George Wells - International Society of Evidence

Transcription

3rd International Society for Evidence-Based
Health Care Conference
NTUH International Convention Center
Taipei, Taiwan
November 9, 2014
George Wells
Application of Systematic
Review and Meta-Analysis in
Health Technology Assessment
Does HTA ‘need’ SR-MA-NMA?
INAHTA
“Health technology can be defined broadly as: any
intervention that may be used to promote health, to prevent,
diagnose or treat disease or for rehabilitation or long-term
care. This includes the pharmaceuticals, devices, procedures
and organizational systems used in health care.”
“Health technology assessment is a multi-disciplinary field of
policy analysis that studies the medical, social, ethical, and
economic implications of development, diffusion, and use of
health technology.”
EUnetHTA
INAHTA
“Despite its policy goals, HTA must always be firmly rooted
in research and the scientific method.”
Does HTA ‘need’ SR-MA-NMA?
•
Health Technology Assessment Process - 2 of the steps identified by
CADTH in the process are:
•
“A protocol is established for the assessment, describing the strategy
to identify and select clinical and economic information, and how this
information will be quality-rated, abstracted, and synthesized. The
protocol may also describe how a primary economic evaluation or
survey will be conducted.”
•
“Data from research studies and other scientific sources are
systematically gathered, analyzed, and interpreted by the review team.
Well-defined and transparent processes are used to minimize potential
bias.”
Outline
Topic
Content
Illustration 1
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Illustration 2
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Illustration 3
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Illustration 4
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Review of the fundamentals
Systematic review (SR)
Meta-analysis (MA)
Network meta-analysis (NMA)
New oral anticoagulants for patients with atrial
fibrillation
Antithrombotic therapies for patients with
atrial fibrillation
Triptans for the treatment of acute migraines
in adults
Risk of serious infection with biologics in
treating patients with rheumatoid arthritis
Types of Reviews
Scoping Review
• a quick literature review to provide an overview of the type, extent
and quantity of evidence available on a given topic
• undertaken when feasibility is an issue - either because the
potentially relevant literature is thought to be vast and diverse or
there is suspicion that not enough literature exists
• entails systematic selection, collection and summaries of existing
knowledge to identify where there is sufficient evidence to conduct a
full synthesis or identify evidence gaps and future research needs
Rapid Review
• a streamlined approach to synthesizing evidence in a timely manner,
typically for the purpose of informing emergent decisions faced by
decision makers in health care settings
• uses methods to accelerate or streamline traditional systematic
review processes
• need to establish transparent methodologies and understand
implications of what is lost when methods associated with full
systematic review are streamlined
Systematic Review
Application of scientific strategies that limit bias to the systematic assembly,
critical appraisal and synthesis of all relevant studies on a specific topic
Steps in a Systematic Review
Clearly formulated
question
Pose question using PICO
Comprehensive data
search
Need well formulated/coordinated effort; various sources; usually begin with
searches of bibliographic databases; publication bias and considering unpublished research
Unbiased selection and
extraction process
Do independently in duplicate for study selection and data extraction; selection
based on PICOS; data extraction includes PICO characteristics, study design/methods,
study results, quality items, all relevant benefits and harms
Critical appraisal of data
Report: Description of Studies - table of characteristics of included studies (reference,
design, PICO elements, quality assessment); Quality Assessment - Report quality
assessment instrument/risk of bias used
Analysis of data
MA and/or NMA
Sensitivity and subgroup
analyses
Subgroup analysis - pre-specify hypothesis-testing subgroup analyses; Sensitivity analysis test robustness of results relative to key features of the studies and key assumptions and
decisions
Interpretation of results
PRISMA; interpret results in context of current health care; state methodological limitations;
interpret results in light of other available evidence; make recommendations clear and
practical; propose research agenda
Types of Analysis
complexity
no
analysis
study
level
analysis
metaanalysis
network
metaanalysis
Meta-Analysis
Outcome: effect estimate (EE)
Binary
Continuous
Odds Ratio (OR)
Risk Ratio (RR)
Risk Difference( RD)
EE, se(EE)
or basic data:
frequency e/n
Mean Difference (MD)
Standardized Mean Difference (SMD)
EE, se(EE)
or basic data:
n, mean, sd
Time to Event
Hazard Ratio
(HR)
EE,
se(EE)
Count
Rate Ratio
Rate Difference
EE, se(EE)
or basic data:
n, count,
duration
Heterogeneity: clinical (PICO), methodological (design/conduct)
Procedures: do not pool, meta-regression, sensitivity, subgroup
Fixed effects model (FE); Random effects model (RE)
Procedures: subgroup
Overall estimates and analyses
Display: Forest Plots, Summary of Findings (SoF) tables
Methods to combine and summarize
the results of several studies
• methods focus on contrasting and
comparing results in anticipation
of identifying consistent patterns
and sources of disagreements
Network Meta-Analysis
Outline
Topic
Content
Illustration 1
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Illustration 2
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Illustration 3
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Illustration 4
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Meta-analysis (MA)
fibrillation
atrial fibrillation
in adults
Illustration 1:
NEW ORAL ANTICOAGULANTS FOR
PATIENTS WITH ATRIAL FIBRILLATION
New oral anticoagulants
• Novel agents have been developed to replace vitamin K
antagonists (VKAs) such as warfarin
– direct thrombin inhibitor, dabigatran
– direct FXa inhibitors, rivaroxaban and apixaban
• Novel agents
– Orally administered
– Do not require monitoring of the anticoagulant effect
– Few drug interactions and no food interactions
– Can be applied at a fixed dose;
– Do not have an antidote in case of bleeding and need
to discontinue the medication in an urgent situation
Questions - clinical evaluation
• What is the clinical effectiveness and safety of new oral
anticoagulants compared to warfarin?
• How do the new oral anticoagulants compare to
warfarin when considering the time spent in the
therapeutic range (TTR)?
• How do the new oral anticoagulants compare to
warfarin by risk level (CHADS2 score ) and age?
Systematic Review - PICO
Inclusion criteria
Population
Patients with non-valvular atrial fibrillation
Intervention
 Apixaban
 Dabigatran
 Rivaroxaban
Comparator
 Warfarin
Outcomes
Stroke or systemic embolism, major bleeding, all-cause mortality,
gastrointestinal bleeding, myocardial infarction, intracranial
hemorrhage, etc.
Study design
Published active and non-active controlled RCTs and Non
Randomized studies of at least 12 weeks in duration
Key Studies
Study
Treatments Compared
N
Design
RE-LY
• Warfarin
• Dabigatran 150mg bid
• Dabigatran 110mg bid
18,113
Randomized, openlabel with blinded
endpoint evaluation,
non-inferiority
ROCKET-AF
• Warfarin
• Rivaroxaban 20mg qd
14,264
Randomized, double
blind, non-inferiority
ARISTOTLE
• Warfarin
• Apixaban 5 mg bid
18,201
Randomized, double
blind, non-inferiority
Evidence Network
Bayesian Mixed Treatment
Comparison (MTC) Network
Meta-Analysis
Network meta-analysis results
*ITT: 0.88
(0.75, 1.04)
Questions – economic evaluation
• What is the cost-effectiveness of the new oral
anticoagulants compared to warfarin?
• What is the cost effectiveness of the new oral
anticoagulants compared to warfarin stratified by TTR,
age and CHADS2 score
Cost Effectiveness Acceptability Curve
100%
Probability Treatment is Optimal
90%
Warfarin
80%
70%
60%
Dabigatran 150mg
50%
Apixaban
40%
30%
20%
10%
Rivaroxaban
Dabigatran 110mg
0%
$0
$20,000
$40,000
$60,000
$80,000
Threshold Value for a QALY
$100,000
Conclusion
• Rivaroxaban and dabigatran 110mg were unlikely to be cost
effective
• In different scenarios, apixaban or dabigatran 150mg were
optimal
• Choice between these two options may come down to the
price of apixaban and further evidence on the impact of major
and minor bleeds with dabigatran
CADTH Recommendations for NOACs in AF
Therapeutic Review
Title
Date
NOACs for the Prevention
of Thromboembolic Events
in Patients with AF
Recommendation
June, 2012 Recommendation 1:
CDEC recommends that new oral anticoagulant agents should be
considered for the prevention of SSE in patients with non-valvular
AF in whom warfarin is indicated, and who meet all of the following
criteria:
1. Are unable to achieve adequate anticoagulation with warfarin,
and
2. Have a CHADS2 score ≥ 2*.
*Of Note: Patients with a CHADS2 score of 1 may be considered for
treatment with warfarin or an appropriate dose of dabigatran, based
on individual clinical factors.
Recommendation 2:
CDEC recommends that the selection of a new oral anticoagulant
agent should be made based on individual clinical factors
.
AF = atrial fibrillation; CADTH = Canadian Agency for Drugs and Technologies in Health; INR = international normalized
ratio; NOAC = new oral anticoagulants; SSE = stroke and systemic embolism; TIA = transient ischemic attack; VEF =
ventricular ejection fraction.
‡Targeted date.
Illustration 2:
ANTITHROMBOTIC THERAPIES FOR
PATIENTS WITH ATRIAL FIBRILLATION
Aims
• To conduct a systematic review and network metaanalysis of the clinical evidence pertaining to
antithrombotic agents for the prevention of morbidity
and mortality in patients with non-valvular AF.
• To assess the impact of age, CHADS2 score and time
spent in the therapeutic range (TTR) on the clinical
safety and efficacy of antithrombotic agents.
• To conduct a cost-effectiveness analysis of
antithrombotic agents based on the results of the
network meta-analysis.
Antithrombotic Drugs Used in AF
Drug Class
Anticoagulants
Generic Drug Name
Mechanism of Action
Dosage and
Administration*
Warfarin
VKA
Dose adjusted to a target
INR of 2.0 to 3.0
Dabigatran
Direct thrombin inhibitor
150 mg BID†
Apixaban
5 mg BID
Direct Factor Xa inhibitor
Rivaroxaban
Antiplatelet
Agents
ASA
Clopidogrel
20 mg OD
Platelet aggregation
inhibitor
80 mg – 325 mg OD
75 mg OD
ASA = acetylsalicylic acid; BID = twice daily; INR = international normalized ratio; OD = once daily; VKA = vitamin K
antagonist.
* All drugs are administered orally.
† Dabigatran 110 mg BID may be considered in elderly patients at risk of bleeding.
Evidence Network
NMA Results - Comparison to standard
dose VKA: OR (95%credible interval)
All cause stroke or
systemic embolism
Major bleeding
NMA Results - Comparison between
antithrombotic therapies: OR (95%credible
interval)
Major Bleeding
Stroke or Systemic Embolism
Summary - Anticoagulants
• Overall, NOACs compare favorably with warfarin:
– NOACs are associated with lower rates of SSE and/or major bleeding
– Different NOACs are not readily distinguishable among one another
• CHADS2 <2
– The benefit/risk of the NOACs is positive compared to warfarin, more
so in terms of reduced bleeding than enhanced prevention of SSE, but
largely similar among the NOACs
– This conclusion should be limited to patients with a CHADS2 score = 1
• CHADS2 ≥2
– As for CHADS2 <2, the benefit/risk of the NOACs is positive compared
to warfarin
Summary - Anticoagulants vs.
Antiplatelets
• Overall, antiplatelets have a less favorable benefit/risk
profile than the NOACs or warfarin
• CHADS2 <2
– Less favorable benefit/risk profile due to failing to reduce the risk of
SSE while being associated with a similar or increased risk of major
bleeding
– This conclusion should be limited to patients with a CHADS2 score = 1
• CHADS2 ≥2
– Consistent CHADS2 <2 subgroup
Cost Effectiveness Acceptability Curve:
CHADS2 score <2
Cost Effectiveness Acceptability Curve:
CHADS2 score ≥2
Conclusions
• Uncertainty over whether apixaban or dabigatran is cost
effective
– Probability of cost effectiveness similar for both
– Each is favoured in different potential sub groups
Major Clinical Recommendations for
Antithrombotic Management in AF
Risk of
stroke
American
Guidelines
ACCP
European Guidelines
ECS
No therapy
Higher risk* = OAC
Lowest risk* = No therapy
OAC
OAC
OAC
Dabigatran, rivaroxaban, apixaban
recommended over warfarin.†
Dabigatran recommended
over warfarin.‡
recommended over warfarin.
OAC
OAC
OAC
Dabigatran recommended
over warfarin.‡
recommended over warfarin.
Canadian Guidelines
CCS
Higher risk* = OAC
Low
(CHADS2 = 0)
Intermediate
(CHADS2 = 1)
High
(CHADS2 ≥2)
Lower risk* = ASA
Lowest risk* = No therapy
ASA = acetylsalicylic acid; OAC = oral anticoagulants; VKA = vitamin K antagonist.
* Based on the consideration of other risk factors (age 65-74 years, female sex and presence of vascular
disease).
† Preference for newer agents less clear in patients under warfarin with stable INR and no bleeding
complications.
‡ At the time the American Guidelines were published (2012), only dabigatran received regulatory approval
for use in AF4 and therefore, the Guidelines do not make recommendations for apixaban and rivaroxaban.
Illustration 3:
TRIPTANS FOR THE TREATMENT OF
ACUTE MIGRAINES IN ADULTS
Question – clinical evaluation
• What is the evidence for the efficacy and safety of triptans
(alone or in combination with other drugs) for acute
treatment of migraines in adults compared to: other
triptans agents, nonsteroidal anti-inflammatory drugs
(NSAIDs), acetylsalicylic acid (ASA), acetaminophen,
ergots, opioids, or antiemetics?
Study Population
Adult patients with acute migraine headache
Index Node
Placebo
Comparisons
Triptans: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan,
zolmitriptan.
•
Triptans vs. placebo
•
Triptans vs. triptans (alone or in combination with other acute migraine
therapies) (e.g., NSAIDs, ASA, acetaminophen, ergots, opioids, antiemetics)
•
Triptans vs. other acute pharmacologic migraine treatment options (e.g.,
NSAIDs, ASA, acetaminophen, ergots, opioids, antiemetics)
•
Self-administered
Outcomes
Efficacy: All headache relief outcomes
will be considered.
•
•
•
•
•
•
•
•
Time to freedom from pain
Headache relief within 2/4 hrs
Freedom from pain within 2 /4 hrs
Sustained headache response at 24
hrs
Sustained freedom from pain at 24
hrs
Use of rescue medication
Headache specific quality of life
(QOL)
Functional health status and health
related QOL
Safety: All drug safety and adverse event
outcomes will be considered.
•
•
•
Participants with any adverse event
during the 24 hours post-dose
Participants with particular adverse
events during the 24 hours post-dose
Withdrawals due to adverse events
Identification
Additional records identified
through other sources
(n = 78 )
Eligibility
Screening
Records after duplicates removed
(n = 1,142 )
Records screened
(n = 1,142)
Records excluded
(n = 730)
Full-text articles assessed
for eligibility
(n = 412)
Full-text articles excluded,
w/ reasons
(n = 210)
Studies included in
qualitative synthesis
(n = 202)
Included
Search
Results
Records identified through
database searching
(n = 1,694 )
Studies included in metaanalysis
(n = 202)
(n = 134 w/ single attack
data)
Abstract = 30
Duplicate = 34
Population = 10
Non-English = 9
Study Design = 108
Intervention = 15
Could not locate = 4
Outcomes Evaluated
Meta-Analysis
No Analysis
2h headache relief
2h headache relief
Time to freedom from pain
2h freedom from pain
2h freedom from pain
Headache-specific QOL
24h sustained headache relief
24h sustained headache relief
Absenteeism
24h sustained freedom from pain
24h sustained freedom from pain
Medication Overuse Headache
Withdrawals due to AE
Use of rescue medications
Functional status
AEs
Use of rescue medications
SAEs
Common AEs
NMA Results - 2h headache relief
NMA Results - Comparisons between Triptans
– SD Tablets
Almotriptan
Elitriptan
Frovatriptan
Naratriptan
Almotriptan
Elitriptan
Frovatriptan
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan
2h
2h
24h
24h
Rescue
Relief F Pain Relief F Pain Meds
Rizatriptan
Sumatriptan Zolmitriptan
MA Results - Withdrawals due to AEs
Some high level thoughts on results of the
NMA analysis
•
SD triptans
– relieved headaches within 2 hours in 43 to 76% of patients
– freedom from pain within 2 hours was less common, with only about 18 to
50% of patients
– provided sustained headache relief at 24 hours in 29 to 50% of patients
– sustained freedom from pain at 24 hours was less common, with only
about 18 to 33% of patients
– significant effect on reducing the use of rescue medications compared to
placebo ranging from 20 to 34%
•
•
•
More favorable results observed for rizatritan and elitriptan
Less favorable results for naratriptanes
SD triptan tablets were associated with equal or more favorable results than
NSAIDs, aspirin, acetaminophen for 2h outcomes; the exception being
naratriptan and frovatriptan
SD triptans were associated with more favorable results than ergots for 2
hour and 24hour outcomes
Limited data for sub-groups and side effects
•
•
ODPRN (Ontario Drug Plan Research
Network)
http://www.odprn.ca/wp-content/uploads/2014/04/triptanconsolidated-final-april-7-21.pdf
Illustration 4:
RISK OF SERIOUS INFECTION WITH
BIOLOGICS IN TREATING PATIENTS
WITH RHEUMATOID ARTHRITIS
Aim – clinical evaluation
• To compare the risk of serious infections with biologics with
non-biologic traditional DMARDs for the treatment of RA
and subpopulations within RA (MTX experienced, MTX
naïve, TNF experienced) using network meta-analysis to
synthesize data from randomized controlled trials
Systematic Review - PICOS
Inclusion criteria
Population
Adults with RA
Intervention
Biologics in any dose included
 tumor necrosis factor blockers (etanercept,
adalimumab, infliximab, golimumab, certolizumab
pegol)
 IL-1 antagonist (anakinra)
 IL-6 antagonist (tocilizumab)
 anti-CD28 (abatacept)
 anti-B cell (rituximab)
Tofacitinib
Comparator
Placebo, traditional DMARDs (including MTX, alone or in
combination), another biologic
Outcomes
Serious infection (mostly included infections associated
with death, hospitalization, or the use of intravenous
antibiotics)
Study design
RCTs
Selection of studies
database searching
(n = 6,474)
(n = 22)
(n = 5,763)
Records screened
(n = 5,785)
for eligibility
(n = 324)
Studies eligible for inclusion
(any outcome)
(n = 148)
Eligible studies reporting
data for serious infection
(n = 106)
Records excluded
(n = 5,461)
Full-text articles excluded:
176
Abstracts (n = 27),
Long-term extension (n =
2), Duplicates (n = 18)
Not one of biologics (n =
15),
No reportable Outcome (n
= 32),
Not randomized (n = 71),
Not RA (n = 5),
Pooled/post-hoc analysis
(n = 5),
Escalation dose (n = 1)
Evidence networks for serious infection
Combined Population
(106 RCTs, N=42,330)
MTX experienced
(71 RCTs, N=29,167)
MTX naïve
(24 RCTs, N=8,375)
TNF Experienced
(11 RCTs, N=4,788)
Summary NMA results – comparison of serious
risk infection with traditional DMARD
monotherapy
Summary NMA results – risk of serious
infection (OR, 95% Crl), all populations
OR for serious infections are
calculated based on rowdefining treatment versus
column-defining treatment
Significant results are in bold
Summary of results
SR identified 106 trials that included any of the biologic and serious
infections
Compared to traditional DMARDs,
• standard-dose biologic and high-dose biologic were associated with
an increased risk of serious infections
• low-dose biologics were not
The risk was lower in patients who are MTX naïve compared with
traditional DMARD- or anti-TNF-biologic-experienced
Next steps …
• Analysis of efficacy and other safety outcomes
• Economic evaluation
• Recommendation to be made by
• Drug Safety and Effectiveness Network (DSEN)
Outline
Topic
Content
Illustration 1
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Illustration 2
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Illustration 3
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Illustration 4
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Meta-analysis (MA)
fibrillation
atrial fibrillation
in adults
Canadian Collaboration for Drug Safety, Effectiveness and Network Meta-Analysis
Questions or Thoughts
Outline
Topic
Content
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Meta-analysis (MA)
Illustration 1
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Illustration 2
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Illustration 3
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Illustration 4
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Illustration 5
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fibrillation
atrial fibrillation
in adults
Testosterone replacement therapies for men
with androgen deficiency
Illustration 5:
TESTOSTERONE REPLACEMENT
THERAPIES FOR MEN WITH ANDROGEN
DEFICIENCY
Question – clinical evaluation
• What is the current evidence for the efficacy and
safety of testosterone replacement therapy in
adult men with androgen deficiency?
Population
Adult men with androgen deficiency (serum total testosterone ≤ 12 nmol/L)
Index Node
Placebo
Comparisons
Testosterone replacement therapies currently available in Canada: testosterone undecanoate (Andriol),
testosterone cypionate (Depo-Testosterone), testosterone enanthate (Delatestryl), testosterone (Androderm,
Testim 1%, Androgel 1%, Axiron).

TRT v. placebo

TRT v. TRT (same TRT at different dose or different TRT)
Outcomes:
Efficacy



Serum testosterone level
Quality of life
Resolution of symptoms (erectile dysfunction, libido, depression, fractures, activities of daily living)
Outcomes:
Safety

Cardiovascular death, myocardial infarction, stroke, erythrocytosis, serious adverse, events, newly
diagnosed disease (diabetes, heart disease, or prostate cancer), skin or site reactions
Study Types:
Efficacy
Randomized controlled trials (RCTs)
Study Types:
Safety
RCTs and non-randomized studies with a comparator
Exclusions
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

Studies not conducted in English
Testosterone products or delivery formulations (e.g., buccal cavity, implantable pellets) not currently
approved by Health Canada.
Studies published only in abstract format
Uncontrolled non-randomized studies
Studies involving less than 10 men
Duration shorter than 3 months
Identification
(n = 0)
Eligibility
Screening
(n = 6,140)
Included
Search
Results
database searching
(n = 9,149)
Records screened
(n = 6,140)
for eligibility
(n = 868)
Included
• RCTs: n = 55 reports
(n = 39 unique RCTs)
• NRS: n = 25 reports
(n = 24 unique studies
Records excluded
(n = 5272)
Full-text articles excluded
(n = 788)
Women or children = 17
Not low T = 190
Did not evaluate TRT = 59
Study design = 208
Non-HC TRT = 64
No original data = 51
Less than 10 participants = 30
Less than 3 mo = 70
Non-English = 57
Other = 39
No full text = 3
Treatments Evaluated
TRT product
Brand specified
Andriol
Included doses
Route
20 mg/d, 40 mg/d, 120–160 mg/d
Oral
Depo-Testosterone
No studies
Intramuscular injection
Delatestryl
125 mg/wk, 150 mg/2 wk, 200 mg/2 wk Intramuscular injection
Androderm
Testim 1%
Androgel 1%
Axiron
Brand not specified
5 mg/d
50–150 mg/d
5 mg/d, 25–100 mg/d
No studies
Patch
Topical gel
Topical gel
Topical solution
Testosterone gel
Testosterone enanthate
125 mg/d
100 mg/wk, 200 mg/2wk, 50–400
mg/1–2 wk, 250 mg/3wk, 300 mg/3wk
Topical gel
Testosterone undecanoate 160 mg/d
Oral
Testosterone cypionate
200 mg/2wk
Outcomes Evaluated
Network
Meta-Analysis
Testosterone level,
Quality of life
Erectile dysfunction
Libido
Meta-Analysis
No Analysis
Cardiovascular death
Myocardial infarction
Stroke
Newly diagnosed prostate cancer
Fracture
Activities of daily living
Newly diagnosed diabetes
Newly diagnosed heart disease
Depression
Serious adverse events
Erythrocytosis
Skin reactions
Evidence network: Total testosterone level at
3 months
• 638 people
• 13 comparisons
• 10 two-arm studies
• 1 three-arm study
NMA Results: Total testosterone level
at 3 months (v. placebo)
Mean difference (SD)
Treatment
Androderm, patch, 5 mg/d
Androgel 1%, gel, 50 mg/d
Testim 1%, gel, 50–150 mg/d + sildenafil
Testim 1%, gel, 50 mg/d
Andriol, oral, 120 mg/d
Delatestryl, IM, 200 mg/2wk
Testosterone enanthate, IM, 100 mg/wk
Testosterone enanthate, IM, 200 mg/2wk
Testosterone cypionate, IM, 200 mg/2wk
Testim 1%, gel, 100 mg/d
Andriol, oral, 120–160 mg/d
Testosterone undecanoate, oral, 160 mg/d
Testosterone enanthate, IM, 300 mg/3wk
*Statistically significant (p < 0.05).
Serum
testosterone
level, 3 mo
Quality of life
(AMS)
Erectile
dysfunction
(IIEF, ED
domain)
Libido (IIEF,
sexual
function
domain)
Depression
(Beck)
5.35 (2.52)*
10.34 (2.72)*
18.46 (3.41)*
10.21 (2.81)*
2.26 (2.77)
7.56 (3.51)*
–4.34 (2.68)
15.66 (3.88)*
6.30 (3.17)
8.66 (2.91)*
–0.16 (3.26)
---------------
--1.53 (19.54)
--1.05 (18.87)
--2.49 (19.16)
----------–0.77 (13.51)
--–18.78 (18.97)
–0.29 (19.35)
----–3.16 (18.78)
--3.29 (8.31)
--1.40 (11.41)
--------------–0.13 (11.48)
----3.62 (8.18)
-------
–0.94 (4.26)
–1.65 (4.30)
--0.28 (5.24)
–0.14 (5.03)
--0.97 (5.22)
--------–1.11 (5.18)
0.51 (7.31)
-----------
–2.01 (4.75)
0.02 (3.41)
------–0.69 (3.43)
------–2.29 (3.36)
--------–3.10 (3.39)
–4.08 (3.40)
–1.20 (3.38)
---
NMA Results: Total testosterone level at 3 mo
Head-to-head comparisons
1
2
3
4
5
6
7
8
9
10
11
1
2
3
The red cell indicates that
the ‘row’ treatment is
significantly worse than
the ‘column’ treatment.
4
5
6
7
8
The grey cell indicates that
there is no significant
difference between the
‘row’ and ‘column’
treatment.
9
10
11
1.
2.
3.
4.
5.
6.
Androderm patch 5 mg/d
Androgel 1% gel 50 mg/d
Testim 1% gel 50-150 mg/d+sildenafil
Testim 1% gel 50 mg/d
The green cell indicates
that the ‘row’ treatment is
significantly better than
the ‘column’ treatment.
7.
8.
9.
10.
11.
Andriol oral 120 mg/d
Delatestryl, IM, 200 mg/2wk
Testosterone enanthate IM 100 mg/wk
Testosterone enanthate IM 200 mg/2wk
Testosterone cypionate IM 200 mg/2wk
MA Results: Safety outcomes
Outcome
CV death
MI
Stroke
Prostate cancer
SAE
Comparison
No. of studies
(no. estimable)
OR (95% CI)
I2
TRT v. placebo
5 (2)
8.62 (1.17–63.77)*
0%
T gel v. placebo
3 (2)
8.62 (1.17–63.77)*
0%
TRT v. placebo
3 (2)
1.85 (0.19–17.86)
64%
T gel v. placebo
2 (2)
1.85 (0.19–17.86)
64%
TRT v. placebo
4 (3)
0.50 (0.05–4.85)
25%
T gel v. placebo
2 (2)
1.04 (0.06–16.60)
47%
TRT v. placebo
7 (6)
1.17 (0.42–3.27)
0%
T gel v. placebo
4 (2)
1.80 (0.19–17.48)
0%
IM v. placebo
2 (2)
0.78 (0.20–3.08)
0%
TRT v. placebo
4 (3)
1.61 (0.77–3.36)
30%
T gel v. placebo
4 (3)
1.61 (0.77–3.36)
30%
Narrative Results: Skin reactions
• 10 studies
• Mild skin irritation, rashes, allergic contact dermatitis,
moderate skin erythema, intense edema, blistering
• Most commonly associated with topical preparations
Summary of efficacy results:
Compared to placebo:
– Several TRTs were associated with a substantive increase in
serum testosterone level at 3 months.
– No significant effects in quality of life, erectile dysfunction, libido,
or depression were identified.
Head-to-head comparisons:
– Androgel 1% (100 mg/d) was associated with more favourable
serum testosterone levels at 3 months than the other TRTs.
– Andriol (120 mg/d) was associated with less favourable serum
testosterone levels at 3 months than the other TRTs.
– No significant differences among the TRTs were identified for
quality of life, erectile dysfunction, libido, and depression.
Summary of safety results:
Meta-Analysis/Narrative
•
Serious adverse events: T gel (19 SAEs) v. placebo (12 SAEs)
OR 1.61 (95% CI 0.77–3.36).
•
Other safety data were limited:
• CV death – 4 deaths in T gel group and zero in placebo.
• MI - 2 events in T gel group and 1 in placebo.
• Stroke – 1 event in T gel group and 1 in the placebo.
• Prostate cancer - 2 cases in T gel group and 1 in placebo; 4 in
testosterone IM and 5 in placebo.
• Heart disease (1 study) – 2 cases in testosterone and 4 in
placebo.
•
Skin reactions ranged from mild irritation to intense edema and blistering
and were primarily associated with topical preparations
ODPRN (Ontario Drug Plan Research
Network)
Recommendation in process
Outline
Topic
Content



Meta-analysis (MA)
Illustration 1

Illustration 2

Illustration 3

Illustration 4

Illustration 5

fibrillation
atrial fibrillation
in adults
Testosterone replacement therapies for men
with androgen deficiency
Features of Various Reviews
Narrative
Rapid
Systematic
QUESTION
Broad
Specified a priori (may
include broad PICOS)
Focused (PICOS)
SOURCES
Usually unspecified;
possibly biased
Sources may be limited
but sources/strategies
made explicit
Comprehensive sources
searched and explicit
strategies
SELECTION
Unspecified;
possibly biased
Criterion-based;
uniformly applied
Criterion-based;
uniformly applied
APPRAISAL
Variable
Rigorous
Rigorous; critical appraisal
SYNTHESIS
Usually qualitative
Descriptive summary/
categorization of data
Quantitative summary +/meta-analysis
INFERFENCE
Sometimes evidence
based
Limited/cautious
interpretation of findings
Usually evidence based
Summary

George Wells - International Society of Evidence

Transcription

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