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What Evidence is Needed to Make Important Medical Decisions?

By Robert J. Glynn, Sc.D. and John Orav, Ph.D.

Medical practice can be influenced by information from a number of different sources, not the least of which are formal observational and experimental studies performed in collaboration with biostatisticians. The role of the biostatistician is fairly clear-cut when there is a single, prominent outcome variable and the efficacy of a proposed treatment can be evaluated in a placebo-controlled randomized trial. Even in this ideal statistical situation, however, the clinical implications can become clouded, if, during the time it takes to put together and complete the trial, the therapy becomes outdated, or if the patient population is so heterogeneous that some subgroups appear to derive less or no benefit. More importantly, there are often other considerations beyond just clinical efficacy: quality of life and functional status of the patient, side effects and tonicities of the treatments, and cost. These factors all weight into the ultimate medical decision of whether or not to adopt a new drug into practice. To complicate the decision process even further, definitive randomized placebo controlled trials are not always feasible. If the primary outcome is rare, it may be necessary to turn to a surrogate endpoint for which there is adequate statistical power, but for which clinical implications are less clear. If competing treatments already exist, then placebo control may no longer be possible, and bio-equivalence designs may be used. Information can also come from observational or case-control studies, where the potential for confounding may lead to unresolvable debates.

Current controversies about the optimal therapy to treat hypertension illustrate the lack of consensus about the amount and type of evidence that is needed to demonstrate the efficacy or hazard of a therapy. Antihypertensive medications are the most widely prescribed drugs in the US with over half of all persons aged 65 or over taking one or more of these drugs at any one time. Several large randomized trials have unequivocally demonstrated the benefit of these drugs in preventing stroke and coronary heart disease and reducing mortality. Greater use of these medications over the past 10 years is likely to have contributed importantly to the continued decline in cardiovascular mortality in this country. However, which of several alternative drugs to use in a specific hypertensive person remains unclear and current treatment practices are diverse.

The large randomized trials that showed the value of drug therapy for the prevention of cardiovascular events primarily compared older antihypertensive drugs, diuretics and beta blockers, to placebo. Even as they studies were published, the specific agents tested were criticized because of apparent lack of efficacy in some subgroups of patients and because of concern about side effects. In some subgroups of patients, those assigned to diuretic therapy (notably those using high doses) had increase rates of coronary events. Similarly, in elderly hypertensives several trials of beta blockers showed no benefit in reducing coronary heart disease deaths. Calcium channel blockers and angiotensin converting inhibitors offer comparable reductions in blood pressure and clear advantages in terms of their immediate effects on glucose tolerance, lipids, and quality of life. However, it is unclear whether these advantages translate to reductions in either clinically meaningful side effects or, more importantly, in number of clinical cardiovascular disease events. Nonetheless, advisory committees, such as the Joint National Committee on Detection, Evaluation, and treatment of High Blood Pressure, at the end of the 1980s recommended any of diuretics, beta blockers, calcium channel blockers, or angiotensin converting enzyme inhibitors as initial therapy for hypertension. At the time of these recommendations, the use of calcium channel blockers and angiotensin converting enzyme inhibitors increased substantially so that by 1989 over 30 percent of hypertensive patients were using one of these drugs.

Additional trials published in the 1990s confirmed the value of diuretics and beta clockers for the primary prevention of both stroke and coronary heart disease. Revised recommendations from the Joint National Committee and other groups now call for initial treatment of hypertension with low doses of diuretics or beta blockers. A fundamental change has occurred in the perceived value of favorable side-effect profiles, upon which the licensing and clinical use of the newer agents was based. Moreover, current recommendations also point to the generally far lower costs of treatment with diuretics and beta blockers.

Much is at stake in the controversy about the optimal drug for hypertension. For example, calcium channel blockers generate an annual world-wide revenue of $8 billion. Regulatory agencies did not require large-scale primary prevention trials in order to grant marketing approval for the newer drugs. The task of evaluating their efficacy now is much more difficult because long-term placebo controlled trials of hypertensives are unethical. Several recent observational studies have compared the relative efficacy of alternative drug therapies. Some, but not all, of these studies have raised the possibility that elderly patients treated with calcium channel blockers have increased rates of coronary heart disease compared to those treated by other agents. However, none of these studies could evaluate and control for the reasons why particular drugs were prescribed.

Large-scale randomized trials are required to address the question of the optimal therapy for hypertension. Several such trials are planned and one such trial, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial, is underway. However, because of the required sample size of 40,000 participants and the long duration of follow-up, results will not be available until after the year 2000 unless the trial is terminated early due to emergence of a clear benefit or hazard. Meanwhile, the important clinical message remains that, while we do not know the optimal approach to treatment, the benefits of drug therapy for hypertension are clear and large.