Placebo-Controls in Short-Term Clinical Trials of Hypertension

Sana Al-Khatib, MD, MHSAssistant Professor of Medicine

Division of CardiologyDuke University Medical Center

“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

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

Outline

Placebo Controls in Short-Term Clinical Trials of Mild to Moderate Hypertension Background Methods Results

Conclusions

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

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”.

Declaration of Helsinki

International document issued in 1964Main features:

Medical care is different from medical research Study subjects should be assured of the best

available treatment

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”.

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

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”.

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

Randomization

Takes care of selection biasBaseline characteristics known or not

known to affect the outcome are evenly distributed between the randomized groups

Blinding

Protects the study from confounding by variables that develop during follow-up

Prevents bias during data collection and assessment

Types of Control

Placebo controlNo treatment controlPositive controlHistorical control

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

Equipoise

Literally means equilibriumIt is not known which treatment is better

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

BackgroundHypertension 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

Background

1991- SHEP and STOP-Hypertension found similar benefits in elderly patients

There is strong evidence that patients with hypertension should be treated

Objective

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

MethodsLiterature 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

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

Methods

Serious adverse events Stroke Myocardial infarction Congestive heart failure Death due to cardiac events or stroke

Methods

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

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

Identification of Studies

267 citations

80 citations

35 studies: placeboin run-in period

2 studies: placebo in maintenance

43 studies: placebo in run-in period +/- maintenance +/- withdrawal

Results

Done in USA 24 IRB approval 64 Signed informed consent 69 Adequate safety data 25 Placebo in run-in period 35 Placebo in maintenance 2Placebo in run-in and maintenance 39Placebo in run-in and withdrawal 1Placebo in run-in, maintenance andwithdrawal 3

N

ResultsSerious adverse event Active (4878) Placebo (1604)

Death 2 2

Stroke 2 0

Myocardial infarction 2 3

Congestive heart failure 0 0

Total 6 5

-0.1000 -0.0500 0.0000 0.0500 0.1000

Difference in Event Rates

Active therapy safer

Placebo safer

-0.006 -0.004 -0.002 0 0.002 0.004 0.006

Difference in Event Rates

Active therapy safer Placebo safer

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