Losartan Heart Failure Survival Study - ELITE-II

Description:

Losartan vs. captopril in patients with congestive heart failure.

Hypothesis:

Losartan compared to captopril would improve survival in patients with congestive heart failure and impaired left ventricular systolic function.

Study Design

Study Design:

Patients Enrolled: 3152
NYHA Class: II (52%) , III (43%), IV (5%).
Mean Follow Up: Median follow-up 555 days
Mean Patient Age: 71 (mean)
Female: 30
Mean Ejection Fraction: <=40%. Mean 31%

Patient Populations:

1. 60 years or older 2. Left-ventricular ejection fraction of 40% or less, measured by echocardiography or radionuclear ventriculography 3. NYHA class II­-IV heart failure

Exclusions:

1. Antecedent ACE-inhibitor or angiotensin-II-antagonist treatment for >= 7 days within the 3 months 2. Intolerance of ACE inhibitors or angiotensin-II-receptor antagonists 3. Systolic blood pressure less than 90 mm Hg or diastolic pressure more than 95 mm Hg 4. Hemodynamically important stenotic valvular heart disease, active myocarditits, or pericarditis 5. Automatic implanted cardioverter defibrillators 6. Coronary angioplasty within 1 week of enrollment 7. coronary artery bypass graft surgery, acute myocardial infarction, or unstable angina pectoris within 2 weeks of enrollment 7. Cerebrovascular accident or transient ischemic attack within 6 weeks of enrollment 8. Documented or suspected significant renal artery stenosis, hematuria, and serum creatinine concentrations higher than 220 mmol/L.

Primary Endpoints:

All-cause mortality

Secondary Endpoints:

1. Sudden death or resuscitated arrest 2. Safety and tolerability

Drug/Procedures Used:

After a run-in period of 1­28 days of single-blind placebo (matched to losartan or captopril tablets) to enable adequate stabilization and assessment of patients and to ensure adherence to study treatment, patients were assigned to losartan 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 daily titrated to 25 mg, and up to 50 mg three times daily (plus lostartan-matched placebo). Titration to the maximum tolerated dose, generally at weekly intervals, was recommended. Clinical assessments were done weekly during titration and every 4 months. Laboratory assessments were done at 1 month and then every 4 months. Patients who discontinued treatment were followed up every 4 months by clinical assessment and mortality and morbidity data were collected until the end of the study.

Concomitant Medications:

Previous ACE Inhibitor 23% Beta-blocker 23% Diuretic 77% Cardiac glycoside 50% Aspirin or salicylates 59% Calcium-channel blockers 23% Potassium-sparing diuretics 22%

Principal Findings:

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% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 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%). There were no significant differences in the frequency of any admission to the hospital or admission for heart failure.

Interpretation:

Losartan was not associated with improved survival compared to captopril in elderly heart-failure patients, but was significantly better tolerated. These surprising findings were in contradistinction to the findings of the ELITE trial, smaller trials and a meta-analysis of losartan in heart failure. Based on these findings, ACE inhibitors continue to be the initial treatment for heart failure, and angiotensin II receptor antagonists may be useful when ACE inhibitors are not well tolerated. Current studies are underway to evaluate te efficacy of other angiotensin II blocking agents compared to ACE inhibitors in heart failure, as well as the use of these medications in combination with ACE inhibitors in patients with heart failure and after myocardial infarction.

References:

Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet 2000 May 6;355(9215):1582-7

Clinical Topics: Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: Losartan, Angiotensin Receptor Antagonists, Myocardial Infarction, Death, Sudden, Captopril, Heart Failure, Maximum Tolerated Dose, Stroke Volume, Cough, Echocardiography


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