Studies of Left Ventricular Dysfunction (SOLVD)
Condition: Cardiovascular Diseases; Coronary Disease; Heart Diseases; Heart Failure; Hypertension; Myocardial Ischemia
MeSH terms: Cardiovascular Diseases; Heart Diseases; Coronary Disease; Myocardial Ischemia; Ischemia
Study type: Interventional
Phase: Phase 3

Summary: 
      To determine if enalapril treatment of left ventricular dysfunction (LVD) due to ischemic or
      hypertensive heart disease led to reduced mortality and morbidity in symptomatic and
      asymptomatic patients. There were a Prevention Trial, a Treatment Trial, and a registry.
    

Detailed description: 
      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.
    

Intervention name(s): enalapril
Intervention type(s): Drug
Intervention MeSH terms: Enalapril
Allocation: Randomized
Masking: Double
Primary purpose: Prevention