Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Enalapril reduced the incidence of heart failure and related hospitalization in left ventricular dysfunction

ACP J Club. 1993 Jan-Feb;118:3. doi:10.7326/ACPJC-1993-118-1-003


Source Citation

SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992 Sep 3;327:685-91.


Abstract

Objective

To determine whether enalapril can reduce mortality, incidence of heart failure, and rate of related hospitalizations in patients with asymptomatic left ventricular dysfunction.

Design

Randomized, double-blind, placebo-controlled trial with mean follow-up of 37 months, part of the Studies of Left Ventricular Dysfunction (SOLVD).

Setting

83 hospitals in North America and Belgium from July 1986 through August 1991.

Patients

Adults with heart disease and ejection fractions ≤ 0.35 but not taking diuretics, digoxin, or vasodilators for heart failure. They could take diuretics for hypertension, digoxin for atrial fibrillation, or nitrates for angina. Patients were excluded if they had overt heart failure at the end of a 3-week run-in period (enalapril for 1 wk, placebo for 2 wk). 4228 patients were randomized (mean age 59 y, 89% men, 86% white); 7 were lost to follow-up.

Intervention

2111 patients were randomized to enalapril, initially 2.5 mg twice a day and increased to 10 mg twice a day if no side effects developed. 2118 patients were assigned to placebo. Patients were seen at 2 and 6 weeks, 4 months, and then every 4 months.

Main outcome measures

Total mortality, cardiovascular mortality, heart failure (by clinical findings, need for drug treatment or hospitalization, or causing death), hospitalization, and side effects.

Main results

The mean dose of enalapril at study end was 12.7 mg/d. Patients in the enalapril group were less likely to develop heart failure and had fewer hospitalizations for heart failure or for cardiovascular reasons (P < 0.001 for all comparisons) (Table). Although other trends favored enalapril, the groups did not differ for the inter-related outcomes of total mortality (313 enalapril vs 334 placebo patients), cardiovascular death (265 vs 298), death from progressive heart failure (85 vs 106), or death from arrhythmia (98 vs 105). Possible adverse effects were similar (76% in the enalapril group vs 72% in the placebo group).

Conclusions

Enalapril reduced the 3-year incidence of heart failure and related hospitalization in patients with asymptomatic left ventricular dysfunction. A trend toward reduced mortality on enalapril was not statistically significant.

Sources of funding: National Heart, Lung, and Blood Institute and Merck Sharp & Dohme.

For article reprint: Dr. S. Yusuf, HGH McMaster Clinic, Hamilton General Hospital, 237 Barton Street E., Hamilton,Ontario L8L 2X2, Canada. FAX 416-521-1551.


Table. Enalapril vs placebo for patients with asymptomatic left ventricular function*

Outcomes at mean 37 mo Enalapril Placebo RRR (95% CI) NNT (CI)
Development of heart failure 21% 30% 31% (24 to 38) 11 (8 to 15)
Hospitalization for heart failure 14% 21% 32% (23 to 41) 14 (11 to 22)
Hospitalization for cardiovascular disease 41.5% 45.7% 9% ( 3 to 15) 24 (14 to 84)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Captopril for left ventricular dysfunction after myocardial infarction reduced mortality and morbidityandEnalapril for myocardial infarction did not improve 6-month mortality

The 3 trials by the SAVE, SOLVD, and CONSENSUS II investigators add substantial new information to the continuing saga of ACE inhibitors and congestive heart failure. Previous trials in a broad spectrum of patients with symptomatic left ventricular dysfunction documented both improved symptoms and survival with these agents (1-4). Now, for the first time, the benefit of long-term ACE inhibitors in patients with decreased ejection fractions but without overtly symptomatic heart failure has been shown.

Specifically, the SAVE investigation by Pfeffer and colleagues showed that captopril, given to patients within days of having an acute myocardial infarction, prevented the development of both symptoms of and hospitalizations for heart failure. Moreover, active treatment reduced cardiovascular and total mortality.

The SOLVD study by Yusuf and colleagues showed that enalapril, given to a broader range of patients with low ejection fractions from various causes but without overt heart failure, showed a nonsignificant trend toward improved survival and prevented hospitalization and slowed progression to symptomatic heart failure.

Finally, the CONSENSUS II trial by Swedberg and colleagues showed that enalapril, given to patients within 24 hours of myocardial infarction, not only failed to produce a significant survival benefit but may possibly have increased mortality.

The seemingly disparate findings of the 2 studies among patients with myocardial infarction (SAVE and CONSENSUS II) may be the result of several factors. In the latter trial, patients were given intravenous enalaprilat within hours of their infarctions; in the former, patients were started on oral captopril 3 to 16 days after infarction. Although it is possible that ACE inhibitors given immediately after infarction have adverse physiologic effects, other points are worth considering. The CONSENSUS II trial had an average follow-up of only 6 months; however, the positive SAVE trial followed patients for at least 2 years and did not find significant survival improvements until approximately 1 year after randomization. Decreased left ventricular ejection fraction, a prerequisite for admission to the positive SAVE trial, was not an entry criterion in the negative CONSENSUS II trial. As a result, some of the patients in the latter study may have had normal systolic function and thus may have been at comparatively lower risk for progression to overt and fatal heart failure. Finally, the wide confidence intervals of the treatment effect in the CONSENSUS II trial do not preclude the possibility of benefit.

Both long-term studies of patients with decreased ejection fractions (SAVE and SOLVD) showed that ACE inhibitors reduced the incidence of symptomatic heart failure; however, the larger study (SOLVD) showed no statistically significant survival benefit. The estimate of the treatment effect in the latter trial showed a trend toward improved survival and may have been reduced by contamination; by the end of the trial, 41% of patients in the placebo group who developed symptomatic heart failure had been placed on open-label ACE inhibitors. Also, the SOLVD trial evaluated enalapril in patients with different causes of heart failure, including some with hypertensive and idiopathic cardiomyopathy, whereas the SAVE trial was confined to postinfarction patients, many of whom were already receiving digitalis, diuretic therapy, or both. Although not clearly elucidated, it is also possible that differences in co-interventions affected survival estimates in patients with decreased ejection fractions.

Summarizing the findings from the 3 studies, clinicians should heed the following messages:

1. Currently, ACE inhibitors should not be used immediately after myocardial infarction (although additional ongoing studies may establish benefit or identify subsets of responsive patients or effective doses of ACE inhibitors in this setting).

2. ACE inhibitors in moderate to high doses should be tried in patients with left ventricular systolic dysfunction who are recovering from a myocardial infarction. Large, clinically important reductions in morbidity and mortality can be expected, as evidenced by the small number of patients (n = 20) needed to treat to show benefit.

3. Finally, ACE inhibitors are reasonable agents to offer patients with asymptomatic left ventricular dysfunction regardless of cause (future studies may delineate causes that do and do not respond to ACE inhibitor therapy).

Cynthia D. Mulrow, MD, MSc
The University of Texas Health Sciences CenterSan Antonio, Texas, USA


References

1. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.

2. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med. 1987;316:1429-35.

3. 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;325:303-10.

4. Kleber FX, Niemoller L, Doering W. Impact of converting enzyme inhibition on progression of chronic heart failure: results of the Munich Mild Heart Failure Trial. Br Heart J. 1992;67:289-96.


Editorial Update

Since publication of this trial several large clinical trials have been published. They have shown, first, that a modest but significant reduction in mortality occurs in unselected patients with acute myocardial infarction, when ACE inhibitors were started within 24 hours of onset of symptoms of acute myocardial infarction (5, 6)—about 5 additional lives are saved for every 1000 patients treated with most benefit derived in patients with higher risk for infarctions. The use of these agents in the acute myocardial infarction was found to be generally safe in the absence of hypertension or renal dysfunction.

Second, additional studies of ACE inhibitors started late (days to weeks) after myocardial infarction in patients with left venticular dysfunction confirm the mortality benefits shown in the SAVE trial and further strengthen the recommendations to use ACE inhibitors in all patients after myocardial infarction if they have systolic left ventricular dysfunction (left ventricular ejection fraction ≤ 40%) or clinical findings of heart failure (7, 8).

5. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected myocardial infarction. Lancet. 1995;345:669-82.

6. Gruppo Italiano per to Studio della Sopravvinenza nell'infarto Miocardico. GISSI-3: effects of lisinopril and transdermal gylceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet. 1994;343:1115-22.

7. Cleland JG, Murray EG, Hall AS, Ball SG, on behalf of the AIRE Study Investigators. Effect of ramipril on morbidity and mode of death among survivors of acute myocardail infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J. 1997;18:41-51.

8. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333:1670-6.