fraction , 40%, anteroapical
wall motion abnormality), who do not undergo
stenting:
• We recommend warfarin (INR 2.0-3.0) plus
low-dose aspirin 75 to 100 mg daily over
single antiplatelet therapy or dual antiplatelet
therapy for the first 3 months (Grade 1B).
Thereafter, we recommend discontinuation
of warfarin and continuation of dual antiplatelet therapy for up to 12 months as per
the ACS recommendations (see recommendations 3.2.1-3.2.5). After 12 months, single
antiplatelet therapy is recommended as
per the established CAD recommendations
(see recommendations 3.1.1-3.1.5).
For patients with anterior MI and LV thrombus,
or at high risk for LV thrombus (ejection fraction , 40%, anteroapical wall motion abnormality), who undergo bare-metal stent (BMS)
placement:
• We suggest triple therapy (warfarin [INR
2.0-3.0], low-dose aspirin, clopidogrel 75 mg
daily) for 1 month over dual antiplatelet
therapy (Grade 2C).
• We suggest warfarin (INR 2.0-3.0) and single
antiplatelet therapy for the second and third
month post-BMS over alternative regimens
and alternative time frames for warfarin
use (Grade 2C). Thereafter, we recommend
discontinuation of warfarin and use of dual
antiplatelet therapy for up to 12 months as
per the ACS recommendations (see recommendations 3.2.1-3.2.5). After 12 months,
antiplatelet therapy is recommended as
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For patients with anterior MI and LV thrombus,
or at high risk for LV thrombus (ejection fraction , 40%, anteroapical wall motion abnormality) who undergo drug-eluting stent (DES)
placement:
• We suggest triple therapy (warfarin INR
2.0-3.0, low-dose aspirin, clopidogrel 75 mg
daily) for 3 to 6 months over alternative
regimens and alternative durations of warfarin therapy (Grade 2C). Thereafter, we
recommend discontinuation of warfarin and
continuation of dual antiplatelet therapy for
up to 12 months as per the ACS recommendations (see recommendations 3.2.1-3.2.5).
After 12 months, antiplatelet therapy is
recommended as per the established CAD
recommendations (see recommendations
3.1.1-3.1.5).
4.0 Antithrombotic Therapy Following Elective PCI
4.1.1-4.3.5. For patients who have undergone
elective PCI with placement of BMS:
• For the first month, we recommend dual
antiplatelet therapy with aspirin 75 to
325 mg daily and clopidogrel 75 mg daily
over single antiplatelet therapy (Grade 1A).
• For the subsequent 11 months, we suggest
dual antiplatelet therapy with combination
of low-dose aspirin 75 to 100 mg daily and
clopidogrel 75 mg daily over single antiplatelet therapy (Grade 2C).
• After 12 months, we recommend single
antiplatelet therapy over continuation of
dual antiplatelet therapy (Grade 1B).
For patients who have undergone elective PCI
with placement of DES:
• For the first 3 to 6 months, we recommend
dual antiplatelet therapy with aspirin 75 to
325 mg daily and clopidogrel 75 mg daily
over single antiplatelet therapy (Grade 1A).
Remarks: Absolute minimum duration will vary based
on stent type (in general, 3 months for -limus stents
and 6 months for -taxel stents).
• After 3 to 6 months, we suggest continuation of dual antiplatelet therapy with lowdose aspirin 75 to 100 mg and clopidogrel
(75 mg daily) until 12 months over single
antiplatelet therapy (Grade 2C).
• After 12 months, we recommend single antiplatelet therapy over continuation of dual
antiplatelet therapy (Grade 1B). Single antiplatelet therapy thereafter is recommended
as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).
For patients who have undergone elective BMS
or DES stent placement:
• We recommend using low-dose aspirin 75
to 100 mg daily and clopidogrel 75 mg daily
alone rather than cilostazol in addition to
these drugs (Grade 1B).
• We suggest aspirin 75 to 100 mg daily or
clopidogrel 75 mg daily as part of dual antiplatelet therapy rather than the use of
either drug with cilostazol (Grade 1B).
• We suggest cilostazol 100 mg twice daily as
substitute for either low-dose aspirin 75 to
100 mg daily or clopidogrel 75 mg daily
as part of a dual antiplatelet regimen in
patients with an allergy or intolerance of
either drug class (Grade 2C).
For patients with CAD undergoing elective PCI
but no stent placement:
• We suggest for the first month dual antiplatelet therapy with aspirin 75 to 325 mg daily
and clopidogrel 75 mg daily over single antiplatelet therapy (Grade 2C). Single antiplatelet therapy thereafter is recommended as
5.0 Antithrombotic Therapy in Patients With Systolic
LV Dysfunction
5.1-5.3. For patients with systolic LV dysfunction without established CAD and no LV thrombus, we suggest not to use antiplatelet therapy
or warfarin (Grade 2C).
Remarks: Patients who place a high value on an
uncertain reduction in stroke and a low value on
avoiding an increased risk of GI bleeding are likely to
choose to use warfarin.
For patients with systolic LV dysfunction without established CAD with identified acute
LV thrombus (eg, Takotsubo cardiomyopathy),
we suggest moderate-intensity warfarin (INR
2.0-3.0) for at least 3 months (Grade 2C).
For patients with systolic LV dysfunction and
established CAD, recommendations are as per
the established CAD recommendations (see recommendations 3.1.1-3.1.5).
Antithrombotic Therapy in
Peripheral Artery Disease
For further details, see Alonso-Coello et al.13
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Executive Summary
2.0 Primary Prevention of Cardiovascular Events
in Patients with Asymptomatic PAD
than avoidance of a high likelihood of drug-related
side effects will be disinclined to take prostanoids.
2.1. For persons with asymptomatic peripheral
arterial disease (PAD), we suggest aspirin 75 to
100 mg daily over no aspirin therapy (Grade 2B).
6.0 Acute Limb Ischemia
10 years. In people at moderate to high risk of cardiovascular events, the reduction in myocardial infarction (MI) is closely balanced with an increase in major
bleeds. Whatever their risk status, people who are
averse to taking medication over a prolonged time
period for very small benefits will be disinclined to
use aspirin for primary prophylaxis. Individuals who
value preventing an MI substantially higher than
avoiding a GI bleed, if they are in the moderate or
high cardiovascular risk group, will be more likely to
choose aspirin.
3.0 Secondary Prevention of Cardiovascular Events
in Patients with Symptomatic PAD
3.1-3.4. For secondary prevention patients with
symptomatic PAD, we recommend one of the
two following antithrombotic regimens to be
continued long term over no antithrombotic
treatment: aspirin 75 to 100 mg daily or clopidogrel 75 mg daily (all Grade 1A). We suggest not
to use dual antiplatelet therapy with aspirin plus
clopidogrel (Grade 2B). We recommend not to
use an antiplatelet agent with moderate-intensity warfarin (Grade 1B).
4.0 Antithrombotic Therapy for the Management of
Patients with Claudication
4.1-4.4. For patients with intermittent claudication refractory to exercise therapy (and smoking
cessation), we suggest the use of cilostazol in
addition to previously recommended antithrombotic therapies (aspirin 75-100 mg daily or
clopidogrel 75 mg daily) (Grade 2C); we suggest
against the use of pentoxifylline, heparinoids,
or prostanoids (Grade 2C).
5.0 Patients With Critical Limb Ischemia
5.1. For patients with symptomatic PAD and
critical leg ischemia/rest pain who are not candidates for vascular intervention, we suggest
the use of prostanoids in addition to previously
recommended antithrombotic therapies (aspirin 75-100 mg daily or clopidogrel 75 mg daily)
(Grade 2C).
Values and preferences: Patients who do not value
uncertain relief of rest pain and ulcer healing greater
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6.1-6.3. In patients with acute limb ischemia
due to arterial emboli or thrombosis, we suggest immediate systemic anticoagulation with
unfractionated heparin over no anticoagulation
(Grade 2C); we suggest reperfusion therapy (surgery or IA thrombolysis) over no reperfusion
therapy (Grade 2C); we recommend surgery
over IA thrombolysis (Grade 1B). In patients
undergoing IA thrombolysis, we suggest recombinant tissue-type plasminogen activator (rt-PA)
or urokinase over streptokinase (Grade 2C).
7.0 Endovascular Revascularization in Patients With
Symptomatic PAD
7.1. For patients undergoing peripheral artery
percutaneous transluminal angioplasty with
or without stenting, we recommend longterm aspirin (75-100 mg/day) or clopidogrel
(75 mg/day) (Grade 1A). For patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, we suggest
single rather than dual antiplatelet therapy
(Grade 2C).
Values and preferences: Patients who place a high
value on an uncertain reduction in the risk of limb
loss and a relatively low value on avoiding a definite
increased risk of bleeding are more likely to choose to
use dual antiplatelet therapy.
8.0 Antithrombotic Therapy Following Peripheral
Artery Bypass Graft Surgery
8.1-8.4. We recommend one of the following
antithrombotic regimens to be continued longterm following peripheral artery bypass graft
surgery over no antithrombotic treatment:
aspirin 75 to 100 mg daily or clopidogrel 75 mg
daily (all Grade 1A). We recommend single antiplatelet therapy over antiplatelet therapy and
warfarin (Grade 1B). In patients undergoing
below-knee bypass graft surgery with prosthetic
grafts, we suggest clopidogrel 75 mg/d plus
aspirin (75-100 mg/d) over aspirin alone for
1 year (Grade 2C). For all other patients, we
suggest single over dual antiplatelet therapy
(Grade 2B).
9.0 Patients With Carotid Artery Stenosis
9.1. For patients with asymptomatic carotid stenosis, we suggest aspirin 75 to 100 mg daily over
no aspirin therapy (Grade 2B).
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10 years. In people at moderate to high risk of cardiovascular events, the reduction in MI is closely balanced with an increase in major bleeds. Whatever
their risk status, people who are averse to taking
medication over a prolonged time period for very
small benefits will be disinclined to use aspirin for
primary prophylaxis.
9.2-9.3. In patients with symptomatic carotid stenosis (including recent carotid endarterectomy),
we recommend long-term antiplatelet therapy
with clopidogrel (75 mg once daily) or aspirinextended-release dipyridamole (25 mg/200 mg bid)
or aspirin (75-100 mg once daily) over no antiplatelet therapy (Grade 1A). We suggest either
clopidogrel (75 mg once daily) or aspirin-extendedrelease dipyridamole (25 mg/200 mg bid) over
aspirin (75-100 mg) (Grade 2B).
VTE, Thrombophilia, Antithrombotic
Therapy, and Pregnancy
For further details, see Bates et al.14
2.0 Maternal Consequences of Antithrombotic Therapy
Use During Pregnancy
2.2.1. For pregnant patients, we recommend
LMWH for the prevention and treatment of
VTE, instead of UFH (Grade 1B).
3.0 Fetal Consequence of Antithrombotic Therapy
Use in Pregnant Women
3.0.1. For women receiving anticoagulation for
the treatment of VTE who become pregnant,
we recommend LMWH over VKAs during the
first trimester (Grade 1A), in the second and
third trimesters (Grade 1B), and during late pregnancy when delivery is imminent (Grade 1A).
3.0.3. For pregnant women, we suggest limiting the use of fondaparinux and parenteral
direct thrombin inhibitors to those with severe
allergic reactions to heparin (eg, HIT) who
cannot receive danaparoid (Grade 2C).
3.0.4. For pregnant women, we recommend
avoiding the use of oral direct thrombin (eg,
dabigatran) and anti-Xa (eg, rivaroxaban, apixaban) inhibitors (Grade 1C).
4.0 Use of Antithrombotic Therapy in Nursing Women
4.0.1. For lactating women using warfarin,
acenocoumarol, or UFH who wish to breastfeed, we recommend continuing the use of warfarin, acenocoumarol, or UFH (Grade 1A).
4.0.2. For lactating women using LMWH, danaparoid, or r-hirudin who wish to breast-feed,
we recommend continuing the use of LMWH,
danaparoid, or r-hirudin (Grade 1B).
4.0.3. For breast-feeding women, we suggest
alternative anticoagulants rather than fondaparinux (Grade 2C).
4.0.4. For breast-feeding women, we recommend alternative anticoagulants rather than
oral direct thrombin (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban)
(Grade 1C).
4.0.5. For lactating women using low-dose aspirin for vascular indications who wish to breastfeed, we suggest continuing this medication
(Grade 2C).
5.0 VTE in Patients Using Assisted Reproductive
Technology
5.1.1. For women undergoing assisted reproduction, we recommend against the use of routine thrombosis prophylaxis (Grade 1B).
3.0.2. For women requiring long-term VKAs who
are attempting pregnancy and are candidates
for LMWH substitution, we suggest performing frequent pregnancy tests and substituting
LMWH for VKAs when pregnancy is achieved
rather than switching to LMWH while attempting pregnancy (Grade 2C).
5.1.2. For women undergoing assisted reproduction who develop severe ovarian hyperstimulation syndrome, we suggest thrombosis
prophylaxis (prophylactic LMWH) for 3 months
postresolution of clinical ovarian hyperstimulation syndrome rather than no prophylaxis
(Grade 2C).
Remarks: Women who place little value on avoiding the risks, inconvenience, and costs of LMWH
therapy of uncertain duration while awaiting pregnancy and a high value on minimizing the risks of
early miscarriage associated with VKA therapy are
likely to choose LMWH while attempting pregnancy.
Remarks: Women who are averse to taking medication for very small benefit and those who consider
self-injecting a considerable burden will be disinclined to use LMWH for extended thrombosis prophylaxis. Given that the absolute benefit decreases as
time from the hyperstimulation event increases, such
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Executive Summary
women will be very disinclined to continue prophylaxis throughout the entire resultant pregnancy.
6.0 VTE Following Cesarean Section
6.2.1. For women undergoing cesarean section
without additional thrombosis risk factors, we
recommend against the use of thrombosis prophylaxis other than early mobilization (Grade 1B).
6.2.2. For women at increased risk of VTE after
cesarean section because of the presence of
one major or at least two minor risk factors,
we suggest pharmacologic thromboprophylaxis
(prophylactic LMWH) or mechanical prophylaxis (elastic stockings or intermittent pneumatic
compression) in those with contraindications
to anticoagulants while in hospital following
delivery rather than no prophylaxis (Grade 2B).
Remarks: The reduced bleeding risk with mechanical
prophylaxis should be weighed against the inconvenience of elastic stockings and intermittent pneumatic compression.
6.2.3. For women undergoing cesarean section
who are considered to be at very high risk for VTE
and who have multiple additional risk factors for
thromboembolism that persist in the puerperium,
we suggest that prophylactic LMWH be combined
with elastic stockings and/or intermittent pneumatic compression over LMWH alone (Grade 2C).
6.2.4. For selected high-risk patients in whom
significant risk factors persist following delivery,
we suggest extended prophylaxis (up to 6 weeks
after delivery) following discharge from the
hospital (Grade 2C).
7.0 Treatment of Patients With Proven Acute VTE
During Pregnancy
7.1.1. For pregnant women with acute VTE,
we recommend therapy with adjusted-dose
SC LMWH over adjusted-dose UFH (Grade 1B).
7.1.2. For pregnant women with acute VTE, we
recommend LMWH over VKA treatment antenatally (Grade 1A).
7.1.3. For pregnant women with acute VTE, we
suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a minimum total duration of therapy of 3 months) in
comparison with shorter durations of treatment (Grade 2C).
7.1.4. For pregnant women receiving adjusteddose LMWH therapy and where delivery is
planned, we recommend discontinuation of
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LMWH at least 24 h prior to induction of labor
or cesarean section (or expected time of neuraxial anesthesia) rather than continuing LMWH
up until the time of delivery (Grade 1B).
8.0 Prevention of Recurrent VTE in Pregnant Women
8.2.1. For all pregnant women with prior VTE,
we suggest postpartum prophylaxis for 6 weeks
with prophylactic- or intermediate-dose LMWH
or VKAs targeted at INR 2.0 to 3.0 rather than
no prophylaxis (Grade 2B).
8.2.2. For pregnant women at low risk of recurrent VTE (single episode of VTE associated with
a transient risk factor not related to pregnancy
or use of estrogen), we suggest clinical vigilance
antepartum rather than antepartum prophylaxis (Grade 2C).
8.2.3. For pregnant women at moderate to high
risk of recurrent VTE (single unprovoked VTE,
pregnancy- or estrogen-related VTE, or multiple prior unprovoked VTE not receiving longterm anticoagulation), we suggest antepartum
prophylaxis with prophylactic- or intermediatedose LMWH rather than clinical vigilance or
routine care (Grade 2C).
8.2.4. For pregnant women receiving longterm VKAs, we suggest adjusted-dose LMWH
or 75% of a therapeutic dose of LMWH throughout pregnancy followed by resumption of longterm anticoagulants postpartum, rather than
prophylactic-dose LMWH (Grade 2C).
9.0 Prevention of VTE in Pregnant Women With
Thrompophilia and No Prior VTE
9.2.1. For pregnant women with no prior history of VTE who are known to be homozygous
for factor V Leiden or the prothrombin 20210A
mutation and have a positive family history for
VTE, we suggest antepartum prophylaxis with
prophylactic- or intermediate-dose LMWH and
postpartum prophylaxis for 6 weeks with prophylactic- or intermediate-dose LMWH or VKAs
targeted at INR 2.0 to 3.0 rather than no prophylaxis (Grade 2B).
9.2.2. For pregnant women with all other thrombophilias and no prior VTE who have a positive
family history for VTE, we suggest antepartum
clinical vigilance and postpartum prophylaxis
with prophylactic- or intermediate-dose LMWH
or, in women who are not protein C or S deficient, VKAs targeted at INR 2.0 to 3.0 rather
than routine care (Grade 2C).
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9.2.3. For pregnant women with no prior history of VTE who are known to be homozygous
for factor V Leiden or the prothrombin 20210A
mutation and who do not have a positive family
history for VTE, we suggest antepartum clinical vigilance and postpartum prophylaxis for
6 weeks with prophylactic- or intermediatedose LMWH or VKAs targeted at INR 2.0 to
3.0 rather than routine care (Grade 2B).
9.2.4. For pregnant women with all other thrombophilias and no prior VTE who do not have a
positive family history for VTE, we suggest
antepartum and postpartum clinical vigilance
rather than pharmacologic prophylaxis (Grade 2C).
10.0 Prevention of Pregnancy Complications in
Women With Thrombophilia
10.2.1. For women with recurrent early pregnancy loss (three or more miscarriages before
10 weeks of gestation), we recommend screening
for antiphospolipid antibodies (APLAs) (Grade 1B).
10.2.2. For women with a history of pregnancy
complications, we suggest not to screen for
inherited thrombophilia (Grade 2C).
10.2.3. For women who fulfill the laboratory
criteria for APLA syndrome and meet the clinical APLA criteria based on a history of three
or more pregnancy losses, we recommend
antepartum administration of prophylactic- or
intermediate-dose UFH or prophylactic LMWH
combined with low-dose aspirin, 75 to 100 mg/d,
over no treatment (Grade 1B).
anticoagulant regimens in preference to no
anticoagulation (all Grade 1A):
(a) Adjusted-dose bid LMWH throughout pregnancy. We suggest that doses be adjusted to
achieve the manufacturer’s peak anti-Xa LMWH
4 h postsubcutaneous-injection or
(b) Adjusted-dose UFH throughout pregnancy
administered subcutaneously every 12 h in
doses adjusted to keep the mid-interval activated partial thromboplastin time at least twice
control or attain an anti-Xa heparin level of
0.35 to 0.70 units/mL or
(c) UFH or LMWH (as above) until the 13th week,
with substitution by VKAs until close to delivery
when UFH or LMWH is resumed.
Remarks: For pregnant women with mechanical heart
valves, the decision regarding the choice of anticoagulant regimen is so value and preference dependent (risk of thrombosis vs risk of fetal abnormalities)
that we consider the decision to be completely individualized. Women of childbearing age and pregnant
women with mechanical valves, should be counseled
about potential maternal and fetal risks associated
with various anticoagulant regimens, including continuation of VKAs with substitution by LMWH or
UFH close to term, substitution of VKAs by LMWH
or UFH until the 13th week and then close to term,
and use of LMWH or UFH throughout pregnancy.
Usual long-term anticoagulants should be resumed
postpartum when adequate hemostasis is assured.
11.0 Prevention of Recurrent Preeclampsia or Pregnancy
Loss in Women Without Known Thrombophilia
12.1.2. In women judged to be at very high risk
of thromboembolism in whom concerns exist
about the efficacy and safety of UFH or LMWH
as dosed above (eg, older generation prosthesis
in the mitral position or history of thromboembolism), we suggest VKAs throughout pregnancy with replacement by UFH or LMWH
(as above) close to delivery rather than one of
the regimens above (Grade 2C).
11.1.1. For women considered at risk for preeclampsia, we recommend low-dose aspirin
throughout pregnancy, starting from the second
trimester, over no treatment (Grade 1B).
Remarks: Women who place a higher value on avoiding fetal risk than on avoiding maternal complications (eg, catastrophic valve thrombosis) are likely to
choose LMWH or UFH over VKAs.
11.2.1. For women with two or more miscarriages but without APLA or thrombophilia, we
recommend against antithrombotic prophylaxis
(Grade 1B).
12.1.3. For pregnant women with prosthetic
valves at high risk of thromboembolism, we
suggest the addition of low-dose aspirin, 75 to
100 mg/d (Grade 2C).
10.2.4. For women with inherited thrombophilia and a history of pregnancy complications,
we suggest not to use antithrombotic prophylaxis (Grade 2C).
12.0 Prevention of Thromboembolism in Pregnant
Women With Mechanical Heart Valves
12.1.1. For pregnant women with mechanical
heart valves, we recommend one of the following
Antithrombotic Therapy in
Neonates and Children
For further details, see Monagle et al.15
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Executive Summary
1.0. We suggest that where possible, pediatric
hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible,
we suggest a combination of a neonatologist/
pediatrician and adult hematologist supported
by consultation with an experienced pediatric
hematologist (Grade 2C).
1.1 Heparin in Neonates and Children
1.1. We suggest that therapeutic unfractionated heparin (UFH) in children is titrated to
achieve a target range of anti-Xa activity of
0.35 to 0.7 units/mL or an activated partial
thromboplastin time range that correlates to
this anti-Xa range or to a protamine titration
range of 0.2 to 0.4 units/mL (Grade 2C). We suggest that when initiating UFH therapy, UFH
boluses be no greater than 75 to 100 units/kg
and that boluses be withheld or reduced if there
are significant bleeding risks (Grade 2C). We
suggest avoiding long-term use of therapeutic
UFH in children (Grade 2C).
1.2 LMWH in Neonates and Children
1.2. We suggest, for neonates and children
receiving either once- or twice-daily therapeutic
LMWH that the drug be monitored to a target
anti-Xa activity range of 0.5 to 1.0 units/mL in a
sample taken 4 to 6 h after SC injection or 0.5
to 0.8 units/mL in a sample taken 2 to 6 h after
SC injection (Grade 2C).
1.3 VKAs in Neonates and Children
1.3. We suggest, for children receiving VKAs,
that the drug be monitored to a target INR of
2.5 (range, 2.0-3.0), except in the setting of prosthetic cardiac valves where we suggest adherence to the adult recommendations outlined in
the article by Whitlock et al in this supplement
(Grade 2C). We suggest that INR monitoring
with point-of-care monitors be made available
where resources make this possible (Grade 2C).
1.5 Aspirin in Children
1.5. We suggest that when aspirin is used for
antiplatelet therapy in children, it is used in
doses of 1 to 5 mg/kg per day (Grade 2C).
2.1 VTE in Neonates
2.1. We suggest that central venous access
devices (CVADs) or umbilical venous catheters
(UVCs) associated with confirmed thrombosis
be removed after 3 to 5 days of therapeutic anticoagulation rather than left in situ (Grade 2C).
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We suggest either initial anticoagulation or
supportive care with radiologic monitoring
for extension of thrombosis rather than no
follow-up (Grade 2C); however, in previously
untreated patients, we recommend the start of
anticoagulation if extension occurs (Grade 2C).
We suggest that anticoagulation should be with
either (1) LMWH or (2) UFH followed by LMWH.
We suggest a total duration of anticoagulation
of between 6 weeks and 3 months rather than
shorter or longer durations (Grade 2C). If either
a CVAD or a UVC is still in place on completion
of therapeutic anticoagulation, we suggest a
prophylactic dose of anticoagulation until such
time as the CVAD or UVC is removed (Grade 2C).
We suggest against thrombolytic therapy for
neonatal VTE unless major vessel occlusion is
causing critical compromise of organs or limbs
(Grade 2C). We suggest if thrombolysis is required,
tissue plasminogen activator (tPA) is used rather
than other lytic agents (Grade 2C), and we
suggest plasminogen (fresh frozen plasma)
administration prior to commencing therapy
(Grade 2C).
2.2-2.3 Renal Vein Thrombosis in Neonates
2.2. For unilateral renal vein thrombosis (RVT)
in the absence of renal impairment or extension
into the inferior vena cava (IVC), we suggest
either (1) supportive care with radiologic monitoring for extension of thrombosis (if extension
occurs we suggest anticoagulation) or (2) anticoagulation with UFH/LMWH or LMWH in
therapeutic doses rather than no therapy. If
anticoagulation is used, we suggest a total duration of between 6 weeks and 3 months rather
than shorter or longer durations of therapy
(Grade 2C). For unilateral RVT that extends into
the IVC, we suggest anticoagulation with UFH/
LMWH or LMWH for a total duration of
between 6 weeks and 3 months (Grade 2C).
2.3. For bilateral RVT with evidence of renal
impairment, we suggest anticoagulation with
UFH/LMWH or initial thrombolytic therapy
with tPA followed by anticoagulation with UFH/
LMWH (Grade 2C).
2.4 CVAD Prophylaxis in Neonates
2.4. For neonates with CVADs, we recommend
to maintain CVAD patency with UFH continuous infusion at 0.5 units/kg per h over no
prophylaxis (Grade 1A) or intermittent local
thrombolysis (Grade 2C). For neonates with
blocked CVADs, we suggest local thrombolysis
after appropriate clinical assessment (Grade 2C).
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2.6 Thromboprophylaxis for Neonates and Children
With Blalock-Taussig Shunts and Modified BlalockTaussig Shunts (MBTS)
2.13. For neonates with umbilical arterial catheters (UACs), we suggest UAC placement in a
high rather than a low position (Grade 2B).
2.6. For neonates and children having modified MBTS, we suggest intraoperative UFH
therapy (Grade 2C). For neonates and children
after MBTS surgery, we suggest either aspirin
or no antithrombotic therapy as compared with
prolonged LMWH or VKAs (Grade 2C).
2.14. For neonates with UAC, we suggest prophylaxis with a low-dose UFH infusion via the
UAC (heparin concentration of 0.25-1 unit/mL,
total heparin dose of 25-200 units/kg per day) to
maintain patency (Grade 2A).
2.9-2.10 Therapy for Femoral Artery Thrombosis in
2.9. For neonates and children with acute femoral artery thrombosis, we recommend therapeutic doses of IV UFH as initial therapy
compared with aspirin or no therapy (Grade 1B)
or LMWH (Grade 2C). We suggest subsequent
conversion to LMWH, or else continuation of
UFH, to complete 5 to 7 days of therapeutic
anticoagulation as compared with a shorter or
longer duration (Grade 2C).
2.10. For neonates and children with limbthreatening or organ-threatening (via proximal
extension) femoral artery thrombosis who fail to
respond to initial UFH therapy and who have
no known contraindications, we recommend
thrombolysis (Grade 1C). For neonates and children with femoral artery thrombosis, we recommend surgical intervention compared with UFH
therapy alone when there is a contraindication
to thrombolytic therapy and organ or limb death
is imminent (Grade 1C).
2.11 Prophylaxis for Peripheral Arterial Catheters in
2.11. For neonates and children with peripheral arterial catheters in situ, we recommend
UFH continuous infusion at 0.5 units/mL at
1 mL/h compared with normal saline (Grade 1A).
2.12 Therapy for Peripheral Artery Thrombosis
Secondary to Peripheral Artery Catheters in Neonates
and Children
2.12. For neonates and children with a peripheral arterial catheter-related thromboembolism,
we suggest immediate removal of the catheter
(Grade 2B). For neonates and children with a
symptomatic peripheral arterial catheter-related
thromboembolism, we suggest UFH anticoagulation with or without thrombolysis or surgical
thrombectomy and microvascular repair with
subsequent heparin therapy (Grade 2C).
2.13-2.14 Prophylaxis of Umbilical Arterial Catheters
in Neonates
2.16 Prophylaxis for Cardiac Catheterization in
2.16. For neonates and children requiring
cardiac catheterization via an artery, we recommend administration of IV UFH as thromboprophylaxis over no prophylaxis (Grade 1A)
or aspirin (Grade 1B). For neonates and children requiring cardiac catheterization via an
artery, we recommend the use of UFH doses
of 100 units/kg as a bolus compared with a
50-unit/kg bolus (Grade 1B). In prolonged procedures, we suggest further doses of UFH rather
than no further therapy (Grade 2B).
2.17 Cerebral Sinovenous Thrombosis in Neonates
2.17. For neonates with cerebral sinovenous
thrombosis (CSVT) without significant intracranial hemorrhage, we suggest anticoagulation,
initially with UFH or LMWH and subsequently
with LMWH, for a total therapy duration
between 6 weeks and 3 months rather than
shorter or longer treatment duration (Grade 2C).
For neonates with CSVT with significant hemorrhage, we suggest either (1) anticoagulation or
(2) supportive care with radiologic monitoring
of the thrombosis at 5 to 7 days and anticoagulation if thrombus extension is noted as compared
with no therapy (Grade 2C).
2.18-2.20 Arterial Ischemic Stroke in Neonates
2.18. For neonates with a first arterial ischemic
stroke (AIS), in the absence of a documented,
ongoing cardioembolic source, we suggest supportive care over anticoagulation or aspirin
therapy (Grade 2C).
2.19. For neonates with a first AIS and a documented cardioembolic source, we suggest anticoagulation with UFH or LMWH (Grade 2C).
2.20. For neonates with recurrent AIS, we suggest anticoagulant or aspirin therapy (Grade 2C).
2.21 Neonates With Purpura Fulminans
2.21. For neonates with clinical presentations of
homozygous protein C deficiency, we recommend administration of either 10 to 20 mL/kg of
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Executive Summary
fresh frozen plasma every 12 h or protein C
concentrate, when available, at 20 to 60 units/kg
until the clinical lesions resolve (Grade 1A). For
neonates with homozygous protein C deficiency,
after initial stabilization, we recommend longterm treatment with VKA (Grade 1C), LMWH
(Grade 1C), protein C replacement (Grade 1B),
or liver transplantation (Grade 1C) compared with
no therapy.
2.22 DVT and PE in Children
2.22.1. In children with first VTE (CVAD and
non-CVAD related) we recommend acute anticoagulant therapy with either UFH or LMWH
(Grade 1B). We recommend initial treatment
with UFH or LMWH for at least 5 days (Grade
1B). For ongoing therapy, we recommend
LMWH or UFH. For patients in whom clinicians
will subsequently prescribe VKAs, we recommend beginning oral therapy as early as day 1
and discontinuing UFH/LMWH on day 6 or later
than day 6 if the INR has not exceeded 2.0 compared with no therapy (Grade 1B).
2.22.2. We suggest that children with idiopathic
VTE receive anticoagulant therapy for 6 to
12 months compared with no therapy (Grade 2C).
Values and preferences: Families who place a high
value on avoiding the unknown risk of recurrence in
the absence of an ongoing risk factor and a lower
value on avoiding the inconvenience of therapy
or potential impact of therapy on growth and development and bleeding risk associated with antithrombotic therapy are likely to choose to continue
anticoagulant therapy beyond 6 to 12 months.
2.22.3. In children with secondary VTE (ie, VTE
that has occurred in association with a clinical
risk factor) in whom the risk factor has resolved,
we suggest anticoagulant therapy be administered for 3 months (Grade 2C) as compared
with no further therapy. In children who have
ongoing, but potentially reversible risk factors,
such as active nephrotic syndrome or ongoing
asparaginase therapy, we suggest continuing
anticoagulant therapy beyond 3 months in either
therapeutic or prophylactic doses until the risk
factor has resolved (Grade 2C).
2.22.4. In children with recurrent idiopathic
VTE, we recommend indefinite treatment with
VKAs (Grade 1A).
2.22.5. In children with recurrent secondary
VTEs with an existing reversible risk factor
for thrombosis, we suggest anticoagulation until
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resolution of the precipitating factor but for a
minimum of 3 months as compared with no further therapy (Grade 2C).
2.22.6. In children with a CVAD in place who
have a VTE, if a CVAD is no longer required or
is nonfunctioning, we recommend it be removed
(Grade 1B). We suggest at least 3 to 5 days of
anticoagulation therapy prior to its removal
rather than no anticoagulation prior to removal
(Grade 2C). If CVAD access is required and the
CVAD is still functioning, we suggest that the
CVAD remain in situ and the patient given
anticoagulants (Grade 2C). For children with a
first CVAD-related VTE, we suggest initial management as for secondary VTE as previously
described.
2.22.7. In children with CVAD in place who
have a VTE and in whom the CVAD remains
necessary, we suggest, after the initial 3 months
of therapy, that prophylactic doses of VKAs
(INR range, 1.5-1.9) or LMWH (anti-Xa level
range, 0.1-0.3 units/mL) be given until the CVAD
is removed (Grade 2C). If recurrent thrombosis
occurs while the patient is receiving prophylactic therapy, we suggest continuing therapeutic doses until the CVAD is removed and
for a minimum of 3 months following the VTE
(Grade 2C).
2.23 Thrombolysis in Pediatric Patients With DVT
2.23. In children with VTE, we suggest that
thrombolysis therapy be used only for life- or
limb-threatening thrombosis (Grade 2C). If thrombolysis is used in the presence of physiologically
low levels or pathologic deficiencies of plasminogen, we suggest supplementation with plasminogen (Grade 2C). In children with VTE in
whom thrombolysis is used, we suggest systemic
thrombolysis or catheter-directed thrombolysis,
depending on institutional experience and, in
the latter case, technical feasibility.
2.24 Thrombectomy and IVC Filter Use in Pediatric
Patients With DVT
2.24. In children with life-threatening VTE, we
suggest thrombectomy (Grade 2C). In children
who have had a thrombectomy, we suggest anticoagulant therapy as per recommendation (2.22)
(Grade 2C). In children . 10 kg body weight with
lower-extremity VTE and a contraindication
to anticoagulation, we suggest placement of a
retrievable IVC filter (Grade 2C). In children
who receive a filter, we suggest that the filter be
removed as soon as possible if thrombosis is not
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present in the basket of the filter and when contraindication to anticoagulation is resolved
(Grade 2C). In children who receive an IVC filter, we recommend appropriate anticoagulation
for VTE (see 1.2) as soon as the contraindication
to anticoagulation is resolved (Grade 1C).
with large (. 2 cm) mobile right atrial thrombosis, we suggest anticoagulation, with appropriately timed CVAD removal, and consideration of
surgical intervention or thrombolysis based on
individualized risk-benefit assessment compared
with no anticoagulation therapy (Grade 2C).
2.25 DVT in Children With Cancer
2.30-2.34 Children With CVADs
2.25. In children with cancer, we suggest that
management of VTE follow the general recommendations for management of VTE in children.
We suggest the use of LMWH in the treatment
of VTE for a minimum of 3 months until the
precipitating factor has resolved (eg, use of asparaginase) (Grade 2C).
2.30. For CVADs, we suggest flushing with normal saline or heparin or intermittent recombinant urokinase to maintain patency as compared
with no therapy (Grade 2C). For blocked CVADs, we
suggest tPA or recombinant urokinase to restore
patency (Grade 2C) . If after at least 30 min
following local thrombolytic instillation CVAD
patency is not restored, we suggest a second
dose be administered. If the CVAD remains
blocked following two doses of local thrombolytic agent, we suggest radiologic imaging to
rule out a CVAD-related thrombosis (Grade 2C).
Remarks: The presence of cancer, the need for surgery,
chemotherapy, or other treatments may modify the
risk-benefit ratio for treatment of VTE, and clinicians
should consider these factors on an individual basis.
2.26 Children With APLAs and DVT
2.26. For children with VTE in the setting of
APLAs, we suggest management as per general
recommendations for VTE management in
children.
2.27 Children With DVT and Positive Inherited
Thrombophilia Testing
2.27. For children with VTE, independent of
the presence or absence of inherited thrombophilic risk factors, we suggest that the duration
and intensity of anticoagulant therapy as per
2.22.
2.28 Children With VTE and Structurally Abnormally
Venous Systems
2.28. For children with first VTE secondary
to structural venous abnormalities, we suggest
anticoagulation as per other “spontaneous” VTE
(2.22) and consideration of subsequent percutaneous or surgical interventions, depending on
patient factors and institutional experience.
For children with recurrent VTE secondary to
structural venous abnormalities, we suggest
indefinite anticoagulation unless successful percutaneous or surgical interventions can be performed (Grade 2C).
2.29 Children With Right Atrial Thrombosis
2.29. For children with right atrial thrombosis
related to CVAD, we suggest removal of the
CVAD with or without anticoagulation, depending on the individual risk factors, compared with
leaving the CVAD in situ (Grade 2C). For children
2.31. For children with short- or medium-term
CVADs, we recommend against the use of routine systemic thromboprophylaxis (Grade 1B).
2.34. For children receiving long-term home
total parenteral nutrition, we suggest thromboprophylaxis with VKAs (Grade 2C).
2.35 Children Undergoing Glenn Procedure or
Bilateral Cavopulmonary Shunt
2.35. For children who have bilateral cavopulmonary shunt, we suggest postoperative UFH
(Grade 2C).
2.36 Children Undergoing Fontan Surgery
2.36. For children after Fontan surgery, we recommend aspirin or therapeutic UFH followed
by VKAs over no therapy (Grade 1C).
2.37 Insertion of Endovascular Stents in Children
2.37. For children having endovascular stents
inserted, we suggest administration of UFH
perioperatively (Grade 2C).
2.38 Pediatric Patients With Dilated Cardiomyopathy
2.38. For pediatric patients with cardiomyopathy,
we suggest VKAs no later than their activation
on a cardiac transplant waiting list (Grade 2C).
Values and preferences: Parents who place a high
value on avoiding the inconvenience, discomfort,
and limitations of anticoagulant monitoring and a
lower value on the uncertain reduction in thrombotic
complications are unlikely to choose VKA therapy for
their children who are eligible for transplant.
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Executive Summary
2.39 Children With Primary Pulmonary Hypertension
2.39. For children with primary pulmonary
hypertension, we suggest starting anticoagulation with VKAs at the same time as other medical therapy (Grade 2C).
2.40-2.42 Children With Biologic and Mechanical
Prosthetic Heart Valves
2.40-2.42. For children with biologic or mechanical prosthetic heart valves, we recommend that
clinicians follow the relevant recommendations
from the adult population.
2.44 Children With Ventricular Assist Devices (VADs)
2.44. For children with VADs we suggest administration of UFH (Grade 2C). We suggest starting UFH between 8 and 48 h following
implantation (Grade 2C). In addition, we suggest
antiplatelet therapy (either aspirin or aspirin
dipyridamole) to commence within 72 h of
VAD placement (Grade 2C). For children with
VAD, once clinically stable, we suggest switching from UFH to either LMWH or VKA (target
INR 3.0 range, 2.5-3.5) until transplanted or
weaned from VAD (Grade 2C).
2.45-2.46 Primary Prophylaxis for Venous Access
Related to Hemodialysis
2.45. For patients undergoing hemodialysis
via an arteriovenous fistula, we suggest routine use of VKAs or LMWH as fistula thromboprophylaxis as compared with no therapy
(Grade 2C).
2.46. For patients undergoing hemodialysis via
CVAD, we suggest routine use of VKAs or
LMWH for thromboprophylaxis as compared
with no therapy (Grade 2C).
2.47 Use of UFH or LMWH in Children Undergoing
Hemodialysis
2.47. For children having hemodialysis, we suggest the use of UFH or LMWH during hemodialysis to maintain circuit patency independent
of type of vascular access (Grade 2C).
2.48-2.50 Children With Kawasaki Disease
2.48. For children with Kawasaki disease, we
recommend aspirin in high doses (80-100 mg/kg
per day during the acute phase for up to 14 days)
as an antiinflammatory agent, then in lower
doses (1-5 mg/kg per day for 6 to 8 weeks) as an
antiplatelet agent (Grade 1B). For children with
Kawasaki disease, we recommend IV g-globulin
(2 g/kg, single dose) within 10 days of the onset
of symptoms (Grade 1A).
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2.49. For children with moderate or giant coronary aneurysms following Kawasaki disease, we
suggest that warfarin in addition to low-dose
aspirin be given as primary thromboprophylaxis
(Grade 2C).
2.50. For children with Kawasaki disease who
have giant aneurysms and acute coronary artery
thrombosis, we suggest thrombolysis or acute
surgical intervention (Grade 2C).
2.51 CSVT in Children
2.51. For children with CSVT without significant
intracranial hemorrhage, we recommend anticoagulation initially with UFH or LMWH and subsequently with LMWH or VKA for a minimum of
3 months relative to no anticoagulation (Grade 1B).
In children who after 3 months of therapy still experience occlusion of CSVT or ongoing symptoms,
we suggest administration of a further 3 months
of anticoagulation (Grade 2C). For children with
CSVT with significant hemorrhage, we suggest initial anticoagulation as for children without hemorrhage or radiologic monitoring of the thrombosis
at 5 to 7 days and anticoagulation if thrombus
extension is noted at that time (Grade 2C). In children with CSVT and potentially recurrent risk
factors (for example, nephrotic syndrome, asparaginase therapy), we suggest prophylactic anticoagulation at times of risk factor recurrence
(Grade 2C). We suggest thrombolysis, thrombectomy, or surgical decompression only in children
with severe CSVT in whom there is no improvement with initial UFH therapy (Grade 2C).
2.52 AIS in Children
2.52. For children with acute AIS, with or without thrombophilia, we recommend UFH or
LMWH or aspirin as initial therapy until dissection and embolic causes have been excluded
(Grade 1C). For children with acute AIS, we suggest, once dissection and cardioembolic causes
are excluded, daily aspirin prophylaxis for a
minimum of 2 years as compared with no antithrombotic therapy (Grade 2C). For children
receiving aspirin who have recurrent AIS or
transient ischemic attacks (TIAs), we suggest
changing to clopidogrel or anticoagulant therapy
with LMWH or VKA (Grade 2C). For children with
AIS, we recommend against the use of thrombolysis (tPA) or mechanical thrombectomy outside of specific research protocols (Grade 1C).
2.53 Embolic Stroke in Children
2.53. For AIS secondary to cardioembolic causes,
we suggest anticoagulant therapy with LMWH
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or VKAs for at least 3 months (Grade 2C). For
AIS secondary to cardioembolic causes in children with demonstrated right-to-left shunts (eg,
PFO), we suggest surgical closure of the shunt
(Grade 2C).
2.54 Cerebral Arterial Dissection Underlying AIS
2.54. For AIS secondary to dissection, we suggest anticoagulant therapy with LMWH or VKAs
for at least 6 weeks (Grade 2C). Ongoing treatment
will depend on radiologic assessment of degree
and extent of stenosis and evidence of recurrent
ischemic events.
2.55 Children With Cerebral Vasculopathies
2.55. For children with acute AIS secondary to
non-Moyamoya vasculopathy, we recommend
UFH or LMWH or aspirin for 3 months as initial
therapy compared with no treatment (Grade
1C). For children with AIS secondary to nonMoyamoya vasculopathy, we suggest ongoing
antithrombotic therapy should be guided by
repeat cerebrovascular imaging.
2.56-2.57 Children With Moyamoya Disease
2.56. For children with acute AIS secondary to
Moyamoya, we suggest aspirin over no treatment as initial therapy (Grade 2C).
2.57. For children with Moyamoya, we suggest
they be referred to an appropriate center for
consideration of revascularization.
Acknowledgments
Dr Crowther has served on various advisory boards, has assisted
in the preparation of educational materials, and has sat on data
safety and monitoring boards. His institution has received research
funds from the following companies: Leo Pharma A/S, Pfizer Inc,
Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals,
Octapharm AG, CSL Behring, and Artisan Pharma. Personal total
compensation for these activities over the past 3 years totals less
than US $10,000. Dr Gutterman has had the following relationships
that are entirely unrelated to the AT9 guidelines: ACCP President,
GlaxoSmithKline plc grant to study vasodilation in adipose tissue,
National Institutes of Health grant to study human coronary dilation, and GE Healthcare consultation on a study for ECG evaluation of chronic heart disease. Drs Guyatt and Schünemann are
co-chairs of the GRADE Working Group, and Dr Akl is a member
and prominent contributor to the GRADE Working Group.
Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot
recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline
panel members, including the chair, and members of the Health
& Science Policy Committee are blinded to the funding sources.
Further details on the Conflict of Interest Policy are available
online at http://chestnet.org.
Association for Clinical Chemistry, the American College of Clin-
ical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International
Society of Thrombosis and Hematosis.
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10. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH.
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e576S-e600S.
11. Lansberg MG, O’Donnell MJ, Khatri P, et al. Antithrombotic
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12. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: antihrombotic
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Executive Summary : Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians
Gordon H. Guyatt, Elie A. Akl, Mark Crowther, David D. Gutterman, Holger
J. Schuünemann and for the American College of Chest Physicians
Antithrombotic Therapy and Prevention of Thrombosis Panel
Chest 2012;141; 7S-47S
DOI 10.1378/chest.1412S3
Supplementary Material
View e-supplements related to this article at:
http://chestjournal.chestpubs.org/content/suppl/2012/02/06/141.2_suppl.7S.DC1.html
References
Cited Bys
found online at:
Reprints
Citation Alerts
Methodology for the Development of
Thrombosis Guidelines : Antithrombotic
Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians
Gordon H. Guyatt, Susan L. Norris, Sam Schulman, Jack Hirsh, Mark H.
Eckman, Elie A. Akl, Mark Crowther, Per Olav Vandvik, John W.
Eikelboom, Marian S. McDonagh, Sandra Zelman Lewis, David D.
Gutterman, Deborah J. Cook and Holger J. Schünemann
Chest 2012;141;53S-70S
DOI 10.1378/chest.11-2288
53S.DC1.html
ISSN:0012-3692
CHEST
Supplement
Methodology for the Development
of Antithrombotic Therapy and
Prevention of Thrombosis Guidelines
Gordon H. Guyatt, MD, FCCP; Susan L. Norris, MD, MPH; Sam Schulman, MD, PhD;
Jack Hirsh, MD, FCCP; Mark H. Eckman, MD; Elie A. Akl, MD, MPH, PhD;
Mark Crowther, MD; Per Olav Vandvik, MD, PhD; John W. Eikelboom, MBBS;
Marian S. McDonagh, PharmD; Sandra Zelman Lewis, PhD; David D. Gutterman, MD, FCCP;
Deborah J. Cook, MD; Holger J. Schünemann, MD, PhD, FCCP
Background: To develop the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
ACCP Evidence-Based Clinical Practice Guidelines (AT9), the American College of Chest Physicians (ACCP) assembled a panel of clinical experts, information scientists, decision scientists, and
systematic review and guideline methodologists.
Methods: Clinical areas were designated as articles, and a methodologist without important intellectual or financial conflicts of interest led a panel for each article. Only panel members without
significant conflicts of interest participated in making recommendations. Panelists specified the
population, intervention and alternative, and outcomes for each clinical question and defined
criteria for eligible studies. Panelists and an independent evidence-based practice center executed systematic searches for relevant studies and evaluated the evidence, and where resources
and evidence permitted, they created standardized tables that present the quality of the evidence
and key results in a transparent fashion.
Results: One or more recommendations relate to each specific clinical question, and each recommendation is clearly linked to the underlying body of evidence. Judgments regarding the quality
of evidence and strength of recommendations were based on approaches developed by the Grades
of Recommendations, Assessment, Development, and Evaluation Working Group. Panel members constructed scenarios describing relevant health states and rated the disutility associated
with these states based on an additional systematic review of evidence regarding patient values
and preferences for antithrombotic therapy. These ratings guided value and preference decisions
underlying the recommendations. Each topic panel identified questions in which resource allocation issues were particularly important and, for these issues, experts in economic analysis provided additional searches and guidance.
Conclusions: AT9 methodology reflects the current science of evidence-based clinical practice
guideline development, with reliance on high-quality systematic reviews, a standardized process
for quality assessment of individual studies and the body of evidence, an explicit process for translating the evidence into recommendations, disclosure of financial as well as intellectual conflicts
of interest followed by management of disclosed conflicts, and extensive peer review.
CHEST 2012; 141(2)(Suppl):53S–70S
Abbreviations: ACCP 5 American College of Chest Physicians; AT8 5 Antithrombotic and Thrombolytic Therapy:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition); AT9 5 Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines; GDP 5 gross domestic product; GRADE 5 Grades of Recommendation, Assessment, Development, and
Evaluation; HSP 5 Health and Science Policy; PICO 5 population, intervention, comparator, and outcome; QALY 5 qualityadjusted life year; RCT 5 randomized controlled trial; WHO 5 World Health Organization
www.chestpubs.org
53S
describes the methodology used for
Thisthe article
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
(AT9). This methodology incorporates current evidencebased approaches to the appraisal and synthesis of
evidence and to the formulation of clinical practice recommendations. The process thus ensures explicit, transparent, evidence-based clinical practice guidelines.
The objective of AT9 is to optimize patientimportant health outcomes and the processes of care
for patients who have experienced or are at risk for
thrombotic events. The targeted users of these guidelines are health-care providers in both primary and
specialty care who assist patients in making treatment
choices that optimize benefits, minimize harms and
burdens, and are consistent with patient values and
preferences.
Figure 1 summarizes the process for the development of the AT9 recommendations. The primary
responsibility for AT9 rests with the American College
of Chest Physicians (ACCP) AT9 Executive Committee. This committee includes two methodologistclinicians from the previous iteration, Antithrombotic
and Thrombolytic Therapy: American College of
and Biostatistics (Drs Guyatt, Akl, Cook, Schulman, and Schünemann)
and Department of Medicine (Drs Guyatt, Schulman, Hirsh,
Crowther, Eikelboom, Cook, and Schünemann), McMaster
University Faculty of Health Sciences, Hamilton, ON, Canada;
Department of Medical Informatics and Clinical Epidemiology
(Drs Norris and McDonagh), Oregon Health & Science University,
Portland, OR; Division of General Internal Medicine and Center
for Clinical Effectiveness (Dr Eckman), University of Cincinnati,
Cincinnati, OH; Departments of Medicine and Family Medicine
(Dr Akl), State University of New York, Buffalo, NY; Department
of Medicine Gjøvik-Innlandet Hospital Trust and Norwegian
Knowledge Centre for the Health Services (Dr Vandvik), Oslo,
Norway; Evidence-Based Clinical Practice Guidelines and
Clinical Standards (Dr Lewis), American College of Chest
Physicians, Northbrook, IL; and Cardiovascular Research Center
(Dr Gutterman), Medical College of Wisconsin, Milwaukee, WI.
and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer,
Disclaimer: American College of Chest Physician guidelines
are intended for general information only, are not medical advice,
and do not replace professional medical care and physician
advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed
at http://chestjournal.chestpubs.org/content/141/2_suppl/1S
DOI: 10.1378/chest.11-2288
54S
Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition) (AT8), published in 20081
(Dr Guyatt, Panel Chair, and Dr Schünemann, Vice
Chair of Methodology); a third methodologist-clinician
(Dr Akl); a leading thrombosis expert (Dr Crowther,
Vice Chair for Thrombosis); and two liaisons with the
ACCP Health and Science Policy (HSP) Committee
who had also served on the previous guideline Executive Committee (Dr Gutterman, Vice Chair and
HSP Liaison, and Dr Lewis, Project Manager).
Articles within AT9 are defined by broad populations (eg, pediatric, obstetric) or clinical conditions
(eg, prevention of VTE in medical patients or stroke
prophylaxis in atrial fibrillation). In addition, AT9
includes three articles addressing the basic science of
oral and parenteral anticoagulants and platelet-active
drugs and an article addressing new antithrombotic
and thrombolytic drugs.
1.0 Composition and Selection
of Topic Panel Members
The ACCP AT9 Executive Committee selected
panel members for each article. A topic editor and a
deputy editor led each of the AT9 panels issuing recommendations. The topic editor was the person primarily responsible for each article and was required
to be a methodologist without serious financial or
intellectual conflict of interest for any of the article’s
recommendations. In all but one case, the topic editor also was a clinician. The Executive Committee
chose these individuals on the basis of their previous
experience with guideline development and, in particular, their familiarity with methods developed by
the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group.2
These topic editors and all panel members were
approved by the ACCP HSP Committee after review
of their conflict of interest disclosures (see section 7.0
“Disclosing and Managing Conflicts of Interest”).
Criteria for selection of the remainder of the panel
members, including the deputy editor-thrombosis
expert, were an established record in the relevant
clinical or research area, international and gender
representation, and an absence of financial conflicts
of interest that were judged unacceptable. Some of the
panelists had prior experience on ACCP guidelines in
this area and represented the thrombosis community,
but there was substantial turnover from the previous
edition. After an international request for applications
broadcast through multiple medical societies, the
Executive Committee nominated individual topic editors and deputy editors and collaborated with them to
identify and nominate other topic panel members.
The ACCP HSP Committee reviewed all nominees
and approved all panel members after review of their
Methodology for the Guidelines
proved as a result of the magnitude of financial conflicts
of interest. Articles associated with recommendations
included from seven to 14 panel members. We did
not include patients or representatives of specific
stakeholder groups on topic panels.
Each topic panel also included a frontline physician
working in the relevant area who was neither an expert
in thrombosis nor a methodologist or clinical investigator. These individuals were chosen in consultation
with the topic editors and the ACCP HSP Committee.
These clinicians were charged with the following:
(1) proposing important real-world clinical questions
on the prevention, diagnosis, and treatment of thrombosis that were not addressed in AT8 and (2) reviewing the draft manuscripts and recommendations to
assess the usability of the guidelines and the feasibility of implementation of AT9 recommendations.
To address issues of economic efficiency we included
six health economist-physicians on the AT9 topic
panels charged with making recommendations. These
resource consultants were selected and approved
through identical procedures to those for topic editors and panel members. We describe their roles
more fully later in this discussion.
2.0 Ensuring Consistency Across Articles
Figure 1. The steps in the process of development of the
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. The Executive Committee, comprising systematic review and guideline methodologists, clinical experts, and ACCP
Health and Science Policy Committee liaisons, coordinated the
process. Information within parentheses indicates who performed
each step in the process. ACCP 5 American College of Chest Physicians; EPC 5 Evidence-Based Practice Center; GRADE 5 Grades
of Recommendations, Assessment, Development, and Evaluation;
PICO 5 population, intervention, comparator, and outcome.
curricula vitae and conflict of interest disclosures.
Of 150 nominees, 137 were approved, 18 were
approved with management of conflicts of interest
(ie, regular disclosures and review of ongoing conflicts as the process progressed), and 13 were disapwww.chestpubs.org
We used a number of strategies to ensure consistency across articles, and one of us (M. C.) participated
extensively in the formulation of clinical questions
for each article. To ensure consistency of judgments
regarding bleeding, one of us (S. S.) was responsible
for standardizing the approach to bleeding outcomes
and participated in multiple topic panels (described
in more detail later in this article). Additionally, to
ensure consistency in the trade-offs between thrombotic and bleeding events, all articles used the same
ratings of values and preferences (also described in
more detail later). Because some of the same evidence summaries were relevant to several articles,
five individuals were chosen to participate in each
of the articles addressing coronary artery disease,
stroke, and peripheral arterial disease.
In AT9, prevention of VTE is addressed in three
articles as opposed to a single article as was done in
AT8. The prevention topic editors and deputy editors
and those of the stroke article (which includes thromboprophylaxis recommendations) participated in multiple conference calls to develop and harmonize the
approach to prevention and to ensure consistency
among final recommendations.3 Topic editors consulted with one another when issues overlapped. For
example, the decision regarding the use of a vitamin K
antagonist, aspirin, and clopidogrel simultaneously in
patients with atrial fibrillation, valvular disease, and
intravascular stents is relevant for the atrial fibrillation,
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coronary, and peripheral arterial disease articles. Topic
panels deferred to the Evidence-Based Management
of Anticoagulant Therapy AT9 topic panel for recommendations related to the dosing and monitoring of
anticoagulation therapies.
The AT9 Executive Committee met at least once a
month and regularly issued statements of clarification
of methods to topic editors and deputy editors (eg,
use of fixed- or random-effects models for metaanalysis), conflict of interest, preparation of tables, and
issues of style and presentation. All these statements
were communicated directly to the topic editors and
deputy editors and made available in a central repository
accessible to all AT9 panelists. The chair of the Executive Committee (G. H. G.) was available for resolving
any challenging issues related to the aforementioned
topics. Between September 2009 and September 2010,
two members of the Executive Committee (E. A. A.
and S. Z. L.) held regular (every 3 months), separate
conference calls with each topic editor and deputy
editor during which they addressed questions and
concerns. Finally, the chair of the Executive Committee reviewed every article to ensure consistency of
evidence presentation, evaluation, and writing style.
In terms of writing style, we used consistent language to describe effects that did not reach statistical
significance. The approach was as follows:
1. For adverse outcomes (such as thrombosis and
bleeding), “A is associated with a trend toward
reduced thrombosis” if the lower boundary of
the CI around a relative effect is ! 0.7 and the
upper boundary of the CI is ! 1.1 or if the lower
boundary of the CI is ! 0.8 and the upper
boundary of the CI is ! 1.05. If the point estimate is . 1.0, the language used was, “A is associated with a trend toward increased bleeding”
if the lower boundary of the CI around a relative
effect is . 0.9 and the upper boundary of the
CI is . 1.3 or if the lower boundary of the CI
is . 0.95 and the upper boundary of the CI is . 1.2.
2. “A appears to have little or no effect on thrombosis” if the above conditions are not met, and the
boundaries of the CI lie between 0.80 and 1.2.
3. For all other results that fail to exclude a relative
risk of 1.0, the language was, “Results failed
to demonstrate or exclude a beneficial effect or
detrimental effect of A on thrombosis.” Alternative wording with regard to an association is
“failed to establish or refute.”
3.0 Evidence Review
3.1 Defining the Clinical Questions—Population,
Intervention, Comparator, and Outcome
The thrombosis expert on the Executive Committee (M. C.) along with the deputy editors took
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primary responsibility for defining the scope of the
clinical questions that each article would address. For
each question, the topic editor and deputy editor
defined the relevant population, alternative management strategies (intervention and comparator), and
the outcomes (ie, population, intervention, comparator, and outcome [PICO] format). Each clinical
question provided the framework for formulating
study inclusion and exclusion criteria and guided the
search for relevant evidence (systematic reviews and
original studies). Panels typically restricted included
studies to randomized controlled trials (RCTs) for
intervention questions but included observational
studies when there was a paucity of RCT data addressing an intervention and for questions of risk assessment. Readers can find these PICO questions in the
first table of each article. One or more recommendations could be formulated for each clinical question.
The next subsections (3.2-3.5) deal with the approach
to selection of outcomes.
3.2 Patient-Important and Surrogate Outcomes
The outcomes for each clinical question were chosen by the topic editors and their panel members and
were generally consistent across articles. Outcomes
were restricted to those of importance to patients.4
Panels considered the burden of anticoagulation therapy as a patient-important outcome when its consideration could tip the balance of benefits and harms.
If we found no data for an outcome considered
at the outset as patient-important, we nevertheless
included uncertainty about the effects of the intervention on that outcome when weighing its benefits
and harms.
In the absence of data on patient-important outcomes, surrogates could contribute to the estimation
of the effect of an intervention on the outcomes that
are important. Examples of surrogate outcomes
include asymptomatic venous thrombosis detected
by venographic or ultrasound surveillance and the
percentage of time that an international normalized ratio was in therapeutic range (used as a surrogate for bleeding and thrombosis in the assessment
of the effectiveness of centralized anticoagulation
services).
The issue of asymptomatic thrombosis detected
by venographic or ultrasound surveillance presented
particular challenges to the articles addressing VTE
prevention in orthopedic and nonorthopedic surgery
populations, an article addressing nonsurgical prophylaxis, and an article addressing stroke prevention. We were explicit in considering the trade-offs
between VTE and bleeding events. An article by
Guyatt et al3 in this supplement addresses these issues
in some detail.
3.3 Mortality
Options considered in summarizing mortal events
were (1) all-cause mortality and (2) mortality related
to antithrombotic therapy (ie, deaths from pulmonary
emboli and deaths from bleeding). Advantages of the
former include its being the most patient-important
outcome and the difficulty of ascertaining cause of
death. Difficulties ascertaining cause of death may
be particularly problematic when adjudication is
unblinded and therefore open to bias.
The disadvantage of all-cause mortality is that the
signal from antithrombotic therapy-related deaths
may be lost in noise from deaths due to other causes.
The decision about which mortal outcome to use
(all-cause mortality or antithrombotic therapy-related
morality) was left to the authors of individual articles.
Availability of data sometimes forced the choice of
less satisfactory mortal outcomes (eg, if death related
to pulmonary embolus but not death related to bleeding was reported). When mortality was one of the
selected outcomes, we avoided double-counting by documenting nonfatal events for the remaining outcomes
(eg, nonfatal thrombosis, nonfatal major bleeding)
rather than all such events (fatal and nonfatal).
3.4 Composite End Points
Many of the primary studies we reviewed, particularly in the cardiovascular area, presented evidence
in the form of composite end points.5 Particularly
when the patient importance of the component end
points and the magnitude of effect of the intervention on the components differ, composite end points
can be misleading.6,7 Therefore, we present results
and base inferences on the effect of interventions on
individual outcomes.
3.5 Bleeding
In view of the wide variation in how bleeding was
assessed and reported in the included primary studies
across chapters, one individual (S. S.) was responsible
for standardizing the approach to bleeding outcomes.
He worked closely with the Executive Committee
and the topic editors and deputy editors to ensure the
uniform application of the approaches that were
developed.
We began by specifying the bleeding outcomes
that we believe patients consider important. We did
not consider minor bleeding as incurring a burden
that was important in comparison with symptomatic
thromboembolic events.
We reported fatal hemorrhage as well as fatal stroke
or pulmonary embolism in treatment-related or allcause mortality. Likewise, hemorrhagic stroke and
ischemic stroke were reported as “stroke.” We spewww.chestpubs.org
cified in footnotes the events attributable to each
component.
We avoided any double-counting of events; for
example, a fatal hemorrhagic stroke would only
be reported under mortality. We also attempted to
report more specific and homogeneous bleeding outcomes than “major bleeding,” which includes events
with a wide range of patient importance and which
investigators have defined in different ways. For
example, in Falck-Ytter et al8 in this supplement, bleeding outcomes of primary interest were (1) bleeding
requiring reoperation and (2) other major bleeding.
Because some authors, particularly in older studies,
failed to define subsets of major bleeding, we were
not always able to achieve the desired specificity.
3.6 Identifying the Evidence
To identify the relevant evidence, a team of methodologists and medical librarians at the Oregon
Health & Science University Evidence-based Practice Center conducted literature searches of Medline,
the Cochrane Library, and the Database of Abstracts
of Reviews of Effects. For each article, the team conducted a search for systematic reviews and another
for original studies encompassing the main populations and interventions for that article. These searches
included studies indexed from week 1, January 2005,
forward because AT8 searches were carried out up to
that date (search strategies are available on request).
Many articles supplemented these searches with
more-focused searches addressing specific clinical
questions. When clinical questions had not been covered in AT8, searches commenced at a date relevant
to each intervention.
Titles and abstracts retrieved from bibliographic
database searches generally were screened in duplicate, and full-text articles were retrieved for further
review. Consensus on whether individual studies fulfilled inclusion criteria was achieved for each study
between two reviewers. If consensus could not be
achieved, the topic editor and other topic panelists
were brought into the discussion. Deputy editors
reviewed lists of included studies from the database
searches in order to identify any potentially missed
studies. Additional studies identified were then
retrieved for further evaluation.
Topic panels also searched the same bibliographic
databases for systematic reviews addressing each PICO
question. The quality of reviews was assessed using
principles embodied in prior instruments addressing
methodologic quality of systematic reviews,9,10 and
wherever possible, current high-quality systematic
reviews were used as the source of summary estimates.
Reviews were also used to identify additional studies
to complement the database searches.
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4.0 Assessing Studies and
Summarizing Evidence
4.1 Evaluating Risk of Bias in Individual Studies
We developed and applied uniform criteria for
evaluating the risk of bias associated with individual
RCTs based on the criteria recommended by the
Cochrane Collaboration11 (Table 1). Although all
authors assessed risk of bias for individual studies,
because of resource limitations, we summarized the
results of the risk of bias (eg, Table 112) for only a
minority of the recommendations. Readers can find
these assessments in the online data supplements. For
most recommendations for which we did not develop
such tables, we developed Evidence Profiles (see
Table 213-15) that typically provide information on the
risk of bias in footnotes.
We also developed specific criteria for assessing
the risk of bias of observational studies (cohort studies
with concurrent controls, cohort studies with historical
controls, case-control studies, or case series). Again,
these were based on the evidence-based domains
recommended by the Cochrane Collaboration for
observational studies (eg, Table 316-18).
Studies without internal comparisons were termed
“cohort studies without internal controls” if they met
the following criteria:
1. A protocol existed before the date of commencement of data collection.
2. A definition of inclusion and exclusion criteria
was available.
3. The study reported the number of excluded
patients.
4. The study conducted a standardized follow-up,
including description of all of the following:
schedule of follow-up, investigation of suspected
outcomes, and criteria used to define outcomes.
5. The study reported all losses to follow-up.
We labeled studies that did not meet these criteria as “case series.” We did not make a distinction
between prospective and retrospective studies because
although prospective studies may on average be of
higher quality, individual prospective studies may
have a significant risk of bias and specific retrospective studies may not. For questions related to
risk assessment, we evaluated the risk of bias of
individual studies using the following criteria: valid
outcome assessment, including blinding when appropriate; adjustment for between-group differences;
and minimal loss to follow-up.
4.2 Evaluating Quality of Bodies of Evidence
We assessed evidence across studies on an outcomeby-outcome basis using criteria suggested by the
GRADE Working Group.19 We defined quality of
evidence as our confidence in the estimate of the
effect to support a recommendation.19 RCTs start
as high-quality evidence and observational studies as
low-quality evidence (Fig 2). Additional factors that
affect this rating of quality include the risk of bias
(as detailed earlier in this article); precision, consistency, and directness of results; likelihood of publication bias; and presence of very large effects.19 The
ACCP adaptation of the GRADE system (Table 4)
differs only in that the quality of a body of evidence
can be high (A), moderate (B), or low (C) (Fig 2);
GRADE also provides a category for very-low-quality
evidence.
Often, we found that the quality of the evidence
differed across outcomes. For example, in assessing
the quality of evidence for thienopyridines vs warfarin in patients undergoing percutaneous coronary
interventions, we determined the evidence to be of
moderate quality for mortality, nonfatal myocardial
infarction, and revascularization but of low quality for
major bleeding.
We then made a rating of the quality of the entire
body of evidence bearing on the effect of alternative
management strategies for each clinical question. In
other words, we assessed the quality across outcomes,
including both benefits and harms. Quality for each
recommendation was the lowest quality rating of the
outcomes judged as critical (as opposed to important,
but not critical).19
Table 1—[Section 4.1] Methodologic Quality of Randomized Trials: Fondaparinux vs No Fondaparinux
for the Treatment of Superficial Vein Thrombosis
Author, Year
Design
RCT: randomization
Decousus
sequence generated
et al12; CALISTO
Study Group,
“using a computer2010
generated
randomization list”
Randomization
Concealed
Stopping Early
for Benefit
Analysis
ITT: DY for efficacy outcomes
No
(as-treated analysis for
safety outcomes)
Data for primary efficacy
assessment available for
98.7% of randomized patients
CALISTO 5 Comparison of ARIXTRA in Lower Limb Superficial Thrombophlebitis with placebo; DY 5 definitely yes; ITT 5 intent to treat;
PN 5 probably no; PY 5 probably yes; RCT 5 randomized controlled trial.
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DY: “Through a
central telephone
system”
Blinding
Patients: PY
Caregivers: PY
Data collectors: PY
Adjudicators: DY
Data analysts: PN
www.chestpubs.org
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2,737 (8 RCTs),
6 mo
2,727 (8 RCTs),
6 mo
2,496 (7 RCTs),
6 mo
Participants
(Studies), Median
Follow-up
Inconsistency
Indirectness
Imprecision
Publication Overall Quality
Bias
of Evidence
With
VKA
With
LMWH
Study Event Rates (%)
Relative
Effect, RR
(95% CI)
Risk With VKA
Risk Difference With
LMWH (95% CI)
Anticipated Absolute Effectsb
Summary of Findings
(Continued)
Overall mortality (critical outcome)
No serious
No serious
Serious
Undetected Moderate
202/1,231 (16.4) 204/1,265 (16.1) 0.96 (0.81-1.13) 164 deaths
7 fewer deaths per
No serious
inconsistency
indirectness
imprecision
due to
per 1,000d
1,000 (from 31
risk of bias
CI includes
imprecision
fewer to 21 more)
Selective
important
outcome
benefit and
reporting
harm
not seriousc
Recurrent symptomatic VTE (critical outcome): DVT and PE
Serious
No serious
No serious
No serious
Undetected Moderate due 105/1,349 (7.8) 67/1,378 (4.9) 0.62 (0.46-0.84)
No cancer
risk of bias
inconsistency
indirectness
imprecision
to risk of
30 VTEs
11 fewer VTE per
No studies
bias
per 1,000d
1,000 (from 5
were blinded
fewer to 16 fewer)
Nonmetastatic cancer
80 VTEs
30 fewer VTE per
per 1,000d
1,000 (from 13
fewer to 43 fewer)
Metastatic cancer
200 VTEs
76 fewer VTE per
per 1,000d
1,000 (from 32
fewer to 108
fewer)
Major bleeding (critical outcome)
No serious
No serious
No serious
Serious
Undetected Moderate
53/1,351 (3.9) 45/1,386 (3.2) 0.81 (0.55-1.2)
No cancer or nonmetastatic cancer
risk of bias
inconsistency
indirectness
imprecision
due to
4 fewer bleeds per
20 bleeds
Lack of
CI includes
imprecision
1,000 (from 9
per 1,000f
blinding not
important
fewer to 4 more)
seriouse
benefit and
Metastatic cancer
harm
80 bleeds
15 fewer bleeds per
per 1,000f
1,000 (from 36
fewer to 16 more)
Risk of Bias
Quality Assessment
Table 2—[Section 4.1] Evidence Profile: Question: Should LMWH Rather Than VKA be Used for Long-term Treatment of VTE?a,13-15
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Inconsistency
Indirectness
Imprecision
Bias
of Evidence
With
VKA
With
LMWH
PTS (important outcome): self-reported leg symptoms and signs
Serious
No serious
Serious
No serious
Undetected Low due
31/44 (70.5)
34/56 (60.7)
risk of bias
inconsistency
indirectness
imprecision
to risk of
Patients and
Predictive
bias and
investigators
value from
indirectness
not blinded
3 mo to
long term
uncertain
Risk of Bias
Risk With VKA
30 fewer per 1,000
(from 12 fewer
to 46 fewer)
LMWH (95% CI)
Anticipated Absolute Effectsb
0.85 (0.77- 0.94) 200 PTS
per 1,000g
Relative
Effect, RR
(95% CI)
Summary of Findings
LMWH 5 low-molecular-weight heparin; PTS 5 postthrombotic syndrome; RCT 5 randomized control trial; RR 5 risk ratio; VKA 5 vitamin K agonist. (Kearon C, unpublished data).h
a Limited to LMWH regimens that used " 50% of the acute treatment dose during the extended phase of treatment.
bTime frame is 6 mo for all outcomes except PTS, which is 2 y.
cOne study did not report deaths: borderline decision.
dControl event rates from cohort study by Prandoni et al,13 adjusted to 6-mo time frame.
eOutcome less subjective: borderline decision.
fControl event rates from cohort studies by Prandoni et al13 and Beth et al14 adjusted to 6-mo time frame.
gControl event rate comes from observational studies in review by Kahn et al15 adjusted to 2-y time frame. All patients wore pressure stockings.
hMeta-analysis is based on RCTs as referenced in the article text. The control event rate for mortality comes from this meta-analysis.
100 (1 RCT),
3 mo
Participants
(Studies), Median
Follow-up
Quality Assessment
Table 2—Continued
Sixty-five percent of cases and
controls tested positive for
HIT antibodies (remainder
tested negative or were not
tested).
None
APTT 5 activated partial thromboplastin time; HIT 5 heparin-induced thrombocytopenia.
aAPTT adjusted to 1.5 to 2.5 times baseline APTT (or the mean laboratory normal range if the baseline APTT was unavailable).
bAPTT adjusted to 1.5 to 3.0 times baseline APTT.
No
None
Very
Lewis
et al18/2001
Cohort with
historical
controls
Not close
HIT antibody data for cases
were not provided.
None
No
None
Somewhat
Lewis
et al17/2003
Cohort with
historical
controls
Not close
Cases and controls both
required positive testing
for HIT antibodies.
None
No
None
Very
Cohort with
historical
controls
Lepirudin: bolus 0.4 mg/kga;
0.15 mg/kg
Control: varied (danaparoid,
n 5 24; phenoprocoumon,
n 5 21; other, n 5 30)
Argatroban: 2 mg/kg per minb
(no bolus)
Control: varied (typically
heparin discontinuation
and oral anticoagulation)
Argatroban: 2 mg/kg per minb
(no bolus)
Control: varied (typically
discontinuation of heparin
and oral anticoagulation)
Lubenow
et al16/2005
Not close
Comments
Loss to
Follow-up
Effectively Blinded
Assessment of Outcomes
Adjustment
Intervention/Control
Time Frame Similar
Setting Similar
Study Design
Author/Year
Table 3—[Section 4.1] Methodologic Quality of Observational Studies: Cohort Studies of the Treatment of Heparin-Induced Thrombocytopenia
www.chestpubs.org
4.3 Estimating Relative and Absolute Effects
Most patient-important outcomes in this guideline
are binary or yes-no outcomes (death, stroke, VTE,
myocardial infarction, bleeding). In general, relative
effects are similar across subgroups of patients,
including those with varying baseline risk.20,21 The
evidence summaries (Evidence Profiles and Summary of Findings tables described later in this article),
therefore, include a presentation of relative effects
(where possible as relative risks because they are
easier to understand than ORs) of intervention vs control management strategies.
Trading off desirable and undesirable consequences
(eg, thrombosis vs bleeding) requires, however, estimates of absolute effect. For example, in patients
with atrial fibrillation, warfarin results in a 66% relative risk reduction in nonfatal stroke. This comes at a
cost of inconvenience, lifestyle restrictions, and risk
of bleeding. For patients with a CHADS (congestive
heart failure, hypertension, age " 75 years, diabetes
mellitus, stroke) score of " 3, the 66% relative risk
reduction translates into an absolute reduction of
6.3% (63 in 1,000) per year. Virtually all patients
will consider this worthwhile. On the other hand, for
patients with a CHADS score of 0, the 66% reduction
translates into an absolute risk reduction of only 0.5%
(5 in 1,000) per year. Many patients may consider this
reduction not worth the undesirable consequences of
warfarin use.
We calculated absolute effects by applying relative
risks to estimates of control group risk. For instance,
if control group risk of thrombosis is 4% and relative
risk with an intervention is 50%, then the absolute
difference between intervention and control is 4% of
50% or 2%, and the number needed to treat to prevent an episode of thrombosis is 100/2 or 50. In many
cases, the Summary of Findings tables present effects
as events prevented (or caused) per 1,000 patients.
In this hypothetical example, the effect would be
20 events per 1,000 patients.
Whenever valid prognostic data were available
from observational studies, they were used to estimate control group risks. When credible results
from observational and prognostic studies were not
available, risk estimates from control groups of RCTs
were used.
4.4 Considering Subgroup-Specific Relative
and Absolute Effects
Whenever we identified credible evidence that the
relative effects vary across distinguishable subgroups
of patients (ie, interaction between the intervention
and a patient characteristic), we considered the respective relative effects separately. We then calculated
the associated absolute effects.
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Figure 2. GRADE approach to rating quality of evidence. See Figure 1 legend for expansion of
abbreviation.
Even when the relative effect is the same, the absolute magnitude of treatment effects may differ in
patients with varying levels of risk. For instance, although
the relative risk reduction of warfarin vs aspirin in stroke
prevention for patients with atrial fibrillation is likely
close to 50% across risk groups, this translates into an
absolute risk reduction of , 1% per year in the lowestrisk groups and ! 5% per year in the highest-risk groups.
Table 4—Strength of the Recommendations Grading System
Grade of Recommendation
Benefit vs Risk and
Burdens
Methodologic Strength of Supporting
Evidence
Implications
Strong recommendation,
Benefits clearly outweigh
high-quality evidence (1A)
risk and burdens or vice
versa.
Consistent evidence from randomized Recommendation can apply to most
controlled trials without important
patients in most circumstances. Further
limitations or exceptionally strong
research is very unlikely to change our
evidence from observational studies.
confidence in the estimate of effect.
Evidence from randomized controlled Recommendation can apply to most
moderate-quality
trials with important limitations
patients in most circumstances.
evidence (1B)
versa.
(inconsistent results, methodologic
Higher-quality research may well have
flaws, indirect or imprecise) or very
an important impact on our confidence
strong evidence from observational
in the estimate of effect and may
studies.
change the estimate.
Evidence for at least one critical
Recommendation can apply to most
low- or very-low-quality
outcome from observational studies,
patients in many circumstances.
evidence (1C)
versa.
case series, or randomized controlled
Higher-quality research is likely to
trials, with serious flaws or indirect
have an important impact on our
evidence.
confidence in the estimate of effect
and may well change the estimate.
Weak recommendation,
Benefits closely balanced
Consistent evidence from randomized The best action may differ depending
high-quality evidence (2A)
with risks and burden.
controlled trials without important
on circumstances or patient or societal
limitations or exceptionally strong
values. Further research is very unlikely
evidence from observational studies.
to change our confidence in the estimate
of effect.
Benefits closely balanced
Evidence from randomized controlled Best action may differ depending on
moderate-quality
with risks and burden.
trials with important limitations
circumstances or patient or societal
evidence (2B)
(inconsistent results, methodologic
values. Higher-quality research may
flaws, indirect or imprecise) or very
well have an important impact on our
strong evidence from observational
confidence in the estimate of effect and
studies.
may change the estimate.
Uncertainty in the estimates Evidence for at least one critical
Other alternatives may be equally
low- or very-low-quality
of benefits, risks, and
outcome from observational studies,
reasonable. Higher-quality research is
evidence (2C)
burden; benefits, risk,
case series, or randomized controlled
likely to have an important impact on
and burden may be
trials, with serious flaws or indirect
our confidence in the estimate of effect
closely balanced.
evidence.
and may well change the estimate.
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www.chestpubs.org
Results
Outcomes
Control
Intervention
Fondaparinux, 2.5 mg Placebo
Primary efficacy outcome:
Primary efficacy outcome:
Patients aged " 18 years with acute symptomatic,
subcutaneous once
for 45 d
-Composite of symptomatic events up to day 47:
13/1,502 vs 88/1,500;
objectively confirmed SVT of the legs
daily for 45 d Use
death from any cause, symptomatic DVT or PE,
RR, 0.15; 95% CI,
Exclusion criteria:
of GCS encouraged
symptomatic extension to the saphenofemoral
0.08-0.26
-Symptoms . 3 wk
for all patients
junction, recurrence of SVT
-DVT or PE at presentation
Secondary efficacy outcomes:
Composite of DVT and
-SVT following sclerotherapy, IV line
-Composite of symptomatic events up to day 77
PE up to day 77: 4/1,502
-SVT within 3 cm of the saphenofemoral junction
-Each component of primary efficacy outcomes
vs 22/1,500; RR, 0.18;
-SVT within the past 3 mo, DVT or PE within the past 6 mo
-Composite of symptomatic PE or DVT
95% CI, 0.06-0.53
-Treated for cancer within the past 6 mo
-Surgery for SVT
-Antithrombotic therapy for . 48 h or NSAID for . 72 h
Safety outcomes (up to day 47 or up to day 77): All other efficacy outcomes:
for current episode of SVT
-Major bleeding
P , .05; major bleeding
-Ligation or stripping
-Nonmajor, minor, total bleeding
by day 47, one event
-Major surgery within 3 mo
-Arterial thromboembolic event
per group; RR, 1
-Bleeding risk
-Pregnant or childbearing age women not using
reliable contraception
GCS 5 graduated compression stockings; NSAID 5 nonsteroidal antiinflammatory drug; PE 5 pulmonary embolism; RR 5 risk ratio; SVT 5 superficial vein thrombosis. See Table 1 for expansion of other
abbreviation.
When resources permitted, we used a standardized
approach for summarizing the evidence and methodology of individual studies (examples in Tables 1, 2, 5).
These summaries appear in the online data supplements. Wherever possible, we report nonfatal events
(eg, nonfatal stroke) so that there is no overlap with
the number of fatal events reported.
For a large number of recommendations, we summarized the quality of the body of evidence (Fig 2)
and estimates of relative and absolute effect of alternative management strategies using the methods
of the GRADE Working Group.23 Evidence Profiles
summarize the quality of the body of evidence and
when evidence comes from randomized trials, generally include a presentation of reviewer assessment of
risk of bias, precision, consistency, directness, and
publication bias associated with each outcome (eg,
see Table 2). As specified in GRADE methodology,19
Decousus et al12;
CALISTO Study
Group/2010
4.6 Summary Tables
Patients
When pooled estimates of effects were not available from existing high-quality systematic reviews,
we performed meta-analyses if the data were sufficiently homogeneous. When pooling two studies,
we used a fixed-effects model. When three or more
studies were available for generating a pooled estimate, we used a random-effects model as the primary
analysis and a fixed-effects model as a secondary
analysis. If there were discrepancies between the
two, we considered the following reasons: If there
was substantial heterogeneity leading to wider CIs
with the random-effects model, we considered that
model more trustworthy, and if the discrepancy was
due to a single large dominant study with a result
substantially different from smaller studies, we considered the fixed-effects model more trustworthy.
We also assessed statistical heterogeneity using both
a x2 test and I2 as well as assessed possible explanations of heterogeneity considering a priori-generated
hypotheses.22
Author/Year
4.5 Conducting Meta-analyses
Table 5—[Section 4.1] Descriptive Table: Randomized Controlled Trials of Fondaparinux vs No Fondaparinux for the Treatment of Superficial Vein Thrombosis
We included control group risks and absolute
effect estimates for different groups in the summaries of effect when (and only when) two conditions
were present. First, we required validated prognostic
models or, at the very least, credible strategies for
clinicians to easily identify higher- and lower-risk
patients. Second, we identified varying risk groups
only when recommendations differed in strength or
direction between groups. Both conditions were met,
for instance, in the atrial fibrillation recommendations in which strong recommendations in favor of
anticoagulation were restricted to the higher-risk
patients.
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The anticipated absolute effect is expressed as risk difference (and its 95% CI) and is based on the baseline risk in the comparison group and the relative effect of the intervention (and its 95% CI). High
quality indicates further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate
of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; and very-low
quality, we are very uncertain about the estimate. ACS 5 acute coronary syndromes; CABG 5 coronary artery bypass graft; GRADE 5 Grades of Recommendations, Assessment, Development, and
Evaluation; MI 5 myocardial infarction; PCI 5 percutaneous coronary intervention; RR 5 risk ratio; TIMI 5 thrombolysis in myocardial infarction.
22 major bleeds per 1,000a
1.32 (1.03-1.68)
High
13,457 (1 study); median, 14.5 mo
Major extracranial bleed Non-CABGrelated TIMI major bleeding
10 strokes per 1,000a
1.02 (0.71-1.45)
13,608 (1 study), 14.5 mo
Nonfatal stroke
Moderate due to imprecision
13,608 (1 study), 14.5 mo
Nonfatal MI
High
0.76 (0.67-0.85)
95 MI per 1,000a
Risk Difference With Prasugrel (95% CI)
3 fewer deaths per 1,000 (from 7 fewer
to 3 more)
22 fewer MI per 1,000 (from 33 fewer
to 14 fewer)
0 fewer strokes per 1,000 (from 3 fewer
to 5 more
6 more major bleeds per 1,000 (from
0 more to 12 more)
Anticipated Absolute Effects (1-y Time Frame)
Risk With Clopidogrel
24 deaths per 1,000a
Relative Effect,
RR (95% CI)
0.89 (0.7-1.12)
Quality of the Evidence
(GRADE)
Moderate due to imprecision
No. of Participants (Studies), Mean
Follow-up
13,608 (1 study), 14.5 mo
Making trade-offs between desirable and undesirable consequences of alternative management
strategies—the fundamental process of making
recommendations—requires making value and preference judgments. For antithrombotic therapy guidelines, this trade-off involves, in most instances, a
reduction in thrombotic events compared with an
increase in bleeding events. Ideally, the values and
preferences applied to this decision would be the
average values and preferences of the patient population. We know, however, that patient values for health
outcomes vary substantially from patient to patient.
Knowledge of the extent to which patient values and
preferences vary is one factor in deciding on the
strength of a recommendation. The greater the variability in values and preferences, the more likely a
weak recommendation is appropriate.23
To inform these decisions, we conducted a systematic review of the literature bearing on patient values
and preferences regarding antithrombotic therapy.26
The methodology of conducting such studies remains
to be fully developed, and the area remains underinvestigated. Nevertheless, the results of the review
provided guidance for the values and preferences
that we adopted for these guidelines.26
As an additional strategy for achieving meaningful
value and preference decisions by each topic panel
and to facilitate consistency across articles, we conducted a values rating exercise. Topic editors and
deputy editors constructed patient scenarios for key
outcomes of thrombosis and bleeding relevant to their
articles. Then informed by the systematic review of
values and preferences, panelists used these
scenarios to rate each outcome from 0 (death) to 100
(full health). The mean values of these ratings
guided the trade-offs between thrombotic and bleeding events and, thus, the determination of strong
Outcomes
Vascular mortality
5.0 Values and Preferences
Table 6—[Section 4.6] Summary of Findings Table: Prasugrel 1 Aspirin vs Clopidogrel 1 Aspirin in Patients With a Recent ACS and PCI24
the overall quality of evidence represents the lowest
quality of any critical outcome.
Evidence Profiles can be found in the online data
supplement. The format for these tables was determined through a formal survey of panelists that
evaluated the panelists’ preferences for alternative
presentations and the impact of these presentations
on their understanding of the evidence. The text in the
printed version of the AT9 recommendations includes
more succinct Summary of Findings tables (eg, see
Table 624), which include the overall quality assessment as well as the relative and absolute effect sizes
for each outcome. Use of an associated computer
program facilitated the production of the Evidence
Profiles and Summary of Findings tables.25
vs weak recommendations. The scenarios and results
of the rating exercise are available in the online data
supplements.
The introductory section in each chapter includes
a summary, quantitative wherever possible, of the
key values and preferences underlying the recommendations. Where value and preference judgments
were particularly relevant or controversial, explicit
statements of values and preferences accompany
individual recommendations.
The literature review26 revealed extensive heterogeneity of results across studies of patient values
and preferences—variability that often is difficult to
explain. Both the variability between studies and
the considerable variability in values and preferences
among patients within studies, mandated circumspection in making strong recommendations. Therefore,
we restricted strong recommendations to situations in
which the desirable consequences of an intervention
substantially and convincingly outweighed the undesirable consequences (or the reverse) and to unusual
situations in which there was reason to believe that
values and preferences are relatively uniform.
6.0 Resource Use Issues
In addressing resource use (cost) issues in AT9, we
followed previously developed principles.27 In particular, we restricted economic evaluation to recommendations in which it was plausible that resource
use considerations might change the direction or
strength of the recommendation and in which highquality economic evaluations were available. When
this was not the case, we did not consider resource
use in the recommendations.
Six clinicians with the requisite expertise in decision
and economic analyses participated in the guideline
development process; each article had the benefit of
one of these experts as a full committee member. In
the following subsections, we present key points in
the process of considering resource allocation issues
in the recommendations.
6.1 Overview of the Process
Panelists, in consultation with resource use consultants, determined questions for which resource use
might change the direction or strength of recommendations. For those questions, we sought high-quality
economic analyses. If such analyses were available,
we applied the evidence regarding resource use to
the relevant recommendation. If net costs or marginal cost-effectiveness ratios were very high, panelists considered rating down the quality of evidence
for an intervention from high to low or possibly changing the direction of the recommendation using guides
www.chestpubs.org
described in section 6.4 “Criteria for Resource Allocation Issues to Affect Recommendations—Thresholds
for Cost-Effectiveness.”
6.2 Identifying the Literature
The Oregon Health & Science University Evidencebased Practice Center conducted thorough literature
searches for economic analyses relevant to the different AT9 articles. The resource use experts supplemented these by searches focused on the specific
questions of interest for each article. The searches
were conducted in Medline and the Cochrane Central Register of Clinical Trials. On the basis that
data from studies appreciably more than a decade old
would not reflect the current situation, searches were
restricted to published studies from 1999 forward.
Thus, bibliographic database searches encompassed
publications from January 1999 forward: The end
date varied across articles and ranged between
November 2009 and March 2010 when the searches
were executed.
6.3 Evaluating the Evidence
A standardized data extraction form was used to
ensure uniform evaluation of the quality of relevant
economic analyses. Quality assessment was based
on published criteria27-33 and included specification of
perspective of analysis (eg, societal, health system),
appropriateness of time horizon (preferably lifetime),
use of high-quality evidence for probabilities and
rates, use of high-quality sources for costs (eg, primary
data, Medicare payments, claims data as proxies),
use of appropriate methods for measurement of
preferences, and performance of sensitivity analyses to explore uncertainty (both deterministic and
probabilistic).
6.4 Criteria for Resource Allocation Issues
To Affect Recommendations—Thresholds
for Cost-Effectiveness
The results of economic analyses may either increase
the strength of an otherwise weak recommendation
or weaken the strength of a strong recommendation. If cost-effectiveness studies bolstered an already
strong recommendation, no change to the recommendation was necessary. We chose the following
thresholds for cost-effectiveness considerations affecting recommendations:
1. When the clinical evidence warrants a strong
recommendation for A over B:
a. Strong recommendation favoring A when highquality evidence from economic evaluations
shows that A costs , 3 times the gross domestic
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product (GDP) per capita (approximately
US $150,000)34 per quality-adjusted life year
(QALY) gained relative to B
b. Weak recommendation favoring A when highquality evidence from economic evaluations
shows that A costs 3 to 5 times the GDP per
capita (!$150,000-$250,000) per QALY gained
relative to B
c. Weak recommendation favoring B when highquality evidence from economic evaluations
shows that A costs . 5 times the GDP per
capita (!$250,000) per QALY gained relative
to B
2. When the clinical evidence warrants a weak
recommendation for A over B:
a. Strong recommendation favoring A if A results
in cost savings of . 10% to 20% of the GDP
per capita (!$5,000-$10,000) relative to B
(Cost savings must represent all downstream
costs and not just the actual cost of the intervention, and analysis must demonstrate a high
level of confidence that there is a cost savings.)
b. Continued weak recommendation favoring A
when B is marginally more costly than A
(, 10% the GDP per capita)
c. Continued weak recommendation favoring A
when A costs 0 to 5 times the GDP per capita
per QALY gained relative to B
d. Weak recommendation favoring B if A
costs . 5 times the GDP per capita (!$250,000)
per QALY gained relative to B
6.5 Extension of Economic Analyses to
Low- and Middle-Income Countries
Although certain interventions may be cost-effective
in high-income countries (eg, , $20,000 per QALY
gained), in poor countries, $20,000 gained per QALY
may be prohibitive. The choice of a threshold will vary
depending on who is making resource allocation decisions. To facilitate the use of already published costeffectiveness analyses, the World Health Organization
(WHO), through its WHO-CHOICE (Choosing Interventions that are Cost Effective) program35 has used
criteria suggested by the Commission on Macroeconomics and Health.36 Interventions that cost , 1 times
the average per-capita income for a given country or
region per QALY gained are considered very costeffective. Interventions that cost up to three times the
average per-capita income per QALY gained are still
considered cost-effective, whereas those that exceed
this level are not considered to be cost-effective. To
facilitate this process, WHO has developed tables of
such threshold values for different regions and
countries around the world.37 Thus, the thresholds
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discussed in the previous section have been defined
in terms of GDP per capita. Although referencing
thresholds for cost-effectiveness to average per-capita
income in middle- and low-income countries can help
to extend results of economic analyses performed in
high-income countries, such analyses may be less relevant in low-income countries because of significantly
different material and labor costs and, thus, may be
difficult to extrapolate. Furthermore, the comparator
strategies may not be feasible or customary in these
locales.
7.0 Disclosing and Managing
Conflicts of Interest
All panelists were required to disclose both financial conflicts of interest, such as receipt of funds for
consulting with industry, and intellectual conflicts of
interest, such as publication of original data bearing
directly on a recommendation. Financial and intellectual conflicts of interest were classified as primary
(more serious) or secondary (less serious).38 The operational definition of primary intellectual conflicts of
interest included authorship of original studies and
peer-reviewed grant funding (government, not-forprofit organizations) directly bearing on a recommendation. The operational definition of primary financial
conflicts of interest included consultancies, advisory
board membership, and the like from industry. Topic
editors had no primary conflicts of interest, as noted.
Some deputy editors, who were clinical experts in the
topic of the article, had relevant primary conflicts of
interest. The ACCP HSP Committee deemed some
of these conflicts serious enough to require “management.” Management involved more frequent updates
of disclosures than required of the approved panelists
without any conflicts and recusal from activities relevant to that conflict.
Topic panel members, including the deputy editor,
with primary conflicts related to a particular recommendation did not participate in the final deliberations that led to the decision regarding the direction
or strength of a recommendation, nor did they vote
on recommendations for which they were primarily
conflicted. Panelists with primary confl icts could,
however, participate in discussions and offer their
opinions on interpretations of the evidence. Readers
will find a record of panelist conflicts of interest on a
recommendation-by-recommendation basis in the
online data supplement.
8.0 Finalizing the Recommendations
8.1 Formulating Recommendations
Following approaches recommended by the GRADE
Working Group,23 the topic editor, in some cases
aided by a panelist without conflicts, formulated the
draft recommendations. The formulation of recommendations considered the balance between the
desirable and undesirable consequences of an intervention; the quality of evidence; the variability in
patient values and preferences; and, on occasion,
resource use issues. The recommendations were
graded as strong when desirable effects were much
greater than undesirable effects or vice versa. Strong
recommendations were worded as “We recommend”
and labeled 1. Recommendations were graded as weak
when desirable effects were not clearly greater or less
great than undesirable effects. Weak recommendations were worded as “We suggest” and labeled 2.
The rating of the quality of the evidence—high, A;
moderate, B; or low, C—is provided with the strength
of each recommendation.
8.2 Finalizing Recommendations
After completing the steps described previously,
the topic panel members without primary conflicts
discussed draft recommendations (Fig 1). Initial discussions generally led to a consensus at the article
level on the quality of evidence and the direction and
strength of recommendations. At least two members
of the Executive Committee reviewed in detail drafts
of articles, including recommendations. Written critiques were prepared and returned to the authors for
revision. Articles were then made available to the
entire AT9 panel.
Recommendations on which topic panels had difficulty coming to a consensus were discussed at a final
conference in February 2011 attended by the topic
editors and deputy editors and at least one other
panel member from each article. Prior to the conference, all AT9 panelists updated their conflict of
interest disclosures. The ACCP invited a number of
clinical organizations with interest in the guideline
topic to attend the final conference as observers.
At this final conference, a representative of each
article presented potentially controversial issues in
their article’s recommendations. Following discussion,
which included those present and those attending by
videoconference, all panelists without primary conflicts of interest voted on each recommendation.
The voting process used a GRADE grid and required
that for a strong recommendation, " 80% of those
voting had to agree that a strong recommendation
was appropriate.39
The AT9 Executive Committee members (G. H. G.,
M. C., E. A. A., and D. D. G.) harmonized the articles
and resolved remaining disagreements among them
through facilitated discussion with topic editors and
deputy editors without primary conflicts. All major
correspondence and decisions at the final conference
www.chestpubs.org
were recorded in written and audio formats and are
available on request to [email protected].
9.0 Review by ACCP and External Reviewers
The ACCP HSP Committee established a process
for the thorough review of all ACCP evidence-based
clinical practice guidelines. After final review by the
AT9 Executive Committee, the guidelines underwent
review by the Cardiovascular and Pulmonary Vascular NetWorks of the ACCP, the HSP Committee, and
the ACCP Board of Regents. The latter two groups
had the right of approval or disapproval but usually
worked with the topic panelists and editors to make
necessary revisions prior to final approval. Both the
HSP Committee and the Board of Regents identified
primary reviewers who read the full set of articles,
and the remaining HSP Committee members were
responsible for reviewing several articles each. The
reviewers considered both content and methodology
as well as whether there was balanced reporting
and adherence to HSP Committee processes. All
reviewers were vetted through the same conflict of
interest disclosure and management process as
described previously. Finally, the Editor in Chief of
CHEST read and forwarded the manuscripts for
independent, external peer review prior to acceptance for publication. No recommendations or assessments of the quality of the evidence could be changed
without the express approval of the topic panel members, AT9 Executive Committee, HSP Committee,
and ACCP Board of Regents.
10.0 Organization of Articles
In order to provide a transparent, explicit link
among PICO questions, evidence, tables, and recommendations, the section numbering in each article
corresponds to numbers in Table 1 in each article,
which specifies the patients, interventions, and outcomes for each question. The section numbering also
corresponds to the numbering of the recommendations themselves. Evidence Profiles and other tables
include these corresponding numbers in brackets
in the title, as is true for the online data supplement
tables.
11.0 Revisions in the Process Since AT8
AT9 includes improvements from AT8 that reflect
the evolution of the science of systematic reviews and
clinical practice guidelines. In this supplement,40 some
of these improvements include augmented provisions
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to decrease the likelihood of conflict of interest influence, more stringent application of GRADE criteria
for evidence and recommendations (both facilitated
by methodologists without primary conflicts taking
the role of topic editor), and a systematic review of
values and preferences to guide the recommendations.
12.0 Limitations of Methods
Although encouraged to use Evidence Profiles and
Summary of Findings tables for all recommendations,
there were some for which the authors were unable
to produce such tables. However, those recommendations used an evidence-based systematic review
and assessment of relevant studies. Some recommendations would have benefited from meta-analyses
that would have clarified aspects of the evidence.
Although panelists were instructed in completing
the value and preference rating exercise to estimate
patient values and preferences rather than to use
their own, we cannot be assured that they succeeded
in all instances.41
13.0 Plans for Updating AT9
We plan to continue the tradition of the antithrombotic guidelines to update recommendations when
important new studies are published that might change
the current recommendations. In March 2011, the
ACCP Board of Regents approved a proposal to
revise the guideline development and updating process to a “living guidelines” process, whereby the
evidence-based guidelines will be periodically assessed
and updated as the literature warrants. From 1 year
after the publication of this ninth edition onward, all
clinical questions or sets of related questions will
become their own units. This process will be discussed in greater depth in future publications.
In addition to the published guidelines, ACCP has
historically provided clinical resources, including a
quick reference to the recommendations, patient
education materials, and slide sets for presentations. These resources will continue to be based
on the guidelines, but they will be accessed online
through the ACCP Web site. In addition, there will
be related resources, tools, and links to make the content more easily useful and searchable.
14.0 Conclusion
For AT9, we used an explicit, transparent process
that seeks to produce highly relevant and unbiased
recommendations for clinical practice. This process
involved the a priori specification of clinical questions
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in the PICO format along with study inclusion and
exclusion criteria, an exhaustive search for relevant
literature, an evaluation of the risk of bias of included
studies, and a rigorous and standardized assessment
of the quality of the body of evidence and its translation into recommendations using GRADE Working
Group methodologies. We incorporated specification
of values and preferences and resource considerations into recommendations where particularly relevant and when such data were available. Finally, we
sought to minimize bias potentially introduced by
intellectual and financial conflicts of interest by comprehensive disclosure requirements and aggressive
management of relevant conflicts.
Acknowledgments
Author contributions: Authors contributed to the AT9 guideline
process in the roles described in the article. As Topic Editor
and Chair of the guideline, Dr Guyatt oversaw the development
of this article.
Dr Guyatt: produced the first draft and was responsible for the
final article.
Dr Norris: undertook a major revision of a late draft of the
article.
Dr Schulman: took responsibility for sections relevant to their role
in AT9 and reviewed and approved the final article.
Dr Hirsh: took responsibility for sections relevant to their role in
AT9 and reviewed and approved the final article.
Dr Eckman: took responsibility for sections relevant to their role
Dr Akl: took responsibility for sections relevant to their role in
Dr Crowther: took responsibility for sections relevant to their role
Dr Vandvik: took responsibility for sections relevant to their role
Dr Eikelbloom: took responsibility for sections relevant to their
role in AT9 and reviewed and approved the final article.
Dr McDonagh: took responsibility for sections relevant to their
Dr Lewis: took responsibility for sections relevant to their role in
Dr Gutterman: took responsibility for sections relevant to their
Dr Cook: took responsibility for sections relevant to their role in
Dr Schünemann: took responsibility for sections relevant to their
Dr Eckman has received the following university grants: “Using
Decision Analytic Modeling to Guide the ACCP Guideline Development Process for Antithrombotic Therapy in Atrial Fibrillation”
(Foundation for Informed Medical Decision Making; October 2011September 2013; $185,000); “Cost-Effectiveness of Screening
for Chronic Hepatitis C Infection” (Merck/Schering-Plough;
October 2011- September 2012; $58,000); “Greater Cincinnati
BEACON Collaborative” (Office of the National Coordinator for
Health Information Technology [90BC0016/01]; September 2010March 2012; !15% effort); “Cincinnati Center for Clinical and
Translational Science and Training (CTSA) ARRA Supplement for
Development of Distance Learning Program in Medical Informatics” (National Institutes of Health [NIH]/National Center for
Research Resources [NCRR] [UL1 RR026314-01S1]; August 2009August 2011; !20% effort); “Cincinnati Center for Clinical
and Translational Science and Training (CTSA)” (NIH/NCRR
[1U54 RR 025216]; January 2009-February 2014; !15% effort);
“A Patient Specific Decision Support Tool for Bariatric Surgery”
(National Institute of Diabetes and Digestive and Kidney Diseases
[K23 DK075599]; August 2007-June 2012; no financial support);
National Heart, Lung, and Blood Institute (K23 HL085387;
June 2008-March 2013; no financial support); and “CostEffectiveness of Screening for Chronic Hepatitis B Infection”
(Gilead Sciences Inc; March 2008-August 2010; !$56,000). He
has also served as consultant for Savient Pharmaceuticals (“Cost
Effectiveness Analysis of Gout Medication”; 2010; !$300) and as
editorial consultant for the ACCP (“Physicians’ Information and
Education Resource [PIER]: Module on Pre-Operative Assessment
for Bleeding Disorders”; 2006-present; !$250/y). Dr Crowther
has served on various advisory boards, has assisted in the preparation of educational materials, and has sat on data safety and management boards. His institution has received research funds from
the following companies: Leo Pharma A/S, Pfizer Inc, Boerhinger
Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm
AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than
US $10,000. Dr Eikelboom has received consulting fees and honoraria from AstraZeneca; Boehringer-Ingelheim GmbH; BristolMyers Squibb; Corgenix; Daiichi-Sankyo, Inc; Eisai Co, Inc;
Eli Lilly and Company; GlaxoSmithKline plc; Haemonetics Corp;
McNeil Consumer Healthcare; and Sanofi-Aventis LLC and grants
and in-kind support from Accumetrics, Inc; AspirinWorks; Bayer
Healthcare Pharmaceuticals; Boehringer Ingelheim GmbH; BristolMyers Squibb; Corgenix; Dade Behring Inc; GlaxoSmithKline
plc; and Sanofi-Aventis LLC. Dr Gutterman has had the following
relationships that are entirely unrelated to the AT9 guidelines:
ACCP President, GlaxoSmithKline plc grant to study vasodilation in adipose tissue, National Institutes of Health grant to study
human coronary dilation, and GE Healthcare consultation on a
study for ECG evaluation of chronic heart disease. Drs Guyatt
and Schünemann are co-chairs of the GRADE Working Group,
and Drs Akl and Vandvik are members and prominent contributors to the Grade Working Group. Dr Lewis is a full-time
employee of the ACCP. Drs Norris, Schulman, Hirsh, McDonagh,
and Cook have reported that no potential conflicts of interest exist
with any companies/organizations whose products or services may
be discussed in this article.
Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication
access to the manuscripts and recommendations. Guideline panel
members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online
at http://chestnet.org.
Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists,
the American Society of Hematology, and the International Society
of Thrombosis and Hematosis.
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39. Jaeschke R, Guyatt GH, Dellinger P, et al; GRADE Working
Group. Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive. BMJ. 2008;337:a744.
40. Guyatt GH, Akl EA, Crowther M, Schünemann HJ,
Gutterman DD, Lewis SZ. Introduction to the ninth edition:
practice guidelines. Chest. 2012;141(2)(suppl):48S-52S.
41. Ubel PA, Angott AM, Zikmund-Fisher BJ. Physicians recommend different treatments for patients than they would
choose for themselves. Arch Intern Med. 2011;171(7):630-634.
Methodology for the Development of Antithrombotic Therapy and
Prevention of Thrombosis Guidelines : Antithrombotic Therapy and
Gordon H. Guyatt, Susan L. Norris, Sam Schulman, Jack Hirsh, Mark H.
Eckman, Elie A. Akl, Mark Crowther, Per Olav Vandvik, John W. Eikelboom,
Marian S. McDonagh, Sandra Zelman Lewis, David D. Gutterman, Deborah
J. Cook and Holger J. Schünemann
Chest 2012;141; 53S-70S
DOI 10.1378/chest.11-2288
http://chestjournal.chestpubs.org/content/suppl/2012/02/06/141.2_suppl.53S.DC1.html
References
Cited Bys
found online at:
Reprints
Citation Alerts
Antithrombotic Therapy for VTE Disease :
Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical
Practice Guidelines
Clive Kearon, Elie A. Akl, Anthony J. Comerota, Paolo Prandoni, Henri
Bounameaux, Samuel Z. Goldhaber, Michael E. Nelson, Philip S. Wells,
Michael K. Gould, Francesco Dentali, Mark Crowther and Susan R. Kahn
Chest 2012;141;e419S-e494S
DOI 10.1378/chest.11-2301
http://chestjournal.chestpubs.org/content/141/2_suppl/e419S.full.html
e419S.DC1.html
ISSN:0012-3692
Downloaded from chestjournal.chestpubs.org at ACCP HQ on February 9, 2012
CHEST
Supplement
Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Anthony J. Comerota, MD;
Paolo Prandoni, MD, PhD; Henri Bounameaux, MD; Samuel Z. Goldhaber, MD, FCCP;
Michael E. Nelson, MD, FCCP; Philip S. Wells, MD; Michael K. Gould, MD, FCCP;
Francesco Dentali, MD; Mark Crowther, MD; and Susan R. Kahn, MD
Background: This article addresses the treatment of VTE disease.
Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on highquality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence.
Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight
heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous
unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension
(Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods
(Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended
therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy
if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend
extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K
antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome
(Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or
LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C).
Conclusion: Strong recommendations apply to most patients, whereas weak recommendations
are sensitive to differences among patients, including their preferences.
CHEST 2012; 141(2)(Suppl):e419S–e494S
Abbreviations: CALISTO 5 Comparison of ARIXTRA in Lower Limb Superficial Thrombophlebitis With Placebo;
CDT 5 catheter-directed thrombolysis; CTPH 5 chronic thromboembolic pulmonary hypertension; HR 5 hazard ratio;
INR 5 international normalized ratio; IVC 5 inferior vena cava; LMWH 5 low-molecular-weight heparin; PE 5 pulmonary embolism; PESI 5 Pulmonary Embolism Severity Index; PREPIC 5 Prevention du Risque d’Embolie Pulmonaire
par Interruption Cave; PTS 5 postthrombotic (phlebitic) syndrome; RR 5 risk ratio; rt-PA 5 recombinant tissue
plasminogen activator; SC 5 subcutaneous; SVT 5 superficial vein thrombosis; tPA 5 tissue plasminogen activator;
UEDVT 5 upper-extremity DVT; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist
Summary of Recommendations
Note on Shaded Text: Throughout this guideline,
shading is used within the summary of recommendations sections to indicate recommendations that are
newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy:
www.chestpubs.org
American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition).
Recommendations that remain unchanged are not
shaded.
with vitamin K antagonist (VKA) therapy, we
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recommend initial treatment with parenteral
anticoagulation (low-molecular-weight heparin
[LMWH], fondaparinux, IV unfractionated heparin [UFH], or subcutaneous [SC] UFH) over no
such initial treatment (Grade 1B).
of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic
tests (Grade 2C).
suspicion of acute VTE, we suggest treatment
(Grade 2C).
Affiliations: From the Departments of Medicine and Clinical
Epidemiology and Biostatistics (Dr Kearon), Michael De Groote
School of Medicine, McMaster University, Hamilton, ON, Canada; Departments of Medicine, Family Medicine, and Social and
Preventive Medicine (Dr Akl), State University of New York at
Buffalo, Buffalo, NY; Department of Surgery (Dr Comerota),
Jobst Vascular Center, Toledo, OH; Department of Cardiothoracic and Vascular Sciences (Dr Prandoni), University of Padua,
Padua, Italy; Department of Medical Specialties (Dr Bounameaux),
University Hospitals of Geneva, Geneva, Switzerland; Department
of Medicine (Dr Goldhaber), Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA; Department of Medicine
(Dr Nelson), Shawnee Mission Medical Center, Shawnee Mission,
KS; Department of Medicine (Dr Wells), University of Ottawa,
Ottawa, ON, Canada; Departments of Medicine and Preventive
Medicine (Dr Gould), Keck School of Medicine, University of
Southern California, Los Angeles, CA; Department of Medicine
(Dr Dentali), University of Insubria, Varese, Italy; Department
of Medicine (Dr Crowther), Michael De Groote School of Medicine, McMaster University, Hamilton, ON, Canada; and Departments of Medicine and Clinical Epidemiology and Biostatistics
(Dr Kahn), McGill University, Montreal, QC, Canada.
and Bayer Schering Pharma AG. Support in the form of educational
grants were also provided by Bristol-Myers Squibb; Pfizer, Inc;
Canyon Pharmaceuticals; and sanofi-aventis US.
Disclaimer: American College of Chest Physician guidelines are
intended for general information only, are not medical advice,
and do not replace professional medical care and physician advice,
which always should be sought for any medical condition. The
complete disclaimer for this guideline can be accessed at http://
chestjournal.chestpubs.org/content/141/2_suppl/1S.
Correspondence to: Elie A. Akl, MD, MPH, PhD, Department of
Medicine, State University of New York at Buffalo, ECMC-CC 142,
462 Grider St, Buffalo, NY 14215; e-mail: [email protected]
DOI: 10.1378/chest.11-2301
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factors for extension, we suggest serial imaging
of the deep veins for 2 weeks over initial anticoagulation (Grade 2C).
for extension (see text), we suggest initial anticoagulation over serial imaging of the deep
veins (Grade 2C).
repeat imaging and a low value on the inconvenience
of treatment and on the potential for bleeding are
likely to choose initial anticoagulation over serial
imaging.
DVT (Grade 1B).
of the leg who are managed with serial imaging,
we recommend no anticoagulation if the thrombus does not extend (Grade 1B); we suggest anticoagulation if the thrombus extends but remains
confined to the distal veins (Grade 2C); we recommend anticoagulation if the thrombus
extends into the proximal veins (Grade 1B).
recommend early initiation of VKA (eg, same day
as parenteral therapy is started) over delayed
initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until
the international normalized ratio (INR) is 2.0 or
above for at least 24 h (Grade 1B).
(Grade 2C) and over SC UFH (Grade 2B for
LMWH; Grade 2C for fondaparinux).
fondaparinux and LMWH.
LMWH and fondaparinux are retained in patients
with renal impairment, whereas this is not a concern
with UFH.
Antithrombotic Therapy for VTE
the approved once-daily regimen uses the same daily
dose as the twice-daily regimen (ie, the once-daily
injection contains double the dose of each twicedaily injection). It also places value on avoiding an
extra injection per day.
whose home circumstances are adequate, we
recommend initial treatment at home over
treatment in hospital (Grade 1B).
adequacy of home circumstances: well-maintained
living conditions, strong support from family or
friends, phone access, and ability to quickly return to
the hospital if there is deterioration. It is also conditional on the patient feeling well enough to be treated
at home (eg, does not have severe leg symptoms or
comorbidity).
the leg, we suggest anticoagulant therapy
alone over catheter-directed thrombolysis (CDT)
(Grade 2C).
CDT (see text), who attach a high value to prevention
of postthrombotic syndrome (PTS), and a lower value
to the initial complexity, cost, and risk of bleeding
with CDT, are likely to choose CDT over anticoagulation alone.
Remarks: Patients who are most likely to benefit
from systemic thrombolytic therapy (see text), who
do not have access to CDT, and who attach a high value
to prevention of PTS, and a lower value to the initial
thrombolytic therapy, are likely to choose systemic
over operative venous thrombectomy (Grade 2C).
the same intensity and duration of anticoagulant therapy as in comparable patients who do
not undergo thrombosis removal (Grade 1B).
www.chestpubs.org
recommend against the use of an inferior vena
cava (IVC) filter in addition to anticoagulants
(Grade 1B).
the leg and contraindication to anticoagulation,
we recommend the use of an IVC filter (Grade
1B).
the leg and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagulant therapy if their
risk of bleeding resolves (Grade 2B).
Remarks: We do not consider that a permanent IVC
filter, of itself, is an indication for extended anticoagulation.
(Grade 2C).
Remarks: If edema and pain are severe, ambulation may need to be deferred. As per section 4.1, we
suggest the use of compression therapy in these
patients.
with anticoagulant therapy, we recommend
long-term therapy (see section 3.1 for recommended duration of therapy) over stopping anticoagulant therapy after about 1 week of initial
therapy (Grade 1B).
with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6 or
(Grade 1B regardless of bleeding risk).
bleeding risk (Grade 1B). We suggest treatment
with anticoagulation for 3 months over extended
therapy if there is a low or moderate bleeding
risk (Grade 2B).
3.1.3. In patients with an isolated distal DVT of
the leg provoked by surgery or by a nonsurgical
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transient risk factor (see remark), we suggest
and recommend treatment with anticoagulation
for 3 months over treatment of a longer timelimited period (eg, 6 or 12 months) (Grade 1B)
or extended therapy (Grade 1B regardless of
bleeding risk).
the leg (isolated distal [see remark] or proximal),
for at least 3 months over treatment of a shorter
duration (Grade 1B). After 3 months of treatment,
patients with unprovoked DVT of the leg should
be evaluated for the risk-benefit ratio of extended
therapy.
have a low or moderate bleeding risk, we suggest
extended anticoagulant therapy over 3 months
of therapy (Grade 2B).
have a high bleeding risk, we recommend
3 months of anticoagulant therapy over extended
therapy (Grade 1B).
3.1.4.3. In patients with a first VTE that is
an unprovoked isolated distal DVT of the leg
(see remark), we suggest 3 months of anticoagulant therapy over extended therapy in those
with a low or moderate bleeding risk (Grade 2B)
and recommend 3 months of anticoagulant
treatment in those with a high bleeding risk
(Grade 1B).
VTE who have a high bleeding risk, we suggest 3 months of anticoagulant therapy over
3.1.5. In patients with DVT of the leg and
active cancer, if the risk of bleeding is not
high, we recommend extended anticoagulant
therapy over 3 months of therapy (Grade 1B),
and if there is a high bleeding risk, we suggest
extended anticoagulant therapy (Grade 2B).
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all patients who are diagnosed with isolated distal DVT
will be prescribed anticoagulants (see section 2.3).
In all patients who receive extended anticoagulant therapy, the continuing use of treatment
should be reassessed at periodic intervals (eg,
annually).
3.3.1. In patients with DVT of the leg and no
cancer, we suggest VKA therapy over LMWH
for long-term therapy (Grade 2C). For patients
with DVT and no cancer who are not treated
with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy
(Grade 2C).
3.3.2. In patients with DVT of the leg and cancer,
we suggest LMWH over VKA therapy (Grade 2B).
In patients with DVT and cancer who are not
treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy
(Grade 2B).
patient’s tolerance for daily injections, need for laboratory monitoring, and treatment costs.
LMWH, rivaroxaban, and dabigatran are retained in
patients with renal impairment, whereas this is not a
concern with VKA.
Treatment of VTE with dabigatran or rivaroxaban, in
addition to being less burdensome to patients, may
prove to be associated with better clinical outcomes
than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the
paucity of currently available data and that new data
are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any
recommendations in favor of one of the new agents
over the other.
3.4. In patients with DVT of the leg who receive
extended therapy, we suggest treatment with the
same anticoagulant chosen for the first 3 months
(Grade 2C).
have asymptomatic DVT of the leg, we suggest
the same initial and long-term anticoagulation
as for comparable patients with symptomatic
DVT (Grade 2B).
4.1. In patients with acute symptomatic DVT
of the leg, we suggest the use of compression
Remarks: Compression stockings should be worn
for 2 years, and we suggest beyond that if patients
have developed PTS and find the stockings helpful.
Patients who place a low value on preventing PTS
or a high value on avoiding the inconvenience
and discomfort of stockings are likely to decline
stockings.
4.2.2. In patients with severe PTS of the leg that
is not adequately relieved by compression stockings, we suggest a trial of an intermittent compression device (Grade 2B).
4.3. In patients with PTS of the leg, we suggest
that venoactive medications (eg, rutosides, defibrotide, and hidrosmin) not be used (Grade 2C).
Remarks: Patients who value the possibility of
response over the risk of side effects may choose to
undertake a therapeutic trial.
initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH)
over no such initial treatment (Grade 1B).
tests (Grade 2C).
(Grade 2C).
acute PE, we suggest not treating with parenteral anticoagulants while awaiting the results
www.chestpubs.org
for LMWH; Grade 2B for fondaparinux) and over
fondaparinux).
fondaparinux and LMWH.
LMWH and fondaparinux are retained in patients
with renal impairment, whereas this is not a concern
with UFH.
In patients with PE where there is concern about the
adequacy of SC absorption or in patients in whom
thrombolytic therapy is being considered or planned,
initial treatment with IV UFH is preferred to use of
SC therapies.
after first 5 days of treatment) (Grade 2B).
Remarks: Patients who prefer the security of the hospital to the convenience and comfort of home are likely
to choose hospitalization over home treatment.
who do not have a high bleeding risk, we
suggest systemically administered thrombolytic
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(Grade 1C).
associated with hypotension and with a low
bleeding risk whose initial clinical presentation,
or clinical course after starting anticoagulant
therapy, suggests a high risk of developing hypotension, we suggest administration of thrombolytic therapy (Grade 2C).
5.6.2.2. In patients with acute PE when a thrombolytic agent is used, we suggest administration
hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis,
or (iii) shock that is likely to cause death
before systemic thrombolysis can take effect
(eg, within hours), if appropriate expertise and
resources are available, we suggest catheterassisted thrombus removal over no such intervention (Grade 2C).
embolectomy over no such intervention if
they have (i) contraindications to thrombolysis,
(ii) failed thrombolysis or catheter-assisted
embolectomy, or (iii) shock that is likely to
cause death before thrombolysis can take effect
(eg, within hours), provided surgical expertise
and resources are available (Grade 2C).
we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter
bleeding risk).
6.2. In patients with PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over
(i) treatment of a shorter period (Grade 1B),
(ii) treatment of a longer time-limited period
(eg, 6 or 12 months) (Grade 1B), and (iii) extended
therapy if there is a high bleeding risk (Grade 1B).
We suggest treatment with anticoagulation for
3 months over extended therapy if there is a
low or moderate bleeding risk (Grade 2B).
6.3. In patients with an unprovoked PE, we
recommend treatment with anticoagulation for
at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment,
patients with unprovoked PE should be evaluated
for the risk-benefit ratio of extended therapy.
unprovoked PE and who have a low or moderate
bleeding risk, we suggest extended anticoagulant
therapy over 3 months of therapy (Grade 2B).
VTE who have a high bleeding risk, we suggest 3 months of therapy over extended therapy
(Grade 2B).
5.9.3. In patients with acute PE and an IVC filter inserted as an alternative to anticoagulation,
we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves
(Grade 2B).
there is a low or moderate bleeding risk, we recommend extended anticoagulant therapy over
3 months of therapy (Grade 1B), and if there is
a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B).
anticoagulation.
Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should
be reassessed at periodic intervals (eg, annually).
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8.1.1. In patients with superficial vein thrombosis (SVT) of the lower limb of at least 5 cm in
length, we suggest the use of a prophylactic
dose of fondaparinux or LMWH for 45 days
over no anticoagulation (Grade 2B).
6.6. In patients with PE and no cancer, we suggest VKA therapy over LMWH for long-term
therapy (Grade 2C). For patients with PE and no
cancer who are not treated with VKA therapy,
we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C).
Remarks: Patients who place a high value on avoiding
the inconvenience or cost of anticoagulation and a
low value on avoiding infrequent symptomatic VTE
patient’s tolerance for daily injections, need for laboratory monitoring, and treatment costs.
Treatment of VTE with dabigatran or rivaroxaban, in
addition to being less burdensome to patients, may
prove to be associated with better clinical outcomes
than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the
paucity of currently available data and that new data
are rapidly emerging, we give a weak recommendation
in favor of VKA and LMWH therapy over dabigatran
and rivaroxaban, and we have not made any recommendation in favor of one of the new agents over the other.
(Grade 2C).
have asymptomatic PE, we suggest the same
initial and long-term anticoagulation as for
comparable patients with symptomatic PE
(Grade 2B).
7.1.1. In patients with chronic thromboembolic pulmonary hypertension (CTPH), we recommend extended anticoagulation over stopping
therapy (Grade 1B).
7.1.2. In selected patients with CTPH, such
as those with central disease under the care of
an experienced thromboendarterectomy team,
we suggest pulmonary thromboendarterectomy
(Grade 2C).
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8.1.2. In patients with SVT who are treated
with anticoagulation, we suggest fondaparinux
2.5 mg daily over a prophylactic dose of LMWH
(Grade 2C).
9.1.1. In patients with acute upper-extremity
DVT (UEDVT) that involves the axillary or more
proximal veins, we recommend acute treatment
with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such acute
treatment (Grade 1B).
(Grade 2C) and over SC UFH (Grade 2B).
9.2.1. In patients with acute UEDVT that involves
the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis (Grade 2C).
the axillary or more proximal veins, we suggest a minimum duration of anticoagulation of
3 months over a shorter period (Grade 2B).
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UEDVT was associated with a central venous catheter that was removed shortly after diagnosis.
is continued as long as the central venous catheter remains over stopping after 3 months of
(Grade 2C).
associated with a central venous catheter or with
cancer, we recommend 3 months of anticoagulation over a longer duration of therapy (Grade 1B).
we suggest against the use of compression
sleeves or venoactive medications (Grade 2C).
10.1. In patients with symptomatic splanchnic vein thrombosis (portal, mesenteric, and/or
splanchnic vein thrombosis (portal, mesenteric,
and/or splenic vein thromboses), we suggest no
anticoagulation over anticoagulation (Grade 2C).
provides recommendations for the
Thisuse ofarticle
antithrombotic agents as well as the use of
devices or surgical techniques in the treatment of
patients with DVT and pulmonary embolism (PE),
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which are collectively referred to as VTE. We also
provide recommendations for patients with (1) postthrombotic syndrome (PTS), (2) chronic thromboembolic pulmonary hypertension (CTPH), (3) incidentally
diagnosed (asymptomatic) DVT or PE, (4) acute
upper-extremity DVT (UEDVT), (5) superficial vein
thrombosis (SVT), (6) splanchnic vein thrombosis,
and (7) hepatic vein thrombosis.
Table 1 describes the populations, interventions,
comparators, and outcomes (ie, PICO elements) for
the questions addressed in this article and the design
of the studies used to address them. Refer to
Garcia et al,1 Ageno et al,2 and Holbrook et al3 in
these guidelines for recommendations on the management of parenteral anticoagulation (dosing and
monitoring) and oral anticoagulation (dosing and
monitoring). Refer to Bates et al4 and Monagle et al5
in these guidelines for recommendations for pregnancy and neonates and children. The current article
builds on previous versions of these guidelines and,
most recently, the eighth edition.6
1.0 Methods
1.1 Presentation as DVT or PE
In addressing DVT, we first review studies that included (1)
only patients who presented with symptomatic DVT or (2) patients
who presented with DVT or PE (ie, meeting the broader criterion
of VTE). For the PE components, we review studies (and subgroups within studies) that required patients to have presented
with symptomatic PE (who may also have had symptoms of DVT).
For this reason and because more patients with VTE present with
symptoms of DVT alone than with symptoms of PE (including
those who also have symptoms of DVT), the DVT section deals
with a larger body of evidence than the PE section.
In the evaluation of anticoagulant therapy, there are a number
of justifications for inclusion of patients who present with DVT
and PE in the same study, and for extrapolating evidence obtained
in patients with one presentation of VTE (eg, DVT) to the other
presentation (eg, PE). First, a majority of patients with symptomatic DVT also have PE (symptomatic or asymptomatic), and
a majority of those with symptomatic PE also have DVT (symptomatic or asymptomatic).7,8 Second, clinical trials of anticoagulant therapy have yielded similar estimates for efficacy and safety
in patients with DVT alone, in those with both DVT and PE, and
in those with only PE. Third, the risk of recurrence appears to
be similar after PE and after proximal DVT.7,9 Consequently, the
results of all studies of VTE have been considered when formulating recommendations for short- and long-term anticoagulation of proximal DVT and PE (Fig 1), and these recommendations
are essentially the same for proximal DVT or PE.
There are, however, some important differences between
patients who present with PE and those who present with DVT
that justify separate consideration of some aspects of the treatment
of PE. First, the risk of early death (within 1 month) from VTE
due to either the initial acute episode or recurrent VTE is much
greater after presenting with PE than after DVT9; this difference
may justify more aggressive initial treatment of PE (eg, thrombolytic therapy, insertion of an inferior vena cava (IVC) filter, more
intensive anticoagulant therapy) compared with DVT. Second,
recurrent episodes of VTE are about three times as likely to be
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Early initiation of VKA
Longer duration
Patients with acute DVT
of the leg
of the leg
of the leg
of the leg
Patients with acute proximal
DVT of the leg
of the leg started on
anticoagulation
Patients with acute DVT of
the leg and a contraindication
to anticoagulation
Patients with acute DVT of the
leg who initially received an
IVC filter, now contraindication
to anticoagulation resolved
leg started on anticoagulant
treatment
Choice and route of initial
anticoagulant (2.5.1, 2.5.2, 2.6)
Setting of initial
anticoagulation (2.7)
Role of thrombolytic and mechanical
interventions (2.9-2.12)
Role of IVC filters in addition to
anticoagulation (2.13.1)
No active thrombus
removal or another
method of thrombus
removal
Catheter directed
thrombolysis
Systemic thrombolytic
therapy
Operative venous
thrombectomy
IVC filter
No IVC filter
No anticoagulation in
addition to IVC filter
Initial bed rest
IVC filter
Anticoagulation in
Early ambulation
No IVC filter
At-home treatment
LMWH, fondaparinux,
rivaroxaban
In-hospital treatment
UFH IV or SQ
Shorter duration
Delayed initiation
of VKA
No anticoagulation
Anticoagulation
Timing of initiation of VKA relative
to the initiation of parenteral
Duration of initial
No anticoagulation
No anticoagulation
Anticoagulation
Patients with suspected acute
DVT of the leg awaiting the
results of diagnostic tests
Patient with acute isolated
distal DVT of the leg
Anticoagulation
Whether to treat while awaiting the
results of the diagnostic work-up
(2.2.1- 2.2.3)
Whether to treat isolated distal
thrombosis (2.3.1-2.3.4)
Role of IVC filters when
anticoagulation is contraindicated
(2.13.2)
Role of anticoagulation in patients
who initially received an IVC
filter when contraindication to
anticoagulation resolves (2.13.3)
Role of early ambulation (2.14)
Comparators
Patient with acute DVT of the leg (2.0-3.0)
Intervention
Patients with acute DVT of
the leg
Population
Initial anticoagulant (2.1)
Issue (Informal Question)
Structured PICO Question
Table 1—Structured Clinical Questions
Recurrent DVT and PE, major
bleeding, mortality, QOL, PTS,
and complications of procedure
DVT extension, PE, major
bleeding, mortality,
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
DVT extension, PE, major bleeding,
mortality, QOL, and PTS
Recurrent DVT and PE,
major bleeding, mortality,
QOL, PTS, shorter ICU
and hospital stays, and
acute complications
QOL, and PTS
PE, major bleeding, and
mortality
Outcome
(Continued)
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs
RCTs and
cohort
studies
RCTs
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs
RCTs
Methodology
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Whether to treat while awaiting the
results of the diagnostic work-up
(5.2.1-5.2.3)
Timing of initiation of VKA relative
to the initiation of parenteral
Duration of initial
Patient with acute PE
Anticoagulation
No initial
anticoagulation
Shorter duration
Longer duration
Patients with acute PE
Initial anticoagulant (5.1)
Venoactive medications
No intermittent
pneumatic
compression
No venoactive
medications
Patients with PTS of the leg
Role of venoactive medications in
PTS (4.3)
Intermittent pneumatic
compression
No compression
stockings
Delayed initiation
of VKA
Role of intermittent pneumatic
compression in PTS (4.2.2)
Compression stockings
Compression stockings
No compression
stockings
No anticoagulation
Early initiation of VKA
leg started on anticoagulant
treatment
Role of compression stocking in
preventing PTS (4.1)
Anticoagulation
VKA
Higher or lower INR
ranges
No anticoagulation
Patients with incidentally
diagnosed asymptomatic
DVT of the leg
Whether to treat an incidentally
diagnosed asymptomatic acute
DVT of the leg (3.5)
LMWH, dabigatran,
rivaroxaban
INR 2-3
Longer duration
Comparators
No long-term
anticoagulation
therapy
Shorter duration
Anticoagulation
of the leg.
Choice of long-term anticoagulant
(3.3.1, 3.3.2, 3.4)
Intervention
Long-term anticoagulation
therapy
Patients with suspected acute
PE awaiting the results of
the diagnostic tests
of the leg
Intensity of VKA (3.2)
Role of compression stocking
in PTS (4.2.1)
Patients with an acute DVT
of the leg
Duration of long-term
anticoagulation (3.1.1- 3.1.5)
Population
Patients with acute VTE of
the leg
Long-term anticoagulation
therapy (3.0)
Table 1—Continued
Outcome
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, PTS, and recurrent
DVT
QOL, symptomatic relief,
ulceration
ulceration
QOL, PTS, and recurrent
DVT
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
(Continued)
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs
RCTs
RCTs
RCTs
RCTs
RCTs
Methodology
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e429S
Longer infusion time
requiring thrombolytic
therapy
requiring thrombolytic
therapy
Choice of long-term anticoagulant
(6.6, 6.7, 6.8)
Whether to treat an incidentally
diagnosed asymptomatic acute PE (6.9)
Patients with incidentally
diagnosed asymptomatic PE
LMWH, dabigatran,
rivaroxaban
Anticoagulation
INR 2-3
Shorter duration
Longer duration
No anticoagulation
VKA
Higher or lower
INR range
No anticoagulation in
Anticoagulation in
No IVC filter
No IVC filter
IVC filter
No use of
catheter-assisted
thrombus removal
No surgical pulmonary
embolectomy
Pulmonary catheter
Shorter infusion time
No thrombolytic
therapy
At-home treatment
IVC filter
Patients with acute PE started
on anticoagulation
Role of IVC filter in addition to
anticoagulation in patients
with acute PE (5.9.1)
Role of IVC filters when
anticoagulation is contraindicated
(5.9.2)
Role of anticoagulation in patients
who initially received an IVC
filter when contraindication to
anticoagulation resolves (5.9.3)
anticoagulation in patients with
acute PE (6.1-6.4)
Intensity of VKA (6.5)
Surgical pulmonary
embolectomy
Use of catheter-assisted
thrombus removal
Peripheral vein
Comparators
LMWH, fondaparinux,
and rivaroxaban
Patients with acute PE and
a contraindication to
anticoagulation
Patients with acute PE who
initially received an IVC
filter, now contraindication
to anticoagulation resolved
Role of surgical pulmonary
embolectomy (5.8)
Role of catheter-assisted thrombus
removal (5.7)
Venous access for thrombolytic
therapy (5.6.2.2)
Thrombolytic therapy
Thrombolytic therapy in patients
with acute PE (5.6.1.1, 5.6.1.2,
5.6.1.3)
Infusion time for thrombolytic
therapy (5.6.2.1)
In-hospital treatment
Intervention
UFH IV or SQ
Setting of initial
Population
of the leg
Choice and route of initial
anticoagulant (5.4.1, 5.4.2)
Table 1—Continued
Outcome
QOL, and PTS
QOL, and PTS
bleeding, mortality, QOL, and PTS
bleeding, mortality, QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
QOL, and PTS
(Continued)
RCTs and
cohorts
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs
RCTs
RCTs
Methodology
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Patients with UEDVT
Patients with UEDVT and
indwelling central venous
catheter
Patients with UEDVT and
indwelling central venous
catheter
Patients with UEDVT
Patients with PTS of
the arm
Role of thrombolytic therapy
(9.2.1, 9.2.2)
Whether indwelling central
venous catheter should be
removed (9.3.1)
anticoagulation (9.3.2-9.3.5)
Prevention of PTS of the arm (9.4)
Treatment of PTS of the arm
(9.5.1, 9.5.2)
No anticoagulation or
other anticoagulant
Shorter duration
No removal of
indwelling central
venous catheter
No systemic thrombolytic
therapy
Anticoagulation
No anticoagulation
Compression sleeves
No compression sleeves
or venoactive
or venoactive
medications
medications
Compression sleeves
No compression sleeves
or venoactive
or venoactive
medications
medications
Patient with thrombosis in unusual sites
Anticoagulation
No anticoagulation
Longer duration
Removal of indwelling
central venous
catheter
Systemic thrombolytic
therapy
Patient with acute UEDVT
Parenteral anticoagulation
No anticoagulation
Patient with SVT
Anticoagulation
No pulmonary
thromboendarterectomy
No oral anticoagulation
Patient with CTPH
Oral anticoagulation
Pulmonary
Comparators
Intervention
Mortality, bowel ischemia,
major bleeding, QOL,
and symptomatic relief
Mortality, liver failure, PE,
major bleeding, QOL,
and symptomatic relief
and ulceration
QOL, and PTS
bleeding, mortality, QOL,
PTS, shorter ICU and hospital
stays, and acute complications
QOL, PTS, and
recurrent DVT
DVT and PE, major
symptomatic relief, and PTS
QOL, and PTS
QOL, and PTS
Outcome
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
RCTs and
cohort
studies
Methodology
CTPH 5 chronic thromboembolic pulmonary hypertension; INR 5 international normalized ratio; IVC 5 inferior vena cava; LMWH 5 low-molecular-weight heparin, PE 5 pulmonary embolism;
PICO 5 population, intervention, comparator, outcome; PTS 5 postthrombotic syndrome, QOL 5 quality of life; RCT 5 randomized controlled trial; SVT 5 superficial vein thrombosis; UEDVT 5 upperextremity DVT; UFH 5 unfractionated heparin, VKA 5 vitamin K antagonist.
Patients with hepatic
vein thrombosis
Patients with UEDVT
Acute anticoagulation (9.1.1, 9.1.2)
Role of anticoagulation in hepatic
vein thrombosis (11.1, 11.2)
Patients with SVT
Role of anticoagulation in SVT
(8.1.1, 8.1.2)
Patients with splanchnic
vein thrombosis
Patients with CTPH
Role of pulmonary
in CTPH (7.1.2)
Role of anticoagulation in splanchnic
vein thrombosis (10.1, 10.2)
Patients with CTPH
Population
Role of oral anticoagulation in
CTPH (7.1.1)
Table 1—Continued
Figure 1. Phases of anticoagulation. LMWH 5 low-molecular-weight heparin.
PE after an initial PE than after an initial DVT (ie, about 60%
after a PE vs 20% after a DVT)7,9,10; this difference may justify
more aggressive, or more prolonged, long-term therapy. Third,
the long-term sequelae of PE are cardiorespiratory impairment,
especially due to pulmonary hypertension, rather than PTS of the
legs or arms. These differences are most important for recommendations about the use of thrombus removal procedures (eg, thrombolytic therapy) in patients who present with DVT and PE.
1.2 Outcomes Assessed
The outcomes important to patients we considered for most recommendations are recurrent VTE, major bleeding, and all-cause
mortality. These outcomes are categorized in two different ways
in the evidence profiles. Whenever data were available, fatal episodes of recurrent VTE and bleeding were included in the mortality outcome, and nonfatal episodes of recurrent VTE and
bleeding were reported separately in their own categories to avoid
reporting an outcome more than once in an evidence profile.
However, many original reports and published meta-analyses
did not report fatal and nonfatal events separately. In this situation, we have reported the outcome categories of mortality, recurrent VTE, and major bleeding, with fatal episodes of VTE and
bleeding included in both mortality and two specific outcomes
(ie, fatal episodes of VTE and bleeding are included in two outcomes of the evidence profile).
With both ways of reporting outcomes, we tried to specifically
identify deaths from recurrent VTEs and major bleeds. As part of
the assessment of the benefits and harms of a therapy, we generally assume that !5% of recurrent episodes of VTE are fatal11,12
and that !10% of major bleeds are fatal,12-14 and if we deviated
from these estimates, we noted the reasons for so doing. We did
not consider surrogate outcomes (eg, vein patency) when there
were adequate data addressing the corresponding outcome of
importance to patients (eg, PTS).
When developing evidence profiles, we tried to obtain the
baseline risk of outcomes (eg, risk of recurrent VTE or major
bleeding) from observational studies because these estimates are
most likely to reflect real-life incidence. In many cases, however,
we used data from randomized trials because observational data
were lacking or were of low quality. Methodologic issues specific
to duration of anticoagulation are addressed in the section 3.1
under the subsection on general consideration in weighing the
benefits and risks of different durations of anticoagulant therapy.
1.3 Patient Values and Preferences
In developing our recommendations, we took into account
average patient values for each outcome and preferences for
different types of antithrombotic therapy. As described in
MacLean et al15 and Guyatt et al16 in these guidelines, these values
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and preferences for the most part were obtained from ratings
that all panelists for these guidelines provided in response to
standardized descriptions of different outcomes and treatments,
supplemented with the findings of a systematic review of the
literature on this topic.15 However, we also took into account that
values and preferences vary markedly among individual patients
and that often there is appreciable uncertainty about the average
patient values we used.
On average, we assumed that patients attach equal value (or
dislike [disutility]) to nonfatal thromboembolic and major bleeding
events. Concern that the panelist rating exercise that attached a
similar disutility to vitamin K antagonist (VKA) therapy (frequent
blood testing and telephone or clinic visits, attention to changes
in other medications) and long-term low-molecular-weightheparin (LMWH) therapy (daily subcutaneous [SC] injection,
injection site bruising or nodules) may have been misguided led
us to request a review of this issue at the final meeting of all panelists.
Our judgment that, on average, patients would prefer VKA therapy
to long-term LMWH therapy was confirmed at that meeting.
1.4 Influence of Bleeding Risk and Cost
Usually, we did not assess how an individual patient’s risk of
bleeding would influence each recommendation because (1) we
considered that most recommendations would be unlikely to
change based on differences in risk of bleeding (eg, anticoagulation vs no anticoagulation for acute VTE, comparison of anticoagulant regimens), (2) there are few data assessing outcomes in
patients with different risks of bleeding, and (3) there is a lack of
well-validated tools for stratifying risk of bleeding in patients with
VTE. However, for a small number of the recommendations in
which the risk of bleeding is very influential (eg, use of extendedduration anticoagulation), we stratified recommendations based
on this risk (Table 2). Unless otherwise stated, the cost (eg, to the
patient, a third-party payer, or society) associated with different
treatments did not influence our recommendations. In most situations of uncertain benefit of a treatment, particularly if it was
potentially harmful, we took the position of primum non nocere
(first do no harm) and made a weak recommendation against the
treatment.
2.0 Treatment of Acute DVT
2.1 Initial Anticoagulation of Acute DVT of the Leg
The first and only randomized trial that compared
anticoagulant therapy with no anticoagulant therapy
in patients with symptomatic DVT or PE was published in 1960 by Barritt and Jordan.50 Trial results
suggested that 1.5 days of heparin and 14 days of
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Table 2—[Section 2.3, 3] Risk Factors for Bleeding With Anticoagulant Therapy and Estimated Risk of Major
Bleeding in Low-, Moderate-, and High-Risk Categories
Risk Factorsa
Age . 65 y17-25
Age . 75 y17-21,23,25-34
Previous bleeding18,24,25,30,33-36
Cancer20,24,30,37
Metastatic cancer36.38,
Renal failure18,24,25,28,30,33
Liver failure19,21,27,28
Thrombocytopenia27,36
Previous stroke18,25,27,39
Diabetes18,19,28,32,34
Anemia18,21,27,30,34
Antiplatelet therapy19,27,28,34,40
Poor anticoagulant control22,28,35
Comorbidity and reduced functional capacity24,28,36
Recent surgery21,41,b
Frequent falls27
Alcohol abuse24,25,27,34
Categorization of Risk of Bleedingc
Anticoagulation 0-3 moe
Baseline risk (%)
Increased risk (%)
Total risk (%)
Anticoagulation after first 3 mog
Baseline risk (%/y)
Increased risk (%/y)
Total risk (%/y)
Low Riskd (0 Risk Factors)
Estimated Absolute Risk of Major Bleeding, %
Moderate Riskd (1 Risk Factor)
High Riskd (! 2 Risk Factors)
0.6
1.0
1.6e
1.2
2.0
3.2
4.8
8.0
12.8f
0.3h
0.5
0.8i
0.6
1.0
1.6i
! 2.5
! 4.0
! 6.5
See Table 1 legend for expansion of abbreviations.
The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, location and extent of metastatic disease,
platelet count), (2) temporal relationships (eg, interval from surgery or a previous bleeding episode),29 and (3) how effectively a previous cause of
bleeding was corrected (eg, upper-GI bleeding).
bImportant for parenteral anticoagulation (eg, first 10 d) but less important for long-term or extended anticoagulation.
cAlthough there is evidence that risk of bleeding increases with the prevalence of risk factors,20,21,25,27,30,33,34,36,42,43 this categorization scheme has not
been validated. Furthermore, a single risk factor, when severe, will result in a high risk of bleeding (eg, major surgery within the past 2 d, severe
thrombocytopenia).
dCompared with low-risk patients, moderate-risk patients are assumed to have a twofold risk and high-risk patients an eightfold risk of major bleed
ing.18,20,21,27,28,30,36,44
eThe 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by VKA therapy (Table S6 Evidence Profile:
LMWH vs IV UFH for initial anticoagulation of acute VTE). We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with
anticoagulation (footnote g in this table).
fConsistent with frequency of major bleeding observed by Hull et al41 in high-risk patients.
gWe estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on comparison of extended anticoagulation with no
extended anticoagulation (Table S27 Evidence Profile: extended anticoagulation vs no extended anticoagulation for different groups of patients with
VTE and without cancer). The relative risk of major bleeding during the first 3 mo of therapy may be greater that during extended VKA therapy
because (1) the intensity of anticoagulation with initial parenteral therapy may be greater than with VKA therapy; (2) anticoagulant control will be
less stable during the first 3 mo; and (3) predispositions to anticoagulant-induced bleeding may be uncovered during the first 3 mo of therapy.22,30,35
However, studies of patients with acute coronary syndromes do not suggest a ! 2.6 relative risk of major bleeding with parenteral anticoagulation
(eg, UFH or LMWH) compared with control.45,46
hOur estimated baseline risk of major bleeding for low-risk patients (and adjusted up for moderate- and high-risk groups as per
footnote d in this table).
iConsistent with frequency of major bleeding during prospective studies of extended anticoagulation for VTE22,44,47,48,49 (and Table S27 Evidence
Profile: extended anticoagulation vs no extended anticoagulation for different groups of patients with VTE and without cancer and Table S24).
a
VKA therapy markedly reduced recurrent PE (0/16
vs 10/19) and appeared to reduce mortality (1/16
vs 5/19) in patients with acute PE. In the early 1990s,
a single randomized trial established the need for an
initial course of heparin in addition to VKA as compared with starting treatment with VKA therapy
alone51 (Table 3, Table S1). (Tables that contain an
e432S
“S” before the number denote supplementary tables
not contained in the body of the article and available instead in an online data supplement. See the
“Acknowledgments” for more information.) The need
for an initial course of heparin is also supported by
the observation that there are high rates of recurrent VTE during 3 months of follow-up in patients
Table 3—[Section 2.1] Summary of Findings: Parenteral Anticoagulation vs No Parenteral Anticoagulation in Acute VTEa,51
Anticipated absolute effects
Outcomes
No. of Participants
(Studies), Follow-up
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
Risk With No Parenteral
Anticoagulation
Risk Difference With Parenteral
Anticoagulation (95% CI)
Mortality
120 (1 study), 6 mo
120 (1 study), 6 mo
RR 0.5
(0.05-5.37)
RR 0.33
(0.11-0.98)
33 per 1,000
VTE symptomatic
extension or
recurrence
Major bleeding
Moderateb,c due to
imprecision
Moderateb,d due to
imprecision
16 fewer per 1,000 (from
31 fewer to 144 more)
4 fewer to 178 fewer)
Moderateb,c due to
imprecision
RR 0.67
(0.12-3.85)
120 (1 study), 6 mo
200 per 1,000
50 per 1,000
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its
95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades
of evidence are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further
research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research
is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are
very uncertain about the estimate. GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; RR 5 risk ratio.
aBoth groups treated with acenocoumarol.
bStudy described as double blinded; outcome adjudicators blinded. None of the study participants were lost to follow-up. Intention-to-treat analysis.
Study was stopped early for benefit.
cCI includes values suggesting no effect as well as values suggesting either appreciable benefit or appreciable harm.
dLow number of events caused by the early stoppage of the trial.
with acute VTE treated with suboptimal heparin
therapy.1,3,52,53 We discuss whether isolated distal (calf)
DVT should be sought and if isolated distal DVT is
diagnosed, whether and how it should be treated in
section 2.3.
Recommendation
with VKA therapy, we recommend initial treatment with parenteral anticoagulation (LMWH,
fondaparinux, IV unfractionated heparin [UFH],
or SC UFH) over no such initial treatment
(Grade 1B).
2.2 Whether to Treat With Parenteral
Anticoagulation While Awaiting the Results
of Diagnostic Work-up for VTE
We identified no trial addressing this question.
The decision regarding treatment while awaiting test
results requires balancing (1) minimizing thrombotic
complications in patients with VTE and (2) avoiding
bleeding in those without VTE. Our recommendations are based on two principles. First, the higher the
clinical suspicion for VTE (use of validated prediction models for probability of having DVT54 or PE55,56
can usefully inform this assessment,57 the shorter the
acceptable interval without treatment until results
of diagnostic testing become available. Second, the
higher the risk of bleeding, the longer the acceptable
interval without treatment until results are available.
Our recommendations assume that patients do
not have major risk factors for bleeding, such as
recent surgery. The recommendations also take into
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account that starting anticoagulant therapy in patients
who ultimately have DVT excluded is costly and is a
burden to patients and the health-care system. Poor
cardiopulmonary reserve may also encourage the use
of anticoagulant therapy while awaiting diagnostic
testing. If clinicians choose to administer anticoagulant therapy and diagnostic testing will be completed
within 12 h, we suggest using a 12-h over a 24-h dose
of LMWH. VKA therapy usually should not be started
before VTE has been confirmed.
Recommendations
of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment while awaiting the results of diagnostic
tests (Grade 2C).
suspicion of acute VTE, we suggest treatment with
parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected
to be delayed for more than 4 h (Grade 2C).
2.3 Whether and How to Prescribe Anticoagulants
to Patients With Isolated Distal DVT
Whether to Look for Isolated Distal DVT and When
to Prescribe Anticoagulants if Distal DVT Is Found:
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Whether patients with isolated distal DVT (DVT of the
calf [peroneal, posterior tibial, anterior tibial veins]
without involvement of the popliteal or more proximal
veins) are identified depends on how suspected DVT
is investigated.57 If all patients with suspected DVT
have ultrasound examination of the calf veins (wholeleg ultrasound), isolated distal DVT accounts for
about one-half of all DVT diagnosed.58 If a diagnostic
approach is used that does not include ultrasound
examination of the calf veins or that only performs
ultrasound examination of the calf veins in selected
patients, isolated distal DVT is rarely diagnosed.59
The primary goal of diagnostic testing for DVT is to
identify patients who will benefit from anticoagulant
therapy. This does not mean that all symptomatic DVT
need to be identified. Isolated distal DVT do not need
to be sought and treated provided that (1) there is
strong evidence that the patient does not have a distal
DVT that will extend into the proximal veins (ie, the
patient is unlikely to have a distal DVT, and if a distal
DVT is present, it is unlikely to extend); (2) if this criterion is not satisfied, a follow-up proximal ultrasound
is done after 1 week to detect distal DVT that has
extended into the proximal veins, in which case anticoagulant therapy is started; and (3) the patient does not
have severe symptoms that would require anticoagulant therapy if the symptoms were due to a distal DVT.
Diagnostic approaches to suspected DVT that do
not examine the calf veins (eg, use of a combination
of clinical assessment, D-dimer testing, single and
serial proximal vein ultrasound examination to manage patients) or only examine the calf veins in selected
patients (eg, those who cannot have DVT excluded
using the previously noted tests) have been proven
safe and are presented in Bates et al57 in these guidelines. If the calf veins are imaged (usually with ultrasound) and isolated distal DVT is diagnosed, there
are two management options: (1) treat patients with
anticoagulant therapy or (2) do not treat patients with
anticoagulant therapy unless extension of the DVT
is detected on a follow-up ultrasound examination
(eg, after 1 and 2 weeks or sooner if there is concern
[there is no widely accepted protocol for surveillance ultrasound testing]).60 Natural history studies
suggest that when left untreated, !15% of symptomatic distal DVT will extend into the proximal veins
and that if extension does not occur within 2 weeks,
it is unlikely to occur subsequently.7,60-62 The risk of
extension of isolated distal DVT will vary among
patients (see later discussion).
As noted in Bates et al,57 these guidelines favor
diagnostic approaches to suspected DVT other
than routine whole-leg ultrasound. If isolated distal DVT is diagnosed, depending on the severity of
patient symptoms (the more severe the symptoms,
the stronger the indication for anticoagulation) and
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the risk for thrombus extension (the greater the
risk, the stronger the indication for anticoagulation), we suggest either (1) anticoagulation or (2)
withholding of anticoagulation while performing surveillance ultrasound examinations to detect thrombus
extension. We consider the following to be risk factors for extension: positive D-dimer, thrombosis that
is extensive or close to the proximal veins (eg, . 5 cm
in length, involves multiple veins, . 7 mm in maximum diameter), no reversible provoking factor for
DVT, active cancer, history of VTE, and inpatient
status.7,60,63,64 Thrombosis that is confined to the muscular veins has a lower risk of extension than true isolated distal DVT.63,65 We anticipate that isolated distal
DVT detected using a selective approach to wholeleg ultrasound often will satisfy criteria for initial anticoagulation, whereas distal DVT detected by routine
whole-leg ultrasound often will not. A high risk for
bleeding (Table 2) favors ultrasound surveillance over
initial anticoagulation, and the decision to use surveillance or initial anticoagulation is expected to be
sensitive to patient preferences. The evidence supporting recommendations to prescribe anticoagulants for isolated calf DVT is low quality because it
is not based on direct comparisons of the two management strategies, and the ability to predict extension of distal DVT is limited.
How to Treat With Anticoagulants: A single controlled trial of 51 patients with symptomatic isolated
distal DVT, all of whom were initially treated with
heparin, found that 3 months of VKA therapy prevented DVT extension and recurrent VTE (29% vs 0%,
P , .01).66 The evidence in support of parenteral anticoagulation and VKA therapy for isolated distal DVT,
which includes indirect evidence from patients with
acute proximal DVT and PE that is presented elsewhere in this article, is of moderate quality (there is
high-quality evidence that anticoagulation is effective, but uncertainty that benefits outweigh risks).
There have not been evaluations of alternatives to
full-dose anticoagulation of symptomatic isolated distal DVT, and it is possible that less-aggressive anticoagulant strategies may be adequate. Duration of
anticoagulation for isolated distal DVT is discussed in
section 3.1.
Recommendations
factors for extension (see text), we suggest serial
imaging of the deep veins for 2 weeks over initial anticoagulation (Grade 2C).
for extension (see text), we suggest initial anticoagulation over serial imaging of the deep
veins (Grade 2C).
repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding
are likely to choose initial anticoagulation over serial
imaging.
Recommendations
DVT (Grade 1B).
2.3.4. In patients with acute isolated distal
DVT of the leg who are managed with serial
imaging, we recommend no anticoagulation
if the thrombus does not extend (Grade 1B);
we suggest anticoagulation if the thrombus
extends but remains confined to the distal veins
(Grade 2C); we recommend anticoagulation if
the thrombus extends into the proximal veins
(Grade 1B).
Until !20 years ago, initiation of VKA therapy was
delayed until patients had received about 5 days of
heparin therapy, which resulted in patients remaining in the hospital until they had received !10 days
of heparin. Three randomized trials41,67,68 provided
moderate-quality evidence that early initiation of
VKA, with shortening of heparin therapy to !5 days,
is as effective as delayed initiation of VKA with about
a 10-day course of heparin (Table 4, Table S2). Shortening the duration of initial heparin therapy from
about 10 to 5 days is expected to have the added advantage of reducing the risk of heparin-induced thrombocytopenia.69 If the international normalized ratio
(INR) exceeds the therapeutic range (ie, INR . 3.0)
prematurely, it is acceptable to stop parenteral therapy
before the patient has received 5 days of treatment.
Recommendation
recommend early initiation of VKA (eg, same day
as parenteral therapy is started) over delayed
initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the
INR is 2.0 or above for at least 24 h (Grade 1B).
www.chestpubs.org
2.5 Choice of Initial Anticoagulant Regimen
in Patients With Proximal DVT
Initial anticoagulant regimens vary according to
the drug, the route of administration, and whether
dose is adjusted in response to laboratory tests of
coagulation. Six options are available for the initial
treatment of DVT: (1) SC LMWH without monitoring, (2) IV UFH with monitoring, (3) SC UFH given
based on weight initially, with monitoring, (4) SC UFH
given based on weight initially, without monitoring,
(5) SC fondaparinux given without monitoring, and
(6) rivaroxaban given orally. We considered the SC
UFH options as a single category because results were
similar in studies that used SC UFH with and without laboratory monitoring (Table 5, Tables S3-S5).
Rivaroxaban is used in the acute treatment of VTE
without initial parenteral therapy; studies of its use
for the acute treatment of VTE are reviewed under
long-term treatment of DVT (section 3.1) and PE
(section 6) of this article. Recommendations for dosing
and monitoring of IV UFH, SC UFH, and SC LMWH
are addressed in Garcia et al1 and Holbrook et al3
in these guidelines. Because LMWH, fondaparinux,
and rivaroxaban have substantial renal excretion, these
agents should be avoided (eg, use UFH instead) or
should be used with coagulation monitoring (test
selection is specific to each agent and requires expert
interpretation) in patients with marked renal impairment (eg, estimated creatinine clearance , 30 mL/min
[in a 70-year-old weighing 70 kg, a creatinine clearance of 30 mL/min corresponds to a serum creatinine of about 200 mmol/L (2.3 mg/dL) in a man and
175 mmol/L (2.0 mg/dL) in a woman] http://www.
nephron.com/cgi-bin/CGSIdefault.cgi).
LMWH Compared With IV UFH for the Initial
Treatment of DVT: A number of meta-analyses72-75
have summarized the trials addressing this question.
The evidence suggests that LMWH is associated with
decreased mortality, lower recurrence of VTE, and
decreased incidence of major bleeding compared
with IV UFH (Table 6, Table S6). However, the quality of supporting evidence is low due to a high risk of
bias in the primary studies, and evidence of publication bias in favor of LMWH. LMWH has the advantage over IV UFH that it is much easier to administer
(which makes outpatient treatment feasible) and
that it has a lower potential for heparin-induced
thrombocytopenia,69 but the disadvantage is that it
accumulates in patients with renal failure.
SC UFH Compared With LMWH for the Initial
Treatment of DVT: Four randomized trials have
compared SC UFH with SC LMWH (Table 6,
Tables S3-S5).70,71,76,77 This evidence suggests that
SC UFH is associated with a similar frequency of
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Table 4—[Recommendation 2.4] Summary of Findings: Early Warfarin (and Shorter Duration Heparin) vs Delayed
Warfarin (and Longer Duration Heparin) for Acute VTEa-d,41,67,68
Anticipated Absolute Effects
Outcomes
No. of Participants
Mortality
688 (3 studies), 3 moe
Recurrent VTE
688 (3 studies), 3 moe
Major bleeding
688 (3 studies), 3 moi
Quality of the
Evidence
(GRADE)
Relative
Effect (95%
CI)
Risk With Delayed Warfarin Risk Difference With Early Warfarin
Initiation (and Longer
Initiation (and Shorter Duration
Duration Heparin)
Heparin) (95% CI)
Moderatef,g due to
imprecision
Moderatef,g due to
imprecision
Highf,j,k
RR 0.9
(0.41-1.95)
RR 0.83
(0.4-1.74)
RR 1.48
(0.68-3.23)
24 per 1,000h
47 per 1,000h
16 per 1,000h
2 fewer per 1,000 (from 14 fewer
to 23 more)
to 35 more)
14 more per 1,000 (from 9 fewer
to 66 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk
(and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confidence in the estimate
of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may
change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect
and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of
abbreviations.
aMost patients had proximal DVT, some had isolated distal DVT, most DVT were symptomatic (asymptomatic DVT included in Hull et al41), and
few had PE (only included in Gallus et al67).
bThe early initiation of VKA was associated with a fewer number of days of heparin therapy (4.1 vs 9.5 in Gallus et al67; 5 vs 10 in Hull et al41) and a
fewer number of days of hospital stay (9.1 vs 13.0 in Gallus et al; 11.7 vs 14.7 in Hull et al; 11.9 vs 16.0 in Leroyer et al68).
cVKA therapy started within 1 day of starting heparin therapy (UFH in two studies and LMWH in one study).
dVKA therapy delayed for 4 to 10 d.
eOutcome assessment was at hospital discharge in the study by Gallus et al67 (although there was also extended follow-up) and 3 mo in the studies
by Hull et al41 and Leroyer et al.68
fPatients and investigators were not blinded in two studies (Gallus et al67 and Leroyer et al68) and were blinded in one study (Hull et al41). Concealment
was not clearly described but was probable in the three studies. Primary outcome appears to have been assessed after a shorter duration of followup in the shorter treatment arm of one study because of earlier discharge from hospital, and 20% of subjects in this study were excluded from the
final analysis postrandomization (Gallus et al).
gThe 95% CI on relative effect includes both clinically important benefit and clinically important harm.
hEvent rate corresponds to the median event rate in the included studies.
iBleeding was assessed early (in hospital or in the first 10 d) in two studies (Gallus et al67 and Hull et al41) and at 3 mo in one study (Leroyer et al68).
jIt is unclear whether bleeding was assessed at 10 d in all subjects or just while heparin was being administered, which could yield a biased estimate
in favor of short-duration therapy in one study (Hull et al41).
kBecause the shorter duration of heparin therapy is very unlikely to increase bleeding, the wide 95% CIs around the relative effect of shorter therapy
on risk of bleeding is not a major concern.
mortality, recurrent VTE, and major bleeding as
LMWH. However, the quality of the evidence is
moderate because of imprecision. LMWH has the
disadvantage of a higher cost but is more convenient to use (LMWH can be administered once daily
[see later discussion]), is more widely available for
use in outpatients, has a lower potential for heparininduced thrombocytopenia,69 and there is much
more experience with its use than with SC UFH.
Fondaparinux Compared With LMWH for the
Initial Treatment of DVT: The Matisse-DVT trial78
compared fondaparinux with LMWH for short-term
treatment of DVT (Table 7, Table S7). This study suggests that fondaparinux is associated with a similar
frequency of mortality, recurrent VTE, and major
bleeding as LMWH. However, the quality of the
evidence from this study was moderate because of
imprecision. Evidence that fondaparinux is effective
for the treatment of PE79 (section 5.4) supports the
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equivalence of fondaparinux to LMWH for the treatment of acute VTE.
Fondaparinux Compared With IV UFH for the Initial Treatment of DVT: In the absence of direct evidence in patients with DVT, indirect evidence in
patients with acute PE (section 5.4) suggests that
fondaparinux is equivalent to IV UFH.79 As noted
previously, we judge that fondaparinux and LMWH
are equivalent; fondaparinux also shares the advantages that LMWH has over IV UFH and the disadvantage that it is renally excreted (section 2.5). The
quality of the evidence regarding the comparison of
fondaparinux and UFH is moderate as, although
there is some indirectness, it is minor.
Fondaparinux Compared With SC UFH for the
Initial Treatment of DVT: There is no direct evidence
for this comparison in any patient population. Our
recommendation is based on our assessment that
Table 5—[Section 2.5.1] Summary of Findings: LMWH vs SC UFH for Initial Anticoagulation of Acute VTE70,71,76,77
No. of Participants (Studies),
Follow-up
Outcomes
All-cause
mortality
Recurrent VTE
1,566 (3 studies), 3 mo
Major bleeding
1,634 (4 studies), 3 mo
1,563 (3 studies), 3 mo
(GRADE)
Moderatea,b due to
imprecision
Moderatea,b due to
imprecision
Moderatea,b due to
imprecision
Relative Effect
(95% CI)
Risk With SC UFH
RR 1.1 (0.68-1.76)
33 per 1,000c
RR 0.87 (0.52-1.45)
42 per 1,000c
RR 1.27 (0.56-2.9)
16 per 1,000c
LMWH (95% CI)
3 more per 1,000 (from
7 fewer to 30 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI)
is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence
are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is
likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is very
likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are very
uncertain about the estimate. SC 5 subcutaneous. See Table 1 and 3 legends for expansion of abbreviations.
aIn the two largest trials (Prandoni et al,70 Kearon et al;71 87% of patients), allocation was concealed, outcome adjudicators and data analysts were
concealed, analysis was intention to treat, and there were no losses to follow-up.
bPrecision judged from the perspective of whether SC heparin is noninferior to LMWH. The total number of events and the total number of
participants were relatively low.
cEvent rate corresponds to the median event rate in the included studies.
fondaparinux and LMWH are equivalent and that
fondaparinux shares the advantages that LMWH has
over SC UFH (section 2.5). This recommendation
does not take into account difference in purchase
cost between SC UFH and fondaparinux and is based
on low-quality evidence.
Once- vs Twice-Daily Administration of LMWH
for Initial Treatment of DVT: Two meta-analyses80,81
summarized six studies comparing once-daily and
twice-daily administrations of the same LMWH.82-87
Table 8 and Table S8 summarize the findings of
five of these studies83-87 that had unconfounded comparisons. This evidence suggests that LMWH once
daily and twice daily are associated with similar mortality, recurrent VTE, and major bleeding. However,
the quality of the evidence is low because of imprecision and inconsistency. The sixth study that used
a lower total daily dose of LMWH with once-daily
compared with twice-daily administration (enoxaparin 1.5 mg/kg once daily vs 1.0 mg/kg bid; enoxaparin 2 mg/kg once daily is not used) suggested
that outcomes might be inferior with this once-daily
regimen.85
Table 6—[Section 2.5.1] Summary of Findings: LMWH vs IV UFH for Initial Anticoagulation of Acute VTE74
Outcomes
Follow-up
All-cause
mortality
Recurrent VTE
7,908 (17 studies), 3 mo
Major bleeding
6,910 (20 studies), 3 mo
7,976 (17 studies), 3 mo
(GRADE)
Relative Effect
(95% CI)
Lowa,b due to risk of bias, RR 0.79 (0.66-0.95)
publication bias
Lowa,b due to risk of bias, RR 0.72 (0.58-0.89)
publication bias
Lowa,b,d due to risk of bias, RR 0.67 (0.45-1)
publication bias
Risk With IV UFH
46 per 1,000c
55 per 1,000c
15 per 1,000c
LMWH (95% CI)
15 fewer per ,1000 (from
8 fewer to 0 more)
uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.
aOf the 20 trials, allocation was concealed in nine and was unclear whether concealed in the remaining 11. In 18 trials, outcome assessors were
blinded. Seven trials did not have any postrandomization exclusions or losses to follow-up. Ten trials reported the number of participants lost to
follow-up, which ranged from 1.0% to 12.7%. One trial did not report the drop-outs.
bInverted funnel plot very suggestive of publication bias. Many of the included studies are of small size, and all were funded by industry.
cEvent rate corresponds to the median event rate in the included studies.
dCI includes values suggesting significant benefit and no effect.
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Table 7—[Section 2.5.1] Summary of Findings: Fondaparinux vs LMWH for Initial Anticoagulation of Acute DVTa-c,78
Outcomes
Follow-up
(GRADE)
Relative Effect
(95% CI)
Risk With LMWH
Mortality
2,205 (1 study), 3 mo
RR 1.25 (0.8-1.97)
30 per 1,000
Recurrent VTE
2,205 (1 study), 3 mo
RR 0.96 (0.64-1.45)
41 per 1,000f
Major bleeding
2,205 (1 study), 3 mo
Moderated,e due to
imprecision
Moderated,e due to
imprecision
Moderated,e due to
imprecision
RR 0.93 (0.43-2.03)
12 per 1,000g
Fondaparinux (95% CI)
6 fewer to 29 more)
7 fewer to 12 more)
aAll patients had acute symptomatic DVT.
bFondaparinux 7.5 mg (5.0 mg in patients weighing , 50 kg and 10.0 mg in patients weighing . 100 kg) SC once daily for at least 5 d and until VKAs
induced an INR . 2.0.
cEnoxaparin 1 mg/kg of body weight SC bid for at least 5 d and until VKAs induced an INR . 2.0.
dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Analysis excluded 0.6% of randomized
patients. Not stopped early for benefit.
eCI includes values suggesting no effect and values suggesting either benefit or harm; relatively low number of events.
fFive fatal VTE in fondaparinux group and five fatal VTE in LMWH group.
g Twelve patients in the fondaparinux group and 13 in the LMWH group had a major bleeding event during the initial period (7 d). Of these, two
in the fondaparinux group and none in the LMWH group were fatal.
Recommendations
(Grade 2C) and over SC UFH (Grade 2B for LMWH;
Grade 2C for fondaparinux).
Table 8—[Section 2.5.2] Summary of Findings: LMWH Once vs Twice Daily for Initial Anticoagulation of Acute VTEa,b,81
Outcomes
No. of Participants
(GRADE)
Relative Effect
(95% CI)
Risk With
Twice Daily
LMWH Once Daily (95% CI)
Mortality
1,261 (3 studies), 3 mo
RR 1.05 (0.57-1.94)
31 per 1,000
VTE recurrence
1,261 (3 studies), 3 mo
RR 0.86 (0.52-1.42)
49 per 1,000
Major bleeding
1,522 (5 studies), 10 d
Lowc-e due to inconsistency
and imprecision
Lowc,e,f due to inconsistency
and imprecision
Moderatec,e due to
imprecision
RR 1.13 (0.48-2.66)
12 per 1,000
6 fewer to 20 more)
aOf the five included studies, one included patients with PE and DVT and four included only patients with DVT. All studies addressed the initial
management of VTE.
bThe five included studies used four brands of LMWH (enoxaparin, tinzaparin, dalteparin, and nadroparin). In Merli et al,85 enoxaparin 1 mg/kg bid
was compared with 1.5 mg/kg once daily. Holmström et al84 adjusted the dose to anti-Xa levels, which resulted in different daily doses after a number of
days. In the remaining studies, the dose of the once-daily administration was double the dose of the twice-daily administration (equal total daily dose).
cAll included studies concealed allocation. Two studies had a double-blind design, and two others were single blind. One study did not mention
blinding. Intention to treat likely used in all studies. Participants were lost to follow-up in only two studies (0.3% and 2.2%).
dI2 5 37%; point effect estimate in favor of twice-daily dose in Merli et al85 and in favor of once-daily dose in Charbonnier et al.83
eImprecision judged relative to no difference.
fI2 5 65%; point effect estimate in favor of twice-daily dose in Merli et al85 and in favor of once-daily dose in Charbonnier.83
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2.6 Initial Treatment With Rivaroxaban
vs Parenteral Therapy
One trial directly compared short- and long-term
rivaroxaban (without initial parenteral anticoagulation) with parenteral anticoagulation (LMWH) and
VKA in patients with acute DVT.88 The findings of
this study and associated recommendations are presented in section 3.3.
2.7 At-Home vs In-Hospital Initial Treatment of DVT
One trial of 201 patients directly compared outpatient and inpatient administration of the same initial
anticoagulant regimen (three LMWH preparations were
used); there were few recurrent VTE and major bleeds
in each group.89 A number of trials90-94 have compared
LMWH administered at home (without hospital admission or after early discharge) in a substantial proportion
of patients, with IV UFH administered in the hospital
(Table 9, Table S9). This evidence suggests that home
treatment is not associated with an increase in mortality,
recurrent VTE, or major bleeding and may be associated with improved outcomes. However, the quality
of the evidence is moderate because of indirectness
(patients were not explicitly randomized to home
therapy in most studies) and imprecision.
Health economic evaluations that have assessed
initial treatment of DVT at home, although they have
weaknesses (eg, industry funded, not derived from
trials in which LMWH was used both in the hospital
and at home, short time horizon (ie, " 3 months), and
limited use of sensitivity analyses), all conclude that
home treatment is cost-saving (about US $500-$2,500
per patient).95-101
Recommendation
whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Grade 1B).
adequacy of the following home circumstances: wellmaintained living conditions, strong support from
family or friends, phone access, and ability to quickly
return to hospital if there is deterioration. It is also
www.chestpubs.org
conditional on the patient feeling well enough to be
treated at home (eg, does not have severe leg symptoms or comorbidity).
2.8 Treatment Strategies of Thrombus
Removal for Acute DVT
Treatments that actively remove thrombus in patients
with acute DVT have the potential to reduce acute
symptoms and the risk of developing PTS. Patients
with DVT that involves the iliac and common femoral
veins are at highest risk for PTS and, therefore, are
the subset with the greatest potential to benefit from
thrombus removal strategies.102 Thrombus removal
strategies are indicated in patients with the very rare
complication of impending venous gangrene despite
optimal anticoagulant therapy; such patients are not
the focus of the following sections. A recent trial that
randomized 183 patients with proximal DVT to percutaneous endovascular intervention or to anticoagulant therapy alone reported reduced acute symptoms,
hospital stay, recurrent VTE, and PTS at 6 months in
the thrombus removal group.103 This trial, which had a
high potential for bias (randomization not described,
no blinding), is not considered further because it was
not possible to determine outcomes in patients treated
with mechanical thrombectomy alone and in those
treated with thrombolytic therapy.
2.9 Catheter-Directed Thrombolysis for Acute DVT
The rationale for catheter-directed thrombolysis
(CDT) is that compared with systemic thrombolysis, it will achieve lysis of thrombus more rapidly and
with lower doses of thrombolytic therapy, thereby
reducing serious bleeding. The addition of mechanical thrombus fragmentation (collectively referred to
as pharmacomechanical thrombolysis) with or without aspiration can further reduce the dose of thrombolytic therapy and shorten the procedure.104
One randomized trial of CDT has been completed,105 and a second has reported short-term
outcomes (but not the development of PTS).106,107
Table 10 and Table S10 present the combined findings from these studies (see also Tables S11 and S12).
This evidence suggests that CDT may reduce PTS
and improve quality of life without being associated
with an unacceptable increase in bleeding. However,
the quality of evidence is low for mortality, recurrent VTE, and major bleeding because of very serious
imprecision, and is low for PTS because of indirectness (ie, use of surrogate outcome [PTS has yet to be
measured directly during follow-up]).
In addition to the two randomized trials,105,106 findings
of observational studies suggest that CDT improves
venous patency and preserves venous valve function
(Tables S11 and S12). Use of CDT, however, requires
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Table 9—[Section 2.7] Summary of Findings: Home Treatment vs Hospital Treatment of Acute DVTa-d,442
Outcomes
Mortality
Recurrent VTE
Major bleeding
QOL
Risk With Hospital
Treatment
Home Treatment (95% CI)
No. of Participants
Quality of the
Evidence(GRADE)
Relative Effect
(95% CI)
1,708 (6 studies),
3 mo
1,708 (6 studies),
3 mo
1,708 (6 studies),
3 mo
0 (3 studiesh),
3 mo
Lowc-f due to indirectness and
imprecision
Moderatec-e due to indirectness
RR 0.72 (0.45-1.15)
46 per 1,000
RR 0.61 (0.42-0.9)
74 per 1,000
Moderatec-e,g due to indirectness RR 0.67 (0.33-1.36)
Lowi-k due to indirectness and
imprecision
Not estimable
21 per 1,000
25 fewer to 7 more)
14 fewer to 8 more)
…
h
aStudies included in the systematic review should have recruited patients whose home circumstances were adequate.
bAll studies included patients with lower-extremity DVT and excluded patients with suspected or confirmed PE. Studies also excluded patients who
were pregnant.
cFour studies had partial hospital treatment of many in the home arm: Koopman et al92 (mean hospital stay, 2.7 in home arm vs 8.1 d in hospital
arm), Levine et al93 (2.1 vs 6.5 d), Boccalon et al89 (1 vs 9.6 d), and Ramacciotti et al94 (3 vs 7 d). In Daskalopoulos et al,91 there was no hospital stay
at all in the home group. Chong et al90 did not report duration of hospital stay.
dOnly one study (Boccalon et al89) used LMWH in both treatment arms. Remaining studies used UFH in the inpatient arm and LMWH in the
outpatient arm.
eOut of six studies, allocation was clearly concealed in three (unclear in remaining three), outcome adjudicators were blinded in the two largest
studies (unclear in remaining four), loss to follow-up was significant in only one small study, intention-to-treat analysis was conducted in four
(unclear in remaining two), and no study was stopped early for benefit. Overall, the judgment was that these limitations would not warrant
downgrading of quality; it has already been downgraded by at least one level based on other factors.
fThe CI includes values suggesting benefit and harm.
gJudged as precise based on the narrow CI around absolute effect.
hBäckman et al95 reported evaluation of health-related QOL using the EQ-5D. They found no differences in mean QOL scores or in the proportion
of patients showing improvement in self-rated health state. Koopman et al92 evaluated health-related QOL using the Medical Outcome Study Short
Form-20 and an adapted version of the Rotterdam Symptom Checklist. The changes over time were similar in both groups, except that the patients
receiving LMWH had better scores for physical activity (P 5 .002) and social functioning (P 5 .001) at the end of the initial treatment. The authors
did not report enough data to assess precision and clinical significance of results. O’Brien et al96 assessed changes in QOL using the Medical
Outcome Study Short Form-36 in 300 patients participating in Levine et al.93 They found that the change in scores from baseline to day 7 was not
significantly different between the treatment groups for seven of the eight domains. The one exception was the domain of social functioning, where
a greater improvement was observed for the outpatient group.
iPotential inconsistency as Bäckman et al95 showed no effect, whereas Koopman et al92 and O’Brien et al96 showed potential benefit.
jTwo of the three studies had partial hospital treatment of many in the home arm: Koopman et al92 (mean hospital stay, 2.7 in home arm vs 8.1 d in
hospital arm) and Levine et al93 (2.1 vs 6.5 d).
kNot able to evaluate, but imprecision is possible. Taken together with the potential inconsistency, we downgraded the quality of evidence by one level.
substantial resources and expertise. Patients who are
most likely to benefit from CDT have iliofemoral DVT,
symptoms for , 14 days, good functional status, life
expectancy of ! 1 year, and a low risk of bleeding
(Table 11). Because the balance of risks and benefits
with CDT is uncertain, anticoagulant therapy alone is an
acceptable alternative to CDT in all patients with acute
DVT who do not have impending venous gangrene.
There is no single standardized approach to performing CDT or pharmacomechanical thrombolysis.
If these interventions are performed, the technique
used will vary with local resources and expertise.
If CDT has been successful but there are residual
lesions in the common femoral or more proximal
veins, balloon angioplasty and stenting often are used
to relieve obstruction. There are inadequate data to
e440S
assess the benefit or risk of inserting an IVC filter in
patients who have CDT performed (recommended
by manufacturer with some endovascular devices and
techniques, whereas not with others). Percutaneous
mechanical venous thrombectomy without concomitant thrombolysis has not been evaluated in randomized trials, and its use is discouraged because small
retrospective studies suggest that it often fails to
remove much of the thrombus115,116 and is associated
with a high risk of PE.117,118
Recommendation
over CDT (Grade 2C).
Table 10—[Section 2.9] Summary of Findings: CDT vs No CDT for Extensive Acute DVT of the Lega,b,105,106
Outcomes
No. of Participants
Quality of the
Evidence (GRADE)
Mortality
153 (2 studies), 3 mo
Nonfatal recurrent VTE
153 (1 study), 3 mo
Nonfatal major bleeding
153 (2 studies), 7 d
PTS
(complete lysis on
venography [Elsharawy
et al73]; patency on
ultrasound and air
plethysmography
[Enden et al74])
QOL
(SF-12, HUI Mark version
2/3 questionnaires)
138 (2 studies), 2 y
Lowc,d due to
imprecision
Lowc,d due to
imprecision
Lowc,d due to
imprecision
Moderatec,g due
to indirectness
98 (1 studyj), 16 mo
Lowk,l
Risk With
No CDT
CDT (95% CI)
RR 0.14 (0.01-2.71)
39 per 1,000e
RR 0.35 (0-8.09)
48 per 1,000f
RR 2.00 (0.19-19.46)
29 per 1,0006,7
RR 0.46 (0-0.79)
588 per 1,000h
123 fewer to 588 fewer)i
Relative Effect
(95% CI)
See footnotem
uncertain about the estimate. HUI 5 Health Utilities Index; SF-12 5 Medical Outcomes Survey Short Form-12; VETO 5 Venous Thrombosis
Outcomes. See Table 1 and 3 legends for expansion of other abbreviations.
aIn selected patients with extensive acute proximal DVT (eg, iliofemoral DVT, symptoms for , 14 d, good functional status, life expectancy ! 1 y)
who have a low risk of bleeding.
bAll patients prescribed anticoagulants per protocol, but the intervention group receives CDT in addition to anticoagulation.
cAllocation was concealed in Enden et al106 but unclear in Elsharawy et al.105 Outcome assessor blinded in both studies. Follow-up rates were 87%
in Enden et al and 100% in Elsharawy et al. Neither of the studies was stopped early for benefit.
dCI includes values suggesting both benefit and harm.
eThree control patients died of cancer.
fBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.108
gSurrogate outcome: absence of patency at 6 mo in Enden et al106 study; absence of complete lysis at 6 mo in Elsharawy et al105 study.
hThis estimate is based on the findings of the VETO study.102 This probably underestimates PTS baseline risk given that overall, 52% of patients
reported the current use of compression stockings during study follow-up.
iSevere PTS: assuming the same RR of 0.46 and a baseline risk of 13.8%,102 the absolute reduction is 75 fewer severe PTS per 1,000 (from 29 fewer
to 138 fewer) over 2 y.
jCamerota et al.109
kParticipation rate was 65%.
lRecall was used to measure QOL prior to the thrombotic event; we did not consider these measurements.
mAt the initial follow-up (mean, 16 mo), patients treated with CDT reported a trend toward a higher mental summary scale (P 5 .087) and improved
HUI (P 5 .078). They reported better overall role physical functioning (P 5 .046), less stigma (P 5 .033), less health distress (P 5 .022), and fewer
overall symptoms (P 5 .006) compared with patients who were treated with anticoagulation alone.
Remarks: Patients who are most likely to benefit
from CDT (see text) and attach a high value to
prevention of PTS and a lower value to the initial
complexity, cost, and risk of bleeding with CDT
are likely to choose CDT over anticoagulation alone.
2.10 Systemic Thrombolytic Therapy for Acute DVT
Many trials of systemic thrombolysis for the treatment of DVT assessed early lysis, often reported
bleeding, but rarely reported recurrent VTE or
development of PTS (Table S13 and S14).119-137
A meta-analysis138 summarized the findings of trials
that assessed mortality, recurrent VTE, major
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bleeding, and PTS (Table 12, Table S15). This evidence suggests that systemic thrombolysis has the
potential to reduce PTS at the expense of an increase
in major bleeding. However, the overall quality of
this evidence is low because of imprecision and risk
of bias.
There have been no direct comparisons of different
thrombolytic agents; however, prolonged infusions of
streptokinase that were used predominantly in the
earlier studies appear to be associated with higher
bleeding rates than other regimens. No randomized trial has compared systemic thrombolysis with
CDT, but a single-center, retrospective study127 suggested that systemic thrombolysis achieves less
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Table 11—[Section 2.9, 2.10, 5.6, 9.2] Risk Factors
for Bleeding With and Contraindications to Use of
Thrombolytic Therapy (Both Systemic and Locally
Administered)
Major contraindicationsa
Structural intracranial disease
Previous intracranial hemorrhage
Ischemic stroke within 3 mo
Active bleeding
Recent brain or spinal surgery
Recent head trauma with fracture or brain injury
Bleeding diathesis
Relative contraindicationsb
Systolic BP . 180 mm Hg
Diastolic BP . 110 mm Hg
Recent bleeding (nonintracranial)
Recent surgery
Recent invasive procedure
Ischemic stroke more that 3 mo previously
Anticoagulation (eg, VKA therapy)
Traumatic cardiopulmonary resuscitation
Pericarditis or pericardial fluid
Diabetic retinopathy
Pregnancy
Age . 75 y
Low body weight (eg, , 60 kg)
Female sex
Black race
Among 32,000 Medicare patients (! 65 y) with myocardial infarction who were treated with thrombolytic therapy, the following factors were independently associated with intracranial hemorrhage:
age ! 75 y (OR, 1.6), black race (OR, 1.6), female sex (OR, 1.4),
previous stroke (OR, 1.5), systolic BP ! 160 mm Hg (OR, 1.8),
women weighing " 65 kg or men weighing " 80 kg (OR, 1.5), and
INR . 4 (OR, 2.2).110 The rate of intracranial hemorrhage increased
from 0.7% with none or one of these risk factors to 4.1% with five or
more of these risk factors. Among 32,000 patients with myocardial
infarction who were treated with thrombolytic therapy in five clinical trials, the following factors were independently associated with
moderate or severe bleeding: older age (OR, 1.04 per year), black race
(OR, 1.4), female sex (OR, 1.5), hypertension (OR, 1.2), and lower
weight (OR, 0.99/kg).111 We estimated that systemic thrombolytic
therapy is associated with a relative risk of major bleeding of 3.5
within 35 d (RR, !7 for intracranial bleeding); about three-fourths
of the excess of major bleeds with thrombolytic therapy occur in the
first 24 h.112 See Table 1 legend for expansion of abbreviations.
aThe presence of major contraindications usually precludes use of
thrombolytic therapy and, consequently, these factors have not been
well studied as risk factors for bleeding associated with thrombolytic
therapy. The factors listed in this table are consistent with other
recommendations for the use of thrombolytic therapy in patients with
PE.72,259,260,454 104,111,113,114
bRisk factors for bleeding during anticoagulant therapy noted in
Table 10 that are not included in this table are also likely to be
relative contraindications to thrombolytic therapy. The increase in
bleeding associated with a risk factor will vary with (1) severity of the
risk factor (eg, extent of trauma or recent surgery) and (2) temporal
relationships (eg, interval from surgery or a previous bleeding episode
believed to decrease markedly after !2 wk). Risk factors for bleeding
at critical sites (eg, intracranial, intraocular) or noncompressible sites
are stronger contraindications for thrombolytic therapy.
lysis (31% vs 50%) and less preservation of valve
function (13% vs 44%) (Tables S13 and S14), and
the higher doses of thrombolytic agent used with
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systemic thrombolysis are expected to be associated with a higher risk of nonprocedure-related
bleeding.
We believe that systemic thrombolysis should
be considered only in patients who meet all of
the following criteria: iliofemoral DVT, symptoms
for , 14 days, good functional status, life expectancy of ! 1 year, and low risk of bleeding (Table 11).
Based on low-quality evidence of greater effectiveness and less bleeding, if resources and expertise
are available to perform CDT, we consider it the
preferable approach. Because the balance of risks
and benefits with systemic thrombolysis is uncertain,
and particularly because of concerns about major
bleeding, anticoagulant therapy alone is an acceptable alternative to systemic thrombolysis in all patients
with acute DVT who do not have impending venous
gangrene.
Recommendation
systemic thrombolytic therapy (see text), who do not
have access to CDT, and who attach a high value
to prevention of PTS and a lower value to the initial
thrombolytic therapy are likely to choose systemic
2.11 Operative Venous Thrombectomy
for Acute DVT
Operative venous thrombectomy, with contemporary operative techniques140 and more effective anticoagulant regimens, appears to achieve improved
outcomes compared with earlier reports.141,142 A single
small randomized trial with extended follow-up compared iliofemoral venous thrombectomy with a temporary arteriovenous fistula plus anticoagulation with
anticoagulation alone.143-145 Results at 6 months, 5 years,
and 10 years suggested improved iliac vein patency,
less leg swelling, and fewer leg ulcers with thrombectomy (Table 13, Tables S16-S18).143-145 Evidence
from this trial is of low quality because of imprecision and risk of bias.
We believe that operative venous thrombectomy should be considered only if all of the
following criteria are met: iliofemoral DVT, symptoms for , 7 days (criterion used in the single
randomized trial), good functional status, life expectancy of ! 1 year, and both resources and expertise
are available. Based on low-quality evidence of
greater effectiveness and less bleeding, we consider
Table 12—[Section 2.10] Summary of Findings: Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg138
Mortality
Risk With No
Systemic Lysis
Systemic Lysis (95% CI)
RR 0.86 (0.27-2.68)
21 per 1,000
Lowd,e,g due to imprecision
RR 1.28 (0.25-6.68)
48 per 1,000h
Moderatec,d,i due to
imprecision
Lowd,e,l,m due to risk of bias
and imprecision
…
RR 1.84 (0.94-3.59)
29 per 1,000h,j
RR 0.71 (0.49-1.04)
588 per 1,000n
…
…
2 fewer to 75 more)
300 fewer to 24 more)o
…
No. of Participants
(GRADE)
Relative Effect
(95% CI)
688 (5 studies), 3 moa
Lowb-e due to imprecision
Outcomes
Nonfatal
687 (3 studies), 3 mof
recurrent VTE
Nonfatal major 688 (10 studies), 3 mof
bleeding
PTS
678 (2 studies), 2 yk
QOL not
measured
…
uncertain about the estimate. See Table 1, 3, and 10 legends for expansion of abbreviations.
aRange of follow-up in included studies, 1 to 72 mo.
bAllocation was concealed in three of five studies. Follow-up inadequate in one of five studies (Common et al139). Excluding this study from the
analysis does not change the effect estimate. All studies had blinded outcome assessors. None of the studies used a placebo control.
cThe population of one study (Schulman et al131) comprised patients with calf vein thrombosis.
dInterventions varied across studies with regard to agent (eg, tissue plasminogen activator, streptokinase, urokinase), dose, use of the pedal vein
administration, duration of treatment, and concomitant drugs (eg, steroids). However, we did not downgrade for indirectness given that there was
no standard regimen and all analyses showed no heterogeneity in results.
eCI included both no effect and a potentially significant effect.
fRange of follow-up in included studies, 1 to 30 d.
gAllocation was concealed in two of three studies. Follow-up adequate in all studies. All studies had blinded outcome assessors. None of the studies
used a placebo control.
hBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.108
iAllocation was concealed in seven of 10 studies. Follow-up inadequate in one of 10 studies (Common et al139). Excluding this study from
the analysis does not affect the effect estimate. All studies had blinded outcome assessors. Two studies used placebo (Turpie et al135 and
Verhaeghe et al136).
jOnly 4% of all major bleeding events were intracranial bleeds.
kRange of follow-up in included studies, 1 to 6 y.
lAllocation was concealed in two of two studies. Follow-up adequate in both studies. Both studies had blinded outcome assessors. Neither study
used placebo control.
mNo use of a standardized validated tool reported.
nThis estimate is based on the findings of the VETO study.102 This probably underestimates PTS baseline risk, given that overall, 52% of patients
oSevere PTS: Assuming the same RR of 0.71 and a baseline risk of 13.8%,102 the absolute reduction is 40 fewer severe PTS per 1,000 (from 70 fewer
to 6 more) over 2 y.
CDT preferable to the operative venous thrombectomy approach.
Recommendation
operative venous thrombectomy (Grade 2C).
2.12 Anticoagulation in Patients Who Have Had
Any Method of Thrombus Removal Performed
There are no randomized trials or observational
studies that have compared different anticoagulant
regimens or durations of therapy in patients with
acute proximal DVT of the leg who have had any
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method of thrombus removal (including systemic
thrombolysis). Mechanical components of these
procedures are associated with a high early risk of
early recurrent thrombosis, and thrombus removal
is not known to alter the long-term risk of recurrent
VTE. We used evidence from patients with DVT
who did not have thrombus removal to guide anticoagulant decisions in those who had thrombus
removal. This evidence is rated down to moderate
quality because of its indirectness in this patient
population.
Recommendation
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Table 13—[Section 2.11] Summary of Findings: Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive
Acute DVT of the Lega,144
Outcomes
Mortality not
reported
Nonfatal
recurrent
VTE
Nonfatal major
bleeding
PTS
QOL not
measured
No. of Participants
Quality of the
Evidence (GRADE)
…
Relative Effect
(95% CI)
Risk With No Surgical
Thrombectomy
Risk Difference With Surgical
Thrombectomy (95% CI)
…
…
…
…
51 (1 study), 3 mo
Lowb,c due to risk of bias
and imprecision
RR 0.37
(0.02-8.75)
48 per 1,000d,e
to 372 more)
51 (1 study), 3 mo
Lowb,c due to risk of bias
and imprecision
Lowf,g due to risk of bias
and imprecision
…
Not estimable
(no events)
RR 0.63
(0.44-0.9)h
…
…
-
51 (1 study), 2 y
…
588 per 1,000i
…
218 fewer per 1,000 (from 59
fewer to 329 fewer)j
…
uncertain about the estimate. See Table 1, 3 and 10 legends for expansion of abbreviations.
aThe study included patients with DVT with symptoms of leg swelling not exceeding 7 d and a proximal extension of the thrombus above the
inguinal ligament but not into the vena cava.
bNot clear whether allocation was concealed. No blinding reported. Not clear whether analysis was intention to treat. Follow-up rate was 88% at
6 mo. Study not stopped early for benefit.
cCI includes values suggesting either harm or benefit.
dBaseline risks for nonfatal recurrent VTE derived from Douketis et al.108
eOne event was a symptomatic PE.
fIn addition to other study limitations, this outcome was assessed by those who did the surgery and anticoagulation. No standardized tool was used.
One surgical patient had an amputation secondary to venous gangrene and was not counted in the PTS assessment.
gFew number of events. This warrants rating down the quality of evidence by a second level when considered along with study limitations.
hThe RR is based on the 6-mo data.
iThis estimate is based on the findings of the VETO study.102 This probably underestimates PTS baseline risk, given that overall, 52% of patients
jSevere PTS: assuming the same RR of 0.63 and a baseline risk of 13.8% over 2 y,102 the absolute reduction is 51 fewer severe PTS per 1,000 (from
14 fewer to 77 fewer) over 2 y.
the same intensity and duration of anticoagulant therapy as in similar patients who do not
undergo thrombosis removal (Grade 1B).
2.13 Vena Caval Filters for the Initial
Treatment of DVT
No randomized trial or prospective observational
study has evaluated IVC filters as sole therapy (ie,
without concurrent anticoagulation) in patients with
DVT. A single, large, randomized controlled trial
evaluated permanent IVC filter insertion as an
adjunct to anticoagulant therapy in patients with
acute DVT who were considered to be at high risk
for PE (Table 14, Table S19). The findings at 2 years146
and 8 years149 of follow-up, suggest that IVC filters
increase the risk of recurrent DVT, reduce the risk
of PE, do not alter the combined frequency of DVT
and PE (ie, recurrent VTE), do not increase the risk
of PTS, and do not alter mortality.
In assessing the role of an IVC filter in patients
who cannot receive anticoagulant therapy (eg, actively
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bleeding), we assume that the relative risk of outcomes will be the same as in patients who received
anticoagulant therapy in the Prevention du Risque
d’Embolie Pulmonaire par Interruption Cave (PREPIC)
study. However, their absolute rate of symptomatic
PE and recurrent DVT will be higher compared with
the PREPIC participants who were prescribed anticoagulants. A comprehensive review of mostly retrospective case series of IVC filter insertions (6,500 patients
in 89 reports) suggested that venous thrombosis at
the site of filter insertion occurs in !10% of patients
and that filters can be placed above the renal veins and
in the superior vena cava if necessary.150 A prospective observational study also suggested that symptomatic VTE and asymptomatic filter thrombosis are
common,151 and a systematic review suggested that
the prevalence of PTS may be increased152 in patients
with permanent IVC filters. A small single-center
randomized trial suggested a higher complication
rate with the Trapease compared with the Greenfield permanent filter.153
Table 14—[Section 2.13] Summary of Findings: Vena Cava Filter vs No Vena Cava Filter for Acute Proximal DVT of
the Leg Treated With Anticoagulationa,b,146,443
Outcomes
No. of Participants
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
Risk With No
vena cava Filters
Risk Difference With Vena
cava Filters (95% CI)
Mortality
400 (1 study), 8 y
304 (1 study), 8 y
Recurrent DVT
310 (1 study), 8 y
Major bleeding
337 (1 study), 8 y
PTS
308 (1 study), 8 y
26 fewer per 1,000
(from 113 fewer to 82 more)
89 fewer per 1,000
(from 21 fewer to 121 fewer)
82 more per 1,000
31 fewer per 1,000
91 fewer per 1,000
Complications
379 (1 study), 2 y
RR 0.95
(0.78-1.16)e
RR 0.41
(0.2-0.86)g
RR 1.3
(0.93-1.82)h
RR 0.83
(0.52-1.34)i
RR 0.87
(0.66-1.13)
…
515 per 1,000
Symptomatic PE
Moderatec,d due to
imprecision
Moderatec,f due to
imprecision
Moderatec,f due to
imprecision
Moderatec,d due to
imprecision
Lowd,j due to risk of
bias and imprecision
Moderatef due to
imprecision
…
QOL not reported
…
…
151 per 1,000
273 per 1,000
185 per 1,000
699 per 1,000
…
k
…
…
uncertain about the estimate. PREPIC 5 Prevention du Risque d’Embolie Pulmonaire par Interruption Cave. See Table 1 and 3 legends for
expansion of other abbreviations.
aAnticoagulation consisted of LMWH or UFH initially (according to a 2 3 2 factorial design) followed by oral anticoagulation for at least 3 mo.
bFour types of permanent vena cava filters were used: Vena Tech LGM (B. Braun Melsugen AG), titanium Greenfield (Boston Scientific Corporation),
Cardial (C.R. Bard, Inc), and Bird’s Nest (Cook Group Incorporated).
cAllocation was concealed. Data collectors and outcome adjudicators were blinded. Intention-to-treat analysis. Data missing for 4% at 2 y and 1%
at 8 y. Enrollment was stopped at 400 instead of targeted 800 because of slow recruitment.
dCI includes both negligible effect and appreciable benefit or appreciable harm.
eRR, 1.0 (95% CI, 0.29-3.4) at 12 d; RR, 1.08 (95% CI, 0.73-1.58) at 2 y.
fSmall number of events.
gRR. 0.23 (95% CI, 0.05-1.05) at 12 d (both symptomatic and asymptomatic PE). RR, 0.54 (0.21-1.41) at 2 y (symptomatic PE).
hRR, 1.78 (95% CI, 1.09-2.94) at 2 y.
iRR, 1.5 (95% CI, 0.54-4.14) at 12 d. RR, 0.74 (95% CI, 0.41-1.36) at 2 y.
jNo standardized validated tool used to measure PTS.
kNo complications directly related to the filter or its insertion reported in the PREPIC trial.146 Mismetti et al147 (prospective study) reported an
incidence of 3.2% (excluding filter tilting and puncture site hematoma) among 220 patients receiving a retrievable vena cava filter for secondary
prevention of VTE, whereas Athanasoulis et al148 (retrospective study) reported an incidence of 0.3% for major complications among 1,731 patients
receiving vena cava filters predominantly for secondary prevention of VTE.
If an IVC filter is indicated in a patient with
acute DVT or PE because anticoagulant therapy is
temporarily contraindicated (eg, active bleeding),
there is the option of inserting a retrievable filter
and removing it when it is safe to start anticoagulant therapy. However, most retrievable filters are
not removed; retrievable filters that are not removed
may have a higher long-term complication rate than
permanent filters, and there currently is no good
evidence that retrievable IVC filters improve patient
outcomes.104,147,154,155
Insertion of an IVC filter does not eliminate the
risk of PE and increases the risk of DVT (Table 14,
Table S19). Consequently, we suggest that patients
who have an IVC filter inserted should receive a conventional course of anticoagulation (eg, parenteral
and long-term anticoagulation) if the contraindication to anticoagulation resolves. Such patients should
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be treated for the same length of time as if the same
patient had not had an IVC filter inserted (see section
3.1). The duration of anticoagulation, therefore, will
vary according to whether the DVT was provoked by
a temporary risk factor, was unprovoked, or was associated with cancer, and may be influenced by the
patient’s ongoing risk of bleeding and preferences.
Our recommendation to treat patients with an IVC
filter with anticoagulants when contraindications to
anticoagulation resolve is weaker than for anticoagulation of most patients with VTE because the risks of
bleeding may remain elevated, and the patient’s risk
of recurrence is expected to be lower if the acute
episode of thrombosis occurred remotely. The evidence
for IVC filter use in patients with acute proximal DVT
who cannot be treated with anticoagulation is moderate because of serious imprecision and indirectness
(ie, extrapolated from the PREPIC study in which
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patients were routinely treated with anticoagulants;
this indirectness, however, is minor).
Recommendations
recommend against the use of an IVC filter in
addition to anticoagulants (Grade 1B).
2.13.2. In patients with acute proximal DVT of the
leg and contraindication to anticoagulation, we
recommend the use of an IVC filter (Grade 1B).
the leg and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional
course of anticoagulant therapy if their risk of
bleeding resolves (Grade 2B).
anticoagulation.
2.14 Early Ambulation of Patients With Acute DVT
Treatment of acute DVT with bed rest and anticoagulation (originally IV UFH) has given way to early
mobilization with anticoagulation (often administered
SC). Two meta-analyses156,157 summarized evidence
from four relevant trials (Table 15, Tables S20-S22).
This evidence is of low quality because of risk of bias
and imprecision. We suggest early ambulation (eg, without a period of bed rest) when feasible because of its
potential to decrease PTS and improve quality of life.
Recommendation
(Grade 2C).
Remarks: If edema and pain are severe, ambulation
may need to be deferred. As per section 4.1, we recommend the use of compression therapy in these
patients.
Table 15—[Section 2.14] Summary of Findings: Early Ambulation vs Delayed Ambulation for Acute DVT
of the Lega,b,273,309,310,314,315
Outcomes
No. of Participants
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
Risk With Delayed
Ambulation
Risk Difference With Early
Ambulation (95% CI)
Mortality
385 (4 studies), 3 moc
385 (4 studies), 4-12 d
RR 1.3
(0.23-7.55)
RR 1.16
(0.66-2.05)
11 per 1,000
PE (symptomatic or
asymptomatic)
QOL questionnaire in
chronic limb venous
insufficiency (CIVIQ)
PTS Villata-Prandoni
scores (value, . 5)
Lowd,e due to risk of
bias, imprecision
Lowd-g due to risk of
bias, imprecision
Lowh,i due to risk of
bias, indirectness
3 more per 1,000
19 more per 1,000
See footnotej
Lowe,h due to risk of
bias, imprecision
RR 0.66
(0.42-1.03)
53 (1 study), 2 y
37 (1 study), 2 y
118 per 1,000
400 per 1,000
136 fewer per 1,000
are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research
is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is
very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are
very uncertain about the estimate. CIVIQ 5 ChronIc Venous Insufficiency Questionnaire. See Table 1 and 3 legends for expansion of other
abbreviations.
aTwo of four eligible studies excluded patients with symptomatic PE; in the third study, 24% of participants had symptomatic PE at baseline. It was
not clear whether the fourth study excluded patients with symptomatic PE.
bIn two of four eligible trials, all patients received early compression therapy (bandages or stockings). In the two other trials, only patients randomized
to early ambulation received early compression therapy.
cThree studies reporting acute-phase mortality reported no deaths.
dConcealment of allocation was reported in one of four studies; blinding of outcome assessors was reported in two of four studies; intention-to-treat
analysis reported in two of four studies. Follow-up was 97% to 100%. In two of four trials, only patients randomized to early ambulation received
early compression therapy (bandages or stockings). In the other two trials, all patients received early compression therapy.
eCI includes both values of clinically significant benefit and values of clinically significant harms.
fPE assessed as both symptomatic and asymptomatic PE.
gFunnel plot reported as not asymmetrical by Aissaoui et al.156
hConcealment of allocation was not reported; outcome assessors were not blinded for this outcome. Seventy percent follow-up rate; compression
stockings used on patients with early mobilization but not in patients with delayed mobilization.
iNo explanation was provided.
jPsychologic and overall somatic QOL did not differ significantly between the treatment groups, whereas DVT-related items, especially those
reflecting the ease of locomotion, showed significantly greater improvement with compression than with bed rest (P , .001 for bandages, P , .05 for
stockings).
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3.0 Long-term Anticoagulation
of Acute DVT of the Leg
In this review, the term long-term treatment refers
to treatments (eg, VKA therapy, LMWH, dabigatran)
that are continued after initial therapy (eg, parenteral
anticoagulation, thrombolytic therapy) (Fig 1). In
addition, we consider treatment with rivaroxaban,
which is used without initial parenteral therapy. Longterm therapy has two goals: (1) to complete treatment of the acute episode of VTE and (2) to prevent
new episodes of VTE that are not directly related to
the acute event. During the early phase of long-term
treatment (ie, first 3 months), treatment of the acute
episode of VTE predominates. During the late phase
of long-term treatment (ie, after the first 3 months),
prevention of new episodes of VTE predominates.
We use the term extended anticoagulation to refer to
anticoagulation that is continued beyond 3 months
without a scheduled stop date. However, regular (eg,
yearly) reassessments are needed to assess whether
a patient’s risk of bleeding increased or the patient’s
preferences changed.
Three lines of evidence from randomized trials support the need for long-term anticoagulant treatment
of DVT (ie, after 5-10 days of initial heparin therapy):
(1) a randomized controlled trial of long-term anticoagulant therapy in 51 patients with symptomatic
calf-vein thrombosis that documented a 25% rate of
symptomatic extension of thrombosis within 3 months
in the control group,66 (2) a randomized trial comparing long-term SC low-dose UFH (5,000 units bid)
with VKA therapy in patients with proximal DVT
that found that low-dose UFH was ineffective and
resulted in a high rate of recurrent VTE (47% within
3 months),158 and (3) randomized trials in which
reduced durations of treatment of 4 or 6 weeks
resulted in important increases in recurrent VTE
compared with conventional durations of treatment of 3 or 6 months (section 3.1).159-161 This evidence is of moderate quality because of imprecision
and indirectness.
Recommendation
with anticoagulant therapy, we recommend longterm therapy (see section 3.1 for recommended
duration of therapy) over stopping anticoagulant therapy after 1 week of initial therapy
(Grade 1B).
3.1 Duration of Long-term Anticoagulant Therapy
Weighing the Benefits and Risks of Different Durations of Anticoagulant Therapy: General Considerations: Anticoagulant therapy for VTE should be
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continued until (1) the reduction of recurrent VTE no
longer clearly outweighs the increase in bleeding or
(2) it is patient preference (which may be influenced by
financial burden) to stop treatment, even if the reduction in VTE would outweigh the increase in bleeding.
Increase in Risk of Recurrent VTE After Stopping
Therapy—Current evidence suggests that the risk of
recurrence after stopping therapy is largely determined by two factors: (1) whether the acute episode
of VTE has been effectively treated (duration of
therapy) and (2) the patient’s intrinsic risk of having a
new episode of VTE (individual risk of recurrence).
Duration of therapy: The primary goal of trials that
compare different time-limited durations of anticoagulation is to identify the shortest duration of therapy
that results in a posttreatment risk of recurrence that
is as low as can be achieved. The findings of these
trials generally are not sensitive to differences in individual patient risk of bleeding.
Individual risk of recurrence: Primary factors
for estimating risk of recurrence: Presence of a
reversible provoking risk factor,47,159,160,162-168,169,170
unprovoked VTE, 47,159,160,162-168,169,170 and presence of
active cancer9,47,165,166 are the most important factors
that influence risk of recurrent VTE after stopping
VKA. Among patients with VTE provoked by a
reversible factor, the risk of recurrence is much lower
if the provoking factor was recent surgery compared with a nonsurgical trigger (eg, estrogen therapy,
pregnancy, leg injury, flight of . 8 h).162,171 In patients
with proximal DVT and PE, the estimated cumulative risk of recurrent VTE after stopping anticoagulant therapy of each of these categories is as follows:
VTE provoked by surgery, 1% after 1 year and 3%
after 5 years; VTE provoked by a nonsurgical reversible risk factor, 5% after 1 year and 15% after 5 years;
and unprovoked VTE, 10% recurrence after 1 year
and 30% after 5 years.
There are sparse data addressing the risk of recurrent VTE after stopping therapy in patients with
cancer because treatment is rarely stopped in these
patients because of a high risk for recurrence.38,47,165,166,172
A reasonable estimate for this risk, expressed as an
annualized rate, may be 15%. However, the risk of
recurrence is expected to vary according to whether
the cancer is metastatic, being treated with chemotherapy, or rapidly progressing.38,165 The high mortality
in patients with VTE and cancer (40% at 6 months
in one large study173) precludes estimating the cumulative risk of recurrence after long-term follow-up.
We categorize patients with VTE according to these
primary individual risk factors for recurrence when
we make recommendations for duration of anticoagulant therapy.
Secondary factors for estimating risk of recurrence:
Additional factors that influence the risk of recurrence
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strongly enough to modify some recommendations
about duration of therapy include (1) whether DVT
was confined to the distal veins (isolated distal [or
calf] DVT), which is estimated to be associated with
about one-half of the risk of recurrence of proximal
DVT and PE,10,164,167,169,170 and (2) whether the VTE
was a second or subsequent episode of VTE, which is
estimated to be associated with about a 50% higher
risk of recurrence compared with a first VTE.9,173,175
Additional factors for estimating risk of recurrence: Other factors predict risk of recurrence, but
not strongly or consistently enough to influence recommendations on duration of therapy once the primary and secondary factors noted previously have
been considered. These factors, which have mostly
been evaluated in patients with unprovoked VTE,
include negative D-dimer testing 1 month after
withdrawal of VKA (risk ratio [RR], !0.4),48,176-181
antiphospholipid antibody (RR, !2),182-185 hereditary thrombophilia (RR, !1.5),162,163,174,177,180-182,185-190
male vs female sex (RR, !1.6),191,192 Asian ethnicity
(RR, !0.8),193 and residual thrombosis in the proximal veins (RR, !1.5).149,182,185,194-198 Combinations
of factors have the potential to be more important
predictions of recurrence risk than single factors
(eg, low risk of recurrence in women with unprovoked proximal DVT or PE who have a negative
D-dimer test before185 or 1 month after180,199 stopping anticoagulant therapy). PTS may be a risk
factor for recurrent VTE,183,185,200 and recurrent
ipsilateral DVT is a risk factor for development of
PTS.201,202 Both associations may contribute to a
decision to use extended therapy in a patient with
established PTS.
Increase in Risk of Bleeding While Remaining on
Anticoagulant Therapy—Although the decision to
treat patients with different time-limited durations of
anticoagulant therapy generally are insensitive to
an individual’s risk of bleeding, the decision to use
extended anticoagulation, particularly in patients
with an unprovoked proximal DVT or PE, is sensitive
to risk of bleeding. There is no validated prediction
tool to stratify the risk of major bleeding during
extended anticoagulant therapy specifically in patients
with VTE, but this risk appears to increase with the
prevalence of the factors noted in Table 2. This table
also provides our estimate of the absolute risk of
bleeding without anticoagulation (baseline risk), the
increase with anticoagulation, and the sum of these
two risks (ie, risk of bleeding on therapy).
Comparisons of Time-Limited Durations of
Therapy: Randomized trials have compared either a
short (eg, 4 or 6 weeks) with an intermediate (eg, 3 or
6 months) duration of therapy, or two intermediate
durations of therapy, (eg, 3 months vs 6 or 12 months).
e448S
VKA therapy targeted to an INR of 2.5 was the anticoagulant regimen in all comparisons.
Short vs Intermediate Durations of Therapy—Five
trials have evaluated shortening the duration of oral
anticoagulant therapy from 3 or 6 months to 4 or
6 weeks in patients with mostly first episodes of VTE
(Table 16, Tables S23-S25).159,160,167,169 This evidence,
which is high quality, indicates that with the shorter
duration of therapy, the absolute decrease in bleeding
was small compared with the absolute increase in
recurrent VTE. Patients with isolated distal DVT
provoked by a major transient risk factor have a very
low risk of recurrence after anticoagulant therapy is
stopped (!1% per year170). It is uncertain whether
this risk is lowered by treating for 3 months compared
with 4 or 6 weeks (hazard ratio [HR] for 4 or 6 weeks
vs ! 3 months at 2 years after stopping therapy, 0.36;
95% CI, 0.09-1.54170). For this reason, we make a
weaker recommendation for 3 months compared
with a shorter duration of therapy in patients with
isolated distal DVT that was provoked by a reversible
risk factor. The evidence supporting this weaker recommendation is rated down to low quality because of
serious imprecision and because it is a post hoc
observation.
Different Intermediate Durations of Therapy (6 or
12 months vs 3 months)—We considered trials that
randomized patients with VTE to 3 months vs to 6 or
12 months of treatment to determine, when using a
time-limited duration of therapy, whether there was
any benefit to treating for . 3 months. Five reports,
which included six randomized comparisons, contributed to this analysis (Table 17, Tables S24S26).167,194,203-205 These studies found that 6 or
12 months of therapy did not convincingly lower risk
of recurrence but increased major bleeding about
2.5-fold. In a meta-analysis of individual patient data
from randomized trials, during the 2 years after stopping anticoagulant therapy, treatment of 3 months
compared with ! 6 months was associated with an
HR of 1.19 (95% CI, 0.86-1.65) in all patients and an
HR of 1.39 (95% CI, 0.96-2.01) in patients with
unprovoked DVT or PE.170 Therefore, although anticoagulants are very effective at preventing recurrence
while patients are receiving therapy, when anticoagulants are stopped, there is a similar risk of recurrence
whether patients have been treated for 3 months or
longer.170 This evidence is of moderate quality because
of serious imprecision.
As an alternative to comparing two time-limited
durations of anticoagulant therapy, the AESOPUS
(Ultrasound Findings to Adjust the Duration of Anticoagulation) trial compared a predefined duration
of therapy with a flexible duration of therapy that
depended on whether there was residual thrombosis during follow-up in patients with a first proximal
Table 16—[Section 3.1.1-3.1.4] Summary of Findings: Four or Six Weeks vs Three or Six Months as Minimum
Duration of Anticoagulation for VTEa,b,16,159,167,169,195
No. of Participants
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
Risk With
Control
Risk Difference With 4 or 6 wk vs 3 or 6 mo
Months of Anticoagulation (95% CI)
Recurrent VTE
2,185 (5 studiesc), 1-2 yd
Highe-g
64 per 1,000
Major bleeding
2,185 (5 studies), 1-2 y
Highf
53 more per 1,000
(from 25 more to 91 more)
5 fewer per 1,000 (from 9 fewer to 4 more)
Mortality
2,098 (5 studies), 1-2 y
Highe,f,h
RR 1.83
(1.39-2.42)
RR 0.54
(0.22-1.32)
RR 0.97
(0.68-1.38)
Outcomes
12 per 1,000
55 per 1,000
2 fewer per 1,000
change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect
and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion
of abbreviations.
aPopulations varied among studies: first provoked isolated distal DVT, proximal DVT, or PE provoked in Kearon et al195; first isolated distal DVT in
Pinede et al167; first isolated distal DVT, proximal DVT, or PE in Schulman et al169; proximal DVT (21% had cancer) in Levine et al159; DVT or PE
(29% not objectively confirmed) in British Thoracic Society.160
bShort vs longer duration of anticoagulation was 6 wk vs 6 mo for Schulman et al169, 6 wk vs 3 mo for Pinede et al,167 and 4 wk vs 3 mo for the other
three studies.
cTiming of randomization relative to the start of treatment varied across studies: Pinede et al,167 Schulman et al,169 and British Thoracic Society160
randomized at diagnosis, and Kearon et al195 and Levine et al159 randomized to stop or to continue treatment for 2 mo more after the initial 4 wk of
treatment.
dFollow-up was for !1 y in all studied except for Schulman et al169 in which it was 2 y.
eGenerally, study design was strong. No study stopped early for benefit; two stopped early because of slow recruitment (Kearon et al,195 Pinede
et al167). In one study (British Thoracic Society160), 44 randomized patients were excluded centrally as they did not satisfy eligibility criteria. Patients
and caregivers were blinded in two studies (Kearon et al, Levine et al159). Adjudicators of outcomes were blinded in all but one study (British
Thoracic Society). All studies appear to have used effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out
frequency.
fNo heterogeneity with I2 5 0%.
gNo imprecision for overall estimates. However, for the subgroup of patients with isolated distal DVT, who are known to have a very low risk of
recurrence, there is imprecision and the possibility that the shorter duration of anticoagulation is adequate and not associated with a clinically
important higher risk of recurrence.
hDifferences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.
DVT206 (Tables S24 and S25). Its findings suggest
that the latter approach may be helpful for tailoring
the duration of therapy.
Extended vs Time-Limited Anticoagulant Therapy:
Five trials compared extended anticoagulation with
VKA therapy (target INR 2.0-2.85,161 2.0-3.0,48,182,207
and 1.5-2.0174) with stopping VKA therapy at 3 or
6 months in patients who were judged to have a high
risk of recurrence (Table 18, Table S24, S25, and S27).
The results indicate that randomization to indefinite
treatment with conventional-intensity VKA (target
INR 2.5) reduces recurrent VTE by about 90% (RR
for the four studies, 0.12; 95% CI, 0.05-0.2548,161,182,207),
and randomization to low-intensity therapy (target
INR 1.75) reduces VTE by 64% (95% CI for HR,
23%-81%),174 with about one-half of recurrent VTE
in the active treatment groups in these studies
occurring in patients who had prematurely stopped
VKA therapy. Extended anticoagulant therapy was
associated with about a 2.6-fold increase in major
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bleeding. The quality of evidence for the reduction in
recurrent VTE with extended therapy is high but is
rated down to moderate for bleeding and mortality
because of imprecision.
Weighing the Benefits and Risks of Extended VKA
Therapy—The decision to extend anticoagulation
therapy beyond 3 months is sensitive to both baseline
risks of recurrent VTE and major bleeding. We did
not identify a validated prediction tool for either
outcome that takes into account all relevant risk factors. As an alternative, for patients without cancer,
we chose to stratify our recommendations according
to four primary risk groups for recurrent VTE (section 3.1) and three risk groups for major bleeding
(section 3.1) (Table 2). This approach resulted in a
total of 12 combinations of risk profiles. Table 19
shows the estimated total (and fatal) number of
recurrent episodes of VTE prevented and the number
of major bleeds caused by 5 years of extended therapy
for each of the 12 combinations. In the absence of
robust trial data for mortality for recurrent VTE and
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Table 17—[Section 3.1.1-3.1.4] Summary of Findings: Six or Twelve Months vs Three Months as Minimum Duration
of Anticoagulation for VTEa,b,167,203,204
No. of Participants
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
Recurrent VTE
2,061 (6 studies), 1-3 y
Major bleeding
2,061 (6 studies), 1-3 y
Moderatec-e due to
imprecision
Highf
Mortalityg
1,331 (5 studies), 1-3 y
RR 0.89
(0.69-1.14)
RR 2.49
(1.2-5.16)
RR 1.3
(0.81-2.08)
Outcomes
Moderated due to
imprecision
Risk With 3 mo
115 per 1,000
9 per 1,000
44 per 1,000
Risk Difference With 6 or
12 mo (95% CI)
13 fewer per 1,000
13 more per 1,000
13 more per 1,000 (from 8
fewer to 47 more)
uncertain about the estimate. See Table 1 and 3 legends for expansion of other abbreviations.
aStudy populations varied across studies: Pinede et al167 enrolled provoked and unprovoked proximal DVT and PE; Campbell et al203 enrolled
provoked and unprovoked isolated distal DVT, proximal DVT, and PE; Agnelli et al194 had separate randomizations for provoked PE (3 vs 6 mo) and
unprovoked (3 vs 12 mo); and Agnelli et al204 enrolled unprovoked proximal DVT.
bTiming of randomization relative to the start of treatment and length of treatment in the non-3 mo group varied across studies: Pinede et al167 and
Campbell et al203 randomized at diagnosis; and Agnelli et al194,204 randomized after the initial 3 mo of treatment to stop or continued treatment. The
longer duration of treatment was 6 mo in Agnelli et al194 (provoked PE) and 12 mo in Agnelli et al204 and Agnelli et al194 (unprovoked PE).
cGenerally, study design was strong. No study stopped early for benefit; two stopped early because of slow recruitment (Campbell et al,203 Pinede
et al167) and one because of lack of benefit (Agnelli et al204). In one study (Campbell et al), 20% of VTE outcomes were not objectively confirmed.
Patients and caregivers were not blinded in any study. Adjudicators of outcomes were blinded in all but one study (Campbell et al). All studies used
effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out frequency.
dCIs include both values suggesting no effect and values suggesting either benefit or harm.
eLow number of events and a total number of participants , 2,000.
fOne study may have confined the assessment of bleeding to when subjects were receiving anticoagulant therapy, which could have inflated the
increase in bleeding associated with the longer duration of therapy (Campbell et al203).
gDifferences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.
bleeding, we assumed that 3.6% of recurrent VTE
and 11.3% of major bleeds will be fatal.12
We make (1) a strong recommendation for extended
therapy when it is associated with a reduction in
VTE that is substantially more frequent than the
increase in major bleeding and with a mortality
advantage, (2) a weak recommendation for extended
therapy when it is associated with a reduction in VTE
that is more frequent than the increase in major
bleeding but the magnitude of this difference and
the suggested mortality advantage are more modest,
(3) a weak recommendation against extended therapy
when extended therapy is associated with a reduction in VTE that is less frequent than the increase in
major bleeding and no mortality advantage exists,
and (4) a strong recommendation against extended
therapy when extended therapy is associated with a
reduction in VTE that is less frequent than the
increase in major bleeding and a mortality disadvantage may exist. We assume that on average, extended
anticoagulation with VKA therapy is a modest burden
to patients.15 However, this differs markedly among
patients; some do not find anticoagulant therapy a
burden and have an enhanced feeling of well-being
because they feel protected from recurrence, whereas
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others find it a major burden that greatly erodes their
sense of well-being.210
The presence of additional risk factors for VTE
recurrence (section 3.1), the patient’s relative value
for the different outcome of interest (recurrence of
VTE, major bleeding, PTS), and the patient’s perceived burden of anticoagulant therapy may influence
decisions about the use of extended anticoagulant
therapy in patient groups for which we provide a
weak recommendation but are unlikely to influence
this decision in patients groups for which we provide
a strong recommendation.16 Similarly, the costs of
therapy and how those costs are paid (eg, patient,
third party) are more likely to influence treatment
decisions when there is a weak recommendation
(Grade 2) in favor of extended therapy.
Patients With VTE and Cancer: As previously noted
(section 3.1), because they have a high risk of recurrence, patients with active cancer (eg, treated within
the past 6 months, persistent or progressive) should
benefit from extended anticoagulant therapy unless
they have a very high risk of bleeding. The quality
of the evidence supporting this recommendation is
moderate because of indirectness (the relative effects
of anticoagulation are based, in part, on evidence
Table 18—[Section 3.1.1-3.1.4] Summary of Findings: Extended Anticoagulation vs No Extended Anticoagulation for
Different Groups of Patients with VTE and Without Cancera,b,48,161,182,207
Outcomes
No. of Participants
Quality of
the Evidence
(GRADE)
Relative Effect
(95% CI)
Risk With No
Extended Duration
Oral Anticoagulation
Extended Duration Oral
Moderatec-e
due to
imprecision
High
RR 0.57 (0.31-1.03)
63 per 1,000
44 fewer to 2 more)
Mortality
1,184 (4 studies),
10-36 mo
Recurrent VTE at
1y
1,184 (4 studies),
10-36 mo
Major bleeding
at 1 y
1,184 (4 studies),
10-36 mo
Moderate
due to
imprecision
RR 2.63 (1.02-6.76)
Recurrent VTE
at 5 y
1,184 (4 studies),
10-36 mo
High
RR 0.12 (0.09-0.38)
Major bleeding
at 5 y
1,184 (4 studies),
10-36 mo
Moderate
due to
imprecision
RR 2.63 (1.02-6.76)
RR 0.12 (0.09-0.38)
First VTE provoked by surgeryf-j
10 per 1,000
6 fewer to 9 fewer)
First proximal DVT or PE provoked nonsurgical/
first unprovoked distal DVTf-j
50 per 1,000
First unprovoked VTEf-j
100 per 1,000
Second unprovoked VTEf-j
150 per 1,000
132 fewer per 1,000
(from 93 fewer to
137 fewer)
Lowk,l (see Table 2)
3 per 1,000
0 more to 15 more)
Moderatek,l (see Table 2)
6 per 1,000
1 more to 29 more)
Highk,l (see Table 2)
25 per 1,000
3 more to 122 more)
30 per 1,000
First proximal DVT or PE provoked nonsurgical/
first unprovoked distal DVTf-j
150 per 1,000
132 fewer per 1,000
(from 93 fewer to
137 fewer)
300 per 1,000
264 fewer per 1,000
(from 186 fewer to
273 fewer)
450 per 1,000
396 fewer per 1,000
(from 279 fewer to
409 fewer)
Lowk,l (see Table 2)
15 per 1,000
2 more to 73 more)
Moderatek,l (see Table 2)
30 per 1,000
4 more to 146 more)
Highk,l (see Table 2)
125 per 1,000
199 more per 1,000
(from 17 more to
609 more)
(Continued)
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e451S
Table 18—Continued
No. of Participants
Quality of
the Evidence
(GRADE)
Relative Effect
(95% CI)
Burden of
anticoagulation
not reported
…
…
PTS not reported
…
…
Outcomes
Risk With No
Extended Duration
Oral Anticoagulation
Extended Duration Oral
…
Warfarin: daily
medication,
dietary and activity
restrictions,
frequent blood
testing/monitoring,
increased hospital/
clinic visitsm
…
…
n
…
uncertain about the estimate. PREVENT 5 Prevention of Recurrent Venous Thromboembolism. See Table 1 and 3 legends for expansion of other
abbreviations.
aStudies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3-6 mo).
bWe excluded PREVENT trial because target INR was 1.75 (low intensity), which has been shown in an RCT44 to be less effective than a target
of 2.5.
cI2 5 0%.
dCI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefit.
eSmall number of events. Decision to rate down also takes into account that two studies were stopped early for benefit.
fAnnual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with first VTE provoked by surgery: 1% (Iorio et al171);
we assumed a 0.5% yearly risk thereafter (3% over 5 y).
gAnnual risk in patients with first VTE provoked by nonsurgical factor: !5% the first year (Iorio et al171); we assumed a 2.5% yearly thereafter (15%
over 5 y).
hAnnual risk in patients with first episode of unprovoked VTE: 9.3% over 1 y in Rodger et al185; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y
in Prandoni et al.208 We assumed a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).
iAnnual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a first episode of unprovoked VTE: 15%
the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).
jCase fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).
kAnnual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates
based on control arms of included studies (see Table 2).
lCase fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral
anticoagulation therapy).
mBurden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop
anticoagulation (no extended duration anticoagulation) who subsequently experienced a recurrent VTE (5%/10%/15% at 1 y; 15%/30%/45% at 5 y).
nPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al 102). There was a threefold (Prandoni et al 202) to 10-fold
(van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.
from patients without cancer). Presence of factors
associated with a lower risk of recurrence that may
support stopping anticoagulant therapy, particularly
if the risk of bleeding was high, include the following:
(1) VTE was associated with a superimposed reversible risk factor (eg, recent surgery, chemotherapy),
(2) the cancer has responded to treatment, (3) the
cancer has not metastasized, and (4) the VTE was an
isolated distal DVT.
Follow-up of Patients on Extended Therapy: Patients
who are treated with extended anticoagulant therapy
should be reviewed regularly (eg, annually) to ensure
that (1) they have not developed contraindications
to extended therapy, (2) their preferences have not
changed (eg, anticoagulation has become an excessive burden), (3) they can benefit from improved ways
e452S
of selecting a patient for extended therapy if these
have become available, and (4) they are being treated
with the anticoagulant regimen that best suits them.
LMWH for Extended Therapy: We identified no
direct evidence for LMWH compared with (1) VKA,
(2) other anticoagulant strategies, or (3) control for
the extended phase of anticoagulation in patients who
were treated with a standardized initial long-term
anticoagulant regimen. Based on indirect evidence
from comparisons of LMWH with VKA therapy during
the initial 3 or 6 months of long-term therapy, we
judged LMWH to be at least as effective in terms of
recurrent VTE and as safe in terms of major bleeding
(Table 20, Table S28). The potential for drug-induced
osteoporosis, however, may be greater with extended
therapy LMWH than with VKA therapy.1
Table 19—[Section 3.1.1-3.1.4] Estimated Absolute Difference in Recurrent VTE and Major Bleeding Events
(Including Fatal Events) With 5 Years of vs No Extended Anticoagulation
Outcomes After
5 y of Treatment
First VTE provoked by
surgery
First VTE provoked by a
nonsurgical factor/first
unprovoked distal DVT
First unprovoked proximal
DVT or PE
second unprovoked VTE
Recurrent VTE reduction
per 1,000
Major bleeding increase
per 1,000
per 1,000
per 1,000
per 1,000
per 1,000
per 1,000
per 1,000
Risk of Bleeding
Low
Intermediate
Higha
↓ 26 (19-27) (1 fatal)b
↓ 26 (19-27) (1 fatal)b
↓ 26 (19-27) (1 fatal)b
↑ 24 (2-73) (3 fatal)b
↑ 49 (1-173) (5 fatal)b
↑ 98 (1-346) (11 fatal)b
↓ 132 (93-137) (5 fatal)c
↓ 132 (93-137) (5 fatal)c
↓ 132 (93-137) (5 fatal)b
↑ 24 (2-73) (3 fatal)c
↑ 49 (1-173) (5 fatal)c
↑ 98 (1-346) (11 fatal)b
↓ 264 (186-273) (10 fatal)d
↑ 24 (2-73) (3 fatal)d
↓ 264(186-273) (10 fatal)b
↑ 49 (1-173) (5 fatal)d
↓ 396 (279-409) (14 fatal)e
↑ 24 (2-73) (3 fatal)e
↓ 264 (186-273) (10 fatal)d
↓ 396 (279-409) (14 fatal)d
↑ 98 (1-346) (11 fatal)b
↓ 396 (279-409) (14 fatal)c
↑ 49 (1-173) (5 fatal)d
↑ 98 (1-346) (11 fatal)c
Recommendations:
Risk of dying in patients with a recurrent VTE or a major bleed:
• Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).
• Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral
anticoagulation therapy).
Annual risks of recurrent VTE after discontinuation of anticoagulation:
• First VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).
• First episode of VTE provoked by nonsurgical factor: !5% the first year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y)
• First episode of unprovoked VTE: 9.3% over 1 y (Rodger et al185); 11.0% over 1 y, 19.6% over 3 y, 29.1% over 5 y (Prandoni et al208). We assumed
a risk of 10% the first year after discontinuation and 5% yearly thereafter (30% over 5 y).
• Second episode of unprovoked VTE: we assumed that this inflicts 1.5 the risk of recurrent VTE relative to first episode of unprovoked VTE: 15%
the first year after discontinuation, 7.5% yearly thereafter (45% over 5 y).
Relative risk reduction with extended anticoagulant therapy:
• 82% based on Table 18
Annual risks of major bleeding in patients not on anticoagulant therapy:
• Low risk, 0.3%/y; intermediate risk 0.6%/y; high risk, 2.4%/y (Table 2).
Relative risk of major bleeding with extended anticoagulant therapy:
• 2.6 based on Table 18.
Criteria used to decide on direction and strengths of recommendations:
• Criterion for a strong recommendation against whenever the estimated number of fatal bleeding events exceeded the estimated number of fatal
recurrent VTE prevented.
• Criterion to go from a strong recommendation against to weak recommendation against: difference between the lower boundary of increased
major bleeding and upper boundary of reduction in recurrent VTE , 2% (risk over 5 y averaged per year).
• Criterion to go from a weak recommendation against to a weak recommendation in favor of: difference between point estimate of reduction of recurrent
VTE and point estimate for increase in major bleeding is . 2% (risk over 5 y averaged per year) (2% to account for the burden and cost of VKA).
• Criterion to go from a weak recommendation for to strong recommendation for: difference between the lower boundary of reduction in VTE and
upper boundary of increased major bleeding . 4% (risk over 5 y averaged per year).
Another way of interpreting the direction and strength of recommendation based on the number of deaths (related to either bleeding or recurrent
VTE) is as follows:
• A strong recommendation against: extended anticoagulation is estimated to be associated with an increase in deaths.
• A weak recommendation against: extended anticoagulation is estimated to be associated with from no effect on deaths to only a very small
reduction in deaths (0-4/1,000 prevented over 5 y or , 0.5%/patient-y).
• A weak recommendation for: extended anticoagulation is estimated to be associated with a small reduction in deaths (5 to 9/1,000 prevented over
5 y or 0.5%-0.9%/patient-y).
• A strong recommendation for: extended anticoagulation is estimated to be associated with a large reduction in deaths (. 10/1,000 prevented over
5 y or . 1%/patient-y).
aWith an eightfold risk of bleeding in the high-risk group compared with the low-risk group, a strong recommendation against extended
anticoagulation for a second unprovoked VTE is justified. The high-risk group, however, includes patients who have a risk of bleeding that is less
than this estimate (eg, patients aged . 75 y without additional risk factors for bleeding [Table 2]) and, therefore, may benefit from extended
anticoagulant therapy. For this reason, we provide a weak rather than a strong recommendation against extended anticoagulation for patients with
a second unprovoked VTE in the high-bleeding-risk group.
bStrong against
cWeak against
dWeak in favor
eStrong in favor
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e453S
Rivaroxaban for Extended Therapy: Use of rivaroxaban compared with initial parenteral therapy
followed by VKA therapy for the short- and longterm treatment of DVT is reviewed in section 3.3
(Table 21, Table S29). In the current section, we consider rivaroxaban compared with no anticoagulation
in patients with proximal DVT or PE who have completed 6 or 12 months of anticoagulant therapy,
which has been evaluated in a single study (Table 22,
Table S30).127 This study found that rivaroxaban
markedly reduced recurrent VTE at the expense of a
modest absolute increase in major bleeding. The evidence from this one study is of moderate quality
because of serious imprecision.
Dabigatran for Extended Therapy: There are no
completed studies that have compared dabigatran
with no anticoagulation for extended treatment of
VTE.
Choice of Anticoagulant Regimen for Extended
Therapy: This question is addressed in section 3.3.
Recommendations
with anticoagulation for 3 months over: (i) treatment of a shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6 or
(Grade 1B regardless of risk of bleeding).
bleeding risk (Table 2) (Grade 1B). We suggest
over extended therapy if there is a low or moderate bleeding risk (Table 2) (Grade 2B).
3.1.3. In patients with an isolated distal DVT of
the leg provoked by surgery or by a nonsurgical
transient risk factor (see remark), we suggest
and recommend treatment with anticoagulation
for 3 months over treatment of a longer timelimited period (eg, 6 or 12 months) (Grade 1B) or
extended therapy (Grade 1B regardless of bleeding
risk).
the leg (isolated distal [see remark] or proximal), we recommend treatment with anticoague454S
lation for at least 3 months over treatment of a
shorter duration (Grade 1B). After 3 months of
treatment, patients with unprovoked DVT of the
leg should be evaluated for the risk-benefit
ratio of extended therapy.
have a low or moderate bleeding risk (Table 2),
we suggest extended anticoagulant therapy over
3 months of therapy (Grade 2B).
have a high bleeding risk (Table 2), we recommend 3 months of anticoagulant therapy over
unprovoked isolated distal DVT of the leg (see
remark), we suggest 3 months of anticoagulant
therapy over extended therapy in those with a
low bleeding risk (Table 2) (Grade 2B), and
recommend 3 months of anticoagulant treatment in those with a moderate or high bleeding
risk (Table 2) (Grade 1B).
have a low bleeding risk (Table 2) (Grade 1B),
and we suggest extended anticoagulant therapy
in those with a moderate bleeding risk (Table 2)
(Grade 2B).
VTE who have a high bleeding risk (Table 2),
we suggest 3 months of anticoagulant therapy
over extended therapy (Grade 2B).
active cancer, if the risk of bleeding is not
high (Table 2), we recommend extended anticoagulant therapy over 3 months of therapy
(Grade 1B), and if there is a high bleeding risk
(Table 2), we suggest extended anticoagulant
therapy (Grade 2B).
all patients who are given a diagnosis of isolated distal
DVT will be prescribed anticoagulants (see section 2.3).
In all patients who receive extended anticoagulant
therapy, the continuing use of treatment should be
reassessed at periodic intervals (eg, annually).
Table 20—[Section 3.3] Summary of Findings: LMWH vs VKA for Long-term Treatment of VTEa-c,173,211,213,223,224,226-228
Outcomes
Death
Recurrent VTE
Major bleeding
No. of
Participants
Quality of the
Evidence
(GRADE)
Relative Effect
(95% CI)
2,496 (7 studies),
6 mo
2,727 (8 studies),
6 mo
Moderated,e due
to imprecision
Moderatef due
to risk of bias
RR 0.96
(0.81-1.13)
RR 0.62
(0.46-0.84)
2,737 (8 studies),
6 mo
Moderateh,i due
to imprecision
RR 0.81
(0.55-1.2)
Burden of
anticoagulation
…
PTS (self-reported
leg symptoms
and signs)
100 (1 study), 2 y
Highk
Lowl,m due to
risk of bias,
indirectness
…
RR 0.85
(0.77-0.94)
Risk With VKA
LMWH (95% CI)
164 per 1,000
7 fewer per 1,000
No cancerg
30 per 1,000
11 fewer per 1,000
Nonmetastatic cancerg
80 per 1,000
30 fewer per 1,000
Metastatic cancerg
200 per 1,000
76 fewer per 1,000
No cancer or nonmetastatic cancerj
20 per 1,000
4 fewer per 1,000
Metastatic cancerj
80 per 1,000
15 fewer per 1,000
Warfarin: daily medication, dietary LMWH: daily injection,
restrictions, frequent blood
no dietary restrictions,
testing/monitoring, increased
no frequent blood
hospital/clinic visits
testing/monitoring
200 per 1,000n
30 fewer per 1,000
aTwo of these studies enrolled only patients without cancer, three enrolled only patients with cancer, and three enrolled both patients with and
without cancer (separate data provided for patients with cancer and without cancer in one study).
bLimited to LMWH regimens that used ! 50% of the acute treatment dose during the extended phase of treatment.
cThe initial parenteral anticoagulation was similar in both arms for all except one study (Hull et al211) in which patients randomized to LMWH
initially received the same LWMH, whereas patients randomized to VKA received initially UFH.
dOne study did not report deaths, which is unusual and could reflect selective reporting of outcomes.
eCI includes both no effect and harm with LMWH.
fNone of the studies were blinded, whereas the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for
diagnosis of recurrent VTE in VKA-treated patients because switching the treatment of such patients to LMWH is widely practiced. At the same
time, there is reluctance to diagnose recurrent VTE in patients who are already taking LMWH because there is no attractive alternative treatment
option.
gRisk of recurrent VTE: low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate
corresponds to patients with local or recently resected cancer (based on average rate across the six studies in this analysis and appears to be
consistent with Prandoni et al38 [particularly if low risk is increased to 4%]), and high corresponds to patients with locally advanced or distant
metastatic cancer (Prandoni et al).
hNo study was blinded; diagnosis of major bleeding has a subjective component.
iThe 95% CIs for the RR for major bleeding includes a potentially clinically important increase or decrease with LMWH and may vary with the dose
of LMWH used during the extended phase of therapy.
jRisk of bleeding: low corresponds to patients without risk factor for bleeding (ie, age . 75 y, cancer, metastatic disease; chronic renal or hepatic
failure; platelet count , 80,0000; requirement for antiplatelet therapy; history of bleeding without a reversible cause) (Table 2). Based on Prandoni
et al38 and Beyth et al212 and adjusted to a 6-mo time frame.
kHull et al213 reported no significant difference in QOL but suggested greater satisfaction with LMWH over VKA (questionnaire did not directly
assess the burden of injections).
lPatients and investigators not blinded. Self-reported leg symptoms and signs after 3 mo of treatment.
mThe association between leg symptoms and signs at 3 mo and long-term PTS is uncertain.
nBaseline risk assumes that patients all wear pressure stockings. Control event rate comes from observational studies in a review by Kahn et al,214
adjusted to a 2-y time frame.
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Table 21—[Section 3.3] Summary of Findings: Rivaroxaban vs LMWH and VKA Therapy for Acute and Long-term
Treatment of VTEa-c,88
Outcomes
No. of
Participants
Mortality
3,449 (1 study),
6-12 mod
Recurrent VTE
3,449 (1 study),
6-12 mod
Major bleeding
3,429 (1 study),
6-12 mod
Burden of
anticoagulation
not reported
…
Quality of
the Evidence
(GRADE)
Relative Effect
(95% CI)
Moderatee,f
HR 0.67
due to
(0.44-1.02)
imprecision
Moderatee,g
HR 0.68
due to
(0.44-1.04)
imprecision
Moderatee,g
HR 0.68
due to
(0.34-1.38)i
imprecision
…
…
Risk With LMWH and
VKA Therapy
Rivaroxaban (95% CI)
29 per 1,000
9 fewer per 1,000
30 per 1,000h
9 fewer per 1,000
11 per 1,000j
4 fewer per 1,000
Warfarin: daily medication,
dietary restrictions, frequent
blood testing/monitoring,
increased hospital/clinic visits
Rivaroxaban: daily medication, no
dietary restrictions, no frequent blood
testing/monitoring
uncertain about the estimate. HR 5 hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.
aIncluded patients had acute, symptomatic, and objectively verified proximal DVT of the legs (unprovoked, 62%; cancer, 6%; previous, VTE
19%).
bRivaroxaban 15 mg bid for 3 wk and then 20 mg/d for a total of 3 (12%), 6 (63%), or 12 (25%) mo.
cEnoxaparin 1 mg/kg bid for !8 d and then VKA therapy targeted to an INR of 2.5 for 3, 6, or 12 mo.
dFollow-up was prespecified to be 3 (12%), 6 (63%), or 12 (25%) mo.
eAllocation was concealed. Patients, providers, and data collectors were not blinded, but outcome adjudicators were blinded. Intention-to-treat
analysis; 1.0% were loss to follow-up. Not stopped early for benefit.
fCI includes values suggesting benefit or no effect; relatively low number of events.
gCI includes values suggesting benefit and harm.
hOne definite or possible fatal VTE in the rivaroxaban group and one in the LMWH/VKA group.
iCalculated from reported data.
jBleeds contributing to death: one in the rivaroxaban group and five in the warfarin group.
3.2 Intensity of Anticoagulant Effect
Ageno et al2 and Holbrook et al3 in these guidelines
present evidence for the optimal intensity of VKA
therapy (ie, target INR) during the long-term (eg,
first 3 months of treatment) and extended phases of
treatment of VTE.
Recommendation
3.3 Choice of Anticoagulant Regimen
for Long-term Therapy
VKA therapy has been the standard method of
anticoagulant therapy for VTE. Adjusted-dose SC
UFH is an effective alternative to VKA therapy, but
it has never been popular because it requires initial
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laboratory monitoring and twice-daily injection
and is associated with osteoporosis.215,216 SC LMWH
has advantages over SC UFH in that it does not
require laboratory monitoring, is less likely to cause
osteoporosis,216 and can be given once a day. For
these reasons, LMWH has been used for the longterm treatment of VTE. The synthetic pentasaccharide, fondaparinux, has not been evaluated or widely
used for long-term treatment of VTE. Idraparinux,
a long-acting pentasaccharide, is effective for the
long-term treatment of VTE,217 but it is not being
marketed because of concerns about bleeding given
its prolonged duration of action (once weekly injection) and lack of reversibility. The direct antithrombin
dabigatran and the direct factor Xa inhibitors apixaban and rivaroxaban have been evaluated for treatment of VTE and are now available in many countries.
In this section, we compare VKA therapy (target
INR 2.5), LMWH, dabigatran, and rivaroxaban for
the long-term treatment of VTE (ie, first 3 months
and extended therapy).
Table 22—[Section 3.3] Summary of Findings: Rivaroxaban vs Placebo for Extended Anticoagulation of VTEa,b,88
Outcomes
Mortality
Recurrent VTE
Major bleeding
Burden of
anticoagulation
not reported
PTS not reported
No. of Participants
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
1,196 (1 study),
6 or 12 moc
1,196 (1 study),
6 or 12 moc
1,188 (1 study),
6 or 12 mo
…
Moderated,e due to
imprecision
Highd
RR 0.49
(0.04-5.4)f
HR 0.18
(0.09-0.39)
RR 4.9
(0.58-42)f
…
Moderated,h due to
imprecision
…
…
Rivaroxaban (95% CI)
Risk With Placebo
3 per 1,000
71 per 1,000g
i
…
2 fewer per 1,000
58 fewer per 1,000
7 more per 1,000
Rivaroxaban: daily medication
j
aIncluded patients had acute, symptomatic, and objectively verified proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE,
19%).
bRivaroxaban 20 mg/d for 6 or 12 mo after initial long-term therapy.
cFollow-up was prespecified to be 6 (60%) or 12 (40%) mo.
dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Intention-to-treat analysis; 0.2% were loss
to follow-up. Not stopped early for benefit.
eCI includes values suggesting benefit or no effect; relatively low number of events.
fCalculated from reported data with addition of one event to each event rate because event rate was 0 in the control group.
gOne definite or possible fatal VTE in the rivaroxaban group and one in the LMWH/VKA group.
hCI includes values suggesting benefit and harm.
iBleeds contributing to death: none in the rivaroxaban group and none in the warfarin group.
jPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There is threefold (Prandoni et al202) to 10-fold (van Dongen
et al209) increase in PTS with recurrent VTE in the ipsilateral leg.
LMWH vs VKA Therapy for the Long-term Treatment of DVT: Two meta-analyses compared LMWH
in widely differing doses with VKAs.218,219 In an
analysis by Iorio and colleagues,218 which included
seven studies168,221-225 and a total of 1,379 patients,
among study differences of mean daily dose of LMWH,
little effect on the efficacy of LMWH compared with
VKA therapy was found, but the dose of LMWH
appeared to influence the risk of major bleeding
(OR, !0.2 with !4,000 International Units/d to !0.7
with 12,000 International Units/d, relative to the
VKA groups; P 5 .03 for dose-dependent interaction). Because prophylactic doses of LMWH are
rarely used as an alternative to VKA therapy in
patients with VTE, we restricted our analysis to
eight studies that used ! 50% of the full therapeutic
dose of LMWH for long-term treatment of VTE
(Table 20, Table S28).173,211,213,223,224,226-228 This evidence
suggests that compared with VKA therapy, LMWH
is associated with a reduction of recurrent VTE
and a similar frequency of major bleeding and mortality. The quality of this evidence is moderate because
of potential for bias in the assessment of recurrent
VTE (nonblinded outcome assessment) and serious
imprecision for major bleeding and mortality.
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Cancer vs No Cancer—There are differences
between patients with and without cancer with VTE
that may influence response to anticoagulant therapies. These include about a 10-fold higher risk of
dying and a threefold higher risk of recurrent VTE
and major bleeding during the first 3 or 6 months of
treatment38; different mechanisms of thrombosis that
may be associated with a poor response to VKA therapy229; use of cancer chemotherapy that is associated
with thrombocytopenia, vomiting, and anorexia and
may have other interactions with VKA therapy; and
the need for invasive therapeutic interventions (eg,
drainage procedures) that require reversal of anticoagulation. Many of these factors make LMWH more
attractive and VKA therapy less attractive in patients
with VTE and cancer and suggest that cancer may
alter the response of VTE to LMWH vs VKA therapy
(ie, presence of an interaction).
Among the eight studies included in Table 20
and Table S28, separate data are provided for
1,114 patients with cancer and 660 patients without cancer. Subgroup analyses suggest the possibility that the response to LMWH vs VKA therapy
may differ between patients with cancer and without cancer (recurrent VTE: RR, 0.52 with cancer
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[95% CI, 0.36-0.76] vs 0.99 without cancer [95% CI,
0.46-2.13]); major bleeding: RR, 0.92 with cancer
[95% CI, 0.59-1.44] vs 0.43 without cancer [95% CI,
0.16-1.17]); mortality: RR, 0.93 with cancer [95% CI,
0.79-1.09] vs 1.85 without cancer [95% CI, 0.595.77]). However, none of these differences is statistically significant, making it less likely that there is
a true difference in response to LMWH vs VKA in
the two patient populations. For this reason, we have
applied the same relative effects for LMWH vs VKA
in patients with and without cancer. The baseline risks
of events, however, are clearly different in the two
populations.
Patient Preferences—As discussed in the Methods
section, the ultimate judgment of the entire Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (AT9)
panel is that most patients prefer VKA therapy over
LMWH therapy. The higher purchase cost of LMWH
compared with VKA therapy is an additional barrier
to the long-term use of LMWH.
Quality of Evidence and Strength of Recommendations—Evidence for the comparison of long-term
LMWH vs VKA therapy in patients without cancer is
of low quality. The subgroup effect discussed previously was not sufficiently convincing to allow us to
generate an effect estimate specifically for patients
without cancer, but still reduced our confidence that
the overall effect estimate applies to the noncancer
subgroup that contributed a minority of data. Considerations favoring use of VKA over LMWH in patients
without cancer include (1) the evidence of benefit
with LMWH is of low quality, (2) the estimated absolute reductions in recurrent VTE events with LMWH
compared with VKA therapy is small, (3) the high
cost of LMWH, and (4) our assessment that LMWH
is a greater burden to patients than VKA therapy.
Considerations favoring use of LMWH over warfarin
in patients with cancer include (1) a large absolute
reduction in recurrent VTE with LMWH over VKA
therapy and (2) that LMWH is better suited to the
care of patients with cancer than is VKA therapy.
Among patients with VTE and cancer, the advantages of LMWH over VKA therapy are expected to
be greatest in patients (1) with metastatic disease,
(2) being treated with aggressive chemotherapy,
(3) presenting with extensive VTE, (4) with liver
dysfunction, (5) with poor or unstable nutritional
status, and (6) who wish to avoid laboratory monitoring of coagulation.
Dabigatran vs VKA Therapy for the Long-term
Treatment of DVT: One completed study has directly
compared dabigatran and VKA for the first 6 months
of treatment of VTE (Table 23, Table S31).343 Like
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patients treated with VKA therapy, patients treated
with dabigatran initially received parenteral therapy
(usually IV UFH or LMWH). This study suggests
that treatment with dabigatran or VKA therapy is
associated with a similar frequency of recurrent VTE,
major bleeding, and death. This evidence is of moderate quality because of serious imprecision for each
outcome and lack of long-term safety data for dabigatran in this patient population. Because the study
included few patients with cancer, we were unable to
assess whether its findings apply equally to patients
with and without cancer. In the absence of evidence
of such an interaction, however, we have not further
rated down the quality of evidence for patients with
VTE and cancer.
Rivaroxaban vs VKA Therapy for the Long-term
Treatment of DVT: A single study has directly compared rivaroxaban (without initial parenteral anticoagulation) with parenteral anticoagulation and VKA
in patients with acute DVT (Table 21, Table S29).88
Results suggested that treatment with rivaroxaban
and VKA therapy are associated with a similar frequency of recurrent VTE, major bleeding, and death.
This evidence is of moderate quality because of
serious imprecision for each outcome. Because the
study included few patients with cancer, we were
unable to assess whether its findings apply equally to
patients with and without cancer. In the absence of
evidence of such an interaction, however, we have
not further rated down the quality of evidence for
patients with VTE and cancer.
Comparisons Among LMWH, Dabigatran, and
Rivaroxaban for the Long-term Treatment of DVT:
There are no direct comparisons of these three agents
for the long-term treatment of VTE. Recommendations
about the use of one of these agents over the other
are based on indirect comparisons, and the evidence
is low quality.
Recommendations
3.3.1. In patients with DVT of the leg and no
cancer, we suggest VKA therapy over LMWH
for long-term therapy (Grade 2C). For patients
with DVT and no cancer who are not treated
with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy
(Grade 2C).
cancer, we suggest LMWH over VKA therapy
(Grade 2B). In patients with DVT and cancer
who are not treated with LMWH, we suggest
VKA over dabigatran or rivaroxaban for longterm therapy (Grade 2B).
Table 23—[Section 3.3] Summary of Findings: Dabigatran vs VKA Therapy for Long-term Treatment of VTEa-c,343
Outcomes
Mortality
Recurrent VTE
Major bleeding
Burden of
anticoagulation
not reported
No. of Participants
2,539 (1 study),
6 mo
2,539 (1 study),
6 mo
2,539 (1 study),
6 mo
Quality of
the Evidence
(GRADE)
Relative Effect
(95% CI)
Risk With Warfarin
Moderated,e due HR 0.98
17 per 1,000
to imprecision
(0.53-1.79)
19 per 1,000f
to imprecision
(0.65-1.84)
19 per 1,000g
to imprecision
(0.45-1.48)
…
…
…
Dabigatran (95% CI)
0 fewer per 1,000
0 more per 1,000
3 fewer per 1,000
Warfarin: daily medication,
Dabigatran: daily medication, no
dietary restrictions, frequent
dietary restrictions, no frequent blood
blood testing/monitoring,
testing/monitoring
increased hospital/clinic visits
aIncluded patients had acute, symptomatic, and objectively verified proximal DVT of the legs or PE.
bDabigatran 150 mg bid taken orally for 6 mo after an initial treatment with LMWH or IV UFH.
cWarfarin adjusted to achieve an INR of 2.0 to 3.0 for 6 mo after an initial treatment with LMWH or IV UFH.
dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Modified intention-to-treat analysis; 1.1%
loss to follow-up. Not stopped early for benefit.
fOne fatal VTE in dabigatran group and three fatal VTE in warfarin group.
gOne fatal major bleeding in dabigatran group and one fatal major bleeding in warfarin group.
with and without cancer is sensitive to individual
patient’s tolerance for daily injections, need for laboratory monitoring, and treatment costs. LMWH, rivaroxaban, and dabigatran are retained in patients with
renal impairment, whereas this is not a concern with
VKA. Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients,
may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these
guidelines were being prepared (October 2011),
postmarketing studies of safety were not available.
Given the paucity of currently available data and that
new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy
over dabigatran and rivaroxaban, and we have not
made any recommendations in favor of one of the
new agents over the other.
3.4 Choice of Anticoagulant Regimen
for Extended Therapy
Other than a comparison of low-intensity (target
INR 1.75) with conventional-intensity VKA therapy44
(Table S24 and S25), there are no completed studies
that have compared different anticoagulant agents
or regimens for extended therapy after a standardized initial period (eg, ! 3 months) of anticoagulation
in either patients without or with cancer. Because a
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decision about using extended therapy occurs after
an initial period of anticoagulation (eg, 3 months) and
because the relative efficacy and safety of anticoagulant
regimens are expected to be similar during the early
and extended phases of therapy, we anticipate that
most patients will continue to use their initial anticoagulant regimen for extended therapy. Possible reasons for switching from LMWH to VKA therapy
include the following: cancer becomes less active,
chemotherapy is completed, patient tires of SC injections, development of renal impairment causes concern about accumulation of LMWH (also applies
to rivaroxaban and dabigatran), and LMWH costs
become prohibitive. Reasons for switching from
VKA therapy to LMWH could include difficulty with
INR control and need for repeated invasive procedures. New anticoagulant therapies may expand indications for extended anticoagulant therapy because
they are less burdensome than VKA or LMWH
therapy and because they may be associated with
improved clinical outcomes (ie, more effective or
safer).
Recommendation
3.4. In patients with DVT of the leg who choose
extended therapy, we suggest treatment with
the same anticoagulant chosen for the first
3 months (Grade 2C).
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3.5 Treatment of Asymptomatic DVT of the Leg
Rather than screen postoperative patients for the
presence of asymptomatic DVT, clinicians should
prescribe primary prophylaxis for VTE to surgical
patients.230,231 If imaging studies performed for other
reasons (eg, CT scanning for staging of cancer) incidentally detect asymptomatic proximal DVT, the high
frequency of false-positive results in patients without
a prior suspicion of DVT dictates caution in assuming
that a DVT is truly present. Reasons for a high rate
of false-positive results include (1) the imaging technique may not have been optimal for the diagnosis of
DVT, (2) incidentally diagnosed DVT often is seen in
the pelvis where DVT is harder to image (eg, unable
to be assessed with compression ultrasound), and
(3) the prevalence of DVT in asymptomatic patients
is much lower than in symptomatic patients. Consequently, when there is evidence of incidental DVT,
additional diagnostic testing (eg, ultrasound) to confirm the presence of DVT may be necessary. Because
many cases of asymptomatic VTE are detected as PE,
see also section 6.9 of this article for recommendations on the management of this condition.
No randomized trials have evaluated anticoagulant therapy in patients with incidental VTE; therefore, evidence is of moderate quality because of
indirectness. Moreover, benefits of anticoagulant
therapy may be less than in symptomatic patients
because asymptomatic DVT may be chronic or less
extensive and because the prevalence of false-positive
results will be higher than in patients who were suspected of having DVT.
Factors that justify a more-aggressive approach to
anticoagulation in patients with incidentally diagnosed
DVT include certainty of diagnosis, extensive thrombosis that appears to be acute (eg, not present on a
previous imaging study), progression of thrombosis
on a follow-up imaging study, ongoing risk factors for
VTE (eg, cancer), and a low risk of bleeding. A lessaggressive approach to anticoagulation could include
(1) withholding of anticoagulation with surveillance
to detect DVT extension or (2) limiting anticoagulant
therapy to 3 months in patients with continuing risk
factors for VTE (eg, cancer). Many patients have left
the hospital by the time incidental DVT is reported.
If it would be difficult for patients to return the same
day, it is often reasonable to defer further assessment
and anticoagulant therapy until the next day.
Recommendation
have asymptomatic DVT of the leg, we suggest
the same initial and long-term anticoagulation
as for comparable patients with symptomatic
DVT (Grade 2B).
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4.0 PTS of the Leg
PTS is a cluster of leg symptoms and signs attributable to previous DVT. PTS occurs in about one-third
of patients after acute DVT and up to two-thirds who
have had an iliofemoral DVT.102,232 The initial treatment of acute DVT, particularly with the use of
thrombus removal strategies, may influence the risk
of developing PTS (section 2.8). The most prominent
symptoms are chronic dependent swelling and pain,
discomfort on walking, and skin discoloration. The
severity of symptoms may vary over time, and the most
severe manifestation is a venous ulcer of the lower
leg. In this section, we address prevention of PTS
first and then its treatment. Unlike the last edition
of these guidelines,6 we do not address treatment of
leg ulcers associated with venous insufficiency.
4.1 Compression Stockings and Bandages
to Prevent PTS
Five randomized trials evaluated compression stockings used at various times after diagnosis of acute
DVT for the prevention of PTS (Tables S32 and
S33).201,202,233-235 Two of these trials163,164 randomized
patients soon after diagnosis of a first episode of
symptomatic proximal DVT to prolonged use of
stockings (30-40 mm Hg pressure at the ankles) or
no stockings and otherwise treated patients the same
way (Table 24, Table S34). These trials suggest that
compression stockings started within 2 weeks of DVT
and continued for 2 years reduce PTS by about 50%
and do not alter the frequency of recurrent VTE.
Patients with proximal DVT and a previous DVT in
the same leg and who have marked symptoms are
expected to gain the most benefit from compression
stockings.102,201,202 The evidence is of moderate quality
because the assessment of PTS, which includes a
large subjective component, was not blinded, and the
estimate for recurrent VTE was imprecise.
Compression stockings applying an ankle pressure
of 30 to 40 mm Hg and a lower pressure higher up
the leg (ie, graduated pressure) should be started as
soon as feasible after starting anticoagulant therapy.
Bandages may be used to provide initial compressive
therapy because it may not be possible to fit compression stockings immediately and if stockings can be
worn, a rapid decrease in leg swelling will require them
to be refitted. The findings from a randomized trial of
69 patients suggest that immediate compression bandaging improves acute symptoms but does not reduce
PTS at 1 year (RR, 0.9; 95% CI, 0.4-1.8).236 Patients or
their caregivers need to be able to apply and remove
stockings for their use to be feasible. Alternative
approaches to the use of stockings, such as routinely
wearing stockings after acute DVT but stopping them
if there are no symptoms of PTS after 6 months235,237 or
only wearing stockings if there is persistent leg swelling, have not been adequately evaluated.
Recommendation
4.1. In patients with acute symptomatic DVT
of the leg, we suggest the use of compression
Remarks: Compression stockings should be worn
for 2 years, and we suggest beyond that if patients
have developed PTS and find the stockings helpful.
Patients who place a low value on preventing PTS or
a high value on avoiding the inconvenience and discomfort of stockings are likely to decline stockings.
4.2 Physical Treatment of PTS
Treatment of PTS with compression stockings
has only been evaluated in two small trials233,238
(Table 25, Tables S35 and S37) (all patients received
rutosides in one study238). These studies did not find
compression stockings to be of benefit. However, the
quality of the evidence is low because of imprecision
and risk of bias. There is anecdotal evidence that
compression therapy is of benefit in many patients
with PTS, and the potential benefit of a trial of compression stockings in individual patients is likely to
outweigh its harm and cost. We suggest below-knee
stockings in most patients, but thigh-length stockings
may be preferable in those with marked thigh swelling.
Two small crossover randomized trials have evaluated the treatment of severe PTS with intermittent
compression devices239,240 (Table 26, Table S36). Both
studies suggested benefit from intermittent compression therapy. The quality of the evidence, however, is
moderate because of imprecision. The goal of intermittent compression therapy is to reduce PTS symptoms rather than to alter the natural history of its
development. These devices can be used with or
without compression stockings, depending on patient
preference. Leg swelling and associated symptoms
(eg, heaviness, tightness) are more likely to respond
to compression stockings or intermittent compression devices than are other symptoms.
Table 24—[Section 4.1] Summary of Findings: Elastic Compression Stockings vs No Elastic Compression Stockings
to Prevent PTS of the Lega,b,451
Outcomes
No. of Participants
Quality of the
Evidence (GRADE)
Relative Effect
(95% CI)
Risk With No Elastic
Compression Stockings
Risk Difference With Elastic
Compression Stockings (95% CI)
PTS
RR 0.46
(0.34-0.63)d
RR 1.01
(0.61-1.67)d
…
479 per 1,000e,f
Recurrent
VTE
QOL not
reported
Moderatec due to risk
of bias
Moderateh,i due to
imprecision
…
259 fewer per 1,000
(from 177 fewer to 316 fewer)g
2 more per 1,000
…
210 per 1,000j
k
uncertain about the estimate. See Table 1, 3 and 10 legends for expansion of abbreviations.
aPrandoni et al202 excluded patients with recurrent ipsilateral DVT, preexisting leg ulcers, or signs of chronic venous insufficiency, bilateral
thrombosis, a short life expectancy or a contraindication for use of stockings (eg, advanced-stage peripheral arterial insufficiency). Brandjes et al201
excluded patients with short life expectancy, paralysis of the leg, bilateral thrombosis, leg ulcers, or extensive varicosis.
bBrandjes201 used graded elastic compression stockings (40 mm Hg of pressure at the ankle, 36 mm Hg at the lower calf, and 21 mm Hg at the upper
calf); stockings were applied 2 to 3 wk after the first episode of proximal DVT. Prandoni et al202 used flat-knitted stockings (30 to 40 mm Hg of
pressure at the ankle); stockings were started at hospital discharge, an average of 1 wk after admission. In both studies, stockings were used for 2 y.
cPatients were not blinded to the treatment assignment, and outcomes were partly based on subjective report of symptoms.
dThe effect estimate shown here results from a meta-analysis (Mantel-Haenszel fixed-effects model) of the two relevant trials. A fixed-effects model
was chosen because of the small number of studies available.
eThis estimate is based on the findings of the VETO study.70 This probably underestimates PTS baseline risk given that overall, 52% of patients
fIn Prandoni et al,202 most events occurred during the first 6 mo. The cumulative incidence of the PTS in the control group was 40% after 6 mo, 47%
after 1 y, and 49% after 2 y.
gSevere PTS: assuming the same RR of 0.46 and a baseline risk of 8.1% over 2 y, the absolute reduction is 44 fewer severe PTS per 1,000 (from
30 fewer to 53 fewer) over 2 y.
hWe did not rate down the quality of evidence for recurrent VTE for the lack of blinding because this a more objective outcome than PTS.
iCI includes both negligible effect and appreciable benefit or appreciable harm.
jThis estimate is the mean of two estimates derived from two studies: 12.4% probable/definite VTE (Heit et al165) and 29.1% confirmed VTE
(Prandoni et al208).
kThis is an important outcome that should be considered in future studies.
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e461S
Recommendations
sion. Furthermore, rutosides may be associated with
important side effects.
Recommendation
4.2.2. In patients with severe PTS of the leg
that is not adequately relieved by compression stockings, we suggest a trial of an intermittent compression device (Grade 2B).
4.3. In patients with PTS of the leg, we suggest
that venoactive medications (eg, rutosides, defibrotide, and hidrosmin) not be used (Grade 2C).
4.3 Pharmacologic Treatment of PTS
Remarks: Patients who value the possibility of response
over the risk of side effects may choose to undertake
a therapeutic trial
Hydroxyrutosides, a class of flavonoid drug produced from plant glycosides, may reduce capillary
permeability, reduce inflammation, improve lymphatic function, and promote ulcer healing in patients
with chronic venous insufficiency.6,241,242 Two studies
compared treatment of PTS (without ulceration) with
rutosides vs control238,243 (all patients wore compression stockings in one study238), and one study compared rutosides with hidrosmina244(Table S37). The
two controlled studies suggest that rutosides do not
reduce most symptoms of PTS, although they may
reduce ankle swelling (Table 27). This evidence is
of low quality because of inconsistency and impreci-
5.0 Initial Treatment of Acute PE
As we noted in Methods (section 1.1), recommendations for management of patients with PE, particularly those addressing anticoagulant therapy and IVC
filter insertion, are based on studies that enrolled
patients with only DVT , patients with both DVT and
PE, and patients with only symptoms of PE. The
following sections emphasize studies that enrolled
only patients with symptoms of PE (who could also
have symptoms of DVT), emphasize differences in
Table 25—[Section 4.2.1] Summary of Findings: Compression Stockings vs No Compression Stockings for Patients
With PTSa-c,233,238
Outcomes
Symptomatic relief
treatment successg
QOL not reported
Recurrent VTE not
reported
Ulcerationh not
reported
No. of Participants
115 (2 studies),
12 to 26 mo
…
…
…
Quality of the
Evidence (GRADE)
Relative Effect
Risk With No
(95% CI)
Lowd-f due to risk of bias RR 0.96
and imprecision
(0.70-1.31)
Not estimable
Not estimable
579 per 1,000
(95% CI)
fewer to 179 more)
Not estimableh
uncertain about the estimate. CLOTS1 5 Clots in Legs or Stocking After Stroke. See Table 1 and 3 legends for expansion of other abbreviations.
aGinsberg et al233 included patients with PTS 1 y after chronic, typical proximal DVT. Frulla et al238 included patients with clinical symptoms and
signs suggestive of PTS.
bGinsberg et al233: Graduated compression stockings (30-40 mm Hg, calf or thigh length, depending on symptoms). Patients were encouraged to
wear stockings as much as possible during waking hours. Frulla et al238: below-knee graded elastic compression stockings (ECS) (30-40 mm Hg at
the ankle). Patients in both study arms received hydroxyethylrutosides (HR) (we considered the ECS 1 HR vs HR comparison).
cGinsberg et al233: placebo stockings (calf or thigh length, depending on symptoms).
dGinsberg et al233: Adequacy of sequence generation and allocation concealment were unclear; patients and outcome assessors were adequately
blinded; unclear whether analysis followed the intention-to-treat principle; unclear whether follow-up was complete. Frulla et al238: outcome
assessors were blinded; follow-up was complete; intention-to-treat principle was adhered to, but sequence generation and allocation concealment
were unclear, and patients were not blinded.
eVery small number of patients
fPublication bias was not detected but not ruled out given that we identified only one small study partially supported by industry (provision of
graduated compression stockings).
gGinsberg et al233 reported treatment failure (defined a priori based on any of five clinical criteria, including symptoms and ulcer development).
Treatment success refers to the absence of treatment failure. Frulla et al238 used the Villalta scale.
hIndirect evidence from the CLOTS1 trial suggests that compression stockings is associated with an RR of 4 for skin complications.
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Table 26—[Section 4.2.2] Summary of Findings: Intermittent Compression Device vs No Intermittent Compression
Device for Patients With Severe PTSa-c,233,240
No. of
Participants
(Studies),
Follow-up
Outcomes
Quality of
the Evidence
(GRADE)
Relative
Effect (95%
CI)
Symptomatic relief: symptom
82 (2 studiesd), Moderatee-i due
8 wk
to imprecision
score includes scoring of pain,
swelling, and limitation of
activity on a scale of 10-70
QOL: VEINES-QOL scale of
0 (1 studyd,j),
Moderateg-i,k,l due
0-100.
8 wk
to imprecision
Recurrent VTEm not reported
Ulcerationn not reported
…
…
Risk With No
Intermittent
Compression Device
Intermittent Compression
Device (95% CI)
The mean symptomatic The mean symptomatic relief in
relief in the control
the intervention groups was
groups was 0
0.41 SDs higher (0.02 lower
to 0.85 higher)
The mean QOL in the The mean QOL in the
control groups was
intervention groups was 2.3
50.2
higher (1.04 lower to 5.64
higher)
Not estimablem
Not estimablen
uncertain about the estimate. VEINES 5 Venous Insufficiency Epidemiological and Economic Study. See Table 1, 3, and 25 legends for expansion
of other abbreviations.
aPatients with previous DVT with symptoms of severe PTS.
bIntervention group: Ginsberg et al239: Extremity pump used bid for 20 min each session; 50 mm Hg (therapeutic pressure) for 1 mo. O’Donnell et al240:
Venowave lower-limb venous return assist device to wear for most of the day for 8 wk.
cControl group: Ginsberg et al239: Extremity pump used bid for 20 min each session; 15 mm Hg (placebo pressure) for 1 mo. O’Donnell et al240:
Venowave lower-limb venous return assist device with no connection between motor and planar sheet for 8 wk.
dCrossover RCTs.
eIn both studies, sequence generation was adequate; patients were blinded, analysis adhered to intention-to-treat principle, and there were no
missing outcome data. In Ginsberg et al239 (but not O’Donnell et al240), outcome assessors were not blinded, and it was not clear whether allocation
was concealed.
fI2 5 0%.
gSome concerns with indirectness, given relatively short follow-up (8 wk).
hVery small number of patients. CI includes both values suggesting no effect and values suggesting a beneficial effect.
iPublication bias not detected but not ruled out given that we identified only two small studies, with one (Ginsberg et al239) partially supported by
industry (provision of devices).
jO’Donnell et al et al.240
kSequence generation was adequate; patients were blinded, analysis adhered to intention-to-treat principle, and there were no missing outcome
data. However, outcome assessors were not blinded, and it was not clear whether allocation was concealed.
lPublication bias was not detected but not ruled out given that we identified only a small study.
mO’Donnell et al240 indicated no cases of recurrent VTE by the end of this study but judged the follow-up period to be short.
nO’Donnell et al240 indicated that one patient in the control group developed a venous ulceration. Three other participants developed nonserious
skin-related side effects. Indirect evidence from the CLOTS1 suggests that compression stockings are associated with an RR of 4 for skin
complications. Common side effects attributed to Venowave were heat sensation, skin irritation, and increased sweating.
the management of patients who present with PE
compared with DVT, and make recommendations
for the management of patients with PE. We do not
repeat evidence that was presented in the corresponding section that addresses treatment of DVT;
instead, the reader is directed to those sections of the
article and to the related tables. We do not comment
in the text on the quality of the evidence that underlies treatment recommendations for PE unless the
quality of this evidence differs from that for patients
who present with DVT.
5.1 Initial Anticoagulation for Acute PE
See section 2.1, Table 3, and Table S1.
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Recommendation
initial treatment with parenteral anticoagulation (LMWH, fondaparinux, IV UFH, or SC
UFH) over no such initial treatment (Grade 1B).
5.2 Whether to Treat With Parenteral
Anticoagulation While Awaiting the
Results of Diagnostic Work-up for PE
See section 2.2. For the purpose of implementing this recommendation, validated prediction rules
help with estimation of clinical probability of having
PE.55,56
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Table 27—[Section 4.3] Summary of Findings: Venoactive Medication vs No Venoactive Medication for Patients With
PTSa,b,202,238
No. of
Participants
(Studies),
Follow-up
Outcomes
Symptomatic relief: PTS score
(Villalta scale) , 5 or decreased by 30%
at 12 mo compared with baseline in
Frulla et al238; improved tiredness of
the leg at 8 wk in de Jongste et al243,c
QOL not reported
Recurrent VTE not reported
Ulceration not reported
Side effects
163 (2 studies)
…
…
…
203 (2 studies)
Quality of
the Evidence
(GRADE)
Lowd-g due to
inconsistency,
imprecision
Moderated,f-h due
to imprecision
Relative Effect
(95% CI)
Risk With No
Venoactive
Medication
Risk Difference
With Venoactive
Medication (95% CI)
RR 1.14 (0.85-1.52)
476 per 1,000
67 more per 1,000
(from 71 fewer to
247 more)
Not estimable
Not estimable
Not estimable
RR 2.04 (0.76-5.51)
61 per 1,000
63 more per 1,000
(from 15 fewer to
275 more)
aPatients with PTS and history of DVT in PTS leg.
bIncluded studies that assessed rutosides.
cInvestigators assessed other symptoms (pain, heaviness, swelling feeling, restless legs, and cramps) but did not report a composite score. The symptom
we chose to report showed the most benefit; the effect estimates for the other symptoms ranged from 0.8 to 1.4, and none were statistically significant.
dIn both studies, sequence generation and allocation concealment were unclear. Both studies blinded outcome assessors and had complete followup. Although de Jongste et al243 blinded patients, the authors did not adhere to the intention-to-treat principle and did not use a validated scale to
measure symptomatic relief. Although Frulla et al238 adhered to the intention-to-treat principle, the author did not blind patients.
eI2 5 77%.
fSmall number of patients. CI included both values suggesting harms and values suggesting benefits.
gPublication bias was not detected but not ruled out given that we identified only two small studies, and it unclear whether they were funded by
industry.
hI2 5 7%.
Recommendations
Recommendation
tests (Grade 2C).
(Grade 2C).
acute PE, we suggest not treating with parenteral
anticoagulants while awaiting the results of
diagnostic tests provided that test results are
See section 2.4, Table 4, and Table S2.
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5.4 Choice of Initial Parenteral Anticoagulant
Regimen in Patients With PE
See section 2.5.
LMWH Compared With IV UFH for the Initial
Treatment of PE: See section 2.5 and Table 6. Consistent with findings in patients with DVT, LMWH
has been found to be as effective and safe as IV UFH
in studies that included both patients with PE
and DVT or only in patients with PE (Table 6).
A meta-analysis of 12 studies85,146,245-254 that included
a total of 1,951 patients with either submassive symptomatic PE or asymptomatic PE in conjunction
with symptomatic DVT failed to demonstrate or
exclude a beneficial or detrimental effect of LMWH
on recurrent VTE (OR, 0.63; 95% CI, 0.33-1.18),
major bleeding (OR, 0.67; 95% CI, 0.36-1.27), and
all-cause mortality (OR, 1.20; 95% CI, 0.59-2.45).255
SC UFH Compared With SC LMWH for the Initial Treatment of PE: See section 2.5, Table 5, and
Tables S3 through S5.
Fondaparinux Compared With IV UFH for the Initial Treatment of PE: The Matisse-PE trial compared
fondaparinux with IV UFH for acute treatment of
PE79 (Table 28, Table S38). This study suggested that
fondaparinux is associated with a similar frequency of
mortality, recurrent VTE, and major bleeding as
LMWH. The quality of this evidence is moderate
because of imprecision. In making recommendations,
we also considered evidence that fondaparinux is equivalent to LMWH for the treatment of DVT (see section 2.5, Table 7, and Table S38) and that fondaparinux
shares the advantages that LMWH has over IV UFH.
Fondaparinux Compared With LMWH for the Initial Treatment of PE: In the absence of direct evidence in patients with PE, indirect evidence in
patients with acute DVT (see section 2.5, Table 7,
and Table S7) suggests that fondaparinux is equivalent to LMWH.
Fondaparinux Compared With SC UFH for the
Initial Treatment of PE: There is no direct evidence
for this comparison. In making recommendations, we
considered that fondaparinux and LMWH are equivalent and that fondaparinux shares the advantages
that LMWH has over IV UFH. We did not take into
account the lower purchase cost of SC UFH compared with fondaparinux.
Once- vs Twice-Daily Administration of LMWH
for Initial Treatment of PE: See section 2.5, Table 8,
and Table S8. Patients who presented with PE were
included in only one of the five studies with an
unconfounded comparison of once- and twice-daily
LMWH85 and in one additional large study that compared once-daily LMWH therapy with IV UFH in
patients who presented with PE.252
Recommendations
for LMWH; Grade 2B for fondaparinux), and over
fondaparinux).
In patients with PE where there is concern about
the adequacy of SC absorption or in patients in whom
Table 28—[Section 5.4] Summary of Findings: Fondaparinux vs IV UFH for Initial Anticoagulation of Acute PEa-c,79
Outcomes
No. of Participants
Mortality
2,213 (1 study), 3 mo
Recurrent VTE
2,213 (1 study), 3 mo
Major bleeding
2,213 (1 study), 3 mo
Quality of the
Evidence
(GRADE)
Moderated,e due
to imprecision
Moderated,e due
to imprecision
Moderated,e due
to imprecision
Relative Effect
(95% CI)
Risk With UFH
RR 1.20 (0.82-1.74)
43 per 1,000
RR 0.75 (0.51-1.12)
50 per 1,000f
RR 0.85 (0.49-1.49)
23 per 1,000g
9 more per 1,000 (from 8 fewer
to 32 more)
to 6 more)
to 11 more)
aAll patients had acute, symptomatic, hemodynamically stable PE.
bFondaparinux (5.0, 7.5, or 10.0 mg in patients weighing , 50, 50 to 100, or . 100 kg, respectively) SC once daily given for at least 5 days and until
the use of VKAs resulted in an INR . 2.0.
cUFH continuous IV infusion (ratio of the activated partial thromboplastin time to a control value of 1.5-2.5) given for at least 5 days and until the
use of VKAs resulted in an INR . 2.0.
dAllocation was concealed. Patients, providers, and data collectors were not blinded. Outcome adjudicators were blinded; 0.6% of randomized
patients were lost to follow-up. Not stopped early for benefit.
fSixteen fatal VTE in fondaparinux group and 15 fatal VTE in UFH group.
gFourteen patients in the fondaparinux group and 12 patients in the LMWH group had a major bleeding event during the initial period (6-7 d). Of
these, one in the fondaparinux group and one in the UFH group were fatal.
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e465S
thrombolytic therapy is being considered or planned,
initial treatment with IV UFH is preferred to use of
SC therapies.
Remarks: This recommendation only applies when the
approved once-daily regimen uses the same daily dose
as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily
injection). It also places value on avoiding an extra
injection per day.
5.5 Early vs Standard Discharge of Patients
With Acute PE
Consistent with our discussion of outpatient treatment of acute DVT (section 2.7), LMWH has made
it feasible to treat acute PE at home either without
admission to the hospital (ie, discharge from the
emergency department) or with admission and early
discharge. However, because acute PE is associated
with much higher short-term mortality than acute
DVT, the safety of treating PE at home is uncertain.
Consequently, PE is treated at home much less often
than DVT, and the proportion of outpatients with PE
that clinical centers treat at home varies from almost
none to about 50%.
Two studies randomized patients with acute PE
and a low risk of complications to receive LMWH
either (1) in the hospital for only 3 days vs entirely in
the hospital256 or (2) entirely out of the hospital (discharged within 24 h) vs at least partly in hospital257
(Table 29, Table S39). This evidence suggests that
treating appropriately selected patients with acute
PE at home does not increase recurrent VTE,
bleeding, or mortality.
There are a number of prediction rules for identifying patients with acute PE who have a low risk of
serious complications and may be suitable for treatment at home.258-263 Of these, the PE Severity Index
(PESI) is best validated261,262,264-266 and was used to
select patients for home treatment in the larger of the
previously noted clinical trials (Table 29, Table S39).
Patients with acute PE who meet the following
criteria appear to be suitable for treatment out of
the hospital: (1) Clinically stable with good cardiopulmonary reserve (eg, PESI score of , 85257 or
simplified PESI score of 0,262 including none of
hypoxia, systolic BP , 100, recent bleeding, severe
chest pain, platelet count , 70,000/mm3, PE while
on anticoagulant therapy, and severe liver or renal
disease)257, (2) good social support with ready access
to medical care, and (3) expected to be compliant
with follow-up. Patients also need to feel well enough
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to be treated at home (eg, absence of severe symptoms or comorbidity).
Consistent with the findings of these two trials, a
systematic review of 11 observational studies (seven
prospective, four retrospective; 928 patients)267 and
four more recent observational studies (two retrospective with 584 patients268,269; two prospective with
449 patients270,271) reported a very low frequency of
complications in low-risk patients with acute PE who
were initially treated partially or entirely at home.
About one-third to one-half of outpatients with acute
PE appear to be in this low-risk group.272 The evidence
from the randomized trials is of moderate quality
(rated down for serious imprecision), with additional
supportive findings from the observational studies.
Recommendation
after the first 5 days of treatment) (Grade 2 B).
Remarks: Patients who prefer the security of the hospital to the convenience and comfort of home are
likely to choose hospitalization over home treatment.
5.6 Systemic Thrombolytic Therapy for PE
5.6.1 Systemic Thrombolytic Therapy vs Anticoagulation Alone for PE: Randomized trials have established that, at 24 h, thrombolytic therapy improves
(1) pulmonary artery hemodynamic measurements
(eg, mean pulmonary artery pressure improvement,
4.4 mm Hg; 95% CI, 24.6-4.2 mm Hg), (2) arteriovenous oxygen (difference of 20.3 [20.4 to 20.2]),
(3) pulmonary perfusion (50% early improvement in
perfusion scan, OR, 3.8; 95% CI, 0.9-15.7), and (4) echocardiographic assessment (OR for improved right
ventricular wall movement, 3.1; 95% CI, 1.5-6.3).273
Thrombolytic therapy, however, does not appear to
reduce the extent of residual thrombosis. It is uncertain whether the benefits of more-rapid resolution of
PE outweigh the risk of increased bleeding associated with thrombolytic therapy. In patients with PE,
severity of presentation is expected to depend on the
extent of embolism (ie, degree of pulmonary artery
obstruction) and the presence and severity of chronic
cardiopulmonary impairment.104,274,275 Patients with
the most severe presentations who have the highest
risk of dying from an acute PE have the most to gain
from thrombolysis.
Prognosis in Patients With Acute PE—Of patients
who are diagnosed with PE and start treatment, !5%
die of the initial PE or another PE within the next
7 days.9,104,276-279 However, although the risk of dying
of PE differs markedly among patients, no validated
Table 29—[Section 5.5] Summary of Findings: Early Discharge vs Standard Discharge in the Treatment of
Acute PEa,b,256,257
Outcomes
No. of Participants
Quality of the
Evidence (GRADE)
Mortality
Nonfatal recurrent PE
Major bleeding
Moderatec,d due to
imprecision
Moderatec,d due to
imprecision
Moderatec,d due to
imprecision
…
…
QOL not reported
PTS not reported
…
…
Relative Effect
(95% CI)
Risk With Standard
Discharge
Risk Difference With Early
Discharge (95% CI)
RR 0.58 (0.17-1.97)
26 per 1,000
RR 1.23 (0.25-6.03)
9 per 1,000
RR 2.74 (0.45-16.71)
4 per 1,000
fewer to 26 more)
fewer to 44 more)
fewer to 69 more)
…
…
…
…
…
…
aThe two RCTs included only patients with low risk: risk classes I or II on the Pulmonary Embolism Severity Index in Aujesky et al216; low risk on
clinical prediction rule by Uresandi et al.258
bMean length of hospital stay: 3.4 (SD 1.1) vs 9.3 (SD 5.7) d in Otero et al256 and 0.5 (SD 1.0) vs 3.9 (SD 3.1) d in Aujesky et al257; low risk on clinical
prediction rule by Uresandi et al258 in Otero et al.
cOtero et al256: allocation concealed; no patients lost to follow-up; intention-to-treat analysis; no blinding of outcome assessors reported; study
stopped early because the rate of short-term mortality was unexpectedly high in the early discharge group (2 [2.8%] vs 0 [0%]). Aujesky et al257:
unclear whether allocation was concealed; three (1%) patients had missing outcome data; intention-to-treat analysis; blinding of outcome
adjudicators; no early stoppage.
dCI includes both values suggesting no effect and values suggesting appreciable harm or appreciable benefit.
risk prediction tool is available. Risk of dying of PE
is estimated to be !70% if cardiopulmonary arrest
occurs (!1% of patients at presentation), 30% if
there is shock requiring inotropic support (!5%
of patients), and !2% in patients who are not
hypotensive.104,276-278,280,281 In the presence of normal
systemic arterial pressure, prognosis can also differ,
depending on (1) clinical evaluation,276 (2) cardiac
biomarkers such as troponin or brain natriuretic
peptide,279,282-291 and (3) assessment of right ventricular size and function.279,280,283,285,290-295
Clinical evaluation involves assessment of general
appearance, BP, heart rate, respiratory rate, temperature, pulse oximetry, and signs of right ventricular
dysfunction (eg, distended jugular veins, tricuspid
regurgitation, accentuated P2).104 Clues on the ECG
include right bundle branch block, S1Q3T3, and
T-wave inversion in leads V1 through V4.296 Elevation
of cardiac troponins indicates right ventricular microinfarction, and echocardiography may show right ventricular hypokinesis; both are risk factors for early
mortality and are associated with a worse outcome
when they occur together.238,241-245,250 Right ventricular
enlargement on the CT pulmonary angiogram, defined
as a right ventricular diameter ! 90% than the left
ventricular diameter may also be an independent risk
factor for death and nonfatal complications.279,291,293,295,297
Risk of Bleeding With Thrombolytic Therapy—
We have not identified any validated risk predicwww.chestpubs.org
tion tool for bleeding with thrombolytic therapy
in patients with PE. However, we assume that the
assessment of bleeding risk with thrombolytic therapy is similar in patients with PE and with acute
ST-segment elevation myocardial infarction.104,110-113,298,299
Table 11 lists risk factors for bleeding with thrombolytic
therapy, categorized as major and relative contraindications.
Trials Evaluating Thrombolytic Therapy in Patients
With Acute PE—The findings of 13 randomized
trials that compared thrombolytic therapy to anticoagulant therapy alone in patients with acute PE are
summarized in Table 30 and Tables S40 through
S42.300-313 A number of meta-analyses of these studies
have been performed.104,273,315,315 This evidence suggests that thrombolysis may be associated with a reduction in mortality and recurrent PE and is associated
with an increase in major bleeding, as has been established in patients with myocardial infarction.112 The
quality of evidence regarding mortality and recurrent
PE is low because of risk of bias, serious imprecision,
and suspected publication bias. A previous metaanalysis that categorized studies as either including,
or not including, patients with cardiopulmonary compromise, suggested that thrombolytic therapy reduced
the composite outcome of death and recurrent PE in
studies that included the sickest patients.315 However,
we found that the data available from these studies
are not sufficiently detailed to enable a subgroup
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analysis evaluating outcomes in patients with hemodynamic compromise or other markers of heightened
risk of death (eg, right ventricular dysfunction).
Balancing Benefits and Harms of Thrombolytic
Therapy—In patients who present with PE and
hypotension (eg, systolic pressure BP , 90 mm Hg or
a documented drop in systolic BP . 40 mm Hg with
evidence of poor perfusion), especially if they have a
low risk of bleeding, even modest efficacy of thrombolytic therapy is likely to reduce deaths from PE
more than it would increase fatal bleeds and nonfatal
intracranial bleeds (Table 30, Tables S40-S42). The
ultimate judgment of the entire AT9 panel was to
issue a weak recommendation for patients with PE
and hypotension given the uncertainty of the benefit.
In most patients with PE, given the certain risks of
bleeding and less-certain benefits, thrombolysis is
likely to be harmful. Selected patients without hypotension may benefit from thrombolysis because their
initial clinical presentation or clinical course after
starting anticoagulant therapy suggest that they are at
high risk of dying.
There is no explicit clinical prediction rule that
identifies this subgroup of patients. We suggest that
such patients are identified predominantly by clinical
evidence of instability (eg, a decrease in systolic BP
that still remains . 90 mm Hg, tachycardia, elevated
jugular venous pressure, clinical evidence of poor
tissue perfusion, hypoxemia) and failure to improve
on anticoagulant therapy. As noted previously, laboratory (eg, troponin, brain natriuretic peptide), ECG,
echocardiography, and CT evidence of right ventricular dysfunction or enlargement, can supplement the
clinical evaluation of instability; however, they are
not sufficiently predictive to serve as indications for
thrombolytic therapy on their own,289 and we do not
recommend that they are routinely measured.
Recommendations
who do not have a high risk of bleeding, we suggest systemically administered thrombolytic
(Grade 1C).
associated with hypotension and with a low risk
of bleeding whose initial clinical presentation
or clinical course after starting anticoagulant
therapy suggests a high risk of developing hypoe468S
tension, we suggest administration of thrombolytic therapy (Grade 2C).
5.6.2 Systemic Thrombolytic Therapy Regimen for
PE: Twelve randomized trials (total of 938 patients)
have compared the rate of thrombus resolution
achieved with various IV thrombolytic regimens.316-327
These regimens included urokinase given over 2 h319,326
or 12 h316,321,326; streptokinase given over 2 h, 12 h,320
or 24 h316; and recombinant tPA (rt-PA) given over
15 min317,322,325 or 2 h,317-325,327 reteplase in two boluses
30 min apart,325 and desmoteplase in three different
doses as a bolus323.
An additional study compared IV with pulmonary
artery catheter administration of rt-PA (50 mg over
2 h).328 The results of studies that compared different
approaches to thrombolysis in patients with PE
(noted previously) suggest that (1) prolonged infusions
of thrombolytic agents (eg, ! 12 h) are associated
with higher rates of bleeding316,318; (2) 2-h infusions achieve more rapid clot lysis than 12- or 24-h
infusions318,320,321; (3) when a high-concentration 2-h
infusion of thrombolysis is administered, there is no
clear difference in the efficacy or safety of rt-PA
vs streptokinase327; (4) bolus rt-PA regimens (eg, !50 mg
in " 15 min) appears to be as effective and safe as
a 2-h infusion of 100 mg of rt-PA313,317,322,325; and (5)
infusion of rt-PA directly into a pulmonary artery as
opposed to a peripheral vein does not accelerate
thrombolysis but does cause more frequent bleeding
at the catheter insertion site (there was no attempt
to infuse rt-PA directly into or to mechanically disrupt the thrombus in this study from 1988).328 When
a lytic agent is appropriate for PE, current evidence
supports that thrombolytic therapy should be infused
into a peripheral vein over " 2 h. At a dose of 100 mg
over 2 h, rt-PA is currently the most widely used and
evaluated regimen. In patients with imminent or
actual cardiac arrest, bolus infusion of thrombolytic
therapy is indicated.
The quality of evidence for comparisons of systemic
thrombolytic agents and regimens (eg, different
doses or durations of infusion) is low based on very
serious imprecision and risk of bias. In addition,
there is substantial potential for publication bias.
Based on this evidence, we provide only weak recommendations for all comparisons of thrombolytic
agents and regimens in the short-term treatment
of PE.
Recommendations
Table 30—[Section 5.6.1] Summary of Findings: Systemic Thrombolytic Therapy vs Anticoagulation Alone in
Patients With Acute PEa-d,273,309,310,314,315
Outcomes
Mortality
No. of Participants
847 (12 studies),
30 d
Quality of the
Evidence (GRADE)
Lowe-h due to risk of
bias and imprecision
Relative Effect
(95% CI)
RR 0.7
(0.37-1.31)
Risk With No
Systemically Administered
Systemically Administered
Thrombolytic Therapy
Thrombolytic Therapy (95% CI)
11 per 1,000
89 per 1,000
Recurrent PE
801 (9 studies),
30 d
Major bleeding 847 (12 studies),
10 d
Lowe-h due to risk of bias
and imprecision
Moderatee,f,h,k due to
risk of bias and
imprecision
RR 0.7
(0.4-1.21)
RR 1.63
(1-2.68)l
57 per 1,000
1 per 1,000
62 per 1,000
Lowi,j
fewer to 3 more)
Highi,j
fewer to 28 more)
fewer to 12 more)
Lowm
1 more per 1000 (from 0 more
to 2 more)
Highm
39 more per 1,000 (from 0 more
to 104 more)
aOne study included exclusively patients with hemodynamic compromise (shock), six excluded them, whereas the rest either included a
number of such patients or did not specify related eligibility criteria. Of studies not restricted to patients with hemodynamic compromise
(n 5 11), only three were clearly restricted to patients with right ventricular dysfunction; the rest either did not specify related eligibility
criteria or included both patients with and without right ventricular dysfunction. As a result, it was not possible to perform reliable
categorization of studies to conduct subgroup analyses based on the presence or absence of right ventricular dysfunction or hemodynamic
compromise.
bStudies included patients at low risk for bleeding.
cIncluded studies that used different thrombolytic agents with varying doses and durations of administration; no statistical heterogeneity was
noted.
dThrombolysis was in addition to anticoagulation (most of the studies used heparin followed by warfarin; three studies used warfarin only).
eReport of methodologic quality was poor in most studies. Of the 12 eligible studies, allocation was concealed in five, three were single blind
(outcome assessor), six were double blind, and three were not blinded. Most studies did not report on missing outcome data. None of the studies
were stopped early for benefit. For the increase in bleeding with thrombolytic therapy, quality of evidence is increased from low to moderate
because there is high quality evidence of this association in patients with myocardial infarction and the indirectness of this evidence to patients with
PE is minor.
fI2 5 0%.
gCI includes values suggesting both benefit and no effect or harm; small number of events.
hInverted funnel plots suggestive of possible publication bias in favor of thrombolytics.
iRecurrent PE stratification based on the simplified Pulmonary Embolism Severity Index validated in the RIETE (Registro
Informatizado de la Enfermedad Tromboembólica) cohort.262
jSome studies suggested that the baseline risk of mortality in patients with hemodynamic instability is as high as 30%.274 In that case, the absolute
number of deaths associated with thrombolytics would be 90 fewer per 1,000 (from 189 fewer to 93 more).
kCI includes values suggesting both harm and no effect; small number of events.
lMajor bleeding risk stratification derived from the RIETE cohort.30 The median risk of bleeding over the first 10 d reported in the eligible trials
was 3.1%. In that case, the absolute number of major bleeding events with thrombolysis would be 20 more per 1,000 (from 0 more to 52 more).
mIndirect evidence from studies of thrombolysis for myocardial infarction and acute stroke provide more precise estimates of increase major
bleeding with thrombolytics use.
5.6.2.2. In patients with acute PE, when a thrombolytic agent is used, we suggest administration
5.6.3 Initial Anticoagulant Therapy in Patients
Treated With Thrombolytic Therapy: Trials that
evaluated thrombolysis for PE used IV UFH in
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conjunction with thrombolytic therapy (Table 30,
Tables S40-S42), and no randomized trials have compared different regimens of IV UFH in this setting.
IV UFH should be given in full therapeutic doses1,3
before thrombolytic therapy is administered, and it
is acceptable to either continue or suspend the
UFH infusion during administration of thrombolytic therapy (these two practices have never been
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compared). During a 2-h infusion of 100 mg of tPA,
US regulatory bodies recommend suspension of IV
UFH, whereas IV UFH is continued during the tPA
infusion in many other countries. US authorities recommend checking the activated partial thromboplastin time immediately after completion of the tPA
infusion and, provided that the activated antithrombin
time is not . 80 s, restarting IV UFH without a bolus
at the same infusion rate as before tPA was started.
5.7 Catheter-Based Thrombus Removal
for the Initial Treatment of PE
Interventional catheterization techniques for massive PE include mechanical fragmentation of thrombus with a standard pulmonary artery catheter, clot
pulverization with a rotating basket catheter, percutaneous rheolytic thrombectomy, or pigtail rotational
catheter embolectomy.329-336 Pharmacologic thrombolysis and mechanical interventions are usually
combined unless bleeding risk is high. Catheter
embolectomy does not result in extraction of intact
pulmonary arterial thrombus; instead, clot fragments
are suctioned through the catheter or displaced distally with modest angiographic improvement.
No randomized trials have evaluated interventional
catheterization techniques for PE. Most observation
studies are retrospective series of , 30 patients.334
Consequently, evidence for the use of interventional
catheter techniques in patients with acute PE is of
low quality, and our recommendations are weak.
Catheter selection, catheter deployment, and adjunctive thrombolytic regimen should be based on local
expertise and resources.
Recommendation
hypotension and who have (i) contraindications
to thrombolysis, (ii) failed thrombolysis, or (iii)
shock that is likely to cause death before systemic
thrombolysis can take effect (eg, within hours),
if appropriate expertise and resources are available, we suggest catheter-assisted thrombus
removal over no such intervention (Grade 2C).
5.8 Surgical Embolectomy for the Initial
Treatment of PE
Emergency surgical embolectomy with cardiopulmonary bypass is another management strategy
for acute PE associated with hypotension.337-340
This operation is also suited for patients with acute
PE who require surgical excision of a right atrial
thrombus, paradoxical arterial embolism, or closure of a patent foramen ovale. Surgical embolectomy also can be performed to rescue patients in
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whom thrombolysis has been unsuccessful. The
procedure is best performed on a warm, beating
heart, without aortic cross-clamping, cardioplegia,
or fibrillatory arrest.
No randomized trials or prospective observational
studies have evaluated surgical embolectomy in patients
with acute PE. Consequently, evidence related to
surgical embolectomy in patients with acute PE is of
low quality, and our recommendations are weak.
Recommendation
embolectomy over no such intervention if
they have (i) contraindications to thrombolysis,
(ii) failed thrombolysis or catheter-assisted
embolectomy, or (iii) shock that is likely to cause
death before thrombolysis can take effect (eg,
within hours), provided surgical expertise and
resources are available (Grade 2C).
5.9. Vena Caval Filters for the Initial
Treatment of PE
As previously noted in section 2.13, IVC filters
can be used instead of initial anticoagulant therapy
in patients with acute PE if there is an unacceptable
risk of bleeding or as an adjunct to anticoagulation.
As in DVT, no randomized trials or prospective
cohort studies have evaluated IVC filters as sole
therapy for acute PE (ie, without concurrent anticoagulation). As described in section 2.13, the PREPIC
study, which evaluated IVC filters as an adjunct to
anticoagulation in 400 high-risk patients with proximal DVT, showed that filters reduced PE, increased
DVT, and did not change overall frequency of VTE
(DVT and PE combined) or mortality146,149 (Table 14;
Table S19).
The PREPIC study included 145 (36%) patients
with symptomatic PE and 52 (13%) patients with
asymptomatic PE at enrollment. If a patient has
an acute PE and a short-term contraindication to
anticoagulation, provided there is no proximal DVT
on ultrasound, it is reasonable not to insert an
IVC filter immediately; serial ultrasound examinations can be performed to ensure that the patient
remains free of proximal DVT while anticoagulation
is withheld.
There is uncertainty about the risk and benefits of
inserting IVC filters as an adjunct to anticoagulant
and thrombolytic therapy in patients with PE and
hypotension. Among patients with hemodynamic
compromise in the International Cooperative Pulmonary Embolism Registry, insertion of an IVC filter
was associated with a reduction of early recurrent
PE and death.280 Consequently, our recommendation
against insertion of an IVC filter in patients with acute
PE who are treated with anticoagulants may not
apply to this select subgroup of patients.
Recommendations
5.9.3. In patients with acute PE and an IVC filter inserted as an alternative to anticoagulation,
we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves
(Grade 2B).
IVC filter of itself is an indication for extended
anticoagulation.
6.0 Long-term Treatment of PE
In the following sections, we emphasize studies
that were performed exclusively in patients with PE
and patients with PE who were enrolled in other
studies. For the reasons noted in section 1.1, we make
the same recommendations for long-term treatment
of PE as for DVT and rate the quality of the underlying evidence as the same (see corresponding sections for treatment of DVT).
VKA for the Long-term Treatment of PE: There
has been only one evaluation of duration of VKA
therapy exclusively in patients with PE. After
3 months of initial treatment, patients with PE provoked by a temporary risk factor were randomized to
stop or to receive 3 more months of therapy, and
those with unprovoked PE were randomized to stop
or to receive 6 more months of therapy (WODIT PE
[Warfarin Optimal Duration Italian Trial in patients
with Pulmonary Embolism]) (Table S24 and S25).194
Consistent with studies that included patients who
presented with DVT, extended VKA therapy was
effective while treatment was being received. However, extending the duration of treatment beyond
3 months did not lower the rates of recurrence that
were observed when anticoagulants were subsequently
stopped.
LMWH for the Long-term Treatment of PE: Two
small studies from the same investigator group have
compared long-term LMWH (enoxaparin 1 mg/kg
SC bid for !14 days followed by 1.5 mg/kg SC daily)
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with long-term VKA exclusively in patients who presented with PE.341,342 The two studies combined found
a similar frequency of recurrent VTE (enoxaparin,
4/60; VKA, 1/40) and major bleeding (enoxaparin,
1/60; VKA, 2/40) with the two treatments.341 Of the
12 other studies that compared LMWH with VKA
therapy for long-term treatment of VTE (see section
3.3), only two173,227 included patients with PE. In
these two studies, all patients had cancer, and 295
had PE (36% of all enrolled patients; some PE may
have been asymptomatic in one study227); subgroup
analyses were not reported for the patients with PE.
Dabigatran for the Long-term Treatment of PE: In
the one completed study that compared dabigatran
with VKA therapy after initial parenteral therapy
(Table 23, Table S31), 786 (31%) patients had symptomatic PE at enrollment.343 Subgroup analysis did
not suggest that patients with symptomatic PE have a
different response to dabigatran vs VKA therapy in
terms of either recurrent VTE or bleeding.
Rivaroxaban for the Long-term Treatment of PE:
In the Einstein Extension study that compared rivaroxaban with placebo after an initial period of longterm anticoagulation (Table 22, Table S30), 454 (38%)
patients had symptomatic PE at enrollment.88 Subgroup analysis did not suggest that patients with
symptomatic PE had a different response to rivaroxaban vs VKA therapy in terms of either recurrent VTE
or bleeding.
Recommendations
bleeding risk).
6.2. In patients with PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i)
treatment of a shorter period (Grade 1B), (ii)
treatment of a longer time-limited period (eg, 6
or 12 months) (Grade 1B), and (iii) extended
therapy if there is a high bleeding risk (Table 2)
(Grade 1B). We suggest treatment with anticoagulation for 3 months over extended therapy
if there is a low or moderate bleeding risk
(Table 2) (Grade 2B).
6.3. In patients with an unprovoked PE, we
recommend treatment with anticoagulation for
at least 3 months over treatment of a shorter
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duration (Grade 1B). After 3 months of treatment, patients with unprovoked PE should be
evaluated for the risk-benefit ratio of extended
therapy.
unprovoked PE and who have a low or moderate
bleeding risk (Table 2), we suggest extended
anticoagulant therapy over 3 months of therapy
(Grade 2B).
have a low bleeding risk (Table 2) (Grade 1B),
and we suggest extended anticoagulant therapy
in those with a moderate bleeding risk (Table 2)
(Grade 2B).
VTE who have a high bleeding risk (Table 2),
we suggest 3 months of therapy over extended
therapy (Grade 2B).
the risk of bleeding is not high (Table 2), we recommend extended anticoagulant therapy over
3 months of therapy (Grade 1B), and if there is a
high bleeding risk (Table 2), we suggest extended
anticoagulant therapy (Grade 2B).
Remarks: In all patients who receive extended
anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals
(eg, annually).
6.6. In patients with PE and no cancer, we suggest
VKA therapy over LMWH for long-term therapy
(Grade 2C). For patients with PE and no cancer
who are not treated with VKA therapy, we suggest
LMWH over dabigatran or rivaroxaban for longterm therapy (Grade 2C).
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with and without cancer is sensitive to individual
patient tolerance for daily injections, need for laboratory monitoring, and treatment costs. Treatment of
VTE with dabigatran or rivaroxaban, in addition to
being less burdensome to patients, may prove to be
associated with better clinical outcomes that VKA
and LMWH therapy. When these guidelines were
being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of
currently available data and that new data are rapidly
emerging, we give a weak recommendation in favor
of VKA and LMWH therapy over dabigatran and
rivaroxaban, and we have not made any recommendations in favor of one of the new agents over the
other.
(Grade 2C).
6.9 Treatment of Asymptomatic PE
Diagnosis of asymptomatic PE occurs in !1% of
outpatients and !4% of inpatients who have contrastenhanced CT scans, with a majority being in patients
with known malignancy.40,344-355 When PE is diagnosed
unexpectedly in patients with cancer, in retrospect,
the clinical history may reveal symptoms that were
aggravated by the PE (eg, an increase in fatigue).345
About one-half of such incidental PE involve the
lobar or more central pulmonary arteries, whereas the
other one-half are more distal.40,353
When there is evidence of an asymptomatic PE,
the first priority is to review the CT scans to determine whether the findings are convincing for acute
PE. Other recent CT scans may be available for comparison, or the current scan may also reveal DVT in
the central deep veins (eg, subclavian vein, IVC, iliac
vein). If there is any uncertainty about the presence of an acute PE, additional diagnostic testing
is required (eg, ultrasonography of the deep veins,
dedicated CT pulmonary angiography, D-dimer).
Consistent with recommendations for the treatment of asymptomatic DVT (section 3.5) in patients
in whom clinicians are convinced that an asymptomatic PE has occurred, based on moderate-quality
evidence, we suggest the same initial and long-term
anticoagulation as for similar patients with symptomatic PE. The indication for anticoagulation is
most compelling when the presence of PE is
unequivocal, PE involves the lobar and more central
pulmonary arteries, PE is a new finding on CT,
ultrasound reveals proximal DVT, there are ongoing
risk factors for VTE such as active cancer, and the
patient is not at high risk for bleeding (Table 2).
Many patients have left the hospital by the time an
incidental PE is reported. If PE is less extensive and
it would be difficult for patients to return the same
day, it often is reasonable to defer further assessment
and anticoagulant therapy until the next day.
Recommendation
have asymptomatic PE, we suggest the same initial and long-term anticoagulation as for similar
patients with symptomatic PE (Grade 2B).
7.0 Chronic Thromboembolic
Pulmonary Hypertension
Prospective studies suggest that CTPH occurs
in !3% of patients who are treated for PE.104,354-358
About one-third of patients have a history of VTE,
whereas two-thirds have had single or recurrent episodes of PE that were not diagnosed and may have
been asymptomatic.359 Patients with CTPH are likely
to have a high risk of recurrent VTE because they
have had previous VTE and have cardiopulmonary
impairment. Recurrent VTE may be fatal more often
in patients with severe cardiopulmonary impairment
than in those without such impairment. After PE initiates CTPH, pulmonary vascular remodeling may
cause severe pulmonary hypertension out of proportion with pulmonary vascular thrombosis.104,359,360
7.1 Pulmonary Thromboendarterectomy,
Anticoagulant Therapy, and Vena Caval
Filter for the Treatment of CTPH
Primary therapy for CTPH is pulmonary thromboendarterectomy, which, if successful, can reduce or
cure pulmonary hypertension and associated symptoms.104,359-367 The operation is lengthy and complex,
requiring a median sternotomy, cardiopulmonary
bypass, deep hypothermia with periods of circulatory arrest, and exploration of both pulmonary
arteries. At the most experienced centers, mortality
is !5%.104,360,363,365-367 Management often includes insertion of a permanent IVC filter before or during pulmonary endarterectomy and indefinite anticoagulant
therapy.359,361,363,365 Patients with CTPH who are not
candidates for pulmonary endarterectomy because of
comorbid disease or surgically inaccessible lesions
may be candidates for vasodilator therapy, balloon
pulmonary angioplasty, or lung transplantation and
may benefit from referral to a center with expertise in
pulmonary hypertension.359,363-365,368-370
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There are no randomized trials of CTPH therapy
and, overall, evidence is low quality. There is, however, high-quality indirect evidence that anticoagulant therapy is very effective at preventing recurrent
VTE in other patient populations (see section 3.1;
Table 18; and Tables S24, S25, and S27). Consequently, the evidence supporting long-term anticoagulation in patients with CTPH is of moderate
quality (rated down for indirectness). Features that
are expected to be associated with greater benefit with
pulmonary thromboendarterectomy include younger
age, central disease, progressive clinical deterioration, and access to an expert multidisciplinary thromboendarterectomy team.
Recommendations
7.1.1. In patients with CTPH, we recommend
extended anticoagulation over stopping therapy
(Grade 1B).
7.1.2. In selected patients with CTPH, such as
those with central disease under the care of an
experienced thromboendarterectomy team, we
suggest pulmonary thromboendarterectomy
(Grade 2C).
8.0 Superficial Vein Thrombosis
SVT has been less well studied than DVT but is
estimated to occur more often.371,372 It usually affects
the lower limbs; often involves a varicose vein; is
associated with chronic venous insufficiency, malignancy, thrombophilia, pregnancy or estrogen therapy,
obesity, sclerotherapy, long-distance travel, and a history of VTE; or may be unprovoked.371-373 The long
saphenous vein is involved in about two-thirds of
lower-limb SVT.374
Although traditionally considered a benign disease,
a number of studies indicate that the consequences
of SVT may be more serious.371,372 A prospective study
of 844 patients with acute SVT of ! 5 cm found that
at initial presentation, !4% of patients had symptomatic PE, and routine ultrasound detected proximal DVT in 10% and distal DVT in an additional
13% of patients.374 In patients without VTE at presentation, despite 90% being treated with anticoagulant
therapy (therapeutic doses in two-thirds, prophylactic doses in one-third, median duration of 11 days),
3.1% developed symptomatic VTE (0.5% PE, 1.2%
proximal DVT, 1.4% distal DVT), 1.9% had recurrent SVT (different location), and 3.3% had an extension of SVT (same location) at 3 months. Male sex,
history of VTE, cancer, and absence of varicose veins
each was associated with about a doubling of the risk
of VTE during follow-up.
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Given the high prevalence of concomitant proximal DVT in patients with SVT and the need to treat
such patients with higher doses of anticoagulant
therapy (ie, therapeutic doses), patients with SVT
above the knee should have ultrasonography to
exclude proximal DVT. Ultrasound can also help with
the diagnosis of SVT if the clinical presentation is
uncertain. With greater appreciation of the seriousness of SVT, investigators have evaluated anticoagulant therapy, often in prophylactic or intermediate
doses, as a way to reduce acute symptoms, extension,
recurrence, and progression to VTE (Table 31, Tables
S43-S45).375
8.1 Treatment of SVT
Most studies that have evaluated anticoagulant
therapy for SVT have been small (eg, " 100 patients
per treatment group), with additional methodologic
weaknesses376-381 (Tables S44, S45). Although these
studies suggest that prophylactic-dose LMWH, intermediate-dose UFH or LMWH, warfarin therapy, and
oral nonsteroidal antiinflammatory agents are beneficial in patients with SVT, the supporting evidence is
of low quality. The recently published Comparison of
ARIXTRA™ in lower LImb Superficial Thrombophlebitis with placebo (CALISTO) study, which compared fondaparinux (2.5 mg/d for 45 days) with
placebo in 3,000 patients with SVT (! 5 cm in length),
has helped to clarify the role of anticoagulants for the
treatment of SVT (Table 31, Table S43), and the natural history of this condition.382
CALISTO found that fondaparinux is very effective at reducing VTE, recurrent SVT, extension of
SVT, and the need for venous surgery, and is associated with little bleeding. In the placebo group, thrombotic complications occurred more often if SVT
involved the greater saphenous vein (92% of patients
in the control group), extended to within 10 cm from
the saphenofemoral junction (9% of patients), and
involved veins above the knee (46% of patients) and
if VTE (7% of patients) or SVT (12% of patients) had
occurred previously.382 Age, sex, and presence of varicose veins were not convincingly associated with the
frequency of thrombotic complications, and there
were too few patients with cancer in CALISTO to
assess that association.
The evidence is moderate quality. We have interpreted the findings of the CALISTO study as evidence for anticoagulation in general and assume
that prophylactic doses of LMWH and fondaparinux
have similar antithrombotic efficacy and safety.
Because it is direct and more extensive, the evidence
in support of fondaparinux is higher quality than the
evidence in support of LMWH. Quality of the evidence for comparison of fondaparinux with LMWH
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is low because there is no direct comparison in
patients with SVT. Factors that favor the use of
anticoagulant therapy in patients with SVT (see
Recommendation 8.1.1) include: extensive SVT;
involvement above the knee, particularly if close
to the saphenofemoral junction; severe symptoms;
involvement of the greater saphenous vein; history
of VTE or SVT; active cancer; and recent surgery.
An economic evaluation found that treatment of
SVT with fondaparinux was not cost-effective; it cost
$500,000 per quality-adjusted life year gained compared with no treatment.383
Graduated compression stockings often are used in
patients with SVT (eg, 83% of patients in the CALISTO study). Oral nonsteroidal antiinflammatory
agents may be used to alleviate symptoms if patients
are not treated with anticoagulants. Topical nonsteroidal antiinflammatory agents may reduce symptoms
and can be used with anticoagulant therapy. Surgical therapy, with ligation of the saphenofemoral
junction or stripping of thrombosed superficial veins
appears to be associated with higher rates of VTE
than treatment with anticoagulants.380,384,385 Anticoagulant therapy generally is not used to treat SVT that
occurs in association with an IV infusion (ie, infusion
thrombophlebitis).
Recommendations
8.1.1. In patients with SVT of the lower limb
of at least 5 cm in length, we suggest the use
of a prophylactic dose of fondaparinux or
LMWH for 45 days over no anticoagulation
(Grade 2B).
Remarks: Patients who place a high value on avoiding the inconvenience or cost of anticoagulation and
a low value on avoiding infrequent symptomatic VTE
8.1.2. In patients with SVT who are treated
with anticoagulation, we suggest fondaparinux
2.5 mg daily over a prophylactic dose of LMWH
(Grade 2C).
9.0 Acute Upper-Extremity DVT
About 5% to 10% of VTE involve the upper extremities.386-390 UEDVT includes two etiologic groups:
primary (unprovoked with or without thrombophilia,
effort-related and thoracic outlet syndrome) and secondary (provoked by central venous catheters, pacemakers, or cancer). Secondary UEDVT accounts
for !75% of cases.386,388,389,391-394
UEDVT involves the subclavian, axillary, or brachial veins and may include extension to the brachiocephalic vein, superior vena cava, or the internal
Table 31—[Section 8.1] Summary of Findings: Fondaparinux vs Placebo for Acute SVTa-c,382
Outcomes
No. of Participants
Quality of the
Evidence (GRADE)
Mortality
3,002 (1 study), 3 mo
VTE
3,002 (1 study), 3 mo
Moderated-g due to
imprecision
Highd
SVT recurrence
3,002 (1 study), 3 mo
Major bleeding
2,987(1 study), 47 d
QOL not measured
…
Relative Effect
(95% CI)
Risk With No
Fondaparinux
RR 1.99 (0.18-21.87)
4 per 1,000h
RR 0.18 (0.06-0.53)
33 per 1,000h
Highd
RR 0.31 (0.14-0.68)
19 per 1,000h
Moderated,e,i due to
imprecision
…
RR 0.99 (0.06-15.86)e
1 per 1,000
…
…
fewer to 83 more)
fewer to 31 fewer)
fewer to 16 fewer)
fewer to 10 more)
…
change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and
is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of
abbreviations.
aPatients with infusion-related SVT were excluded from CALISTO (Comparison of ARIXTRA in lower Limb Superficial Thrombophlebitis with
Placebo).
bFondaparinux 2.5 mg for 45 d.
cPatients in the two treatment groups benefited from close clinical monitoring with adequate diagnostic procedures in the event of new or persistent
symptoms.
dAllocation concealed. Outcome adjudicators, steering committee, patients, providers, and data collectors blinded. Follow-up rate was 98%.
Intention-to-treat analysis for efficacy outcomes. Not stopped early for benefit.
eCI includes values suggesting large benefit and values suggesting large harm.
fWe rated down by only one level because of the low event rate and large sample size.
gSmall number of events.
hBaseline risk derived from a large prospective cohort study.374
iThe upper limit of the CI for absolute effect (10 more bleeds) is not low enough to suggest a clear balance of benefits vs harms.
jugular vein. Clinical manifestations include acute
and chronic arm pain, swelling, discoloration, and
dilated collateral veins over the arm, neck, or chest.
UEDVT may lead to complications, including symptomatic PE (!5% of patients387-389,393,395), recurrent
UEDVT (!8% at 5 years of follow-up389,390,395), and
PTS of the arm (!20% of patients).386,387,395,396 In the
absence of a central venous catheter, the dominant
arm is more often affected.387 Complications of
UEDVT are expected to occur much more often and
to be more severe when UEDVT involves the axillary
or more-proximal veins than if thrombosis is confined
to the brachial vein. In general, when we refer to
UEDVT, we are referring to thrombosis that involves
the axillary or more-proximal veins.
The most frequent risk factor for UEDVT is a central venous catheter.386,388,397,398 If UEDVT occurs in
association with a central venous catheter and the
catheter is no longer required, it should be removed.
There are no data to guide whether catheter removal
should be preceded by an initial period of anticoagulation, and we do not have a preference for immediate or deferred removal. If UEDVT occurs in
association with a central venous catheter and there is
a continuing need for the catheter, the catheter need
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not be removed. If the catheter is not functioning and
cannot be made to function (even after a period of
systemic anticoagulation), it should be removed.
As with treatment of leg DVT and PE, treatment of
UEDVT may be divided into acute (eg, parenteral
anticoagulants, thrombolytic therapy) and long-term
phases (eg, anticoagulation, treatment of upperextremity PTS). Because no randomized trials have
evaluated treatment of UEDVT, recommendations are
based on indirect evidence from studies performed
in patients with leg DVT, observational studies (generally small), and understanding of the natural history of UEDVT. Therefore, quality of evidence is, at
best, moderate.
9.1 Acute Anticoagulation for UEDVT
No randomized controlled studies have evaluated
acute anticoagulation for initial treatment of UEDVT.
Several small prospective cohort studies have reported
low rates of recurrent DVT, PE, and major bleeding
when UEDVT was treated similarly to leg DVT
(Tables S46 and S47).395,399-401 Anticoagulant therapy
is used to treat UEDVT because (1) UEDVT causes
acute symptoms, can cause PE (including fatal
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episodes), and is associated with PTS; (2) observational studies support its use; and (3) there is strong
evidence for benefit in patients with leg DVT.
Uncertainty exists about the need to prescribe anticoagulants to patients with thrombosis confined to the
brachial vein. Acceptable alternatives to full-dose anticoagulation in such patients include clinical or ultrasound surveillance to detect extension of UEDVT
while withholding anticoagulation, or treatment with
prophylactic-dose anticoagulation, or treatment with
therapeutic doses of anticoagulation for , 3 months.
We favor anticoagulation if isolated brachial vein
thrombosis is symptomatic, associated with a central
venous catheter that will remain in place, or associated with cancer in the absence of a central venous
catheter. A high risk of bleeding argues against fulldose anticoagulation.
Recommendations
involves the axillary or more proximal veins,
we recommend acute treatment with parenteral anticoagulation (LMWH, fondaparinux,
IV UFH, or SC UFH) over no such acute treatment (Grade 1B).
the axillary vein, symptoms for , 14 days, good functional status, life expectancy of ! 1 year, and low risk
for bleeding (Table 11). If thrombolysis is used, in
order to reduce the dose of thrombolytic therapy
and the associated risk of bleeding, we encourage catheter-based therapy over systemic thrombolysis. In
addition, because the balance of risks and benefits
with all forms of thrombolytic therapy is uncertain,
anticoagulant therapy alone is acceptable initial therapy in all patients with UEDVT. There is no evidence
to suggest that thrombolysis reduces the risk of recurrent VTE.
Resection of the first rib has been advocated when
UEDVT is believed to have been due to entrapment
of the subclavian vein as it passes between the clavicle and the first rib.6,386,411-421 Insertion of a filter in
the superior vena cava has also been used in patients
with acute UEDVT who cannot be given anticoagulants. Complications, however, may be more than
with IVC filters.389,413,422 The evidence in support of
these procedures is of low quality, and because there
is the potential to cause harm, their use should be
confined to exceptional circumstances in specialized
centers.
Recommendations
9.1.2. In patients with acute UEDVT that involves
the axillary or more proximal veins, we suggest
LMWH or fondaparinux over IV UFH (Grade 2C)
and over SC UFH (Grade 2B).
suggest anticoagulant therapy alone over thrombolysis (Grade 2C).
9.2 Thrombolytic Therapy for the
Initial Treatment of UEDVT
No randomized controlled studies have evaluated
thrombolytic therapy compared with anticoagulation alone in patients with UEDVT. A number of
retrospective and small prospective observational
studies have evaluated streptokinase, urokinase,
or rt-PA administered with varying doses, methods
of administration (IV, catheter directed), and infusion durations.402-409 Three of these studies included
nonrandomized control groups who received anticoagulation alone.402,407,408 In some studies, a few patients
also had venous angioplasty405 or surgical decompression402,405,408 (Tables S48 and S49).
These studies suggest that thrombolysis can
improve early and late venous patency but is associated with increased bleeding. However, it is not
known whether thrombolytic therapy reduces PTS of
the arm or recurrent VTE. PTS of the arm appears to
be a less common complication of thrombosis than
PTS of the leg.386-388,393,395,410 We believe that thrombolysis should be considered only in patients who
meet all of the following criteria: severe symptoms,
thrombus involving most of the subclavian vein and
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9.3 Long-term Anticoagulation for UEDVT
No randomized studies have evaluated duration or
intensity of long-term anticoagulation in patients
with UEDVT. In prospective observational studies,
patients with UEDVT generally were treated with
VKA (target INR 2.5) for periods of 3 to 6 months.393,399401,423 Rates of recurrent VTE and PTS varied (Tables
S50 and S51), but as previously noted, these rates
generally were lower than those observed in patients
with leg DVT.
The factors that influence long-term anticoagulation in patients with leg DVT (section 3.1) are
relevant to long-term treatment of UEDVT. Some
differences between UEDVT and leg DVT are worthy of emphasis, especially that UEDVT often is associated with a central venous catheter that may or may
not be removed (section 9.0). The most important
continuing risk factors for UEDVT are (1) the presence of a central venous catheter in the same arm and
(2) active cancer in patients with UEDVT not associated with a central venous catheter.
Another important distinction between UEDVT
and leg DVT relates to long-term anticoagulation in
patients with unprovoked thrombosis. Because the
risk of recurrent VTE is substantially lower in patients
with UEDVT compared with in those with proximal
leg DVT,387,388,393,395 we discourage extended anticoagulant therapy (ie, beyond 3 months) in patients with
an unprovoked UEDVT.
No data are available for the long-term use of
LMWH monotherapy or newer anticoagulants for
the long-term treatment of UEDVT. We make the
same recommendations for choice of initial, long-term,
and extended anticoagulant regimens for UEDVT
as for leg DVT (recommendations 3.1.1, 3.1.2, and
3.1.4) and note that the supporting evidence for these
weak recommendations is further weakened in this
population because of indirectness.
Recommendations
9.3.2. In patients with UEDVT that involves the
axillary or more proximal veins, we suggest a
minimum duration of anticoagulation of 3 months
over a shorter period (Grade 2B).
UEDVT is associated with a central venous catheter
that was removed shortly after diagnosis.
is continued as long as the central venous cathwww.chestpubs.org
eter remains over stopping after 3 months of
(Grade 2C).
associated with a central venous catheter or
with cancer, we recommend 3 months of anticoagulation over a longer duration of therapy
(Grade 1B).
9.4 Prevention of PTS of the Arm
PTS of the arm occurs in !20% of patients after
treatment for UEDVT38,395,396 and can be a disabling condition that adversely affects quality of life,
particularly if the dominant arm is involved.410,424
No randomized trials have evaluated compression
bandages, compression sleeves, or venoactive drugs
to prevent PTS after UEDVT. We have not considered indirect evidence from the legs for use of
compression therapy to prevent PTS of the arms
because (1) the pathophysiology of PTS is believed
to be different in the arms than in the legs (less
dependent venous hypertension), (2) arm sleeves
are more difficult to fit than stockings, and (3) PTS
occurs less often after UEDVT than after leg DVT.
Recommendation
we suggest against the use of compression sleeves
or venoactive medications (Grade 2C).
9.5 Treatment of PTS of the Arm
Symptoms of PTS of the arm include swelling,
heaviness, and limb fatigue with exertion.395,410 No
randomized trials have evaluated compression bandages, compression sleeves (as are used for lymphedema), or venoactive drugs to treat PTS after
UEDVT. We considered anecdotal evidence that
compression therapy benefits some patients with PTS
of the arm and that the benefits of a trial of compression therapy will outweigh its harms and costs. There
is no evidence that venoactive drugs are of benefit in
PTS of the arm.
Recommendations
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10.0 Splanchnic Vein Thrombosis
Thrombosis in the portal venous system, which
includes the superior mesenteric, inferior mesenteric, splenic, and portal veins, is collectively termed
splanchnic vein thrombosis. Depending on the location
and extent of thrombosis, how rapidly thrombosis
develops, speed and extent of thrombus recannulation, presence of collateral portal venous drainage,
and adequacy of arterial inflow, splanchnic vein
thrombosis may result in bowel or splenic infarction
and chronic portal hypertension.425-430 Acute and
chronic splanchnic vein thrombosis may be symptomatic, but many episodes are detected incidentally
in imaging studies performed for other indications,
such as assessing response to surgical or medical
therapy in patients with cancer.348,429 Limited understanding of the natural history of both symptomatic
and incidentally detected splanchnic vein thrombosis
in patients who are not treated with anticoagulants
(ie, frequency of bowel infarction, development of
portal hypertension, recurrence), a paucity of data
from prospective cohort studies,428,431 and a lack of
randomized trials of standardized anticoagulant therapy
for splanchnic vein thrombosis result in uncertainty
about the role of anticoagulation for this condition.
Increased risk of bleeding associated with esophageal
varices (secondary to portal hypertension), thrombocytopenia (secondary to hypersplenism), and the presence of cirrhosis and malignancy (which predispose to
splanchnic vein thrombosis) add to this uncertainty.
A number of retrospective,425,429,430 and two prospective,428,431 studies suggested that bowel ischemia
is uncommon in patients with symptomatic splanchnic
vein thrombosis who are treated with anticoagulants
(!2%428), that recurrent venous thrombosis (both
involving the splanchnic and nonsplanchnic veins) is
common without anticoagulation or after stopping
anticoagulation (!5% per year425,429,430), and that anticoagulation is effective at preventing progression
and recurrent thrombosis,425,428-431 although it is associated with an increased (particularly GI), but usually
acceptable, frequency of bleeding.428-431 Efficacy of
anticoagulant therapy in other forms of symptomatic venous thrombosis also provides indirect evidence for anticoagulation of patients with symptomatic
splanchnic vein thrombosis and, supported by the
previously noted observational studies, this evidence
is of moderate quality. We are not aware of studies of
treated or untreated asymptomatic splanchnic vein
thrombosis.
Factors that may encourage anticoagulant therapy
in patients with incidental splanchnic vein thrombosis include extensive thrombosis that appears to be
acute (eg, not present on a previous imaging study,
presence of an intraluminal filling defect, lack of cave478S
ernous transformation), progression of thrombosis on
a follow-up imaging study, and ongoing cancer chemotherapy. Esophageal varices secondary to acute
portal vein thrombosis are not necessarily a contraindication to anticoagulant therapy because such treatment may improve the portal hypertension. LMWH
may be preferred over VKA if there is active malignancy, liver disease, or thrombocytopenia.431 The presence of a reversible provoking factor for splanchnic
vein thrombosis, such as intraabdominal sepsis or
recent surgery, supports stopping anticoagulant therapy
after 3 months. Absence of a reversible risk factor
(eg, “unprovoked” thrombosis or presence of a persistent risk factor, such as myeloproliferative disease)
and a low risk of bleeding support extended anticoagulant therapy.
Recommendations
10.1. In patients with symptomatic splanchnic
vein thrombosis (portal, mesenteric, and/or
splanchnic vein thrombosis (portal, mesenteric,
and/or splenic vein thromboses), we suggest no
anticoagulation over anticoagulation (Grade 2C).
11.0 Hepatic Vein Thrombosis
Hepatic vein thrombosis, particularly Budd-Chiari
syndrome with occlusion of the main hepatic vein,
can result in impairment of liver function and an
associated coagulopathy.432,433 Because there is limited
understanding of the natural history of this condition
and a paucity of prospective studies that have evaluated anticoagulant therapy, the role of anticoagulant
therapy is uncertain.432
In a prospective registry of 163 patients with BuddChiari syndrome of variable extent, of whom 86%
were treated with anticoagulation, one-half of patients
did not require invasive interventions (ie, transjugular intrahepatic portosystemic shunting in 34% of all
patients, surgical portosystemic shunting in 2% of
patients, liver transplantation in 12% of patients), and
survival was 82% after 2 years.432 In an earlier retrospective study of 237 patients with Budd-Chiari syndrome performed when use of surgical portosystemic
shunting was common (49% of patients), use of anticoagulant therapy (72% of patients) had no apparent
effect on survival (RR, 1.05; 95% CI, 0.62-1.76).
Factors that encourage anticoagulant therapy in
patients with incidental hepatic vein thrombosis
include extensive thrombosis that appears to be acute
(eg, not present on a previous imaging study, presence of an intraluminal filling defect), progression
of thrombosis on a follow-up imaging study, and
ongoing cancer chemotherapy. Coagulopathy due to
liver dysfunction caused by hepatic vein thrombosis
is not a contraindication to anticoagulant therapy
because anticoagulants may improve hepatic function. LMWH usually will be preferred to VKA therapy
when there is hepatic dysfunction and if there is
active malignancy. Presence of a reversible provoking
factor for hepatic vein thrombosis, such as oral contraceptive therapy, encourages a time-limited course
of therapy. Absence of a reversible risk factor encourages the use of extended therapy. Treatment of
hepatic vein obstruction is complex and best undertaken by a multidisciplinary team.
Recommendations
12.0 Future Research
Several questions in the treatment of VTE need to
be answered. Current evidence relating to these
questions is of moderate or low quality. We list the
questions roughly as they arise in this article rather
than in order of importance. We do not present the
rationale for each question because this is addressed
in the corresponding sections of the article. We have
confined ourselves to the primary question (eg, Should
patients with proximal DVT be treated with anticoagulant therapy alone, or should they be treated
with pharmacomechanical CDT?); however, once
the primary question is answered, we anticipate that
secondary questions will need to be addressed (eg,
Which patients with proximal DVT should, or should
not, be treated with CDT?). We are pleased to note
that many of the these questions are being addressed
in ongoing trials.
• Should patients with an isolated distal DVT routinely be treated with anticoagulant therapy, or
should they have serial testing to determine
whether the DVT is extending and only be
treated if extension is detected?
• Should patients with proximal DVT be treated
with anticoagulant therapy alone, or should they
be treated with pharmacomechanical CDT?
• Which patients with unprovoked proximal DVT
or PE or cancer-associated VTE should stop
anticoagulant therapy at 3 months, and which
should remain on extended anticoagulant therapy?
www.chestpubs.org
• Which patients with unprovoked VTE or cancerassociated VTE have an unacceptable risk of
bleeding if they remain on extended anticoagulant therapy?
• How should risk of recurrent VTE if anticoagulant therapy is stopped be balanced against risk
of bleeding is anticoagulant therapy is continued?
• What is the preferred anticoagulant regimen for
the short- and long-term treatment of VTE in
patients with and without cancer?
• Should patients receiving an incidental diagnosis of asymptomatic VTE routinely be treated
with anticoagulant therapy, or should they have
serial testing to determine whether they have
evolving DVT and only be treated if this is
detected?
• Should patients with symptomatic DVT routinely wear graduated compression stockings
from the time of diagnosis, or should stockings
be used selectively (eg, in selected patients, in
patients whose symptoms do not rapidly resolve)?
• Should patients with PE that causes right ventricular dysfunction be treated with anticoagulant therapy alone, or should they be treated
with thrombolytic therapy?
• If patients have catheter-associated UEDVT
and the catheter is removed, should they be
treated with anticoagulant therapy or can they
be treated without anticoagulant therapy?
• Can UEDVT be treated with less-intense or a
shorter duration of anticoagulant therapy than
leg DVT?
Acknowledgments
Author contributions: As Topic Editor, Dr Akl oversaw the
development of this article, including the data analysis and subsequent development of the recommendations contained herein.
Dr Kearon: served as Deputy Editor.
Dr Akl: served as Topic Editor.
Dr Comerota: served as a panelist.
Dr Prandoni: served as a panelist.
Dr Bounameaux: served as a panelist.
Dr Goldhaber: served as a panelist.
Dr Nelson: served as a frontline clinician.
Dr Wells: served as a panelist.
Dr Gould: served as a resource consultant.
Dr Dentali: served as a panelist.
Dr Crowther: served as a panelist.
Dr Kahn: served as a panelist.
Financial/nonfinancial disclosures: The authors of this guideline provided detailed conflict of interest information related to
each individual recommendation made in this article. A grid of these
disclosures is available online at http://chestjournal.chestpubs.
org/content/141/2_suppl/e419S/suppl/DC1. In summary, the authors
have reported to CHEST the following conflicts of interest: Dr Kearon is a
consultant to Boehringer Ingelheim and has received peer-reviewed
funding for studies in the treatment of VTE. Dr Bounameaux
has received grant monies and honoraria for consultancy or lectures from Bayer Schering Pharma AG; Daiichi-Sankyo Co, Ltd;
Sanofi-Aventis LLC; Pfizer Inc; Bristol-Myers Squibb; Servier;
and Canonpharma Production Ltd. Dr Goldhaber has received
funds from Eisai Co, Ltd; EKOS Corporation; Sanofi-Aventis LLC;
e479S
and Johnson & Johnson. He serves as a consultant for Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi Sankyo Co, Ltd; Eisai Co, Ltd; EKOS Corporation; Medscape; Merck
& Co, Inc; Portola Pharmaceuticals, Inc; and Sanofi-Aventis LLC.
Dr Wells has received peer-reviewed and investigator-initiated
industry research funding for projects related to venous thrombosis treatment. He has received honoraria for industry-sponsored
(Bayer, Boehringer-Ingelheim, Pfizer, BioMerieux, sanofi-aventis)
talks pertaining to venous thrombosis and has attended advisory
boards for Bayer, Boehringer-Ingelheim, Pfizer and Bristol-MyersSquibb. Dr Crowther has served on various advisory boards, has
assisted in the preparation of educational materials, has sat on
data safety management boards, and his institution has received
research funds from the following companies: Leo Pharma A/S,
Pfizer Inc, Boerhinger Ingelheim GmbH, Bayer Healthcare
Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma.
Personal total compensation for these activities over the past 3 years
totals less than US $10,000. Dr Kahn has received peer-reviewed
and investigator-initiated industry research funding for projects
related to venous thrombosis and postthrombotic syndrome prevention and treatment. She has received honoraria for industrysponsored talks pertaining to venous thrombosis. Dr Akl is a
member of and prominent contributor to the GRADE Working
Group. Dr Comerota discloses that he is a consultant to and
speaker for Covidien, Inc. Drs Prandoni, Nelson, Gould, and Dentali
have reported that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.
Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication
access to the manuscripts and recommendations. Guideline panel
members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online
at http://chestnet.org.
Other contributions: We acknowledge the contributions of the
writing groups of previous editions of this guideline and thank
Gordon H. Guyatt, MD, FCCP, for his comments and suggestions
and Aman Rajpal, MD, for his help with reviewing the proofs.
Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International
Society of Thrombosis and Hematosis.
Additional information: The supplement Tables can be found
in the Online Data Supplement at http://chestjournal.chestpubs.
org/content/141/2_suppl/e419S/suppl/DC1.
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CHEST
Online Data Supplement
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines
Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Anthony J. Comerota, MD;
Paolo Prandoni, MD; Henri Bounameaux, MD; Samuel Z. Goldhaber, MD, FCCP;
Michael Nelson, MD, FCCP; Philip Wells, MD; Michael K. Gould, MD, MS, FCCP;
Francesco Dentali, MD; Mark Crowther, MD; and Susan R. Kahn, MD
1
© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American
College of Chest Physicians
(http://www
.chestpubs
.org/site/misc/reprints.xhtml
). DOI:HQ
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2
Risk of
Bias
Inconsistency
Seriousc
Imprecision
Overall Quality
of Evidence
Undetected
Moderateb,c
due to
imprecision
Mortality (important outcome)
Publication
Bias
2/60 (3.3)
1/60 (1.7)
No serious
indirectness
No serious
120 (1 study), No serious
inconsistency
6 mo
risk of biasb
Seriousc
Seriousd
Moderateb,d
due to
imprecision
12/60 (20)
Undetected
Moderateb,c
due to
imprecision
3/60 (5)
Undetected
2/60 (3.3)
4/60 (6.7)
RR 0.67
(0.12-3.85)
RR 0.33
(0.11-0.98)
50 per 1,000
200 per 1,000
33 per 1,000
a
Bibliography: Brandjes et al.1 RR 5 risk ratio.
Both groups treated with acenocoumarol.
b Study described as double blinded; outcome adjudicators blinded. None of the study participants were lost to follow-up. Intention-to-treat analysis. Study was stopped early for benefit.
c CI includes values suggesting no effect as well as values suggesting either appreciable benefit or appreciable harm.
d Low number of events caused by the early stoppage of the trial.
No serious
indirectness
RR 0.5
(0.05-5.37)
Risk With No
Parenteral
Anticoagulation
16 fewer
per 1,000
(from 44 fewer
to 142 more)
134 fewer
per 1,000
(from 4 fewer
to 178 fewer)
16 fewer
per 1,000
(from 31 fewer
to 144 more)
Risk Difference
With Parenteral
Anticoagulation
(95% CI)
Summary of Findings
With No
Parenteral
With Parenteral Relative Effect
Anticoagulation Anticoagulation
(95% CI)
Recurrent VTE (critical outcome; assessed with symptomatic extension or recurrence)
No serious
indirectness
Indirectness
No serious
6 mo
risk of biasb
inconsistency
No serious
6 mo
risk of biasb
inconsistency
Participants
(Studies),
Follow-up
Quality Assessment
Table S1—[Section 2.1] Evidence Profile: Parenteral Anticoagulation vs No Parenteral Anticoagulation in Acute VTEa
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3
Risk of Bias
Inconsistency
Indirectness
Imprecision
Overall
Quality of
Evidence
13/338 (3.8)
14/338 (4.1)
15/350 (4.3)
12/350 (3.4)
12/350 (3.4)
RR 1.48
(0.68-3.23)
RR 0.83
(0.4-1.74)
RR 0.9
(0.41-1.95)
16 per 1,000i
47 per 1,000i
24 per 1,000i
14 more
per 1,000
(from 9 fewer
to 66 more)
8 fewer
per 1,000
(from 28 fewer
to 35 more)
2 fewer
per 1,000
(from 14 fewer
to 23 more)
Bibliography: Gallus et al,2 Hull et al,3 Leroyer et al.4 Excluded Mohiuddin et al5 because 34% of subjects had mural thrombus rather than VTE, in addition to major methodologic limitations).
LMWH 5 low-molecular-weight heparin; PE 5 pulmonary embolism; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist. See Table S1 legend for expansion of other abbreviation.
a VKA therapy started within 1 day of starting heparin therapy (UFH in two studies and LMWH in one study).
b VKA therapy delayed for 4 to 10 d.
c Most patients had proximal DVT, some had isolated distal DVT; most DVT were symptomatic (asymptomatic DVT included in Hull et al), and few had PE (only included in Gallus et al).
d The early initiation of VKA was associated with a lower number of days of heparin therapy (4.1 vs 9.5 in Gallus et al; 5 vs 10 in Hull et al) and a lower number of days of hospital stay (9.1 vs 13.0 in Gallus;
11.7 vs 14.7 in Hull; 11.9 vs 16.0 in Leroyer et al).
e Differences in death, independently of differences in recurrent VTE and major bleeding, is unlikely.
f Outcome assessment was at hospital discharge in the study by Gallus et al (although there was also extended follow-up) and 3 mo in the studies by Hull et al and Leroyer et al.
g Patients and investigators were not blinded in two studies (Gallus et al and Leroyer et al) and were blinded in one study (Hull et al). Concealment was not clearly described but was probable in the
three studies. Primary outcome appears to have been assessed after a shorter duration of follow-up in the shorter treatment arm of one study because of earlier discharge from the hospital, and 20% of
subjects in this study were excluded from the final analysis postrandomization (Gallus).
h The 95% CI on relative effect includes both clinically important benefit and clinically important harm.
i Event rate corresponds to the median event rate in the included studies.
j Bleeding was assessed early (in hospital or in the first 10 d) in two studies (Gallus et al, Hull et al) and at 3 mo in one study (Leroyer et al).
k It is unclear whether bleeding was assessed at 10 d in all subjects or just while heparin was being administered, which could yield a biased estimate in favor of short-duration therapy in one study (Hull et al).
l Because the shorter duration of heparin therapy is very unlikely to increase bleeding, the wide 95% CIs around the relative effect of shorter therapy on risk of bleeding is not a major concern.
10/338 (3.0)
Undetected Moderateg,h
due to
imprecision
Recurrent VTE (critical outcome)
Undetected Moderateg,h
due to
imprecision
Summary of Findings
With Early
Risk With
Risk Difference
Warfarin
Delayed
With Early
With Delayed
Initiation
Warfarin
Warfarin Initiation
Warfarin Initiation (and Shorter
Initiation (and
(and Shorter
(and Longer
Duration Relative Effect Longer Duration Duration Heparin)
Duration Heparin) Heparin)
(95% CI)
Heparin)
(95% CI)
Mortality (important outcomee)
Publication
Bias
No serious
No serious
Undetected Highg,k,l
688 (3 studies), No serious risk No serious
of biasg,k
inconsistency
indirectness
imprecisionl
3 moj
No serious
Serioush
of biasg
inconsistency
indirectness
3 mof
h
No serious
Serious
3 mof
of biasg
inconsistency
indirectness
Participants
(Studies),
Follow-up
Quality Assessment
Table S2—[Section 2.4] Evidence Profile: Early Warfarin (and Shorter Duration Heparin) vs Delayed Warfarin (and Longer Duration Heparin) for Acute VTEa-d
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4
No serious
risk of biasa
No serious
risk of biasa
No serious
risk of biasa
1,566 (3 studies),
3 mo
1,563 (3 studies),
3 mo
1,634 (4 studies),
3 mo
No serious
inconsistency
No serious
inconsistency
No serious
inconsistency
Inconsistency
No serious
indirectness
No serious
indirectness
No serious
indirectness
Indirectness
Seriousb
Seriousb
Seriousb
Imprecision
Overall Quality
of Evidence
Moderatea,b
due to
imprecision
Moderatea,b
due to
imprecision
Undetected
Moderateb,c
due to
imprecision
Undetected
Undetected
Publication
Bias
15/815 (1.8)
31/777 (4)
31/780 (4)
With SC UFH
19/819 (2.3)
26/786 (3.3)
34/786 (4.3)
With LMWH
RR 1.27
(0.56-2.9)
RR 0.87
(0.52-1.45)
RR 1.1
(0.68-1.76)
Relative
Effect
(95% CI)
16 per 1,000c
42 per 1,000c
33 per 1,000c
4 more
per 1,000
(from 7 fewer
to 30 more)
5 fewer
per 1,000
(from 20 fewer
to 19 more)
3 more
per 1,000
(from 11 fewer
to 25 more)
Risk Difference
With LMWH
(95% CI)
Risk With SC
UFH
Summary of Findings
Bibliography: Lopaciuk et al,21 Faivre et al,2 Prandoni et al,23 Kearon et al.24 SC 5 subcutaneous. See Table S1 and S2 legends for expansion of other abbreviations.
a In the two largest trials (Prandoni et al and Kearon et al, 87% of patients), allocation was concealed, outcome adjudicators and data analysts were concealed, analysis was intention to treat, and there were
no losses to follow-up.
b Precision judged from the perspective of whether SC heparin is noninferior to LMWH. The total number of events and the total number of participants are relatively low.
c Event rate corresponds to the median event rate in the included studies.
Risk of Bias
Participants
(Studies),
Follow-up
Quality Assessment
Table S3—[Section 2.5.1] Evidence Profile: LMWH vs SC UFH for Initial Anticoagulation of Acute VTE
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5
13/345 (3.8%)
12/352 (3.4%) RR 1.1
(0.5-2.3)
345/355
352/353
UFH 333 units/kg SC
followed by 250 units/kg
SC bid (no adjustment)
for 6.3 d
Dalteparin (n 5 261)
or enoxaparin (n 5 91)
100 International Units/kg
SC bid for 7.1 d
12/352 (3.4%) RR 0.5
(0.2-1.3)
6/348 (1.7%)
7/360 (1.9%) RR 0.7
(0.2-2.2)
5/360 (1.4%)
0/33 RR 6.6 (0.3-123)
3/35
0/74RR 3.1 (0.1-7.5)
1/72 (1.4%)
Major Bleeding
aPTT 5 activated prothrombin time; FIDO 5 Fixed Dose Heparin. See Table S1 and S2 legends for expansion of other abbreviations.
aFollow-up was for 3 mo except for the study by Faivre et al22 in which it was 10 d.
14/360 (3.9%) RR 1.1
(0.5-2.2)
360/360
Kearon et al24/2006 (FIDO)
15/360 (4.2%)
360/360
UFH IV (, 50 kg: 4,000 units;
50-70 kg: 5,000 units;
. 70 kg: 6,000 units)
followed by SC bid doses
(initially , 50 kg: 12,500 units;
50-70 kg: 15,000 units;
. 70 kg: 17,500 units)
adjusted to aPTT
for ! 6.5 d
Nadroparin 85 International
Units/kg SC bid for ! 6.5 d
1/33 RR 0.9 (0.1-14.5)
30/33
Prandoni et al23/2004
(Galilei)
1/35
29/35
0/74 RR 3.1 (0.1-7.5)
UFH 5,000 units IV followed
by 250 units/kg
SC bid and adjusted to
aPTT for 10 d
CY222 2,000 International
Units IV followed by 150
International Units/kg
SC bid for 10 d
74/74
Fraxiparine 97 International
Units/kg SC bid for 10 d
1/72 (1.4%)
Recurrent DVT or PE
Faivreet al22/1988
72/75
UFH 5,000 units IV followed
by 250 units/kg SC bid
initially and adjusted to
aPTT for 10 d
Lopaciuk et al21/1992
Patients Analyzeda
Interventions
Author/Year (Acronym)
22/352 (6.3%) RR 0.8
(0.4-1.5)
18/348 (5.2%)
12/360 (3.3%) RR 1.0
(0.5-2.2)
12/360 (3.3%)
0/33 RR 2.8 (0.1-67)
1/35
0/74RR 7.2 (0.4-137)
3/72 (4.2%)
Total Mortality
Comments
Population: Proximal DVT in
77%, asymptomatic or distal
DVT in 4%, and PE in 19%.
Seventy percent of patients
were treated entirely as an
outpatient (76% of DVT
and 39% of PE) Postrandomization exclusions in
10 patients receiving UFH
and one patient receiving
LMWH.
Population: Proximal DVT in
65%, distal DVT in 18%,
and PE in 17%.
Population: DVT (proportion
of proximal and distal not
reported). Primary outcome
was repeat venography.
Population: Femoral DVT in
81% and popliteal or more
distal DVT in 19%. Primary
outcome was repeat
venography.
Table S4—[Section 2.5.1] LMWH vs SC UFH for Initial Anticoagulation of Acute VTE: Clinical Description and Results
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6
UFH 5,000 units IV followed by
250 units/kg SC bid and
adjusted to aPTT for 10 d
CY222 2,000 International Units
IV followed by 150 International
Units/kg SC bid for 10 d
UFH IV (, 50 kg: 4,000 units;
50-70 kg: 5,000 units; . 70 kg:
6,000 units) followed by SC bid
doses (initially , 50 kg: 12,500
units; 50-70 kg: 15,000 units;
. 70 kg: 17,500 units) adjusted
to aPTT for ! 6.5 d
Nadroparin 85 International
Units/kg SC bid for ! 6.5 d
Faivre et al22/1988
(Galilei)
RCT
RCT
RCT
Study Design
CY
PN
PY
Randomization
Concealed
Patients: CN
Caregivers: CN
Adjudicators: CY
Data Analysts: PY
Patients: PN
Caregivers: PN
Adjudicators: PN
Data Analysts: PN
Patients: CN
Caregivers: CN
Adjudicators: CN
Data Analysts: PN
Blinding
Nil
Three of CY222 group and six
of UFH group who did not
have repeat venography are
assumed to have completed
clinical follow-up
Not described
Loss to Follow-up
ITT
ITT
ITT
Analysis
Comments
UFH 333 units/kg SC followed
RCT
CY
Patients: CN
Nil
ITT
Postrandomization exclusions
by 250 units/kg SC bid (no
Caregivers: CN
from the efficacy analysis
adjustment) for 6.3 d
Adjudicators: CY
were 10 (2.8%) for the UFH
Data Analysts: PY
and one (0.2%) for the
Dalteparin (n 5 261) or enoxaparin
LMWH group.
(n 5 91) 100 International
Units/kg SC bid for 7.1 d
CN 5 certainly no; CY 5 certainly yes; ITT 5 intention to treat; PN 5 probably no; PY 5 probably yes; RCT 5 randomized controlled trial. See Table S1, S2, and S4 legends for expansion of other
abbreviations.
UFH 5,000 units IV followed by
250 units/kg SC bid initially and
adjusted to aPTT for 10 d
Fraxiparine 97 International
units/kg SC bid for 10 d
Lopaciuk et al21/1992
Kearon et al24/2006
(FIDO)
Interventions
Table S5—[Section 2.5.1] LMWH vs SC UFH for Initial Anticoagulation of Acute VTE: Methodologic Quality
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Risk of
Bias
Inconsistency
Indirectness
Imprecision
Risk With IV
UFH
LMWH (95% CI)
69/3,517 (2)
41/3,393 (1.2)
RR 0.67
(0.45-1)
15 per 1,000c 5 fewer per 1,000
(from 8 fewer to 0
more)
Bibliography: van Dongen et al.6 Included studies.7,20 See Table S1 and S2 legends for expansion of abbreviations.
a Of the 20 trials, allocation was concealed in nine and was unclear whether concealed in the remaining 11. Eighteen trials had blinded outcome assessors. Seven trials did not have any postrandomization
exclusions or losses to follow-up. Ten trials reported the number of participants lost to follow-up, which ranged from 1.0% to 12.7%. One trial did not report the drop-outs.
b Inverted funnel plot very suggestive of publication bias. Many of the included studies are of small size, and all are funded by industry.
c Event rate corresponds to the median event rate in the included studies.
d CI interval includes values suggesting significant benefit and no effect.
Lowa,b,d due to
risk of bias,
publication bias
Lowa,b due to
208/3,869 (5.4) 151/4,107 (3.7) RR 0.72
55 per 1,000c 15 fewer per 1,000
risk of bias,
(0.58-0.89)
(from 6 fewer to
publication bias
23 fewer)
Reporting bias
strongly
suspectedb
Relative
Effect
(95% CI)
Summary of Findings
Lowa,b due to
232/3,789 (6.1) 187/4,119 (4.5) RR 0.79
46 per 1,000c 10 fewer per 1,000
risk of bias,
(0.66-0.95)
(from 2 fewer to
publication bias
16 fewer)
Reporting bias
strongly
suspectedb
With LMWH
Overall Quality of
Publication Bias
Evidence
With IV UFH
6,910
Seriousa No serious
No serious
No serious
Reporting bias
(20 studies),
inconsistency
indirectness
imprecisiond
strongly
3 mo
suspectedb
7,976
Seriousa No serious
No serious
No serious
(17 studies),
inconsistency
indirectness
imprecision
3 mo
7,908
Seriousa No serious
No serious
No serious
(17 studies),
inconsistency
indirectness
imprecision
3 mo
Participants
(Studies),
Follow-up
Quality Assessment
Table S6—[Section 2.5.1] Evidence Profile: LMWH vs IV UFH for Initial Anticoagulation of Acute VTE
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Serious
2,205 (1 study), No serious risk No serious
No serious
3 mo
of biasd
inconsistency
indirectness
Moderated,e due 45/1,107 (4.1)f 43/1,098 (3.9)f RR 0.96
to imprecision
(0.64-1.45)
Undetected
Moderated,e due 13/1,107 (1.2)g 12/1,098 (1.1)g RR 0.93
to imprecision
(0.43-2.03)
Undetected
41/1,098 (3.7) RR 1.25
(0.8-1.97)
2 fewer per 1,000
(from 15 fewer
to 18 more)
7 more per 1,000
(from 6 fewer to
29 more)
12 per 1,000g 1 fewer per 1,000
(from 7 fewer to
12 more)
41 per 1,000f
30 per 1,000
Risk Difference
With Fondaparinux
(95% CI)
Bibliography: Büller et al.25 INR 5 international normalized ratio. See Table S1 and S2 legends for expansion of other abbreviations.
a Fondaparinux 7.5 mg (5.0 mg in patients weighing , 50 kg and 10.0 mg in patients weighing . 100 kg) SC once daily for at least 5 d and until VKAs induced an INR . 2.0.
Enoxaparin 1 mg/kg of body weight SC bid for at least 5 d and until VKAs induced an INR . 2.0.
c All patients had acute symptomatic DVT.
d Allocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Analysis excluded 0.6% of randomized patients. Not stopped early for benefit.
e CI includes values suggesting no effect and values suggesting either benefit or harm; relatively low number of events.
f Five fatal VTE in fondaparinux group and five fatal VTE in LMWH group.
g Twelve patients in the fondaparinux group and 13 in the LMWH group had a major bleeding during the initial period (7 d). Of these, two in the fondaparinux group and none in the LMWH group were
fatal.
e
Moderated,e due 33/1,107 (3.0)
to imprecision
Undetected
Risk With
LMWH
Summary of Findings
With
Relative Effect
Fondaparinux
(95% CI)
Overall Quality
of Evidence
With LMWH
Imprecision Publication Bias
Seriouse
Indirectness
No serious
3 mo
of biasd
inconsistency
indirectness
Inconsistency
Seriouse
Risk of Bias
No serious
3 mo
of biasd
inconsistency
indirectness
Participants
(Studies),
Follow-up
Quality Assessment
Table S7—[Section 2.5.1] Evidence Profile: Fondaparinux vs LMWH for Initial Anticoagulation of Acute DVTa-c
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Seriouse
1,522 (5 studies), No serious risk No serious
No serious
10 d
of biasc
inconsistency
indirectness
Lowc,e,f due to
inconsistency,
imprecision
Undetected
Moderatec,e due
to imprecision
Undetected
Lowc-e due to
inconsistency,
imprecision
Undetected
9/772 (1.2)
32/647 (4.9)
20/647 (3.1)
With Bid
RR 0.86
(0.52-1.42)
RR 1.05
(0.57-1.94)
10/750 (1.3) RR 1.13
(0.48-2.66)
26/614 (4.2)
20/614 (3.3)
12 per 1,000
49 per 1,000
31 per 1,000
2 more per 1,000
(from 6 fewer to
20 more)
7 fewer per 1,000
(from 24 fewer
to 21 more)
2 more per 1,000
(from 13 fewer
to 29 more)
Risk Difference
With LMWH
Once (95% CI)
With LMWH Relative Effect
Once
(95% CI)
Risk With Bid
Summary of Findings
Bibliography: van Dongen et al.26 See Table S1, S2, and S5 legends for expansion of other abbreviations.
a The five included studies used four brands of LMWH (enoxaparin, tinzaparin, dalteparin, and nadroparin). In Merli et al, enoxaparin 1 mg/kg bid was compared with 1.5 mg/kg once daily. Holmström 27 et al
adjusted the dose to anti-Xa levels, which resulted in different daily doses after a number of days. In the remaining studies, the dose of the once-daily administration was double the dose of the twice-daily
administration (equal total daily dose).
b Of the five included studies, one included patients with PE and DVT, and four included only patients with DVT. All studies addressed the initial management of VTE.
c All included studies concealed allocation. Two studies had a double-blind design, and two others were single blind. One study did not mention blinding. ITT likely used in all studies. Participants were lost
to follow-up in only two studies (0.3% and 2.2%).
d I2 5 37%; point effect estimate in favor of bid dose in Merli et al16 and in favor of once-daily dose in Charbonnier et al.28
e Imprecision judged relative to no difference.
f I2 5 65%; point effect estimate in favor of bid dose in Merli et al16 and in favor of once-daily dose in Charbonnier et al.28
Seriouse
Seriouse
No serious
indirectness
Indirectness
1,261 (3 studies), No serious risk Seriousf
3 mo
of biasc
Inconsistency
No serious
indirectness
Risk of Bias
Overall Quality
Imprecision Publication Bias of Evidence
1,261 (3 studies), No serious risk Seriousd
3 mo
of biasc
Participants
(Studies),
Follow-up
Quality Assessment
Table S8—[Section 2.5.2] Evidence Profile: LMWH Once vs Twice Daily for Initial Anticoagulation of Acute VTEa,b
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Seriousj
0 (3 studiesh),
3 mo
Undetected Lowa,b,e,f due to
indirectness,
imprecision
Overall Quality
of Evidence
Seriousk
Seriousf
Undetected Lowi-k due to
indirectness,
imprecision
Quality of life (important outcome)
Undetected Moderatea,b,e,g
due to
indirectness
No serious
Undetected Moderatea,b,e due
imprecision
to indirectness
Seriousf
Imprecision
Publication
Bias
…
18/851 (2.1)
63/851 (7.4)
39/851 (4.6)
Relative
Effect
(95% CI)
Risk
With Hospital
Treatment
74 per 1,000
…
Not pooled
7 fewer per 1,000
(from 14 fewer to
8 more)
29 fewer per 1,000
(from 7 fewer to
43 fewer)
See commenth-k See commenth-k
12/857 (1.4) RR 0.67
21 per 1,000
(0.33-1.36)
39/857 (4.6) RR 0.61
(0.42-0.9)
13 fewer per 1,000
(from 25 fewer to
7 more)
Risk Difference
With Home
Treatment (95% CI)
28/857 (3.3) RR 0.72
46 per 1,000
(0.45-1.15)
With Hospital With Home
Treatment
Treatment
Summary of Findings
a
Bibliography: Othieno et al29; included studies.13,14,30-33 Quality of life.13,34,35 See Table S1 and S2 for expansion of abbreviations.
Four studies had partial hospital treatment of many in the home arm: Koopman et al (mean hospital stay 2.7 in home arm vs 8.1 d in hospital arm), Levine et al (2.1 vs 6.5 d), Boccalon et al (1 vs 9.6 d), and
Ramacciotti et al (3 vs 7 d). In Daskalopoulos et al, there was no hospital stay at all in the home group. Chong et al did not report duration of hospital stay.
b Only one study (Boccalon et al) used LMWH in both treatment arms. Remaining studies used UFH in the inpatient arm and LMWH in the outpatient arm.
c Studies included in the systematic review should have recruited patients whose home circumstances were adequate.
d All studies included patients with lower-extremity DVT and excluded patients with suspected or confirmed PE. Studies also excluded patients who were pregnant.
e Out of six studies, allocation was clearly concealed in three (unclear in remaining three). Outcome adjudicators were blinded in the two largest studies (unclear in remaining). Four reported loss to follow-up
(was significant in only a small study). ITT analysis was conducted in four (unclear in remaining two). No study was stopped early for benefit. Overall, the judgment was that these limitations would not
warrant downgrading of quality because it has already been downgraded by at least one level based on other factors.
f The CI includes both values suggesting benefit and harm.
g Judged as precise based on the narrow CI around absolute effect.
h Bäckman et al34 reported evaluation of health-related quality of life using the EQ-5D. They found no differences in mean quality-of-life scores or in the proportion of patients showing improvement in
self-rated health state. Koopman et al evaluated health-related quality of life using the Medical Outcome Study Short Form-20 and an adapted version of the Rotterdam Symptom Checklist. The changes
over time were similar in both groups except that the patients receiving LMWH had better scores for physical activity (P 5 .002) and social functioning (P 5 .001) at the end of the initial treatment. The
authors did not report enough data to assess precision and clinical significance of results. O’Brien et al35 assessed changes in quality of life using the Medical Outcome Study Short Form-36 in 300 patients
participating in Levine et al.14 They found that, the change in scores from baseline to day 7 was not significantly different between the treatment groups for seven of the eight domains. The one exception
was the domain of social functioning, where a greater improvement was observed for the outpatient group.
i Potential inconsistency as Bäckman et al34 showed no effect, whereas Koopman et al13 and O’Brien et al35 showed potential benefit.
j Two of the three studies had partial hospital treatment of many in the home arm: Koopman et al13 (mean hospital stay 2.7 in home arm vs 8.1 d in hospital arm) and Levine et al (2.1 vs 6.5 d).
k Not able to evaluate but imprecision is possible. Taken together with the potential inconsistency, we downgraded the quality of evidence by one level.
No serious risk No serious
of bias
inconsistencyi
Seriousa,b
3 mo
of biase
inconsistency
a,b
Serious
Indirectness
3 mo
of biase
inconsistency
Inconsistency
Seriousa,b
Risk of Bias
inconsistency
3 mo
of biase
Participants
(Studies),
Follow-up
Quality Assessment
Table S9—[Section 2.7] Evidence Profile: Home Treatment vs Hospital Treatment of Acute DVTa-d
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Risk of Bias
Inconsistency
Indirectness
Imprecision
Lowc,d due to
imprecision
Undetected
3/76 (3.9)e
Lowc,d due to
imprecision
1/76 (1.3)
Lowc,d due to
imprecision
0/76 (0)
1/77 (1.3)g
0/77 (0)
48 per 1,000f
31 fewer per 1,000
(from 48 fewer to
340 more)
39 per 1,000e 34 fewer per 1,000
(from 39 fewer to
67 more)
RR 2.00
29 per 1,000f,h 29 more per 1,000
(0.19-19.46)
(from 23 fewer to
535 more)
RR 0.35
(0-8.09)
RR 0.14
(0.01-2.71)
Seriousi
2y
of biasc
inconsistency
No serious
Undetected
imprecision
Moderatec,i due 49/70 (70)
to indirectness
23/68 (33.8)
RR 0.46
(0-0.79)
(Continued)
588 per 1,000j 318 fewer per 1,000
(from 123 fewer
to 588 fewer)k
Postthrombotic syndrome (critical outcome; assessed with: complete lysis on venography (Elsharawy et al); patency on ultrasound and air plethysmography (Enden et al))
Undetected
Nonfatal major bleeding (critical outcome)
Undetected
0/77 (0)
Risk Difference
With CatheterDirected
Thrombolysis
(95% CI)
Summary of Findings
With No
Risk With No
CatheterWith CatheterCatheterOverall Quality
Directed
Directed
Relative Effect
Directed
Publication Bias of Evidence Thrombolysis Thrombolysis
(95% CI)
Thrombolysis
Nonfatal recurrent VTE (critical outcome)
No serious
Very seriousd
of biasc
inconsistency
indirectness
No serious
Very seriousd
7d
of biasc
inconsistency
indirectness
153 (1 study),
3 mo
No serious
Very seriousd
3 mo
of biasc
inconsistency
indirectness
Participants
(Studies),
Follow-up
Quality Assessment
Table S10—[Section 2.9] Evidence Profile: Catheter-Directed Thrombolysis vs No Catheter-Directed Thrombolysis for Extensive Acute DVT of the Legab
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Risk of Bias
Inconsistency
Indirectness
Imprecision
Risk Difference
With CatheterDirected
Thrombolysis
(95% CI)
With No
Risk With No
CatheterWith CatheterCatheterOverall Quality
Directed
Directed
Relative Effect
Directed
Publication Bias of Evidence Thrombolysis Thrombolysis
(95% CI)
Thrombolysis
Summary of Findings
No serious
No serious
Undetected
of biasm,n
inconsistency
indirectness
imprecision
Lowm,n
30
68
...
See footnoteo
Bibliography: Elsharawy et al,36 Enden et al,37 Comerota et al.38 CDT 5 catheter-directed thrombolysis; PTS 5 postthrombotic syndrome. See Table S1 legend for expansion of other abbreviations.
a All patients were anticoagulated per protocol, but the intervention group received CDT in addition to anticoagulation.
b In selected patients with extensive acute proximal DVT (eg, iliofemoral DVT, symptoms for , 14 d, good functional status, life expectancy ! 1 y) who have a low risk of bleeding.
c Allocation was concealed in Enden et al and unclear in Elsharawy et al. Outcome assessor blinded in both studies. Follow-up rates were 87% in Enden et al and 100% in Elsharawy et al. None of the
studies was stopped early for benefit.
d CI includes values suggesting both benefit and harm.
e Three control patients died of cancer.
f Baseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.39
g In the Enden et al study, one patient had “durable and partial impairment of sensibility of the foot” immediately after receiving CDT, and nine patients had minor bleeding complications.
h Most of bleeding events occur during the first 7 d.
i Surrogate outcome: absence of patency at 6 mo in Enden et al study; absence of complete lysis at 6 mo in Elsharawy et al study.
j This estimate is based on the findings of the VETO (Venous Thrombosis Outcomes) study.40 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of
compression stockings during study follow-up.
k Severe PTS: assuming the same RR of 0.46 and a baseline risk of 13.8%, the absolute reduction is 75 fewer severe PTS per 1,000 (from 29 fewer to 138 fewer) over 2 y.
l Camerota et al.38
m Participation rate was 65%.
n Recall was used to measure quality of life prior to the thrombotic event; we did not consider these measurements.
o At the initial follow-up (mean, 16 mo), patients treated with CDT reported a trend toward a higher mental summary scale (P 5 .087) and improved Health Utilities Index (P 5 .078). They reported better overall
role physical functioning (P 5 .046), less stigma (P 5 .033), less health distress (P 5 .022), and fewer overall symptoms (P 5 .006) compared with patients who were treated with anticoagulation alone.
98 (1 studyl),
16 mo
Quality of life (important outcome; measured with the Medical Outcome Survey Short Form-12, Health Utilities Index MARK version 2/3 questionnaires; better indicated by lower values)
Participants
(Studies),
Follow-up
Quality Assessment
Table S10—Continued
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Prospective registry
Prospective study
Verhaeghe et al42/1997
Bjarnason et al43/1997
Type of Publication
Semba et al41/1994
Author/Year
77 patients (87 limbs) with
iliofemoral DVT " 14 d
(69) or . 14 d (18) duration
24 patients with iliofemoral
DVT " 14 d (16)
or . 14 d (8) duration
iliofemoral DVT " 14 d
(20) or . 14 d (7) duration
Participants
Clot lysis, bleeding
Clot lysis,
complications
Outcomes
2,000-2,500 units/kg per h
Clot lysis, PE,
urokinase infused for 75 h (mean)
bleeding
with 5,000 International Units bolus
heparin plus infusion
adjusted to aPTT
Adjunctive therapy: angioplasty
(52 limbs), stent (38), AVF (15),
surgical thrombectomy (13),
mechanical thrombectomy (4),
surgical bypass (3)
3 mg/h rt-PA (mean 86 mg) infused
with 1,000 U/h IV heparin,
followed by heparin, adjusted
to APTT
Adjunctive therapy: hydrodynamic
thrombectomy (3) and stents (9)
4.9 million units urokinase
(mean) infused over 30 h (mean),
followed by heparin and then
warfarin for 8-12 wk
Adjunctive therapy: limbs with
residual stenoses . 50% received
angioplasty (2) or stenting (14)
Interventions
1y
13 mo (mean)
3 mo
Follow-up
(Continued)
Early results:
Significant lysis: 69/87 (79%)
Iliac (63%)
Femoral (40%)
No lysis: 18/87 (21%)
PE: 1 (1%)
Bleeding: major, 5/77 (6%);
minor, 11/77 (14%)
Patency at 1 y:
Iliac: 63%
Femoral, 40%
Partial lysis: 5/24 (21%)
Bleeding: 6/24 (25%)
Patency:
3 mo: 84%
1 y: 78%
Significant lysis: 18/25a (72%)
No lysis: 2/25 (8%)
Complications: 1 small hematoma
at puncture site, no intervention/
transfusion
Results
Table S11—[Section 2.9] CDT vs No CDT for Extensive Acute DVT of the Leg: Clinical Description and Results (All Randomized Trials and Prospective
Observational Studies of at Least 20 Patients)
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Prospective study
RCT, single center
AbuRahma et al45/2001
Elsharawy et al36/2002)
Type of Publication
Prospective
multicenter registry
44
Mewissen et al /1999
(National Multicenter
Registry)
Author/Year
35 patients with DVT , 10 d
duration randomized to
CDT or anticoagulation
alone
iliofemoral DVT given choice
between conventional therapy
(heparin 1 warfarin) orlysis
1 angio/stent (if needed).
Lysis offered only to patients
with DVT " 14 d duration
and no contraindications
287 patients (312 infusions)
with lower limb DVT " 10 d
(188) or . 10 d (99) duration
Participants
CDT: 18 patients received ! 1
million units SK pulse-spray for
1 h, followed by 100,000
units/h SK infusion until complete lysis, no change in 12 h, or
complication
Adjunctive therapy:
angioplasty/stent (1)
Adjunctive therapy: patients with
residual stenosis . 50% received
stents (10)
CDT: 18 patients given loading
dose 4,500 units urokinase
followed by 4,500 units/kg per h
for 24-48 h or 4-8-mg bolus of rtPA followed by 2-4-mg/h infusion
Anticoagulation: 33 patients given
1,000-2000 units/h heparin
infusion for 5-7 d.
7.8 million units urokinase
(mean) infused for 53.4 h
(mean) in 297 limbs
In 6 limbs, only systemic infusion
(no CDT)
Adjunctive therapy: stents (104),
systemic infusion (54)
Interventions
Clot lysis, PE,
bleeding
Clot lysis, PE,
bleeding
Clot lysis, PE,
bleeding, death
Outcomes
1 wk and 6 mo
CDT: 6 mo?
Anticoag: 6 mo
1y
Follow-up
(Continued)
CDT, 1 wk
Complete lysis: 11/18 (61%)
No lysis: 0 (0%)
PE: 0 Bleeding: 0
Anticoagulation, 1 wk:
No lysis: 17/17 (100%)
PE: 1/17 (6%)
Bleeding: 0
CDT:
30-d significant lysis: 15/18 (83%)
6-mo patency: 15/18 (83%)
Anticoagulation:
30-d significant lysis: 1/33 (3%)
6-mo patency: 8/33 (24%)
Bleeding: 2/33 (6%)
PE: 2/33 (6%)
Early results:
50%-100% lysis: 258/312 (83%)
, 50% lysis: 54/312 (17%)
PE: 6/473b (1%)
Bleeding: 54/473b (11%)
Death: 2/473b (, 1%)
Patency at 1 y:
Iliac: 64%
Femoral: 47%
Results
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RCT, multicenter
Type of Publication
Iliofemoral DVT , 21 d
duration
Participants
Anticoagulation alone: usual
practice, administered locally
CDT: tPA 0.01 mg/kg per h,
maximum of 20 mg/24 h for 4 d.
Treated in four referral centers
Anticoagulation: 17 patients
received 5,000 units heparin
bolus, followed by heparin
adjusted to aPTT
Interventions
Follow-up
Clot lysis, PE,
1 wk and 6 mo
bleeding (PTS at 24
mo pending)
Outcomes
CDT, 1 wk
! 50%lysis: 44/50 (68%)
PE: 0
Major bleeding: 1/50
Anticoagulation, 1 wk:
Lysis not assessed
PE: 0
Major bleeding: 0
(puncture site nerve damage: 0)
CDT, 6 mo
Iliofemoral patency:
32/50 (64%)
Anticoagulation, 6 mo
Iliofemoral patency:
19/53 (36%)
CDT, 6 mo
No lysis: 0 (0%)
Anticoagulation, 6 mo
Significant lysis:2/17 (12%)
No lysis: 7/17 (41%)
Results
Early prospective observational studies with , 20 patients and retrospective studies are described in Table 3 of the eighth edition of these guidelines.46 AVF 5 arteriovenous fistula; CaVenT 5 CatheterDirected Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis; rt-PA 5 recombinant tissue plasminogen activator; SK 5 streptokinase. See Table S2, S4, S5, and S10 legends for expansion of other
abbreviations.
a Twenty-five of 27 limbs treated with CDT; two could not be crossed with the guidewire.
b Calculated from total number of patients in Venous Registry.
Enden et al37/2009
(CaVenT)
Author/Year
Table S12—[Section 2.9] CDT vs No CDT for Extensive Acute DVT of the Leg: Methodologic Quality
Author/Year
Randomization
Allocation Concealment
Blinding
Loss to follow-up
Semba et al /1994
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Bjarnason et al43/1997
N/A
N/A
N/A
N/A
Mewissen et al44/1999
N/A
N/A
N/A
N/A
AbuRahma et al45/2001
N/A
N/A
N/A
N/A
Elsharawy et al36/2002
Computer-designated
cards
PN
N for patients, caregivers,
and probably data analysts.
Y for vascular imaging
0
Enden et al37/2009
Computer-designated
cards
Y
No for patients and
caregivers. Yes for
vascular imaging.
One loss to follow-up
(CDT), five
withdrawals, five
postrandomization
exclusions
41
N 5 no; N/A 5 not applicable; Y 5 yes. See Table S10 legend for expansion of other abbreviation.
16
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RCT, single
center
RCT, single
center
RCT, single
center
Robertson et al53/1968
Kakkar et al54/1969
52
Type of
Publication
Browse et al /1968
Author/Year
30 patients with
DVT of , 4 d
16 patients with
DVT
10 patients with
lower-extremity
DVT confirmed
by phlebography
Participants
Thrombolysis: SK 500,000 units
IV over 30 min; 900,000 units
every 6 h 3 5 d
(10 patients)
Thrombolysis: SK 200,000
units over 90 min, then
100,000 units as
maintenance dose for
22.5 h; heparin 500 mg
given during 24 h, plus
prednisone (8 patients)
Anticoagulation: Heparin
plus prednisone
(8 patients)
Lysis: 600,000 units SK plus
100 mg hydrocortisone
for first hour, then
continued every 6 h
for 3 d (5 patients)
Anticoagulation: 4-6 hourly
doses of heparin
5,000 units for 48 h
followed by warfarin
(5 patients)
Interventions
Clot lysis, PE,
bleeding, death
Clot lysis,
bleeding
Clot lysis, PE,
bleeding
Outcomes
6-12 mo
7d
7-10 d
Follow-up
(Continued)
Thrombolysis:
Complete clot lysis: 6/9 (67%)
No lysis: 2/9 (22%)
PE: 0
Death: 2/9 (22%)
Note: (1 patient excluded from treatment)
Thrombolysis:
No lysis: 1/8 (12%)
Bleeding: Major: 2/8 (25%)
Minor: 2/8 (25%)
Anticoagulation:
No lysis: 5/8 (63%)
Bleeding: Major: 1/8 (12%)
Minor: 1/8 (12%)
Thrombolysis:
No lysis: 1 (20%)
PE: 0
Bleeding: 0
Anticoagulation:
Complete clot lysis: 0/5
Partial lysis: 0/5
No lysis: 5/5 (100%))
PE: 0
Bleeding: 0
Results
Table S13—[Section 2.10] Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg: Clinical Description and Results (Randomized Trials That
Compared Systemic Thrombolytic Therapy With No Thrombolytic Therapy)
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RCT, single
center
Prospective
study
Duckert et al56/1975
Type of
Publication
Tsapogas et al55/1973
Author/Year
134 patients with acute
or subacute DVT
34 patients with
DVT of , 5 d
Participants
Thrombolysis: initial dose
SK calculated according
to tolerance injected over
15-30 min; maintenance
dose at 30 mL/h was
two-thirds of first dose
(92 patients)
Anticoagulation: 5,000 units
heparin for initial dose
followed by 25,000 units/24 h
infusion (42 patients).
Thrombolysis: titrated
initial dose of SK IV,
then SK 100,000 units/h
maintained and adjusted
up to 72 h IV heparin for
1 wk 6-12 h post SK
(19 patients)
Anticoagulation: Heparin IV
into affected limb, 7,000 units
bolus then 1,500 units/h
adjusted; continued
for 7 d (15)
Arvin: Arvin loading dose
80 units IV over 6 h;
80 units over 15 min;
40-80 units every
6 h 3 5 d (10 patients)
Anticoagulation: Heparin
10,000 units IV over
5 min, then 10,000-15,000
units every 6 h 3 5 d
(10 patients)
Interventions
Outcomes
Clot lysis, PE,
bleeding
Clot lysis, PE,
bleeding
!7 d
7d
Follow-up
Thrombolysis:
No lysis: 30/92 (33%)
PE: 7 (8%)
Major bleeding: 58 (62%)
Minor bleeding: 24 (26%)s
Anticoagulation:
No lysis: 38/42 (90%)
PE: 5/42 (12%)
Major bleeding: 2/42 (5%)
Minor bleeding: 4/42 (10%)
(Continued)
Thrombolysis:
Complete/partial lysis: 10/19 (53%)
No lysis: 9/19 (47%)
PE: 0
Minor bleeding: 3 (16%)
Anticoagulation:
Complete/partial lysis: 1/15 (7%)
No lysis: 14/15 (93%)
PE: 1/15 (7%)
Bleeding: 0
Arvin:
No lysis: 6/10 (60%)
PE: 0
Bleeding: 0
Death: 0
Anticoagulation:
No lysis: 5/9 (55%)
PE: 1/10
Death: 2/9 (22%)
Bleeding: 2/9 (22%)
Note: (1 patient excluded from treatment)
Results
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RCT, single
center
RCT, single
center
Marder et al58/1977
Arnesen et al59/1978
57
RCT, single
center
Type of
Publication
Porter et al /1975
Author/Year
42 patients with
proximal DVT
of , 5 d.
24 patients with
DVT
50 patients with
DVT , 14 d
duration
Participants
Outcomes
Thrombolysis: loading dose
of SK 250,000 units IV,
then 100,000 International
Units/h IV for 72-96 h
(21 patients)
Anticoagulation: heparin
15,000 International Units
IV bolus, then total of
IV infusion for 72-90 h
(21 patients)
Thrombolysis: initial dose of
250,000 units SK for
20 min, followed by
100,000 units/h for
72 h (12 patients)
Anticoagulation: initial dose
heparin 150 units/kg IV,
followed by titrated
infusion for 72 h
Cotreatment: 100 mg bolus
hydrocortisone prior
to treatment
Clot lysis, PE,
bleeding
Clot lysis,
death due to
treatment
Thrombolysis: SK 250,000 units IV Clot lysis, PE,
over 30 min, then
bleeding,
100,000 units/h titrated
death due to
for 72 h followed by
treatment
IV heparin titrated over
7 d (23 patients)
Anticoagulation: IV heparin
150 units/kg loading dose
then titrated for 10 d
(26 patients)
Interventions
21 d-6 y
5d
10 d
Follow-up
Thrombolysis:
No lysis: 6/21 (29%)
PE: 1/21 (5%)
Bleeding: 2/21 (9%)
Anticoagulation:
No lysis: 16/21 (76%)
PE: 0
Bleeding: 2/21 (9%)
Thrombolysis:
No lysis: 5/12 (42%)
Death: 1/12 (8%)
Anticoagulation:
No lysis: 9/12 (75%)
Death: 0
Thrombolysis
No lysis: 2/23 (9%)
PE: 0
Death: 1 (4%)
Anticoagulation:
No lysis: 5/26 (19%)
PE: 0
Bleeding: 1/26 (4%)
Death: 0
Results
(Continued)
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Prospective
study
Watz et al61/1979
60
RCT, single
center
Type of
Publication
Elliot et al /1979
Author/Year
35 patients with
DVT
51 patients with
clinical history
of DVT of , 8 d
Participants
Thrombolysis: initial dose of
SK 250,000 units in 30 min,
followed by maintenance
100,000 units/h (18 patients)
45,000 units daily with
warfarin (17)
Thrombolysis: loading dose
of SK 600,000 units infused
over 30 min, followed by
100,000/h for 3 d; heparin
for 4 d following SK
(26 patients)
10,000 units IV initially,
followed by 10,000 units
IV daily for a 6-h infusion
to maintain clotting time
of 2.5-3 times normal for
7 d (25 patients)
Interventions
Outcomes
Clot lysis, PE,
bleeding
Immediate:
clot lysis,
PE, bleeding
Long term:
symptom free
1-2 mo
Immediate: 5 d
Long term:
19 mo (mean)
Follow-up
Thrombolysis:
No lysis: 6/18 (34%)
PE: 1/18 (5%)
Anticoagulation:
No lysis: 11/17 (65%)
PE: 1/17 (6%)
Immediate:
Thrombolysis:
Significant lysis:17/26 (65%)
No lysis: 8/26 (31%)
PE: 0
Bleeding: 2 (8%)
Anticoagulation:
No lysis: 25/25 (100%)
PE: 0
Bleeding: 2/21 (9%)
Long term:
Thrombolysis:
Symptom-free: 12/20a (60%)
Treatment 2
Symptom-free: 2/21b (9%)
Results
(Continued)
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RCT, single
center
Prospective
32 patients with
cohort study
DVT of , 10 d
(A) and multicenter
RTC (B)
Schulman et al49/1986
36 patients with calf
DVT of , 7 d
35/42 patients from
RCT
Follow-up
to RCT of
Arnesen
(1978)
Participants
20 patients with
DVT of , 72 h
RCT, single
center
Type of
Publication
Kiil et al62/1981
Author/Year
Study A: open-label study
with rt-PA 100 mg over
IV 8 h (day 1), 50 mg rt-PA
over 8 h (day 2); 10% dose
as bolus (11 patients)
Thrombolysis: SK 50,000
International Units IV
over 15 min, then 100,000
International Units over
12 h for up to 7 d, titrated;
given with heparin 5,000
International Units IV over
12 h (17 patients)
IV for 15 min then 30,000
International Units/d,
titrated over 7 d
(19 patients)
Phlebography and clinical
examination by blinded
evaluators
Thrombolysis: urokinase
200,000 units IV for 24 h;
after 18 h, heparin loading
dose of 15,000 units, then
40,000 units/d for 5 d
(11 patients)
40,000 units/day 4 for
6 d (9 patients)
Interventions
Outcomes
Clot lysis,
bleeding
Clot lysis,
bleeding, PE
Normal legs, PTS
symptoms
Clot lysis, PE,
bleeding
Follow-up
72 h
5y
6.5 y
2 wk
Results
(Continued)
Note: Authors assigned veins a relative value
reflecting degree of thrombosis
(maximum, 40 units: complete
thrombosis). The unit scores
reflect the reduction
in thrombosis postlysis.
Thrombolysis:
Bleeding:3/17 (18%)
PE: 0
Anticoagulation:
Bleeding: 1/19 (5%)
PE: 0
Thrombolysis:
Normal legs: 13/17 (77%)
PTS symptoms (moderate): 4/17 (24%)
Anticoagulation:
Normal legs: 6/18 (33%)
PTS symptoms (moderate): 9/18 (50%)
Thrombolysis:
No lysis: 10/11 (91%)
PE: 0
Anticoagulation:
No lysis: 7/8 (88%)
PE: 0
Bleeding: 3/9 (33%)
Note: 1 patient excluded from group
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Goldhaber et al64/1990
Author/Year
RCT,
multicenter
Type of
Publication
64 patients
(65 randomizations)
with DVT of , 14 d
Participants
rt-PA: rt-PA 0.05 mg/kg per h
IV for 24 h, then heparin
100 units/kg bolus, then
1,000 units/h, adjusted
(36 patients)
rt-PA 1 heparin: rt-PA as
in group 1 plus heparin
concomitantly (17 patients)
100 units/kg bolus, then
1,000 units/h (12 patients)
Study B: rt-PA 100 mg: IV of
100 mL containing rt-PA
100 mg infused over 8 h
(day 1), IV of 100 mL
containing 50 mg rt-PA
infused over 8 h (day 2);
10% dose as bolus
(8 patients)
rt-PA 50 mg: IV of 100 mL
containing rt-PA 50 mg
infused over 8 h on both
days 1 and 2; 10% dose
as bolus (6 patients)
Placebo: IV of 100 mL
containing placebo infused
over 8 h on both days 1
and 2 (7 patients)
Co-treatment: heparin 5,000 units
IV bolus then continuous
infusion 1,000 units/h
for up to 72 h
Interventions
Outcomes
Clot lysis,
bleeding
36 h
Follow-up
(Continued)
rt-PA:
No lysis: 12/32 (38%)
Bleeding: 1/32 (3%)
rt-PA 1 heparin:
No lysis:8/17 (48%)
Bleeding: 0
Anticoagulation:
No lysis: 9/11 (89%)
Bleeding: 0
Note: 5/65 venograms not analyzed
Study A
Change in unit score: 2 3.2
Study B
rt-PA 100 mg:
Bleeding: 6
rt-PA 50 mg:
Bleeding: 3
Placebo:
Bleeding: 0
Results
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RCT,
multicenter
RCT, single
center
Schweizer et al65/1998
Type of
Publication
Turpie et al50/1990
Author/Year
69 patients with
DVT of , 7 d
83 patients with
DVT of , 7 d
Participants
rt-PA 20 mg IV into pedal
vein 4 h/d for 7 d; heparin
IV given concomitantly;
warfarin day 7-12 mo
Urokinase 100,000
International Units/hr
IV into pedal vein
continuously 7 d; heparin
IV 7 d; plasminogen
monitored; warfarin
day 7-12 mo
7 d: clot lysis,
bleeding
1 y: PTS
symptoms
7 d and 1 y
rt-PA:
Bleeding: 1/22 (5%) PTS
symptoms: 14/22 (64%)
Urokinase:
Bleeding: 1/22 (5%)
PTS symptoms: 9/22 (41%)
Placebo 1 heparin
! 50% lysis: 2/30 (7%)
, 50 lysis:5/30 (17%)
No lysis: 23/30 (77%)
Bleeding: 1/30 (3%)
Placebo 1 heparin (30 pts)
Cotreatment: heparin
5,000-unit IV bolus then
30,000 units/24 h,
adjusted for 7-10 d
Phase 2:
Lysis 1 heparin:
! 50% lysis: 6/29 (21%)
, 50% lysis: 7/29 (24%)
No lysis: 15/29 (52%)
Bleeding: 1/29 (3%)
Phase 1:
Lysis 1 heparin:
! 50% lysis: 7/12 (58%)
, 50% lysis: 2/12 (17%)
No lysis: 3/12 (25%)
Results
Phase 2: Lysis 1 heparin:
one-chain rt-PA 0.5 mg/kg
IV for 8 h and repeated
in 24 h (29 patients)
24-48 h
Follow-up
Placebo 1 heparin:
, 50% lysis: 2/12 (17%)
No lysis: 10/12 (83%)
Bleeding: 1/12 (8%)
Clot lysis,
bleeding
Outcomes
Placebo 1 heparin
(12 patients)
Phase 1: Lysis 1 heparin:
two-chain rt-PA 0.5 mg/kg
IV for 4 h (12 patients)
Interventions
(Continued)
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RCT,
multicenter
Type of
Publication
250 patients with
DVT of , 9 d
Participants
See Table S1, S2, and S11 legends for expansion of abbreviations.
Four deaths, other causes, two lost to follow-up.
b Four deaths, two PEs, two other causes.
a
Author/Year
Anticoagulation: heparin IV,
adjusted.
Cotreatment: bed rest,
compression bandages,
compression therapy,
warfarin for 12 mo
Systemic urokinase: 5 million
International Units/d for 4 h
up to 7 d; IV heparin given
concomitantly
rt-PA: locoregional rt-PA
20 mg/day for 4 h through
pedal vein for 4-7 d;
IV heparin given
simultaneously at 1,000
International Units/h, adjusted
Urokinase: locoregional
urokinase 100,000
International Units infused
continuously; fibrinogen and
plasminogen monitored;
IV heparin given concomitantly
Systemic SK: 3 million units/d
for 6 h with heparin for up to
7 d. Premedications:
hydrocortisone 100 mg,
ranitidine 50 mg,
clemastine 2 mg
Anticoagulation: heparin IV
adjusted for 7 d; warfarin
day 1-12 mo
Interventions
Outcomes
Clot lysis,
bleeding,
mortality
1y
Follow-up
rt-PA:
! 50% lysis: 7/50 (14%)
, 50% lysis: 16/50 (32%)
No lysis: 13/50 (26%)
Bleeding: 2/50 (4%)
Urokinase:
! 50% lysis: 9/50 (18%)
, 50% lysis: 17/50 (34%)
No lysis: 11/50 (22%)
Bleeding: 1/50 (2%)
Systemic SK:
! 50% lysis: 7/50 (14%)
, 50% lysis: 13/50 (26%)
No lysis: 8/50 (16%)
PE: 5/50 (10%)
Systemic urokinase:
! 50% lysis:10/50 (20%)
, 50% lysis: 13/50 (26%)
No lysis: 8/50 (16%)
Bleeding: 4/50 (8%)
PE: 4/50 (8%)
Anticoagulation:
Complete lysis: 0
Bleeding: 0 PTS
Symptoms: 15/22 (68%)
Results
Table S14—[Section 2.10] Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg: Methods
Author/Year
Randomization
Allocation concealment
Blinding
Loss to follow-up
Browse et al /1968
N/A
N/A
N/A
0
Robertson et al53/1968
Patients given consecutive
code numbers and divided
into equal groups of 2—not
truly randomized
Labels on SK and
heparin coded
Y, data assessors; unclear
for patients, caregivers,
analysts
0
Kakkar et al54/1969
Sequential sealed envelope
Adequate
Y, patients No, caregivers,
assessors, analysts
0
Tsapogas et al55/1973
Sealed envelope
Adequate
Not blinded
Duckert et al56/1975
N/A
N/A
N/A
N/A
Porter et al57/1975
Assigned at random to one of
two groups
N/A
N/A
N/A
Marder et al58/1977
Assigned at random to one
of two groups. Five-day
follow-up venograms were
not performed in 3 of the
SK patients, so an additional 3
patients were added to SK
group in nonrandomized fashion.
Unclear
Not blinded
23
Assigned at random to either
group by sealed envelope
Adequate
Y, radiologic assessors No,
patients, caregivers, analysts
Elliot et al60/1979
two groups
Unclear
Y, assessors N, patients,
caregivers, analysts
N/A
N/A
52
0
0
Watz et al61/1979
N/A
N/A
N/A
Kiil et al62/1981
group
Unclear
Y, assessors, analysts N,
patients, caregivers
0
N/A
N/A
Evaluator blinded
7
group by sealed envelope
Adequate
Single blind
0
three groups
Unclear
Y, patients, assessors N,
0
Assigned at random to one of three
groups through sealed envelope
2:2:1 allocation
scheme
Not blinded
0
Turpie et al50/1990
Assigned at random to one of two
groups in each phase of study
Unclear
Y, patients, assessors N,
37
Assigned at random to one of three
groups
Adequate
1
Assigned at random to one of five
groups
Unclear
Single blind—not sure who
12
Y 5 yes. See Table S5 and S12 legends for expansion of other abbreviations.
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Lowb-e due to
imprecision
Undetected
5/233 (2.1)
Lowd,e,g due to
imprecision
2/233 (0.9)
Undetected
Moderatec,d,i due 10/234 (4.3)
to imprecision
Undetected
No serious
Very seriouse
of biasg
inconsistency
indirectnessd
No serious
Serious
3 mof
of biasi
inconsistency
indirectnessc,d
687 (3 studies),
3 mof
No serious
Very seriouse
of biasb
inconsistency
indirectnessc,d
688 (5 studies),
3 moa
Indirectness
Risk of Bias
Relative Effect
(95% CI)
Summary of Findings
(Continued)
38/454 (8.4) RR 1.84 (0.94-3.59) 29 per 1,000h,j 24 more per
1,000 (from
2 fewer to 75
more)
10/454 (2.2) RR 1.28 (0.25-6.68) 48 per 1,000h 13 more per
1,000 (from
36 fewer to
273 more)
3 fewer per
1,000 (from
16 fewer to
36 more)
Risk With Risk Difference
No Systemic With Systemic
Lysis
Lysis (95% CI)
4/455 (0.9) RR 0.86 (0.27-2.68) 21 per 1,000
With
Systemic
Lysis
Overall Quality
With No
of Evidence Systemic Lysis
Participants
(Studies),
Follow-up
Inconsistency
Quality Assessment
Table S15—[Section 2.10] Evidence Profile: Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg
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…
Seriousl,m
Risk of Bias
Indirectness
…
…
…
No serious
No serious
Seriouse4
inconsistency
indirectnessd3
Inconsistency
Lowd,e,l,m due to
risk of bias,
imprecision
…
…
Quality of life not measured
Undetected
…
24/230 (10.4)
Postthrombotic syndrome (critical outcome)
Overall Quality
With No
of Evidence Systemic Lysis
…
27/448 (6)
With
Systemic
Lysis
Risk With Risk Difference
No Systemic With Systemic
Lysis
Lysis (95% CI)
-
…
…
RR 0.71 (0.49-1.04) 588 per 1,000n 171 fewer per
1,000 (from
300 fewer to
24 more)o
Relative Effect
(95% CI)
Summary of Findings
Bibliography: Watson et al.47 We excluded Elsharawy et al36 from the analysis because it used catheter directed thrombolysis.36 We identified no studies published since the search date of the systematic
review. See Table S1, S10, and S11 legends for expansion of abbreviations.
a Range of follow-up in included studies, 1 to 72 mo.
b Allocation concealed in three of five studies. Follow-up inadequate in one of five (Common et al48). Excluding this study from the analysis does not change the effect estimate. All studies had blinded
outcome assessors. None of the studies used a placebo control.
c The population of one study (Schulman et al49) consisted of patients with calf vein thrombosis.
d Interventions varied across studies with regard to agent (eg, tPA, SK, urokinase), dose, use of the pedal vein administration, duration of treatment, and concomitant drugs (eg, steroids). However, we did
not downgrade for indirectness given that there is no standard regimen, and all analyses showed no heterogeneity in results.
e CI included both no effect and a potentially significant effect.
f Range of follow-up in included studies, 1 to 30 d.
g Allocation concealed in two of three studies. Follow-up adequate in all studies. All studies had blinded outcome assessors. None of the studies used a placebo control.
h Baseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.39iAllocation concealed in seven of 10 studies. Follow-up inadequate in one 10 studies (Common et al48).
Excluding this study from the analysis does not affect the effect estimate. All studies had blinded outcome assessors. Two studies used placebo (Turpie et al; 50Verhaeghe et al51).
j Only 4% of all major bleeding events were intracranial bleeds.
k Range of follow-up in included studies: 1 to 6 y.
l Allocation concealed in two of two studies. Follow-up adequate in all studies. All studies had blinded outcome assessors. None of the studies used placebo control.
m No use of a standardized validated tool reported.
n This estimate is based on the findings of the VETO (Venous Thrombosis Outcomes) study.40 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of
o Severe PTS: assuming the same RR of 0.71 and a baseline risk of 13.8%,40 the absolute reduction is 40 fewer severe PTS per 1,000 (from 70 fewer to 6 more) over 2 y.
…
678 (2 studies),
2 yk
Participants
(Studies),
Follow-up
Quality Assessment
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…
Imprecision
…
…
…
Lowb,c due to
risk of bias,
imprecision
Lowg,h due to
risk of bias,
imprecision
…
…
Undetected
PTS (critical outcome)
See comment
…
1/27 (3.7)d
…
25/27 (92.6)
0/27 (0)
Very seriousc Undetected
Serioush
...
…
Mortality not reported
Publication Bias
…
14/24 (58.3)
0/24 (0)f
0/24 (0)
…
-
RR 0.63
(0.44-0.9)i
Not estimable
RR 0.37
(0.02-8.75)
…
...
…
588 per 1,000j
See comment
…
218 fewer per
1,000 (from
59 fewer to
329 fewer)k
…
48 per 1,000d,e 30 fewer per
1,000 (from
47 fewer to
372 more)
...
Risk Difference
With No
Risk With
With Surgical
Overall Quality
Surgical
With Surgical Relative Effect No Surgical
Thrombectomy
of Evidence Thrombectomy Thrombectomy
(95% CI)
Thrombectomy
(95% CI)
Summary of Findings
a
67
Bibliography: Plate et al. See Table S1, S5, and S10 legends for expansion of abbreviations.
The study included patients with DVT with symptoms of leg swelling not exceeding 7 d and a proximal extension of the thrombus above the inguinal ligament, but not into the vena cava.
b Not clear whether allocation was concealed. No blinding reported. Not clear whether analysis was ITT. Follow-up rate 88% at 6 mo. Study not stopped early for benefit.
c CI includes values suggesting either harm or benefit.
d One event, which was a symptomatic PE.
e Baseline risks for nonfatal recurrent VTE derived from Douketis et al.39
f No severe bleeding complications were recorded in either group. Three patients in thrombectomy group developed local wound hematoma.
g In addition to other study limitations, this outcome was assessed by those who did the surgery and anticoagulation. No standardized tool was used. One surgical patient had an amputation secondary to
venous gangrene and was not counted in the PTS assessment.
h Few number of events. This warrants rating down the quality of evidence by a second level when considered along with study limitations.
i The RR is based on the 6-mo data.
j This estimate is based on the findings of the VETO (Venous Thrombosis Outcomes study.40 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of
k Severe PTS: assuming the same RR of 0.63 and a baseline risk of 13.8% over 2 y,40 the absolute reduction is 51 fewer severe PTS per 1,000 (from 14 fewer to 77 fewer) over 2 y.
…
No serious
No serious
inconsistency
indirectness
51 (1 study), 2 y Seriousg
…
No serious
No serious
inconsistency
indirectness
Seriousb
51 (1 study), 3
mo
…
Indirectness
No serious
No serious
Very seriousc Undetected
inconsistency
indirectnessc
…
Inconsistency
Seriousb
…
Risk of Bias
51 (1 study), 3
mo
…
Participants
(Studies),
Follow-up
Quality Assessment
Table S16—[2.11] Evidence Profile: Surgical Thrombectomy Vs No Surgical Thrombectomy for Extensive Acute DVT of the Lega
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Prospective registry 70 patients (71 legs) with
iliofemoral DVT (age of
clot mean, 3 d)
prior operative venous
thrombectomy and AVF
closed at 6-8 wk for
iliofemoral DVT
Einarsson et al68/1986
Plate et al70/1990
Five-year follow41/58 patients (22 medical,
up to RCT (Plate,
19 surgical) available for
198467)
evaluation at 5 y
58 patients with acute
iliofemoral venous
thrombosis
RCT, multicenter
Plate et al /1984
Participants
Type of Publication
67
Author/Year
PTS sequelae: iliofemoral
patency, valve competence
Outcomes
Prior treatment: Medical:
anticoagulation alone vs
Surgical: operative venous
thrombectomy plus
anticoagulation
Clinical PTS, venography,
venous pressure,
venous plethysmography,
foot volumetry
PTS sequelae, iliac patency,
venous pressure
Foot volumetry: Normal,
abnormal
Plethysmography: Normal,
abnormal
Venous pressure: Normal,
abnormal
Venography (vein segment):
Normal, postthrombotic,
occluded
Venous insufficiency:
Good, fair, poor
Iliofemoral venous thrombectomy Venous patency, hematoma,
with temporary AVF closed
AVF patency, PE, wound
at 6-8 wk, heparin preoperatively
infection
and postoperatively plus
warfarin postoperatively
Surgical: operative venous thrombectomy with temporary AVF
plus anticoagulation as above
(27 patients)
Medical: 5,000-unit bolus heparin
followed by 500 units/kg per
24 h adjusted to aPTT, and oral
anticoagulation (31 patients)
Interventions
Medical:
PTS sequelae: 25/27 (93%)
Iliofemoral patency: 9/26 (35%)
Valve competence: 7/27 (26%)
(PE in 1 patient)
Surgical:
PTS sequelae: 14/24 (58%, P , .005)
Iliofemoral patency: 16/21 (76%, P , .025)
Valve competence: 13/23, (52% P , .05)
(venous gangrene in 1 patient)
Results
5y
9-10 mo
(Continued)
Medical:
Iliac patency: 11/22 (50%)
Venous pressure: 60 mm Hg (mean)
Venography (iliofemoral):
Normal: 61%
Postthrombotic: 23%
Occluded: 39%
IV pressure:
Normal: 82%
Abnormal: 18%
Plethysmography:
Normal: 29%
Abnormal: 71%
Foot volumetry:
Normal: 29%
Abnormal: 71%
Venous insufficiency:
Good: 75%
Fair: 20%
Poor: 5%
56 d (mean) Patent iliac vein: 88%
Hematoma: 11%
AVF patency: 86%
PE: 4%
Wound infection: 26%:
6 mo
Follow-up
Table S17—[Section 2.11] Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive Acute DVT of the Leg: Clinical Description and Results
(All Randomized Trials and Prospective Observational Studies of at Least 20 Patients)
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Ten-year follow30/58 patients (17 from
up to RCT (Plate,
medical arm, 13 from
1984 [10] and
surgical arm) available
1990 [20])
for evaluation
Plate et al72/1997
Patency, PE, clinical
symptoms, normal
photoplethysmography,
successful AVF closure
Outcomes
Prior treatment Medical:
PTS sequelae, iliac patency,
anticoagulation alone vs Surgical:
venous pressure
operative venous thrombectomy
plus anticoagulation
Adjunctive therapy: transvenous
percutaneous dilatation of
severe iliac stenosis (3 patients)
Operative venous thrombectomy
with temporary AVF
(closed 6-12 wk postoperative)
Interventions
10 y
24 mo
(mean)
Follow-up
Results
Medical:
Surgical:
Patency:
Iliofemoral: 88%
Popliteal: 94%
PE: 16% symptomatic, 31%
asymptomatic Symptom-free: 81%
Normal photoplethysmography
(no reflux): 56% AVF closure
success rate: 87%
Surgical:
Venous pressure: 43 mm Hg (mean,
P , .05)
Early prospective observational studies with , 20 patients and retrospective studies are described in Table 5 of the eighth edition of these guidelines.46 See Table S1, S2, S4, S10, and S11 legends for
expansion of abbreviations.
48 patients with iliofemoral
DVT of 1-14 d
Neglén et al71/1991
Participants
Type of Publication
Author/Year
Table S18—[Section 2.11 ] Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive Acute DVT
of the Leg: Methodologic Quality
Author/Year
Randomization
Blinding
Loss to Follow-up
7
Plate et al67/1984
ND
PN
N, patients, caregivers,
assessors, and data analysts
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Plate et al70/1990
N/A
N/A
N/A
17
Neglén et al71/1991
N/A
N/A
N/A
N/A
Plate et al72/1997
N/A
N/A
N/A
28
See Table S5 and S12 legends for expansion of abbreviations.
31
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Seriousf
Seriousf
Seriousd
304 (1 study), 8 y No serious risk No serious
No serious
of biasc
inconsistency
indirectness
No serious
of biasc
inconsistency
indirectness
No serious
of biasc
inconsistency
indirectness
Indirectness Imprecision
Serious
Inconsistency
No serious
inconsistency
indirectness
of biasc
Risk of Bias
d
Participants
(Studies),
Follow-up
Quality Assessment
With No
Vena Cava
Filters
With Vena
Cava Filters
Undetected Moderatec,d due 31/168 (18.5)
to imprecision
Major bleeding (important outcome)
Undetected Moderatec,f due 41/150 (27.3)
to imprecision
Recurrent DVT (important outcome)
Undetected Moderatec,f due 24/159 (15.1)
to imprecision
Symptomatic PE (critical outcome)
26/169 (15.4)
57/160 (35.6)
9/145 (6.2)
Undetected Moderatec,d due 103/200 (51.5) 98/200 (49.0)
to imprecision
Bias
of Evidence
RR 0.83
(0.52-1.34)i
RR 1.3
(0.93-1.82)h
RR 0.41
(0.2-0.86)g
RR 0.95
(0.78-1.16)e
Relative
Effect
(95% CI)
185 per 1,000
273 per 1,000
151 per 1,000
515 per 1,000
(Continued)
31 fewer per 1,000
(from 89 fewer
to 63 more)
82 more per 1,000
(from 19 fewer
to 224 more)
89 fewer per 1,000
(from 21 fewer
to 121 fewer)
26 fewer per 1,000
(from 113 fewer
to 82 more)
Risk Difference
With Vena Cava
Filters (95% CI)
Risk With No
Vena Cava
Filters
Summary of Findings
Table S19—[Section 2.13] Evidence Profile: Vena Cava Filter vs No Vena Cava Filter for Acute Proximal DVT of the Leg Treated With Anticoagulationa,b
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Risk of Bias
…
8
…
73
…
…
…
…
Quality of life not reported
Undetected Moderatef due to
imprecision
With Vena
Cava Filters
…
0/186 (0)
…
0/193 (0)
107/153 (69.9) 109/155 (70.3)
With No
Vena Cava
Filters
Complications (important outcome)
Undetected Lowd,j due to
risk of bias,
imprecision
PTS (important outcome)
Bias
of Evidence
-
…
RR 0.87
(0.66-1.13)
Relative
Effect
(95% CI)
…
…
699 per 1,000
…
…k
91 fewer per 1,000
(from 238 fewer
to 91 more)
Risk Difference
With Vena Cava
Filters (95% CI)
Risk With No
Vena Cava
Filters
Summary of Findings
Bibliography: Decousus et al, The PREPIC Investigators. See Table S1, S2, S5, and S10 legends for expansion of abbreviations.
a Four types of permanent vena cava filters were used: Vena Tech LGM (B. Braun Melsugen AG), titanium Greenfield (Boston Scientific Corporation), Cardial (C.R. Bard, Inc), and Bird’s Nest (Cook
Group Incorporated).
b Anticoagulation consisted of LMWH or UFH initially (according to a 2 3 2 factorial design) followed by oral anticoagulation for at least 3 mo.
c Allocation concealed. Data collectors and outcome adjudicators blinded. ITT analysis. Data missing for 4% at 2 y and 1% at 8 y. Enrollment was stopped at 400 instead of targeted 800 due to slow
recruitment.
d CI includes both negligible effect and appreciable benefit or appreciable harm.
e RR, 1.0 (95% CI, 0.29-3.4) at 12 d; RR, 1.08 (95% CI, 0.73-1.58) at 2 y.
f Small number of events.
g RR, 0.23 (95% CI, 0.05-1.05) at 12 d (both symptomatic and asymptomatic PE). RR, 0.54 (95% CI, 0.21-1.41) at 2 y (symptomatic PE)
h RR, 1.78 (95% CI, 1.09-2.94) at 2 y.
i RR, 1.5 (95% CI, 0.54-4.14) at 12 d. RR, 0.74 (95% CI, 0.41-1.36) at 2 y.
j No standardized validated tool used to measure PTS.
k No complications directly related to the filter or its insertion reported in the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) trial.8 Mismetti et al74 (prospective study)
reported an incidence of 3.2% (excluding filter tilting and puncture site hematoma) among 220 patients receiving retrievable vena cava filter for secondary prevention of VTE, whereas while
Athanasoulis et al75 (retrospective study) reported an incidence of 0.3% for major complications among 1,731 patients receiving vena cava filters predominantly for secondary prevention of VTE.
…
Seriousf
No serious
of bias
inconsistency
indirectness
Indirectness Imprecision
Seriousd
Inconsistency
No serious
No serious
inconsistency
indirectness
308 (1 study), 8 y Seriousj
Participants
(Studies),
Follow-up
Quality Assessment
Table 19—Continued
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Risk of
Bias
Inconsistency
Indirectness
Imprecision
Undetected
Lowd,e due to
risk of bias,
imprecision
2/186 (1.1)
Publication Overall Quality With Delayed
Bias
of Evidence
Ambulation
3/199 (1.5)
With Early
Ambulation
Undetectedg Lowd-g due to
risk of bias,
imprecision
22/186 (11.8)
Risk With
Delayed
Ambulation
Risk Difference
With Early
Ambulation (95% CI)
27/199 (13.6) RR 1.16 (0.66-2.05) 118 per 1,000 19 more per 1,000 (from
RR 1.3 (0.23-7.55) 11 per 1,000 3 more per 1,000 (from
8 fewer to 70 more)
Relative
Effect
(95% CI)
Summary of Findings
Lowh,i due to
risk of bias,
indirectness
17
36
No serious
No serious
Seriouse
inconsistency
indirectness
Undetected
Lowe,h due to
risk of bias,
imprecision
9/11 (81.8)
-
14/26 (53.8) RR 0.66 (0.42-1.03)
PTS (important outcome; assessed with Villata-Prandoni score [value . 5])
No serious
Undetected
imprecision
400 per 1,000 136 fewer per 1,000 (from
Moderate
See footnotej
a
Bibliography: Kahn et al,76 Aissaoui et al.77 Included studies.78-82 See Table S1, S2, S5, and S10 legends expansion of other abbreviations.
In two of four eligible trials, all patients received early compression therapy (bandages or stockings). In the two other trials, only patients randomized to early ambulation received early compression
therapy.
b Two of four eligible studies excluded patients with symptomatic PE; in the third study, 24% of participants had symptomatic PE at baseline. It was not clear whether the fourth study excluded patients
with symptomatic PE.
c Three studies reporting acute phase mortality reported no deaths.
d Concealment of allocation reported in one of four studies; blinding of outcome assessors reported in two of four studies; ITT analysis reported in two of four studies. Follow-up 97%-100%. In two of
four trials, only patients randomized to early ambulation received early compression therapy (bandages or stockings). In the two other trials, all patients received early compression therapy.
e CI includes both values of clinically significant benefit and values of clinically significant harms.
f PE assessed as both symptomatic and asymptomatic PE.
g Funnel plot reported as not asymmetrical by Aissaoui et al.77
h Concealment of allocation not reported, outcome assessors not blinded for this outcome; 70% follow-up rate; compression stockings used on patients with early mobilization but in patients with delayed
mobilization.
iNo explanation was provided.
j Psychologic and overall somatic quality of life did not differ significantly between the treatment groups, whereas DVT-related items, especially those reflecting the ease of locomotion, showed significantly
greater improvement with compression than with bed rest (P , .001 for bandages, P , .05 for stockings).
h
37 (1 study) 2 y Serious
53 (1 study), 2 y Serioush No serious
Seriousi
inconsistency
Quality of life (important outcome; measured with quality of life questionnaire in chronic limb venous insufficiency [CIVIQ]; better indicated by lower values)
385 (4 studies), Seriousd No serious
No serious
Seriouse
4-12 d
inconsistency
indirectnessf
PE (critical outcome; assessed with symptomatic or asymptomatic PE)
385 (4 studies), Seriousd No serious
No serious
Very
3 moc
inconsistency
indirectness
seriouse
Participants
(Studies),
Follow-up
Quality Assessment
Table S20—[Section 2.14] Evidence Profile: Early Ambulation vs Delayed Ambulation for Acute DVT of the Lega,b
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RCT, single
center
RCT,
multicenter
RCT, single
center
Prospective
study
RCT
Partsch et al81/2000
Aschwanden et al78/2001
Blättler et al79/2003
82
Type of
Publication
Schellong et al /1999
Author/Year
Ambulation ! 4 h/d for 4 d
under supervision, LMWH
(69 patients)
Bed rest for 4 d (60 patients)
Bed rest, no compression,
LMWH (15 patients)
53 patients with
proximal DVT
Ambulation 1 bandages:
firm inelastic bandages,
ambulation (18 patients)
Ambulation 1 stockings:
elastic compression
stockings, ambulation
(18 patients)
1,289 patients with All treated with LMWH,
acute DVT
compression, and
immediate ambulation
129 patients with
acute DVT
Outcomes
Walking distance,
well-being, and
DVT-related quality of
life, leg pain by visual
analog scale, edema,
clinical scores, thrombus
progression
PE on / scan at
admission and after
10 d of treatment,
New PE between baseline
and day 4 by / scan
Walking distance, pain
levels, leg circumference,
clinical scores, PE, side
effects
Ambulation: leg elevation until PE by / scan
day 2, then ambulation and
compression (64 patients)
Bed rest for 8 d with leg
elevation and compression
(62 patients)
Interventions
45 patients with
Ambulation 1 bandages:
proximal DVT
inelastic Unna boot
, 14 d duration
bandages plus walking
exercises (15 patients)
Ambulation 1 stockings:
elastic compression
stockings plus walking
exercises (15 patients)
126 patients with
acute proximal
DVT
Participants
9d
10 d
3 mo
9d
10 d
Follow-up
(Continued)
Well-being/quality of life: Improved with stockings (P , .05),
bandages (P , .01)
Leg pain: Decreased faster during first 4 d w/ bandages
and stockings vs bed rest (P , .01); near absence of pain
at 9 d achieved with bandages only
PE at admission: 629/1,270 (50%) PE at 10 d: 77/1,256 (61%)
Note: initial lung scans were performed in 1,270/1,289 patients;
follow-up scans were performed in 1,256/1,289 patients
Bed rest: PE: 6/60 (10%)
Note: new PEs were asymptomatic; 12/16 patients had
baseline PEs
Ambulation: PE: 10/69 (14%)
PE, group A: 2/15 (13%)
PE, group B: 1/15 (7%)
PE, group C: 1/15 (7%)
Summary results between groups: Walking distance, pain,
leg circumference and clinical scores significantly improved
in groups A and B compared with group C
Bed Rest: PE: 14/63 (22%)
Ambulation: PE: 10/59 (17%)
Results
Table S21—[Section 2.14] Early Ambulation vs Delayed Ambulation for Acute DVT of the Leg: Clinical Description and Results
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2-y follow-up
to RCT (77)
Type of
Publication
Interventions
RCT, multicenter 103 patients with
open design
proximal DVT
stratified by age
Outcomes
Bed rest: 50 patients received
5 d of strict bed rest,
LMWH, compression
bandages.
Ambulation: 52 patients
ambulated for 5 d, LMWH,
compression bandages
PE, progression of or new
thrombosis, infection or
serious adverse event
Symptomatic, confirmed
PE during first 15 d of
therapy
Anticoagulation and bed
PTS assessment
rest vs anticoagulation and
(Villalta-Prandoni scale)
ambulation with compression
bandages or stockings
Pain assessment by visual
analog scale and modified
Lowenberg test
Thrombus regression
Bed rest only (17 patients)
2,650 patients with DVT group, bed rest or
acute DVT
ambulation: 1,050 (52%)
(2,038 [77%]) or patients received bed rest,
PE (612 [23%])
and 988 (48%) ambulated.
All received LMWH.
PE group, bed rest or
ambulation: 385 (63%)
patients received bed rest,
and 227 (37%) ambulated.
All received LMWH.
37 patients
followed up
2 y post-RCT
Participants
ns 5 not significant; / 5 ventilation/perfusion. See Table S2, S5, and S10 legends for expansion of other abbreviations.
Jünger et al80/2006
Trujillo-Santos et al85/2005 Prospective
study
Author/Year
5d
3 mo
2y
Follow-up
Results
Primary target variable: Bed rest: 14/50 (28%)
Ambulation: 7/52 (13%)
New PE bed rest: 8/50 (16%) ambulation: 2/52 (4%)
DVT group, bed rest: PE: 7/1050 (0.7%)
DVT group, ambulate: PE: 4/988 (0.4%)
PE group, bed rest: PE: 2/385 (0.5%)
PE group, ambulate: PE: 2/227 (0.9%)
Thrombus extension: No difference in thrombus regression of
thrombus remnants between groups
Pain: Lower pain levels in mobile group vs bed rest (ns)
PTS scores: Ambulatory group (mean score, 5.1) had improved
outcome vs bed rest group (mean score, 8.2; P , .01)
Edema: Marked reduction in leg size with bandages and
stockings vs bed rest (P , .001)
Clinical scores: Improved with bandages and stockings vs bed
rest (P , .001)
Thrombus progression: Improved with bandages and stockings
vs bed rest (P , .01)
PE: No difference between groups
Table S22—[Section 2.14] Early Ambulation vs Delayed Ambulation for Acute DVT of the Leg: Methodologic Quality
Randomization
Allocation
Concealment
Schellong et al82/1999
Patients randomized to 1 of 2 study groups
Author/Year
Blinding
Loss to Follow-up
Unclear
4
by sealed envelope
Unclear
0
Aschwanden et al78/2001
Sealed envelope
Partsch et al83/200
N/A
Blättler et al79/2003
by sealed envelope
N/A
Not specified
Not blinded
N/A
5
N/A
0
N/A
N/A
N/A
21
Trujillo-Santos et al85/2005
N/A
N/A
N/A
N/A
Jünger et al80/2006
by sealed envelope
Unclear
Y, analysts N, patients,
caregivers, assessors
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Risk of
Bias
Indirectness
Imprecision
13/1,090 (1.2)
Risk With
Control
Risk Difference With 4
or 6 wk vs 3 or 6 mo of
55/998 (5.5)
57/1,100 (5.2)
7/1,095 (0.6)
RR 0.97 (0.68-1.38) 55 per 1,000 2 fewer per 1,000 (from
RR 0.54 (0.22-1.32) 12 per 1,000 5 fewer per 1,000 (from
9 fewer to 4 more)
Bibliography: Kearon et al,86 Pinede et al,87 Schulman et al,88 Levine et al,89 British Thoracic Society.90 See Table S1, S5, and S2 legends for expansion of abbreviations.
a Short vs longer duration of anticoagulation was 6 wk vs 6 mo for Schulman et al, 6 wk vs 3 mo for Pinede et al, and 4 wk vs 3 mo for the other three studies.
b Populations varied among studies: first provoked isolated distal DVT, proximal DVT or PE provoked in Kearon et al; first isolated distal DVT in Pinede et al; first isolated distal DVT, proximal DVT, or PE
in Schulman et al; proximal DVT (21% had cancer) in Levine et al; and DVT or PE (29% not objectively confirmed) in British Thoracic Society.
c Timing of randomization relative to the start of treatment varied across studies: Pinede et al, Schulman et al, and British Thoracic Society randomized at diagnosis; Kearon et al and Levine et al randomized
to stop or to continue treatment of 2 more months after the initial 4 wk of treatment.
e Generally, study design was strong. No study stopped early for benefit; two stopped early because of slow recruitment (Kearon et al, Pinede et al). In one study (British Thoracic Society), 44 randomized
patients were excluded centrally as they did not satisfy eligibility criteria. Patients and caregivers were blinded in two studies (Kearon et al, Levine et al). Adjudicators of outcomes were blinded in all but
one study (British Thoracic Society). All studies appeared to have used effective randomization concealment, ITT analysis, and appears to have a low unexplained drop-out frequency.
f No heterogeneity with I2 5 0%.
g No imprecision for overall estimates. However, for the subgroup of patients with isolated distal DVT, who are known to have a very low risk of recurrence, there is imprecision and the possibility that the
shorter duration of anticoagulation is adequate and not associated with a clinically important higher risk of recurrence.
d Follow-up was for ! 1 y in all studied except for Schulman et al in which it was 2 y.
h Differences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.
No serious
No serious
Undetected Highe,f,h
1-2 yd
of biase
inconsistencyf
indirectness
imprecisionh
Highf
Relative
Effect
(95% CI)
Summary of Findings
70/1,090 (6.4) 127/1,095 (11.6) RR 1.83 (1.39-2.42) 64 per 1,000 53 more per 1,000 (from
25 more to 91 more)
Highe-g
No serious
No serious
No serious
Undetected
inconsistencyf
indirectness
imprecisiong
Inconsistency
Overall
With 4 or 6 wk
Publication quality of
vs 3 or 6 mo of
Bias
Evidence With Control Anticoagulation
No serious
No serious
Undetected
1-2 yd
of bias
inconsistencyf
indirectness
imprecision
2,185 (5 studiesc), No serious
1-2 yd
risk of biase
Participants
(Studies),
Follow up
Quality Assessment
Table S23—[Sections 3.1.1-3.1.4] Evidence Profile: Four or Six Weeks vs Three or Six Months as Minimum Duration of Anticoagulation for VTEa,b
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454/454
VKA (INR 2.0-2.85)
for 6 mo
British Thoracic Society
et al90/1992
Levine et al89/1995
443/443
VKA (INR 2.0-2.85)
for 1.5 mo
(DURAC 1)
358/358
354/354
VKA (INR 2.0-3.0)
for 3 mo
109/113
VKA (INR 2.0-3.0)
for 2 more mo.
VKA (INR 2.0-3.0)
For 1 mo
105/107
VKA stopped (placebo)
92/92
105/105
81/81
VKA (INR 2.0-3.0)
For 2 more mo.
VKA (INR 2.0-3.0)
for 1.5 mo
VKA (INR 2.0-3.0)
for 3 mo
84/84
Length
Follow-up
Recurrent DVT or PE
Major Bleeding
1y
1y
9 mo
2y
15 mo
11 mo
11 mo
14/354 (4%) RR
0.5
(0.3-0.9)
28/358 (11%)
7/109 (6%) RR 0.6
(0.2-1.4)
12/105 (11%)
43/454 (9%) RR 0.5
(0.4, 0.7)
80/443 (18%)
3/92 RR 1.7
(0.3-10.0)
2/105 (2%)
3/81 (4%) RR 0.6
(0.1-2.5)
5/84 (6%)
4/354 (1%)
RR 0.8 (0.2-3.0)
5/358 (1%)
1/109 (1%) RR 2.9
(0.1-70.2) (within
2 mo of randomization)
0/105
5/454 (1%)
RR 4.9 (0.6-41.6)
1/443
3/92 RR 3.4
(0.4-33.4)
1/105 (1%)
0/81 RR 1.0
(0.0-51.6)
0/84
Short (4 or 6 wk) vs intermediate (3 or 6 mo) durations of anticoagulation
No. Patients
Analyzed
Intervention
Pinede et al87/2001
(DOTAVK)
Kearon et al86/2004
(SOFAST)
28/354 (8) RR 1.1
(0.6-1.8)
26/358 (7%)
9/109 (8%) RR 1.0
(0.4-2.5)
9/105 (9%)
17/454 (4%) RR
(0.7-1.4)
22/443 (5%)
Not specified
1/81 (1%) RR 3.1
(0.1-74.4)
0/84
Total Mortality
(Continued)
Population: DVT or PE; only 71%
objectively diagnosed; proportion
with a previous VTE not known.
All bleeds were on VKA. Only 1
recurrent VTE among 116
patients with postoperative VTE.
Proximal DVT (first episode in
91%). Cancer in 21%.
First VTE: DVT (distal or proximal)
or PE. Only asked about bleeding
while on VKAs.
Population: first isolated calf DVT.
Population: first DVT or PE.
Treated for 1 mo. VTE was
asymptomatic in 9% and isolated
calf DVT in 18%. One VTE
occurred while on warfarin.
Comments
Table S24—[Sections 3.1.1-3.1.4] Comparison of Durations of Anticoagulant Therapy for DVT and PE: Clinical Description and Results
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Siragusa et al94/2008
(DACUS)
Pinede et al87/2001
(DOTAVK)
Agnelli et al93/2001
(WODIT DVT)
92/92
269/269
VKA (INR 1.0-3.0)
for 6 mo
VKA stopped
270/270
134/134
VKA (INR 2.0-3.0)
for 9 mo
VKA (INR 2.0-3.0)
for 3 mo
133/133
VKA stopped
1.8 y
15 mo
3.1 y (mean)
3.2 y (mean)
2.9 y (mean)
2.8 y (mean)
70/70
75/75
2.9 y (mean)
90/90
VKA (INR 2.0-3.0)
for 9 more mo
VKA stopped
2.6 y (mean)
1y
1y
91/91
VKA (INR 2.0-3.0)
for 3 more mo
Recurrent DVT or PE
Major Bleeding
27/92 (29%)
23/269 (9%) RR 1.1
(0.6-1.9)
21/270 (8%)
21/134 (16%) RR 1.0
(0.6-1.7)
21/133 (16%)
4/75 (5%) RR 0.5
(0.2-1.7)
11/90 (12%) RR 1.0
(0.5-2.2)
7/70 (10%)
11/91 (12%)
29/380 (8%) RR0.9
(0.6-1.5)
31/369 (8%)
1/92 (1%)
7/269 (3%)) RR 1.4
(0.4-4.4)
5/270 (2%)
4/134 (3%) RR 2.0
(0.4-10.7)
2/133 (2%)
1/75 (1%) RR 1.9
(0.1-56)
2/90 (2%) RR 2.0
(0.5-21.9)
0/70 (0%)
1/91 (1%)
8/380 (2%) (during 6 mo.
treatment) RR 16.5
(1.0-285)
0/369 (during 3 mo.
treatment)
Different intermediate durations (6 or 12 mo vs 3 mo) of anticoagulation
Length
Follow-up
VKA stopped
380/414
VKA (INR 2.0-3.5)
for 6 mo
(WODIT PE)
369/396
VKA (INR 2.0.0-3.5)
for 3 mo
Campbell et al91/2007
No. Patients
Analyzed
Intervention
Not specified
(total of 3 nonVTE/bleed deaths)
Not specified
7/134 (5%) RR 1.0
(0.4-2.8)
7/133 (5%)
4/75 (5%) RR 8.4
(0.5-153)
8/90 (9%) RR 1.16
(0.4-3.0)
0/70 (0%)
7/91 (8%)
19/369 (5%) RR 1.3
(0.6-2.5)
15/369 (4%)
Total Mortality
(Continued)
Population: first proximal DVT
(provoked, 24%; unprovoked,
76%) treated for 3 mo and
residual DVT on baseline
ultrasound
Population: first proximal DVT or
PE. Recurrent VTE occurred
after VKA in 26/28 of the short
duration groups and 21/27 of the
long duration groups.
Population: first unprovoked proximal DVT treated for 3 mo. One
patient had recurrent VTE on
VKA. Bleeding in the intervention group was while on VKA.
Population: first provoked PE.
Treated for ! 3 mo (see above)
Population: first unprovoked PE.
Treated for ! 3 mo. Among the
4 groups, only 1 recurrent VTE
while on VKA.
Population: DVT or PE; proportion
with calf DVT not known. Only
bleeding during treatment is
reported; 20% of VTE outcomes
were not objectively verified.
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Farraj et al98/2004
(DURAC 2)
Kearon et al96/1999
(LAFIT)
Palareti et al95/2006
(PROLONG)
32/36
32/36
VKA (INR 2.0-2.85) for
24 mo
116/116
VKA (INR 2.0-2.85)
indefinitely
6 mo
111/111
79/79
VKA (INR 2.0-3.0) for 2
more years
6 mo
83/83
120/122
Restart indefinite VKA
(INR 2.0-3.0) (not
blinded)
103/105
Length
Follow-up
Recurrent DVT or PE
Major Bleeding
17/83 (20%)
2/103 (2%) RR 0.1
(0.0-0.4)
18/120 (15%)
3y
4y
3/32 (3%) RR 0.4
(0.1-1.5)
7/32 (22%)
3/116 (3%) RR 0.1
(0.0-0.4)
23/111 (2%)
(maximum, 2 y) 1/79 (1%) RR 0.1
(0.0-0.5)
10 mo (mean)
(maximum,
1.5 y)
1.4 y (mean)
2/32 (6%) RR 1.0
(0.2-6.7)
2/32 (6%)
10/116 (9%) RR 3.2
(0.9-11.3)
3/111 (3%)
3/79 (4%) RR 7.4
(0.4-140)
0/83
1/120 (1%) RR 2.6
(0.1-62.6)
0/103
Indefinite vs intermediate durations of anticoagulation (INR ! 2.0-3.0)
No. Patients
Analyzed
Remain off (stop) VKA
Intervention
0/32
0/32
10/116 (9%) RR 0.6
(0.3-1.3)
16/111 (14%)
1/79 (1%) RR 0.3
(0.0-3.3)
3/83 (4%)
1/120 (1%) RR 0.9
(0.1-13.6)
1/103 (1%)
Total Mortality
(Continued)
In total: 2 VTE after 24 mo
(24 mo group); 1 VTE on therapy
(24 mo group)
Second VTE: DVT (distal or proximal) or PE. All recurrent VTE
in the indefinite VKA group were
after stopping VKAs. Bleeding
during the first 6 mo of VKA in 1
of 6 mo group and 6 of indefinite
group (only asked about bleeding
while on VKAs).
Population: first unprovoked
proximal DVT or PE (5% had
previous provoked VTE). The
recurrent VTE in the VKA
patient was after stopping VKA.
Population: first unprovoked proximal DVT or PE. Treated for ! 3
mo. VKA stopped and D-dimer
positive 1 mo later. Eight control
patient. Restarted VKA, some
after superficial phlebitis. One
recurrent VTE in VKA group
after VKA stopped.
Comments
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No. Patients
Analyzed
Length
Follow-up
Recurrent DVT or PE
Major Bleeding
Total Mortality
33 mo
32/270 (12%) RR 0.7
(0.4-1.1)
46/268 (17%)
4/270/255 (1%)
RR 2.0 (0.4-10.8)
2/268 (1%)
4/255 (6%) RR 1.5
(0.7-3.2)
11/268 (4%)
369/369
369/369
VKA INR 2.0-3.0
(blinded)
255/255
VKA INR 1.5-2.0
VKA INR 1.5-1.9
253/253
VKA stopped or not
restarted (placebo)
14/255 (5%) RR 0.4
(0.2-0.7)
37/253 (15%)
5/255 (2%) RR 2.5
(0.5-12.7)
2/253 (1%)
2.4 y (mean)
6/369 (2%)RR 0.4
(0.1-0.9)
16/369 (4%)
8/369 (2%) RR 0.9
(0.3-2.3)
9/369 (2%)
Low intensity (INR 1.5-1.9) vs conventional intensity (INR 2.0-3.0)
(maximum,
4.3 y)
2.1 y (mean)
8/369 (2%) RR 0.5
(0.2-1.2)
16/369 (4%)
4/255 (2%)
RR 0.5 (0.1-1.6)
8/253 (3%)
Indefinite vs intermediate durations of anticoagulation (INR ! 1.5-2.0, after initial INR 2.0-3.0 in both groups)
Stopped if no residual vein 270/270
thrombosis and until
resolved or 9 more mo if
provoked or 21 more mo
if unprovoked
VKA stopped if provoked 268/268
and 3 more months if
unprovoked
Fixed vs flexible duration, depending on presence of residual thrombosis on follow-up ultrasound (INR 2.0-3.0)
Intervention
Population: unprovoked proximal
DVT or PE (first episode in
31%). Treated for ! 3 mo. VKA
(INR 2.0-3.0) (mean 12 mo). Five
recurrent VTE in INR 1.5-1.9
and three in the INR 2.0-3.0
group after stopping VKAs.
Population: unprovoked DVT
(distal or proximal) or PE (first
episode in 38%). Eight recurrent
VTE in the VKA group after
stopping VKAs.
Population: first provoked (43%)
or unprovoked (57%) proximal
DVT treated for 3 mo. One VTE
in each group while on VKAs.
The flexible group was treated for
a mean of 4 mo (provoked) and
5 mo (unprovoked) longer.
Comments
AESOPUS 5 Ultrasound Findings to Adjust the Duration of Anticoagulation; DACUS 5 Duration of Anticoagulation based on Compression UltraSonography; DOTAVK 5 Durée Optimale du Traitement
AntiVitamines K; DURAC 5 Duration of Anticoagulation; ELATE 5 Anticoagulation for Thrombo-Embolism; LAFIT 5 Long-term Anticoagulation for a First episode of Idiopathic venous Thromboembolism; PREVENT 5 Prevention of Recurrent Venous Thromboembolism; SOFAST 5 First Acute Secondary Thrombosis; WODIT DVT 5 Warfarin Optimal Duration Italian Trial in patients with DVT;
WODIT PE 5 Warfarin Optimal Duration Italian Trial in patients with Pulmonary Embolism. See Table S1, S2, and S7 legends for expansion of other abbreviations.
Kearon et al101/2003
(ELATE)
Ridker et al /2003
(PREVENT)
100
(AESOPUS)
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RCT
RCT
VKA (INR 2.0-3.0)
for 2 more mo
VKA (INR 2.0-3.0)
for 1.5 and 3 mo
3 and 6 mo
VKA (INR2.0-2.85)
for 1.5 mo
VKA (INR 2.0-2.85)
for 6 mo
VKA (INR 2.0-3.0)
for 2 more mo.
VKA (INR 2.0-3.0) For 1 mo VKA
(INR 2.0-3.0) for 3 mo
VKA (INR 2.0.0-3.5) for 3 mo
VKA (INR 2.0-3.5) for 6 mo
VKA stopped
VKA (INR 2.0-3.0)
for 9 more mo.
VKA stopped
Kearon et al86/2004
(SOFAST)
Pinede et al87/2001
(DOT AVK)
(DURAC 1)
Levine et al89/1995
British Thoracic
Society et al90/1992
Campbell et all91/2007
(WODIT PE)
(WODIT DVT)
RCT
RCT
RCT
RCT
RCT
RCT
Intervention
Study
Design
CY
CY
CY
CY
CY
CY
CY
CY
Randomization
Concealed
Patients: CN
Caregivers: CN
Adjudications: CY
Data Analysts: PN
Patients: CN
Caregivers: CN
Adjudications: CY
Data Analysts: PN
Patients: CN
Caregivers: CN
Adjudications: CN
Data Analysts: PN
Patients: CN
Caregivers: CN
Adjudications: CN
Data Analysts: PN
Patients: CY Caregivers: CY
Adjudications: VTE, CY
Data Analysts: PN
Patients: CN
Caregivers: CN
Other: PN
Data Analysts: PN
Patients: CN
Caregivers: CN
Adjudications: CY
Data Analysts: PN
Patients: CY
Caregivers: CY
Adjudications: CY
Data Analysts: CY
Blinding
Not specified
Probably low or nil
Not specified
Probably low or nil
3- mo VKA: 6/369
6- mo VKA: 4/380
No VKA: 27/354
VKA: 30/358
Placebo: 1/105
VKA: 6/109
(did not complete
11-mo follow-up)
Total of 44 patients
dropped out during
follow-up but partial
follow-up achieved
Not specified
Probably low or nil
Placebo: 0/84
VKA: 0/81
Loss to Follow-up
ITT
ITT
ITT
ITT
ITT
ITT
ITT
ITT
Analysis
(Continued)
Trial stopped early for lack of adequate
benefit. Four patients in the
intervention and 2 patients in the
control group crossed over.
Two patients in the control groups and
2 patients in the intervention groups
crossed over. Five patients in the
intended group did not stop VKA.
Four patients in the control groups
restarted VKAs.
Sixty-one randomized patients
excluded centrally as did not satisfy
entry criteria. Stopped early because
of low recruitment.
Forty-four randomized patients
excluded centrally as did not satisfy
entry criteria.
Two placebo and 4 warfarin patients
withdrew consent shortly after
randomization.
Five patient were excluded because
protein C found after randomization.
Stopped early because of slow
recruitment. Patient withdrawals:
4 in short- and 16 in long-duration
groups. Total of 22 patients
dropped out.
Stopped early because of slow
recruitment.
Comments
Table S25—[Sections 3.1.1-3.1.4] Comparison of Durations of Anticoagulant Therapy for DVT and PE: Methodologic Quality
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VKA stopped
VKA (INR 1.0-3.0)
for 9 mo.
Remain off (stop) VKA
Restart indefinitely VKA
(INR 2.0-3.0) (not blinded)
VKA (INR 2.0-3.0) for 2 more y
VKA (INR 2.0-2.85) indefinitely
VKA stopped if provoked and
3 more mo if unprovoked
Stopped if no residual vein
thrombosis and until
resolved or 9 more mo
if provoked or 21 more
mo if unprovoked
VKA stopped or not
restarted (placebo)
VKA INR 1.5-2.0
VKA (INR 2.0-2.85) for 24 mo
VKA INR 1.5-1.9
VKA INR 2.0-3.0 (blinded)
Siragusa et al /2008
(DACUS)
Palareti et al95/2006
(PROLONG)
Kearon et al96/1999
(LAFIT)
(DURAC 2)
(AESOPUS)
Ridker et al100/2003
(PREVENT)
Farraj et al98/2004
Kearon et al101/2003
(ELATE)
RCT
RCT
RCT
RCT
RCT
RCT
RCT
RCT
Study
Design
See Table S1, S2, S7, and S24 legends for expansion of abbreviations.
94
Intervention
CY
PY
CY
CY
CY
CY
CY
PY
Randomization
Concealed
Patients: CY
Caregivers: CY
Adjudications: CY
Data Analysts: CY
Patients: CN
Caregivers: CN
Data Collectors: PN.
Adjudicators: PN
Data Analysts: PN
Patients: CY
Caregivers: CY
Adjudications: CY
Data Analysts: CY
Patients: CN
Caregivers: CN
Data Analysts: PY
Patients: CN
Caregivers: CN
Other, PN
Data Analysts: PN
Patients: CY
Caregivers: CY
Adjudications: CY
Data Analysts: CY
Patients: CN
Caregivers: CN
Adjudications: CY
Data Analysts: PN
Patients: CN
Caregivers: CN
Adjudications: PY
Data Analysts: PN
Blinding
INR 1.5-1.9: " 1/369 INR
1.5-1.9: " 1/369
0/32 (see comments)
0/32
Probably low or nil
Not specified
4 subjects in each group
Total of 14 patients
dropped out during
follow-up, but
partial follow-up
achieved
None
No VKA: , 3/105
VKA: 0/122
None
Loss to Follow-up
ITT
ITT
ITT
ITT
ITT
ITT
ITT
ITT
Analysis
Crossover to INR 2.0-3.0 in 21 patients
Four postrandomization exclusions
for each group because of poor
compliance.
Trial stopped early because of overall
benefit. Number of crossovers not
described.
Actual mean duration of VKA was
7.7 mo in 6-mo group and 42.7 mo
in indefinite (48 mo) group.
Trial stopped early because of overall
benefit. After recurrent VTE,
patients were not followed. resulting
in shorter follow-up and potential for
underestimation of bleeding in the
no-VKA group.
Four patients excluded because
lupus anticoagulant found after
randomization.
Not known whether the many
postenrollment exclusions were
postrandomization. Trial stopped
early because recurrent VTE was
higher than expected.
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Risk of Bias
Inconsistency
Indirectness
Imprecision
Overall
Quality
of Evidence
No serious
No serious
Serious
inconsistency
indirectness
Relative
Effect
(95% CI)
Risk With
3 mo
Risk Difference
With 6 or 12 mo
(95% CI)
Undetected Moderated
due to
imprecision
Mortality (important outcomeg)
29/663 (4.4)
9/1,025 (0.9)
38/668 (5.7)
24/1,036 (2.3)
RR 1.3
(0.81-2.08)
RR 2.49
(1.2-5.16)
44 per 1,000
9 per 1,000
13 more per 1,000
(from 8 fewer to
47 more)
13 more per 1,000
(from 2 more to
37 more)
Bibliography: Pinede et al,87 Campbell et al,91 Agnelli et al,93 Agnelli et al,92 Siragusa.94 See Table S1, S2, and S5 legends for expansion of abbreviations.
a Timing of randomization relative to the start of treatment and length of treatment in the non-3-mo group varied across studies: Pinede et al and Campbell et al randomized at diagnosis, and Agnelli et al
randomized after the initial 3 mo of treatment to stop, or continue, treatment. The longer duration of treatment was 6 mo in Pinede, Campbell, and Agnelli et al (2003) (provoked PE), and 12 mo in Agnelli
(2001) and Agnelli (2003) (unprovoked PE).
b Study populations varied across studies: Pinede et al enrolled provoked and unprovoked proximal DVT and PE; Campbell et al enrolled provoked and unprovoked isolated distal DVT, proximal DVT and
PE; Agnelli et al (2003) had separate randomizations for provoked PE (3 vs 6 mo) and unprovoked (3 vs 12 mo); and Agnelli et al (2001) enrolled unprovoked proximal DVT.
c Generally, study design was strong. No study stopped early for benefit; two stopped early because of slow recruitment (Campbell et al, Pinede et al), and one stopped because of lack of benefit (Agnelli
et al [2001]). In one study (Campbell), 20% of VTE outcomes were not objectively confirmed. Patients and caregivers were not blinded in any study. Adjudicators of outcomes were blinded in all but one
study (Campbell). All studies used effective randomization concealment and ITT analysis and appear to have a low unexplained drop-out frequency.
d CIs include both values suggesting no effect and values suggesting either benefit or harm.
e Low number of events and a total number of participants , 2,000.
f One study may have confined the assessment of bleeding to when subjects were receiving anticoagulant therapy, which could have inflated the increase in bleeding associated with the longer duration of
therapy (Campbell et al).
g Differences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.
1,331 (5 studies), No serious
1-3 y
risk of bias
d
With 3 mo
With 6 or
12 mo
Summary of Findings
Undetected Moderated-e
118/1,025 (11.5) 105/1,036 (10.1) RR 0.89
115 per 1,000 13 fewer per 1,000
due to
(0.69-1.14)
(from 36 fewer
imprecision
to 16 more)
Publication
Bias
No serious
No serious
No serious
Undetected Highf
1-3 y
risk of biasf
inconsistency
indirectness
imprecision
No serious
No serious
Seriousd,e
1-3 y
risk of biasc
inconsistency
indirectness
Participants
(Studies),
Follow-up
Quality Assessment
Table S26—[Sections 3.1.1-3.1.4] Evidence Profile: Six or Twelve Months vs Three Months as Minimum Duration of Anticoagulation for VTEa,b
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Inconsistency
Indirectness
Imprecision
1,184 (4
No serious
No serious
No serious
Serious
studies),
risk of bias
inconsistency
indirectness
10-36 mo
Moderatec-e
38/599 (6.3)
due to
imprecision
102/599 (17)
Undetected
Moderate
7/599 (1.2%)
due to
imprecision
Major bleeding at 1 y (critical outcome)
High
Recurrent VTE at 1 y (critical outcome)
Undetected
Summary of Findings
21/585 (3.6%)
21/585 (3.6)
16/585 (2.7)
RR 2.63
(1.02-6.76)
RR 0.12
(0.09-0.38)
RR 0.57
(0.31-1.03)
44 fewer to 2 more)
10 per 1,000
132 fewer per 1,000
(from 93 fewer to
137 fewer)
more to 17 more)
0 more to 35 more)
12 per 1,000
(Continued)
0 more to 69 more)
High risk of bleedingk,l
6 per 1,000
Moderate risk of bleedingk,l
3 per 1,000
Low risk of bleedingk,l
150 per 1,000
100 per 1,000
50 per 1,000
First VTE provoked nonsurgical/first
unprovoked distal DVTf-j
10 per 1,000
63 per 1,000
With No
Risk With
Risk Difference
Overall Quality
Extended
With Extended Relative Effect No Extended
With Extended
of Evidence Anticoagulation Anticoagulation
(95% CI)
Anticoagulation Anticoagulation (95% CI)
Publication
Bias
1,184 (4
No serious
No serious
No serious
No serious
Undetected
studies),
risk of bias
inconsistency
indirectness
imprecision
10-36 mo
1,184 (4
No serious
No serious
No serious
Seriousd,e
studies),
risk of bias
inconsistencyc
indirectness
10-36 mo
Participants
(Studies),
Follow-up Risk of Bias
Quality Assessment
Table S27—[Sections 3.1.1-3.1.4] Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients With VTE and Without Cancera,b
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Inconsistency
Indirectness
Imprecision
1,184 (4
No serious
No serious
No serious
Serious
studies),
risk of bias
inconsistency
indirectness
10-36 mo
High
102/599 (17%)
Burden of anticoagulation not reported
Moderate
7/599 (1.2%)
due to
imprecision
Major bleeding at 5 y (critical outcome)
Undetected
Summary of Findings
21/585 (3.6%)
21/585 (3.6%)
RR 2.63
(1.02-6.77)
RR 0.12
(0.09-0.38)
132 fewer per 1,000
(from 93 fewer to
137 fewer)
264 fewer per 1,000
(from 186 fewer to
273 fewer)
396 fewer per 1,000
(from 279 fewer to
409 fewer)
0 more to 87 more)
1 more to 173 more)
60 per 1,000
(Continued)
1 more to 346 more)
High risk of bleedingk,l
30 per 1,000
Moderate risk of bleedingk,l
15 per 1,000
Low risk of bleedingk,l
450 per 1,000
300 per 1,000
150 per 1,000
First VTE provoked nonsurgical/first
unprovoked distal DVTf-j
30 per 1,000
With No
Risk With
Risk Difference
Overall Quality
Extended
With Extended
(95% CI)
Recurrent VTE at 5 y (critical outcome)
Publication
Bias
1,184 (4
No serious
No serious
No serious
No serious
Undetected
studies),
risk of bias
inconsistency
indirectness
imprecision
10-36 mo
Participants
(Studies),
Quality Assessment
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…
…
…
…
Inconsistency
…
…
Indirectness
…
…
Imprecision
…
…
Publication
Bias
…
PTS not reported
…
…
…
…
…
…
…
See commentn
See commentm
See commentn
See commentm
With No
Risk With
Risk Difference
Overall Quality
Extended
With Extended
(95% CI)
Summary of Findings
a
Bibliography: Schulman et al (DURAC 2),97 Kearon et al (LAFIT),96 Farraj,98 Palareti (PROLONG).95 See Table S1, S2, S7, and S10 legends for expansion of abbreviations.
Studies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3 to 6 mo).
bWe excluded Ridker et al (PREVENT)100 because target INR was 1.75 (low intensity), which has been shown in an RCT to be less effective than a target of 2.5.
cI2 5 0%.
dCI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefit.
eSmall number of events. Decision to rate down also takes into account that two studies were stopped early for benefit.
fAnnual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with first VTE provoked by surgery: 1% (Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode
of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170(19):1710-1716); we assumed a 0.5% yearly risk thereafter (3% over 5 y).
gAnnual risk in patients with first VTE provoked by non surgical factor: about 5% the first year (Iorio et al); we assumed 2.5% yearly thereafter (15% over 5 y).
hAnnual risk in patients with first episode of unprovoked VTE: 9.3% over 1 y in Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can
discontinue anticoagulant therapy. CMAJ. 2008;179(5):417-426; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in Prandoni et al (2007). We assumed a risk of 10% the first year after discontinuation
and 5% yearly thereafter (30% over 5 y).
iAnnual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a first episode of unprovoked VTE: 15% the first year after discontinuation, 7.5% yearly thereafter
(45% over 5 y).
jCase fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier 2010).
kAnnual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 3).
lCase fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al) (no data available for after discontinuing oral anticoagulation therapy).
mBurden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended-duration anticoagulation) who
subsequently experience a recurrent VTE (5%, 10%, 15% at 1 y; 15%, 30%, 45% at 5 y).
nBaseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (VETO [Venous Thrombosis Outcomes study]; Ann Intern Med. 2008) and threefold (Prandoni. Ann Intern Med. 2004) to 10-fold
(Van Dongen. J Thromb Haemost. 2005) increase in PTS.
…
…
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No serious
No serious
No serious
Seriousi
risk of biash
inconsistency
indirectness
No serious
No serious
No serious
inconsistency
indirectness
imprecision
2,737
(8 studies),
6 mo
Imprecision
Seriousf
Indirectness
2,727
(8 studies),
6 mo
Inconsistency
No serious
No serious
No serious
Seriouse
risk of biasd
inconsistency
indirectness
Risk of Bias
2,496
(7 studies),
6 mo
Participants
(Studies),
Follow-up
Quality Assessment
Overall Quality
of Evidence
Moderatef due 105/1,349 (7.8)
to risk of bias
Undetected
Moderateh,i due 53/1,351 (3.9%)
to imprecision
Undetected
With VKA
to imprecision
Undetected
Publication
Bias
Relative
Effect
(95% CI)
Risk With
VKA
Risk Difference
With LMWH
(95% CI)
30 fewer per 1,000
(from 13 fewer
to 43 fewer)
4 fewer per 1,000
(from 9 fewer
to 4 more)
80 per 1,000
(Continued)
15 fewer per 1,000
(from 36 fewer
to 16 more)
Metastatic cancerj
20 per 1,000
No cancer or nonmetastatic
cancerj
200 per 1,000 76 fewer per 1,000
(from 32 fewer
to 108 fewer)
Metastatic cancerg
80 per 1,000
Nonmetastatic cancerg
RR 0.62
No cancerg
(0.46-0.84) 30 per 1,000 11 fewer per 1,000
(from 5 fewer
to 16 fewer)
45/1,386 (3.2%) RR 0.81
(0.55-1.2)
67/1,378 (4.9)
204/1,265 (16.1) RR 0.96
164 per 1,000 7 fewer per 1,000
(0.81-1.13)
(from 31 fewer
to 21 more)
With LMWH
Summary of Findings
Table S28—[Section 3.3] Evidence Profile: LMWH vs VKA for Long-term Treatment of VTEa-c
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Inconsistency
No serious
limitations
Indirectness
Overall Quality
of Evidence
With VKA
Not applicable High
Warfarin: daily
LMWH: daily
medication, dietary
injection,
interactions,
no dietary
frequent blood
interactions,
testing/monitoring,
no frequent
increased hospital/
blood testing/
clinic visits
monitoring
With LMWH
No serious
imprecision
Undetected
Lowl,m due to
risk of bias,
indirectness
31/44 (70.5%)
34/56 (60.7%)
PTS (important outcome; assessed with self-reported leg symptoms and signs)
No serious
limitations
k
Burden of anticoagulation (important outcome)
Imprecision
Publication
Bias
…
Risk With
VKA
Risk Difference
With LMWH
(95% CI)
RR 0.85
Moderaten
(0.77-0.94) 200 per 1,000 30 fewer per 1,000
(from 12 fewer
to 46 fewer)
…
Relative
Effect
(95% CI)
Summary of Findings
Bibliography: Included studies: Deitcher et al,102 Hull et al,103 Hull et al,104 Lee et al,105 Lopaciuk et al,106 Lopez-Beret et al,107 Meyer G et al,108 Romera et al109 Two of these studies enrolled only patients
without cancer,104,107 3 enrolled only patients with cancer108,102,105, and 3 enrolled both patients with and without cancer103,106,109 (separate data provided for cancer and non-cancer patients in one study103,110).
Excluded studies (less than 50% of therapeutic dose LMWH during extended phase): Pini et al,111 Das et al,112 Gonzalez-Fajardo et al,113 Veiga et al,114 Kakkar et al,115 (Cesarone 2003 Circ abstract). PTS
data from: Hull et al.104 See Table S1, S2, S5, and S10 legends for expansion of abbreviations.
aLimited to LMWH regimens that used ! 50% of the acute treatment dose during the extended phase of treatment.
bThe initial parenteral anticoagulation was similar in both arms for all except one study (Hull et al [2007]) in which patients randomized to LMWH received initially the same LWMH, whereas patients
randomized to VKA received initially UFH.
cTwo of these studies enrolled only patients without cancer, three enrolled only patients with cancer, and three enrolled both patients with and without cancer (separate data provided for cancer and noncancer patients in one study).
dOne study did not report deaths, which is unusual and could reflect selective reporting of outcomes.
eCI includes both no effect and harm with LMWH.
fNone of the studies were blinded, although the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA-treated patients because
switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients who are already on LMWH because there is no attractive
alternative treatment option.
gRisk of recurrent VTE: low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate corresponds to patients with local or recently resected
cancer (based on average rate across the six studies in this analysis and appears to be consistent with Prandoni et al [particularly if low risk is increased to 4%]), and high to patients with locally advanced or
distant metastatic cancer (Prandoni et al116).
hNo study was blinded; diagnosis of major bleeding has a subjective component.
iThe 95% CIs for the RR for major bleeding includes a potentially clinically important increase or decrease with LMWH and may vary with the dose of LMWH used during the extended phase of therapy.
jRisk of bleeding: low corresponds to patients without risk factor for bleeding (ie, . 75 y, cancer, metastatic disease; chronic renal or hepatic failure; platelet count , 800,000; requires antiplatelet therapy;
history of bleeding without a reversible cause) (Table 2) (based on Prandoni et al116 and Beyth et al,117 adjusted to a 6-mo time frame).
kHull et al reported no significant difference in quality of life but suggested greater satisfaction with LMWH over VKA (questionnaire did not directly assess the burden of injections).
lPatients and investigators not blinded. Self-reported leg symptoms and signs after 3 mo of treatment.
mThe association between leg symptoms and signs at 3 mo and long-term PTS is uncertain.
nBaseline risk assumes that patients all wear pressure stockings. Control event rate comes from observational studies in review by Kahn et al,118 adjusted to 2-y time frame.
No serious
Seriousm
inconsistency
No serious
No serious
limitations
limitations
Risk of Bias
100
Seriousl
(1 study), 2 y
…
Participants
(Studies),
Follow-up
Quality Assessment
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51
…
…
49/1,718 (2.9)
51/1,718 (3)h
19/1,711 (1.1)i
…
…
…
13/1,718 (0.8)i
36/1,731 (2.1)h
38/1,731 (2.2)
With
Rivaroxaban
Warfarin: daily
Rivaorxaban: daily
medication,
medication,
dietary interactions,
no dietary
frequent blood
interactions,
testing/monitoring,
no frequent
increased hospital/
blood testing/
clinic visits
monitoring
Burden of anticoagulation (important outcome) not reported
Undetected Moderatee,g
due to
imprecision
Undetected Moderatee,g
due to
imprecision
Undetected Moderatee,f
due to
imprecision
Death (important outcome)
With LMWH
and VKA
Therapy
…
HR 0.68
(0.34-1.38)j
HR 0.68
(0.44-1.04)
HR 0.67
(0.44-1.02)
9 fewer per 1,000
(from 16 fewer
to 1 more)
…
11 per 1,000i
…
4 fewer per 1,000
(from 7 fewer
to 4 more)
30 per 1,000h 9 fewer per 1,000
(from 17 fewer
to 1 more)
29 per 1,000
Risk With
Risk Difference
Relative Effect LMWH and With Rivaroxaban
(95% CI)
VKA Therapy
(95% CI)
Summary of Findings
Bibliography: Einstein DVT.119 HR 5 hazard ratio. See Table S1, S2, S5, and S7 legends for expansion of other abbreviations.
aRivaroxaban 15 mg bid for 3 wk and then 20 mg/d for a total of 3 (12%), 6 (63%), or 12 (25%) months.
bEnoxaparin 1 mg/kg bid for ! 8 d and then VKA therapy targeted to INR 2.5 for 3, 6, or 12 mo.
cIncluded patients had acute, symptomatic, objectively verified proximal DVT of the legs (unprovoked, 62%; cancer, 6%; previous VTE, 19%).
dFollow-up was prespecified to be 3 mo (12%), 6 mo (63%), or 12 mo (25%).
eAllocation was concealed. Patients, providers, and data collectors were not blinded, but outcome adjudicators were blinded. ITT analysis; 1.0% loss to follow-up. Not stopped early for benefit.
fCI includes values suggesting benefit or no effect; relatively low number of events.
gCI includes values suggesting benefit and harm.
hOne definite or possible fatal VTE in rivaroxaban group and one in LMWH/VKA group.
iBleeds contributing to death: one in the rivaroxaban group and five in the warfarin group.
jCalculated from reported data.
…
Seriousg
3,429 (1 study), No serious
No serious
No serious
6-12 mod
risk of biase
inconsistency
indirectness
…
Seriousg
Indirectness
No serious
No serious
6-12 mod
risk of biase
inconsistency
indirectness
Inconsistency
Seriousf
Risk of Bias
Imprecision
Bias
of Evidence
No serious
No serious
6-12 mod
risk of biase
inconsistency
indirectness
Participants
(Studies)
Follow up
Quality Assessment
Table S29—[Section 3.3] Evidence Profile: Rivaroxaban vs LMWH and VKA Therapy for Short- and Long-term Treatment of VTEa-c
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…
…
…
Moderated,e
due to
imprecision
Highd
Moderated,h
due to
imprecision
…
…
PTS (important outcome) not reported
…
…
Undetected
0/590 (0)i
42/594 (7.1)g
Undetected
2/594 (0.34)
4/598 (0.7)i
8/602 (1.3)g
1/602 (0.17)
With
With Placebo Rivaroxaban
Undetected
Bias
of Evidence
Rivaroxaban: daily
medication,
no dietary
interactions,
no frequent
blood testing/
monitoring
RR 4.9
(0.58-42)f
HR 0.18
(0.09-0.39)
RR 0.49
(0.04-5.4)f
Relative Effect
(95% CI)
2 fewer per 1,000
(from 3 fewer
to 15 more)
…
i
…
7 more per 1,000
(from 3 more
to 16 more)
71 per 1,000g 58 fewer
per 1,000
(from 43 fewer
to 64 fewer)
3 per 1,000
Risk Difference
With Rivaroxaban
(95% CI)
Risk With
Placebo
Summary of Findings
j
…
…
…
…
…
…
…
…
…
…
…
Bibliography: Einstein DVT.119 See Table S1, S2, S5, S10, and S29 legends for expansion of abbreviations.
aRivaroxaban 20 mg/d for 6 or 12 mo after initial long-term therapy.
bIncluded patients had acute, symptomatic, objectively verified proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE, 19%).
cFollow-up was prespecified to be 6 mo (60%) or 12 mo (40%).
dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. ITT analysis; 0.2% loss to follow-up. Not stopped early for benefit.
eCI includes values suggesting benefit or no effect; relatively low number of events.
fCalculated from reported data with addition of one event to each event rate as event rate 0 in control group.
gOne definite or possible fatal VTE in rivaroxaban group and one in LMWH/VKA group.
hCI includes values suggesting benefit and harm.
iBleeds contributing to death: none in the rivaroxaban group and none in the warfarin group.
jPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al40). There is threefold (Prandoni et al120) to 10-fold (van Dongen et al121) increase in PTS with recurrent VTE in the ipsilateral leg.
…
No serious
No serious
Serioush
inconsistency
indirectness
6 or 12 mo
risk of biasd
e
Imprecision
No serious
No serious
No serious
inconsistency
indirectness
imprecision
Indirectness
6 or 12 moc
risk of biasd
Inconsistency
No serious
No serious
Serious
inconsistency
indirectness
Risk of Bias
6 or 12 moc
risk of biasd
Participants
(Studies),
Follow-up
Quality Assessment
Table S30—[Section 3.3] Evidence Profile: Rivaroxaban vs Placebo for Extended Anticoagulation of VTEa,b
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…
…
…
Undetected Moderated,e
due to
imprecision
due to
imprecision
24/1,265 (1.9)g
24/1,265 (1.9)f
…
…
…
20/1,274 (1.6)g
30/1,274 (2.4)f
21/1,274 (1.6)
Warfarin: daily
Dabigatran: daily
medication,
medication,
dietary restrictions,
No dietary
frequent blood
restrictions,
testing/monitoring,
no frequent
increased hospital/
blood testing/
clinic visits
monitoring
Seriouse
21/1,265 (1.7)
due to
imprecision
Death (important outcome)
With Warfarin
With
Dabigatran
…
HR 0.82
(0.45-1.48)
HR 1.01
(0.65-1.84)
HR 0.98
(0.53-1.79)
Relative Effect
(95% CI)
Summary of Findings
a
0 fewer per 1,000
(from 8 fewer
to 13 more)
Risk Difference
With Dabigatran
(95% CI)
…
…
19 per 1,000g 3 fewer per 1,000
(from 10 fewer
to 9 more)
19 per 1,000f 0 more per 1,000
(from 7 fewer
to 16 more)
17 per 1,000
Risk With
Warfarin
Bibliography: Schulman et al.122 See Table S2, S5, and S29 legends for expansion of abbreviations.
Dabigatran 150 mg bid taken orally for 6 mo after an initial treatment with LMWH or IV UFH.
bWarfarin adjusted to achieve an INR of 2.0 to 3.0 for 6 mo after an initial treatment with LMWH or IV UFH.
cIncluded patients had acute, symptomatic, objectively verified proximal DVT of the legs or PE.
dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Modified ITT analysis; 1.1% loss to follow-up. Not stopped early for benefit.
fOne fatal VTE in dabigatran group and three fatal VTEs in warfarin group.
gOne fatal major bleeding event in dabigatran group and one fatal major bleeding event in warfarin group.
…
No serious
No serious
6 mo
risk of biasd
inconsistency
indirectness
e
Serious
Indirectness
No serious
No serious
6 mo
risk of biasd
inconsistency
indirectness
Inconsistency
Seriouse
Risk of Bias
Imprecision
Bias
of Evidence
No serious
No serious
6 mo
risk of biasd
inconsistency
indirectness
Participants
(Studies),
Follow-up
Quality Assessment
Table S31—[Section 3.3] Dabigatran vs VKA Therapy for Long-term Treatment of VTEa-c
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RCT
RCT
2-y follow-up to RCT
RCT, single center
Ginsberg et al124/2001
Ashwanden et al130/2008
169 first or recurrent
proximal DVT without
PTS after 6 mo of
compression stockings
37 symptomatic patients
with acute DVT followed
long term
180 patients with first
episode of symptomatic,
acute proximal DVT
47 asymptomatic patients
with valvular incompetence
1 y post-DVT
194 patients
with first symptomatic
proximal DVT
Participants
See Table S1, S2, S5, S10, and S29 legends for expansion of other abbreviations.
RCT
Type of
Publication
Brandjes et al127/1997
Author/Year
Compression stockings:
below-knee,
26-36 mm Hg (84 patients)
Control group: stopped
stockings (85 patients)
Bed rest for 9 d,
no compression
(11 patients)
Elastic stockings
(30 mm Hg)
1 early ambulation
(13 patients)
All anticoagulated with
LMWH followed by
oral anticoagulation
Inelastic bandages 1 early
ambulation (13 patients)
below-knee elastic
Control group: no
intervention (90 patients)
below-knee elastic
Placebo: placebo stocking
(23 patients)
below-knee customized
elastic compression
stockings with ankle
pressure 30-40 mm Hg
(96 patients)
Control group:
no intervention
(98 patients)
Interventions
PTS shin changes (! C4 on
CEAP)
PTS score
(Villalta-Prandoni)
Leg circumference
Overall leg pain
Cumulative incidence
of mild to moderate
and severe PTS
PTS symptoms
Cumulative incidence
of mild to moderate
and severe PTS
Outcomes
Results
0-7 y (mean, 3 y)
2y
3-5 y
57 mo (mean)
Control group: 20% HR:
0.8 (95 % CI, 0.3-1.3)
PTS compression
stockings: 13%
Calf circumference:
No difference between
groups
PTS score: Significantly
better outcome with
ambulation and bandaging
or stockings compared with
bed rest (P , .01)
Leg pain: No difference
between groups
Control group: PTS symptoms:
49% (CI, 38.7%-59.4%)
PTS symptoms: 25%
(CI, 15.6%-33.4%)
Placebo: PTS symptoms: 4%
PTS symptoms: 0%
3 and 6 mo,
then every 6 mo
Mild-moderate PTS: 20%
to a median
(RR, 0.42; 95% CI 0.27-0.66;
of 76 mo
P , .001) Severe PTS: 11%
(RR, 0.49; 95% CI, 0.25-0.95;
P , .001)
Control group: Mild-moderate
PTS: 47% Severe PTS: 23%
Follow-up
Table S32—[Section 4.1] Elastic Stocking for Prevention of PTS: Clinical Description and Results
Table S33—[Section 4.1] Elastic Stocking for Prevention of PTS: Methodologic Quality
Author/Year
Randomization
Blinding
Loss to Follow-up
Brandjes et al /1997
Y
Y (sealed envelopes)
Patients: N
Caregivers: N
Assessors: Y
Data analysis: PY
Intervention group: 4 lost
to follow-up, 19 died
Control group: 2 lost to
follow-up, 18 died
Ginsberg et al124/2001
Y
Probably, but not
specified
Patients: Y
Caregivers: Y
Assessors: Y
data analysis: PY
Intervention: lost to
follow-up not reported,
3 died
Control group: lost to
follow-up not reported
Y
Y
Patients: N
caregivers: N
Assessors: Y
Data analysis: PY
Intervention: 2 lost to
follow-up, 6 died
Control group: 13 lost
to follow-up
Ashwanden et al130/2008
Y
Y
Patients: N
Caregivers: N
Assessors: N
Data analysis: N
Intervention:
19 (described)
Control group:
13 (described)
127
See Table S5 legend for expansion of abbreviations.
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Risk of Bias
Indirectness
Quality of life (important outcome)
…
26/188 (13.8)
…
26/186 (14)
…
RR 1.01
(0.61-1.67)e
41/210 (19.5) RR 0.46
(0.34-0.63)e
Elastic Compression
Stockings (95% CI)
See commentk
210 per 1,000j
…
2 more per 1,000
(from 82 fewer
to 141 more)
479 per 1,000d,f 259 fewer per 1,000
(from 177 fewer
to 316 fewer)g
Risk With
No Elastic
Compression
Stockings
Bibliography: Kolbach et al.123 We excluded Ginsberg et al124 and Belcaro et al125 because they respectively randomized patients 7 and 12 mo after their DVT rather than at the time of the acute DVT. We
also excluded Arpaia et al126 because they randomized patients to receive stockings at the time of diagnosis of DVT vs 2 wk later.126 See Table S1 and S5 legends for expansion of abbreviations.
aBrandjes127 used graded elastic compression stockings (40 mm Hg of pressure at the ankle, 36 mm Hg at the lower calf, and 21 mm Hg at the upper calf); stockings were applied 2 to 3 wk after the first
episode of proximal DVT. Prandoni120 used flat-knitted stockings (30-40 mm Hg of pressure at the ankle); stockings were started at hospital discharge an average of 1 wk after admission. In both studies,
stockings were used for 2 y.
bPrandoni120 excluded patients with recurrent ipsilateral DVT, preexisting leg ulcers, or signs of CVI, bilateral thrombosis, a short life expectancy, or a contraindication for use of stockings (eg, advanced-stage
peripheral arterial insufficiency). Brandjes et al excluded patients with short life, paralysis of the leg, bilateral thrombosis, leg ulcers, or extensive varicosis.
cPatients were not blinded to the treatment assignment, and outcomes were partly based on subjective report of symptoms.
d In Prandoni,120 most events occurred during the first 6 mo: the cumulative incidence of PTS in the control group was 40% after 6 mo, 47% after 1 y, and 49% after 2 y.
e The effect estimate shown here results from a meta-analysis (Mantel-Haenszel fixed-effects model) of the two relevant trials. A fixed-effects model was chosen because of the small number of studies available.
fThis estimate is based on the findings of the VETO (Venous Thrombosis Outcomes) study.40 This probably underestimates the PTS baseline risk given that overall, 52% of patients reported the current use
of compression stockings during study follow-up.
gSevere PTS: assuming the same RR of 0.46 and a baseline risk of 8.1% over 2 y, the absolute reduction is 44 fewer severe PTS per 1,000 (from 30 fewer to 53 fewer) over 2 y.
hWe did not rate down the quality of evidence for recurrent VTE for the lack of blinding because this a more objective outcome than PTS.
iCI includes both negligible effect and appreciable benefit or appreciable harm.
jThis estimate is the mean of two estimates derived from two studies: 12.4% probable/definite VTE (Heit128) and 29.1% confirmed VTE (Prandoni129).
kThis is an important outcome that should be considered in future studies.
0 (0k)
Undetected Moderateh,i
due to
imprecision
91/211 (43.1)d
PTS (critical outcome; assessed with Villalta Score)
Imprecision
Summary of Findings
With No Elastic With Elastic
Publication Overall Quality Compression Compression Relative Effect
Bias
of Evidence
Stockings
Stockings
(95% CI)
No serious
No serious
No serious
Undetected Moderatec
inconsistency
indirectness
imprecision
due to
risk of bias
Inconsistency
374 (2 studies), No serious
No serious
No serious
Seriousi
5y
risk of biash
inconsistency
indirectness
421 (2 studies), Seriousc
2y
Participants
(Studies),
Follow-up
Quality Assessment
Table S34—[Section 4.1] Evidence Profile: Elastic Compression Stockings vs No Elastic Compression Stockings To Prevent PTS of the Lega,b
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…
…
…
…
Indirectness
…
…
…
…
…
…
No serious
No serious
inconsistency
indirectness
Inconsistency
…
…
…
Seriousf
Lowe-g due to
risk of bias,
imprecision
...
…
…
h
...
...
…
…
…
…
33/57 (57.9)
Undetectedg
…
…
…
32/58 (55.2)
…
…
…
RR 0.96
(0.70-1.31)
With No
Overall Quality Compression With Compression Relative Effect
of Evidence
Stockings
Stockings
(95% CI)
Symptomatic relief (critical outcome; assessed with treatment successd)
Imprecision
Publication
Bias
...
...
...
579 per 1,000
...
...
...
23 fewer per 1,000
(from 174 fewer
to 179 more)
Risk With No
Risk Difference
Compression With Compression
Stockings
Stockings (95% CI)
Summary of Findings
Bibliography: Ginsberg 2001124; Frulla. 2005131 See Table S1, S2, S5, and S10 legends for expansion of abbreviations.
aGinsberg et al: graduated compression stockings, 30-40 mm Hg (calf or thigh length, depending on symptoms). Patients were encouraged to wear stockings as much as possible during waking hours. Frulla
(2005): below-knee graded elastic compression stockings (ECS) (30-40 mm Hg at the ankle). Patients in both arms of the study received hydroxyethylrutosides (HR) (we considered the ECS 1 HR vs HR
comparison).
bGinsberg et al: placebo stockings (calf or thigh length, depending on symptoms).
cGinsberg et al included patients with PTS 1 y after chronic, typical proximal DVT. Frulla (2005) included patients with clinical symptoms and signs suggestive of PTS.
dGinsberg et al reported treatment failure (defined a priori based on any of five clinical criteria, including symptoms and ulcer development). Treatment success refers to the absence of treatment failure.
Frulla used the Villalta scale.
eGinsberg et al: Adequacy of sequence generation and allocation concealment were unclear; patients and outcome assessors were adequately blinded; unclear whether analysis followed the ITT principle;
unclear whether follow-up was complete. Frulla (2005): outcome assessors were blinded; follow-up was complete. ITT principle was adhered to, but sequence generation and allocation concealment were
unclear, and patients were not blinded.
fVery small number of patients.
gPublication bias not detected but not ruled out given that we identified only one small study partially supported by industry (provision of graduated compression stockings).
hIndirect evidence from the CLOTS1 (Clots in Legs Or sTockings after Stroke) trial suggests that compression stockings is associated with an RR of 4 for skin complications.
iAbsence of ulcer included in the treatment success outcome in Ginsberg et al.
…
Seriouse
Risk of Bias
…
115 (2 studies),
12-26 mo
Participants
(Studies),
Follow-up
Quality Assessment
Table S35—[Section 4.2.1] Evidence Profile: Compression Stockings vs No Compression Stockings for Patients With PTSa-c
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Risk of Bias
Inconsistency
Indirectness
With No
Intermittent With Intermittent
Publication Overall Quality Compression
Compression
Relative Effect
Imprecision
Bias
of Evidence
Device
Device
(95% CI)
Risk Difference
With Intermittent
Compression
Device (95% CI)
Risk With No
Intermittent
Compression
Device
Summary of Findings
0 (1 studyd,j),
8 wk
Serioush
Undetectedi Moderatee-i
due to
imprecision
41d
41d
…
The mean
The mean
symptomatic
symptomatic
relief in the
relief in the
control groups
intervention groups
was 0
was 0.41 SDs
higher (0.02 lower
to 0.85 higher)
No serious
No serious
No serious
risk of biask
inconsistency
indirectnessg
Serioush
Undetectedi,l Moderatef-h,k,l
due to
imprecision
…
0
…
(Continued)
The mean quality The mean
of life in the
quality of life in the
control groups
intervention groups
was 50.2
was 2.3 higher
(1.04 lower to
5.64 higher)
Quality of life (critical outcome; measured with VEINES-QOL; range of scores, 0-100; better indicated by higher values)
82 (2 studiesd), No serious
No serious
No serious
8 wk
risk of biase
inconsistencyf
indirectnessg
Symptomatic relief (critical outcome; measured with symptom score (includes scoring of pain, swelling, and limitation of activity); range of scores, 10-70; better indicated by higher values)
Participants
(Studies),
Follow-up
Quality Assessment
Table S36—[Section 4.2.2] Evidence Profile: Intermittent Compression Device vs No Intermittent Compression Device for Patients With Severe PTSa-c
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…
…
…
…
Inconsistency
…
…
Indirectness
…
…
…
…
n
...
...
…
…
Recurrent VTE not reportedm
…
…
…
…
With No
Intermittent With Intermittent
Publication Overall Quality Compression
Compression
Relative Effect
Imprecision
Bias
of Evidence
Device
Device
(95% CI)
...
...
...
...
Risk Difference
With Intermittent
Compression
Device (95% CI)
Risk With No
Intermittent
Compression
Device
Summary of Findings
Bibliography: Ginsberg 1999,132 O’Donnell, 2008.133 See Table S1, S5, and S10 legends for expansion of other abbreviations.
aGinsberg et al: Extremity pump used bid for 20 min each session; 50 mm Hg (therapeutic pressure) for 1 mo. O’Donnell et al: Venowave lower-limb venous return assist device to wear for most of the day
for 8 wk.
bGinsberg et al: Extremity pump used bid for 20 min each session; 15 mm Hg (placebo pressure) for 1 mo. O’Donnell et al: Venowave lower-limb venous return assist device with no connection between
motor and planar sheet for 8 wk.
cPatients with previous DVT with symptoms of severe PTS.
dCrossover RCTs.
eIn both studies, sequence generation was adequate; patients were blinded. Analysis adhered to ITT principle, and there were no missing outcome data. In Ginsberg et al (but not in O’Donnell et al), outcome assessors were not blinded, and it was not clear whether allocation was concealed.
fI2 5 0%.
gSome concerns with indirecteness given relatively short follow-up (8 wk).
hVery small number of patients. CI includes both values suggesting no effect and values suggesting a beneficial effect.
iPublication bias not detected but not ruled out given that we identified only two small studies with one (Ginsberg et al) partially supported by industry (provision of devices).
jO’Donnell et al.
kSequence generation was adequate; patients were blinded; analysis adhered to ITT principle; and there were no missing outcome data. However, outcome assessors were not blinded, and it was not clear
whether allocation was concealed.
lPublication bias not detected but not ruled out given that we identified only one small study.
mO’Donnell et al indicated no cases of recurrent VTE by the end of this study but judged the follow-up period to be short.
nO’Donnell et al indicated that one patient in the control group developed a venous ulceration. Three other participants developed nonserious skin-related side effects. Indirect evidence from the CLOTS1
(Clots in Legs Or sTockings after Stroke) trial suggests that compression stockings are associated with an RR of 4 for skin complications: Common side effects are attributed to Venowave were heat sensation, skin irritation, and increased sweating.
…
Risk of Bias
…
Participants
(Studies),
Follow-up
Quality Assessment
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Risk of Bias
Inconsistency
Indirectness
Imprecision
Venoactive Medication
(95% CI)
Summary of Findings
With No
Risk With No
Publication Overall Quality Venoactive With Venoactive Relative Effect Venoactive
Bias
of Evidence Medication
Medication
(95% CI)
Medication
…
…
…
…
…
…
…
Seriouse
…
…
…
No serious
indirectness
Seriousf
…
…
…
Seriousf
...
...
...
Undetectedg Moderated,f-h
due to
imprecision
…
…
…
5/82 (6.1%)
Side effects (critical outcome)
…
…
…
Undetectedg Lowd-g due to
39/82 (47.6)
inconsistency,
imprecision
13/121 (10.7%)
…
…
…
44/81 (54.3)
RR 2.04
(0.76-5.51)
…
…
…
RR 1.14
(0.85-1.52)
61 per 1,000
...
...
...
476 per 1,000
63 more per 1,000
(from 15 fewer to
275 more)
...
...
...
67 more per 1,000
(from 71 fewer to
247 more)
a
Bibliography: Frulla 2005131 de Jongste 1989.134 See Table S1, S5, and S10 legends for expansion of abbreviations.
Included studies assessed rutosides; we excluded Monreal et al135 because it compared two venoactive medications.
bPatients with PTS and history of DVT in PTS leg.
cInvestigators assessed other symptoms (pain, heaviness, swelling feeling, restless legs, and cramps) but did not report a composite score. The symptom we chose to report showed the most benefit; the effect
estimates for the other symptoms ranged from 0.8 to 1.4, and none was statistically significant.
dIn both studies, sequence generation and allocation concealment were unclear. Both studies blinded outcome assessors and had complete follow-up. Although de Jongste et al blinded patients, they did not
adhere to the ITT principle and did not use a validated scale to measure symptomatic relief. Although Frulla (2005) adhered to the ITT principle, it did not blind patients.
eI2 5 77%.
fSmall number of patients. CI including both values suggesting harms and values suggesting benefits.
gPublication bias not detected but not ruled out given that we identified only two small studies, and it was unclear whether they were funded by industry.
hI2 5 7%.
203 (2 studies) No serious
No serious
No serious
risk of biasd
inconsistencyh
indirectness
…
…
163 (2 studies) No serious
risk of biasd
Symptomatic relief (critical outcome; assessed with PTS score (Villalta scale) , 5 or decreased by 30% at 12 mo compared with baseline in Frulla et al; improved tiredness of the leg at 8 wk in de Jongste et alc)
Participants
(Studies),
Follow-up
Quality Assessment
Table S37—[Section 4.3] Evidence Profile: Venoactive Medication vs No Venoactive Medication for Patients With PTSa,b
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to imprecision
Moderated,e due 56/1,110 (5.0)f
to imprecision
Undetected
Moderated,e due 26/1,110 (2.3)g
to imprecision
Undetected
Undetected
With UFH
22/1,103 (2.0)g
42/1,103 (3.8)f
57/1,103 (5.2)
RR 0.85
23 per 1,000g 4 fewer per 1,000
(0.49-1.49)
(from 12 fewer to
11 more)
RR 0.75
50 per 1,000f 13 fewer per 1,000
(0.51-1.12)
(from 25 fewer to
6 more)
RR 1.20
43 per 1,000 9 more per 1,000
(0.82-1.74)
(from 8 fewer to
32 more)
Risk With
UFH
Risk
Difference With
Fondaparinux
(95% CI)
Summary of Findings
With
Relative Effect
Fondaparinux
(95% CI)
Bibliography: Büller et al.136 See Table S1, S2, S4, and S7 legends for expansion of abbreviations.
aFondaparinux (5.0, 7.5, or 10.0 mg in patients weighing , 50, 50 to 100, or > 100 kg, respectively) SC once daily given for at least 5 days and until the use of VKAs resulted in an INR . 2.0.
bUFH continuous IV infusion (ratio of the aPTT to a control value, 1.5-2.5) given for at least 5 days and until the use of VKAs resulted in an INR . 2.0.
cAll patients had acute symptomatic hemodynamically stable PE.
dAllocation was concealed. Patients, providers, and data collectors not blinded. Outcome adjudicators were blinded; 0.6% of randomized patients were lost to follow-up. Not stopped early for benefit.
fSixteen fatal VTE in fondaparinux group and 15 fatal VTE in UFH group.
gFourteen patients in the fondaparinux group and 12 in the LMWH group had a major bleeding during the initial period (6-7 d). Of these, one in the fondaparinux group and one in the UFH group were fatal.
Seriouse
No serious
3 mo
of biasd
inconsistency
indirectness
Overall Quality
of Evidence
Seriouse
Indirectness
No serious
3 mo
of biasd
inconsistency
indirectness
Inconsistency
Seriouse
Risk of Bias
No serious
3 mo
of biasd
inconsistency
indirectness
Participants
(Studies),
Follow-up
Quality Assessment
Table S38—[Section 5.4] Evidence Profile: Fondaparinux vs IV UFH for Initial Anticoagulation of Acute PEa-c
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Seriousc
471 (2 studies),
3 mo
Indirectness
…
…
No serious
No serious
inconsistency indirectness
No serious
No serious
No serious
No serious
Inconsistency
…
Seriousd
Seriousd
Seriousd
Imprecision
Overall
Quality of
Evidence
Moderatec,d due
to imprecision
6/228 (2.6)
With Standard
Discharge
Moderatec,d due
to imprecision
Moderatec,d due
to imprecision
…
…
Undetected
Undetected
1/228 (0.4)
2/228 (0.9)
Nonfatal recurrent PE (critical outcome)
Undetected
Mortality (critical outcome)
Publication
Bias
…
4/243 (1.6)
3/243 (1.2)
4/243 (1.6)
With Early
Discharge
…
RR 2.74
(0.45-16.71)
RR 1.23
(0.25-6.03)
RR 0.58
(0.17-1.97)
Relative Effect
(95% CI)
…
4 per 1,000
9 per 1,000
26 per 1,000
Risk With
Standard
Discharge
…
8 more per 1,000
(from 2 fewer
to 69 more)
2 more per 1,000
(from 7 fewer
to 44 more)
11 fewer per 1,000
(from 22 fewer
to 26 more)
Risk Difference
With Early Discharge
(95% CI)
Summary of Findings
Bibliography: Otero et al,137 Aujesky et al.138 See Table S1, S2, and S5 legends for expansion of abbreviations.
aMean length of hospital stay: 3.4 (SD 1.1) vs 9.3 (SD 5.7) in Otero et al and 0.5 (SD 1.0) vs 3.9 (SD 3.1) in Aujesky et al.
bThe two RCTs included only patients with low risk: risk classes I or II on the Pulmonary Embolism Severity Index in Aujesky et al139; low risk on clinical prediction rule by Uresandi et al140 in Otero et al.
cOtero et al: allocation concealed, no patients lost to follow-up, ITT analysis, no blinding of outcome assessors reported, study stopped early because the rate of short-term mortality was unexpectedly high
in the early discharge group (2 [2.8%] vs 0 [0%]). Aujesky et al: unclear whether allocation was concealed, three (1%) patients had missing outcome data, ITT analysis, outcome adjudicators blinded, no
early stoppage.
dCI includes both values suggesting no effect and values suggesting appreciable harm or appreciable benefit.
…
Seriousc
471 (2 studies),
3 mo
…
Seriousc
Risk of Bias
471 (2 studies),
3 mo
Participants
(Studies),
Follow-up
Quality Assessment
Table S39—[Section 5.5] Evidence Profile: Early Discharge vs Standard Discharge in the Treatment of Acute PEa,b
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Seriouse
Seriouse
Seriouse
801 (9 studies),
30 d
847 (12 studies),
10 d
Risk of Bias
847 (12 studies),
30 d
Participants
(Studies),
Follow-up
Indirectness
No serious
No serious
inconsistencyf
indirectness
No serious
No serious
inconsistencyf
indirectness
No serious
No serious
inconsistencyf
indirectness
Inconsistency
Summary of Findings
Seriousk
Seriousg
Seriousg
Lowe-h due
to risk of
bias and
imprecision
26/423 (6.1)
Lowe-h due
to risk of
bias and
imprecision
30/404 (7.4)
Undetectedh
Moderatee,f,h,k
due to risk
of bias and
imprecision
24/423 (5.7)
Undetectedh
Recurrent PE (important outcome)
Undetectedh
Mortality (critical outcome)
38/424 (9)
18/397 (4.5)
15/424 (3.5)
RR 1.63
(1-2.68)l
RR 0.7
(0.4-1.21)
RR 0.7
(0.37-1.31)
1 per 1,000
57 per 1,000
89 per 1,000
11 per 1,000
1 more per 1,000
(from 0 more to
2 more)
(Continued)
Lowm
17 fewer per 1,000
(from 34 fewer
to 12 more)
27 fewer per 1,000
(from 56 fewer
to 28 more)
Highi,j
3 fewer per 1,000
(from 7 fewer to
3 more)
Lowi,j
With No
Risk With No Risk Difference
Systemically With Systemically
Administered
Administered
Administered
Administered
Overall Quality Thrombolytic
Thrombolytic
Relative Effect Thrombolytic
Thrombolytic
Therapy
Therapy
(95% CI)
Therapy
Therapy (95% CI)
Quality Assessment
Table S40—[Section 5.6.1] Evidence Profile: Systemic Thrombolytic Therapy vs Anticoagulation Alone in Patients With Acute PEa-d
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Risk of Bias
Inconsistency
Indirectness
62 per 1,000
39 more per 1,000
(from 0 more to
104 more)
Highm
Bibliography: Nine earlier studies141-149 extracted from three systematic reviews (Dong et al,150 Wan et al,151 Agnelli et al152) and two recently published studies (Becattini C et al,153 Fassulo et al154). See Table
S1 and S2 legends for expansion of abbreviations.
aIncluded studies used different thrombolytic agents with varying doses and durations of administration; no statistical heterogeneity was noted.
bThrombolysis was in addition to anticoagulation (most of the studies used heparin followed by warfarin; three studies used warfarin only).
cOne study included exclusively patients with hemodynamic compromise (shock); six excluded them, whereas the rest either included a number of such patients or did not specify related eligibility. criteria.
Of studies not restricted to patients with hemodynamic compromise (n 5 11), only three were clearly restricted to patients with right ventricular dysfunction; the rest either did not specify related eligibility
criteria or included both patients with and without right ventricular dysfunction. As a result, it was not possible to perform reliable categorization of studies to conduct subgroup analyses based on the presence or absence of right ventricular dysfunction or hemodynamic compromise.
dStudies included patients at low risk of bleeding.
eReport of methodologic quality was poor in most studies. Of the 12 eligible studies, allocation was concealed in five, three were single blinded (outcome assessor), six were double blinded, and three were
not blinded. Most studies did not report on missing outcome data. None of the studies was stopped early for benefit. For the increase in bleeding with thrombolytic therapy, quality of evidence is increased
from low to moderate because there is high quality evidence of this association in patients with myocardial infarction and the indirectness of this evidence to patients with PE is minor.
fI2 5 0%.
gCI includes values suggesting both benefit and no effect or harm; small number of events.
hInverted funnel plots suggested possible publication bias in favor of thrombolytics.
iRecurrent PE stratification based on the simplified Pulmonary Embolism Severity Index validated in the RIETE (Registro Informatizado de la Enfermedad Tromboembólica) cohort.155
jSome studies suggest that the baseline risk of mortality in patients with hemodynamic instability is high as 30% (Wood et al).156 In that case, the absolute number of death associated with thrombolytics
would be 90 fewer per 1,000 (from 189 fewer to 93 more).
kCI includes values suggesting both harm and no effect; small number of events.
lIndirect evidence from studies of thrombolysis for myocardial infarction and acute stroke provide more-precise estimates of increase major bleeding with thrombolytics use.
mMajor bleeding risk stratification derived from the RIETE cohort.157 The median risk of bleeding over the first 10 d reported in the eligible trials was 3.1%. In that case, the absolute number of major bleeds
with thrombolysis would be 20 per 1,000 (from 0 more to 52 more).
Participants
(Studies),
Follow-up
Summary of Findings
With No
Risk With No Risk Difference
Administered
Administered
Administered
Administered
Overall Quality Thrombolytic
Thrombolytic
Relative Effect Thrombolytic
Thrombolytic
Therapy
Therapy
(95% CI)
Therapy
Therapy (95% CI)
Quality Assessment
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Jerjes-Sanchez
et al145/1995
Dotter et al143/1979
Ly et al146/1978
Tibbutt et al148/1974
Author/Year
SK: 11/13 (84.6%)
No. Patients
Analyzed
SK: 4/4
Heparin: 4/4
Heparin 10,000 units
followed by 1,000 units/h
Heparin: 16/16
Heparin 1,500 units per kg
for 2-7 d
SK 1,500,000 units over
1 h followed by a bolus of
heparin 10,000 units 1
constant infusion of 1,000
units/h
SK: 15/15
Heparin: 11/11
Heparin 15,000 units
for 7 d
SK 250,000 units followed by
100,000 units/h for 18-72 h
SK: 14/14
SK 250,000 units followed
by 100,000 units/h for 72 h
Heparin 5,000 units
Heparin: 12/17
intrapulmonary followed by
(70.6%)
2,500 units for 72 h
SK 600,000 units
intrapulmonary followed
by 100,000 units for 72 h
Interventions
Recurrent DVT and
PE (%) RR (95% CI)
In hospital
SK: 4/14 (28.6%)
SK: 3/15 (20.0%)
SK: 0/4 (0%)
Heparin: 4/4 (100%)
Heparin: 0/4 (0%)
RR 9.00 (0.64-126.85)
SK: 0/4 (0%)
Heparin: 1/16 (6.3%)
Heparin: 4/16 (25.0%)
RR 2.82 (0.12-64.39)
RR 1.25 (0.33-4.68)
SK: 0/15
SK: 0/11
Total Mortality (%)
RR (95% CI)
Primary outcome was angiographic reperfusion.
Some 6-mo follow-up data
available
Patients reporting major
bleeding required a blood
transfusion.
Seven patients who failed to
complete the treatment
regimen were excluded
from the analysis.
All hydrocortisone 100 mg and
at 60 h of treatment warfarin
initial dose 25 mg for 6 mo.
Comments
Heparin: 4/4 (100%)
RR 9.00 (0.64-126.85)
SK: 0/4 (0%)
Heparin: 2/16 (12.5%)
RR 1.88 (0.19-18.60)
SK: 1/15 (6.7%)
(Continued)
Primary outcome not stated.
Trial stopped early for
benefit. All patients had
cardiogenic shock
at randomization.
Heparin-treated patients
appear to have failed
heparin therapy before
randomization, whereas
the SK patients had not.
All: warfarin/VKA.
Primary outcome was
angiographic reperfusion
(not clearly stated).
Heparin: 2/11 (18.2%) Five of the 25 patients
RR 2.55 (0.26-24.56)
received nonrandomized
therapy. Uncertain if
deaths were in patients
who were randomized or
not randomized.
SK: 1/14 (7.1%)
Heparin: 1/12 (8.3%)
Heparin: 0/12
RR 0.92 (0.06-12.95)
SL: 1/11 (9.1%)
Major Bleeding (%)
RR (95% CI)
Heparin: 2/11 (18.2%) Heparin: 2/11 (18.2%)
RR 2.55 (0.26-24.56)
RR 0.64 (0.14-2.86)
SK: 1/14 (7.1%)
Heparin: 0/12
SK: 0/11
SK 1 heparin vs heparin
In hospital
10 d
72 h
Length of
Follow-up
Table S41—[Section 5.6.1] Systemic Thrombolytic Therapy vs Anticoagulation Alone in Patients With Acute PE: Clinical Description and Results
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Alteplase: 118/118
Heparin 1 placebo:
138/138
Alteplase 100 mg followed
by alteplase 90 mg over
2 h 1 heparin 1,000
units/h
Heparin 5,000 units followed
by 1,000 units/h 1 placebo
Konstantinides
et al159/2002
Heparin: 55/55
30 d
In hospital
14-21 d
rt-PA: 46/46
rt-PA alteplase 100 mg over
2 h followed by heparin
1,000 units/h
by 1,000 units/h
Urokinase: 37/82
(45.1%)
Major Bleeding (%)
RR (95% CI)
Urokinase: 6/82 (7.3%)
Total Mortality (%)
RR (95% CI)
High-dose urokinase:
0/10
Low-dose urokinase:
0/10
Heparin: 0/10
Heparin 1 placebo:
4/138 (2.9%)
RR 1.17 (0.30-4.57)
Alteplase: 4/118 (3.4%)
Heparin: 5/55 (9.1%)
RR 0.11 (0.01-1.91)
rt-PA: 0/46
rt-PA alteplase: 1/20
(5.0%)
Heparin: 0/16 RR 2.43
(0.11-55.89)
Heparin 1 placebo:
5/138 (3.6%)
RR 0.23 (0.03-1.97)
Alteplase: 1/118
(0.8%)
Heparin: 1/55
(1.8%) RR 3.59
(0.39-33.33)
rt-PA: 3/46 (6.5%)
(15.0%)
Heparin: 2/16 (12.5%)
RR 1.20 (0.23-6.34)
0/10
Low-dose urokinase:
0/10
Heparin: 0/10
Primary outcome was
echocardiographic right
ventricular function.
Primary outcome was
angiographic reperfusion.
Primary outcome was lung
scan perfusion.
Thrombolysis arms did not
receive heparin.
All patients: OACs
continued for 1 y.
All: heparin for a minimum
of 5 d.
The major bleeding reported
includes moderate 1
severe bleeding.
Angiographic follow-up data
available up to 12 mo.
Comments
Alteplase: 4/118 (3.4%) Primary outcome was death
or need for escalation of
therapy (later decision
could be made after
unblinding).
Heparin 1 placebo:
3/138 (2.2%)
RR 1.56 (0.36-6.83)
(Continued)
Heparin: 2/55 (3.6%)
RR 0.24 (0.01-4.84)
rt-PA: 0/46
(10.0%)
Heparin: 0/16 RR 4.05
(0.21-78.76)
0/10
Low-dose urokinase:
0/10
Heparin: 0/10
Heparin: 15/78 (19.2%) Heparin: 21/78 (26.9%) Heparin: 7/78 (8.9%)
RR 1.31 (0.66-2.63)
RR 0.60 (0.39-0.92)
RR 1.23 (0.43-3.49)
Urokinase: 12/82
(14.6%)
Urokinase vs heparin
Recurrent DVT and
PE (%) RR (95% CI)
rt-PA (alteplase) 1 heparin vs heparin
7d
2 wk
Length of
Follow-up
30 d
High-dose
urokinase: 10/10
Low-dose
urokinase: 10/10
Heparin: 10/10
Heparin: 78/78
Heparin: infusion of
75 units/lb followed by
10 units/lb per h
High dose: urokinase
3,300,000 units over 12 h
Low dose: urokinase 800,000
units over 12 h daily for 3 d
Heparin 30,000 units/d for
7 d followed by OAC
Urokinase 82/82
No. Patients
Analyzed
Urokinase: infusion of 2,000
CTA units/lb followed by
2,000 CTA units/lb per h
Interventions
Dalla-Volta et al142/1992 rt-PA 10 mg followed by
rt-PA alteplase:
90 mg over 2 h
20/20
Heparin 10,000 units followed Heparin: 16/16
by 1,750 units/h for 7-10 d
Marini et al147/1988
UPET Study Group
et al141/1970
Author/Year
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Tenectaplase: 2/28
Placebo: 1/32
Placebo: 32/32
Placebo 1 heparin
(80 International Units/kg
and 18 International
Units/kg per h)
Placebo: 1/32
Tenectaplase: 2/28
Placebo: 1/35 (2.9%)
Alteplase: 2/37 (5.4%)
Placebo: 0/4 RR 1.50
(0.07-30.59)
rt-PA: 1/9 (11.1%)
Placebo: 0/25
rt-PA: 0/33
Major Bleeding (%)
RR (95% CI)
Placebo: 1/32
Tenectaplase: 0/28
Placebo: 5/35 (14.2%)
Alteplase: 0/37
Placebo: 0/4
rt-PA: 0/9
Placebo: 0/25 RR 2.29
(0.10-54.06)
rt-PA: 1/33 (3.0%)
Total Mortality (%)
RR (95% CI)
All had right ventricular
dysfunction. Primary
outcome was
echocardiographic
changes.
No fatal PE or major
bleeding; one intracranial
bleed (tenectaplase).
All had right ventricular
dysfunction. Primary
outcome was
echocardiographic
changes.
Three recurrent PE were
fatal. One additional fatal
and nonfatal PE in
heparin arm by 180 d.
No fatal or intracranial
bleeds.
Primary outcome not stated
(serial angiographic and
lung scans were assessed).
Heparin doses determined
by attending physician in
both groups
One death occurred 19 d
after treatment
Primary outcome was lung
scan reperfusion
Comments
CTA 5 Committee on Thrombolytic Agents; OAC 5 oral anticoagulant; PIOPED 5 Prospective Investigation of Pulmonary Embolism Diagnosis; UPET 5 Urokinase Pulmonary Embolism Trial. See Table
S1, S2, and S11 legends for expansion of other abbreviations.
Tenectaplase 1 heparin vs heparin
Tenectaplase: 28/28 30 d
Tenectaplase: ! 2 mg/kg
bolus
Becattini et al153/2010
Placebo: 35/35 Placebo: 3/35 (8.5%)
Placebo 1 heparin
5,000 units
followed by
1,000 units/h
Alteplase: 0/37
10 d
Placebo: 0/4
rt-PA: 0/9
Placebo: 0/25
rt-PA: 0/33
Recurrent DVT and
PE (%) RR (95% CI)
Alteplase: 37/37
Placebo: 4/4
Placebo 1 heparin
(doses determined
by physician)
7d
10 d
Length of
Follow-up
Alteplase 100 mg over 2 h
rt-PA: 9/9
Placebo: 25/25
Placebo plus heparin
5,000 units followed
by 30,000/d
rt-PA 40-80 mg at 1 mg/min
rt-PA: 33/33
No. Patients
Analyzed
rt-PA 0.6mg/kg over 2 min
Interventions
Fasullo et al154/2011
PIOPED
Investigators144/1990
160
Levine et al /1990
Author/Year
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UPET Study
Group141,149/1970
Jerjes-Sanchez et al145/1995
Dotter et al143/1979
Lyet al146/1978
Tibbutt et al148/1974
Author/Year
Urokinase: infusion of 2,000
CTA units/lb followed by
2,000 CTA units/lb per h Heparin:
infusion of 75 units/lb followed
by 10 units/lb per h
by 1,000 units/h
SK 1,500,000 units over 1 h followed
by a bolus of heparin 10,000 units
1 constant infusion of
1,000 units/h
Heparin 1,500 units per kg for 2-7 d
100,000 units/h for 18-72 h
Heparin 15,000 U followed by
1250 U/h for 7days
100,000 units/h for 72 h
Heparin 5,000 units intrapulmonary
followed by 2,500 units for 72 h
SK 600,000 units intrapulmonary
followed by 100,000 units for 72 h
Intervention
RCT
RCT
RCT
RCT
RCT
Study Design
Blinding
Patients: PY
Caregivers: PN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
Patients: PY
Caregivers: PN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
Patients: PY
Caregivers: PN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
Patients: PY
Caregivers: PN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
CY
Patients: CY
Caregivers: CN
Data Collectors: CY
Adjudicators: CY
Data Analysts: CY
Urokinase vs heparin
CY
PY
CY
PY
SK 1 heparin vs heparin
Randomize
Concealed
Urokinase: 0/82 (0%)
Heparin: 0/78 (0%)
Heparin: 0/4 (0%)
SK 1 heparin: 0/4 (0%)
Heparin: 0/16 (0%)
SK plus heparin: 0/15 (0%)
Heparin: 0/11 (0%)
SK: 0/14 (0%)
Heparin: 0/12 (0%)
SK: 0/11 (0%)
Lost to Follow-up
As treated
ITT
ITT
As treated
Per protocol
Analysis
(Continued)
Included 5 nonrandomized
patients, and uncertain if
deaths occurred in those
who were randomized or
not randomized.
Seven patients who failed to
complete the treatment
regimen were excluded
from the analysis.
All hydrocortisone 100 mg
and at 60 h of treatment,
warfarin initial dose
25 mg for 6 mo.
Comments
Table S42—[Section 5.6.1] Systemic Thrombolytic Therapy vs Anticoagulation Alone in Patients With Acute PE: Methodologic Quality
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Levine et al160/1990
Konstantinides et al159/2002
Dalla-Volta et al142/1992
Author/Year
Marini et al147/1988
Placebo 1 heparin 5,000 units
followed by 30,000/d
rt-PA 0.6 mg/kg over 2 min
by 1,000 units/h
rt-PA (alteplase) 100 mg followed
by alteplase 90 mg over
2 h 1 heparin 1,000 units/h
Heparin 5,000 units followed by 1,000
units/h
rt-PA 100 mg over 2 h followed
by heparin 1,000 units/h
by 1,750 units/h for 7-10 d
rt-PA (alteplase) 10 mg followed
by 90 mg over 2 h
RCT
RCT
RCT
RCT
PY
CY
CY
PY
Patients: CY
Caregivers: CY
Data Collectors: CY
Adjudicators: CY
Data Analysts: CY
Patients: PY
Caregivers: CN
Data Collectors: PY
Adjudicators: PN
Data Analysts: PY
Patients: PN
Caregivers: CN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
Patients: PN
Caregivers: CN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
Lost to Follow-up
0/10 (0%)
Heparin: 0/25(0%)
rt-PA: 0/33(0%)
UFH: 0/138 (0%)
rt-PA: 0/118 (0%)
Heparin: 0/55 (0%)
rt-PA: 0/46 (0%)
Heparin: 0/16 (0%)
rt-PA: 0/20 (0%)
Heparin: 0/10 (0%)
Blinding
Patients: PN
Caregivers: CN
Data Collectors: PN
Adjudicators: PN
Data Analysts: PN
Heparin 30,000 units/d for 7 d
followed by OAC
Randomize
Concealed
PY
Low-dose urokinase:
0/10 (0%)
Study Design
RCT
Low dose: urokinase 800,000 units
over 12 h daily for 3 d
Intervention
High dose: urokinase 3,300,000 units
over 12 h
ITT
ITT
ITT
ITT
Analysis
ITT
(Continued)
All: UFH initial bolus of
5,000 units followed by
continuous infusion at
starting dose of 30,000
for the first 24 h.
All: UFH 5,000 units.
Comments
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Placebo 1 heparin (80 International
Units/kg and 18 International
Units/kg per h)
Tenectaplase: ! 2 mg/kg bolus
Placebo 1 heparin 5,000 units
Alteplase 100 mg over 2 h
Placebo plus heparin (doses
determined by physician)
rt-PA 40-80mg at 1 mg/min
Intervention
RCT
RCT
RCT
CY
PY
Randomize
Concealed
Blinding
Patients: CY
Caregivers: CY
Data Collectors: PY
Adjudicators: CY
Data Analysts: PY
Patients: CY
Caregivers: CY
Data Collectors: PY
Adjudicators: PY
Data Analysts: PY
CY
Patients: CY
Caregivers: CY
Data Collectors: CY
Adjudicators: CY
Data Analysts: PY
Study Design
See Table S1, S2, S5, S11, and S41 legends for expansion of other abbreviations.
Becattini et al153/2010
Fasullo et al154/2011
PIOPED
Investigators144/1990
Author/Year
Lost to Follow-up
Heparin: 0/30(0%)
Tenectaplase: 0/28(0%)
Heparin: 0/35
rt-PA: 0/37
Heparin: 0/4(0%)
rt-PA: 0/9(0%)
ITT
ITT
ITT
Analysis
Comments
Primary outcome was
echocardiographic changes.
Primary outcome was
echocardiographic changes.
All: heparin doses determined
by attending physician.
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Imprecision
…
161
…
…
22/1,500 (1.5)
1/1,500 (0.1)
Highd due to
imprecision
Moderated,e,i due
to imprecision
…
…
Undetected
Undetected
1/1,488 (0.1)
26/1,500 (1.7)
SVT recurrence (important outcome)
Highd
VTE (critical outcome)
Moderated-g due
to imprecision
With No
Fondaparinux
…
1/1,499 (0.1)
8/1,502 (0.5)
4/1,502 (0.3)
2/1,502 (0.1)
With
Fondaparinux
19 per 1,000h
33 per 1,000h
…
…
RR 0.99
1 per 1,000
(0.06-15.86)e
RR 0.31
(0.14-0.68)
RR 0.18
(0.06-0.53)
RR 1.99
4 per 1,000h
(0.18-21.87)
Relative Effect Risk With No
(95% CI)
Fondaparinux
…
0 fewer per 1,000
(from 1 fewer
to 10 more)
13 fewer per
1,000 (from
6 fewer to
16 fewer)
27 fewer per
1,000 (from
16 fewer to
31 fewer)
4 more per 1,000
(from 3 fewer
to 83 more)
Risk Difference
With Fondaparinux
(95% CI)
Summary of Findings
Bibliography: CALISTO study by Decousus et al. CALISTO 5 Comparison of ARIXTRA™ in lower LImb Superficial Thrombophlebitis with placebo; SVT 5 superficial vein thrombosis. See Table S1
and S5 legends for expansion of other abbreviations.
aFondaparinux 2.5 mg for 45 d.
bPatients in the two treatment groups benefited from close clinical monitoring with adequate diagnostic procedures in the event of new and persistent symptoms.
cPatients with infusion-related SVT were excluded if from CALISTO.
dAllocation concealed. Outcome adjudicators, steering committee, patients, providers, and data collectors blinded. Follow-up rate was 98%. ITT analysis for efficacy outcomes. Not stopped early for
benefit.
eCI includes values suggesting large benefit and values suggesting large harm.
fWe rated down by only one level because the low event rate and large sample size.
gSmall number of events.
hBaseline risk derived from a large prospective cohort study.162
iThe upper limit of the CI for absolute effect (10 more bleeds) is not low enough to suggest a clear balance of benefits vs harms.
…
Seriouse,i
No serious
No serious
47 d
risk of biasd
inconsistency
indirectness
…
Seriousf,g
No serious
No serious
3 mo
risk of biasd
inconsistency
indirectness
Overall Quality
of Evidence
Undetected
No serious
Undetected
imprecision
Indirectness
No serious
No serious
3 mo
risk of biasd
inconsistency
indirectness
Inconsistency
Seriouse,f
Risk of Bias
Publication
Bias
No serious
No serious
inconsistency
indirectness
3 mo
risk of biasd
Participants
(Studies),
Follow-up
Quality Assessment
Table S43—[Section 8.1] Evidence Profile: Fondaparinux vs Placebo for Acute SVTa-c
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STENOX Study163
Group/2003
Author/Year
Parallel RCT,
multicenter
Type of
Publicationa
436 patients with
ultrasound-confirmed
acute symptomatic
SVT (! 5 cm length)
of the lower extremity
Participants
Enoxaparin 40 mg SC daily
Enoxaparin 1.5 mg/kg SC daily
Tenoxicam, 20 mg po daily
Placebo once daily
All given for 8-12 d
All patients prescribed elastic
bandages or compression
stockings for at least 15 d
Interventionb
Follow-up
Day 12 (end of treatment):
3 mo
Screening ultrasound or
symptomatic recurrence: VTE
SVT recurrence/extension to
saphenofemoral junction
3-mo VTE SVT recurrence/
extension
Major bleeding
Death
Outcomesc
(Continued)
VTE day 12: Placebo: 4/112 (3.6%) (PE 0)
Enoxaparin 40 mg: 1/110 (0.9%) (PE 0);
RR 0.25 (95% CI, 0.03-2.24)
Enoxaparin 1.5 mg/kg: 1/106 (0.9%)
(PE 0); RR 0.26 (95% CI, 0.03-2.33)
Tenoxicam: 2/99 (2.0%) (PE 1);
RR 0.57 (95% CI, 0.11-3.02)
P 5 ns for all comparisons of active
treatment vs placebo
SVT recurrence/extension day 12:
Placebo: 33/112 (29.5%)
Enoxaparin 40 mg: 9/110 (8.3%);
RR 0.28 (95% CI, 0.14-0.55)
Enoxaparin 1.5 mg/kg: 6/106 (5.7%);
RR 0.19 (95% CI, 0.08-0.44)
Tenoxicam: 13/99 (13.1%); RR 0.45
(95% CI, 0.25-0.80)
VTE 3 mo:
Placebo: 5/112 (4.5%) (PE 0)
Enoxaparin 40 mg: 6/110 (5.7%); (PE 2);
RR 1.22 (95% CI, 0.38-3.89)
Enoxaparin 1.5mg/kg: 4/106 (3.9%)
(PE 0); RR 0.85 (95% CI, 0.23-3.06)
Tenoxicam: 4/99 (4.3%) (PE 1);
RR 0.91 (95% CI, 0.25-3.28)
P 5 ns for all comparisons of active
treatment vs placebo
SVT recurrence/extension 3 mo: Placebo:
37/112 (33.0%)
Enoxaparin 40 mg: 16/110 (14.5%);
RR 0.44 (95% CI, 0.26-0.74)
Results
Table S44—[Section 8.1] Superficial Vein Thrombosis Treatment: Clinical Description and Results (Randomized Trials Comparing Treatments)
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Parallel RCT,
multicenter
Parallel RCT,
multicenter
Prandoni for Vesalio
Investigators
Group165/2005
Type of
Publicationa
Titon et al164 /1994
Author/Year
Interventionb
PE
Major bleeding
Changes in symptoms and clinical
signs (warmth, flushing, edema,
pain on palpation)
DVT
Echocardiographic extension of
thrombus at day 7 and at 8 wk
Outcomesc
164 patients with
High-dose weight-adjusted
Composite outcome of
nadroparin (190 anti-Xa
asymptomatic or symptomatic
acute SVT of the
International Units/kg for
SVT extension, asymptomatic
greater
10 d followed by 95 anti-Xa
or symptomatic DVT,
saphenous vein
International Units/kg for 20 d)
symptomatic PE at 3 mo
Treatments given for 6 d
All patients wore compression
stockings for 7 d
117 patients with
Nadroparin fixed dose, 6,150
anti-Xa International
SVT of the lower
Units daily
extremities
Nadroparin 31.5 anti-Xa
International Units/kg
SC daily
Naproxen 500 mg po daily
Participants
3 mo
8 wk
Follow-up
Results
3 mo follow-up:
(Continued)
Naproxen: 1/39 (2.6%); RR 0.97
(95% CI, 0.06-15.02)
P 5 ns
8-wk extension of thrombus or new SVT:
Fixed-dose nadroparin: 2/36 (5.6%)
Weight-based nadroparin: 0/40 (0%);
RR 0.18 (95% CI, 0.01-3.64)
Naproxen: 0/39 (0%); RR (95% CI)
0.19 (0.01-3.73)
No DVT, PE, or major bleeding in any group
Intensity of symptoms/signs: Overall
improvement in score from day 0 to day 7:
Fixed-dose nadroparin: 79.1% improved
Weight-based nadroparin: 63.0% improved
Naproxen: 46.4% improved
P" .01 in favor of nadroparin vs naproxen;
this difference was maintained at 8 wk
Weight-based nadroparin: 2/40 (5%);
RR 1.90 (95% CI, 0.18-20.1)
Day 7 extension of thrombus: Fixed-dose
nadroparin: 1/38 (2.6%)
Tenoxicam: 15/99 (15.2%); RR 0.46
(95% CI, 0.27-0.78)
Major bleeding: 0 Death: 0
Enoxaparin 1.5 mg/kg: 16/106 (15.1%);
RR 0.46 (95% CI, 0.27-0.77)
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Type of
Publicationa
Marchiori et al166/2002 Parallel RCT,
single center
Author/Year
No placebo group NSAIDS
and aspirin use discouraged
Low-dose nadroparin
(2,850 anti-Xa International
Units for 30 d)
Interventionb
Use of concomitant systemic
or local antiinflammatory
drugs permitted but use
not described
60 patients with
Low-dose UFH (5,000
International Units bid
first acute SVT of
SC for 4 wk)
greater saphenous vein
High-dose UFH (12,500
International Units for 1 wk
then 10,000 International
Units for 3 wk)
Participants
Outcomesc
Death
HIT
Extension/Recurrence
of thrombosis
Major bleeding
VTE
Death
Major bleeding
Improvement in clinical
symptoms and signs at 1 mo
6 mo
Follow-up
(Continued)
Overall VTE during follow-up period:
Low dose: 6/30 (20%)
High dose: 1/30 (3.3%);
RR 0.17 (95% CI, 0.02-1.30; P 5 ns)
Overall extension/recurrence SVT during
follow-up period: Low dose: 11/30 (36.7%)
High dose: 8/30 (26.7%); RR 0.73
(95% CI, 0.34, 1.55; P 5 ns)
Extension/recurrence SVT during
treatment period:
Low dose: 7/30 (23.3%)
High dose: 3/30 (10%); RR 0.40
(95% CI, 0.11-1.40; P 5 ns)
High dose: 0/30 (0%); RR 0.11
(95% CI, 0.01-1.98; P 5 ns)
VTE during treatment period: Low dose:
4/30 (13.3%) (3 asymptomatic DVT, 1 PE)
VTE High dose: 4/83 (4.8%)
(3 symptomatic events; 1 [PE] occurred
while on treatment)
Low dose: 2/81 (2.5%) (both
symptomatic DVT) RR 0.51 (95% CI,
0.10-2.72)
Rate of improvement in clinical
symptoms and signs similar both groups
Major bleeding: 0
Death: 0
SVT High dose: 2/83 (2.4%) (1 occurred
while on treatment) Low dose: 5/81 (6.2%)
(all occurred while on treatment) RR 2.56
(95% CI, 0.51-12.83)
Results
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Parallel RCT,
multicenter
Parallel RCT,
single center
Lozano et al168/2003
Type of
Publicationa
Belcaro et al167/1999
Author/Year
Interventionb
60 patients with
Saphenofemoral disconnection
under local anesthesia with
above-knee internal
short-term use of a
saphenous SVT
compression bandage
E. Elastic compression stockings
and LMWH
F. Elastic compression stockings
and VKA
Doses and duration of
anticoagulants not specified
C. Elastic compression stockings
and complete stripping
and perforator ligation
D. Elastic compression stockings
and low-dose SC heparin
562 patients with
A. Elastic compression stockings
alone
SVT and large
varicose veins or
venous incompetence B. Elastic compression stockings
and simple flush ligation
Participants
Outcomesc
Complications of surgery
VTE
Recurrence/extension of SVT
New DVT at 3 mo
Extension of SVT at 6 mo
Extension of SVT at 3 mo
6 mo
6 mo
Follow-up
(Continued)
Recurrent SVT Surgical group: 1/30 (3.3%)
Enoxaparin group: 3/30 (10%);
RR 3.0 (95% CI, 0.33-27.24)
P 5 ns
New DVT at 3 mo: A: 6/78 (7.7%)
B: 2/78 (2.5%); RR 0.33 (95% CI,
0.07-1.60) C: 2/70 (2.8%); RR 0.37
(95% CI, 0.08-1.78) D: 0/71 (0%);
RR 0.08 (95% CI, 0.0-1.47) E: 0/76 (0%);
RR 0.08 (95% CI, 0.0-1.38) F: 0/71 (0%);
RR 0.08 (95% CI, 0.0-1.47)
P not stated
Extension at 6 mo: A: 13/78 (16.7%)
B: 6/78 (7.7%); RR 0.46 (95% CI,
0.18-1.15) C: 1/70 (1.4%); RR 0.09
(95% CI, 0.01-0.64) D: 2/71 (2.8%);
RR 0.17 (95% CI, 0.04-0.72) E: 1/76
(1.3%); RR 0.08 (95% CI, 0.01-0.59)
F: 5/71 (7%); RR 0.42 (95% CI, 0.16-1.13)
P , .05 for groups C, D, E, F vs A or B
Extension of thrombus at 3 mo:
A: 32/78 (41%) B: 11/78 (14.1%);
RR 0.34 (95% CI, 0.19-0.63) C: 0/70;
RR 0.02 (95% CI, 0.00-0.27) D: 4/71
(5.6%); RR 0.14 (95% CI, 0.05-0.37)
E: 4/76 (5.2%); RR 0.13 (95% CI,
0.05-0.35) F: 5/71 (7.0%); RR 0.17
(95% CI, 0.07-0.42)
No major bleeding, HIT, or death in
any group
Results
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Sullivan et al169/2001
Author/Year
Participants
All patients were instructed to
wear elastic compression
stockings and used
acetaminophen for pain
No placebo/control group
Outpatient enoxaparin 1 mg/kg
bid for 1 wk then once daily
for 3 wk
Interventionb
Anticoagulation (IV heparin
followed by VKA for
6 wks-6 mo) (n 5 88)
Systematic review
Patients with objectively Ligation of greater saphenous
of 6 studies
confirmed above-knee
vein at saphenofemoral
(includes Belcaro
SVT
junction with or without
(14 patients) and
vein stripping (n 5 246)
5 small case series)
Type of
Publicationa
Outcomesc
Surgical complications
Bleeding complications
PE
DVT
SVT progression
Costs
Death
Major bleeding
Results
Cost of treatment: Surgical group: $ 1,400/
patient; mean, 1.6 d in hospital
Enoxaparin group: $ 300/patient;
0 d in hospital
Death: 0
Major bleeding: 0
Wound infections: Surgical group:
2/30 (6.7%)
VTE Surgical group: 2/30 (6.7%) (both
symptomatic PE) Enoxaparin group:
0/30 (0%); RR 0.20 (95% CI, 0.01-4.0)
(Continued)
SVT progression: Surgical group:
18/148 (12%) Medical group: 10/71 (14%);
RR 1.16 (95% CI, 0.56-2.38)
DVT: Surgical group: 7/204 (3.4%) Medical
group: 2/88 (2.2%) RR 0.66 (95% CI,
Medical
0.14-3.13)
group: 6 d
PE: Surgical group: 2/98 (2.0%) Medical
to 14 mo
group: 0/17 (0%); RR 1.10 (95% CI,
0.06-21.98)
Surgical complications: 6/78 (7.7%)
(hematoma, seroma, infection)
Bleeding complications: 0/17 (0%)
Surgical
group:
4-6 mo
Follow-up
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Parallel RCT,
multicenter
Andreozzi
et al171/1996
170
Parallel RCT,
multicenter
Type of
Publicationa
Górski et al /2005
Author/Year
Interventionb
56 patients with SVT
of the lower limbs
B: Dermatan sulfate 100 mg
SC bid
C: Dermatan sulfate 200 mg
intramuscular once daily
A: Dermatan sulfate 100 mg
SC once daily
Treatment given for 7-14 d
Enoxaparin 40 mg SC once daily
46 patients with
Topical liposomal heparin
spray gel (4 sprays of
SVT
458 International Units tid)
Participants
Outcomesc
Follow-up
Increase in functional ability
Local edema
Pain
Adverse events
Death
DVT
Area of erythema
Subjective efficacy assessment
by investigator and patient
Duplex assessment for thrombus
regression day 21
30 d
Pain by visual analog scale (0-10) 21 d
(Continued)
Resolution of pain, day 30: Group A:
47% Group B: 83% Group C: 79%
P not stated
Data extrapolated from graphs and figures in
article by reviewer
Subjective efficacy assessment: Majority of
patients (. 75%) reported good or very
good treatment efficacy, no significant
difference between groups
Thrombus regression: Topical heparin:
10/21 (47.6%) LMWH: 9/23 (39.1%);
RR 0.82 (95% CI, 0.42-1.62)
DVT: Topical heparin: 3/21 (14.3%) LMWH:
1/23 (4.3%); RR 0.30 (95% CI, 0.03-2.70)
Adverse events: Allergic reaction in 1 patient
in enoxaparin group
Death: 0
Pain by visual analog scale, day 21: Topical
heparin: 0 LMWH: 0
Improvement noted at each time point;
no pain at 21 d, no significant difference
between groups
Area of erythema: Improvement noted at
each time point; no erythema at 21 d,
no significant difference between groups
Data extrapolated from graphs and figures
in article by reviewer
Results
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Type of
Publicationa
Participants
Treatment given for 30 d
Interventionb
Outcomesc
Follow-up
Increase in ability to perform normal daily
activities, day 30: Group A: 44% Group B:
67% Group C: 84%
P , .05 groups B and C vs group A
Local edema, day 30: Progressive
improvement in all 3 groups; no significant
differences between groups
Results
The CALISTO study that compared fondaparinux with no fondaparinux is described in Table 28 and Table S42. HIT 5 heparin-induced thrombocytopenia; NSAID 5 nonsteroidal antiinflammatory drug;
STENOX 5 Superficial Thrombophlebitis Treated by Enoxaparin. See Table S1, S2, S5, S21, and S43 legends for expansion of other abbreviations.
aStudy design: RCT, cohort.
bDrugs: VKA, UFH, LMWH, NSAIDs, aspirin, topical treatments, surgery vs placebo, no treatment, each other or different durations or regimens of the same agent.
cOutcomes: extension of thrombus, symptomatic relief, DVT and PE, major bleeding, surgical complications, and death.
Author/Year
Table S45—[Section 8.1] SVT Treatment: Methodologic Quality
Author/Year
Randomization
Blinding
Loss to Follow-up/ ITT
STENOX Study
Group163/2003
Central randomization
Visually identical drugs
and packaging; triple
dummy design
Investigators, patients, and
assessors blinded
9 lost to follow-up/ ITT
Titon et al164/1994
Randomized to one of
three treatment groups;
method of randomization
not specified
Open label
Not blinded
8 lost to follow-up/ not
specified
Prandoni for Vesalio group Computer-generated random
et al165/2005
number sequence assigned
to each patient to determine
treatment group
Double dummy
Patients and adjudicators of
outcome events blind
0 lost to follow-up/ ITT
Marchiori et al166/2002
Randomized to treatment
group by computergenerated list
Not specified
Assessors blinded
0 lost to follow-up/ not
specified
Belcaro et al167/1999
Not specified
Not blinded
Not blinded
118 lost to follow-up/not
specified
Lozano et al168/2003
Method not specified
Not blinded
Not blinded
3 lost to follow-up/not
specified
Sullivan et al169/2001
Review of six studies;
includes one RCT
(Belcaro [14 patients])
and five small case series
N/A
N/A
N/A
Andreozzi et al170/1996
Patients randomly assigned
to one of three therapeutic
groups (method
not specified)
Open label
Not blinded
Not specified/not
specified
Górski et al171/2005
Performed according to
Open trial
a prespecified randomization
list; treatment allocated
according to next number
on list; no stratification was
performed
Not blinded
6 lost to follow-up/ITT
See Table S5, S12, S43, and S44 legends for expansion of abbreviations.
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Prospective cohort,
two center
Prospective cohort,
single center
Prospective cohort,
number of centers
not stated
Savage et al /1999
Karabay et al173/2003
172
Type of Publicationa
Author/Year
53 patients with first UEDVT
(included 6 with CVC)
36 inpatients with UEDVT
(includes 13 with CVC)
46 outpatients with UEDVT
Participants
Therapeutic-dose heparin
(81% received UFH, 19%
received LMWH) then VKA
(median, 3 mo)
Nadroparin SC bid, 86 anti-Xa
International Units/kg for
up to 7 d, then VKA (started
on day 3; target INR 2-2.5)
for mean of 4.7 mo
Dalteparin daily for 5-7 d
(200 International Units/kg)
and VKA with target INR of
2.0-3.0
Duration of VKA not provided
Interventionb
Recurrent VTE
Death
Symptom relief
Lysis of thrombus on
ultrasound
Recurrent DVT
PE
Death
Symptomatic
recurrence/extension
of DVT
PE
Major bleeding
Death
Outcomesc
Median of 48 mo
1y
3 mo
Follow-up
(Continued)
Results not presented according to initial
treatment with UFH vs LMWH
Recurrent VTE: 3/53 (5.7%)
(2 arm, 1 leg)
Cumulative incidence 1, 2, and 5 y:
2.0%, 4.2%, 7.7%
Death: 11/53 (20.8%) (due to cancer,
PE, congestive heart failure [numbers
not provided])
Significant symptom relief, day 7:
32/36 (89%)
Lysis, day 10: ! 35%: 16/36 (45%)
, 35%: 17/36 (47%) None: 3/36 (8%)
Recurrent DVT: 0/36
PE: 0/36
Death: 9/36 (25%) (none due to PE
or bleeding)
Recurrence/extension DVT: 1/46 (2%)
PE: 0/46
Major bleeding: 1/46 (2%) (on VKA)
Death: 7/46 (15%) (none from PE or
bleeding)
Results
Table S46—[Section 9.1] Initial Treatment of Acute UEDVT With Anticoagulant Therapy: Clinical Description and Results (Randomized Trials [None Performed]
and Prospective Observational Studies of at Least 20 Patients)
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81
Prospective cohort,
multicenter
Kovacs et al /2007
Interventionb
174
74 cancer patients with
Dalteparin daily for 5-7 d
confirmed UEDVT (all had
(200 International Units/kg)
CVC)
and VKA to achieve target
INR of 2.0-3.0
Participants
Outcomesc
Recurrent VTE
PE
Major bleeding
Death
Catheter failure due
to DVT or
inability to infuse
CVC 5 central venous catheter; UEDVT 5 upper-extremity DVT. See Table S2, S7, and S41 legends for expansion of other abbreviations.
aStudy design: prospective cohort studies.
bDrugs: IV UFH or LMWH followed by OACs.
cOutcomes: recurrent DVT and PE, major bleeding, total mortality, and early symptom relief.
Author/Year
3 mo
Follow-up
Recurrent VTE: 0/74
PE: 0/74
Death: 7/74 (6 cancer, 1 major bleed)
Catheter failure due to DVT or inability
to infuse: 0/74
Results
Table S47—[Section 9.1] Initial Treatment of Acute UEDVT With Anticoagulant Therapy: Methodologic Quality
Author/Year
Randomization
Blinding
Loss to Follow-up/ ITT
Savage et al /1999
N/A
N/A
N/A
1 lost to follow-up/N/A
N/A
N/A
N/A
N/A
N/A
N/A
Kovacs et al174/2006
N/A
N/A
N/A
172
Table S48—[Section 9.2] Initial Treatment of Acute UEDVT With Thrombolytic Therapy: Clinical Description and
Results (Randomized Trials [None Performed] and Prospective Observational Studies of at Least 10 Patients)
Author/Year
Horne et al175/2000 Prospective cohort,
single center
Lee et al176/2006
Prospective case
series, single
center
Participants
18 patients with
axillary or
subclavian DVT
Interventionb
Catheter-directed
rt-PA (2 mg/cm
of thrombus
to maximum of
20 mg) then
VKA for 3 mo
Outcomesc
Follow-up
Immediate patency
6 mo
Results
Immediate patency:
10/18 (56%)
Establishment of
antegrade flow
Antegrade flow: 11/18
(61%)
Bleeding events
Bleeds (all minor):
5/18 (28%)
35 patients
Oral VKA for mean Recurrent DVT
with primary
of 5.2 mo
UEDVT who
had complete
resolution of acute
symptoms with
CDT (n 5 29) or
IV heparin (n 5 6)
54 mo
Ipsilateral recurrent
DVT: 8/35 (23%)
Early prospective observational studies with , 10 patients and retrospective studies are described in Table 3 of the eighth edition of these guidelines.46 See Table S2, S10, S11, and S46 legends for expansion of abbreviations.
aStudy design: retrospective and prospective cohort studies.
bDrugs: thrombolytic therapy compared with different types of lytic therapy or with anticoagulants.
cOutcomes: recurrent DVT and PE, vein patency, major bleeding, total mortality, and PTS of the arm.
Table S49—[Section 9.2] Initial Treatment of Acute UEDVT With Thrombolytic Therapy: Methodologic Quality
Author/Year
Randomization
Blinding
Horne et al /2000
No
N/A
N/A
Not specified
Lee et al176/2006
No
N/A
N/A
0 lost to follow-up
175
Loss to Follow-up
See Table S12 legend for expansion of abbreviation.
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Prospective cohort,
two center
Prospective cohort,
single center
Case-control study with
prospective follow-up
of cases, single center
Prospective cohort,
number of centers
not stated
Martinelli et al177/2004
Type of Publication
Savage et al172/1999
Author/Year
53 patients with confirmed
first UEDVT (included
6 with CVC)
98 patients with
primary UEDVT
(none with CVC)
36 inpatients with
confirmed UEDVT
46 outpatients with
confirmed UEDVT
Participants
Therapeutic-dose heparin
(81% received UFH, 19%
received LMWH) then
VKA (median, 3 mo)
VKA for mean 6 mo
(77 patients), heparin
SC (14 patients), or
antiplatelet agents
(7 patients) for " 3 mo
Nadroparin SC bid, 86
anti-Xa International
Units/kg for up to 7 d,
then VKA (started on
day 3; target INR 2-2.5)
for mean of 4.7 mo
Dalteparin 200 International
Units/kg daily for 5-7 d
INR of 2.0-3.0 for 3 mo
Duration of VKA
not provided
Interventiona
Recurrent VTE
Recurrent VTE after
anticoagulants stopped
Symptom relief
Lysis of thrombus on
ultrasound
Recurrent DVT
PE
Death
PTS
Symptomatic recurrence/
extension of DVT
PE
Major bleeding
Death
Outcomesb
Recurrent VTE: 12/98 (12%)
overall (all UEDVT)
Annual incidence recurrent VTE:
2.4% (95% CI, 1.2%-4.0%)
(results not provided by
treatment group)
Significant symptom relief, day 7:
32/36 (89%)
Lysis, day 10: ! 35%: 16/36 (45%)
, 35%: 17/36 (47%)
None: 3/36 (8%)
Recurrent DVT: 0
PE: 0
Death: 9/36 (25%) (none due to
PE or bleeding)
PTS: 0
Recurrence/extension: 1/46 (2%)
PE: 0
(on VKA)
Death: 7/46 (15%) (none from PE
or bleeding)
Results
(Continued)
Median of 48 mo Results not presented according
to initial treatment with UFH vs
LMWH
Median of 5.1 y
1y
3 mo
Follow-up
Table S50—[Section 9.3] Long-term Treatment of Acute UEDVT: Clinical Description and Results
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Prospective cohort,
multicenter
Type of Publication
74 cancer patients with
confirmed UEDVT
(all had CVC)
Participants
Dalteparin 200 International
Units/kg daily for 5-7 d
INR of 2.0-3.0
Interventiona
Death
PTS
Outcomesb
Follow-up
Recurrent VTE: 3/53 (5.7%)
(2 arm, 1 leg)
Cumulative incidence 1, 2, and 5 y:
2.0%, 4.2%, 7.7%
Death: 11/53 (20.8%) (due to cancer,
PE, congestive heart failure
[breakdown not provided])
PTS: 13/53 (24.5%); 2 y
Cumulative incidence: 27.3%
Results
Recurrent VTE
3 mo
Recurrent VTE: 0
PE
PE: 0
Major bleeding
Major bleeding: 3 (4%)
Death
Death: 7 (6 cancer, 1 major bleed)
Catheter failure due to
Catheter failure due to DVT or
DVT or inability
inability to infuse: 0
to infuse
Early prospective observational studies with , 20 patients, and retrospective studies, are described in Table 3 of the Eight edition of these guidelines46 See Table S2, S7, S10, and S46 legends for expansion
of abbreviations.
aDrugs: VKA, UFH, LMWH vs placebo, control or each other.
bOutcomes: recurrent DVT and PE, major bleeding, total mortality, and PTS of the arm.
Author/Year
Table S51—[Section 9.3] Long-term Treatment of Acute UEDVT: Methodologic Quality
Author/Year
Randomization
Blinding
Loss to Follow-up
Savage et al /1999
N/A
N/A
N/A
1 lost to follow-up
N/A
N/A
N/A
0 lost to follow-up
Martinelli et al177/2004
N/A
N/A
N/A
Not specified
N/A
N/A
N/A
2 patients lost to follow-up
N/A
N/A
N/A
0 lost to follow-up
172
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91
DOI:HQ
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Antithrombotic Therapy for VTE Disease : Antithrombotic Therapy and
Clive Kearon, Elie A. Akl, Anthony J. Comerota, Paolo Prandoni, Henri
Bounameaux, Samuel Z. Goldhaber, Michael E. Nelson, Philip S. Wells,
Michael K. Gould, Francesco Dentali, Mark Crowther and Susan R. Kahn
Chest 2012;141; e419S-e494S
DOI 10.1378/chest.11-2301
http://chestjournal.chestpubs.org/content/suppl/2012/02/03/141.2_suppl.e419S.DC1.html
http://chestjournal.chestpubs.org/content/141/2_suppl/e419S.full.html
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Selected Abstracts
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Selected Abstracts
Abstract 1
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: AMERICAN COLLEGE OF CHEST PHYSICIAN EVIDENCEBASED CLINICAL PRACTICE GUIDELINES ONLINE ONLY ARTICLES
ARTICLES::
Samantha MacLean, Sohail Mulla, Elie A. Akl, Milosz Jankowski, Per Olav Vandvik, Shanil Ebrahim, Shelley McLeod, Neera Bhatnagar,
and Gordon H. Guyatt
Patient Values and Preferences in Decision Making for Antithrombotic Therapy: A Systematic Review
Review:: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Chest February 2012 141:2 suppl e1S-e23S; doi:10.1378/chest.11-2290
Abstract
Full Text
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Abstract 2
ARTICLES::
David A. Garcia, Trevor P. Baglin, Jeffrey I. Weitz, and Meyer Michel Samama
Parenteral Anticoagulants
Anticoagulants:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Abstract
Full Text
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Abstract 3
ARTICLES::
Walter Ageno, Alexander S. Gallus, Ann Wittkowsky, Mark Crowther, Elaine M. Hylek, and Gualtiero Palareti
Oral Anticoagulant Therapy
Therapy:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest
Abstract
Full Text
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Abstract 4
ARTICLES::
John W. Eikelboom, Jack Hirsh, Frederick A. Spencer, Trevor P. Baglin, and Jeffrey I. Weitz
Antiplatelet Drugs
Drugs:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Abstract
Full Text
Full Text (PDF)
Abstract 5
ARTICLES::
Jeffrey I. Weitz, John W. Eikelboom, and Meyer Michel Samama
New Antithrombotic Drugs
Drugs:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest
Abstract
Full Text
Full Text (PDF)
Abstract 6
ARTICLES::
Anne Holbrook, Sam Schulman, Daniel M. Witt, Per Olav Vandvik, Jason Fish, Michael J. Kovacs, Peter J. Svensson, David L. Veenstra, Mark Crowther,
and Gordon H. Guyatt
Evidence-Based Management of Anticoagulant Therapy
Therapy:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
Abstract 7
ARTICLES::
Gordon H. Guyatt, John W. Eikelboom, Michael K. Gould, David A. Garcia, Mark Crowther, M. Hassan Murad, Susan R. Kahn, Yngve Falck-Ytter,
Charles W. Francis, Maarten G. Lansberg, Elie A. Akl, and Jack Hirsh
Approach to Outcome Measurement in the Prevention of Thrombosis in Surgical and Medical Patients
Patients:: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
Abstract 8
ARTICLES::
http://chestjournal.chestpubs.org/gca?gca=chest%3B141%2F2_supp…hest%3B141%2F2_suppl%2Fe737S&submit=Get+All+Checked+Abstracts
Pagina 1 di 19
Selected Abstracts
07/02/12 22:14
Susan R. Kahn, Wendy Lim, Andrew S. Dunn, Mary Cushman, Francesco Dentali, Elie A. Akl, Deborah J. Cook, Alex A. Balekian, Russell C. Klein,
Hoang Le, Sam Schulman, and M. Hassan Murad
Patients:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
Abstract 9
ARTICLES::
Michael K. Gould, David A. Garcia, Sherry M. Wren, Paul J. Karanicolas, Juan I. Arcelus, John A. Heit, and Charles M. Samama
Prevention of VTE in Nonorthopedic Surgical Patients
Patients:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
Abstract 10
ARTICLES::
Yngve Falck-Ytter, Charles W. Francis, Norman A. Johanson, Catherine Curley, Ola E. Dahl, Sam Schulman, Thomas L. Ortel, Stephen G. Pauker,
and Clifford W. Colwell, Jr
Prevention of VTE in Orthopedic Surgery Patients
Patients:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
Abstract
Full Text
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Abstract 11
ARTICLES::
James D. Douketis, Alex C. Spyropoulos, Frederick A. Spencer, Michael Mayr, Amir K. Jaffer, Mark H. Eckman, Andrew S. Dunn, and Regina Kunz
Perioperative Management of Antithrombotic Therapy
Therapy:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
Abstract
Full Text
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Abstract 12
ARTICLES::
Shannon M. Bates, Roman Jaeschke, Scott M. Stevens, Steven Goodacre, Philip S. Wells, Matthew D. Stevenson, Clive Kearon, Holger J. Schunemann,
Mark Crowther, Stephen G. Pauker, Regina Makdissi, and Gordon H. Guyatt
Diagnosis of DVT
DVT:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Abstract
Full Text
Full Text (PDF)
Online Data Supplements
Abstract 13
ARTICLES::
Clive Kearon, Elie A. Akl, Anthony J. Comerota, Paolo Prandoni, Henri Bounameaux, Samuel Z. Goldhaber, Michael E. Nelson, Philip S. Wells,
Michael K. Gould, Francesco Dentali, Mark Crowther, and Susan R. Kahn
Disease:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
Abstract 14
ARTICLES::
Lori-Ann Linkins, Antonio L. Dans, COL Lisa K. Moores, Robert Bona, Bruce L. Davidson, Sam Schulman, and Mark Crowther
Treatment and Prevention of Heparin-Induced Thrombocytopenia
Thrombocytopenia:: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
Abstract 15
ARTICLES::
John J. You, Daniel E. Singer, Patricia A. Howard, Deirdre A. Lane, Mark H. Eckman, Margaret C. Fang, Elaine M. Hylek, Sam Schulman, Alan S. Go,
Michael Hughes, Frederick A. Spencer, Warren J. Manning, Jonathan L. Halperin, and Gregory Y. H. Lip
Antithrombotic Therapy for Atrial Fibrillation
Fibrillation:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College
of Chest Physicians Evidence-Based Clinical Practice Guidelines
Abstract
Full Text
Full Text (PDF)
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Abstract 16
ARTICLES::
Richard P. Whitlock, Jack C. Sun, Stephen E. Fremes, Fraser D. Rubens, and Kevin H. Teoh
Antithrombotic and Thrombolytic Therapy for Valvular Disease
Disease:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
Abstract
Full Text
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Abstract 17
ARTICLES::
Maarten G. Lansberg, Martin J. O’Donnell, Pooja Khatri, Eddy S. Lang, Mai N. Nguyen-Huynh, Neil E. Schwartz, Frank A. Sonnenberg, Sam Schulman,
Per Olav Vandvik, Frederick A. Spencer, Pablo Alonso-Coello, Gordon H. Guyatt, and Elie A. Akl
Antithrombotic and Thrombolytic Therapy for Ischemic Stroke
Stroke:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
Abstract
Full Text
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Abstract 18
ARTICLES::
Per Olav Vandvik, A. Michael Lincoff, Joel M. Gore, David D. Gutterman, Frank A. Sonnenberg, Pablo Alonso-Coello, Elie A. Akl, Maarten G. Lansberg,
Gordon H. Guyatt, and Frederick A. Spencer
Primary and Secondary Prevention of Cardiovascular Disease
Disease:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
Abstract
Full Text
Full Text (PDF)
Abstract 19
ARTICLES::
Pablo Alonso-Coello, Sergi Bellmunt, Catherine McGorrian, Sonia S. Anand, Randolph Guzman, Michael H. Criqui, Elie A. Akl, Per Olav Vandvik,
Maarten G. Lansberg, Gordon H. Guyatt, and Frederick A. Spencer
Antithrombotic Therapy in Peripheral Artery Disease
Disease:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
Abstract
Full Text
Full Text (PDF)
Abstract 20
ARTICLES::
Shannon M. Bates, Ian A. Greer, Saskia Middeldorp, David L. Veenstra, Anne-Marie Prabulos, and Per Olav Vandvik
VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Pregnancy:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
Abstract
Full Text
Full Text (PDF)
Abstract 21
ARTICLES::
Paul Monagle, Anthony K. C. Chan, Neil A. Goldenberg, Rebecca N. Ichord, Janna M. Journeycake, Ulrike Nowak-Göttl, and Sara K. Vesely
Antithrombotic Therapy in Neonates and Children
Children:: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
Abstract
Full Text
Full Text (PDF)
Abstract 1 of 21
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: AMERICAN COLLEGE OF CHEST PHYSICIAN EVIDENCE-BASED
CLINICAL PRACTICE GUIDELINES ONLINE ONLY ARTICLES
Patient Values and Preferences in Decision Making for Antithrombotic Therapy: A Systematic
Review
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines
Background: Development of clinical practice guidelines involves making trade-offs between desirable and undesirable consequences of alternative
management strategies. Although the relative value of health states to patients should provide the basis for these trade-offs, few guidelines have
systematically summarized the relevant evidence. We conducted a systematic review relating to values and preferences of patients considering
antithrombotic therapy.
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Methods: We included studies examining patient preferences for alternative approaches to antithrombotic prophylaxis and studies that examined, in
the context of antithrombotic prophylaxis or treatment, how patients value alternative health states and experiences with treatment. We conducted a
systematic search and compiled structured summaries of the results. Steps in the process that involved judgment were conducted in duplicate.
Results: We identified 48 eligible studies. Sixteen dealt with atrial fibrillation, five with VTE, four with stroke or myocardial infarction prophylaxis, six
with thrombolysis in acute stroke or myocardial infarction, and 17 with burden of antithrombotic treatment.
Conclusion: Patient values and preferences regarding thromboprophylaxis treatment appear to be highly variable. Participant responses may depend
on their prior experience with the treatments or health outcomes considered as well as on the methods used for preference elicitation. It should be
standard for clinical practice guidelines to conduct systematic reviews of patient values and preferences in the specific content area.
Accepted August 31, 2011.
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Abstract 2 of 21
Parenteral Anticoagulants
This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH),
low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban.
UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation
of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable
pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and
osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin.
Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and
are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without
coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic
pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to
antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when
administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation
monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.
Full Text
Abstract 3 of 21
Oral Anticoagulant Therapy
Background: The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral
anticoagulant drugs that are currently available for clinical use and other aspects related to their management.
Methods: We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the
direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban
Results: The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in
detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of
oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects,
and available strategies for reversal.
Conclusions: There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is
becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.
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Abstract 4 of 21
Antiplatelet Drugs
The article describes the mechanisms of action, pharmacokinetics, and pharmacodynamics of aspirin, dipyridamole, cilostazol, the thienopyridines, and
the glycoprotein IIb/IIIa antagonists. The relationships among dose, efficacy, and safety are discussed along with a mechanistic overview of results of
randomized clinical trials. The article does not provide specific management recommendations but highlights important practical aspects of antiplatelet
therapy, including optimal dosing, the variable balance between benefits and risks when antiplatelet therapies are used alone or in combination with
other antiplatelet drugs in different clinical settings, and the implications of persistently high platelet reactivity despite such treatment.
Full Text
Abstract 5 of 21
New Antithrombotic Drugs
This article focuses on new antithrombotic drugs that are in or are entering phase 3 clinical testing. Development of these new agents was prompted by
the limitations of existing antiplatelet, anticoagulant, or fibrinolytic drugs. Addressing these unmet needs, this article (1) outlines the rationale for
development of new antithrombotic agents; (2) describes the new antiplatelet, anticoagulant, and fibrinolytic drugs; and (3) provides clinical
perspectives on the opportunities and challenges faced by these novel agents.
Full Text
Abstract 6 of 21
Evidence-Based Management of Anticoagulant Therapy
Background: High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as
possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to
guide best practices.
Methods: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of
Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines in this supplement.
Results: Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed
by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak
recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist
therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal
with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal
function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also
address anticoagulation management services and intensive patient education.
Conclusions: We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have
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not been adequately studied.
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Abstract 7 of 21
Approach to Outcome Measurement in the Prevention of Thrombosis in Surgical and Medical
Patients
This article provides the rationale for the approach to making recommendations primarily used in four articles of the Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines: orthopedic surgery, nonorthopedic
surgery, nonsurgical patients, and stroke. Some of the early clinical trials of antithrombotic prophylaxis with a placebo or no treatment group used
symptomatic VTE and fatal PE to measure efficacy of the treatment. These trials suggest a benefit of thromboprophylaxis in reducing fatal PE. In
contrast, most of the recent clinical trials comparing the efficacy of alternative anticoagulants used a surrogate outcome, asymptomatic DVT detected at
mandatory venography. This outcome is fundamentally unsatisfactory because it does not allow a trade-off with serious bleeding; that trade-off
requires knowledge of the number of symptomatic events that thromboprophylaxis prevents. In this article, we review the merits and limitations of four
approaches to estimating reduction in symptomatic thrombosis: (1) direct measurement of symptomatic thrombosis, (2) use of asymptomatic events for
relative risks and symptomatic events from randomized controlled trials for baseline risk, (3) use of baseline risk estimates from studies that did not
perform surveillance and relative effect from asymptomatic events in randomized controlled trials, and (4) use of available data to estimate the
proportion of asymptomatic events that will become symptomatic. All approaches have their limitations. The optimal choice of approach depends on
the nature of the evidence available.
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Abstract 8 of 21
Background: This guideline addressed VTE prevention in hospitalized medical patients, outpatients with cancer, the chronically immobilized, longdistance travelers, and those with asymptomatic thrombophilia.
Methods: This guideline follows methods described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis
Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines in this supplement.
Results: For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with lowmolecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending
the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). For acutely ill hospitalized medical
patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). For acutely ill
hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical
thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C). For critically ill
patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major
bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C). In outpatients with
cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the
prophylactic use of vitamin K antagonists (Grade 1B).
Conclusions: Decisions regarding prophylaxis in nonsurgical patients should be made after consideration of risk factors for both thrombosis and
bleeding, clinical context, and patients’ values and preferences.
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Abstract 9 of 21
Prevention of VTE in Nonorthopedic Surgical Patients
Background: VTE is a common cause of preventable death in surgical patients.
Methods: We developed recommendations for thromboprophylaxis in nonorthopedic surgical patients by using systematic methods as described in
Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines. Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
Results: We describe several alternatives for stratifying the risk of VTE in general and abdominal-pelvic surgical patients. When the risk for VTE is very
low (< 0.5%), we recommend that no specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation. For
patients at low risk for VTE (∼1.5%), we suggest mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis
(Grade 2C). For patients at moderate risk for VTE (∼3%) who are not at high risk for major bleeding complications, we suggest low-molecular-weight
heparin (LMWH) (Grade 2B), low-dose unfractionated heparin (Grade 2B), or mechanical prophylaxis with IPC (Grade 2C) over no prophylaxis. For
patients at high risk for VTE (∼6%) who are not at high risk for major bleeding complications, we recommend pharmacologic prophylaxis with LMWH
(Grade 1B) or low-dose unfractionated heparin (Grade 1B) over no prophylaxis. In these patients, we suggest adding mechanical prophylaxis with elastic
stockings or IPC to pharmacologic prophylaxis (Grade 2C). For patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer, we
recommend extended-duration, postoperative, pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B). For
patients at moderate to high risk for VTE who are at high risk for major bleeding complications or those in whom the consequences of bleeding are
believed to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding
diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). For patients in all risk groups, we suggest that an inferior vena cava filter not be
used for primary VTE prevention (Grade 2C) and that surveillance with venous compression ultrasonography should not be performed (Grade 2C). We
developed similar recommendations for other nonorthopedic surgical populations.
Conclusions: Optimal thromboprophylaxis in nonorthopedic surgical patients will consider the risks of VTE and bleeding complications as well as the
values and preferences of individual patients.
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Abstract 10 of 21
Prevention of VTE in Orthopedic Surgery Patients
Background: VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to
reduce postoperative pulmonary embolism and DVT.
Results: In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis:
low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture
surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device
(IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have
recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay
(Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no
prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using
inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis
(Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated
lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy
without a history of VTE, we suggest no thromboprophylaxis (Grade 2B).
Conclusions: Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.
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Abstract 11 of 21
Perioperative Management of Antithrombotic Therapy
Background: This guideline addresses the management of patients who are receiving anticoagulant or antiplatelet therapy and require an elective
surgery or procedure.
Methods: The methods herein follow those discussed in the Methodology for the Development of Antithrombotic Therapy and Prevention of
Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines article of this supplement.
Results: In patients requiring vitamin K antagonist (VKA) interruption before surgery, we recommend stopping VKAs 5 days before surgery instead of a
shorter time before surgery (Grade 1B). In patients with a mechanical heart valve, atrial fibrillation, or VTE at high risk for thromboembolism, we
suggest bridging anticoagulation instead of no bridging during VKA interruption (Grade 2C); in patients at low risk, we suggest no bridging instead of
bridging (Grade 2C). In patients who require a dental procedure, we suggest continuing VKAs with an oral prohemostatic agent or stopping VKAs 2 to 3
days before the procedure instead of alternative strategies (Grade 2C). In moderate- to high-risk patients who are receiving acetylsalicylic acid (ASA)
and require noncardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C).
In patients with a coronary stent who require surgery, we recommend deferring surgery > 6 weeks after bare-metal stent placement and > 6 months
after drug-eluting stent placement instead of undertaking surgery within these time periods (Grade 1C); in patients requiring surgery within 6 weeks of
bare-metal stent placement or within 6 months of drug-eluting stent placement, we suggest continuing antiplatelet therapy perioperatively instead of
stopping therapy 7 to 10 days before surgery (Grade 2C).
Conclusions: Perioperative antithrombotic management is based on risk assessment for thromboembolism and bleeding, and recommended
approaches aim to simplify patient management and minimize adverse clinical outcomes.
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Diagnosis of DVT
Background: Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious.
This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults.
Practice Guidelines.
Results: We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the
diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend
initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US
(Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or
whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal
compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B).
Conclusions: Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality
evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.
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Abstract 13 of 21
Background: This article addresses the treatment of VTE disease.
Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and lowquality (Grade C) evidence.
Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with
rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous
unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend
treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk
factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is
unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high
(Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH
over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression
stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or
LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C).
Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including
their preferences.
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Abstract 14 of 21
Treatment and Prevention of Heparin-Induced Thrombocytopenia
Background: Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic
complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke.
Methods: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis
Results: Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to
be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs
first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored
(Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or
danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other
nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin
over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C).
Conclusions: Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.
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Antithrombotic Therapy for Atrial Fibrillation
Background: The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for
stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for
patients with AF at varying levels of stroke risk and in a number of common clinical scenarios.
Methods: We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis
Guidelines article of this supplement.
Results: For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS2 [congestive heart
failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than
antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy
with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS2 score of 1), we recommend oral anticoagulation rather than no therapy, and
we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS2
score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we
recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy.
Conclusions: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS2 score of ≥ 2). At
lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach.
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Antithrombotic and Thrombolytic Therapy for Valvular Disease
Background: Antithrombotic therapy in valvular disease is important to mitigate thromboembolism, but the hemorrhagic risk imposed must be
considered.
Thrombosis Guidelines. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Results: In rheumatic mitral disease, we recommend vitamin K antagonist (VKA) therapy when the left atrial diameter is > 55 mm (Grade 2C) or when
complicated by left atrial thrombus (Grade 1A). In candidates for percutaneous mitral valvotomy with left atrial thrombus, we recommend VKA therapy
until thrombus resolution, and we recommend abandoning valvotomy if the thrombus fails to resolve (Grade 1A). In patients with patent foramen ovale
(PFO) and stroke or transient ischemic attack, we recommend initial aspirin therapy (Grade 1B) and suggest substitution of VKA if recurrence (Grade 2C).
In patients with cryptogenic stroke and DVT and a PFO, we recommend VKA therapy for 3 months (Grade 1B) and consideration of PFO closure (Grade
2C). We recommend against the use of anticoagulant (Grade 1C) and antiplatelet therapy (Grade 1B) for native valve endocarditis. We suggest holding
VKA therapy until the patient is stabilized without neurologic complications for infective endocarditis of a prosthetic valve (Grade 2C). In the first 3
months after bioprosthetic valve implantation, we recommend aspirin for aortic valves (Grade 2C), the addition of clopidogrel to aspirin if the aortic
valve is transcatheter (Grade 2C), and VKA therapy with a target international normalized ratio (INR) of 2.5 for mitral valves (Grade 2C). After 3 months,
we suggest aspirin therapy (Grade 2C). We recommend early bridging of mechanical valve patients to VKA therapy with unfractionated heparin (DVT
dosing) or low-molecular-weight heparin (Grade 2C). We recommend long-term VKA therapy for all mechanical valves (Grade 1B): target INR 2.5 for
aortic (Grade 1B) and 3.0 for mitral or double valve (Grade 2C). In patients with mechanical valves at low bleeding risk, we suggest the addition of lowdose aspirin (50-100 mg/d) (Grade 1B). In valve repair patients, we suggest aspirin therapy (Grade 2C). In patients with thrombosed prosthetic valve, we
recommend fibrinolysis for right-sided valves and left-sided valves with thrombus area < 0.8 cm2 (Grade 2C). For patients with left-sided prosthetic
valve thrombosis and thrombus area ≥ 0.8 cm2, we recommend early surgery (Grade 2C).
Conclusions: These antithrombotic guidelines provide recommendations based on the optimal balance of thrombotic and hemorrhagic risk.
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Antithrombotic and Thrombolytic Therapy for Ischemic Stroke
Objectives: This article provides recommendations on the use of antithrombotic therapy in patients with stroke or transient ischemic attack (TIA).
Methods: We generated treatment recommendations (Grade 1) and suggestions (Grade 2) based on high (A), moderate (B), and low (C) quality
evidence.
Results: In patients with acute ischemic stroke, we recommend IV recombinant tissue plasminogen activator (r-tPA) if treatment can be initiated within
3 h (Grade 1A) or 4.5 h (Grade 2C) of symptom onset; we suggest intraarterial r-tPA in patients ineligible for IV tPA if treatment can be initiated within 6
h (Grade 2C); we suggest against the use of mechanical thrombectomy (Grade 2C) although carefully selected patients may choose this intervention;
and we recommend early aspirin therapy at a dose of 160 to 325 mg (Grade 1A). In patients with acute stroke and restricted mobility, we suggest the
use of prophylactic-dose heparin or intermittent pneumatic compression devices (Grade 2B) and suggest against the use of elastic compression
stockings (Grade 2B). In patients with a history of noncardioembolic ischemic stroke or TIA, we recommend long-term treatment with aspirin (75-100
mg once daily), clopidogrel (75 mg once daily), aspirin/extended release dipyridamole (25 mg/200 mg bid), or cilostazol (100 mg bid) over no
antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B). Of the
recommended antiplatelet regimens, we suggest clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or cilostazol (Grade 2C).
In patients with a history of stroke or TIA and atrial fibrillation we recommend oral anticoagulation over no antithrombotic therapy, aspirin, and
combination therapy with aspirin and clopidogrel (Grade 1B).
Conclusions: These recommendations can help clinicians make evidence-based treatment decisions with their patients who have had strokes.
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Primary and Secondary Prevention of Cardiovascular Disease
Background: This guideline focuses on long-term administration of antithrombotic drugs designed for primary and secondary prevention of
cardiovascular disease, including two new antiplatelet therapies.
Results: We present 23 recommendations for pertinent clinical questions. For primary prevention of cardiovascular disease, we suggest low-dose
aspirin (75-100 mg/d) in patients aged > 50 years over no aspirin therapy (Grade 2B). For patients with established coronary artery disease, defined as
patients 1-year post-acute coronary syndrome, with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for
cardiac ischemia on diagnostic testing, we recommend long-term low-dose aspirin or clopidogrel (75 mg/d) (Grade 1A). For patients with acute
coronary syndromes who undergo percutaneous coronary intervention (PCI) with stent placement, we recommend for the first year dual antiplatelet
therapy with low-dose aspirin in combination with ticagrelor 90 mg bid, clopidogrel 75 mg/d, or prasugrel 10 mg/d over single antiplatelet therapy
(Grade 1B). For patients undergoing elective PCI with stent placement, we recommend aspirin (75-325 mg/d) and clopidogrel for a minimum duration
of 1 month (bare-metal stents) or 3 to 6 months (drug-eluting stents) (Grade 1A). We suggest continuing low-dose aspirin plus clopidogrel for 12
months for all stents (Grade 2C). Thereafter, we recommend single antiplatelet therapy over continuation of dual antiplatelet therapy (Grade 1B).
Conclusions: Recommendations continue to favor single antiplatelet therapy for patients with established coronary artery disease. For patients with
acute coronary syndromes or undergoing elective PCI with stent placement, dual antiplatelet therapy for up to 1 year is warranted.
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Antithrombotic Therapy in Peripheral Artery Disease
Background: This guideline focuses on antithrombotic drug therapies for primary and secondary prevention of cardiovascular disease as well as for
the relief of lower-extremity symptoms and critical ischemia in persons with peripheral arterial disease (PAD).
Results: The most important of our 20 recommendations are as follows. In patients aged ≥ 50 years with asymptomatic PAD or asymptomatic carotid
stenosis, we suggest aspirin (75-100 mg/d) over no therapy (Grade 2B) for the primary prevention of cardiovascular events. For secondary prevention
of cardiovascular disease in patients with symptomatic PAD (including patients before and after peripheral arterial bypass surgery or percutaneous
transluminal angioplasty), we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A). We recommend against the use of
warfarin plus aspirin in patients with symptomatic PAD (Grade 1B). For patients undergoing peripheral artery percutaneous transluminal angioplasty
with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C). For patients with refractory claudication despite exercise therapy and
smoking cessation, we suggest addition of cilostazol (100 mg bid) to aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 2C). In patients with
critical limb ischemia and rest pain unable to undergo revascularization, we suggest the use of prostanoids (Grade 2C). In patients with acute limb
ischemia due to acute thrombosis or embolism, we recommend surgery over peripheral arterial thrombolysis (Grade 1B).
Conclusions: Recommendations continue to favor single antiplatelet therapy for primary and secondary prevention of cardiovascular events in most
patients with asymptomatic PAD, symptomatic PAD, and asymptomatic carotid stenosis. Additional therapies for relief of limb symptoms should be
considered only after exercise therapy, smoking cessation, and evaluation for peripheral artery revascularization.
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Abstract 20 of 21
VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Background: The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications.
This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy.
Methods: The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis
Results: We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin
(Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration
of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid
antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum
administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose
aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not
to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against
antithrombotic prophylaxis (Grade 1B).
Conclusions: Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an
urgent need for appropriately designed studies in this population.
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Antithrombotic Therapy in Neonates and Children
Background: Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences
of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children.
Methods: The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of
Practice Guidelines.
Results: We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with
thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported
by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to
achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a
protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight
heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or,
alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C).
Conclusions: The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing
appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis
management strategies.
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Practice Guidelines Chest Physicians Evidence-Based

Transcription

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