Elsevier

The Lancet

Volume 355, Issue 9215, 6 May 2000, Pages 1582-1587
The Lancet

Articles
Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II

https://doi.org/10.1016/S0140-6736(00)02213-3Get rights and content

Summary

Background

The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated.

Methods

We undertook a double-blind, randomised, controlled trial of 3152 patients aged 60 years or older with New York Heart Association class II–IV heart failure and ejection fraction of 40% or less. Patients, stratified for β-blocker use, were randomly assigned losartan (n=1578) titrated to 50 mg once daily or captopril (n=1574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat.

Findings

Median follow-up was 555 days. There were no significant differences in all-cause mortality (11·7 vs 10·4% average annual mortality rate) or sudden death or resuscitated arrests (9·0 vs 7·3%) between the two treatment groups (hazard ratios 1·13 [95·7% Cl 0·95–1·35], p=0·16 and 1·25 [95% Cl 0·98–1·60], p=0·08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9·7 vs 14·7%, p < 0·001), including cough (0·3 vs 2·7%).

Interpretation

Losartan was not superior to captopril in improving survival in elderly heart-failure patients, but was significantly better tolerated. We believe that ACE inhibitors should be the initial treatment for heart failure, although angiotensin II receptor antagonists may be useful to block the renin angiotensin aldosterone system when ACE inhibitors are not tolerated.

Introduction

Angiotensin-converting-enzyme (ACE) inhibitors, generally given with diuretics and digoxin, are the standard treatment for patients with heart failure and systolic left-ventricular dysfunction.1, 2, 3 Despite the established benefits of ACE-inhibitor treatment, physicians do not prescribe these agents to all their patients because of concerns related to adverse effects.4, 5, 6 The benefit of ACE inhibition has been attributed largely to blockade of the production of angiotensin II, but also to bradykinin accumulation.7 Bradykinin accumulation, however, has been implicated as a contributor to the adverse effects associated with ACE-inhibitor treatment and has also been suggested to result in prejunctional norepinephine release.8, 9 Since angiotensin II antagonists, such as losartan, directly block angiotensin II at the AT1 receptor with no accumulation of bradykinin, these drugs should provide similar benefits to ACE inhibitors in blocking the harmful effects of angiotensin II with fewer side-effects.6, 7, 10, 11, 12 By direct blockade of AT1-receptor activation, angiotensin II antagonists block angiotensin II irrespective of its generation by ACE-dependent or non-ACE-dependent pathways, and allow unopposed stimulation of AT2 receptors, which theoretically would prevent ventricular remodelling associated with progression of heart failure.6, 12, 13

In the 48-week ELITE study in 722 ACE-inhibitor-naïve elderly patients with symptomatic heart failure, we saw an unexpected 46% lowering of mortality (a secondary endpoint) with losartan compared with the ACE inhibitor captopril (losartan 17 [4·8%] vs captopril 32 [8·7%] deaths; risk reduction 46% [95% CI 5–69]; p=0·035).14 In addition, losartan reduced the rate of all-cause hospital admissions, and, as anticipated, was generally better tolerated than captopril with significantly fewer discontinuations because of adverse effects, despite a similar rate of persistent rise in serum creatinine concentrations (primary endpoint of study). The rate of hospital admissions for heart failure and improvements in functional status (measured by changes in New York Heart Association [NYHA] functional class and quality of life) were similar.

The survival benefit with losartan in the ELITE study seemed to be attributable primarily to a reduction in sudden cardiac death (losartan 5 [1·4%] vs captopril 14 [3·8%], relative risk reduction 64% [3–86]). In patients with heart failure, ACE inhibitors do not always lower the frequency of this outcome.15, 16 Although preclinical data suggested that losartan, its metabolite, or both, may possess antiarrhythmic properties,17, 18 which is supported by the ELITE QT dispersion study,19 the explanation for the observed reduction in sudden death with losartan in ELITE remains uncertain. The apparent superior effects seen with losartan on morbidity and mortality were based on a small number of events that were not the primary endpoint. Therefore, we designed a large, randomised, double-blind trial—the Losartan Heart Failure Survival Study ELITE II—to compare the effects of losartan with those of captopril on mortality and morbidity, safety, and tolerability.

Section snippets

Study population

We enrolled patients, from June, 1997, to May, 1998, aged 60 years or older (we required that 85% be aged >65 years) with NYHA class II–IV heart failure and left-ventricular ejection fraction of 40% or less, measured by echocardiography or radionuclear ventriculography. Most patients were to be ACE-inhibitor and angiotensin-II-antagonist naïve. Some patients were eligible, however, if such treatment had been recently started and the exposure period was 7 days or less within the 3 months before

Results

Of the 3152 patients enrolled, 1578 were assigned losartan and 1574 captopril (figure 1). Median follow-up was 1·5 years for each group. We saw all patients at a final visit within 6 weeks of the end of the study or established vital status. Only two patients were lost to follow-up. The baseline characteristics were similar in the two groups (table 1). 85% of patients were aged 65 years and older, mean left-ventricular ejection fraction was 31%, 69% were men, and 79% had a history of ischaemic

Discussion

Losartan treatment did not prove superior to captopril in improving survival in elderly patients with chronic symptomatic heart failure and systolic left-ventricular dysfunction, as was suggested by the findings of the ELITE study. Mortality and sudden cardiac death or resuscitated cardiac arrest did not differ significantly between groups. ELITE II did, however, confirm the superior tolerability of losartan seen in ELITE, with a significantly lower rate of discontinuation of treatment because

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