1. Why Grade Recommendations? strong recommendationsstrong recommendations –strong methods –large precise effect –few down sides of therapy weak recommendationsweak recommendations –weak methods – imprecise estimate – small effect – substantial down sides

2. Why Grade Recommendations? strong recommendationstrong recommendation –one size fits all –expect uniform clinician behavior weaker recommendationweaker recommendation –expect action to vary

3. Grading recommendations is not grading studies developing recommendationsdeveloping recommendations –grade (assess) individual studies –grade (assess) overall evidence –grade recommendations that flow from evidence rating schemes for individual studiesrating schemes for individual studies –prognosis, diagnosis, management recommendations focus on patient outcomerecommendations focus on patient outcome –showing a test, or prognostic tool, is accurate generally not enough –RCTs of screening tests

4. An ideal grading system simplesimple clear and separate consideration of two issuesclear and separate consideration of two issues –methodological quality of evidence likelihood of biaslikelihood of bias –trade-off between benefits and risks

5. Which grading system to use? many availablemany available –Australian National and MRC –Oxford Center for Evidence-based Medicine –Scottish Intercollegiate Guidelines (SIGN) –US Preventative Services Task Force –American Heart Association conflict of interest (point of view)conflict of interest (point of view) –American College of Chest Physicians –Cochrane-related group led by Andy Oxman

6. What makes weaker evidence? weaker study designweaker study design –basic –detailed design and execution inconsistencyinconsistency indirectnessindirectness reporting biasreporting bias

7. Methodological Quality study designstudy design –randomization –quasi-randomization –observational study detailed design and executiondetailed design and execution –concealment –balance in known prognostic factors –intention to treat principle observed –blinding –completeness of follow-up

8. Consistency evidence weaker if results differevidence weaker if results differ if inconsistency, look for explanationif inconsistency, look for explanation –patients –intervention – outcome –methods

9. Relative Risk of Conversion to Sinus Rhythm Amiodarone vs Placebo or Digoxin or CCB Favours Control Favours Amiodarone ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' Cowan 1986 1.11 (0.78 to 1.58) Noc 1990 18.0 (1.17 to 276) Capucci 1992 0.77 (0.37 to 1.62) Cochrane 1994 1.15 (0.91 to 1.44) Donovan 1995 1.05 (0.69 to 1.60) Hou 1995 1.29 (0.97 to 1.72) Kondili 1995 1.33 (0.71 to 2.47) Galve 1996 1.13 (0.84 to 1.52) Kontoyannis 1998 1.42 (1.08 to 1.85) Bellandi 1999 1.41 (1.15 to 1.72) Cotter 1999 1.43 (1.15 to 1.80) Kochiadakis 1999 1.46 (1.19 to 1.78) Bianconi 2000 2.04 (0.19 to 22.00) Galperin 2000 33.70 (2.08 to 546) Hohnloser 2000 3.13 (1.50 to 6.70) Joseph 2000 1.32 (0.95 to 1.80) Natale 2000 5.12 (2.60 to 10.00) Peukurinen 2000 2.45 (1.49 to 4.02) Vardas 2000 2.01 (1.55 to 2.60) Villani 2000 4.75 (1.60 to 14.00) Cybulski 2001 1.87 (1.37 to 2.55) 0.1110100 n = 83 n = 95 n = 203 n = 85 n = 120 n = 34 n = 24 n = 40 n = 30 n = 64 n = 39 n = 42 n = 100 n = 42 n = 120 n = 100 n = 204 n = 75 n = 62 n = 208 n = 160

10. Relative Risk of Conversion to Sinus Rhythm Amiodarone vsPlacebo orDigoxinor CCB FavoursControlFavours Amiodarone ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' Bianconi2000 2.04 (0.19 to 22.00) Galperin2000 33.70 (2.08 to 546) Hohnloser2000 3.13 (1.50 to 6.70) Natale2000 5.12 (2.60 to 10.00) Villani2000 4.75 (1.60 to 14.00) Pooled Estimate 4.33 (2.76 to 6.77) Cowan 1986 1.11 (0.78 to 1.58) Noc1990 18.0 (1.17 to 276) Capucci1992 0.77 (0.37 to 1.62) Cochrane1994 1.15 (0.91 to 1.44) Donovan 1995 1.05 (0.69 to 1.60) Hou1995 1.29 (0.97 to 1.72) Kondili1995 1.33 (0.71 to 2.47) Galve1996 1.13 (0.84 to 1.52) Kontoyannis1998 1.42 (1.08 to 1.85) Bellandi1999 1.41 (1.15 to 1.72) Cotter 1999 1.43 (1.15 to 1.80) Kochiadakis1999 1.46 (1.19 to 1.78) Joseph 2000 1.32 (0.95 to 1.80) Peukurinen2000 2.45 (1.49 to 4.02) Vardas2000 2.01 (1.55 to 2.60) Cybulski2001 1.87 (1.37 to 2.55) Pooled Estimate 1.40 (1.25 to 1.57) 0.1110100 AF Duration > 48 hrs AF Duration =/< 48 hrs n = 83 n = 95 n = 203 n = 85 n = 120 n = 34 n = 24 n = 40 n = 30 n = 64 n = 39 n = 42 n = 100 n = 42 n = 120 n = 100 n = 204 n = 75 n = 62 n = 208 n = 160 '

11. Directness of Evidence indirect treatment comparisonsindirect treatment comparisons –interested in A versus B –have A versus C and B versus C alendronate vs risedronatealendronate vs risedronate –both versus placebo, no head-to-head

12. Who are the patients? If different, weaker evidence patients meet trials’ eligibility criteriapatients meet trials’ eligibility criteria minor question of directnessminor question of directness –slight age difference –comorbidity –race –closely related underlying condition valvular atrial fibrillationvalvular atrial fibrillation serious question about biologyserious question about biology –heart failure trials applicability to aortic stenosis

13. Interventions: if differ, weaker evidence identical interventionidentical intervention –captopril 100 mg minor question of directnessminor question of directness –captopril, lower dose –other ACE inhibitor serious question of biologyserious question of biology –angiotensin receptor blocker

14. Outcome differs, weaker evidence outcomes of direct interestoutcomes of direct interest –survival of long duration –valid measure of HRQL minor question of directnessminor question of directness –follow-up shorter than ideal –functional status measure serious question of biologyserious question of biology –short duration of follow-up –laboratory exercise capacity

15. Magnitude, Precision, Reporting Bias magnitude not generally part of qualitymagnitude not generally part of quality –but very large magnitude can upgrade precision not generally part of qualityprecision not generally part of quality –but sparse data can lower quality reporting biasreporting bias –high likelihood can lower quality

16. Grading System high qualitywell done RCThigh qualitywell done RCT intermediatequasi-RCTintermediatequasi-RCT lowwell done observationallowwell done observational insufficient anything elseinsufficient anything else

17. Moving Down study execution – –serious flaws can lower by one level – –fatal flaws can lower by two levels consistency – –important inconsistency can lower by one level directness of evidence – –some uncertainty re relevance lower by one level – –major uncertainty re relevance lower by two levels selection bias – –strong suspicion lower by 1 level

18. Moving Up very strong association, up 2 levels – –insulin in diabetic ketoacidosis strong, consistent association with no plausible confounders, up 2 levels – –fluoride for preventing cavities strong association can move up 1 level – –? HRT ?

19. Risk/Benefit tradeoff aspirin after myocardial infarctionaspirin after myocardial infarction –meta-analysis of high quality RCTs –clear positive treatment effect –unequivocal recommendation to treat, uniform practice accelerated TPA vs streptokinase after MIaccelerated TPA vs streptokinase after MI –very large single trial –clear positive effect –uncertainty whether to treat, varying practice

20. Risk/Benefit tradeoff Aspirin after myocardial infarctionAspirin after myocardial infarction –25% reduction in relative risk –side effects minimal, cost minimal –benefit obviously much greater than risk/cost TPA vs streptokinase after MITPA vs streptokinase after MI –12% reduction in relative risk –increased rate of intracranial hemorrhage –large increase in cost –benefit vs risk/cost a judgment call

21. Strength of Recommendations Aspirin after MI – do it TPA rather than SK in MI -- probably do it -- probably don’t do it -- probably don’t do it

22. Grade of Recommendations do it or don’t do itdo it or don’t do it –strong recommendation probably do it, or probably don’tprobably do it, or probably don’t –weaker recommendation

23. Strong or Weak Recommendation? seriousness of outcomeseriousness of outcome magnitude of effectmagnitude of effect precision of treatment effectprecision of treatment effect risk of target eventrisk of target event risk of adverse eventsrisk of adverse events cost of therapycost of therapy values and preferencesvalues and preferences

24. Weak recommendation practice will varypractice will vary –according to what? interpretation of evidenceinterpretation of evidence –breast cancer patients’ values and preferencespatients’ values and preferences –atrial fibrillation inclination to gambleinclination to gamble –HRT

25. Conclusion challenges in gradingchallenges in grading –simple system –consider quality of evidence –consider benefit/risk tradeoff methodological quality of evidencemethodological quality of evidence –study design, execution, –consistency, directness –reporting bias balance of benefits and risks/costbalance of benefits and risks/cost –magnitude and precision of effects; –values and preferences

26. Way forward an internationally accepted grading scheme?an internationally accepted grading scheme? reliability of grading schemereliability of grading scheme –will observers come to same grade? acceptability and usefulnessacceptability and usefulness –workshop this afternoon