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

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

An ideal grading system simplesimple clear separation of two issuesclear separation of two issues –evidence weak or strong? methodological quality of evidencemethodological quality of evidence likelihood of biaslikelihood of bias –recommendation weak or strong trade-off between benefits and riskstrade-off between benefits and risks

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 –international group led by Andy Oxman Australian NMRC, SIGN, USPSTF, WHO, NICE, Oxford CEBM, CDC, CCAustralian NMRC, SIGN, USPSTF, WHO, NICE, Oxford CEBM, CDC, CC

Evidence weak or strong? study designstudy design –basic –detailed design and execution consistencyconsistency directnessdirectness reporting biasreporting bias

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

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

Relative Risk of Conversion to Sinus Rhythm Amiodarone vs Placebo or Digoxin or CCB Favours Control Favours Amiodarone ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' Cowan (0.78 to 1.58) Noc (1.17 to 276) Capucci (0.37 to 1.62) Cochrane (0.91 to 1.44) Donovan (0.69 to 1.60) Hou (0.97 to 1.72) Kondili (0.71 to 2.47) Galve (0.84 to 1.52) Kontoyannis (1.08 to 1.85) Bellandi (1.15 to 1.72) Cotter (1.15 to 1.80) Kochiadakis (1.19 to 1.78) Bianconi (0.19 to 22.00) Galperin (2.08 to 546) Hohnloser (1.50 to 6.70) Joseph (0.95 to 1.80) Natale (2.60 to 10.00) Peukurinen (1.49 to 4.02) Vardas (1.55 to 2.60) Villani (1.60 to 14.00) Cybulski (1.37 to 2.55) 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

Relative Risk of Conversion to Sinus Rhythm Amiodarone vsPlacebo orDigoxinor CCB FavoursControlFavours Amiodarone ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' Bianconi (0.19 to 22.00) Galperin (2.08 to 546) Hohnloser (1.50 to 6.70) Natale (2.60 to 10.00) Villani (1.60 to 14.00) Pooled Estimate 4.33 (2.76 to 6.77) Cowan (0.78 to 1.58) Noc (1.17 to 276) Capucci (0.37 to 1.62) Cochrane (0.91 to 1.44) Donovan (0.69 to 1.60) Hou (0.97 to 1.72) Kondili (0.71 to 2.47) Galve (0.84 to 1.52) Kontoyannis (1.08 to 1.85) Bellandi (1.15 to 1.72) Cotter (1.15 to 1.80) Kochiadakis (1.19 to 1.78) Joseph (0.95 to 1.80) Peukurinen (1.49 to 4.02) Vardas (1.55 to 2.60) Cybulski (1.37 to 2.55) Pooled Estimate 1.40 (1.25 to 1.57) 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 '

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

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

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

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

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

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

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

Moving Up extremely strong, consistent association; no plausible threats to validity, up 2 grades – –insulin in diabetic ketoacidosis strong, consistent association with no plausible confounders (or confounders would all reduce effect) up 1 grade – –investor-owned for-profit dialysis increases death rates in comparison to not-for-profit

Overall level of evidence most systems just use evidence about primary benefit outcomemost systems just use evidence about primary benefit outcome but what about others (risk)?but what about others (risk)? optionsoptions –ignore all but primary –weakest of any outcome –some blended approach –weakest of crucial outcomes

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

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

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

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

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

Grades Translations strong - 90% or more would make the same choicestrong - 90% or more would make the same choice weak - more than 10% would vary in choiceweak - more than 10% would vary in choice

How to represent grades? words onlywords only –recommendation strong or weakstrong or weak do it, probably do it, don’t do it, probably don’t do itdo it, probably do it, don’t do it, probably don’t do it –quality high, moderate, low, very low numbers and lettersnumbers and letters –recommendation 1 and 2 –quality A, B, C, D symbolssymbols –  ,  ?,  ,  ?

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