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

This talk discusses the principles of evidence-based guidelines in antithrombotic and thrombolytic therapy, including high vs low-quality evidence, strong vs weak recommendations, and the influence of values, preferences, and cost. It also explores the grading system used in guidelines.

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

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  1. 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

  2. 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

  3. 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. 2004;126 Suppl 3:688S-696S.

  4. 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.

  5. Schünemann HJ, et al. Chest. 2004;126 Suppl 3:174S-178S.

  6. Schünemann HJ, et al. Chest. 2004;126 Suppl 3:174S-178S.

  7. 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. 2004;126 Suppl 3:483S-512S.

  8. 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.

  9. Schunemann HJ, et al. Chest. 2004;126 Suppl 3:174S-178S Schünemann HJ et al. Chest 2004

  10. 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.org GRADE = Grading of Recommendations Assessment,Development and Evaluation. GRADE Working Group. BMJ. 2004;328:1490-9.

  11. 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.

  12. 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.

  13. RCT starts high –what moves quality down? • Flawed design and execution • Inconsistency • Indirectness • Imprecision • Reporting bias GRADE Working Group. BMJ. 2004;328:1490-9.

  14. Design and execution • Concealment • Intention-to-treat principle observed • Blinding • Completeness of follow-up • Early stopping GRADE Working Group. BMJ. 2004;328:1490-9.

  15. 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.

  16. 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

  17. 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. 2004;126 Suppl 3:483S-512S.

  18. 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.

  19. Clopidogrel better (Aspirin better) STROKE MI PAOD Total p = 0.26 0.66 0.0028 0.043 CAPRIE trial results:relative risk reduction PAOD = peripheral arterial occlusive disease. CAPRIE Steering Committee. Lancet. 1996;348:1329-39.

  20. CAPRIE trial results:absolute risk NNT 200 *p < 0.05 *p < 0.05 NNT = number needed to treat. CAPRIE Steering Committee. Lancet. 1996;348:1329-39.

  21. 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

  22. Audience at a prior thrombosis meeting

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

  24. Judgements about recommendations

  25. 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.

  26. 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

  27. Guyatt G, et al. Chest. 2004;126 Suppl 3:179S-187S.

  28. 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

  29. End

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