Elsevier

The Lancet

Volume 352, Supplement 1, August 1998, Pages SI29-SI33
The Lancet

Supplement
15 years of heart-failure trials: what have we learned?

https://doi.org/10.1016/S0140-6736(98)90016-2Get rights and content

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Overview of heart-failure trials 1983-98

We have listed 26 important heart-failure trials (table). This listing is not meant to be a complete listing, nor will all of the cited studies meet everyone's definition of a clinical trial. However, all these trials are randomised, controlled, double-blind studies. The results, alone or in conjunction with other results, have significantly influenced our thinking and practices.

Vasodilators

The first major heart-failure trial, the Veterans Administration Heart Failure Trial (V-HeFT-I),1 a randomised survival trial of hydralazine plus isosorbide dinitrate and prazosin compared with placebo, was published in 1986. This landmark study showed the feasibility of mortality trials for heart failure and, for the first time, suggested that survival could be improved with drug treatment. The mechanism of benefit was assumed to be haemodynamic, with hydralazine and nitrates leading a

Angiotensin-converting-enzyme (ACE) inhibitors

The largest proportion of trials have involved ACE inhibitors. The Captopril-Multicenter Study7 started the present era of heart-failure trials and showed for the first time in a rigorously designed protocol that endpoints such as exercise capacity and symptoms could be improved. Mortality was not assessed in that study, and only in a post-hoc analysis was a favourable effect recognised.8 Subsequently, improved survival with ACE-inhibitor therapy has been documented in patients with mild,

Positive inotropic agents

The digitalis glycosides are the oldest recognised therapy for heart failure, but their efficacy in patients who are in sinus rhythm has long been controversial. Few studies of these agents, until the past decade, had been of sufficient size and done with sufficient rigour to provide convincing evidence of benefits. Three trials with a withdrawal design have shown that during periods of 3-6 months, fewer patients maintained on digoxin had worsening heart failure and are more likely to maintain

β-blockers

Although β-blockers have been used to treat heart-failure patients in Scandinavia for more than two decades, their acceptance for this disorder elsewhere has been limited. In the Metroprolol in Dilated Cardiomyopathy (MDC) trial28 and the Cardiac Insufficiency Bisoprolol Study (CIBIS-I) trial29 however, which studied two β-1 selective agents (metoprolol and bisoprolol), ejection fraction rose and the number of admissions to hospital were decreased but neither reached significance for the

Insights into mechanisms of drugs

There is much potential for benefit and harm in the treatment of heart failure. Increase of cardiac contractility with positive inotropic agents and improvement of cardiac performance by decrease of afterload and preload with vasodilators, together with diuresis, have long been taken as therapeutic targets in heart failure. These approaches may produce striking short-term haemodynamic improvement and may also improve symptoms and exercise tolerance. However, with the exception of hydralazine

HOW should heart-failure drugs be studied?

Perhaps as important as the clinical results of these trials are the lessons that they provide about trial design and conduct.

As noted previously, haemodynamic measurements have not proven to be useful endpoints. Exercise tolerance, although a better measure of clinical status, has not been a useful predictor of mortality or morbidity outcomes. Indeed, exercise capacity has been improved by drugs that either increase or produce small decreases in mortality and morbidity (flosequinan, digoxin,

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References (33)

  • PackerM et al.

    Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study

    Circulation

    (1993)
  • A placebo controlled trial of captopril in refractory chronic congestive heart failure

    J Am Coll Cardiol

    (1983)
  • Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

    N Engl J Med

    (1987)
  • Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

    N Engl J Med

    (1991)
  • Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions

    N Engl J Med

    (1992)
  • PfefferMA et al.

    Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction

    N Engl J Med

    (1992)
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