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


Therapeutics

Lisinopril reduced mortality after myocardial infarction

ACP J Club. 1995 Jan-Feb;122:9. doi:10.7326/ACPJC-1995-122-1-009

Related Content in the Archives
Review: Survival benefit for early ACE inhibitor therapy is greater in some subgroups of patients with acute MI


Source Citation

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. Lancet. 1994 May 7;343:1115-22.


Abstract

Objective

To determine the effectiveness of the angiotensin-converting-enzyme (ACE) inhibitor lisinopril and transdermal glyceryl trinitrate (GTN) in patients with acute myocardial infarction (MI).

Design

6-week, 2 × 2 factorial design, randomized controlled trial.

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 treatments. Exclusion criteria were severe heart failure requiring any study drugs, Killip class 4 status, systolic blood pressure ≥ 100 mm Hg, history of bilateral renal artery stenosis, allergy to a study drug, other serious disorders, or previous randomization. 18 895 patients (97.4%) completed the study.

Intervention

Patients were assigned to oral lisinopril (5 mg/d at randomization and at 24 hours, then 10 mg/d thereafter); GTN (administered intravenously until systolic blood pressure decreased by 10% but remained above 90 mm Hg, then GTN patch, 10 mg/d after 24 hours); both treatments; or neither.

Main outcome measures

All-cause mortality and a combined end point of mortality and either congestive heart failure or left ventricular ejection fraction ≤ 35%.

Main results

Patients receiving lisinopril had lower mortality than did control patients (P = 0.03) (Table). Lisinopril also lowered the risk for the combined end point (P = 0.01) (Table). In a 4-way comparison, patients receiving lisinopril and GTN had lower mortality and combined end point rates than did control patients (6.0% vs 7.2%, {95% CI for the 1.2% difference 0.2% to 2.2%}* and 14.8% vs 17.0%, {CI for the 2.0% difference, 0.8% to 4.0%}*, respectively).

Conclusions

Lisinopril was effective in reducing mortality and clinical or echocardiographic ventricular dysfunction in patients with acute myocardial infarction. Transdermal glyceryl trinitrate was beneficial only when given in combination with lisinopril.

Sources of funding: Zeneca Pharmaceutical and Schwarz Pharma.

For article reprint: GISSI-3 Coordinating Centre, Via Eritrea 62, 20157 Milan, Italy. FAX 39-2-3546277.

*Numbers calculated from data in article.


Table. Lisinopril, transdermal glyceryl trinitrate (GTN), or lisinopril plus GTN vs neither treatment (control) in patients with acute myocardial infarction†

Outcomes at 6 wk Comparisons Event rates RRR (95% CI) NNT (CI)
Mortality Lisinopril vs control 6.3% vs 7.1% 11% (1 to 20) 127 (67 to 1376)
Lisinopril and GTN vs control 6.0% vs 7.2% 16% ( 3 to 28) 85 (46 to 579)
Combined end point† Lisinopril vs control 16% vs 17% 8.2% (2 to 14) 72 (41 to 292)
Lisinopril and GTN vs control 15% vs 17% 13% (5 to 21) 45 (27 to 130)

†Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.
†Mortality and either congestive heart failure or left ventricular ejection fraction < 35%.


Commentary

Results of the GISSI-3 study indicate that initiation of ACE inhibitors within the first 24 hours after MI is safe and is associated with a modest improvement in survival in patients treated with fibrinolytic agents, aspirin, and β-blockers, findings confirmed in the recent ISIS-4 trial (1). These results differ from those of the CONSENSUS II trial, in which treatment with intravenous enalapril within 24 hours of infarction, then with oral enalaprilat, did not improve survival (2), perhaps because of the adverse effects of hypotension associated with the early intravenous use of enalaprilat.

Although a meta-analysis of 7 randomized trials in which most patients were not treated with thrombolytic agents suggested that intravenous nitrates improved survival in patients with acute infarction (3), in GISSI-3 the administration of immediate intravenous nitroglycerin followed by 6 weeks of transdermal nitrates did not improve survival or reduce the incidence of congestive heart failure compared with controls. 57% of control patients, however, received nitrates, usually within the first 24 hours, potentially masking a benefit. The addition of nitrates to ACE inhibitors resulted in a modest additional survival benefit.

The results of GISSI-3 and other similar large trials were recently reviewed, and 2 strategies for translating these findings into clinical practice were suggested (4). One is to use the GISSI-3 approach in which all patients with an acute MI are treated if there are no clear contraindications (primarily those that would result in hypotension). Decisions regarding long-term treatment with ACE inhibitors should be based on clinical assessment of whether the patient is at high risk for cardiac complications either because of left ventricular dysfunction or other criteria defined by randomized clinical trials (i.e., diabetes). Alternatively, treatment with ACE inhibitors early in acute MI can be restricted to patients who present with anterior infarction, signs of left ventricular dysfunction, or other risk factors such as hypertension or diabetes (4).

Paul R. Eisenberg, MD, MPH
Edward Geltman, MDWashington University School of MedicineSt. Louis, Missouri, USA


References

1. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669-85.

2. 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. N Engl J Med. 1992;327:678-84.

3. Yusuf S, Collins R, MacMahon S, Peto R. Effect of intravenous nitrates on mortality in acute myocardial infarction: an overview of the randomised trials. Lancet. 1988;1:1088-92.

4. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE Inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation 1998;97:2202-12.


Authors' Response

This commentary ends with an opinion based on inappropriate post hoc analysis of GISSI-3 and ISIS-4 results. A Consensus Conference held in Berlin, September 10, 1994, favored broader application of the ACE inhibitor treatment. A report of the meeting will be published in the near future.