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


Therapeutics

Captopril for left ventricular dysfunction after myocardial infarction reduced mortality and morbidity

ACP J Club. 1993 Jan-Feb;118:2. doi:10.7326/ACPJC-1993-118-1-002


Source Citation

Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement [SAVE] Trial. N Engl J Med. 1992 Sep 3;327:669-77.


Abstract

Objective

To determine whether captopril, begun 3 to 16 days after myocardial infarction, can reduce mortality and morbidity in patients with left ventricular dysfunction.

Design

Randomized, double-blind, placebo-controlled trial with mean follow-up of 42 months.

Setting

45 centers (112 hospitals) in North America from January 1987 through January 1992.

Patients

Patients were enrolled 3 to 16 days after myocardial infarction if they had a left ventricular ejection fraction of ≤ 0.40 and were aged 21 to 80 years. Exclusion criteria were unstable clinical course, overt heart failure, ischemic symptoms, compelling indications or contraindications for captopril, serum creatinine > 221 µmol/L, or other conditions believed to limit survival. Any revascularization had to be done before randomization. 2231 patients (mean age 59 y, 82% men) were randomized; follow-up was 99.7%.

Intervention

1115 patients were randomized to captopril, initially 12.5 mg 3 times/d and increased to 50 mg 3 times/d if no side effects developed. 1116 patients were assigned to placebo. Follow-up was at 2 weeks, every 3 months for 1 year, and then every 4 months.

Main outcome measures

Total mortality, fatal and nonfatal major cardiovascular events, and heart failure (requiring hospitalization or more than digitalis and diuretics for control).

Main results

Patients in the captopril group had lower total 42-month mortality than placebo patients (P = 0.019) and had fewer cardiovascular deaths (P = 0.014), fewer cases of serious heart failure (P < 0.001), fewer hospitalizations for congestive heart failure (P = 0.019), and fewer myocardial infarctions (P = 0.015) (Table). The groups did not differ for use of β-blockers, aspirin, digitalis, and nitrates or for discontinuation of medication because of side effects. Patients on placebo used more diuretics (38% vs 32%, P = 0.002).

Conclusion

Captopril reduced 42-month mortality and cardiovascular morbidity when started 3 to 16 days after myocardial infarction in patients who had left ventricular dysfunction but no overt heart failure.

Source of funding: Bristol-Myers Squibb Institute for Pharmaceutical Research.

For article reprint: Dr. M.A. Pfeffer, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. FAX 617-732-7134.


Table. Captopril vs placebo for patients with left ventricular dysfunction who had had a myocardial infarction*

Outcomes at 42 mo Captopril Placebo RRR (95% CI) NNT (CI)
Death 20.4% 24.6% 17% (3 to 29) 24 (13 to 138)
Cardiovascular deaths 17% 21% 20% (4 to 32) 24 (14 to 116)
Progression to heart failure or death 3.4% 5.2% 34% (2 to 56) 56 (28 to 936)
Hospitalization for heart failure 14% 17% 20% ( 2 to 34) 29 (16 to 257)
Myocardial infarction 12% 15% 22% (3 to 37) 30 (16 to 216)

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


Commentary

Enalapril reduced the incidence of heart failure and related hospitalization in left ventricular dysfunctionandEnalapril 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. ISI-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.