The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.
The SOLVD Investigators. 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;327:685-91.
Bottom line: In patients with HFrEF, enalapril reduced the risk of death and HF hospitalization (NNT 11) over 3-4 years. Patients with asymptomatic reduced EF did not experience a reduced risk of death with enalapril, but did have a reduced risk of progressing to HF (NNT 10) and HF hospitalization (NNT 24).
Patients (n=2569 in SOLVD, 4228 in SOLVD-Px)
- Inclusion
- HF (SOLVD) or no "overt" HF (SOLVD-Px)
- EF 0.35 or less (mesaured by nuclear testing, angiography or echo)
- Exclusion
- Age >80 y
- MI <1 month
- Hemodynamically serious valvular disease requiring surgery
- Unstable angina or angina severe enough to require revascularization
- Severe pulmonary disease
- SCr >177 umol/L
- "Any other disease that might substantially shorten survival"
- "Average" patient
- SOLVD (overt HF)
- Age 61 y
- Female 20%
- BP 125/77 mm Hg
- HF characteristics
- NYHA functional class I (11%), II (57%), III (30%), IV (<2%)
- LVEF 25%
- PMHx
- CAD 70%, previous MI 66%
- Dilated cardiomyopathy 18%
- AF 10%
- HTN 42%
- Meds
- Diuretics 85%
- Digoxin 66%
- Nitrate 40%
- Beta-blocker 8%
- SOLVD-Px
- Age 59 y
- Female 11%
- BP 125/78 mm Hg
- NYHA functional class I (67%), II (33%)
- LVEF 28%
- PMHx
- CAD 83%, MI 80%
- Dilated cardiomyopathy 9%
- AF 4%
- HTN 37%
- Meds
- Diuretics 17%
- Digoxin 12%
- Nitrate 30%
- Beta-blocker 24%
Interventions
- I: Enalapril uptitrated up to maximum of 10 mg PO BID
- SOLVD: At end of study, ~33% had discontinued study drug & ~50% were taking 10 mg PO BID
- SOLVD-Px: 24% had discontinued study drug at end of study
- C: Matching placebo
Results
- SOLVD (overt HF) @ mean follow-up 3.4 y
- Death or HF hospitalization: 47.7% vs 57.3% (NNT 11)
- Death (primary outcome): 35.2% vs 39.7% (NNT 23)
- All hospitalizations: 69% vs 74% (NNT 20)
- Safety
- Any adverse event: 87% vs 82% (NNH 20)
- Dizziness or fainting: 57% vs 50% (NNH 15)
- Cough: 37% vs 31% (NNH 17)
- SCr >177 umol/L: 10.7% vs 7.7% (NNH 34)
- Serum K >5.5 mmol/L: 6.4% vs 2.5% (NNH 26)
- SOLVD-Px @ mean follow-up 3.1 y
- Death or HF hospitalization: 2.7% vs 4.8% (NNT 48)
- Death (primary outcome): 14.8% vs 15.8% (p=0.30)
- HF hospitalization: 8.7% vs 12.9% (NNT 24)
- All hospitalizations: 41.5% vs 45.7% (NNT 23)
- Development of HF: 20.7% vs 30.2% (NNT 10)
- Safety
- Any adverse event: 76% vs 72% (NNH 25)
- Dizziness or fainting: 45.8% vs 39.2%
- Cough: 33.8% vs 27.3%
Issues with internal validity?
- No: Randomized, allocation-concealed, blinded trial with blinded outcome adjudication, low loss-to-follow-up (<0.5%) analyzed using the intention-to-treat population
- Run-in phases:
- Patients received enalapril 2.5 mg PO BID x2-7 days to identify intolerant individuals (only 4% excluded during this phase)
- Then switched to placebo x14-17 days to identify patients who'd acutely decline off an ACEI (4% excluded during this phase)
Additional considerations
- A subsequent systematic review and meta-analysis including CONSENSUS, SOLVD, as well as numerous smaller trials of ACE inhibitors in patients with HFrEF confirmed a consistent 23% relative risk reduction in death with ACE inhibitors in HFrEF
- Subgroup analyses suggested greatest relative mortality benefit in subgroups of individuals with NYHA class IV symptoms (dominated by CONSENSUS trial) and those with LVEF <25%
