Deutsches Cochrane Zentrum From levels of evidence to grades of recommendation – The GRADE Working Group Yngve Falck-Ytter Deutsches Cochrane Zentrum EBM in der Inneren Medizin 13. Januar 2004

Hintergrund Wieweit können wir Aussagen trauen? Experten vs. Evidenz Narrativ vs. Systematische Reviews Explizit vs. Implizit Sollen wir Aussagen als Empfehlungen übernehmen? Spielt dabei ein „level of evidence“ eine Rolle?

Hintergrund Klinische Entscheidungen sind komplex: Soll ich eine Kalziumarme Diät bei Nierensteinen verordnen, nur weil es einleuchtet? Soll ich bei vaso-vagaler Synkope einen Herzschrittmacher implantieren? Welche outcomes sind wichtig? Habe mehr positive Effekte als negative (harm)? Wie stehen limitierte Ressourcen im Verhältnis zum Benefit? Daher brauchen wir klinische Leitlinien

Hintergrund Evidenzhierarchien Werden jedoch uneinheitlich erstellt Canadian Task Force on Periodic Health Examinations United States Preventive Services Task Force Oxford Center of Evidence Based Medicine Scottish Intercollegiate Guidelines Network American Heart Association Werden jedoch uneinheitlich erstellt Verwenden uneinheitliche Empfehlungskategorien (z.B.: II-2 = B = C+ = strong evidence = strongly recommended)

Oxford Centre of Evidence Based Medicine; http://www.cebm.net Example Level of evidence Studies on therapy Recom-mendation I RCTs A II Cohort studies B III Case-control-studies IV Case-series C V Expert opinion D Oxford Centre of Evidence Based Medicine; http://www.cebm.net

Up- and downgrading of grades of recommendation in clinical practice guidelines from the Association of the Scientific Medical Societies in Germany (n = 10/>1200 Clinical Practice Guidelines; total number of recommendations: 295 [mean: 30; range 5 to 61]. Levels of evidence: I = randomized controlled trials, II = observational studies, III = expert opinion; grades of recommendation: A = good evidence, B = fair evidence, C = poor evidence).

Committee of Ministers of the Council of Europe. Oct 2001.

Ziele von GRADE Simple Sensible Explicit Reliable Address shortcoming of other schemes (e.g explicitly include trade offs between benefit and risks)

Definitionen Qualität der Evidenz: Ausmaß des Vertrauens in die Richtigkeit des Effektschätzers (extent to which one can be confident that an estimate of effect is correct) Härtegrad einer Empfehlung: Ausmaß des Vertrauens, dass das Befolgen der Empfehlung mehr Nutzen wie Schaden ermöglicht (extent to which one can be confident that adherence to the recommendation will do more good than harm)

Grundlegender Ansatz 5 Schritte: Qualität der Evidenz jedes wichtigen Outcomes der Studien Quality of evidence across studies for each important outcome Welche Outcomes sind kritisch für eine Entscheidung Which outcomes are critical to a decision Ermittelte Qualität der Evidenz dieser kritischen Outcomes The overall quality of evidence across these critical outcomes Abwägung von Nutzen und Schaden The balance between benefits and harm Härtegrad der Empfehlung Strength of recommendation

1. Qualität der Evidenz jedes wichtigen Outcomes Studiendesign RCTs vs Beobachtungsstudien Studienqualität Critical appraisal (alloc. concealment, blinding, f/u…) Übereinstimmung Gleichgerichteter Effekt aller Studien (Homogenität) Vergleichbarkeit Personen, Interventionen & Outcome sind vergleichbar Und… Spärliche Daten, hohes Risiko eines Publikationsbias Example RCT: HRT. Example Cohort: biopsy rates post mamography (false positives), Example Case-series: perforations post colonoscopies.

Quality of evidence across outcomes Observational studies Quality of evidence Randomized trials High Extremely strong association and no major threats to validity No serious flaws in study quality Strong, consistent association and no plausible confounders Serious flaws in design or execution or quasi-randomized trials Moderate Low No serious flaws in study quality Very serious flaws in design or execution Very low Serious flaws in design and execution Very serious flaws and at least one other serious threat to validity

...continued Zusätzliche Faktoren, die die Qualität verringern: Important inconsistency of results Uncertainty about directness Some uncertainty Major uncertainty can lower the quality by two levels High probability of reporting bias Sparse data Zusätzliche Faktoren, die die Qualität vergrößern: All plausible residual confounding, if present, would already have reduced the observed effect Evidence of a dose-response gradient

2. Outcomes critical to a decision Outcomes may be important, but sometimes not critical to a decision Only outcomes critical to a decision should provide a basis for recommendation If information on harm is critical, it should be included even if uncertainty exists

3. Overall quality of evidence The lowest quality of evidence for any critical outcome should provide the basis for grading However, if evidence favors the same alternative and there is high quality for some but not all of those outcomes, overall quality should still be high Weak evidence about implausible putative harms should not lower the overall grade of evidence

4. The balance between benefits and harm Net benefits: Clearly does more good than harm Trade-offs: Important trade-offs between benefits and harm Uncertain trade-offs: It is not clear whether the intervention does more good than harm No net benefits: Clearly does not do more good than harm

5. Grades of recommendation „Do it“ or „Don‘t do it“ Indicating a judgment that a majority of well informed people will make the same choice Medical practice is expected to not to vary much „Probably do it“ or „Probably don‘t do it“ Indicating a judgment that a majority of well informed people will make the same choice, but a substantial minority will not Medical practice is expected to vary to some degree No „toss-up“