Authors
Cohn JN, Johnson G, Ziesche S, et al.
Title
A Comparison of Enalapril with Hydralazine-Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure
References
N Engl J Med 1991;325:303-10.
Background
At the time of initiation of this landmark trials, previous trials had demonstrated that vasodilators hydralazine and isosorbide dinitrate increase survival rates in patients with mild-to-moderate symptoms and that enalapril increases survival rates in patients with severe symptoms.
Purpose
To compare the effects of enalapril with that of hydralazine and isosorbide dinitrate (H+ISDN), when added to standard medication therapy (digoxin and diuretic), in chronic heart failure patients with mild-to-moderate symptoms.
Design
  • Randomized, double-blind, active-controlled trial
  • 804 male patients, age 18-75 years with chronic heart failure and on digoxin and diuretic ≥4 weeks, cardiac dysfunction (defined as cardiothoracic ratio ≥0.55 on chest radiography, LVIDd >2.7 cm/m2 or LVEF <0.45) and reduced exercise tolerance (VO2 max<25 mL/kg/min)
Exclusion Criteria
  • MI or cardiac surgery in the preceding three months
  • angina limiting exercise or requiring long-term medical therapy
  • valvular disease, obstructive lung disease (FEV1/FVC <0.6)
  • aside from study drugs, no other vasodilators or antihypertensives
Follow-Up
Average of 2.5 years (6 months – 5.7 years)
Treatment Regimen
  • Enalapril 5 mg twice daily vs. hydralazine 37.5 mg and isosorbide dinitrate 20 mg QID
  • If tolerated, doses titrated at two weeks to target of: enalapril 20 mg per day vs. hydralazine 300 mg per day and ISDN 160 mg per day
Results

Death from all causes: 18% (enalapril) vs. 25% (H+ISDN); p=0.016 (at year 2) and p=0.08 at end of trial (overall)

  • Mortality rates with enalapril was significantly lower and primarily driven by the reduction of sudden cardiac death without warning (p=0.015) and with warning (p=0.032); death due to pump failure was not significantly different
  • Enalapril reduced mortality by 33.6%, 28.2%, 14%, 10.3% and 11.1% after year 1, 2, 3, 4 and at end of follow-up, respectively
  • a trend for decreased mortality with enalapril was seen in the absence of coronary disease and less severe (NYHA class I or II) symptoms
  • LVEF significantly increased in both arms for three years (p=0.0001) and was significantly greater (p=0.026) in the first 13 weeks with H+ISDN (0.033) than with enalapril (0.021)
  • oxygen consumption at peak exercise was significantly increased after 13 weeks (0.6 mL/kg/min, p<0.0001) and after 6 months (0.8 mL/kg/min, p<0.0001) with H+ISDN
Summary
Enalapril therapy in patients with mild-to-moderate HF symptoms significantly increases survival rates, primarily due to a reduction in sudden cardiac death, as compared to hydralazine-ISDN. A significant improvement in LVEF and oxygen consumption was seen with hydralazine-ISDN in comparison to enalapril.