In patients with severe HFrEF and NYHA class IV symptoms, does enalapril improve survival?
Enalapril improves survival in NYHA class IV HFrEF when added to standard therapy.
The treatment of heart failure up until the 1980s focused primarily on symptom control through use of diuretics and digoxin. The effect of the newer class of ACE inhibitors on heart failure was not well understood.
CONSENSUS (1987) randomized 253 patients with HFrEF and NYHA class IV symptoms to enalapril or placebo in addition to standard medical therapy. The intervention group had a 40% reduction in mortality at 6 months with a NNT of 6. A mortality benefit was subsequently demonstrated by the SOLVD trial (1991) in patients with moderate HFrEF.
AHA/ACCF Heart Failure Guidelines (2013, adapted)
- ACE-inhibitors for all patients with HFrEF with with current or prior symptoms unless contraindicated (class I, level A)
- Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
- Enalapril (n=127)
- Placebo (n=126)
- Setting: 35 centers in Finland, Norway, and Sweden
- Enrollment: 1985-1986
- Average follow-up: 188 days
- Range: 1 day to 20 months
- Patients lost to follow-up: None
- Analysis: Intention-to-treat
- Primary outcome: Mortality
- NYHA class IV HFrEF
- Optimal treatment with at least diuretics and digitalis though patients may also be on other non-ACE inhibitor medications (eg, nitrates, prazosin, and hydralazine).
- Heart size on CXR >600 mL/m² BSA in men and >550 mL/m² BSA in women.
- Acute pulmonary edema
- Hemodynamically important aortic or mitral valve stenosis
- Myocardial infarction within the previous two months
- Unstable angina
- Planned cardiac surgery
- Right heart failure due to pulmonary disease
- Serum creatinine 3.39mg/dl
Derived from the enalapril group, which was similar to the placebo group.
- Age: 71 years
- Female: 30%
- Weight: 66 kg
- Heart size: 875 mL/m2
- SBP: 118 mmHg
- DBP: 74 mmHg
- HR: 79 bpm
- Na: 138 mmol/L
- K: 4.0 mmol/L
- Creatinine: 132 umol/L
- CAD: 72%
- MI: 47%
- Cardiomyopathy: 14%
- Valvular heart disease: 23%
- HTN: 24%
- A fib: 53%
- DM: 24%
- Digitalis: 92%
- Beta-blocker: 4%
- Furosemide: 98%
- Spironolactone: 50%
- Other: 14%
- ISDN: 47%
- Hydralazine: 1%
- Prazosin: 8%
- Antiarrhythmics: 13%
- Anticoagulants: 33%
- Duration of symptoms:
- <6 months: 4%
- 6-17 months: 24%
- 18-47 months: 23%
- ≥48 months: 47%
- Unknown: 2%
- Hospitalized patients were randomly assigned to receive enalapril or placebo, stratified by use of vasodilators
- Patients received either enalapril or placebo at 5mg twice daily for one week then 10mg twice daily if the patient did not become hypotensive. The dose could increase up to 20mg twice daily according to clinical response.
- Evaluations occurred after weeks 1, 2, 3, 6, and 16 weeks, then at 6, 9, and 12 months, as well as at the end of the study.
- Patients with worsening symptoms were recommended to start on vasodilators (ISDN, hydralazine, and then prazosin).
- Of note, a protocol revision occurred because of occasional symptomatic hypotension. This happened after 67 patients had been randomly assigned. Revisions included an initial dose of 2.5mg daily with an increase to 2.5mg twice daily if hypotension or creatinine elevation did not occur. This was applied to those at high risk" (defined as sodium <130mmol/L, creatinine 150 to 300 μmol/l, an increase in diuretics within the previous week, or treatment with potassium sparing agents).
Comparisons are enalapril vs. placebo.
- 6-month mortality
- 26% vs. 44% (RR 0.60; P=0.002; NNT=6)
- 12-month mortality
- 36% vs. 52% (RR 0.69; P=0.001)
- Total mortality
- 39% vs. 54% (RR 0.73; P=0.003)
- Duration of beneficial effect of reduction of mortality could not be assessed due to the small amount of follow-up data
- Benefit of enalapril in NYHA class I-III was not evaluated
Merck Sharp and Dohme Research Laboratories