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


Therapeutics

Zofenopril reduced mortality and morbidity after myocardial infarction

ACP J Club. 1995 May-June;122:61. doi:10.7326/ACPJC-1995-122-3-061


Source Citation

Ambrosioni E, Borghi C, Magnani B, for the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med. 1995 Jan 12;332:80-5.


Abstract

Objective

To determine whether zofenopril reduces mortality and morbidity if given within 24 hours of anterior myocardial infarction (MI) to patients ineligible for thrombolytic therapy.

Design

Randomized, placebo-controlled trial with 1-year follow-up.

Setting

154 centers in Italy.

Patients

1556 patients (mean age 64 y, 73% men) hospitalized within 24 hours of onset of an electrocardiographic-proven anterior MI. Patients were ineligible for thrombolytic therapy because of time considerations or contraindications to fibrinolysis. Exclusion criteria were cardiogenic shock, systemic blood pressure (SBP) < 100 mm Hg, serum creatinine levels > 221 mmol/L, history of congestive heart failure (CHF), or treatment with or contraindications to angiotensin-converting-enzyme (ACE) inhibitors.

Intervention

All patients received standard therapy. 772 patients were assigned to zofenopril, 15 mg/d for 6 weeks, which was increased to 60 mg/d if SBP > 100 mm Hg. Patients unable to tolerate the first dose were taken off medication but were included in the intention-to-treat analysis. 784 patients were assigned to placebo. Follow-up was complete.

Main outcome measures

Mortality and severe CHF.

Main results

At 6 weeks, patients receiving zofenopril had a lower rate of mortality or severe CHF compared with patients assigned to placebo (P = 0.018) (Table). Most of this difference was because of a 1.9% reduction in severe CHF (P = 0.018) (Table). At 1 year, fewer patients receiving zofenopril had died compared with patients receiving placebo (P = 0.011) (Table). The groups did not differ for compliance or adverse effects. Subgroup analysis showed that zofenopril was beneficial for patients who used calcium-channel blockers (RR 0.14, CI 0.03 to 0.66), had had a previous MI (RR 0.17, CI 0.05 to 0.52), or used nitrates (RR 0.48, CI 0.29 to 0.79).

Conclusion

Zofenopril, given for 6 weeks after anterior myocardial infarction, reduced the combined risk for death and congestive heart failure at 6 weeks and total mortality at 1 year.

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

For article reprint: Dr. C. Borghi, Clinica Medica 3rd, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy.


Table. Zofenopril vs placebo after myocardial infarction*

Outcomes Zofenopril Placebo RRR (95% CI) NNT (CI)
Mortality or severe CHF at 6 wk 7.1% 10.6% 33% (7 to 51) 29 (16 to 155)
Severe CHF at 6 wk 2.2% 4.1% 46% (11 to 71) 53 (27 to 668)
Mortality at 1 y 10.0% 14.1% 29% (8 to 46) 24 (13 to 105)

*CHF = congestive heart failure. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

The SMILE study adds to the growing evidence calling for the widespread use of ACE inhibitors in all patients who have had an MI and do not have contraindications for the inhibitors. The recent large-scale GISSI-3 (1) and ISIS-4 (2) studies also initiated early use of various ACE inhibitors and showed a decrease in mortality similar to that seen in the SMILE study. This study is important in providing a therapy that reduces mortality in a high-risk population ineligible for thrombolytics. It also confirms the survival benefit of starting the therapy soon after MI so as not to lose the early decrease in mortality. Any increased risk for side effects, such as hypotension, is also offset by this survival benefit.

Previous studies have proved the benefit of ACE inhibitors in various subsets of patients with MI. The SAVE trial (3) initiated treatment from 3 to 14 days after MI in patients with ejection fractions ≤ 40% regardless of symptoms and continued therapy for a mean of 42 months. A reduction in mortality and cardiac morbidity occurred that was not influenced by the use of other treatments, such as thrombolytics. This finding is confirmed in the SMILE study. The AIRE trial (4), which treated patients with overt heart failure from day 3 to day 10 for a mean of 15 months, also showed a reduction in mortality.

The observed reduction in mortality may have been caused, in part, by ventricular remodeling and reduced ventricular volumes. The greatest change in volume occurred in the first 4 months, as shown in the SOLVD trial (5), a time course that may explain the benefit seen in this report with zofenopril therapy for only 6 weeks. A decrease in recurrent MI also was seen in the SOLVD trial, which might fit this short therapeutic course.

The use of ACE inhibitors in patients soon after MI should move from research to usual clinical practice.

Robert J. Weiss, MD
Androscoggin Cardiology AssociatesAuburn, Maine, USA


References

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

2. ISIS Collaborative Group. Randomised study of oral captopril in over 50,000 patients with suspected acute myocardial infarction.Circulation. 1993;88(Suppl I):394.

3. Pfeffer MA, Braunwald E, Moye 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 trial. The SAVE Investigators. N Engl J Med. 1992;327:669-77.

4. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-8.

5. Konstam MA, Kronenberg MW, Rousseau MF, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. SOLVD (Studies of Left Ventricular Dysfunction) Investigators. Circulation. 1993;88:2277-83.