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Therapeutics

Early treatment with lisinopril for 6 weeks reduced mortality at 6 months in acute MI

ACP J Club. 1996 July-Aug;125:7. doi:10.7326/ACPJC-1996-125-1-007


Source Citation

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Six-month effects of early treatment with lisinopril and transdermal glyceryl trinitrate singly and together withdrawn six weeks after acute myocardial infarction: the GISSI-3 Trial. J Am Coll Cardiol. 1996 Feb;27:337-44. [PubMed ID: 8557903]


Abstract

Objective

To evaluate the effectiveness of a 6-week course of lisinopril or transdermal glyceryl trinitrate (GTN), or both, in reducing 6-month mortality and severe left ventricular dysfunction in patients with acute myocardial infarction (MI).

Design

6-month randomized controlled trial with a 2 × 2 factorial design.

Setting

200 coronary care units (CCUs) in Italy.

Patients

19 394 patients (78% men) with chest pain and ST-segment elevation or depression of ≥ 1 mm in ≥ 1 peripheral lead or ≥ 2 mm in ≥ 1 precordial lead who were admitted to a CCU within 24 hours and had no contraindications to the study medications. Exclusion criteria were systolic blood pressure ≤ 100 mm Hg; serum creatinine > 177 µmol/L or proteinuria > 500 mg per 24 hours, or both; {severe heart failure requiring any study drugs; Killip class 4 status; or other serious disorders}*.

Intervention

Patients were allocated to 5 mg/d of oral lisinopril at randomization and at 24 hours and to 10 mg/d thereafter; GTN administered intravenously for the first 24 hours, followed by 10 mg/d via a transdermal patch that was applied each morning and removed at bedtime; both treatments; or neither. Treatment was stopped at the 6-week visit in the absence of specific indications.

Main outcome measure

Combined end point of mortality, clinical heart failure, or severe left ventricular dysfunction.

Main results

At 6 months, among patients allocated to lisinopril, 18.1% died or developed severe ventricular dysfunction compared with 19.3% of those allocated to no lisinopril (P = 0.03) (Table). No difference existed in mortality or in the development of severe ventricular dysfunction between patients allocated to GTN or no GTN (P = 0.39) (Table). The combination of lisinopril and GTN led to a reduced event rate for the combined end point when compared with the control group (P = 0.03) (Table).

Conclusion

Early treatment with lisinopril for 6 weeks reduced mortality or severe ventricular dysfunction at 6 months in patients with acute myocardial infarction.

Sources of funding: Zeneca Pharmaceutical and Schwarz Pharma.

For article reprint: Dr. M.G. Franzosi, GISSI-3 Coordinating Centre, Via Eritrea, 62, 20157 Milan, Italy. FAX 39-2-3320-0049.

*Information published in Lancet. 1994;343: 1115-22.


Table. Lisinopril and glyceryl trinitrate (GTN) in patients with acute myocardial infarction†

Outcomes at 6 mo Comparisons Event rates RRR (95% CI) NNT( CI)
Mortality or severe ventricular dysfunction Lisinopril vs no lisinopril 18.1% vs 19.3% 6.3% (0.7 to 11.7) 82 (43 to 807)
Mortality or severe ventricular dysfunction GTN vs no GTN 18.4% vs 18.9% Not significant
Mortality or severe ventricular dysfunction Lisinopril and GTN vs control 17.8% vs 19.5% 8.8% (0.8 to 16.1) 59 (31 to 652)

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


Commentary

Lisinopril or captopril started within 24 hours of the onset of acute MI was associated with an absolute reduction in mortality of 0.5% in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-3) and the International Study of Infarct Survival (ISIS-4) (1, 2). In the ISIS-4, treatment with captopril, 50 mg twice daily for 1 month, reduced mortality from 7.7% to 7.2% at 5 weeks; and the benefit was maintained at 12 months (2). In the current follow-up study of the GISSI-3, a significant decrease occurred in the combined end point of mortality and development of severe left ventricular dysfunction at 6 months. In addition, a modest positive interaction between treatment with intravenous GTN for 24 hours and then with GTN and lisinopril for 6 weeks was noted at 6 months. A potentially confounding factor was that more patients who were initially treated with either lisinopril or GTN continued receiving the drug at the end of the treatment phase. Therefore, it is possible that the observed treatment effect is partially attributable to having > 6 weeks of treatment.

The results of this study provide additional support for the recommendation that treatment with angiotensin-converting enzyme (ACE) inhibitors be started as soon as possible after acute MI in hemodynamically stable patients after initial treatment with thrombolytics, aspirin, or β-blockers (3). In patients with a left ventricular ejection fraction < 40%, ACE inhibitors should be taken long term and probably for life. With lesser degrees of left ventricular dysfunction in asymptomatic patients, ACE inhibitors may be discontinued after 4 to 6 weeks. Although additional data are needed in patients with minimal left ventricular dysfunction after acute MI, the results of these studies provide compelling evidence that ACE inhibitors have a beneficial effect on the morbidity and mortality of virtually all patients who present with acute MI.

Paul R. Eisenberg, MD, MPH
Washington University School of MedicineSt. Louis, Missouri, USA


References

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

2. 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 acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group.Lancet. 1995;345:669-82.

3. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials.Circulation. 1995;92:3132-7.