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)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)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)64% reduction in sudden death (5 vs 14 for losartan and captopril, respectively) Similar improvement in functional status (NYHA, quality of life)Similar improvement in functional status (NYHA, quality of life) Superior tolerability with losartanSuperior tolerability with losartan Lancet 2000;355:1582-87

3. ELITE II Study Design > 60 yrs; NYHA II-IV; EF 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 Captopril Captopril 50 mg 3 times daily (N = 1574) (N = 1574) Losartan Losartan 50 mg daily (N = 1578) Primary endpoint: All Cause-Mortality Secondary endpoint: Sudden Cardiac Death or Resuscitated Arrest Other endpoints: All-cause Mortality/Hospitalizations Safety and Tolerability Safety and Tolerability Event Driven (Target 510 Deaths) 1.5 years follow-up Lancet 2000;355:1582-87

4. ELITE II Baseline 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 50 Analgesic/Salicylates (%) 59 59 Lancet 2000;355:1582-87 *85% > 65 years of age

5. ELITE II Endpoint Results Endpoint Losartan Captopril HazardsP (n=1578) (n=1574) ratio (n=1578) (n=1574) ratio All-cause mortality (primary endpoint) Total mortality280 (17.7%)250 (15.9%)1.13 (0.95-1.35)0.16 Sudden death130 (8.2%)101 (6.4%)1.30 (1.00-1.69) Sudden death130 (8.2%)101 (6.4%)1.30 (1.00-1.69) Progressive heart failure46 (2.9%)53 (3.4%)0.88 (0.59-1.30) Progressive heart failure46 (2.9%)53 (3.4%)0.88 (0.59-1.30) Myocardial infarction31 (2.0%)28 (1.8%)1.11 (0.66-1.85) Myocardial infarction31 (2.0%)28 (1.8%)1.11 (0.66-1.85) Stroke18 (1.1%)11 (0.7%)1.65 (0.78-3.49) Stroke18 (1.1%)11 (0.7%)1.65 (0.78-3.49) Other cardiovascular5 (0.3%)6 (0.4%)0.84 (0.26-2.76) Other cardiovascular5 (0.3%)6 (0.4%)0.84 (0.26-2.76) Non-cardiovascular50 (9.0%)51 (3.2%)0.99 (0.67-1.47) Non-cardiovascular50 (9.0%)51 (3.2%)0.99 (0.67-1.47) Sudden death or resuscitated cardiac arrest142 (9.0%)115 (7.3%)1.25 (0.98-1.50)0.08 Combined total mortality or hospital admission for any reason752 (47.7%)707 (44.9%)1.07 (0.97-1.19)0.18 Hospital admissions Any reason659 (41.8%)638 (40.5%)1.04 (0.94-1.16)0.45 Heart failure270 (17.1%)293 (18.6%)0.92 (0.78-1.08)0.32 Lancet 2000;355:1582-87

6. ELITE II Primary Endpoint: All-Cause Mortality 0100200300400500600700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Probability of Survival Losartan Captopril Hazard Ratio (95-7% C.I.) = 1.13 (0.95-1.35) P = 0.16 Lancet 2000;355:1582-87

7. ELITE II Secondary Endpoint: Sudden Death / Resuscitated Arrest 0100200300400500600700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Event-Free Probability Hazard Ratio (95% C.I.) = 1.25 (0.98-1.50) P = 0.08 Losartan Captopril Lancet 2000;355:1582-87

8. ELITE II Tertiary Endpoint: All-Cause Mortality / Hospitalization 0100200300400500600700 Days of Follow-up 0.0 0.2 0.4 0.6 0.8 1.0 Event-Free Probability Hazard Ratio (95% C.I.) = 1.07 (0.97-1.19) P = 0.18 Losartan Captopril Lancet 2000;355:1582-87

9. Hazard Ratio Age Gender NYHA Class. % EF Beta Blockers Overall  70  70 Male Female III/IV II < 25 > 25 With Without 1.05 1.33 1.12 1.14 1.19 1.37 1.00 1.19 1.77 1.05 1.13 Hazard Ratio 3.01.00.80.62.0 Hazard Ratio of Death with 95% C.I. Subgroups at Baseline Favors Losartan Favors Captopril ELITE II Mortality by Subgroup Lancet 2000;355:1582-87 913 661 1083 491 798 776 290 1284 325 1249 1574 N Captopril 901 677 1102 476 801 777 267 1311 354 1224 1578 N Losartan

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

11. ELITE II Discussion 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.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.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.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 II Discussion Losartan was not superior to captopril in improving survival in elderly heart-failure patients, but was significantly better tolerated.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.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