Factor Xa inhibitors for acute coronary syndromes (Review) The Cochrane Library

Transcription

Factor Xa inhibitors for acute coronary syndromes (Review)
Brito V, Ciapponi A, Kwong J
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 3
http://www.thecochranelibrary.com
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
Figure 2.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
Figure 3.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
Figure 4.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
Figure 5.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
Figure 6.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
Figure 7.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
Figure 8.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
Analysis 1.1. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 1 All-cause mortality at 30 days. . . . .
43
Analysis 1.2. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 2 All-cause mortality at 90 to 180 days. . .
44
Analysis 1.3. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 3 Non-fatal AMI or re-infarction at 9 days.
45
Analysis 1.4. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 4 Non-fatal AMI or re-infarction at 30 days.
46
Analysis 1.5. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 5 Combined endpoint of all-cause mortality, nonfatal AMI or re-infarction at 9 days. . . . . . . . . . . . . . . . . . . . . . . . . . .
47
Analysis 1.6. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 6 Major bleeding at 9 days. . . . . . .
48
Analysis 1.7. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 7 Major bleeding at 30 days. . . . . .
49
Analysis 1.8. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 8 Minor bleeding at 30 days. . . . . .
50
Analysis 2.1. Comparison 2 Low dose fondaparinux vs. anticoagulants, Outcome 1 All-cause mortality at 30 days. .
51
Analysis 2.2. Comparison 2 Low dose fondaparinux vs. anticoagulants, Outcome 2 Non-fatal AMI or re-infarction at 30
days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
Analysis 2.3. Comparison 2 Low dose fondaparinux vs. anticoagulants, Outcome 3 Major bleeding at 9 days. . . .
53
Analysis 3.1. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 1 All-cause mortality at 30 days. . .
54
Analysis 3.2. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 2 Non-fatal AMI or re-infarction at 30
days. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
Analysis 3.3. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 3 Major bleeding at 9 days. . . . .
56
Analysis 3.4. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 4 Catheter thrombosis. . . . . .
57
Analysis 4.1. Comparison 4 Sensitivity analyses, Outcome 1 All-cause mortality at 30 days. . . . . . . . . .
58
Analysis 4.2. Comparison 4 Sensitivity analyses, Outcome 2 Major bleeding at 9 days. . . . . . . . . . . .
59
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
63
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
i
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
ii
[Intervention Review]
Factor Xa inhibitors for acute coronary syndromes
Viviana Brito1 , Agustín Ciapponi2 , Joey Kwong3
1
Coronary Care Unit, Hospital de Clinicas, Universidad de Buenos Aires, Ciudad Autonoma Buenos Aires, Argentina. 2 Argentine
Cochrane Centre IECS - Family and Community Medicine Service, Institute for Clinical Effectiveness and Health Policy - Hospital
Italiano de Buenos Aires, Buenos Aires, Argentina. 3 Department of Non-Communicable Disease Epidemiology, London School of
Hygiene & Tropical Medicine, London, UK
Contact address: Viviana Brito, Coronary Care Unit, Hospital de Clinicas, Universidad de Buenos Aires, Avenida Cordoba 2351 Piso
Sala 1, Ciudad Autonoma Buenos Aires, Capital Federal, Argentina. [email protected].
Editorial group: Cochrane Heart Group.
Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 3, 2011.
Review content assessed as up-to-date: 30 April 2009.
Citation: Brito V, Ciapponi A, Kwong J. Factor Xa inhibitors for acute coronary syndromes. Cochrane Database of Systematic Reviews
2011, Issue 1. Art. No.: CD007038. DOI: 10.1002/14651858.CD007038.pub2.
ABSTRACT
Background
The activation of coagulation mechanisms plays a central role in the pathogenesis of acute coronary syndromes (ACS). Administration of
unfractionated heparin (UFH) and low molecular weight heparins (LMWH), agents preventing the progression of thrombus formation,
is a crucial therapeutic strategy. However, some limitations related to their use have recently stimulated the development of new synthetic
agents.
Objectives
To evaluate the clinical efficacy and safety of factor Xa inhibitors for treatment of ACS compared to UFH or LMWH.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) of the Cochrane Library (Issue 1, 2008), PubMed,
EMBASE and LILACS as well as the publications from International Congresses and the reference lists of the selected studies in
December 2008.
Selection criteria
We used randomized controlled trials (RCTs) comparing factor Xa inhibitors to UFH or LMWH during the course of ACS. Outcome
measures included all-cause mortality, myocardial infarction, re-infarction, ischemia recurrence, and adverse events.
Data collection and analysis
The selection, quality assessment and data extraction of the included trials were done independently by two authors and disagreements
were resolved by consensus. Data were analysed by the use of risk ratio (RR) with 95% confidence interval (CI), and the numbers
needed to treat (NNT) were reported as needed.
1
Main results
A total of four RCTs involving 27,976 subjects were included. Fondaparinux was the only factor Xa inhibitor identified in our included
RCTs. Fondaparinux appeared to be related to a lower risk in all-cause mortality at 90 to 180 days (RR 0.89; 95% CI 0.81 to 0.97),
especially in the group where enoxaparin (a LMWH) was the control drug. Fondaparinux was also associated with a lower risk in major
and minor bleeding at 30 days compared to enoxaparin (RR 0.63, 95% CI 0.55 to 0.73; RR 0.34, 95% CI 0.28 to 0.43, respectively),
but not when compared to UFHs (RR 1.41; 95% CI 0.49 to 4.10; RR 0.70, 95% CI 0.14 to 3.39 respectively).
Authors’ conclusions
The therapeutic efficacy of factor Xa inhibitors in ACS seemed to be related to a reduced risk in all-cause mortality at 90 to 180 days,
with a better safety profile than enoxaparin in terms of reduce incidence of major and minor bleeding.
PLAIN LANGUAGE SUMMARY
The use of unfractionated heparin and low molecular weight heparins greatly reduces the risk of mortality and morbidity in acute
coronary syndromes. However, their use has been associated with a risk of adverse events such as major bleeding, which has prompted
researchers to seek safer alternative anticoagulants such as the synthetic inhibitors of the Xa factor - a crucial enzyme in the coagulation
cascade. We systematically reviewed efficacy and safety of factor Xa inhibitors in treating acute coronary syndromes when compared to
unfractionated heparins or low molecular weight heparins. A total of four trials involving 27,976 subjects was included. Xa inhibitors
reduced all-cause mortality at 30 days, with the effect becoming more significant at 180 days. However, no significant differences
were observed in the incidence of myocardial infarction or reinfarction at 30 days. Factor Xa inhibitors were found to be safer than
enoxaparin, a low molecular weight heparin, due to reduced incidences of major and minor bleeding at 30 patients in patients receiving
conservative treatment.
2
3
Factor Xa inhibitors
Control
All causes of mortality at Study population
30 days - Enoxaparin
Follow-up: 30 days
40 per 1000
Medium risk population
30 days - UFH
67 per 1000
Follow-up: 30 days
24 per 1000
39 per 1000
(33 to 47)
66 per 1000
(55 to 79)
22 per 1000
(19 to 24)
38 per 1000
(34 to 42)
Corresponding risk
Assumed risk
Illustrative comparative risks* (95% CI)
30 days
42 per 1000
Follow-up: 30 days
Outcomes
Patient or population: Anticoagulants in ACS
Settings:
Intervention: Factor Xa inhibitors
RR 0.85
(0.73 to 0.98)
RR 0.98
(0.82 to 1.18)
RR 0.9
(0.8 to 1.01)
Relative effect
(95% CI)
Factor Xa inhibitors compared to Anticoagulants in ACS for acute coronary syndromes
21216
(2 studies)
6760
(2 studies)
27976
(4 studies)
No of Participants
(studies)
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
⊕⊕⊕⊕
high
⊕⊕⊕⊕
high
⊕⊕⊕⊕
high
Quality of the evidence
(GRADE)
Comments
4
49 per 1000
Major bleeding at 30 Study population
days - Enoxaparin
49 per 1000
Follow-up: 30 days
47 per 1000
days - UFH
47 per 1000
Follow-up: 30 days
48 per 1000
days
49 per 1000
Follow-up: 30 days
24 per 1000
35 per 1000
50 per 1000
(49 to 50)
50 per 1000
(49 to 50)
46 per 1000
(43 to 49)
46 per 1000
(43 to 49)
48 per 1000
(47 to 50)
49 per 1000
(48 to 51)
20 per 1000
(18 to 24)
30 per 1000
(26 to 34)
RR 1.02
(1.01 to 1.02)
RR 0.98
(0.92 to 1.04)
RR 1.01
(0.98 to 1.04)
20078
(1 study1 )
326
(1 study1 )
20404
(2 studies1 )
⊕⊕⊕⊕
high
⊕⊕⊕⊕
high2
⊕⊕⊕⊕
high
5
11 per 1000
(9 to 14)
11 per 1000
(9 to 14)
62 per 1000
(18 to 208)
62 per 1000
(18 to 208)
24 per 1000
(5 to 115)
22 per 1000
(4 to 108)
RR 0.34
(0.28 to 0.43)
RR 1.76
(0.52 to 5.94)
RR 0.7
(0.14 to 3.39)
20078
(1 study1 )
326
(1 study1 )
20404
(2 studies1 )
⊕⊕⊕⊕
high
⊕⊕⊕
moderate2
⊕⊕⊕⊕
high
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
32 per 1000
Minor bleeding at 30 Study population
days - Enoxaparin
32 per 1000
Follow-up: 30 days
35 per 1000
days - UFH
35 per 1000
Follow-up: 30 days
34 per 1000
days
32 per 1000
Follow-up: 30 days
6
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Even though the control group was on anticoagulant treatment, all of them have had an acute coronary syndrome so the risk was
assumed as medium
2
Although the total number of events is less than 300, the narrow 95% confidence interval of the RR is lower than 25% between study
drug group and control one
1
GRADE Working Group grades of evidence
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.
BACKGROUND
Acute coronary syndromes (ACS) are life-threatening disorders
which remain as a common cause of cardiovascular morbidity
and mortality, accounting for half of all deaths due to cardiovascular diseases and contributing to high economic burden to
global health care systems (ACC/AHA 2009; ACCP 2008; ESC
Guideline 2007). ACS include three clinical entities: unstable
angina, non ST-elevation myocardial infarction (Non-STEMI)
and ST-elevation myocardial infarction (STEMI) (ESC Guideline
2007). The syndromes are the result of vulnerable atherosclerotic
plaques with high risk of fissures or erosion, leaving large areas
of the subendothelial connective tissue of the plaque exposed,
which predisposes to development of a total or partially occlusive thrombus as a consequence of the exposure to the thrombogenic blood stream constituents (ACC/AHA 2007; Davies 2000;
Hamm 2000).
The appropriate management of ACS requires intensive medical therapy often associated to invasive cardiovascular procedures.
Since the patients with the disorder exhibit high levels of markers
produced by thrombin generation, the activation of coagulation
mechanisms seems to play a central role in the pathogenesis of ACS
(ACCP 2008; Bonaca 2009). According to this, the administration of unfractionated heparin (UFH) and low molecular weight
heparins (LMWH) in the treatment of unstable angina and NonSTEMI has the objective of inhibiting thrombin generation and/
or preventing the progression of thrombus formation, via their activity in accelerating the activation of the proteolytic enzyme antithrombin, an inhibitor of anticoagulation factors IIa, Ixa, and Xa
(ACC/AHA 2007; Hamm 2000). In STEMI, heparins are used as
an adjuvant therapy to fibrin-specific thrombolytic agents in order
to avoid paradoxical activation of the blood coagulation cascade
(ACC/AHA 2009; ESC Guidelines 2008; Goodman 2008).
Although UFH and LMWH have shown clinical efficacy and safety, some limitations are associated with their use. The pharmacokinetic profile of UFH is characterized by poor bioavailability
at low doses and short half life via the subcutaneous route, which
determine its intravenous route necessary. Moreover, after treatment discontinuation, the recurrence of clinical events as a consequence of reactivation of the coagulation process has been described (ACCP 2008). On the other hand, enoxaparin, a LMWH,
has a predictable dose-effect relationship so it is effectively administrated subcutaneously without the need to monitor activated
partial thromboplastin time (aPTT or APTT), although its intravenous administration is necessary in urgent situations because its
maximum plasma levels occur three to five hours after subcutaneous administration (ACCP 2008). It must also be noted that
enoxaparin is associated with a lower risk of thrombocytopenia
and osteoporosis than UFH, but with a higher frequency of minor
bleeding as well as some uncertainty about its use in obese subjects and patients with renal insufficiency, particularly if creatinine
clearance is lower than 30 mL/min. Therefore monitoring of its
plasma levels may be useful in these special populations to avoid
inadequate drug concentrations during treatment (Bassand 2008;
Lim 2006; McCaan 2008; Warkentin 2008).
To overcome the limitations of these anticoagulants, development
of new synthetic agents with better efficacy and safety profiles
has been pursued (Bassand 2008; Hirsh 2005). These new agents
target the inhibition of anticoagulation by blocking its initiation
through preventing thrombin generation or inhibiting thrombin
action (ACCP 2008; Barantke 2008). Inhibitors of activated factor X (Xa), such as fondaparinux, exert their antithrombotic activity by selectively binding to the co-factor antithrombin to induce
the neutralization of factor Xa (Blick 2008). Neutralization of factor Xa interrupts the blood coagulation cascade and thus inhibits
thrombin generation and thrombus development (Hirsh 2005).
Xa inhibitors also prevent the interaction of factor Xa with other
substrates by binding directly to its active sites (Barantke 2008;
Comp 2003).
These newer synthetic agents may have numerous potential advantages compared to UFH or LMWH, such as having no requirement to monitor coagulation parameters because there is no binding to plasma proteins, and low drug interactions which allows a
predictable dose-effect ratio and an easier administration regimen
(Crowther 2004; Eikelboom 2010; Hirsh 2007). The most common adverse effect reported with the use of Xa inhibitors has been
major/minor bleeding (major 2.7%, minor 3%) and secondary
local bruising, which in clinical trials have been reported doubled
in patients weighing less than 50 kg (Brown 2007). The absence
of thrombocytopenia with the use of fondaparinux makes it an
attractive alternative (Franchini 2005). Nevertheless, the future
role of these new anticoagulants and their clinical utility and safety profiles in the treatment of ACS is still a matter of current
investigation (Crowther 2004; Eikelboom 2010; Franchini 2005;
Hirsh 2007; Linkins 2005; Warkentin 2008).
In this review we systematically reviewed the evidence and data
available to investigate the impact of Xa inhibitors in the management of unstable angina, Non-STEMI and STEMI.
OBJECTIVES
To evaluate the efficacy and safety of factor Xa inhibitors in the
treatment of ACS.
METHODS
Criteria for considering studies for this review
Types of studies
7
Randomised controlled trials (RCTs) in which factor Xa inhibitors
have been compared with other anticoagulant strategies, where
both the control and study groups have received currently accepted
standards of care for ACS ( ACC/AHA 2008; ACC/AHA 2009;
ESC Guideline 2007; ESC Guidelines 2008). Quasi-experimental
studies and other non-randomised designs were not included.
Types of participants
Adults (≥ 18 years) admitted for ACS, including unstable angina,
STEMI and Non-STEMI.
Types of interventions
Administration of direct and indirect factor Xa inhibitors at any
dose, compared against LMWH or UFH.
Types of outcome measures
Primary outcome
• All-cause mortality at 30 days and 90 - 180 days
• Non fatal acute myocardial infarction or re-infarction at 30
days
• Recurrent angina at 30 days
Secondary outcome
• Stroke
• Heart failure
• Need of revascularization in the following 30 days after
discharge
• Flow grade of the infarct related vessel according to the
Thrombolysis in Myocardial Infarction (TIMI) flow grading
system, assessed during the first week as an angiographic efficacy
endpoint
• Combined endpoint: cardiovascular mortality, non-fatal
acute myocardial infarction, recurrent angina
• Length of hospitalisation
• Readmission to hospital
• Quality of life
Primary adverse effects endpoints
• Major bleeding
• Thrombocytopenia development, taking into account
immune as well as non-immune mediated forms, defined as a
drop of the platelet count to below of 100x109 /L or more than
50% from the patient’s baseline platelet count which resolved
after cessation of heparin (Franchini 2005).
Secondary adverse effects endpoints
• Drop-out due to adverse effects
• Minor bleeding
• Other adverse events: such as allergic reactions, or
withdrawal from intervention
Accepted definitions:
Myocardial Infarction (AMI): Elevation of cardiac enzyme creatine
kinase isoenzyme MB (CK-MB) ≥ two higher than the normal
superior limit (NSL), ≥ three after a percutaneous coronary procedure, ≥ five after a coronary artery bypass graft, or complete left
brunch block or new Q waves on electrocardiogram with twofold
or greater elevation of cardiac enzymes compared to the NSL.
Myocardial re-Infarction in patients admitted with a STEMI: recurrent chest pain associated to new ST-segment elevation or elevation of creatine kinase or creatinine kinase-MB levels to up to
50%.
Recurrent Ischemia: ST-segment depression of 1 mm at least one
minute during the continuous electrocardiographic of 12 hours
monitoring (asymptomatic), chest pain combined to ST-segment
depression of at least 1mm, or elevation of this segment (symptomatic episodes), or new admission at the hospital due to unstable angina.
Urgent Revascularization: recurrence of Ischaemic symptoms
evolving to a percutaneous coronary artery intervention or coronary artery bypass graft.
Major Bleeding: evident bleeding associated with death, risk of
death, surgery or need of a new surgical intervention to control the
bleeding; retroperitoneal, intracerebral or in other critical organ;
an haemoglobin fall ≥1.2 mmol/L (2 g/L), or requiring blood
transfusion with ≥2 units of entire blood or red globular packs,
using a modified TIMI or major bleeding definition criteria (
Cannon 2001; Yusuf 2006 OASIS 5; Yusuf 2006 OASIS 6).
Minor Bleeding: any bleeding other than major bleeding, minor
bleedings on venipuncture area were not considered.
†TIMI bleeding definition criteria:
1. Major: Overt clinical bleeding (or documented intracranial or
retroperitoneal haemorrhage) associated with a drop in haemoglobin of greater than 5 g/dL (50 g/L) or in hematocrit of greater
than 15% (absolute)
Note: A patient who experiences an intracranial haemorrhage
should be considered to have a major haemorrhage.
2. Minor: Overt clinical bleeding associated with a fall in haemoglobin of 3 to 5 g/dl (50 g/l) or in hematocrit of 9% to
15% (absolute)
3. None: No bleeding event that meets the major or minor definition
Note: In calculating the fall in haemoglobin or hematocrit, a transfusion of whole blood or packed red blood cells is counted as 1
g/dL (10 g/L) haemoglobin or 3% absolute in hematocrit. This
would be in addition to the actual fall in haemoglobin or hemat-
8
ocrit.
Stroke: new neurological deficit lasting more than 24 hours.
TIMI Flow Grading System: flow in the culprit artery is defined
as follows (Cannon 2001):
1. Grade 0 (no perfusion): There is no antegrade flow beyond the
point of occlusion
2. Grade 1 (penetration without perfusion): The contrast material
passes beyond the area of obstruction but “hangs up” and fails to
opacify the entire coronary bed distal to the obstruction for the
duration of the cineangiographic filming sequence
3. Grade 2 (partial perfusion): The contrast material passes across
the obstruction and opacifies the coronary bed distal to the obstruction. However, the rate of entry of contrast material into the
vessel distal to the obstruction or its rate of clearance from the
distal bed (or both) is perceptibly slower than its entry into or
clearance from comparable areas not perfused by the previously
occluded vessel (e.g., the opposite coronary artery or the coronary
bed proximal to the obstruction)
4. Grade 3 (complete perfusion): Antegrade flow into the bed
distal to the obstruction occurs as promptly as antegrade flow into
the bed from the involved bed and is as rapid as clearance from an
uninvolved bed in the same vessel or the opposite artery.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL) on The Cochrane Library (Issue 1, 2008), PubMed
(January 1980 to December 2008), EMBASE (January 1980 to
December 2008) and LILACS (January 2000 to December 2008).
No language restrictions were applied.
The search strategies are detailed in Appendix 1.
Citations retrieved by the searches and full-text papers retrieved
were examined by two authors independently (AC, VB). The lists
of those chosen were compared and disagreements resolved by
consensus.
Data extraction and management
Data from the included studies were extracted by two authors (AC,
VB) independently using a pre-prepared data extraction form. The
form was piloted on three trial reports to ensure that it was suitable
for use. Dsagreements were resolved by consensus. Trialists were
contacted for further information and clarification if data were
missing.
The following information was recorded:
1. Trial design, including method of generation and
concealment of allocation sequences, and type of control
intervention; report of excluded and loss to follow-up cases;
publication type and source, including language of publication,
year of publication, method of retrieval of the report; sources of
support; setting, including country and level of care and analysis,
including whether analysis was done according to the intentionto-treat principle, statistical test and P-values for comparisons
within and between groups.
2. Intervention, including dose, route of administration, and
duration of treatment, modalities and schedule of assessments of
outcome measures.
3. Demographic and clinical variables of the patients such as:
age, sex, history of diabetes, arterial hypertension, smoking,
hyperlipemias, coronary artery disease, heart failure, and the
selection criteria used.
4. Variables related to the outcomes of interest: global and
cardiac mortality, new non-fatal myocardial infarction or
reinfarction, refractory angina, urgent or elective
revascularization needed, quality of life, major or minor bleeding,
development of thrombocytopenia, and other adverse events.
Searching other resources
We handsearched material from the International Congresses of
the European Society of Cardiology, American Heart Association
and American College of Cardiology (2002 to December 2008).
Authors as well as pharmaceutical companies producing relevant
drugs were contacted by electronic and/or postal mail for unpublished data or any missing data where necessary. The reference lists
of included studies have also been considered as a source of relevant information. Published or unpublished studies were considered for inclusion in the review.
Data collection and analysis
Selection of studies
Assessment of risk of bias in included studies
Two authors (AC, VB) independently assessed the risk of bias
in included studies using the Cochrane Collaboration’s tool for
assessing risk of bias (Higgins 2009). Disagreements were resolved
by discussion. The following criteria were considered:
Selection bias (randomization method and allocation concealment);
Performance bias (blinded of patients and people administering
the treatment);
Attrition bias (lost to follow-up);
Detection bias (blinding of outcome assessors).
The risk of bias in each study was graded as follows (Table 1):
A - all quality criteria met (low risk of bias);
B - one or more criteria partly met (moderate risk of bias); and
C - one or more criteria not met (high risk of bias).
9
Measures of treatment effect
RESULTS
For normally distributed outcomes, summary estimates of the
treatment effect were calculated using the inverse variance method.
Dichotomous data were analysed by the use of risk ratio (RR)
with confidence interval (CI) of 95%, while continuous data were
analysed by weighted or standardised mean difference according
to the available data. Numbers needed to treat for an additional
beneficial outcome (NNTB) as well as numbers needed to treat
for an additional harmful outcome (NNTH) were estimated. All
of the analyses was based on the intention-to-treat data from individual clinical trials. Heterogeneity was classified on statistical
and clinical grounds, by two independent reviewers (AC, VB).
Description of studies
Subgroup analysis and investigation of heterogeneity
The following subgroup analyses were performed where possible:
• By different drugs;
• By doses of the drugs; doses < 5 mg were considered as low
and ≥ 5 mg as high;
• Patients aged 75 years or older compared to younger
patients;
• Patients referred to in-hospital percutaneous coronary
intervention (PCI);
• Patients on treatment with Xa inhibitors receiving drugs
other than heparins, which could also affect the platelet
aggregation or interfere with the coagulation cascade, potentially
increasing the risk of adverse events.
Statistical heterogeneity was examined using the I² statistic (a
threshold of 50% was used to define significant heterogeneity)
and the Chi² statistic (with significance being set at P < 0.10).
If there was no statistical or clinical heterogeneity, a fixed-effect
model was reported. Otherwise a random-effects model was applied. Both clinical and methodological sources of heterogeneity
were explored.
Sensitivity analysis
Sensitivity analyses were performed to explore the impact of
methodological quality on treatment effects.
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of studies awaiting classification.
Our search strategy yielded 171 titles after de-duplication. Two
additional records were retrieved through handsearching and from
the reference lists of pre-selected studies, thus a total of 173
records was screened. After reviewing the titles and abstracts, 15
full-text papers were retrieved. Articles in which the outcomes
considered were unrelated to our analyses (Mehta 2007; Cohen
2007; Vuillemenot 1999) or the interventions involved investigative agents (Alexander 2005) were excluded. Further information on these four excluded studies are available in the section
Characteristics of excluded studies.
A total of four RCTs in 11 papers was included in our review. These
four included studies are multi-centre RCTs involving 27,976 subjects in different countries conducted in America and in Europe
(Characteristics of included studies). Fondaparinux, an indirect
factor Xa inhibitor, was the agent used in all four trials and it was
compared against UFH or enoxaparin as controls. The range of
age of the participants was 48 to 68 years old. The male gender was
represented by nearly 80%, and co-morbidities such as diabetes,
arterial hypertension, heart failure or history of previous coronary
events were present in a proportion usual for the population taking
part of this kind of trials.
Two studies have been identified outside of our search period (
Oasis 8; Sabatine 2009). Conscious of their importance and of
timing to publish this review, we decided to group these studies
as studies awaiting classification. The corresponding data will be
extracted and analysed in our next update. Details on these two
studies are given in the section Characteristics of studies awaiting
classification.
The study selection process in the form of a PRISMA flow chart
is shown in Figure 1.
10
Figure 1. Flow chart of selection studies
Risk of bias in included studies
Allocation
An appropriated method of randomization and allocation concealment through a central telephonic or computerized voice system was reported in three of the four trials evaluated. In one trial
(Yusuf 2006 OASIS 6) the mechanism of randomization was not
described in detail (Figure 2; Figure 3; Summary of findings for the
main comparison). According to this, additional information has
been requested from the authors about the mechanisms involved
in these processes, which we hope to be available for updates of
this review.
11
Figure 2. Methodological quality graph: review authors’ judgements about each methodological quality
item presented as percentages across all included studies.
12
Figure 3. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.
Blinding
Four studies were double blind and one was not blinded (
Coussement 2001).
Incomplete outcome data
One of the studies had only 82% of the information completed
during follow-up (Simoons 2004), but the rest of the trials contained information from as much as 99.9% of the recruited par-
ticipants.
Other potential sources of bias
The funnel plots showed asymmetry in all-cause mortality, AMI/
re-AMI, and major/minor bleeding at 30 days. This reflects fundamental methodological heterogeneity such as different clinical
conditions and treatment strategies used, but we did not think the
assymetry was attributed to publication bias (Figure 4; Figure 5;
Figure 6; Figure 7; Figure 8).
13
Figure 4. Funnel plot of comparison: 1 xa factor inhibitors vs Anticoagulants in ACS, outcome: 1.1 All
causes of mortality at 30 days.
14
Figure 5. Funnel plot of comparison: 1 xa factor inhibitors vs Anticoagulants in ACS, outcome: 1.2 All
causes of mortality at 90 to 180 days.
15
Figure 6. Funnel plot of comparison: 1 Xa factor inhibitors vs Anticoagulants in ACS, outcome: 1.4 AMI or
Re- AMI at 30 days.
16
Figure 7. Funnel plot of comparison: 1 xa factor inhibitors vs Anticoagulants in ACS, outcome: 1.7 Major
bleeding at 30 days.
17
Figure 8. Funnel plot of comparison: 1 xa factor inhibitors vs Anticoagulants in ACS, outcome: 1.8 Minor
bleeding at 30 days.
All the included studies were either funded by for-profit organizations or the authors received research support or consultant fees
from the pharmaceutical companies that are associated with the
study drug. However, the studies were conducted and the data
analysed in an independent fashion by steering or safety committees and/or the research institutes in charge. There was no clear
rationale to suggest biased reporting based on this link between
the authors and the companies which funded the research.
Effects of interventions
See: Summary of findings for the main comparison Factor Xa
inhibitors compared to Anticoagulants in ACS for acute coronary
syndromes
Outcomes evaluating clinical efficacy and safety of fondaparinux
were assessed as below. We also analysed the clinical effectiveness
and safety of fondaparinux at low dose. Sensitivity analyses exploring the effect measures related to fondaparinux were performed
where appropriate. Summary of our findings are given in Summary
of findings for the main comparison.
Primary clinical outcomes
All-cause mortality at 30 and 90 to 180 days
All four trials (two trials comparing against enoxaparin involving
6,760 patients; two comparing against UFH involving 21,216)
reported all-cause mortality as an outcome measure (Coussement
2001; Simoons 2004; Yusuf 2006 OASIS 5; Yusuf 2006 OASIS 6).
A lower mortality rate was observed with the use of fondaparinux
(RR 0.90, 95% CI 0.80 to 1.01, P = 0.07; Analysis 1.1), possibly
attributed to the large sample size and weight of the enoxaparin
subgroup (RR 0.85, 95% CI 0.73 to 0.98, P = 0.03; Analysis 1.1).
However, a reduction of all-cause mortality at 90 to180 days from
two trials involving 26,512 subjects was more evident (RR 0.89,
95% CI 0.81 to 0.97; Analysis 1.2), with a NNTB of 126 (95%
CI 75 to 506), possibly due to the large sample size and weight of
Yusuf 2006 OASIS 5 (RR 0.90, 95% CI 0.80 to 1.00, P = 0.05).
Non-fatal AMI or re-infarction at 9 and 30 days
Only one trial reported the incidences of AMI or re-infarction at
nine days (Yusuf 2006 OASIS 6). Fondaparinux showed a beneficial effect compared to UFH (RR 0.69, 95% CI 0.47 to 1.01,
P = 0.06; Analysis 1.3). However, no significant difference was
18
seen between fondaparinux and enoxaparin (two trials for 21,216
subjects; Simoons 2004; Yusuf 2006 OASIS 5).
Data on non-fatal AMI and re-infarction at 30 days were available from three studies reporting a total of 26,638 patients
(Coussement 2001; Yusuf 2006 OASIS 5; Yusuf 2006 OASIS 6).
Fondaparinux were not superior to UFH or enoxaparin in reducing the risk of non-fatal AMI or re-infarction at 30 days (RR 0.92,
95% CI 0.81 to 1.04, P = 0.20; Analysis 1.4).
Secondary clinical outcomes
Combined endpoint of all-cause mortality, non-fatal AMI or
re-infarction at nine days
A total of three trials (27,650 participants) reported combined
endpoint of all-cause mortality, non-fatal AMI or re-infarction
at nine days (Simoons 2004; Yusuf 2006 OASIS 5; Yusuf 2006
OASIS 6). However, they showed no statistically significant difference between fondaparinux and anticoagulants groups (RR 0.97,
95% CI 0.87 to 1.08, P = 0.60; Analysis 1.5).
95% CI 0.28 to 0.43, P = 0.00001; Analysis 1.8), with a risk
difference of 2% and a NNTB of 50 (95% CI 48 to 59).
Efficacy and safety of low dose fondaparinux
All-cause mortality at 30 days
Separate analysis was conducted to study the effect of low dose
fondaparinux on all-cause mortality at 30 days. Data from four
studies (n=27,357) showed no statistically significant difference
between treatment groups (RR 0.92, 95% CI 0.75 to 1.12, P=
0.40; Analysis 2.1).
Non-fatal AMI or re-infarction at 30 days
Simiarly, we analysed the effect of low dose fondaparinux on the
risk of non-fatal AMI or re-infarction at 30 days (n=26,678). No
statistically significant difference was found between the fondaparinux and the anticoagulants groups (RR 0.90, 95% CI 0.65 to
1.23, P = 0.10; Analysis 2.2).
Adverse effects
Major bleeding at nine days
Major bleeding at 9 and 30 days
Major bleeding at 9 days was reported in three trials of 27,650
participants (Simoons 2004; Yusuf 2006 OASIS 5; Yusuf 2006
OASIS 6). Substantial heterogeneity was observed and the random
effects model was applied. There was no signifIcant difference on
the risk of major bleeding at nine days between the fondaparinux
and the anticoagulants groups (RR 0.74, 95% CI 0.42 to 1.31, P
= 0.30; Analysis 1.6).
Two trials studied the risk of major bleeding at 30 days (
Coussement 2001; Yusuf 2006 OASIS 5). There was no statistically significant difference on the risk of major bleeding at 30 days
between fondaparinux and UFH (RR 1.41, 95% CI 0.49 to 4.10,
P = 0.53; Analysis 1.7). However, fondaparinux was associated
with a 37% reduction in the risk of major bleeding at 30 days
when compared to enoxaparin (RR 0.63, 95% CI 0.55 to 0.73, P
= 0.0001; Analysis 1.7), with a risk reduction of 2% (95% CI 1%
to 2%) and a NNTB of 50 (95% CI 50 to 100).
All four trials reported the effect of low dose fondaparinux on major bleeding at nine days (Coussement 2001; Simoons 2004; Yusuf
2006 OASIS 5; Yusuf 2006 OASIS 6). Our meta-analysis showed
no statistically significant difference between fondaparinux and
anticoagulants (RR 0.75, 95% CI 0.45 to 1.26, P = 0.28; Analysis
2.3).
Efficacy and safety of fondaparinux in PCI
Yusuf 2006 OASIS 5 and Yusuf 2006 OASIS 6 (n=9,945) reported
the all-cause mortality rate at 30 days associated with the use of
fondaparinux in PCI. Our meta-analysis showed no significant
reduction of mortality by fondaparinux (RR 1.05, 95% CI 0.83
to 1.32, P = 0.68; Analysis 3.1).
Minor bleeding at 30 days
Coussement 2001 and Yusuf 2006 OASIS 5 reported the risk
of minor bleeding at 30 days, comparing fondaparinux against
UFH and enoxaparin, respectively. Meta-analysis of the two trials
showed no significant effect with fondaparinux (RR 0.70, 95% CI
0.14 to 3.39, P = 0.65; Analysis 1.8). However, Yusuf 2006 OASIS
5 (20,078 participants) reported a significant low risk of minor
bleeding with fondaparinux compared with enoxaparin (RR 0.34,
Non-fatal AMI and re-infarction at 30 days
Yusuf 2006 OASIS 5 and Yusuf 2006 OASIS 6 (n=9,945) also
compared the effect of fondaparinux compared to UFH and
enoxaparin on infarction and re-infarction at 30 days. No statistically significant difference was observed between the treatment
groups (RR 1.08, 95% CI 0.89 to 1.30, P = 0.42; Analysis 3.2).
19
Meta-analysis of data on major bleeding at nine days from Yusuf
2006 OASIS 5 and Yusuf 2006 OASIS 6 (n=9,945) showed no
difference on risk of bleeding with the administration of fondaparinux compared against UFH and enoxaparin (RR 0.76, 95%
CI 0.28 to 2.05, P = 0.59; Analysis 3.3). However, fondaparinux
was associated with a lower risk of bleeding when compared against
enoxaparin in Yusuf 2006 OASIS 5 (RR 0.47, 95% CI 0.35 to
0.61, P < 0.00001).
Since arterial thrombosis has a principal role in ACS, antithrombotic therapy is pivotal to avoid total or partial vessel occlusion by
the developing thrombus (Maan 2009). UFH has been the main
antithrombotic agent to reduce the occurrence of major ischemic
events in ACS for nearly 60 years, but its usage requires careful
monitoring and adverse effects include thrombocytopenia and osteoporosis (ACCP 2008). This prompted the development of new
antithrombotic agents such as LMWH and factor Xa inhibitors
(ACCP 2008; Eikelboom 2010; Harm 2007; Hirsh 2007).
Catheter thrombosis
Summary of main results
We also analysed the difference in catheter thrombosis associated
with fondaparinux and anticoagulants in PCI. Catheter thrombosis was more common in the fondaparinux group in both Yusuf
2006 OASIS 5 (n=6,238) and Yusuf 2006 OASIS 6 (n=3,768) although the overall effect was not statistically significant (RR 9.42,
95% CI 0.64 to 139.63, P = 0.10; Analysis 3.4).
A number of studies evaluating the role of factor Xa inhibitors in
ACS has not been included in our review because their methodological characteristics were not suitable (Alexander 2005; Cohen
2007) or because trial data are yet to be published (e.g. Sabatine
2009). Therefore, our review is not a complete representation of
all the available evidence on the clinical efficacy and safety profiles
of factor Xa inhibitors.
Fondaparinux, an indirect factor Xa inhibitor, when administrated
in the beginning of ACS development (six to eight days) showed an
effect in reducing all-cause mortality at 30 days compared against
enoxaparin, but we concluded that there was possibly no significant impact on the clinical outcome. However, a long-term reduction of mortality at 90 to 180 days was apparent, especially
when compared to enoxaparin, resulting in an NNTB of at least
126. Fondaparinux did not reduce the risk of non-fatal AMI or
re-infarction at 9 and 30 days, neither did it reduce the incidence
of combined endpoint of all-cause mortality and non-fatal AMI at
nine days. Use of low dose fondaparinux showed equivalent effect
in reducing the risk of all-cause mortality, non-fatal AMI or reinfarction at 9 days to UHF or enoxaparin.
For participants undergoing PCI, fondaparinux demonstrated
similar clinical efficacy on the risk of all-cause mortality, non-fatal
AMI or re-infarction at 30 days to UFH or enoxaparin. On the
other hand, an increased risk of catheter thrombosis was clearly
associated with the use of fondaparinux.
Our results indicate that the factor Xa inhibitor fondaparinux
might be a safe alternative to enoxaparin in terms of the risk of
minor and major bleeding at 30 days, but this was not evident
when compared to UFH. This could be useful amidst concerns
associated with an increased risk of bleeding related to their use
(Brown 2007).
Sensivity Analyses
Sensivity analyses were conducted to evaluate the impact of heterogeneity by excluding studies with methodological discordance
against the majority of the studies taking part in the evaluation. A
few interesting findings:
When studies with high levels of heterogeneity were excluded (
Coussement 2001; Simoons 2004), the effect of fondaparinux on
all-cause mortality at 30 days became statistically significant (RR
0.89; 95% CI 0.79 to 1.00; P = 0.05; Analysis 4.1). The effect
was more apparently in Yusuf 2006 OASIS 5 where enoxaparin
was used as the control drug (RR 0.84; 95% CI 0.72 to 0.97; P =
0.02; Analysis 4.1).
Simiarly, we excluded Coussement 2001 and Simoons 2004 which
are studies with high heterogeneity from the analyses. The remaining studies Yusuf 2006 OASIS 5 and Yusuf 2006 OASIS 6, both of
which used low doses of fondaparinux, did not show a significant
benefit reducing the adverse event at nine days (RR 0.69, 95% CI
0.39 to 1.21, P = 0.19; Analysis 4.2). Lower risk of major bleeding
was shown to be associated with the use of fondaparinux in Yusuf
2006 OASIS 5 where enoxaparin was the control drug (RR 0.53;
95% CI 0.45 to 0.62; P < 0.00001; Analysis 4.2).
DISCUSSION
Overall completeness and applicability of
evidence
In addition to their clinical effectiveness and safety profile, the
newer antithrombotic agents need to be more economically attractive than UFH (Nutescu 2006). Health economic analyses on
fondaparinux have been limited to secondary cost-effectiveness
20
analyses, based on data from published RCT as well as analytical
models such as decision trees or Monte Carlo modelling; fondaparinux appeared to be cost-effective in participants with nonSTEMI when compared against enoxaparin (Latour-Perez 2009;
Maxwell 2009; Yusuf 2006 OASIS 5).
Quality of the evidence
The limitations related to the assignment of the participants to
one of the two control groups in Yusuf 2006 OASIS 6 and the
lack of blinding of participants in Coussement 2001 could be potential sources of bias. The external validity in Yusuf 2006 OASIS
6 could be affected because the stratification of the control group
to receive UFH or placebo was achieved based on the investigator’s judgment other than randomization. In Coussement 2001,
absence of blinding led to an adjusted dose-finding study. Nevertheless, in both cases, the confidence in the resulting outcomes of
interest seemed not to be affected by these shortcomings in our
analyses.
The presence of heterogeneity in some of the outcome analyses
could be explained by the diverse methodological designs of the
studies, including varied agents used in the treatment and control
groups, as well as different co-morbidities in the included participants.
All the studies were sponsored by pharmaceutical companies associated with the study drug, or the authors received research support or consultant fees from the pharmaceutical companies related
to it. There was no rational evidence to suggest the results published could be seriously affected. Nonetheless, the data presented
should be interpreted with caution.
Potential biases in the review process
A broad and systematic literature search for potentially relevant
studies was performed. This was followed by careful selection of
eligible studies based on set inclusion/exclusion criteria. We evaluated the risk of publication bias using funnel plots. However, interpretation of these should be done cautiously because the number
of studies included in relation to our selection criteria was limited.
Therefore, although there was asymmetry in our funnel plots, it
was possibly due to methodological heterogeneity and not due to
publication bias.
UFH and enoxaparin in reducing the risk of death, AMI, re-infarction, or recurrence of ischemia at 30 days. However, substantial
reduction was seen in mortality rates at 180 days as well as in major
and minor bleeding when factor Xa inhibitors were compared to
enoxaparin. This reduced association of factor Xa inhibitors with
adverse bleeding was thought to be caused by two potential factors: a lack of thrombin interference, or the relatively low dose that
were deemed effective compared to standard enoxaparin dosage
(ACC/AHA 2007; Bonaca 2009; Karthikeyan 2009).
Published reviews on the role of factor Xa inhibitors in ACS all
commented on their use in patients undergoing PCI as well as
cost effectiveness (ACCP 2008; Barantke 2008; Bonaca 2009;
Karthikeyan 2009). The increased risk of catheter thrombosis associated with factor Xa inhibitors in the patients undergoing PCI
could be explained by the unavoidable contact-pathway activation
triggered by contact of the blood to catheters during PCI. This
finding is in agreement with ours. UFH was useful in inhibiting contact coagulation through factors XIa and XIIa inhibition
(Bonaca 2009; Karthikeyan 2009). Consequently, it was recommended that fondaparinux should be administered in adjunction
to UFH for patients undergoing invasive treatments such as PCI
(ACC/AHA 2007; ACC/AHA 2008; ESC Guideline 2007; ESC
Guidelines 2008). Nevertheless, more substantial data from wellplanned trials in appropriate settings are needed.
AUTHORS’ CONCLUSIONS
Implications for practice
The findings of this systematic review suggest that administration
of fondaparinux appeared to be at least as effective as UFH and
enoxaparin in ACS, with the added benefit of a reduced risk of
long-term mortality at six months and reduced rates of adverse
effects (major and minor bleeding). However, we need to emphasize that more evidence, specifically about their clinical and
safety profile in populations with a higher risk of thrombotic or
bleeding complications (e.g. those receiving concomitant treatment with drugs affecting the coagulation process, those undergoing revascularization and the elderly), are required (Alexander
2007a; Alexander 2007b; Maan 2009).
Implications for research
Agreements and disagreements with other
studies or reviews
Numerous overviews have recently focused on the potential role
of factor Xa inhibitors in ACS by reviewing studies that have investigated the clinical effectiveness and safety of these new agents
(Barantke 2008; Bonaca 2009). Similar to our findings, these
overviews concluded that factor Xa inhibitors were not inferior to
New clinical trials, some of them on development, evaluating the
following items should be considered:
• The efficacy and safety of the use of the factor Xa inhibitors
associated with glycoprotein (GP) IIa/IIIb inhibitors, in order to
explore their safety profile when they are combined with drugs
which could also affect platelet aggregation and so interfere with
the coagulation process
21
• Fatal and non-fatal outcomes related to the use of factor Xa
inhibitors in patients undergoing to revascularization therapy,
especially PCI, and in subgroups with increased risk of bleeding
such as the elderly
• Head-to-head studies on the efficacy and safety of the
different types of factor Xa inhibitors (direct and indirect), in
order to investigate potential relationship between their clinical
efficacy and safety profiles and drug types.
We would like to thank the following persons for their great help
with preparing this review:
Mr Daniel Comandé, reference librarian of the Coordinating Centre of the Ibero-American Cochrane Network in the Argentine
Institute for Clinical Effectiveness and Health Policy.
Ms Margaret Burke and Ms Nicole Ackermann from the Cochrane
Heart Group, for their help with preparing the protocol.
Ms Janet Wale from the Cochrane Consumer Network, for her
contribution in the plain language summary elaboration.
Professor Dr Lerman Jorge for his initial contributions to this
meta-analyses.
ACKNOWLEDGEMENTS
REFERENCES
References to studies included in this review
Coussement 2001 {published data only}
Coussement PK, Bassand JP, Convens C. A synthetic
factor-xa inhibitor (ORG31540/SR9017A) as an adjunct
to fibrinolysis in acute myocardial infarction: the Pentalyse
study. European Heart Journal 2001;22(18):1716–24.
Simoons 2004 {published data only}
Simoons ML, Bobbink IW, Boland J, Gardien M, Klootwijk
P, Lensing AW, et al.A dose-finding study of fondaparinux
in patients with non-ST-segment elevation acute coronary
syndromes: the Pentasaccharide in Unstable Angina
(PENTUA) Study. Journal of the American College of
Cardiology 2004;43(12):2183–90.
Yusuf 2006 OASIS 5 {published data only}
Fox KA, Bassand JP, Mehta SR. Influence of renal function
on the efficacy and safety of fondaparinux relative to
enoxaparin in non ST-segment elevation acute coronary
syndromes. Annals of Internal Medicine 2007;147(5):
304–10.
Genth-Zotz S, Rupprecht HJ, Mehta SR. Abstract Nª
V1744: Early benefit of fondaparinux in patients with
non-ST elevation acute coronary syndromes: a secondary
analysis of the OASIS 5 trial. Clinical Research in Cardiology
2007;96:Suppl 1.
Mehta SR, Granger CB, Eikelboom JW. Efficacy and safety
of fondaparinux versus enoxaparin in patients with acute
coronary syndromes undergoing percutaneous coronary
intervention: results from the OASIS-5 trial. Journal of the
American College of Cardiology 2007;50(18):1742–51.
Mehta SR, Yusuf S, Granger CB. Design and rationale of
the MICHELANGELO Organization to Assess Strategies
in Acute Ischemic Syndromes (OASIS)-5 trial program
evaluating fondaparinux, a synthetic factor xa inhibitor, in
patients with non-ST-segment elevation acute coronary
syndromes. American Heart Journal 2005;150(6):1107.
Sculpher MJ, Lozano-Ortega G, Sambrook J, et
al.Fondaparinux versus Enoxaparin in non ST-elevation
acute coronary syndromes: Short-term cost and long-term
cost-effectiveness using data from the Fifth Organization to
Assess Strategies in Acute Ischemic Syndromes Investigators
(OASIS-5) trial. American Heart Journal 2009;157(5):
845–52.
∗
Yusuf S, Mehta SR, Chrolavicius S. Comparison of
fondaparinux and enoxaparin in acute coronary syndromes.
New England Journal of Medicine 2006;354(14):1464–76.
Yusuf 2006 OASIS 6 {published data only}
Oldgren J, Wallentin L, Afzal R. Effects of fondaparinux
in patients with ST-segment elevation acute myocardial
infarction not receiving reperfusion treatment. European
Heart Journal 2008;29(3):315–23.
Peters RJ, Joyner C, Bassand JP. The role of fondaparinux
as an adjunct to thrombolytic therapy in acute myocardial
infarction: a subgroup analysis of the OASIS-6 trial.
European Heart Journal 2008;29(3):324–31.
∗
Yusuf S, Mehta SR, Chrolavicius S. Effects of fondaparinux
on mortality and reinfarction in patients with acute STsegment elevation myocardial infarction: the OASIS-6
randomized trial. JAMA 2006;295(13):1519–30.
References to studies excluded from this review
Alexander 2005 {published data only}
Alexander JH, Yang H, Becker RC. First experience with
direct, selective factor xa inhibition in patients with
non-ST-elevation acute coronary syndromes: Results of
the XANADU-ACS Trial. Journal of Thrombosis and
Haemostasis 2005;3(3):439–47.
Cohen 2007 {published data only}
Cohen M, Bhatt DL, Alexander JH. Randomized, doubleblind, dose-ranging study of otamixaban, a novel, parenteral,
short-acting direct factor xa inhibitor, in percutaneous
coronary intervention: the SEPIA-PCI trial. Circulation
2007;115(20):2642–51.
Mehta 2007 {published data only}
Mehta SR, Steg PG, Granger CB. Randomized, blinded trial
comparing fondaparinux with unfractionated heparin in
22
patients undergoing contemporary percutaneous coronary
intervention: Arixtra Study in Percutaneous Coronary
Intervention: a Randomized Evaluation (ASPIRE) Pilot
Trial. Circulation 2007;111(11):1390–7.
Vuillemenot 1999 {published data only}
Vuillemenot A, Schiele F, Meneveau N. Efficacy of a
synthetic pentasaccharide, a pure factor Xa inhibitor, as
an antithrombotic agent--a pilot study in the setting of
coronary angioplasty. Thrombosis and Haemostasis 1999;81
(2):214–20.
References to studies awaiting assessment
Oasis 8 {published data only}
NCT00790907. Fondaparinux Trial With UFH During
Revascularization in Acute Coronary Syndromes
(FUTURA/OASIS 8). http://clinicaltrials.gov/ct2/show/
NCT00790907 (accessed 18 March 2010).
Sabatine 2009 {published data only}
Sabatine MS, Antman EM, Widimsky P, Ebrahim IO, Kiss
RG, Saaiman A, et al.Otamixaban for the treatment of
patients with non-ST-elevation acute coronary syndromes
(SEPIA-ACS1 TIMI 42): a randomised, double-blind,
active-controlled, phase 2 trial. Lancet 2009;374(9692):
787–95. [: NCT00317395]
Additional references
ACC/AHA 2007
Anderson JL, Adams CD, Antman EM, Bridges CR, Califf
RM, Casey DE Jr, et al.ACC/AHA 2007 Guidelines for
the management of patients with unstable angina/non-STelevation myocardial infarction. Journal of the American
College of Cardiology 2007;50(7).
ACC/AHA 2008
Antman EM, Hand M, Armstrong PW, Bates ER, Green
LA, Halasyamani LK, et al.2007 Focused Update of
the ACC/AHA 2004 Guidelines for the Management
of Patients With ST-Elevation Myocardial Infarction.
Circulation 2008;117(2):296–329.
ACC/AHA 2009
Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson
JL, Antman EM, et al.2009 Focused Updates: ACC/
AHA Guidelines for the Management of Patients With
ST-Elevation Myocardial Infarction (updating the 2004
Guideline and 2007 Focused Update) and ACC/AHA/
SCAI Guidelines on Percutaneous Coronary Intervention
(updating the 2005 Guideline and 2007 Focused Update).
Circulation 2009;122(22):2271–306.
in the elderly, part I: Non-ST-segment-elevation acute
coronary syndromes: a scientific statement for healthcare
professionals from the American Heart Association Council
on Clinical Cardiology: in collaboration with the Society of
Geriatric Cardiology. Circulation 2007;115(19):2549–69.
Alexander 2007b
Alexander KP, Newby LK, Armstrong PW, Cannon CP,
Gibler WB, Rich MW, et al.Acute coronary care in the
elderly, part II: ST-segment-elevation myocardial infarction:
a scientific statement for healthcare professionals from
the American Heart Association Council on Clinical
Cardiology: in collaboration with the Society of Geriatric
Cardiology. Circulation 2007;115(19):2570–89.
Barantke 2008
Barantke M, Bonnemeier H. Factor Xa inactivation in acute
coronary syndrome. Current Pharmaceutical Design 2008;
14:1186–90.
Bassand 2008
Bassand JP. The place of fondaparinux in the ESC and
ACC/AHA guidelines for anticoagulation in patients with
non-ST elevation acute coronary syndromes. European
Heart Journal Supplements 2008;Suppl 10:C22–9.
Blick 2008
Blick SA, Orman JS, Wagstaff A. Fondaparinux Sodium.
American Journal of Cardiovascular Drugs 2008;8(2):
113–25.
Bonaca 2009
Bonaca MP, Steg PG, Feldman LJ, Canales JF, Ferguson
JJ, Wallentin L, et al.Antithrombotics in acute coronary
syndromes. Journal of the American College of Cardiology
2009;54(11):969–84.
Brown 2007
Brown CH. A new era of anticoagulation. Factor xa and
direct thrombin inhibitors. US Pharmacist 2007;32(3):
35–48.
Cannon 2001
Cannon CP, Battler A, Brindis RG, Cox JL, Ellis SG, Every
NR, et al.American College of Cardiology key data elements
and definitions for measuring the clinical management and
outcomes of patients with acute coronary syndromes. A
report of the American College of Cardiology Task Force
on Clinical Data Standards (Acute Coronary Syndromes
Writing Committee). Journal of the American College of
Cardiology 2001;38(7):2114–30.
Comp 2003
Comp PC. Selective factor xa inhibition improves efficacy
of venous thromboembolism prophylaxis in orthopedic
surgery. Pharmacotherapy 2003;23(6):772–87.
ACCP 2008
Hirsh J, Guyatt G, Albers GW, Harrington R, Schünemann
HJ. Executive Summary: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines (8th
Edition). Chest 2008;133(6):71S-105S. [DOI: 10.1378/
chest.08-0693]
Crowther 2004
Crowther M, Weitz JI. New anticoagulants: an update.
Clinical Advances in Hematology & Oncology 2004;2(11):
743–9.
Alexander 2007a
Alexander KP, Newby LK, Cannon CP, Armstrong
PW, Gibler WB, Rich MW, et al.Acute coronary care
Davies 2000
Davies MJ. The pathophysiology of acute coronary
syndromes. Heart 2000;83:361–6.
23
Eikelboom 2010
Eikelboom W, Weitz JI. Update on antithrombotic.
Therapy new anticoagulants. Circulation 2010;121:
1523–32.
ESC Guideline 2007
Bassand JP, Hamm CW, Ardissino D, et al.Guidelines for
the diagnosis and treatment of Non-ST-segment elevation
acute coronary syndromes.The Task Force for the Diagnosis
and Treatment of Non-ST-SegmentElevation Acute
Coronary Syndromes of the European Societyof Cardiology.
European Heart Journal 2007;28:1598-660.
ESC Guidelines 2008
Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist
C, Crea F, Falk V, et al.Management of acute myocardial
infarction in patients presenting with persistent ST-segment
elevationThe Task Force on the management of ST-segment
elevation acute myocardial infarction of the European
Society of Cardiology. European Heart Journal 2008;29:
2909-45.
Franchini 2005
Franchini M. Heparin-induced thrombocytopenia: an
update. Thrombosis Journal 2005;3:14.
Goodman 2008
Goodman SG, Menon V, Cannon CP, Steg G, Ohman
EM, Harrington RA, et al.Acute ST-Segment Elevation
Myocardial Infarction: American College of Chest
Physicians Evidence-Based Clinical PracticeGuidelines (8th
Edition). Chest 2008;133(6 Suppl):708S-75S.
Hamm 2000
Hamm CW, Braunwald E. A classification of unstable
angina revisited. Circulation 2000;102(1):118–22.
Harm 2007
Harm Wienbergen, Uwe Zeymer. Management of acute
coronary syndromes with fondaparinux. Vascular Health
and Risk Management 2007;3(3):329.
Higgins 2009
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.0.2 [updated
September 2009]. The Cochrane Collaboration, 2009.
Available from www.cochrane-handbook.org.
Hirsh 2005
Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood
2005;105(2):453–63.
Hirsh 2007
Hirsh J, O’Donnell M, Eikelboom JW. Beyond
unfractionated heparin and warfarin current and future
advances. Circulation 2007;116:552–60.
Karthikeyan 2009
Karthikeyan G, Mehta SR, Eilelboom JW. Fondaparinux in
the treatment of acute coronary syndromes: evidence from
Oasis 5 and 6. Expert review of cardiovascular therapy 2009;
7(3):241–9.
Latour-Perez 2009
Latour-Perez J, de-Miguel-Balsa E. Cost effectiveness
of fondaparinux in non-ST-elevation acute coronary
syndrome. Pharmacoeconomics 2009;27(7):585–95.
Lim 2006
Lim W, Dentali F, Eikelboom JW, Crowther MA. Metaanalysis: low-molecular-weight heparin and bleeding in
patients with severe renal insufficiency. Annals of Internal
Medicine 2006;144(9):673–84.
Linkins 2005
Linkins LA, Weitz JI. New anticoagulant therapy. Annual
Review of Medicine 2005;56:63–77.
Maan 2009
Jokhadar M, Wenger NK. Review of the treatment of acute
coronary syndrome in elderly patients. Clinical Interventions
in Aging 2009;4:435–44.
Maxwell 2009
Maxwell CD, Holdford DA, Crouch MA. Cost effectiveness
analysis of anticoagulation strategies in Non ST elevation
acute coronary syndromes. Annals of pharmacotherapy 2009;
43(4):586–95.
McCaan 2008
McCann CJ, Menown IBA. New anticoagulant strategies
in ST elevation myocardial infarction: Trials and clinical
implications. Vascular Health and Risk Management 2008;4
(2):305–13.
Nutescu 2006
Nutescu EA. Easing the economic burden of acute coronary
syndromes: cost-effectiveness of emerging therapies.
American Journal of Managed Care 2006;12(Suppl):
S444–50.
Warkentin 2008
Warkentin TE, Greinacher A, Koster A, Lincoff AM,
American College of Chest Physicians. Treatment
and prevention of heparin-induced thrombocytopenia:
American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines (8th Edition). Chest 2008;133
(6 Suppl):340S–380S.
∗
Indicates the major publication for the study
24
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Coussement 2001
Methods
Allocation using an interactive voice randomisation system
Phase II Study, randomised, open label
Study aim: To prove the hypothesis that factor Xa inhibition with pentasaccharide would
be an effective and safe antithrombotic therapy in conjunction with alteplase and that
prolonged administration of pentasaccharide may better prevent rethrombosis of the
infarct related coronary artery
Participants
Total 333 participants with STEMI during the first six hours of evolution
Twenty-four centres in Europe
Fondaparinux: 4 mg
Age (years) 61 (53, 68)
GenderMale 85
Gender Female 15
Race Caucasian 98
Other 2
Current smoker 62
H/o of Hypertension 35
Hypercholesterolaemia 47
Prior infarction 16
Diabetes 9
Infarct-related artery
LAD 37
RCA 47
LCX 15
Normal 1
Unknown 0
Fondaparinux: 8 mg
Age (years) 55 (48, 66)
GenderMale 83
Gender Female 17
Race Caucasian 100
Other 0
Current smoker 53
Prior infarction 8
Diabetes 12
LAD 40
RCA 47
LCX 15
Normal 1
Unknown 0
25
Coussement 2001
(Continued)
Fondaparinux:12 mg
Age (years) 59 (49, 67)
Gender Male 83
Gender Female 17
Race Caucasian 100
Other 0
Current smoker 42
History of (H/o) Hypertension 28
Hypercholesterolemia 49
Prior infarction 11
Diabetes 8
Left anterior descendent (LAD) 36
Right coronary artery (RCA) 43
Left circumflex (LCX ) 17
Normal 1
Unknown 2
Fondaparinux: combined (4 mg-8 mg-12 mg)
Age (years) 59 (50, 67)
GenderMale 84
Gender Female 16
Race Caucasian 99
Other 1
Current smoker 52
Hypercholesterolemia 45
Prior infarction 12
Diabetes 10
LAD 38
RCA 46
LCX 15
Normal 1
Unknown1
UFH
Age (years) 55 (48, 65)
Gender Male 80
Gender Female 20
Race Caucasian 100
Other 0
Current smoker 59
Prior infarction 9
Diabetes 9
LAD 44
RCA 45
26
Coussement 2001
(Continued)
LCX 11
Normal 0
Unknown 1
Data are shown as % for dichotomous variables and median (25, 75th percentile) for
continuous variables. PS=pentasaccharide;
UFH=unfractionated heparin.
Interventions
All patients received alteplase (ALT) over 90 minutes, the control group received a
standard dose of UFH (Bolus of 5000 previous ALT+ 1000U.H during 48-72 hrs)
adjusted to APTT 50-70 seconds. Experimental groups low dose (4 mg or 6 mg if >90
kg-/ medium dose-8 mg or 6 mg if < 60 kg or 10 mg if >90 kg-) or high dose (12 mg
or 10 mg if< 60 KG ) of fondaparinux (ORG 31540/SR 9017 A) administered daily
during 5 to 7 days. First doses were given intravenously previously to ALTEPLASE then
subcutaneously
All participants were given aspirin (150 - 325 mg).
Outcomes
TIMI flow in artery related to myocardial infarction at 90 MIN and on 5th and 7th
days
Clinical efficacy end points: all- cause mortality, reinfarction, urgent revascularization
Final safety end point bleeding.
Notes
UFH compared to fondaparinux in STEMI during the first 6 hrs. in pts receiving
thrombolytic treatment Pentalyse
STEMI UFH
All participants thrombolysis- TIMI flow evaluated at 90min/ days 5 and 7
Clinical efficacy end points through 30 days.
98.7% of the participants received at least one dose of the study drug
Sponsorship Sanofi Synthelabo
Risk of bias
Item
Authors’ judgement
Description
Adequate sequence generation?
Yes
Interactive voice randomisation system
Allocation concealment?
Yes
By the use of the interactive voice randomisation system
Blinding?
All outcomes
No
Open-label dose finding trial without
blinding of participants and personnel but
the angiographic efficacy endpoints were
evaluated by the angiographic core laboratory which remained blinded to the allocated treatment. Even though the outcome
assessors of angiographic efficacy end-point
were blinded, the report of some clinical ef-
27
Coussement 2001
(Continued)
ficacy ones such as urgent revascularization
needed or the minor safety end-point any
bleeding could likely be influenced by the
lack of blinding of some personnel
Incomplete outcome data addressed?
All outcomes
Yes
326/333 of the enrolled participants received the study medication, this population was considered the intention to treat
population for analysis of the clinical endpoints
No missing data of clinical events through
day 30 in the 326 participants, and in those
101 pts who underwent coronary interventions at 90 minutes
Free of selective reporting?
Yes
Study financially supported by Sanofi Synthelabo, but there is insufficient rationale
or evidence that this situation could have
introduced bias
Free of other bias?
Yes
The study appears to be free of other
sources of bias.
Simoons 2004
Methods
Study Phase II. Pts randomised to one of four doses of fondaparinux dosages or enoxaparin in blocks of five through a central computerized service. Treatment was doubleblind, using a double-dummy technique, and was administered for a minimum of three
days and a maximum of seven days, to allow revascularization procedures or early patient
discharge
Study aim: To compare for different dosages of fondaparinux with the LMWH enoxaparin in patients with Non ST segment elevation acute coronary syndromes through a
dose- finding study
Participants
Total 1138 participants older than 21 years old without persistent ST elevation, with
rest angina or at minimum movements and with the last episode during the 24 hrs
previous to be enrolled and with ST dynamic changes or ST depression ≥ 0.1mV and /
or troponin T or I concentrations > 0.1 ng/ml
Fondaparinux: 2.5 mg
Intention-to-treat population (n) 229
Mean age (y.o) 62.3
Male gender (%) 63.8
Mean body weight (kg) 78.4
Clinical characteristics
Dynamic ST-segment depression (%) 46.3; ST-segment depression (%) 55.9
Troponin-positive (%) 42.7
History of
Myocardial infarction (%) 24.6
Angina (%) 52.6 Heart failure (%) 6.1
28
Simoons 2004
(Continued)
PTCA (%) 6.1
CABG (%) 9.2
Hypertension (%) 50.4
Hypercholesterolemia (%) 43.9
Diabetes (%) 21.5
Currently smoking (%) 25.9
Fondaparinux: 4 mg
Mean age (y.o) 61.3
Dynamic ST-segment depression (%) 46.8
ST-segment depression (%) 58.6
History of
Myocardial infarction (%) 36.1 Angina (%) 59.8 Heart failure (%) 5.9
PTCA (%) 17.4
CABG (%) 9.1
Diabetes (%) 14.6
Fondaparinux: 8 mg
Mean age (y.o) 62.0
History of
PTCA (%) 8.6
CABG (%) 11.3
Diabetes (%) 17.1
Fondaparinux:12 mg
Mean age (y.o) 61.1
29
Simoons 2004
(Continued)
History of
PTCA (%) 9.7
CABG (%) 5.1
Diabetes (%) 14.4
Enoxaparin: 1 mg/kg
Demographics
Mean age (y.o) 60.3
History of
Angina (%) 51.5
Heart failure (%) 3.5
PTCA (%) 14.8
CABG (%) 8.3
Diabetes (%) 16.6
y.o years old; CABG coronary artery bypass graft surgery; PTCA percutaneous coronary
intervention
Interventions
Participants randomised to one of four fondaparinux doses (2.5 mg; 4 mg; 8 mg, or 12
mg) O.D or Enoxparin 1 mg TD, minimum three days maximum seven days to allow
revascularization or early discharge
At enrolment in the study, 58% of patients had already received aspirin, 42% had received
HFH or LMWH, and 5% had received lipid-lowering drugs. The fondaparinux and
enoxaparin treatment groups were comparable regarding these
characteristics. After randomisation, all patients received aspirin and most patients received nitrates (95%) and beta-blockers (91%). Lipid-lowering drugs were given in 54%;
angiotensin-converting enzyme inhibitors in 45%, calcium channel blockers in 40%,
thienopyridines in 19%, and glycoprotein IIb/IIIa receptor blockers in 3.4% of patients.
There were no significant differences in medication among the treatment groups
Outcomes
Clinical efficacy: Primary final end-point composite of mortality nor related to bleeding,
AMI, or recurrent symptomatic or asymptomatic myocardial ischemia till day nine. Secondary endpoint: each of the primary end-points but individually and revascularization
at 30 days
30
Simoons 2004
(Continued)
Primary safety end point : major bleeding till day nine.
Secondary safety end point: minor bleedings.
Notes
Fondaparinux versus enoxaparin in Non-STEMI up to 30 days after the event
This report describes the efficacy and safety results according to the intention-to-treat
group (N1,138), as well as a per-protocol analysis (N 929), but only the first was consider
in the meta- analyses
82% of the information was complete during follow-up
Sponsorship Organon
y.o years old; O.D once a daily; TD: twice daily
Risk of bias
Item
Description
Yes
Patients were randomised to one of four
fondaparinux dosages or enoxaparin in
blocks of five through a central computerized service
Yes
Central computerized allocation
Blinding?
All outcomes
Yes
Treatment was double blind using a double
dummy technique.
To
ensure double blinding (double dummy)
fondaparinux treated patients also received
placebo- enoxaparin injections twice daily,
and enoxaparin-treated patients received a
placebo- fondaparinux injection once daily
with the first dose given intravenously
All potential study outcomes were reviewed
by a central adjudication committee,and
ECG recordings were analysed by a central
core laboratory. Both were blinded as to patient allocation
All outcomes
Yes
The analysis was by the intention to treat
principle for all randomised patients. In addition a per- protocol analysis for the primary efficacy endpoint (composite of mortality, acute myocardial infarction, or recurrent symptomatic or asymptomatic ischemia up to day nine), was defined with
exclusion of patients with incomplete administration of study treatment (N=22)
, use of prohibited concomitant medication (N=110), or inadequate continuous
ECG monitoring defined as less than 12 hrs
31
Simoons 2004
(Continued)
recording (N=71).Safety analysis was based
on all patients who received study medication
Yes
The study was financially supported by
Organon but the evidence is not enough to
sustain that this situation could be bias related. The data were presented for all randomised patients - intention to treat population- and the per - protocol analysis
Free of other bias?
Yes
No sources of bias are identified.
Yusuf 2006 OASIS 5
Methods
Randomised by a central telephone system. It was a double blind double dummy trial
comparing fondaparinux to enoxaparin in pts with ACS
Study aim: To compare the efficacy and safety of fondaparinux and enoxaparin in high
risk patients with unstable angina or myocardial infarction without ST segment elevation
Participants
Total 20,078 participants from 576 centres in 41 countries with U.A or AMI without
ST elevation. Pts were allocated in a randomised fashion to one of the treatments during
the first 24 hrs following the symptoms, but at least two of the following criteria to be
included: at least 60 y.o, elevated levels of CK-MB or troponin,or electrocardiographic
changes secondary to myocardial ischemia
Enoxaparin:(N = 10,021)
Age - y.o 66.6±11.0
Male sex - no. (%) 6148 (61.4)
Diagnosis at study entry - no. (%)
Unstable angina 4517 (45.1)
Suspected myocardial infarction 5502 (54.9)
Medical history - no. (%)
Myocardial infarction 2580 (25.7)
CABG or PCI 1953 (19.5)
Stroke 647 (6.5)
Heart failure 1386 (13.8)
Hypertension 6721 (67.1)
Diabetes 2503 (25.0) Current or former smoker 5473 (54.6)
Fondaparinux: (N = 10,057)
Age - y.o 66.6±10.8
Male sex - no. (%) 6231 (62.0)
Diagnosis at study entry - no. (%)
Unstable angina 4581 (45.6)
Suspected myocardial infarction 5474 (54.4)
Medical history - no. (%)
CABG or PCI 2022 (20.1)
Stroke 597 (5.9)
32
Yusuf 2006 OASIS 5
(Continued)
Diabetes 2575 (25.6)
Current or former smoker 5440 (54.1)
y.o years old; CABG coronary bypass graft
Interventions
Participants were randomised to fondaparinux 2.5 subcutaneously but 5 mg if PCI
without glycoprotein IIB IIIa (GP IIB/ IIIA) was planned, or enoxaparin 1 mg/kg day
subcutaneously TD for six days
Randomisation was stratified according to the planned use of GP IIB/ IIIA, so the doses
of UFH were100 u/KfgW/O GPIIBIIIA OR 65U/ KG with the use of inhibitors and
if more than six hours has spent after the last dose of enoxaparin. If fondaparinux was
going to be administrated and if the pt was going to a percutaneous intervention during
the next six hours 2.5 or 5 mg of fondaparinux were administrated additionally related
to the administration of glycoprotein inhibitors, but if more than six hours had spent
those extra doses were given endovenously.
Enoxaparin (%),n = 10021
Aspirin (ASA)
97.5
GPIIb/IIIa inhibitor
17.6
During PCI
41.0
Clopididogrel / ticlopidine
66.7
Beta-Blockers 87.7
Calcium channel blockers
26.8
IECA or ARB*
76.1
Statins
77.5
Fondaparinux (%),n = 10057
ASA
97.5
GPIIb/IIIa inhibitor
18.6
During PCI
41.7
Clopididogrel/ticlopidine
67.1
Beta-Blockers
87.1
Calcium channel blockers
26.9
IECA or ARB*
74.9
Statins
78.0
* Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers
Outcomes
Primary clinical efficacy end-point composed: death, MI or refractory ischemia and each
individual component at 30 days and at the end of study. Safety outcome major bleeding
at nine days
Notes
Fondaparinux compared to enoxaparin in participants suffering from Non-STEMI with
symptoms in the last 24 hrs
OASIS 5 follow up minimum 90 days, maximum 180 days. Assesing outcomes by a
committee in a blinded fashion to the allocated treatment
fondaparinux group 99.2% received at least once the study drug and the 99.4% in the
enoxaparin group
Sponsorship Sanofi-Synthelabo, Organon NV, and Glaxo-Smith-Kline
Risk of bias
33
Yusuf 2006 OASIS 5
(Continued)
Item
Description
Yes
Patients were randomly assigned by means
of a 24 hrs computerized central telephone
system to receive either fondaparinux plus
placebo enoxaparin or enoxaparin plus
placebo fondaparinux
Yes
Allocation by a central telephone system according to a compute generated randomisation list stratified by centre
Blinding?
All outcomes
Yes
Double blind - Double dummy. So patients received either fondaparinux once
daily plus placebo enoxaparin twice daily by
subcutaneous injection or enoxaparin twice
daily plus placebo fondaparinux once daily
by subcutaneous injection. In case of percutaneous coronary intervention the double blind arrangement was maintained
All outcomes
Yes
“Vital status was ascertained for 20066 of
the 20078 randomly assigned patients (99.
9%); seven patients in the fondaparinux
group and five in the enoxaparin group
were lost to follow - up by nine days”
“At least one dose of allocated study drug
was administered to 99.2% to the patients
in the fondaparinux group and 99.4% of
those in the enoxaparin group”
Yes
The authors received research support or
consultant fees from the pharmaceutical
company related to the study drug, but
there was insufficient rationale or evidence
that this situation could have introduced
bias
Free of other bias?
Yes
No sources of bias were identified.
34
Yusuf 2006 OASIS 6
Methods
Randomised double blind trial evaluating fondaparinux against usual care in pts suffering
from STEMI
Study aim: To evaluate the impact of fondaparinux compared with standard approaches
to antithrombotic therapy in a broad range of patients with STEMI in preventing the
primary and composite outcome of death or reinfarction at 30 days
Participants
Total 12,092 participants suffering from STEMI enrolled in 447 centres in 41 countries
during the first 24 hrs of initial symptoms. The window time was shortened to 12 hrs
after 4300 participants, when results from trials evaluating the use of heparin in ACS
were evaluated, but without an internal analyses of the OASIS trial
Placebo or Unfractionated Heparin (n = 6056)
Age, mean (SD),y.o 61.5 (12.2)
Men, No. (%) 4353 (71.9)
Medical history, No. (%)
Stroke 385 (6.4)
CABG surgery or PCI 237 (3.9)
Fondaparinux (n = 6036)
Age, mean (SD),y.o 61.6 (12.3)
Men, No. (%) 4393 (72.8)
Medical history, No. (%)
Stroke 416 (6.9)
CABG surgery or PCI 235 (3.9)
y.o years old; CABG coronary artery by pass
Interventions
6036 pUFts. were randomised to 2.5 mg of fondaparinux once daily subcutaneously till
the 8th day, and 6056 were assigned to the control group. Randomization was stratified
according to the investigator criteria about the administration of UFH or placebo so
• STRATUM I (No UFH according to the investigator criteria) receiving
fondaparinux vs placebo
• STRATUM II ( UFH yes) receiving first fondaparinux dose by IV route, the rest
subcutaneously vs a shoot of 60UI/kg of UFH followed by 12 UI/kg/ hour during 24
to 48 hours.
Fondaparinux eight days or till discharge, UFH 24- 48 hours.
Medications within seven days of randomisation, No. (%)
Placebo or Unfractionated Heparin (n = 6056)
Aspirin 3741 (61.8)
Beta-Blockers 1593 (26.3) ACE inhibitor or ARB 1560 (25.8)
Clopidogrel or ticlopidine 1006 (16.6)
UFH 880 (14.5)
35
Yusuf 2006 OASIS 6
(Continued)
Lipid-lowering agents 689 (11.4)
Calcium channel blockers 598 (9.9)
LMWH 107 (1.8)
Gp IIb/IIIa receptor antagonist 117 (1.9)
Bivalirudin or hirudin 2 (0.1)
Aspirin 3728 (61.8)
Beta-Blockers 1597 (26.5)
ACE inhibitor or ARB 1516 (25.1)
UFH 907 (15.0)
LMWH 114 (1.9)
Medications in hospital after randomisation, No. (%)
Aspirin 5841 (96.8)
UFH 651 (10.8)
LMWH 322 (5.3)
Placebo or UFH (n = 6036)
Aspirin 5839 (96.4)
UFH 681 (11.2)
LMWH 384 (6.3)
ACE inhibitor or ARB Angiotensin-converting enzyme inhibitors or angiotensin receptor
blockers,
Gp IIb/IIIa receptor antagonist glycoprotein IIb/ IIIa receptor antagonist
Outcomes
Clinical efficacy: primary end point composite of death and re-infarction at 30 days,
secondary endpoints death and re-infarction at nine days, three months and six months
Safety outcome: severe bleeding, major bleeding.
Notes
OASIS 6
Follow up till to hospital discharge, 30, 90 and 180 days.
36
Yusuf 2006 OASIS 6
(Continued)
Analysis according to intention to treat
Analyses of subgroup related to primary percutaneous coronary procedures
The UFH group had 11 participants lost to follow up, the group fondaparinux had 11
participants lost to follow up
This study was conducted independently by the Steering Committee and the Population
Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario.
No direct compensation was received by these individuals. The study was jointly funded
by Sanofi-Aventis, Organon, and GlaxoSmithKline
Risk of bias
Item
Description
Unclear
Randomization was stratified by indication for the use of UFH based on the
investigator´ s judgment. There is no detailed information about the sequence of
generation process to permit its judgment
Unclear
Participants deemed ineligible for reperfusion therapy by the investigator criteria.
Randomization was stratified by the indication for unfractionated heparin(stratum
II) or not (stratum I) based on the investigator‘s judgment
The method of concealment was not described in details to allow a definite judgment
Blinding?
All outcomes
Yes
Double blind - double dummy.
Those patients with indication for UFH
(enrolled as stratum 2) were assigned
to receive either blinded fondaparinux
or matching placebo, initial dose intravenous and subsequent doses subcutaneously. Those in the control group received a bolus injection of UFH followed
by an infusion per 24 to 48 hours. Equivalent placebo bolus and injections were used
in the fondaparinux group. To maintain
the double blind criteria patients receiving
UFH or placebo infusion have regular activated partial thromboplastin time monitoring using a “hemachron” device. A central computerized system produced either
real or sham activated partial thromboplastin time values,which were used to adjust
the rate of infusion
37
Yusuf 2006 OASIS 6
(Continued)
All outcomes
Yes
Vital status was ascertained in 6032 fondaparinux and 6428 UFH- placebo patients
at 30 days
Yes
The authors received research support or
consultant fees from the pharmaceutical
company related to the study drug, but
there was insufficient rationale or evidence
that this situation could have introduced
bias
Free of other bias?
Yes
No sources of bias were identified.
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Alexander 2005
Small phase II trial to determine a dose of DX-9065 with a favourable safety profile when given with standard non
ST elevation ACS medical therapy; and to compare the effect of heparin vs DX-9065a on ischemic endpoints
in patients with non-ST elevation ACS
The direct factor Xa inhibitor, though promising DX 9065 has not undergone further clinical evaluation (ACCP
2008).
Cohen 2007
The objective was to determine the optimal anticoagulant regimen for percutaneous coronary intervention (PCI)
of otamixaban, a selective and direct inhibitor of factor Xa, investigated in patients undergoing non urgent PCI
The primary end points were change in prothrombin fragments 1+2 (F1+2), and anti-factor Xa activity
Mehta 2007
It was a randomised trial performed to determine the safety and feasibility of fondaparinux in the percutaneous
coronary intervention (PCI) setting, so it included patients who were allocated to urgent percutaneous coronary
proceedings or elective ones because of ACS or stable angina respectively
Vuillemenot 1999
It was a Phase IIa, open label, non-controlled, pilot study assessing a 12 mg iv bolus of SR90107/ORG31540.
(Fondaparinux), including patients with a history of stable angina, > 7-day unstable angina or MI and a 70%
stenosis in an epicardial vessel selected for conventional balloon. The aim of the study was to test the antithrombotic properties of SR90107/ORG31540 (fondaparinux) during percutaneous transluminal coronary
angioplasty (PTCA), a procedure known to be associated with an increased risk of arterial thrombosis, abrupt
coronary vessel closure during or within 24 h. after
38
Characteristics of studies awaiting assessment [ordered by study ID]
Oasis 8
Methods
Phase IV study, Interventional, Randomised, Double blind
The purpose of this study is to compare the safety of two different dose regimens of unfractionated heparin (UFH)
during a PCI procedure in patients with UA (unstable angina)/NSTEMI (non ST segment elevation myocardial
infarction) who have been initially treated with fondaparinux
Subjects presenting at hospital with suspected UA or NSTEMI and who are likely to undergo angiography (ideally
within 72 hours) will be assessed for eligibility and consented. Suitable subjects will be enrolled and commence
treatment with open-label fondaparinux, 2.5 mg, subcutaneous (s. c)., once daily. Following angiography subjects
indicated for PCI and meeting the additional requirements for randomisation will be randomised to receive one of
two dose regimens of UFH either standard dose or low dose immediately prior to the PCI procedure. Post-PCI,
therapy with fondaparinux (2.5 mg, s.c.) may be resumed at the investigator’s discretion for up to a maximum of
eight days or hospital discharge, whichever is earlier
Subjects not indicated for PCI, will continue treatment with fondaparinux, 2.5mg, s.c, once daily for up to 8 days
or hospital discharge, whichever is earlier
All subjects will be followed up for 30 days after randomisation/angiography
Participants
Estimated 4000.
Both genders.
21 y.o or older.
Interventions
Standard dose UFH: Experimental No planned GPIIb/IIIa use: 85 U/kg bolus with additional bolus (2,000 U - 4,
000U) if needed to achieve a target ACT of 300 - 350 seconds (using the HEMOCHRON device) or ACT of 250 300 seconds (using the HEMOTECH device). Planned GPIIb/IIIa use: 60 U/kg bolus with additional bolus of (2,
000 U - 4,000U) if needed to achieve target ACT of ?200 seconds (using the HEMOCHRON or HEMOTECH
device)
• Intervention: Drug: Unfractioned heparin Fondaparinux treated patients, eligible for PCI, will be randomised
to receive one of two doses of unfractionated heparin (UFH) at least 1 minute prior to insertion of the guidewire
Low Dose UFH: Experimental - All subjects irrespective of planned GPIIb/IIIa use: 50 U/kg bolus
• Intervention: Drug: Unfractioned heparin Fondaparinux treated patients, eligible for PCI, will be randomised
to receive one of two doses of unfractionated heparin (UFH) at least one minute prior to insertion of the guidewire.
Outcomes
Standard dose UFH: Experimental
• No planned GPIIb/IIIa use: 85 U/kg bolus with additional bolus (2,000 U - 4,000U) if needed to achieve a
target ACT of 300 - 350 seconds (using the HEMOCHRON device) or ACT of 250 - 300 seconds (using the
HEMOTECH device).
• Planned GPIIb/IIIa use: 60 U/kg bolus with additional bolus of (2,000 U - 4,000U) if needed to achieve
target ACT of ?200 seconds (using the HEMOCHRON or HEMOTECH device)
Notes
ClinicalTrials.gov identifier: NCT00790907
39
Sabatine 2009
Methods
Phase II double blind randomised controlled trial
Study aim: To assess efficacy and safety in non-ST elevation acute coronary syndromes of Otamixaban, intravenous
direct factor Xa inhibitor, compared to UFH. To identify its optimum dose range for future assessment in a phase 3
study
Participants
3241 in 196 sites in 36 countries
Interventions
Patients were randomly assigned via a central, telephone- based interactive voice response system, to one of five doses
of otamixaban or to a control of UFH
Outcomes
Primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularization, or bailout
glycoprotein IIb- IIIa inhibitor use up to seven days by intention to treat
Primary safety endpoint was TIMI major or minor bleeding not related to coronary -artery bypass grafting in treated
patients
Notes
NCT00317395
40
DATA AND ANALYSES
Comparison 1. Fondaparinuxs vs. anticoagulants
Outcome or subgroup title
1 All-cause mortality at 30 days
1.1 UFH
1.2 Enoxaparin
2 All-cause mortality at 90 to 180
days
2.1 UFH
2.2 Enoxaparin
3 Non-fatal AMI or re-infarction
at 9 days
3.1 UFH
3.2 Enoxaparin
at 30 days
4.1 UFH
4.2 Enoxaparin
5 Combined endpoint of all-cause
mortality, non-fatal AMI or
re-infarction at 9 days
5.1 UFH
5.2 Enoxaparin
6 Major bleeding at 9 days
6.1 UFH
6.2 Enoxaparin
7.1 UFH
7.2 Enoxaparin
8 Minor bleeding at 30 days
8.1 UFH
8.2 Enoxaparin
No. of
studies
No. of
participants
4
2
2
2
27976
6760
21216
26512
Risk Ratio (M-H, Fixed, 95% CI)
0.90 [0.80, 1.01]
0.98 [0.82, 1.18]
0.85 [0.73, 0.98]
0.89 [0.81, 0.97]
1
1
3
6434
20078
27650
Risk Ratio (M-H, Random, 95% CI)
0.88 [0.75, 1.03]
0.90 [0.80, 1.00]
0.89 [0.68, 1.17]
1
2
3
6434
21216
26838
0.69 [0.47, 1.01]
1.00 [0.84, 1.18]
0.92 [0.81, 1.04]
2
1
3
6760
20078
27650
0.84 [0.62, 1.15]
0.94 [0.82, 1.07]
0.97 [0.87, 1.08]
1
2
3
1
2
2
1
1
2
1
1
6434
21216
27650
6434
21216
20404
326
20078
20404
326
20078
0.92 [0.77, 1.11]
1.00 [0.87, 1.14]
0.74 [0.42, 1.31]
0.93 [0.67, 1.29]
0.92 [0.15, 5.66]
0.79 [0.39, 1.59]
1.41 [0.49, 4.10]
0.63 [0.55, 0.73]
0.70 [0.14, 3.39]
1.76 [0.52, 5.94]
0.34 [0.28, 0.43]
Statistical method
Effect size
Comparison 2. Low dose fondaparinux vs. anticoagulants
1.1 UFH
1.2 Enoxaparin
at 30 days
No. of
studies
No. of
participants
4
2
2
3
27357
6600
20757
26678
Statistical method
Effect size
0.92 [0.75, 1.12]
0.98 [0.82, 1.17]
1.53 [0.29, 8.25]
0.90 [0.65, 1.23]
41
2.1 UFH
2.2 Enoxaparin
3.1 UFH
3.2 Enoxaparin
2
1
4
2
2
6600
20078
27357
6600
20757
0.85 [0.40, 1.83]
0.99 [0.84, 1.17]
0.75 [0.45, 1.26]
0.94 [0.68, 1.29]
0.76 [0.17, 3.38]
Comparison 3. Fondaparinux vs. anticoagulants in PCI
1.1 UFH
1.2 Enoxaparin
at 30 days
2.1 UFH
2.2 Enoxaparin
3.1 UFH
3.2 Enoxaparin
4 Catheter thrombosis
4.1 UFH
4.2 Enoxaparin
No. of
studies
No. of
participants
2
1
1
2
9945
3768
6177
9945
1.05 [0.83, 1.32]
1.14 [0.84, 1.55]
0.94 [0.67, 1.33]
1.08 [0.89, 1.30]
1
1
2
1
1
2
1
1
3768
6177
9945
3768
6177
10006
3768
6238
1.23 [0.76, 2.00]
1.05 [0.86, 1.29]
0.76 [0.28, 2.05]
1.28 [0.81, 2.04]
0.47 [0.35, 0.61]
9.42 [0.64, 139.63]
44.71 [2.71, 736.57]
3.59 [1.64, 7.84]
Statistical method
Effect size
Comparison 4. Sensitivity analyses
1.1 UFH
1.2 Enoxaparin
2.1 UFH
2.2 Enoxaparin
No. of
studies
No. of
participants
2
1
1
2
1
1
26512
6434
20078
26512
6434
20078
Statistical method
Effect size
0.89 [0.79, 1.00]
0.98 [0.81, 1.17]
0.84 [0.72, 0.97]
0.69 [0.39, 1.21]
0.93 [0.67, 1.29]
0.53 [0.45, 0.62]
42
Analysis 1.1. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 1 All-cause mortality at 30 days.
Review:
Comparison: 1 Fondaparinuxs vs. anticoagulants
Outcome: 1 All-cause mortality at 30 days
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
6/241
1/85
0.3 %
2.12 [ 0.26, 17.32 ]
213/3213
219/3221
37.9 %
0.98 [ 0.81, 1.17 ]
3454
3306
38.1 %
0.98 [ 0.82, 1.18 ]
19/908
3/230
0.8 %
1.60 [ 0.48, 5.37 ]
295/10057
352/10021
61.0 %
0.84 [ 0.72, 0.97 ]
10965
10251
61.9 %
0.85 [ 0.73, 0.98 ]
13557
100.0 %
0.90 [ 0.80, 1.01 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Coussement 2001
Yusuf 2006 OASIS 6
Subtotal (95% CI)
Total events: 219 (Fondaparinux), 220 (Anticoagulants)
Heterogeneity: Chi2 = 0.52, df = 1 (P = 0.47); I2 =0.0%
Test for overall effect: Z = 0.19 (P = 0.85)
2 Enoxaparin
Simoons 2004
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Heterogeneity: Chi2 = 1.10, df = 1 (P = 0.29); I2 =9%
Total (95% CI)
14419
0.05
0.2
1
Favours fondaparinux
5
20
Favours anticoagulants
43
Analysis 1.2. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 2 All-cause mortality at 90 to 180
days.
Review:
Outcome: 2 All-cause mortality at 90 to 180 days
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
262/3213
299/3221
31.8 %
0.88 [ 0.75, 1.03 ]
3213
3221
31.8 %
0.88 [ 0.75, 1.03 ]
574/10057
638/10021
68.2 %
0.90 [ 0.80, 1.00 ]
10057
10021
68.2 %
0.90 [ 0.80, 1.00 ]
13242
100.0 %
0.89 [ 0.81, 0.97 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
Heterogeneity: not applicable
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
13270
0.5
0.7
1
1.5
2
44
Analysis 1.3. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 3 Non-fatal AMI or re-infarction at
9 days.
Review:
Outcome: 3 Non-fatal AMI or re-infarction at 9 days
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
44/3213
64/3221
31.6 %
0.69 [ 0.47, 1.01 ]
3213
3221
31.6 %
0.69 [ 0.47, 1.01 ]
263/10057
264/10021
63.9 %
0.99 [ 0.84, 1.17 ]
14/908
3/230
4.5 %
1.18 [ 0.34, 4.08 ]
10965
10251
68.4 %
1.00 [ 0.84, 1.18 ]
100.0 %
0.89 [ 0.68, 1.17 ]
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Simoons 2004
Subtotal (95% CI)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%
Total (95% CI)
14178
13472
Heterogeneity: Tau2 = 0.02; Chi2 = 3.09, df = 2 (P = 0.21); I2 =35%
0.1 0.2
0.5
1
2
5
10
45
Analysis 1.4. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 4 Non-fatal AMI or re-infarction at
30 days.
Review:
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
9/241
3/85
0.9 %
1.06 [ 0.29, 3.82 ]
69/3213
83/3221
16.6 %
0.83 [ 0.61, 1.14 ]
3454
3306
17.5 %
0.84 [ 0.62, 1.15 ]
387/10057
411/10021
82.5 %
0.94 [ 0.82, 1.07 ]
10057
10021
82.5 %
0.94 [ 0.82, 1.07 ]
13327
100.0 %
0.92 [ 0.81, 1.04 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Coussement 2001
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
13511
0.1 0.2
0.5
1
2
5
10
46
Analysis 1.5. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 5 Combined endpoint of all-cause
mortality, non-fatal AMI or re-infarction at 9 days.
Review:
Outcome: 5 Combined endpoint of all-cause mortality, non-fatal AMI or re-infarction at 9 days
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
205/3213
223/3221
34.7 %
0.92 [ 0.77, 1.11 ]
3213
3221
34.7 %
0.92 [ 0.77, 1.11 ]
25/908
4/230
1.0 %
1.58 [ 0.56, 4.50 ]
409/10057
412/10021
64.3 %
0.99 [ 0.87, 1.13 ]
10965
10251
65.3 %
1.00 [ 0.87, 1.14 ]
13472
100.0 %
0.97 [ 0.87, 1.08 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Simoons 2004
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
14178
0.02
0.1
1
10
50
47
Analysis 1.6. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 6 Major bleeding at 9 days.
Review:
Outcome: 6 Major bleeding at 9 days
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
68/3213
73/3221
45.3 %
0.93 [ 0.67, 1.29 ]
3213
3221
45.3 %
0.93 [ 0.67, 1.29 ]
8/908
0/230
3.7 %
4.32 [ 0.25, 74.57 ]
217/10057
411/10021
51.0 %
0.53 [ 0.45, 0.62 ]
10965
10251
54.7 %
0.92 [ 0.15, 5.66 ]
100.0 %
0.74 [ 0.42, 1.31 ]
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Simoons 2004
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
14178
13472
0.01
0.1
1
10
100
48
Analysis 1.7. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 7 Major bleeding at 30 days.
Review:
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
16/241
4/85
27.5 %
1.41 [ 0.49, 4.10 ]
241
85
27.5 %
1.41 [ 0.49, 4.10 ]
313/10057
494/10021
72.5 %
0.63 [ 0.55, 0.73 ]
10057
10021
72.5 %
0.63 [ 0.55, 0.73 ]
10106
100.0 %
0.79 [ 0.39, 1.59 ]
1 UFH
Coussement 2001
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Test for overall effect: Z = 6.49 (P < 0.00001)
Total (95% CI)
10298
0.05
0.2
1
5
20
49
Analysis 1.8. Comparison 1 Fondaparinuxs vs. anticoagulants, Outcome 8 Minor bleeding at 30 days.
Review:
Outcome: 8 Minor bleeding at 30 days
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
15/241
3/85
43.0 %
1.76 [ 0.52, 5.94 ]
241
85
43.0 %
1.76 [ 0.52, 5.94 ]
111/10057
321/10021
57.0 %
0.34 [ 0.28, 0.43 ]
10057
10021
57.0 %
0.34 [ 0.28, 0.43 ]
10106
100.0 %
0.70 [ 0.14, 3.39 ]
1 UFH
Coussement 2001
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
10298
0.01
0.1
1
10
100
50
Analysis 2.1. Comparison 2 Low dose fondaparinux vs. anticoagulants, Outcome 1 All-cause mortality at 30
days.
Review:
Comparison: 2 Low dose fondaparinux vs. anticoagulants
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
213/3213
219/3221
46.2 %
0.98 [ 0.81, 1.17 ]
2/81
1/85
0.7 %
2.10 [ 0.19, 22.70 ]
3294
3306
46.9 %
0.98 [ 0.82, 1.17 ]
1 UFH
Yusuf 2006 OASIS 6
Coussement 2001
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Simoons 2004
Subtotal (95% CI)
295/10057
352/10021
52.2 %
0.84 [ 0.72, 0.97 ]
10/449
1/230
0.9 %
5.12 [ 0.66, 39.77 ]
10506
10251
53.1 %
1.53 [ 0.29, 8.25 ]
100.0 %
0.92 [ 0.75, 1.12 ]
Total (95% CI)
13800
13557
0.05
0.2
1
5
20
51
Analysis 2.2. Comparison 2 Low dose fondaparinux vs. anticoagulants, Outcome 2 Non-fatal AMI or reinfarction at 30 days.
Review:
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
5/81
3/85
4.8 %
1.75 [ 0.43, 7.08 ]
44/3213
64/3221
35.3 %
0.69 [ 0.47, 1.01 ]
3294
3306
40.0 %
0.85 [ 0.40, 1.83 ]
1 UFH
Coussement 2001
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
263/10057
264/10021
60.0 %
0.99 [ 0.84, 1.17 ]
10057
10021
60.0 %
0.99 [ 0.84, 1.17 ]
13327
100.0 %
0.90 [ 0.65, 1.23 ]
Total (95% CI)
13351
0.2
0.5
1
2
5
52
Analysis 2.3. Comparison 2 Low dose fondaparinux vs. anticoagulants, Outcome 3 Major bleeding at 9 days.
Review:
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
4/81
4/85
11.0 %
1.05 [ 0.27, 4.06 ]
68/3213
73/3221
40.2 %
0.93 [ 0.67, 1.29 ]
3294
3306
51.2 %
0.94 [ 0.68, 1.29 ]
1 UFH
Coussement 2001
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Simoons 2004
Yusuf 2006 OASIS 5
Subtotal (95% CI)
3/449
0/230
2.8 %
3.59 [ 0.19, 69.27 ]
217/10057
412/10021
46.0 %
0.52 [ 0.45, 0.62 ]
10506
10251
48.8 %
0.76 [ 0.17, 3.38 ]
100.0 %
0.75 [ 0.45, 1.26 ]
Total (95% CI)
13800
13557
0.02
0.1
1
10
50
53
Analysis 3.1. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 1 All-cause mortality at 30
days.
Review:
Comparison: 3 Fondaparinux vs. anticoagulants in PCI
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
85/1890
74/1878
53.2 %
1.14 [ 0.84, 1.55 ]
1890
1878
53.2 %
1.14 [ 0.84, 1.55 ]
62/3105
65/3072
46.8 %
0.94 [ 0.67, 1.33 ]
3105
3072
46.8 %
0.94 [ 0.67, 1.33 ]
4950
100.0 %
1.05 [ 0.83, 1.32 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
4995
0.05
0.2
1
5
20
54
Analysis 3.2. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 2 Non-fatal AMI or reinfarction at 30 days.
Review:
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
36/1890
29/1878
14.7 %
1.23 [ 0.76, 2.00 ]
1890
1878
14.7 %
1.23 [ 0.76, 2.00 ]
179/3105
168/3072
85.3 %
1.05 [ 0.86, 1.29 ]
3105
3072
85.3 %
1.05 [ 0.86, 1.29 ]
4950
100.0 %
1.08 [ 0.89, 1.30 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
4995
0.5
0.7
1
1.5
2
55
Analysis 3.3. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 3 Major bleeding at 9 days.
Review:
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
40/1890
31/1878
48.2 %
1.28 [ 0.81, 2.04 ]
1890
1878
48.2 %
1.28 [ 0.81, 2.04 ]
73/3105
155/3072
51.8 %
0.47 [ 0.35, 0.61 ]
3105
3072
51.8 %
0.47 [ 0.35, 0.61 ]
4950
100.0 %
0.76 [ 0.28, 2.05 ]
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
4995
0.01
0.1
1
10
100
56
Analysis 3.4. Comparison 3 Fondaparinux vs. anticoagulants in PCI, Outcome 4 Catheter thrombosis.
Review:
Outcome: 4 Catheter thrombosis
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
22/1890
0/1878
38.2 %
44.71 [ 2.71, 736.57 ]
1890
1878
38.2 %
44.71 [ 2.71, 736.57 ]
29/3134
8/3104
61.8 %
3.59 [ 1.64, 7.84 ]
3134
3104
61.8 %
3.59 [ 1.64, 7.84 ]
4982
100.0 %
9.42 [ 0.64, 139.63 ]
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
5024
0.001 0.01 0.1
1
10 100 1000
57
Analysis 4.1. Comparison 4 Sensitivity analyses, Outcome 1 All-cause mortality at 30 days.
Review:
Comparison: 4 Sensitivity analyses
Study or subgroup
Fondaparinux
Anticoagulants
n/N
n/N
Risk Ratio
Weight
213/3213
219/3221
38.3 %
0.98 [ 0.81, 1.17 ]
3213
3221
38.3 %
0.98 [ 0.81, 1.17 ]
295/10057
352/10021
61.7 %
0.84 [ 0.72, 0.97 ]
10057
10021
61.7 %
0.84 [ 0.72, 0.97 ]
13242
100.0 %
0.89 [ 0.79, 1.00 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
13270
0.05
0.2
1
5
20
58
Analysis 4.2. Comparison 4 Sensitivity analyses, Outcome 2 Major bleeding at 9 days.
Review:
Comparison: 4 Sensitivity analyses
Study or subgroup
Fondaparinux
Anticoagulants
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
68/3213
73/3221
46.8 %
0.93 [ 0.67, 1.29 ]
3213
3221
46.8 %
0.93 [ 0.67, 1.29 ]
217/10057
411/10021
53.2 %
0.53 [ 0.45, 0.62 ]
10057
10021
53.2 %
0.53 [ 0.45, 0.62 ]
13242
100.0 %
0.69 [ 0.39, 1.21 ]
1 UFH
Yusuf 2006 OASIS 6
Subtotal (95% CI)
2 Enoxaparin
Yusuf 2006 OASIS 5
Subtotal (95% CI)
Total (95% CI)
13270
0.01
0.1
1
10
100
ADDITIONAL TABLES
Table 1. QUALITY ASSESSMENT CRITERIA
ASSESMENT
A
ALLOCATION CONCEAL- ADEQUATE
MENT
B
NOT
UNCLEAR
C
REPORTED/ INADEQUATE
TREATMENT BLINDING
STATEMENT FINAL CON- NOT
TAINERS WERE IDENTI- UNCLEAR
CAL
OUTCOME ASSESSMENT
BLINDED, STANDARSED ASSESSMENT
ASSESSASSESSMENT
PROCEDURES NOT STAN- MENT NOT BLINDED OR
DARISED
NOT STANDARIZED
REPORTED/ STUDY / CONTROL DRUG
NOT IDENTCIAL
59
Table 1. QUALITY ASSESSMENT CRITERIA
(Continued)
BASELINE EQUALITY
GROUP BALANCED
TERMS OF AGE, ETC
IN BALANCE
REPORTED
LOSSES TO FOLLOW UP
LOSSES OF 10%
NOT
UNCLEAR
BASIS FOR ANALYSIS
INTENTION TO TREAT
UNCLEAR
NOT GROUPS NOT BALANCED
REPORTED/ LOSSES OF MORE THAN
10%
NON- INTENTION
TREAT
TO
APPENDICES
Appendix 1. Search strategies
CENTRAL
# MeSH descriptor Myocardial Ischemia explode all trees
# 2 angina
# 3 myocardial next infarct*
# 4 heart next infarct*
# 5 acute next coronary
# 6 coronary next syndrome*
# 7 Preinfarction
# 8 STEMI
# 9 NONSTEMI
# 10 NON-STEMI
# 11 NSTEMI
# 12 ACS
# 13 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12)
# 14 fondaparinux
# 15 idraparinux
# 16 Arixtra
# 17 otamixaban
# 18 (xa near/6 inhibit*)
# 19 (10a near/6 inhibit*)
# 20 (xa near/6 antagonist*)
# 21 (10a near/6 antagonist*)
# 22 (xa near/6 block*)
# 23 (“factor x” near/ 6 inhibit*)
# 24 Fxa next inhibitor*
# 25 vaso flux
# 26 Razaxaban
# 27 Fondaparin
# 28 “Dx 9065*”
# 29 (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21)
60
# 30 (#22 or #23 or #24 or #25 or #26 or #27 or #28)
# 31 (#29 or #30)
# 32 (#13 and #31)
PubMed
(Myocardial Ischemia[Mesh] OR Myocardial Ischemi*[tw] OR heart muscle ischemi*[tw] OR angina*[tw] OR myocardial infarct*[tw]
OR heart infarct*[tw] OR acute coronar*[tw] OR coronary syndrome*[tw] OR Preinfarct*[tw] OR Pre Infarct*[tw] OR STEMI[tw]
OR NONSTEMI[tw] OR NON-STEMI[tw] OR NSTEMI[tw] OR ACS[tiab] OR Acute Coronary Syndrome[Mesh]) AND (Fondaparinux[nm] OR Fondaparinux[tw] OR Idraparinux[tw] OR Arixtra[tw] OR Otamixaban[tw] OR xa inhibit*[tw] OR 10a inhibit*[tw] OR xa antagonist*[tw] OR 10a antagonist*[tw] OR xa block*[tw] OR factor x inhibit*[tw] OR Fxa inhibit*[tw] OR vaso
flux*[tw] OR Razaxaban[tw] OR Fondaparin[tw] OR Dx 9065*[tw]) AND (Randomized controlled trial[pt] OR controlled clinical
trial[pt] OR Randomized controlled trials[Mesh] OR Random allocation[Mesh] OR Double-blind method[Mesh] OR Single-blind
method[Mesh] OR clinical trial[pt] OR Clinical trials[Mesh] OR (“clinical trial”[tw]) OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw]
OR tripl*[tw]) AND (mask*[tw] OR blind*[tw])) OR (Placebos[Mesh] OR placebo*[tw] OR random*[tw] OR Research design [mh:
noexp]) NOT (Animals[Mesh] NOT Human[Mesh]))
EMBASE
1 # exp heart muscle ischemia/
2 # Myocardial Ischemi$.mp.
3 # angina.ti,ab.
4 # myocardial infarct$.mp.
5 # heart infarct$.mp.
6 # acute coronar$.mp.
7 # coronary syndrom$.mp.
8 # (Preinfarct$ or pre infarct$).mp.
9 # (STEMI or NONSTEMI or NON-STEMI or NSTEMI).mp.
10 # ACS.ti,ab.
11 # exp acute coronary syndrome/
12 # or/1-11
13 # exp fondaparinux/
14 # (fondaparinux or idraparinux or Arixtra or otamixaban or Razaxaban or Fonadaparin or Dx 9065$).mp.
15 # xa inhibit$.mp.
16 # 10a inhibit$.mp.
17 # xa antagonist$.mp.
18 # 10a antagonist$.mp.
19 # xa block$.mp.
20 # factor x inhibit$.mp.
21 # Fxa inhibit$.mp.
22 # vaso flux.mp.
23 # or/13-22
24 # 12 and 23
25 # (random$ or placebo$).ti,ab.
26 # (single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab.
27# controlled clinical trial$.ti,ab.
28 # RETRACTED ARTICLE/
29 # or/25-28
30 # (animal$ not human$).sh,hw.
31 # 29 not 30
32 # 24 and 31
61
LILACS
(MH Isquemia Miocárdica OR Myocardial Ischemi$ OR Isquemia Miocardi$ OR heart muscle ischemi$ OR angina$ OR myocardial
infarct$ OR heart infarct$ OR Cardiopatia Isquemi$ OR isquemia cardi$ OR Doença Isquemi$ OR MH Síndrome Coronario Agudo
OR Acute Coronar$ OR Síndrome Coronari$ OR Coronario Agudo$ OR Coronaria Agud$ OR Preinfarct$ OR Preinfart$ OR
Pre Infart$ OR Pre infarct$ OR ST OR STEMI OR NONSTEMI OR NON-STEMI OR NSTEMI OR SCA OR ACS) AND
(Fondaparinux or Idraparinux or Arixtra or Otamixaban OR xa inhibi$ OR xa inhibit$ OR xa inibi$ OR 10a inhibit$ OR 10a inhibi$
OR 10a inibi$ OR xa antagonist$ OR 10a antagonist$ OR xa block$ OR xa bloque$ OR factor X inhibit$ OR Inhibidor del factor X
OR Inibidor do fator X OR Fxa inhibit$ OR Inhibidor del FX$ OR Inibidor do FX$ OR vaso flu$ OR Razaxaban OR Fonadaparin
OR Dx 9065$)
WHAT’S NEW
Last assessed as up-to-date: 30 April 2009.
Date
Event
Description
15 February 2011
Feedback has been incorporated
Added a link to the Cochrane Editorial Unit’s report on feedback on anticoagulants reviews in the ’Published notes’ section
HISTORY
Protocol first published: Issue 2, 2008
Review first published: Issue 1, 2011
CONTRIBUTIONS OF AUTHORS
Viviana Brito and Agustin Ciapponi: conception and design of study, analysis and interpretation of data.
Viviana Brito, Agustin Ciapponi developed and executed the search strategies and drafted the review.
Viviana Brito, Agustin Ciapponi and Joey Kwong revised the review and approved the final review version to be published.
DECLARATIONS OF INTEREST
None of the authors has any known conflict of interest.
62
SOURCES OF SUPPORT
Internal sources
• No form of support is provided to the authors of this review, Argentina.
External sources
• No form of support is provided to the authors of this review, Argentina.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
The angiographic efficacy of the agents on study compared to UFH or LMWH in patients suffering from ACS, was not reported since
the available information to make an appropriate analyses was not enough. Similarly no reports could be done about their impact on
revascularization at 30 days, length of hospitalisation, readmission after discharge, risk of adverse events such as thrombocytopenia or
allergic reactions, as well as their effect on quality of life.
Subgroups analyses to explore efficacy and safety in patients older than 75 years, in those on treatment with high doses of factor Xa
inhibitors, or receiving other drugs which affect the coagulation cascade could not be analysed because not enough information was
available.
NOTES
Feedback was received on the protocol for this review. This feedback, along with those on other reviews and protocols on anticoagulants,
is available on the Cochrane Editorial Unit website at http://www.editorial-unit.cochrane.org/anticoagulants-feedback.
INDEX TERMS
Medical Subject Headings (MeSH)
Acute Coronary Syndrome [∗ drug therapy]; Anticoagulants [∗ therapeutic use]; Coronary Thrombosis [prevention & control]; Factor Xa [∗ antagonists & inhibitors]; Heparin [therapeutic use]; Heparin, Low-Molecular-Weight [therapeutic use]; Polysaccharides
[∗ therapeutic use]; Randomized Controlled Trials as Topic
MeSH check words
Humans
63

Factor Xa inhibitors for acute coronary syndromes (Review) The Cochrane Library

Transcription

Similar documents

Dr. Deng Xi Wei , MACC Chief Consultant in Cardiology Kiang Wu

ACIC2014 flyer3

Personal Disclosure

Cardiovascular Trends - Cardiac and Vascular Institute Symposium

Coding Cardiac Catheterization

Phidippides Cardiomyopathy and Beyond Feb 06, 2016

Imaging

PDF - European Echocardiography Course

T The clinical application of ACE inhibitors in coronary artery disease

Contents - Molecular Cancer Therapeutics