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Lancet 2000;355:1582-87

Effects of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial -- the Losartan Heart Failure Survival Study ELITE II.

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Lancet 2000;355:1582-87

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  1. Effects of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial -- the Losartan Heart Failure Survival Study ELITE II Bertram Pitt, Philip A Poole-Wilson, Robert Segal, Felipe A Martinez, Kenneth Dickstein, A John Camm, Marvin A Konstam, Gunter Riegger, George H Klinger, James Neaton, Divakar Sharma, Balasamy Thiyagarajan on behalf of the ELITE II investigators Lancet 2000;355:1582-87

  2. Background 48-week ELITE Study: In 722 ACEI naïve elderly patients with heart failure due to systolic left ventricular dysfunction comparing losartan to captopril: • No difference in persistent rise in serum creatinine concentrations (primary endpoint) • 46% reduction in all-cause mortality (17 vs 32 for losartan and captopril, respectively) • 64% reduction in sudden death (5 vs 14 for losartan and captopril, respectively) • Similar improvement in functional status (NYHA, quality of life) • Superior tolerability with losartan Lancet 2000;355:1582-87

  3. ELITE IIStudy Design > 60 yrs; NYHA II-IV; EF < 40% ACE I/AIIA naive or < 7 days in 3 months prior to entry Standard Rx (+ Dig/Diuretics ), B-Blocker stratification Losartan 50 mg daily (N = 1578) Captopril 50 mg 3 times daily (N = 1574) Event Driven (Target 510 Deaths) 1.5 years follow-up Primary endpoint: All Cause-Mortality Secondary endpoint: Sudden Cardiac Death or Resuscitated Arrest Other endpoints: All-cause Mortality/Hospitalizations Safety and Tolerability Lancet 2000;355:1582-87

  4. ELITE IIBaseline Characteristics Losartan (n=1578) Captopril (n=1575) Age (mean, yrs)* 71.4 71.5 Gender (male/female %) 70/30 69/31 Ejection Fraction (mean %) 31 31 NYHA Funct. Class II/III/IV (%) 52/43/5 52/43/5 Ischemic History (%) 79 79 Prior ACE Inhibitor 23 24 Beta Blocker (%) 23 21 Diuretic (%) 77 79 Cardiac Glycoside (%) 50 50Analgesic/Salicylates (%) 59 59 *85% > 65 years of age Lancet 2000;355:1582-87

  5. ELITE IIEndpoint Results Endpoint Losartan Captopril Hazards P (n=1578) (n=1574) ratio All-cause mortality (primary endpoint) Total mortality 280 (17.7%) 250 (15.9%) 1.13 (0.95-1.35) 0.16 Sudden death 130 (8.2%) 101 (6.4%) 1.30 (1.00-1.69) Progressive heart failure 46 (2.9%) 53 (3.4%) 0.88 (0.59-1.30) Myocardial infarction 31 (2.0%) 28 (1.8%) 1.11 (0.66-1.85) Stroke 18 (1.1%) 11 (0.7%) 1.65 (0.78-3.49) Other cardiovascular 5 (0.3%) 6 (0.4%) 0.84 (0.26-2.76) Non-cardiovascular 50 (9.0%) 51 (3.2%) 0.99 (0.67-1.47) Sudden death or resuscitated cardiac arrest 142 (9.0%) 115 (7.3%) 1.25 (0.98-1.50) 0.08 Combined total mortality or hospital admission for any reason 752 (47.7%) 707 (44.9%) 1.07 (0.97-1.19) 0.18 Hospital admissions Any reason 659 (41.8%) 638 (40.5%) 1.04 (0.94-1.16) 0.45 Heart failure 270 (17.1%) 293 (18.6%) 0.92 (0.78-1.08) 0.32 Lancet 2000;355:1582-87

  6. Captopril Losartan ELITE II Primary Endpoint: All-Cause Mortality 1.0 0.8 0.6 Probability of Survival 0.4 Hazard Ratio (95-7% C.I.) = 1.13 (0.95-1.35) P = 0.16 0.2 0.0 0 100 200 300 400 500 600 700 Days of Follow-up Lancet 2000;355:1582-87

  7. Captopril Losartan ELITE IISecondary Endpoint: Sudden Death / Resuscitated Arrest 1.0 0.8 0.6 Event-Free Probability 0.4 Hazard Ratio (95% C.I.) = 1.25 (0.98-1.50) P = 0.08 0.2 0.0 0 100 200 300 400 500 600 700 Days of Follow-up Lancet 2000;355:1582-87

  8. Captopril Losartan ELITE IITertiary Endpoint: All-Cause Mortality / Hospitalization 1.0 0.8 0.6 Event-Free Probability 0.4 Hazard Ratio (95% C.I.) = 1.07 (0.97-1.19) P = 0.18 0.2 0.0 0 100 200 300 400 500 600 700 Days of Follow-up Lancet 2000;355:1582-87

  9. ELITE II Mortality by Subgroup Hazard Ratio of Death Losartan Captopril Hazard Subgroups at Baseline with 95% C.I. N N Ratio Age  70 901 913 1.05  70 677 661 1.33 Gender Male 1102 1083 1.12 Female 476 491 1.14 NYHA Class. III/IV 801 798 1.19 II 777 776 1.37 % EF < 25 267 290 1.00 > 25 1311 1284 1.19 Beta Blockers With 354 325 1.77 Without 1224 1249 1.05 Overall 1578 1574 1.13 0.6 0.8 1.0 2.0 3.0 Hazard Ratio Favors Losartan Favors Captopril Lancet 2000;355:1582-87

  10. ELITE II Withdrawal for Adverse Experience (Excluding Death) ** ** p0.001 between groups ** ** Lancet 2000;355:1582-87

  11. ELITE IIDiscussion • In controlled clinical trials involving about 5000 patients, of whom 2800 received losartan, acute and sustained hemodynamic benefits with chronic dosing have been seen, as well as effects similar to enalapril on exercise duration. • The ELITE II findings, together with previous experience in heart failure and the known pharmacology of losartan, make it probable that losartan resembles an ACE inhibitor in heart failure. • It still remains to be established, however, whether angiotensin II antagonists are a fully effective substitute for ACE inhibitors in heart failure. Lancet 2000;355:1582-87

  12. ELITE IIDiscussion • Losartan was not superior to captopril in improving survival in elderly heart-failure patients, but was significantly better tolerated. • Based on extensive randomized, placebo-controlled observations, 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. Lancet 2000;355:1582-87

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