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Cohn JN, et al. "A Comparison of Enalapril with Hydralazine–Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure". The New England Journal of Medicine. 1991. 325(5):303-310.
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Clinical Question

Among patients with mild-to-moderate HFrEF on diuretics and digoxin, does enalapril improve survival compared to the combination of isosorbide dinitrate (ISDN) and hydralazine?

Bottom Line

In patients with mild-to-moderate HFrEF, enalapril improved survival compared to the combination of ISDN and hydralazine.

Major Points

In the era before ACE inhibitors, the V-HeFT trial demonstrated that vasodilator therapy with ISDN/hydralazine conferred a modest survival benefit in patients with chronic heart failure with reduced ejection fraction (HFrEF). Subsequently, CONSENSUS (1987) demonstrated a survival benefit with ACE inhibition in patients with severe, class IV heart failure. Until V-HeFT II, no study prospectively compared survival with ACE inhibitors versus ISDN/hydralazine in patients with less severe HFrEF.

Published in 1991, the Vasodilator-Heart Failure Trial II (V-HeFT II) trial randomized 804 men with mild-to-moderate chronic heart failure (51% NYHA class II, 43% class III) on a stable regimen of diuretics and digoxin to receive enalapril or ISDN/hydralazine. Follow-up in the trial ranged from 6 months to 5.7 years with a mean follow-up of 2.5 years. Two years after randomization, mortality in the enalapril group was significantly lower than in the ISDN/hydralazine group (18% vs. 25%, NNT 14; P=0.016), though this benefit did not achieve statistical significance for the entire duration of the follow-up (P=0.08). Reduction in mortality with enalapril was largely driven by a lower incidence of sudden death. There were no significant differences in rates of hospitalizations between the two groups (18.9% vs 18.4%). ISDN/hydralazine was associated with significant improvements in exercise performance (P<0.0001) and left ventricular function (P<0.0001) compared to enalapril at 13 weeks. Enalapril use was associated statistically significant elevations in BUN (P<0.01) and creatinine (P=0.02) compared to ISDN/hydralazine therapy at one year.

Simultaneously published, the V-HeFT II and SOLVD trials were landmark studies that were the first to demonstrate mortality benefit with ACE inhibition in patients with mild-to-moderate heart failure. Specifically, the V-HeFT II trial demonstrated that enalapril was superior to ISDN/hydralazine in patients with mild-to-moderate heart failure. Of interest, a subgroup analysis published separately demonstrated a statistically significant benefit of ISDN/hydralazine among self-identified black patients, which was the basis of the prospective, randomized A-HeFT trial.[1]


AHA/ACCF Heart Failure Guidelines (2013, adapted)[2]

  • ACE inhibitors are recommended in patients with HFrEF and current or prior symptoms, unless contraindicated, to reduce morbidity and mortality (class 1, level A)
  • The combination of ISDN/hydralazine is recommended to reduce morbidity and mortality for patients self-described as African Americans with NYHA class III–IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated (class 1, level A)
  • A combination of ISDN/hydralazine can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or ARB because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated. (class IIa, level B)


  • N=804 men with symptomatic HF receiving diuretics and digoxin
    • Enalapril group: 403
    • ISDN/hydralazine group: 401
  • Setting: 13 VA Medical Centers in the United States
  • Enrollment: 1986-1990
  • Mean follow-up: 2.5 years
  • Analysis: Intention-to-treat
  • Primary endpoint: 2-year mortality
  • Secondary endpoints: Hemodynamic effects, ejection fraction, exercise tolerance, cardiothoracic ratio, adherence to medical regimen, hospitalization


Inclusion Criteria

  • Men ages 18-75 years
  • Reduced exercise tolerance (assessed by a progressive maximal exercise test with a bicycle ergometer during breath-by-breath monitoring of gas exchange)
  • Cardiac dysfunction (cardiothoracic ratio ≥0.55 on chest radiography, left ventricular internal diameter >2.7 cm per square meter of body-surface area at diastole on echocardiography, or ejection fraction less than 0.45 as determined with radionuclide methods)
  • Receiving optimal and stable diuretic and digoxin

Exclusion Criteria

  • Myocardial infarction or cardiac surgery within the previous three months
  • Angina pectoris limiting exercise or requiring long-term medical therapy
  • Serious obstructive valvular disease
  • Obstructive lung disease (ratio of forced expiratory volume in one second to forced vital capacity, <0.60)
  • Other diseases likely to limit life expectancy.

Baseline Characteristics

From the enalapril group unless otherwise specified.

  • Age 61 years
  • Duration of congestive heart failure
    • <6 months: 18%
    • 6mo-1 year: 19%
    • 1-2 years: 20%
    • 2-4 years: 20%
    • >4 years: 25% (31% in ISDN/hydralazine group)
  • NYHA class:
    • I: 6%
    • II: 50%
    • III: 44%
    • IV: 0.2%
  • Race: 73% white, 26% black
  • Past medical history:
    • CAD: 54%
    • MI: 48%
    • CABG: 21%
    • Stroke: 11%
    • HTN: 50%
    • DM: 21%
    • Alcohol abuse: 34%
    • Tobacco use: 34%
  • Drug therapy (prior 6 months):
    • Vasodilators: 61%
    • Nitroglycerin: 16%
    • Antiarrhythmic agents: 25%
    • Anticoagulants: 21%
  • Baseline clinical assessment:
    • BP: 126/78 mmHg
    • HR: 78
    • Cardiothoracic ratio: 0.527
    • LVIDD: 3.6 cm/m2
    • Atrial fibrillation: 12%
    • S3 gallop: 21%
    • VO2max: 13.8 ml/kg/min


Patients were randomized to:

  • Enalapril
  • ISDN/hydralazine

Dose titration:

  • Enalapril initial dose 5 mg PO BID, increased to 10 mg BID after 2 weeks if tolerated
  • ISDN initial dose 20 mg PO QID, increased to 40 mg PO QID after 2 weeks if tolerated
  • Hydralazine initial dose 37.5 mg PO QID, increased to 75 mg PO QID after 2 weeks if tolerated

Placebo control:

  • All patients received 3 bottles of medications
  • Enalapril patients also received 2 bottles of placebo
  • ISDN/hydralazine patients received 1 bottle of placebo


  • After initial dose titration, all patients were followed at 3-month intervals
  • Laboratory data, ejection fractions, cardiothoracic ratios, and gas-exchange measurements were recorded


Comparisons are enalapril vs. ISDN/hydralazine, unless otherwise specified

Primary Outcomes

All-cause mortality at 2 years
18% vs. 25% (P=0.016; NNT 14)

Secondary Outcomes

Hemodynamic effects
BP reduction (change in systolic/diastolic): 5/4 vs. 0/1 (significant but p-value not specified)
Significant increase in HR in ISDN/hydralazine group (p-value not specified)
Ejection fraction increase
2.1% vs. 3.3% (P=0.026)
Exercise Tolerance
Significant change in oxygen consumption greater with hydralazine by 0.6 ml/kg/min at 13 weeks; P<0.0001 and after 6 months, 0.8 ml/kg/min; P<0.0001. No changes noted with enalapril.
After one year, oxygen consumption began to decline progressively in both treatment arms. P values for the difference between hydralazine—isosorbide dinitrate and enalapril with respect to peak exercise capacity during the first 2 years were 0.01 after 13 weeks, 0.02 after 6 months, 0.1 after 1 year, and 0.02 after 2 years.
Cardiothoracic ratio decreased significantly at 13 weeks and 1 year in both groups (P<0.0001) with no significant differences between groups
Discontinuation, 22% vs. 29/31%
Reduction in dose, 8% vs. 10/10%
18.9% vs. 18.4% (not significant, p-value not specified)

Adverse Events

Comparisons are enalapril vs. ISDN/hydralazine, unless otherwise specified

  • Nausea, 52% vs. 44%
  • Fatigue, 79% vs. 76%
  • Headache, 54% vs. 73% (P<0.05)
  • Palpitations, 46% vs. 51%
  • Symptomatic hypotension, 28% vs. 20% (P<0.05)
  • Taste disturbance, 28% vs. 28%
  • Joint pain, 65% vs. 63%
  • Rash, 33% vs. 31%
  • Nasal congestion, 63% vs. 63%
  • Cough, 37% vs. 29% (P<0.05)
  • BUN higher in enalapril, increased by 2.6mg/dL at 4 weeks and 3.4mg/dL at one year vs. 0 (P<0.01)
  • Cr higher in enalapril, significant increase at 4 weeks (P=0.08), 1 year (P=0.02)

Subgroup Analysis

A subgroup analysis published separately demonstrated a statistically significant benefit of ISDN/hydralazine among self-identified black patients.[3]


  • Mortality benefit with enalapril to ISDN/hydralazine was significant at the primary specified time point of 2 years but not during entire trial period (p=0.08)
  • Only included men, to the exclusion of women with heart failure


Funded by the Cooperative Studies Program of the Medical Research Study of the VA Central Office in Washington, DC.

Further Reading