Elsevier

The Lancet

Volume 349, Issue 9054, 15 March 1997, Pages 747-752
The Lancet

Articles
Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)*

https://doi.org/10.1016/S0140-6736(97)01187-2Get rights and content

Summary

Background

To determine whether specific angiotensin II receptor blockade with losartan offers safety and efficacy advantages in the treatment of heart failure over angiotensin-converting-enzyme (ACE) inhibition with captopril, the ELITE study compared losartan with captopril in older heart-failure patients.

Methods

We randomly assigned 722 ACE inhibitor naive patients (aged 65 years or more) with New York Heart Association (NYHA) class II-IV heart failure and ejection fractions of 40% or less to double-blind losartan (n=352) titrated to 50 mg once daily or captopril (n=370) titrated to 50 mg three times daily, for 48 weeks. The primary endpoint was the tolerability measure of a persisting increase in serum creatinine of 26·5 μmol/L or more (≥0·3 mg/dL) on therapy; the secondary endpoint was the composite of death and/or hospital admission for heart failure; and other efficacy measures were total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina.

Findings

The frequency of persisting increases in serum creatinine was the same in both groups (10·5%). Fewer losartan patients discontinued therapy for adverse experiences (12·2% vs 20·8% for captopril, p=0·002). No losartan-treated patients discontinued due to cough compared with 14 in the captopril group. Death and/or hospital admission for heart failure was recorded in 9·4% of the losartan and 13·2% of the captopril patients (risk reduction 32% [95% CI -4% to +55%], p=0·075). This risk reduction was primarily due to a decrease in all-cause mortality (4·8% vs 8·7%; risk reduction 46% [95% CI 5–69%], p=0·035). Admissions with heart failure were the same in both groups (5·7%), as was improvement in NYHA functional class from baseline. Admission to hospital for any reason was less frequent with losartan than with captopril treatment (22·2% vs 29·7%).

Interpretation

In this study of elderly heart-failure patients, treatment with losartan was associated with an unexpected lower mortality than that found with captopril. Although there was no difference in renal dysfunction, losartan was generally better tolerated than captopril and fewer patients discontinued losartan therapy. A further trial, evaluating the effects of losartan and captopril on mortality and morbidity in a larger number of patients with heart failure, is in progress.

Introduction

Angiotensin-converting-enzyme (ACE) inhibitors reduce morbidity and mortality in patients with chronic heart failure and systolic left-ventricular dysfunction as well as in patients who have had a myocardial infarction.1, 2, 3, 4, 5, 6, 7, 8, 9 The benefits of ACE inhibitors have been mostly attributed to blockade of angiotensin II production and/or to a decrease in the breakdown of bradykinin.10, 11 Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide and prostacyclin, which may contribute to the haemodynamic effects of ACE inhibition. Bradykinin may, however, also be responsible for some of the adverse reactions to ACE inhibitors such as cough, angio-oedema, renal dysfunction, and hypotension,10, 11, 12, 13, 14 and these sideeffects may explain in part why ACE inhibitors are used in less than 30% of patients with heart failure despite the proven clinical benefit of these agents.15

Orally active, non-peptide angiotensin II type 1 receptor antagonists such as losartan can block this receptor specifically without increasing bradykinin levels,16 and since angiotensin II may be produced by alternate pathways17, 18, 19, 20 such drugs may have additional advantages over ACE inhibitors where blockade of the effects of angiotensin II is incomplete. Losartan is licenced for the treatment of hypertension in many countries, and in earlier studies in patients with symptomatic heart failure, oral losartan produced beneficial haemodynamic effects both acutely and with chronic dosing.21, 22

The Evaluation of Losartan in the Elderly (ELITE) study has compared effects on renal function, morbidity/mortality, and tolerability of long-term treatment with losartan or captopril in patients aged 65 years and older with symptomatic heart failure. The primary endpoint was the tolerability measure of a persisting increase in serum creatinine of 0·3 mg/dL (26·5 μmol/L) or more on therapy; the secondary endpoint was the composite efficacy measure of death and/or hospital admissions for heart failure. Other prespecified efficacy measures included total mortality and hospital admission for heart failure separately, New York Heart Association (NYHA) functional class, and admission to hospital for myocardial infarction or unstable angina.

Section snippets

Patients and methods

The ELITE study10 was a prospective double-blind, randomised, parallel, captopril-controlled clinical trial conducted at 125 centres in the United States, Europe and South America. The study was approved by institutional review boards at each site; all patients gave written informed consent. An independent Data and Safety Monitoring Committee monitored the progress of the study.

Results

Recruitment began in May, 1994; the last patient was enrolled in July, 1995; and follow-up was completed in June, 1996. Enrolment of patients at the 125 participating centres ranged from 1 to 93 (median of 4); recruitment proved difficult and a substantial number of sites were required to achieve the study sample. Of the 722 patients enrolled, 352 were randomised to losartan and 370 to captopril (figure 1). The two treatment groups were similar with respect to all baseline characteristics (

Discussion

ELITE is the first long-term (48 weeks) study comparing an angiotensin II type 1 receptor antagonist with an ACE inhibitor in patients with symptomatic heart failure and systolic left-ventricular dysfunction. Captopril was chosen as the comparison ACE inhibitor drug because it may have fewer renal effects than longer-acting ACE inhibitors.24 The incidence of persistent renal dysfunction was not different between the losartan and captopril groups (both 10·5%), and fewer than 2% of patients

References (30)

  • 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)
  • ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate and intravenous magnesium sulphate in over 58 050 patients with suspected acute myocardial infarction. ISIS-4 (fourth International Study of Infant Survival) Collaborative Group

    Lancet

    (1995)
  • B Pitt et al.

    Angiotensin II receptor antagonists in heart failure: rationale and design of the Evaluation of Losartan in the Elderly (ELITE) trial

    Cardiovasc Drugs Ther

    (1995)
  • ZH Israili et al.

    Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology

    Ann Intern Med

    (1992)
  • D Chalmers et al.

    Post-marketing surveillance of captopril (for hypertension): a preliminary report

    Br J Clin Pharmacol

    (1987)
  • Cited by (1682)

    View all citing articles on Scopus
    *

    Investigators listed at end of paper

    View full text