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


Therapeutics

Enalapril for myocardial infarction did not improve 6-month mortality

ACP J Club. 1993 Jan-Feb;118:4. doi:10.7326/ACPJC-1993-118-1-004


Source Citation

Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992 Sep 3;327: 678-84.


Abstract

Objective

To determine whether enalapril, when begun within 24 hours of a myocardial infarction, can reduce mortality over the next 6 months.

Design

6-month, randomized, double-blind, placebo-controlled trial.

Setting

103 Scandinavian medical centers between March 1990 and March 1991.

Patients

All patients who presented within 24 hours of the onset of chest pain suggesting acute myocardial infarction, accompanied by characteristic electrocardiographic or enzyme changes. Exclusions were supine blood pressure <100/60 mm Hg requiring vasopressors; severe valvular stenosis; untreated third-degree atrioventricular block; other serious comorbidity; or clear indications for or against use of angiotensin-converting enzyme (ACE) inhibitors. All 6090 patients (mean age 66 y, 73% men) were followed for 6 months (48%) or to the end of the study (minimum 41 d).

Intervention

In addition to standard care (thrombolytics, analgesics, nitrates, β-blockers, calcium-channel blockers, aspirin, anticoagulants, and diuretics), 3044 patients received a 2-hour intravenous infusion of enalaprilat, 1 mg, within 24 hours of onset of chest pain, followed 6 hours later by oral enalapril, in incremental doses to 20 mg/d over 4 days if hypotension did not occur. 3046 patients were randomized to placebo.

Main outcome measure

6-month mortality, with the cause of death ascertained blindly.

Main results

The target dose of 20 mg of enalapril was reached in 82% of patients after 10 days. The trial was stopped early because of a trend toward higher mortality among patients aged ≥ 70 years assigned to enalapril (17.3% vs 14.7% for placebo, P = 0.07). At 6 months, 11% of enalapril patients died compared with 10.2% of placebo patients (relative risk 1.10, 95% CI 0.93 to 1.29), and enalapril patients were more likely to die from heart failure (4.3% vs 3.4%, P = 0.06). No subgroup was identified that benefited from enalapril, whether based on the site or severity of the infarction or on the history of previous infarction. Early hypotension was more common among enalapril patients (12% vs 3%, P <0.001), and worsening heart failure that prompted changes in treatment occurred in 27% and 30% of enalapril and placebo patients, respectively (P< 0.006).

Conclusions

Enalapril did not improve 6-month survival when given within 24 hours after a myocardial infarction and may have done more harm than good, especially in elderly patients.

Source of funding: Merck Sharp & Dohme.

For article reprint: Dr. K. Swedberg, Department of Medicine, University of Göteborg, Östra Hospital, S-416 85 Göteborg, Sweden. FAX 46-31-258933.


Commentary

Captopril for left ventricular dysfunction after myocardial infarction reduced mortality and morbidityandEnalapril reduced the incidence of heart failure and related hospitalization in left ventricular dysfunction

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. 199718:41-51.

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.