Review of the V-HEFT II trial
A Comparison of Enalapril with Hydralazine-Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure
N Engl J Med 1991; 325:303-10
Background Enalapril was found to be superior to placebo for patients with severe, class IV heart failure in the CONSENSUS trial and the regimen of Hydralazine-Isosorbide dinitrate was found to be superior to Prazosin as well as placebo for stable patients with mild heart failure in the original V-HEFT I trial. No sufficiently powered trials in this space had been performed to assess whether Enalapril improved long-term morbidity or mortality for heart failure patients with milder symptoms and the CONSENSUS trial had important limitations. The V-HEFT II trial was undertaken to compare 2 vasodilator regimens (Enalapril and Hydralazine-Isosorbide dinitrate) in patients with chronic congestive heart failure. Besides comparing efficacy of these agents on mortality, investigators sought to understand how these agents affected physiologic endpoints. The trial was sponsored by the Veterans Administration and enrolled men and the patient population and methods were identical to the original V-HEFT trial.
Patients Men between the ages of 18 and 75 were recruited from 13 participating Veterans Administration hospitals and had to have chronic congestive heart failure based on either evidence of cardiac dilatation or left ventricular dysfunction (EF <45%) in association with reduced exercise tolerance. Patients were excluded if 1) they had a heart attack or cardiac surgery within the previous 3 months, 2) had angina pectoris limiting exercise or requiring long term medical therapy, 3) substantial obstructive valvular disease, 4) chronic obstructive lung disease, 5) other diseases likely to limit life expectancy.
Baseline characteristics Only 29% of screened patients were ultimately enrolled. The average age of patients in the trial was 61 years. Over 50% of patients had coronary artery disease and/or previous MI and about 20% had previous bypass surgery. Excess alcohol use as well as hypertension were also present in about 40% of patients and diabetes was present in about 20%. Prior to randomization, about 60% of patients were taking vasodilators, 25% antiarrhythmics, 20% sublingual nitroglycerin and 20% anticoagulants. The average BP was about 126/78 mmHg, HR 78 bpm, and EF 30%.
Procedures After screening, a baseline period of at least 4 weeks was required to establish optimal therapy with digoxin and a diuretic agent and to allow any non-study drugs to be discontinued. Clinical evaluations and exercise-tolerance tests on 2 consecutive visits, two weeks apart, had to reveal clinical and exercise stability before randomization could occur.
Randomized patients received three bottles of medication, the first containing 5 mg of enalapril or matching placebo, the second containing 37.5 mg of hydralazine or matching placebo, and the third containing 40 mg of isosorbide dinitrate or matching placebo. Each patient received either a bottle of enalapril and 2 bottles of placebo or a bottle of hydralazine, a bottle of isosorbide dinitrate, and a bottle of placebo.
They began treatment by taking 1 tablet 2 times daily from the first bottle, 1 tablet 4 times daily from the second bottle, and one-half tablet from the third bottle 4 times daily. After 2 weeks, if the patient tolerated these doses of each medication, the doses were doubled, so that the full daily treatment consisted other either 20 mg (10 mg bid) of enalapril or 300 mg (75 mg qid) of hydralazine plus 160 mg (80 mg bid) of isosorbide dinitrate.
Follow up visits were scheduled at 3 months intervals after the titration of the initial dose at 2 weeks. In addition to clinical and laboratory evaluation, they also had exercise testing with gas exchange after 13 weeks and at 6 month intervals, yearly chest radiography, radionuclide EF measurements and assays of plasma norepinephrine levels and quality of life questionnaires every 6 months.
Endpoints The primary endpoint was mortality, which was assessed on an intention-to-treat basis. All deaths were reviewed blindly by the investigator at the local site and classified as: 1) sudden (observed or unobserved), 2) sudden but with some premonitory worsening of cardiac status, 3) progressive pump failure, 4) another cardiovascular event, and 5) non-cardiovascular.
Secondary endpoints included changes over time in clinical measurements, which were analyzed at each follow up visit by comparing the mean changes from base line in the two treatment arms with use of a t-test. It is unclear from the methods whether secondary endpoints were assessed on an ITT basis.
Results 804 patients were enrolled (403 in the enalapril group and 401 in the hydralazine-isosorbide dinitrate group). Twenty-two percent of patient discontinued enalapril prior to their final visit and an additional 8% reduced the dose. Twenty-nine percent of patients discontinued hydralazine and 10% reduced the dose whereas 31% discontinued isosorbide and 10% had reduced the dose. Adherence with the prescribed regimen, based on pill counts, averaged 86%. The average daily dose of enalapril was 15 mg, hydralazine was 199 mg and isosorbide was 100 mg.
The mean follow-up was 2.5 years (range 6 months to 5.7 years). Six patients in the enalapril arm and 2 in the hydralazine-isosorbide arm received a heart transplant and their data were censored from the analysis at that time. There were 132 deaths in the enalapril group (33%; 13 per 100 patient years) and 153 in the hydralazine-dinitrate group (39%; 15 per 100 patient years). A statistically significant reduction in mortality was observed at 2 years (p = 0.016) but not over the duration of the trial (p = 0.08). The reduction in mortality was highest after 1 year and began to diminish thereafter.
There were 245 patients who were also included in the original V-HEFT I trial. There was no interaction on survival between subgroups of those who did versus did not participate.
The reduction in death in the enalapril group was driven by sudden death; there was no difference between groups in death due to pump failure.
Prespecified subgroup analysis in CAD vs no CAD stratification showed no significant treatment effect heterogeneity for hydralazine-nitrate among those with CAD although the absolute difference in mortality between groups was numerically higher for patients with CAD.
BP was reduced more in the enalapril group whereas ejection fraction increased in both groups but was greater in the hydralazine-isosorbide group. Exercise tolerance was also better in the hydralazine-isosorbide group.
Hospitalization for heart failure was unchanged in both groups at approximately 18%.
Headaches were more common in the hydralazine-isosorbide group whereas symptomatic hypotension and cough were higher in the enalapril group.
Conclusions This study compared enalapril to hydralazine-isosorbide in patients with chronic congestive heart failure who were optimized on digoxin and diuretic therapy. In this young (60 years) and highly selected population of clinically stable male veterans with dilated cardiomyopathies and NYHA class II and III symptoms, enalapril reduced death by 2 per 100 patient years compared to hydralazine-isosorbide but this was not statistically significant over the duration of the trial. This difference was driven by sudden death and not pump failure. The external validity is limited by intensive monitoring following enrollment and the fact that this is a population of male veterans whose etiologic distribution of cardiomyopathy and heart failure is likely different from a general heart failure population. Furthermore, like V-HEFT I, the population is likely highly selected and it’s unclear how many patients from the general heart failure population would meet study criteria. It’s probable that the majority would not. Similar to V-HEFT I, results from this study provide no guidance on the management of heart failure patients in the inpatient setting. Finally, differences in mortality were not correlated with differences in the physiologic endpoints of EF and exercise tolerance.