SOLVD

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Yusuf S, et al. "Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure". The New England Journal of Medicine. 1991. 325(5):293-302.
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Clinical Question

Among patients with HFrEF, does the addition of enalapril to conventional medical therapy reduce mortality or HF hospitalizations?

Bottom Line

Enalapril reduces 4-year mortality by 16% and reduces HF hospitalizations when added to conventional therapy in patients with HFrEF.

Major Points

The earlier V-HeFT trial in 1986 demonstrated a trend towards reduced mortality when vasodilators were added to conventional therapy for HF, and the subsequent CONSENSUS trial in 1987 demonstrated a statistically significant reduction in mortality with the vasodilator and ACE inhibitor enalapril among patients NYHA class IV HFrEF.

The 1991 Studies of Left Ventricular Dysfunction (SOLVD) trial investigated the effect on mortality of enalapril among HF patients with EF ≤35% and NYHA class II-IV symptoms at the time of diagnosis. SOLVD randomized 2,569 such patients to either enalapril or placebo, in addition to conventional medical therapy consisting chiefly of digitalis, diuretics, and nitrates. At 4 years of follow up, the study demonstrated a 16% reduction in mortality associated with enalapril, predominantly due to a reduction in the risk of death due to worsening HF. There was also a reduction in the risk of hospitalizations, especially CV hospitalization. The authors estimate that treating 1,000 CHF patients with enalapril for approximately 3 years would prevent 350 hospitalizations and 50 premature deaths.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[1]

  • ACE-inhibitors for all patients with HFrEF with with current or prior symptoms unless contraindicated (class I, level A)

Design

  • Double-blind, placebo-controlled, randomized clinical trial
  • N=2,569
    • Enalapril (n=1,285)
    • Placebo (n=1,284)
  • Setting: 83 hospitals in the US, Canada, and Belgium
  • Enrollment: 1986 to 1989
  • Analysis: intention-to-treat
  • Mean follow-up: 3.5 years

Population

Inclusion Criteria

  • HF
  • LVEF ≤35%
  • Receiving conventional medical therapy without ACE inhibitor

Exclusion Criteria

  • Age >80
  • Hemodynamically serious valvular disease requiring surger
  • Unstable angina
  • Angina requiring revascularization
  • MI during prior month
  • Severe pulmonary disease
  • Cr >2 mg/dL
  • Other disease that would shorten survival or otherwise impede participation in long-term trial

Baseline Characteristics

Comparisons are enalapril vs. placebo.

  • Age: 61 years
  • Weight: 80kg
  • EF: 25%
  • BP: 125/76-77
  • HR: 80
  • Serum Na: 140 mmol/L
  • Serum K: 4.3 mmol/L
  • Serum Cr: 1.2 mg/dL
  • Male: 80-81%
  • Race
    • White: 79-81%
    • Black: 15-16%
    • Other: 4%
  • NYHA class
    • I: 11%%
    • II: 57%
    • III: 30-31%
    • IV: 2%
  • Medical history
    • CAD: 70-72%
    • MI: 65-66%
    • HTN: 42-43%
    • DM: 25-27%
    • Idiopathic DCM: 18-19%
  • Current smoker: 21-23%
  • Current angina: 36-39%
  • Atrial fibrillation: 8% vs. 12%
  • Drug therapy
    • Digitalis: 66-68%
    • Diuretics: 85-86%
    • K-sparing diuretics: 9%
    • Vasodilators
      • Any: 50-52%
      • Nitrates: 40-44%
      • Others: 15%
    • Antiarrhythmics: 21-23%
    • β-blockers: 7-8%
    • CCBs: 29-32%
    • Anticoagulants: 16%
    • Antiplatelet agents: 33-34%
    • K supplements: 49-52%

Interventions

  • Run-in phase wherein patients were given enalapril 2.5mg bid, to which placebo was subsequently added; patients were excluded from the study for intolerance to regimen
  • At the end of the run-in phase, patients were classified as having HF symptoms or not; those with HF continued in the study; those without were enrolled in the prevention study, SOLVD-P.
  • Randomized to enalapril or placebo
  • Enalapril started at 2.5mg to 5mg bid and titrated to maximum 10mg bid
  • Patients seen at 2 weeks, 6 weeks, 4 months, and then q 4 months until study completion
  • Worsening HF symptoms prompted additional diuretics and vasodilators; refractory patients were given open-label ACE inhibitors and the study drug was discontinued

Outcomes

Comparisons are enalapril vs. placebo at 4 years of follow-up.

Primary Outcomes

All-cause mortality
35% vs. 40% (RR 0.84; 95% CI 0.74-0.95; P=0.0036)
(Most of the mortality benefit appeared during the first 2 years of therapy)

Secondary Outcomes

CV death
31% vs. 36% (RR 0.82; 95% CI 0.72-0.94; P<0.002)
Death due to MI
3.1% vs. 4.1% (RR 0.72; 95% CI 0.48-1.08; P<0.07)
Arrhythmia without worsening HF
8.2% vs. 8.8% (RR 0.90; 95% CI 0.69-1.17; P=0.81)
HF or arrhythmia with HF
16.3% vs. 19.5% (RR 0.78; 95% CI 0.65-0.94; P<0.0045)
Death due to stroke
0.8% vs. 0.9% (P not specified)
Non-CV death
4.1% vs. 3.8% (P not specified)
Death or HF hospitalization
48% vs. 57% (RR 0.74; 95% CI 0.66-0.82; P<0.0001)
Patients with ≥1 hospitalization
69% vs. 74% (RR 0.93; P=0.006)
CV hospitalization
57% vs. 63% (RR 0.90; P<0.001)
Non-CV hospitalization
31% vs. 36% (RR 0.86; P=0.006)

Adverse Events

Any side effect
82% vs. 87%
Dizziness or fainting
57% vs. 50% (P not specified)
Cough
37% vs. 31% (P not specified)
Angioedema
3.8% vs. 4.1% (P not specified)
Cancer
2.6% vs. 1.7% (P=NS)
Cr >2 mg/dl
10.7% vs. 7.7% (P<0.01)
K>5.5 mmol/L
6.4% vs. 2.5% (P<0.01)

Funding

Funding from NHLBI and Merck Sharp and Dohme, who supplied the study drug.

Further Reading

  1. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.