Review of the SOLVD trials
Enalapril in Patients with Reduced Left Ventricular Ejection Fraction
Background: Systolic heart failure affects millions worldwide and is associated with high mortality and morbidity. If left untreated, the one-year mortality ranges from 15-50%, depending on the severity of the disease.
The CONSENSUS trial found mortality benefit with the use of the angiotensin converting enzyme inhibitor (ACEi) enalapril in patients with New York Heart Association (NYHA) class IV heart failure. Data on less severe heart failure were lacking.
The Studies of Left Ventricular Dysfunction (SOLVD) sought to assess whether an ACEi, enalapril, would reduce mortality in patients with low left ventricular ejection fractions defined as 35% of less.
Patients: Eligible patients had left ventricular ejection fraction of 35% or less. The ejection fraction was measured using radionuclide techniques in 68% of the patients, contrast angiography in 11%, and two-dimensional echocardiography in 21%.
Patients were excluded if they were over 80 years of age, or if they had significant valvular disease requiring surgery, unstable angina pectoris, angina requiring revascularization procedures, myocardial infarction during the previous month, severe pulmonary disease, serum creatinine >2 mg/ dl, or any other disease that might significantly impact survival.
At the end of the run-in period for placebo, patients who had overt congestive heart failure were enrolled in the Treatment trial, and patients who were not having overt congestive heart failure were enrolled in the Prevention trial.
Baseline characteristics: Patients were recruited from 83 hospitals linked to 23 centers in the United States, Canada, and Belgium.
The Treatment trial randomized 2,569 patients – 1,285 patients randomized to receive enalapril and 1,284 randomized to receive placebo. The average age of patients was 61 years and 80% were men. The average left ventricular ejection fraction was 25%. Approximately 42% had hypertension, 26% had diabetes, 71% had ischemic heart disease and 22% were current smokers. The NYHA class was I in 11% of the patients, II in 57% of the patients, III in 30% and IV 2%. At the time of enrollment, 8% were taking beta-blockers, 67% were taking digitalis, 85% were taking diuretics, 9% were taking potassium-sparing diuretics and 51% were taking vasodilators (other than ACEi).
The Prevention trial randomized 4,228 patients – 2,111 patients randomized to receive enalapril and 2,117 randomized to receive placebo. The average age of patients was 59 years and 89% were men. The average left ventricular ejection fraction was 28%. Approximately 37% had hypertension, 15% had diabetes, 83% had ischemic heart disease and 23% were current smokers. The NYHA class was I in 67% of the patients and II in 33%. At the time of enrollment, 24% were taking beta-blockers, 12% were taking digitalis, 17% were taking diuretics, 4% were taking potassium-sparing diuretics and 46% were taking vasodilators (other than ACEi).
Procedures: A total of 7,402 patients were deemed eligible across both the Treatment and Prevention trials.
Eligible patients for either trial entered a run-in and stabilization phase. Patients were given enalapril 2.5 mg twice daily in a single-blind fashion for 2 - 7 days to identify patients who could not tolerate even a small dose of the drug or those who were unable to comply with the regimen. A total of 310/7402 patients (4.2%) were excluded from the study during this phase. Following the active dosing phase, patients were placed on a regimen of matching placebo in a single-blind manner for 14 - 17 days. This allowed identification of individuals whose clinical condition deteriorated after drug withdrawal or who demonstrated poor compliance. During this phase, 295/ 7,092 patients (4.2%) were excluded from the study.
At the end of the run-in period for placebo, patients who had overt congestive heart failure were enrolled in the Treatment trial, and patients who were not having overt congestive heart failure were enrolled in the Prevention trial.
After that patients were randomized in a 1:1 ratio to receive enalapril or placebo.
Treatment with enalapril or placebo was initiated at 2.5 mg or 5 mg twice daily, based on the patient's clinical status and physician judgment. The dose was titrated up to 10 mg twice daily if tolerated without symptomatic hypotension or worsening renal function. After randomization, follow-up visits occurred at two weeks, six weeks, four months, and every four months thereafter until study completion.
Endpoints: The primary outcome for both trials was all-cause mortality. Heart failure hospitalization was assessed as a secondary outcome.
The estimated sample size was 2,500 patients for the treatment trial and 4,600 for the prevention trial. These sample sizes would provide 90% power at 5% two-sided alpha to detect 25% relative risk reduction in mortality, with the use of enalapril. The estimated 3-year mortality in the control group was 32% in the Treatment trial and 17% in the Prevention trial.
Authors reported risk reduction which was calculate as (1 – relative risk)*100.
Results: A total of 39,924 patients with a left ventricular ejection fraction of 35% or less were identified. Of these, 6.4% were enrolled in the Treatment trial and 7.4% in the Prevention trial. Among the excluded patients, the main reasons were prior use of an ACEi (28%), cardiovascular problems (12%), contraindications to using ACEi (11%), lack of patient consent (11%), administrative reasons (21%), cancer or other life-threatening illnesses (12%), and other miscellaneous reasons (5%).
The average follow up time was 41.4 months in the Treatment trial and 37.4 months in the Prevention trial.
In the Treatment trial, enalapril reduced all-cause mortality (35.2% vs 39.7%, risk reduction: 16%, 95% CI: 5% – 26%; p< 0.0036). The majority of deaths (89%) were cardiovascular and the majority of these (79%) were heart failure or arrhythmia related. Enalapril also reduced all-cause hospitalization (69.5% vs 74.0%; p= 0.006). The total number of hospitalizations for heart failure was also reduced with enalapril – 683 vs 971. Subgroup analysis showed a numerical increase in death, with enalapril, in patients with an ejection fraction of 30-35% - this was not statistically significant.
In the Prevention trial, enalapril did not have a significant effect on mortality (14.8% with enalapril vs 15.8% with placebo, risk reduction: 8%, 95% CI: -8% – 21%; p= 0.30). Enalapril significantly reduced the development of heart failure (20.7% vs 30.2%; p< 0.001). Total number of hospitalizations for heart failure was also significantly reduced with enalapril – 306 vs 454. The reduction in the development of heart failure was seen across all ejection fractions below 35%, although the benefit was larger with lower ejection fractions.
In both trials, the benefit of enalapril was seen early after treatment initiation.
Conclusion: In patients with left ventricular ejection fraction of 35% or less and overt congestive heart failure, enalapril reduced all-cause mortality with a number needed to treat of approximately 22 patients. In patients with a left ventricular ejection fraction of 35% or less and without overt congestive heart failure, enalapril had no significant effect on mortality but it reduced the development of heart failure with an number needed to treat of approximately 11 patients.
The SOLVD trials provide strong evidence supporting the use of ACEi in patients with systolic heart failure. The role of ACEi in systolic heart failure has been examined across diverse patient groups, and the totality of evidence consistently supports their use. However, when examining the SOLVD trials in isolation, it is important to recognize the selective nature of enrollment, which limits the trials’ external validity. Additionally, the use of a run-in period introduces bias in favor of enalapril, although this concern is less significant when the primary outcome is all-cause mortality.
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