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Heart Disease

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Researchers recount lessons learned from the past two decades of cardiovascular clinical research

Cardiovascular clinical trials conducted in the past two decades have revealed insights that can be put to use to improve future trials. These trials also have suggested guidelines for clinicians who care for patients with heart disease. These lessons and guidelines are detailed in four recently published articles by Robert Califf, M.D., of the Duke Center for Education and Research on Therapeutics, and his colleague David L. DeMets, Ph.D., of the University of Wisconsin. Their work was supported in part by the Agency for Healthcare Research and Quality (HS10548).

DeMets, D.L., and Califf, R.M. (2002). "Lessons learned from recent cardiovascular clinical trials: Part I." Circulation 106, pp. 746-751.

These authors provide evidence that clinical trials should not rely on unproven surrogate outcome measures, such as improved cardiac output. They caution that subgroup findings should be regarded with suspicion unless they are independently confirmed or expected on the basis of prior findings.

In several trials, for example, improved cardiac function (as estimated by cardiac output) was named as a surrogate outcome in patients with chronic heart failure. Several drugs that improved various heart function measures, such as cardiac output, were later tested in a series of trials. Despite the demonstration that these drugs would improve cardiac output in the short term, many of them increased mortality. Thus, improved cardiac output was not a valid surrogate outcome for evaluating this new class of drugs. The researchers caution that relying on nonvalidated surrogates only encourages the use of ineffective therapies and may even promote the use of harmful treatments.

Researchers often evaluate treatment effect in subgroups of patients based on demographics or risk factors. However, when a trial demonstrates either a significant benefit or a harmful treatment effect, this effect is usually consistent within subgroups. For example, in studies of primary or secondary prevention of heart disease with aspirin, fewer women were randomized, and the results in women were not statistically significant. Interpretation of this subgroup analysis led to undertreatment of women for years, although we now know that aspirin is effective in women.

DeMets, D.L., and Califf, R.M. (2002). "Lessons learned from recent cardiovascular clinical trials: Part II." Circulation 106, pp. 880-886.

This paper examines several structural issues involved in administering multicenter clinical trials in cardiovascular disease, such as ways to minimize bias, roles and responsibilities for monitoring patient safety and evaluating evidence of efficacy, conflict of interest, managing trials with emerging negative trends, publication of negative trials, noninferiority trials (comparison of equally effective treatments to detect other clinically important differences), confirmation trials (trials conducted to confirm the results of an initial trial), and specification of primary and secondary end points. The article stresses the artificial nature of proactive checks and balances in the organization of clinical trials. It suggests that trials lacking these systems may not be as effective at producing balanced results in the public interest.

Califf, R.M., and DeMets, D.L. (2002). "Principles from clinical trials relevant to clinical practice: Part I." Circulation 106, pp. 880-886.

In this paper, the investigators cite six principles from clinical trials that are relevant to clinicians working with patients with cardiovascular disease. The trials show that the benefits of most cardiovascular therapies are modest. For example, risk is rarely reduced by more than 25 percent for patients who have suffered a heart attack. On the other hand, for epidemic diseases such as acute coronary syndromes, even small improvements can be clinically important.

Therapies shown to benefit patients with a given clinical condition can be applied systematically to all patients with that condition in clinical practice. Contrary to what clinicians intuit in their own patients, sicker and older patients usually benefit most.

Therapy is typically aimed at blocking or augmenting some aspect of a biological pathway, but it often affects additional unintended targets. Relying on clinical experience to decide which therapies to use is not adequate.

Clinical trials tend to assess one treatment at a time, yet most patients are treated with multiple therapies simultaneously, and interactions are often unpredictable. Assumptions by clinicians about untested combinations of potent therapies may not only be incorrect, but they also could lead to widespread patient problems. Long-term effects of therapies may differ from short-term effects and deserve evaluation.

The effect of drugs in the same class (that is, with the same biological target) can be uncertain. For example, in the treatment of heart failure, three beta-blockers reduced mortality, but a fourth failed in a major trial. Clinicians should consider uncertainty when substituting a less-expensive but unproven agent from the same class for a given condition.

Califf, R.M., and DeMets, D.L. (2002). "Principles from clinical trials relevant to clinical practice: Part II." Circulation 106, pp. 1172-1175.

The investigators discuss five principles derived from cardiovascular clinical trials to guide clinicians caring for patients with heart disease.

Most therapies produce a combination of helpful and harmful effects, and clinical characteristics can identify patients with greater expected benefit or risks.

Most beneficial therapies may not save money, but they are incrementally cost-effective. For example, using an accelerated infusion of alteplase (which costs $2,000 more than streptokinase) would reduce risk of death from blocked coronary arteries by 15 percent compared with a standard infusion of streptokinase. The cost would be $30,000 per year of life saved, well below the $70,000 spent to save a year of life with renal dialysis. Thus, the widespread belief that beneficial treatment saves money is inaccurate, but the benefits achieved are often worth the extra cost.

Systematically using therapies demonstrated to be effective in clinical trials leads to better patient outcomes.

Some areas of cardiovascular medicine are underserved. Fewer than 30 randomized clinical trials have been completed in pediatric cardiology; in contrast, more than 80 percent of children with cancer are enrolled in clinical trials, and tremendous gains in longevity for these children have occurred.

More practitioners and patients need to participate in clinical trials to optimize treatment of patients with heart disease.

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