Hierarchy of Clinical Evidence

1. Hierarchy of Clinical Evidence Systematic Reviews Metaanalysis Double-blindRandomized Controlled Trials Cohort StudiesCase-Control StudiesCases Report/Series Physiologic Studies Intuition or Beliefs Observational

2. Design of a cohort study TIME direction of inquiry people exposed disease population without the no disease disease not exposed disease no disease “at risk”

3. Design of a case-control study TIME direction of inquiry Start with: Exposed cases (people with disease) Not exposed Population Exposed controls (people without disease) Not exposed

4. Questions to ask when an association is reported in the literature (eg estrogen and CHD) Explanation Finding Association Bias in selection Yes No or measurement Chance Likely Unlikely Confounding Yes No Cause Cause

5. Case report? Association and cause Explanation Finding Association Bias in selection Yes No or measurement Chance Likely Unlikely Confounding Yes No Cause Cause Case series?

6. Association and cause Explanation Finding Association Bias in selection Yes No or measurement Chance Likely Unlikely Confounding Yes No Cause Cause P value

7. Association and cause Explanation Finding Association Bias in selection Yes No or measurement Chance Likely Unlikely Confounding Yes No Cause Cause

8. Criteria for causation 1.Is there evidence from true experimentation in humans? 2. Is the association strong? 3. Is the association consistent from study to study? 4. Is the temporal association correct? 5. Is there a dose-response gradient? 6. Does the association make biological sense? 7. Is the association specific? (Adapted from Bradford Hill)

9. Randomization 1. Guarantees equal probability of receiving control/experimental treatment to all participants (removes investigator bias) 2. Protects against imbalances in known and unknown confounders 3. Provides basis for statistical analysis

10. Hierarchy of study methods for clinical decision-making Systematic reviews

11. Is observational evidence equivalent to experimental evidence? Benson NEJM 2000;342:1877 Concato NEJM 2000;342:1887 In some cases -YES In others- NO !

12. Clinical trials are selective! -Select group gets in - chance decides who gets treatment; treatment effect decides who does better Observational evidence is also selective: self-selection of exposure: this may decide who does better

13. How much of Medicine is Evidence-Based ? Matzen P. Ugeskr laeger 2003;165:1431-5 • General Internal Medicine - 50% • Psychiatry- 65% • Others (surgery, general practice, dermatology) - less Lai Br. J Ophthal . 2003;4:385-90: • 42.9% of patient interventions were based on evidence from RCT, meta-analysis or systematic reviews (23% on no evidence)

14. Major Disadvantage of RCTs:Selectivity

15. Clinical trials Should not be performed unless there is a realistic chance of providing a valid/reliable answer to a well-defined medical question

16. But…SHEP study Of 447,921 (100%)identified 31,960 (11.6%)met initial criteria 4,736 (1.03%)randomized

17. % of Pop Men, gen’l pop DM CVD CHF MI Angina Wom., gen’l pop SHEP pop

18. Coke tastes better…….! Than what?

19. Coke tastes better…….!

20. 1. Tendency to extend application of new treatments to patient groups other that those for whom data exist 2.Extrapolation of data to agents of the same class but untested for specific indication CAVEATS in using RCT evidence to guide patient management

21. Don’t drown in the evidence ACP J Club, Bandolier, POEMS, clinical evidence, Cochrane Reviews, Clinical guidelines clearinghouse Use predigested sources

22. Good luck!