The Science of Guidelines The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines

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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

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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

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What makes guidelines evidence based in 2005?

• 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

Schünemann J, et al. Chest. 2004126 Suppl
3688S-696S.
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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.
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Schünemann HJ, et al. Chest. 2004126 Suppl
3174S-178S.
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Schünemann HJ, et al. Chest. 2004126 Suppl
3174S-178S.
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The clinical question

• Transparent link from evidence to
  recommendations
• Explicit inclusion criteria

MI myocardial infarction RCTs randomized
controlled trials TIA transient ischaemic
attack.
Albers GW, et al. Chest. 2004126 Suppl
3483S-512S.
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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.
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Schunemann HJ, et al. Chest. 2004126 Suppl
3174S-178S
Schünemann HJ et al. Chest 2004
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The ACCP grading systemGRADE 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.org
GRADE Grading of Recommendations
Assessment,Development and Evaluation.
GRADE Working Group. BMJ. 20043281490-9.
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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. 20043281490-9.
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Grades of recommendationmethodological 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. 20043281490-9.
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RCT starts high what moves quality down?

• Flawed design and execution
• Inconsistency
• Indirectness
• Imprecision
• Reporting bias

GRADE Working Group. BMJ. 20043281490-9.
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Design and execution

• Concealment
• Intention-to-treat principle observed
• Blinding
• Completeness of follow-up
• Early stopping

GRADE Working Group. BMJ. 20043281490-9.
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Moving quality upobservational studies high
or moderate quality?

• Strong association
• strong association RR gt 2 or RR lt 0.5
• very strong association RR gt 5 or RR lt 0.2
• Doseresponse relationship
• bleeding risk associated with increasing INR
  (blood thinning with warfarin)
• Plausible confounders would have reduced the
  effect

INR International Normalized RatioRR
relative risk.
GRADE Working Group. BMJ. 20043281490-9.
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Grades of recommendationstrength 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 dont 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 dont do it we
  suggest
• Grade 2

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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?

XR extended release.
Albers GW, et al. Chest. 2004126 Suppl
3483S-512S.
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CAPRIE trial

• Aspirin vs clopidogrel in patients at risk for
  cardiovascular event
• 19,185 patients, 3 subgroups with gt 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.
19963481329-39.
CAPRIE Clopidogrel versus Aspirin in Patients
at Risk of Ischaemic Events.
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CAPRIE trial resultsrelative risk reduction
PAOD peripheral arterial occlusive disease.
CAPRIE Steering Committee. Lancet.
19963481329-39.
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CAPRIE trial resultsabsolute risk
NNT 200
p lt 0.05
p lt 0.05
NNT number needed to treat.
CAPRIE Steering Committee. Lancet.
19963481329-39.
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Which of the following recommendations should be
given?

• Aspirin over clopidogrel in patients with prior
  history of TIA/stroke?
• OPTION 1
• Clopidogrel over aspirin in patients with prior
  history of TIA/stroke?
• OPTION 2

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Audience at a prior thrombosis meeting
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Values and preferences

• Underlying values and preferences always present
• Sometimes crucial
• Important to make explicit

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Judgements about recommendations
1. Benefit and downside evaluation 1. Benefit and downside evaluation 1. Benefit and downside evaluation 1. Benefit and downside evaluation 1. Benefit and downside evaluation
Benefits ltlt downsides Benefits ?? downsides Benefits ?? downsides Benefits ?? downsides Benefits gtgt downsides
?? ?? ?? ?? ??
2. Recommendation (wording) 2. Recommendation (wording) 2. Recommendation (wording) 2. Recommendation (wording) 2. Recommendation (wording)
STRONG Recommend dont do it / should not do it WEAK Suggest probably dont do it / might not do it WEAK Suggest probably dont do it / might not do it WEAK Suggest probably do it / might do it STRONG Recommend do it / should do it
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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. 2004126 Suppl
3483S-512S.
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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
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Guyatt G, et al. Chest. 2004126 Suppl
3179S-187S.
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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

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End
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Disclosure

• Research funding
• AstraZeneca, Pfizer, Amgen
• Honoraria/consultant fees ? deposited in
  University at Buffalo or McMaster University
  research accounts
• AstraZeneca, Boehringer Ingelheim, Pfizer, Amgen

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Values and preferences

• If available, should be integrated into
  recommendations and described by guideline
  developers
• If unavailable, adequate representation of
  patients or societys interests is assumed
• To increase the likelihood of adequate
  representation, the process included review of
  recommendations by research methodologists,
  practicing generalists, and specialists

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Schünemann HJ et al. Chest 2004
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Grades of recommendation
Guyatt G, et al. Chest. 2004126 Suppl
3179S-187S.
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Grades of recommendation
Guyatt G, et al. Chest. 2004126 Suppl
3179S-187S.