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Improved survival at 2 years in mild-to-moderate heart failure for enalapril as compared with hydralazine-isosorbide dinitrate

ACP J Club. 1991 Nov-Dec;115:68. doi:10.7326/ACPJC-1991-115-3-068

Source Citation

Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991 Aug 1;325:303-10.



To compare the effects of enalapril with hydralazine-isosorbide dinitrate for treatment of mild-to-moderate congestive heart failure in men receiving digoxin and diuretics.


Randomized, double-blind, controlled trial.


13 Veterans Affairs medical centers.


Patients were recruited between March 1986 and September 1990. 2741 men, aged 18 to 75 years, met the inclusion criteria of reduced exercise tolerance and cardiac dysfunction, defined as a cardiothoracic ratio ≥ 0.55 on chest radiography, left ventricular internal diameter > 2.7 cm/m2 of body surface area, or ejection fraction < 0.45. Of these patients, 1937 were excluded for myocardial infarction or surgery during the previous 3 months, angina pectoris limiting exercise or requiring long-term medical therapy, serious valvular disease, obstructive lung disease, or other diseases that would limit life expectancy.


Patients initially received either enalapril, 10 mg (n = 403), or hydralazine, 150 mg, with isosorbide dinitrate, 80 mg (n = 401), after a minimum 4-week run-in period. If the initial doses were tolerated, the doses were doubled after 2 weeks. Assessments done at 3-month intervals included exercise testing and determination of cardiothoracic ratios, ejection fractions, and plasma norepinephrine levels.

Main outcome measure

Mortality, with an intention-to-treat analysis. Causes of death were reviewed blindly.

Main results

Average follow-up was 2.5 years (range, 0.5 to 5.7 years). The average daily dose of enalapril was 15 mg; hydralazine, 199 mg; and isosorbide dinitrate, 100 mg. 33% of patients on enalapril and 38% of patients on hydralazine-isosorbide dinitrate died (P = 0.08). {Absolute risk reduction (ARR) 5%, 95% CI -1% to 12%, (P = 0.08).}* At 2 years, a predetermined time for analysis, mortality was lower for patients receiving enalapril (18%) compared with those receiving hydralazine-isosorbide (25%) (P = 0.02). A greater protective effect for sudden death was observed for enalapril both with warning (P = 0.03) and without (P = 0.015), but there was no difference for death caused by pump failure.


In men with mild-to-moderate congestive heart failure who received digoxin and diuretic therapy, enalapril reduced mortality at 2-year follow-up compared with hydralazine-isosorbide dinitrate. The mortality difference did not remain statistically significant over the full course of the trial.

Source of funding: Department of Veterans Affairs.

Address for article reprint: Dr. J.N. Cohn, University of Minnesota Medical School, Box 488 UMHC, 420 Delaware Street SE, Minneapolis, MN 55455, USA.

*Numbers calculated from data in article.


Placebo-controlled trials have shown that the addition of vasodilator therapy with enalapril or isosorbide with hydralazine to standard medical therapy reduces mortality in patients with moderate-to-severe congestive heart failure (CHF). This randomized, blinded trial directly compared enalapril with isosorbide and hydralazine in patients with mild-to-moderate CHF. No difference existed in the rate of rehospitalization for worsening symptoms. Adherence to therapy was slightly better with enalapril; side-effect profiles were comparable. A slight benefit occurred in terms of improvement in ejection fraction and exercise tolerance with hydralazine-isosorbide dinitrate. These changes were small and difficult to interpret in light of the mortality benefit shown with enalapril. A "sicker" group of survivors in the enalapril group with poor left ventricular function may limit the mean improvement of the group as a whole.

In general, the vasodilator regimen of first choice in patients with mild-to-severe CHF and reduced left ventricular function is an angiotensin-converting enzyme inhibitor. The costs and treatment adherence favor enalapril. Although the relative risk reduction for overall mortality was not statistically significant, this does not mean that the regimens are clinically equivalent. The differences in mortality, particularly at 1- and 2-year follow-up, were clinically important, and the study lacked the power to reliably detect modest but clinically important differences. Hydralazine-isosorbide dinitrate should be reserved for patients who cannot tolerate angiotensin-converting enzyme inhibitors.

David Massel, MD
Victoria HospitalLondon, Ontario, Canada