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