The Science of Guidelines The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy:...
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Transcript of The Science of Guidelines The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy:...
The Science of GuidelinesThe 7th ACCP Conference on Antithrombotic and
Thrombolytic Therapy: Evidence-Based Guidelines
Holger Schünemann, MD, PhD
Italian National Cancer Institute, Rome, Italy McMaster University, Hamilton, Canada
University at Buffalo, NY, USA
Topics for this talk
What makes guidelines evidence basedin 2005?
High- vs low-quality evidence Strong vs weak recommendations Example recommendation Example of the influence of values,
preferences, and cost Grading system
Evidence – recommendation: transparent link
Explicit inclusion criteria Comprehensive search
Standard consideration of study quality
Conduct/use meta-analysis
Grade recommendations
Acknowledge values and preferences underlying recommendations
What makes guidelines evidence based in 2005?
Schünemann J, et al. Chest.
2004;126 Suppl 3:688S-696S.
Background First ACCP guidelines in 1986 (J. Hirsh; J. Dalen) Initially aimed at consensus Group of experts and methodologists formally
convening every 2 to 3 years ~260,000 copies in 2001 7th conference held in 2003 87 panel members 22 chapters Across subspecialities Over 500 recommendations; 230 new Evidence-based recommendations
ACCP = American College of Chest Physicians.
Schünemann HJ, et al. Chest. 2004;126 Suppl 3:174S-178S.
Schünemann HJ, et al. Chest. 2004;126 Suppl 3:174S-178S.
The clinical question
Table 1 Eligibility criteria
Section Inclusion criteria
Population Intervention(s) or exposure
Outcome Methodology
… … … … …
4.1. Patients with unstable
angina, MI, TIA, and non-acute stroke
Any antiplatelet drug compared with placebo
or one or more other antiplatelet drug(s)
Death Stroke or recurrent stroke Other vascular events
RCTs
4.2 Patients with
cardioembolic stroke Oral anticoaluation
Death Stroke or recurrent stroke
RCTs
… … … … …
Albers GW, et al. Chest. 2004;126 Suppl 3:483S-512S.
Transparent link: from evidence to recommendations Explicit inclusion criteria
MI = myocardial infarction; RCTs = randomized controlled trials; TIA = transient ischaemic attack.
Comprehensive search for evidence Use questions to develop search strategy
– e.g. identify all search terms (MeSH and keywords) for antiplatelet drugs or MI
Search– Cochrane Database of Systematic Reviews– Database of Abstracts of Reviews of Effectiveness
– Cochrane Central Register of Controlled Trials – MEDLINE and EMBASE (1966 to December 2002)– ACP Journal Club
Provide search results– use EndNote® software – e.g. 490 citations on thrombolysis in acute stroke
ACP = American College of Physicians; MeSH = Medical Subject Headings.
Schünemann HJ et al. Chest 2004
Schunemann HJ, et al. Chest. 2004;126 Suppl 3:174S-178S
The ACCP grading system:GRADE* approach
Clear separation of 2 issues: Evidence: very low, low, moderate, or high
quality?– methodological quality of evidence– likelihood of bias
Recommendation: weak or strong?– trade-off between benefits and downsides– patient values and preferences
*www.GradeWorking-Group.orgGRADE = Grading of Recommendations Assessment,Development and Evaluation. GRADE Working Group. BMJ. 2004;328:1490-9.
Why grade recommendations?
People draw conclusions about the– quality of evidence and strength of recommendations
Systematic and explicit approaches can help– protect against errors, resolve disagreements
– communicate information
Change practitioner behaviour Strong: apply uniformly
– just do it
Weak: think about it– examine evidence yourself, consider patient circumstances
very carefully and explore with the patient
However, wide variation in approaches (GRADE)
GRADE Working Group. BMJ. 2004;328:1490-9.
Grades of recommendation:methodological quality
High (A): consistent results from RCTs or observational studies with very strong association and secure generalization
Moderate (B): inconsistent results from RCTs or RCTs with methodological limitations
Low (C): unbiased observational studies (e.g. well-executed cohort studies)
Very low (D): other observational studies (e.g. case series)
GRADE Working Group. BMJ. 2004;328:1490-9.
RCT starts high –what moves quality down?
Flawed design and execution Inconsistency Indirectness Imprecision Reporting bias
GRADE Working Group. BMJ. 2004;328:1490-9.
Design and execution
Concealment Intention-to-treat principle observed Blinding Completeness of follow-up Early stopping
GRADE Working Group. BMJ. 2004;328:1490-9.
Moving quality up:observational studies – high or moderate quality?
Strong association– strong association: RR > 2 or RR < 0.5– very strong association: RR > 5 or RR < 0.2
Dose–response relationship– bleeding risk associated with increasing INR
(blood thinning with warfarin)
Plausible confounders would have reduced the effect
INR = International Normalized Ratio;RR = relative risk. GRADE Working Group. BMJ. 2004;328:1490-9.
Grades of recommendation:strength of recommendations
Stronger recommendations (we recommend)– high-quality methods with large, precise effect – benefits much greater than downsides, or downsides much
greater than benefits– do it or don’t do it – we recommend– Grade 1
Weak recommendations (we suggest)– lower-quality methods with imprecise estimate– benefits not clearly greater or smaller than downsides– values and preferences very important– probably do it or probably don’t do it – we suggest– Grade 2
Example: stroke prevention
In patients with history of non-cardioembolic stroke or TIA…, we recommend treatment with an antiplatelet agent (Grade 1A). Aspirin, aspirin + XR dipyridamole, or clopidogrel are all acceptable options for initial therapy.
Clopidogrel: higher cost
If we had to make a choice between aspirin and clopidogrel, what would that choice be?
Albers GW, et al. Chest. 2004;126 Suppl 3:483S-512S. XR =extended release.
CAPRIE trial
Aspirin vs clopidogrel in patients at risk for cardiovascular event
19,185 patients, 3 subgroups with > 6,300 patients each (TIA/stroke; MI; peripheral arterial occlusive disease)
Mean duration of follow-up: 1.9 years Primary outcome: ischaemic stroke, MI,
or vascular death
CAPRIE Steering Committee.Lancet. 1996;348:1329-39. CAPRIE = Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events.
7.3
23.8
8.7
-3.7
-30
-20
-10
0
10
20
30
40
Relative risk reduction
%Relative risk
increase
Clopidogrel better
(Aspirin better) STROKE MI PAOD Total
p = 0.26 0.66 0.0028 0.043
CAPRIE trial results:relative risk reduction
CAPRIE Steering Committee. Lancet. 1996;348:1329-39. PAOD = peripheral arterial occlusive disease.
CAPRIE trial results:absolute risk
0
2
4
6
8
10
Absolute risk%
Clopidogrel 7.15 5.03 3.71 5.32
Aspirin 7.71 4.84 4.86 5.83
Stroke MI PAOD Total
*p < 0.05
*p < 0.05
NNT 200
CAPRIE Steering Committee. Lancet. 1996;348:1329-39. NNT = number needed to treat.
Which of the following recommendations should be given?
1. Aspirin over clopidogrel in patients with prior history of TIA/stroke?– OPTION 1
2. Clopidogrel over aspirin in patients with prior history of TIA/stroke?– OPTION 2
Audience at a prior thrombosis meeting
57% 43%
0%
20%
40%
60%
80%
100%
Aspirin Clopidogrel
Preferred recommendation
Values and preferences
Underlying values and preferences always present
Sometimes crucial
Important to make explicit
Judgements about recommendations
1. Benefit and downside evaluation
Benefits << downsides
Benefits ? downsides
Benefits ? downsides
Benefits >> downsides
? ?
2. Recommendation (wording)
STRONG
Recommend
don’t do it / should not do it
WEAKSuggestprobably don’t do it / might not do it
WEAKSuggestprobably do it/ might do it
STRONGRecommenddo it / should do it
Example: stroke prevention
In patients with history of non-cardioembolic stroke or TIA…
…we recommend treatment with an antiplatelet agent (Grade 1A). Aspirin, aspirin + XR dipyridamole, or clopidogrel are all acceptable options for initial therapy
…, we suggest use of clopidogrel over aspirin (Grade 2B)
Underlying values and preferences: This recommendation places a relatively high value on a
small absolute risk reduction in stroke rates, and a relatively low value on minimizing drug expenditures
Albers GW, et al. Chest. 2004;126 Suppl 3:483S-512S.
Judgement: benefits vs downsides*
(Quality of evidence) Relative importance of the outcomes
(benefits, harms, and burden) Baseline risk of outcomes Magnitude of the effect (RR) Absolute benefit and harm Precision of the estimates Cost
*Downsides include harm, burden, and cost
Grade of Recommendation Clarity of risk/benefit Quality of supporting evidence Strong recommendation High-quality evidence 1A
Benefits clearly outweigh risk and burdens, or vice versa
Consistent evidence from well-performed RCTs or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk.
Strong recommendation Moderate-quality evidence 1B
Benefits clearly outweigh risk and burdens, or vice versa
Evidence from RCTs with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design.
Strong recommendation Low-quality evidence 1C
Benefits appear to outweigh risk and burdens, or vice versa
Evidence from observational studies, or from RCTs with serious flaws. Any estimate of effect is uncertain.
Strong recommendation Very low-quality evidence 1D
Benefits possibly outweigh risk and burdens, or vice versa
Evidence from unsystematic clinical observations
Weak recommendation High-quality evidence 2A
Benefits closely balanced with risks and burdens
Consistent evidence from well-performed RCTs or overwhelming evidence of some other form. Further research is unlikely to change our confidence in the estimate of benefit and risk.
Weak recommendation Moderate-quality evidence 2B
Benefits closely balanced with risks and burdens, some uncertainly in the estimates of benefits, risks and burdens
Evidence from RCTs with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design.
Weak recommendation Low-quality evidence 2C
Uncertainty in the estimates of benefits, risks, and burdens;
Evidence from observational studies, or from RCTs with serious flaws. Any estimate of effect is uncertain.
Very weak recommendation Very low-quality of evidence 2D
Major uncertainty in the estimates of benefits, risks, and burdens;
Evidence from unsystematic clinical observations,
Guyatt G, et al. Chest. 2004;126 Suppl 3:179S-187S.
Summary
Guidelines require evidence-based methods GRADE approach to grading Integration of values and preferences Grade 1: strong recommendation Grade 2: weaker recommendation/suggestion High transparency between evidence and
recommendations
End