COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial Purpose To assess the effect of carvedilol, a β 1 -, β 2 - and α 1 -receptor blocker, on mortality in patients with severe chronic heart failure Reference Packer M, Coats AJS, Fowler M et al. for the COPERNICUS Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8.

COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial - TRIAL DESIGN - Design Multicenter, multinational, randomized, double-blind, placebo- controlled Patients 2289 patients with symptoms of heart failure at rest or on minimal exertion and left ventricular ejection fraction <25%, receiving standard therapy (diuretic plus ACE inhibitor/angiotensin II-receptor antagonist) Follow up and primary end point Mean 10.4 months follow up. Primary endpoint all-cause mortality Treatment Placebo or carvedilol mg twice daily for 2 weeks, increased stepwise over several weeks as tolerated to target dose 25 mg twice daily

COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial - RESULTS - Study halted early on recommendation of data and safety monitoring board because beneficial effect of carvedilol exceeded prespecified interim monitoring boundaries Significant reduction in all-cause mortality in carvedilol group (130 deaths vs. 190 in placebo group, 35% relative risk reduction, P=0.0014), equating to 11.4% cumulative risk of death at 1 year vs. 18.4% with placebo Significant reduction in combined endpoint of death or hospitalization for any reason (425 vs. 507, 24% relative RR, P<0.001) These beneficial effects seen in all subgroups examined, including patients at highest risk Permanent discontinuation of treatment 23% lower in carvedilol group than placebo group at 1 year (14.8 vs. 18.5%, P=0.02)

COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial - RESULTS continued - Months Survival (%) Months Event-free survival (%) All-cause mortality and hospitalization for any reason Packer et al.N Engl J Med 2001;344:1651–8. 35% relative risk reduction (95% CI 19–48%) P= P= adjusted for interim analysis 24% relative risk reduction (95% CI 13–33%) P<0.001 Placebo Carvedilol

COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial - RESULTS continued Subgroup analysis 1.5 Packer et al.N Engl J Med 2001;344:1651–8. Male Female <65 years old > 65 years old North or South America Other continents LVEF <0.20 LVEF > 0.20 Ischemic Non-ischemic No recent hospitalization Recent hospitalization All patients Hazard ratio (and 95% CI) Favors carvedilol Favors placebo Favors carvedilol Favors placebo All-cause mortality Death or hospitalization

COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival trial - SUMMARY - In patients with severe chronic heart failure, carvedilol in addition to standard therapy reduced: All-cause mortality Combined endpoint of all-cause mortality and hospitalization for any reason Effects were similar across all subgroups