BACKGROUND:
Approximately two million Americans suffer from heart failure. Since the prevalence of congestive heart failure is known to increase with age, improvements in the average life expectancy would be expected to increase the magnitude of the problem over the next few decades. While advances in the treatment of hypertension, coronary artery disease, and surgical treatment of congenital and valvular heart disease have prolonged survival, many of these patients ultimately develop heart failure in later life.
The therapy of congestive heart failure has undergone rapid change. Until the early 1970s, the mainstay of therapy for the patient with acute and chronic congestive heart failure was digitalis and diuretics. The use of digitalis in patients with heart failure secondary to ischemic heart disease and in those with severe left ventricular failure of either nonischemic or ischemic origin was, however, controversial.
Controversy over the acute and long-term effects of digitalis led to the introduction of a variety of alternative and supplemental therapeutic approaches for the patient with heart failure. In the mid 1980s, a wide spectrum of vasodilators was available. New, at that time, inotropic agents, also found applications as alternatives or supplements to digitalis administration. Although all of these drugs had been shown to be of some benefit in the management of patients with chronic heart failure, there was inadequate information as to the long-term hemodynamic effects of some of these agents and practically no information regarding their effect on survival.
The recognition that patients with congestive heart failure often have elevated peripheral vascular resistance led to the introduction of vasodilator therapy. Of the vasodilators, the angiotensin-converting enzyme (ACE) inhibitors appeared to be the most promising because they had been shown to counteract some of the major adverse hormonal and vasoconstrictor mechanisms, relieve symptoms, diminish cardiac dilatation after myocardial infarction, and improve exercise capacity and ejection fraction.
SOLVD was initiated in 1986 primarily to evaluate the effects of enalapril, an angiotensin-converting enzyme (ACE) inhibitor. Two considerations influenced the design of SOLVD: it was possible that drug treatment given to patients who already had manifest congestive heart failure might not be as beneficial as initiating treatment in asymptomatic left ventricular dysfunction patients; early treatment of such asymptomatic patients might be less beneficial, as the patient might not have measurable activation of the renin-angiotensin axis.
The Request for Proposals was released in August 1984 with the first awards made in July 1985. A second Request for Proposals for additional clinical centers was released in March 1985.
DESIGN NARRATIVE:
Both trials were randomized and double-blind. Prior to randomization, all patients received enalapril, and placebo for two weeks to enable early detection of non-compliant patients, those unable to tolerate the drug, and those with early side-effects. After completion of the pre-randomization period, participants were allocated to enalapril or placebo using a permuted block randomization within each of the clinical centers. Follow-up visits were scheduled for two and six weeks after randomization and then at four, eight, and twelve months. Thereafter, clinic visits were scheduled at four-month intervals. Patients were followed for a minimum of two years and a maximum of five years. Primary outcome for each trial was all-cause mortality. Secondary endpoints included cardiovascular mortality, sudden death due to worsening congestive heart failure, hospitalization for congestive heart failure, myocardial infarction, stroke, need for cardiac transplantation, and quality of life. Onset of congestive heart failure was an additional outcome in the Prevention Trial. Seven substudies were conducted among subsets of participants and included: diastolic function; echocardiography; exercise; neurohumoral; quality of life; radionuclide; sudden death. Patient recruitment began in July 1986. Recruitment in the Treatment Trial ended six months ahead of schedule in February 1989, and follow-up ended in February 1991. The Prevention Trial ended recruitment in April 1990 and completed follow-up in July 1991. Data analysis continued through November 1994.
The trial also included a registry which enrolled 6,300 patients to study the influence of a number of patient characteristics on mortality. Eighteen of the clinical centers participated. Data were collected from consecutive patients with ejection fraction less than .45 or with radiologic evidence of congestive heart failure over a twelve month period. At one year, patient's vital status was ascertained by mail and, if necessary, by telephone follow-up. One year follow-up was completed on all registry patients by May 1990. Longer term follow-up was done through the National Death Index.
