Effect of Losartin Compared with Captopril on Mortality in Patients with Symptomatic Heart Failure
abstract & commentary
Synopsis: In a previous study (ELITE I), the angiotensin II antagonist losartin showed an unexpected survival benefit in elderly patients with heart failure when compared with captopril, an angiotensin-converting enzyme inhibitor. This follow-up study, designed to examine this benefit, did not show that losartin was superior to captopril in improving survival in elderly heart failure patients but was significantly better tolerated.
Source: Pitt B, et al. Lancet 2000;355:1582-1587.
An unexpected finding of the original evaluation of losartin in the elderly (ELITE I) study, in which the primary end point was the effect of treatment on renal function, was an unexpected survival benefit for the angiotensin II antagonist losartin over captopril, an ACE inhibitor. This study, ELITE II, was a large trial designed to confirm whether losartin is superior to captopril for all-cause mortality.
The study examined 3152 patients from 289 outpatient centers in 46 countries. Patients were aged 60 or older with New York Heart Association Class II to Class IV heart failure and an ejection fraction of 40% or less. Exclusion criteria included previous intolerance to either drug, systolic pressures less than 90.msl Hg, diastolic pressure more than 95 mm Hg, significant stenotic valvular disease, renal artery stenosis, active myocarditis or pericarditis, and recent angioplasty, coronary artery bypass surgery, myocardial infarction, or unstable angina. The study was designed as an event-driven superiority trial with 90% power to detect a relative 25% difference in all-cause mortality between treatments.
After a run-in period of 1-28 days of single-blind placebo to enable adequate stabilization of patients, patients were randomly assigned to either losartin 12.5 mg once daily, titrated to 25 mg and up to 50 mg once daily (plus captopril-matched placebo), or captopril 12.5 mg three times a day, titrated to 25 mg, and up to 50 mg daily (plus losartin-matched placebo).
Of the 3152 patients, 1578 were randomized to receive losartin and 1574 captopril. Clinical assessment was done weekly during titration and then every four months. The primary end point was all-cause mortality. Secondary end points were the composite of sudden cardiac death or resuscitated cardiac arrest. Other outcome variables included hospital admission, cardiovascular hospital admission, quality of life, discontinuation of treatment, and worsening heart failure.
The treatment groups were well matched and only one patient from each group was lost to follow-up during a median follow-up period of 18 months. A total of 280 deaths (17.5%) occurred in the losartin group compared with 250 (15.9%) in the captopril group, with an annual mortality rate of 11.7% and 10.4%, respectively, which was not a statistically significant difference. Likewise, there were no significant differences in sudden death or resuscitated arrest (9.0% vs 7.3%) between the treatment groups. Significantly fewer patients in the losartin group discontinued treatment because of adverse effects (9.7% vs 4.7%; P < 0.001), including cough 0.3% vs. 2.7%. Pitt and colleagues concluded that losartin was not superior to captopril in improving survival in elderly heart failure patients, but was significantly better tolerated.
Comment by Martin Lipsky, md
In the first ELITE study, with 722 ACE inhibitor-naive elderly patients with symptomatic heart failure, there was an unexpected 46% decrease in mortality with losartin compared with the ACE inhibitor captopril. This follow-up study was rapidly planned in order to see if this finding was real. The results were completely neutral with the exception that losartin was less likely to be discontinued. Although it might be tempting for physicians to initiate a better tolerated drug, Pitt et al still strongly recommend an ACE inhibitor as first-line therapy. They point out that there is substantial evidence that the use of an ACE inhibitor benefits patients with heart failure and systolic left-ventricular dysfunction and that it remains to be established where the angiotensin II antagonists are a fully effective substitute. However, for those people who cannot take or tolerate an ACE inhibitor, this study supports the contention that an angiotensin II antagonist is a beneficial alternative.