Authors
Cohn JN, Archibald DG, Ziesche S, et al.
Title
Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure
References
N Engl J Med 1986;314:1547-52.
Background
At the time of initiation of this landmark trial, vasodilators have been shown to improve symptoms and exercise tolerance in patients with HF, however, their effects on survival have not yet been established. ACE inhibitor (ACEi) was not yet available at the time.
Purpose
To determine the effects of prazosin vs. hydralazine and isosorbide dinitrate (H+ISDN) vs. placebo on mortality rates in chronic HF patients already receiving standard therapy (digoxin + diuretic).
Design
  • Randomized, double-blind, placebo-controlled trial
  • 642 male patients, age 18-75 years with chronic HF while on optimal digoxin and diuretic therapy (serum digoxin >0.7 ng/mL)
  • Cardiac dilatation (defined as cardiothoracic ratio >0.55 on chest radiography or LVIDd >2.7 cm/m2) or LVEF <0.45, reduced exercise tolerance (VO2 max<25 mL/kg/min)
Exclusion Criteria
  • MI in the preceding three months or angina limiting exercise
  • obstructive valvular, MI or lung diseases, other diseases preventing completion of study
  • use of nitrates, calcium antagonists, β-blockers and antihypertensives other than diuretics
Follow-Up
Mean of 2.3 years (range, 6 months – 5.7 years)
Treatment Regimen
  • Prazosin 2.5 mg QID (titrated to target of 5 mg QID) vs. Hydralazine 37.5 mg + ISDN 20 mg QID (titrated to target of 75 mg + 40 mg QID, respectively) vs. placebo
  • stratified to presence/absence of coronary artery disease
Results

Death from all causes (overall):

  • 44% (placebo) vs. 49.7% (prazosin) vs. 38.7% (H+ISDN).
  • No difference between prazosin vs. placebo; borderline statistical significance between H+ISDN vs. placebo, p=0.093 (log-rank test) and p=0.046 (generalized Wilcoxon test).

Cumulative mortality (at two years): 34.3% (placebo) vs. 25.6% (H+ISDN); 34% risk reduction in H+ISDN group, p<0.028

  • patients receiving full doses of treatment at 6 months: 83% (placebo), 75% (prazosin), 55% (H+ISDN)
  • mortality higher in presence of coronary artery disease (p<0.02); reduction in mortality with H+ISDN slightly higher in presence of coronary artery disease but not significant (p=0.47)
  • LVEF increased significantly at week 8 and year 1 with H+ISDN, but did not change with placebo or prazosin.
Summary
No significant difference in mortality was seen with prazosin as compared to placebo, whereas a significant reduction in cumulative mortality was seen with hydralazine + isosorbide dinitrate at two years (and of borderline statistical significance throughout the study) in HF patients receiving optimal digoxin + diuretic therapy.