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Therapeutics

Trandolapril reduced mortality and progression to severe heart failure in MI with left ventricular dysfunction

ACP J Club. 1996 May-June;124:61. doi:10.7326/ACPJC-1996-124-3-061


Source Citation

Køber L, Torp-Pedersen C, Carlsen JE, et al., for the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995 Dec 21;333:1670-6.


Abstract

Objective

To evaluate the effectiveness of trandolapril in reducing mortality in patients with left ventricular dysfunction after myocardial infarction (MI).

Design

Randomized, double-blind, placebo-controlled trial with 24- to 50-month follow-up.

Setting

27 centers in Denmark.

Patients

1749 patients (mean age 67 y, 72% men) with MI confirmed by enzyme studies and left ventricular systolic dysfunction determined by echocardiogram (wall-motion index ≤ 1.2, corresponding to an ejection fraction ≤ 35%). Exclusion criteria were contraindication to angiotensin-converting enzyme (ACE) inhibition, a definite need for ACE inhibition, hyponatremia, an elevated serum creatinine level, pregnancy or lactation, unstable angina pectoris requiring immediate invasive therapy, major noncardiac illnesses, drug or alcohol abuse, or treatment with another investigational drug.

Intervention

876 patients were allocated to 1 mg/d of trandolapril. After 2 days, the dose of trandolapril was increased as tolerated to 2 mg/d, and after 4 weeks, the dose was increased as tolerated to 4 mg/d. 873 patients were allocated to matching placebo 3 to 7 days after MI.

Main Outcome Measures

Mortality, progression to severe heart failure, and reinfarction.

Main Results

Analysis was by intention to treat. During the study period, trandolapril led to fewer deaths than did placebo (35% vs 42%, P = 0.001). {This absolute risk reduction (ARR) of 7% means that 13 patients would need to be treated (NNT) with trandolapril (rather than placebo) to prevent 1 additional death, 95% CI 8 to 33; the relative risk reduction (RRR) was 18%, CI 8% to 27%.}* Trandolapril also reduced the number of deaths from cardiovascular causes (26% vs 33%, P = 0.001) {ARR 7%; NNT 14, CI 9 to 34; RRR 22%, CI 9% to 32%}* and from sudden death (12% vs 15%, P = 0.03) {ARR 3%; NNT 31, CI 15 to 2864; RRR 21%, CI 0.3% to 38%}*. Progression to severe heart failure was also reduced in the trandolapril group (14% vs 20%; P = 0.003) {ARR 6%; NNT 19, CI 11 to 55; RRR 27%, CI 10% to 41%}*. 99 fatal or nonfatal MIs (11%) occurred in the trandolapril group compared with 113 (13%) in the placebo group (P = 0.29). Apart from patients who died during follow-up, 37% of patients were withdrawn from the trandolapril group, and 36% were withdrawn from the placebo group.

Conclusion

In patients with myocardial infarction and left ventricular systolic dysfunction, trandolapril reduced all-cause mortality, including death from cardiovascular causes and sudden death, and reduced the development of severe heart failure.

Sources of funding: Roussel-Uclaf and Knoll.

For article reprint: TRACE Study Office, Svanemøllevej 2, DK-2100 Copenhagen, Denmark. FAX 45-3977-7621.

*Numbers calculated from data in article.


Commentary

The effectiveness of ACE inhibitors given soon after MI has been studied in almost 100 000 patients in randomized controlled trials. Some studies only included patients with high risk based on the anterior location of infarction or the presence of symptomatic heart failure or asymptomatic left ventricular systolic dysfunction. Others included unselected patients with MI. Enrollment times ranged from the first day to during the index hospitalization to later. Treatment and follow-up periods were as short as 1 month and as long as 4 years.

By systematically screening all patients with MI who met the inclusion criteria, the study by Køber and colleagues attempted to avoid the tendency found in some trials to enroll healthier patients and exclude sicker ones. As a result of this thorough screening and the requirement for significant left ventricular dysfunction that was established by echocardiogram, the patients studied had a high mortality rate during the 2 to 4 years of follow-up, which was significantly reduced by trandolapril.

The TRACE study is compatible with the existing body of evidence that supports the use of ACE inhibitors to reduce mortality in patients with MI. Although controversy exists about whether ACE inhibitors should be used universally or selectively (1), absolute benefit is greatest when treatment is long-term in patients with left ventricular dysfunction, whether assessed clinically or by objective measures. Small but worthwhile additional benefits accrue when treatment is started within the first or second day after MI rather than later. Patients with low risk as defined by clinical factors (e.g., young age, nonanterior location, first MI, absence of heart failure) for whom ACE inhibitors are not prescribed should have left ventricular performance measured and should have prompt initiation of ACE inhibitors if left ventricular function is more than mildly impaired.

Steven Borzak, MD
Henry Ford HospitalDetroit, Michigan, USA


Reference

1. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. Circulation. 1995;92:3132-7.