1. Placebo-Controls in Short-Term Clinical Trials of Hypertension Sana Al-Khatib, MD, MHS Assistant Professor of Medicine Division of Cardiology Duke University Medical Center

2. “Is it ethical to use a placebo? The answer to this question will depend, I suggest, upon whether there is already available an orthodox treatment of proved or accepted value. If there is such an orthodox treatment the question will hardly arise, for the doctor will wish to know whether a new treatment is more, or less, effective than the old, not that it is more effective than nothing”. Sir A. Bradford Hill, BMJ 1963

3. Outline  Historical background  1948 - Nuremberg Code  1964 - Declaration of Helsinki  1979 - The Belmont Report  Placebo controls in randomized clinical trials  Randomization and blinding  Types of control  Importance of placebo controls

4. Outline  Placebo Controls in Short-Term Clinical Trials of Mild to Moderate Hypertension  Background  Methods  Results  Conclusions

5. Nuremberg Code  Issued in 1948 in response to the experiments of Nazi doctors  Main features:  Voluntary consent of the human subject is absolutely essential  Risks can not outweigh the benefits  Animal experimentation should precede human experimentation

6. Nuremberg Code “ The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury… Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death”.

7. Declaration of Helsinki  International document issued in 1964  Main features:  Medical care is different from medical research  Study subjects should be assured of the best available treatment

8. Declaration of Helsinki “ In any medical study, every patient- including those of a control group, if any- should be assured of the best proven diagnostic and therapeutic method”.

9. The Belmont Report  Issued in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research  Identifies three basic ethical principles  Respect for persons  Beneficence  Justice

10. The Belmont Report “ Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well- being…(1) do not harm and (2) maximize possible benefits and minimize possible harms”.

11. Randomized Clinical Trial  The most powerful experiment for assessing the effectiveness of an intervention  A prospective study comparing the effect of an intervention against a control

12. Randomization  Takes care of selection bias  Baseline characteristics known or not known to affect the outcome are evenly distributed between the randomized groups

13. Blinding  Protects the study from confounding by variables that develop during follow-up  Prevents bias during data collection and assessment

14. Types of Control  Placebo control  No treatment control  Positive control  Historical control

15. Importance of Placebo Controls  Placebo controls offer a clear reference point  They increase the likelihood of attaining statistical significance with a smaller sample size. Trials may be done:  More quickly  Less cost

16. Equipoise  Literally means equilibrium  It is not known which treatment is better

17. Placebo Controls in Short-Term Clinical Trials of Mild to Moderate Hypertension

18. Background  Hypertension is a common disorder  It is a risk factor for stroke, myocardial infarction, CHF, and premature cardiovascular death  1990 review of 14 randomized clinical trials of antihypertensive therapy showed:  42% risk reduction of stroke  14% risk reduction of coronary artery disease  21% risk reduction in vascular mortality

19. Background  1991- SHEP and STOP-Hypertension found similar benefits in elderly patients  There is strong evidence that patients with hypertension should be treated

20. Objective To determine whether the use of placebo controls in short-term clinical trials of Mild to moderate hypertension is safe and ethically appropriate

21. Methods  Literature review (1/97 through 12/98)  MEDLINE database  Inclusion Criteria  Randomized clinical trial  Objective was to assess efficacy of an agent in the treatment of mild to moderate hypertension  Use of placebo  Non-pregnant adults  Arbitrarily pre-specified a trial duration of 20 weeks or less

22. Methods  Data extraction  Duration and location of the study  Number and type of patients enrolled  Type of anti-hypertensive medications used  Whether IRB approval and informed consent were obtained  Number of serious adverse events

23. Methods  Serious adverse events  Stroke  Myocardial infarction  Congestive heart failure  Death due to cardiac events or stroke

24. Methods Safety data were considered adequate if the number and nature of adverse events were given for both the placebo and active treatment groups

25. Statistical Analysis  We used the maximum likelihood method to combine the estimates of risk differences  This method assumes a fixed-effects model and requires numerical multiplication of the likelihood functions  Because the event rates in the combined studies were so small, we repeated the analysis using the Bayesian method

26. Identification of Studies 267 citations 80 citations 35 studies: placebo in run-in period 2 studies: placebo in maintenance 43 studies: placebo in run-in period +/- maintenance +/- withdrawal

27. Results Done in USA24 IRB approval64 Signed informed consent69 Adequate safety data25 Placebo in run-in period 35 Placebo in maintenance 2 Placebo in run-in and maintenance 39 Placebo in run-in and withdrawal 1 Placebo in run-in, maintenance and withdrawal 3 N

28. Results Serious adverse eventActive (4878) Placebo (1604) Death22 Stroke20 Myocardial infarction23 Congestive heart failure00 Total65

29. Active therapy safer Placebo safer

30. Active therapy saferPlacebo safer

31. Conclusions  Short term exposure to placebo in clinical trials of mild to moderate hypertension does not seem to be associated with an increased risk of serious adverse events  Several possible explanations:  Short duration  Patients with mild to moderate hypertension with few co-morbidities  Close monitoring during the study