Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support SURVIVE-WSURVIVE-W Presented at The American Heart Association Scientific Sessions, November 2005 Presented by Dr. Alexandre Mebazaa

www. Clinical trial results.org SURVIVE-W: Background Levosimendan, a calcium-sensitizing agent that has both vasodilator and inotropic effects, has been proposed as an alternative to the standard treatment of dobutamineLevosimendan, a calcium-sensitizing agent that has both vasodilator and inotropic effects, has been proposed as an alternative to the standard treatment of dobutamine Two small pilot trials, LIDO and CASINO, showed lower rates of mortality with levosimendan compared with dobutamine and placeboTwo small pilot trials, LIDO and CASINO, showed lower rates of mortality with levosimendan compared with dobutamine and placebo The goal of the trial is to compare treatment with levosimendan to treatment with dobutamine in patients with acute heart failure who are in need of intravenous inotropic supportThe goal of the trial is to compare treatment with levosimendan to treatment with dobutamine in patients with acute heart failure who are in need of intravenous inotropic support SURVIVE is the first prospective randomized mortality trial of IV drug therapy in acute decompensated heart failureSURVIVE is the first prospective randomized mortality trial of IV drug therapy in acute decompensated heart failure

www. Clinical trial results.orgLevosimendan (12 µg/kg bolus plus µg/kg/min infusion for 24 hours) n=663Levosimendan n=663 Endpoints:  Primary – All cause mortality at 6 months  Secondary – All-cause mortality at 31 days, BNP at 24 hours, days alive out of hospital, change in patient dyspnea assessment, change in patient global assessment Endpoints:  Primary – All cause mortality at 6 months  Secondary – All-cause mortality at 31 days, BNP at 24 hours, days alive out of hospital, change in patient dyspnea assessment, change in patient global assessment SURVIVE-W: Design Dobutamine (≥5 µg/kg/min infusion for ≥ 24 hours) n=664Dobutamine n= patients with acute decompensated heart failure, left ventricular ejection fraction ≤ 30%, clinical need for inotropic therapy after intravenous diuretics and/or vasodilators

www. Clinical trial results.org SURVIVE-W: Primary endpoint There was no significant difference in the primary endpoint of all-cause mortality between the levosimendan and dobutamine groups All-Cause Mortality at 6 months (% of treatment arm) ESC 2005 p = 0.401

www. Clinical trial results.org SURVIVE-W: Secondary Endpoint ESC 2005 All-cause mortality at 31 days (% of treatment arm) HR 0.85; p = NS There was no difference in all- cause mortality between treatment groups at 31 days

www. Clinical trial results.org SURVIVE-W: Post-hoc Analysis ESC 2005 All-cause mortality at 5 days (% of treatment arm) p = NS In a post-hoc analysis, all- cause mortality at 5 days was not significantly different between treatment groups

www. Clinical trial results.org SURVIVE-W: Limitations REVIVE-2, the complement trial to SURVIVE, compared levosimendan against placebo and showed no mortality benefit. Thus, although levosimendan is not associated with increased mortality compared to dobutamine, it does not improve mortality compared to placebo.REVIVE-2, the complement trial to SURVIVE, compared levosimendan against placebo and showed no mortality benefit. Thus, although levosimendan is not associated with increased mortality compared to dobutamine, it does not improve mortality compared to placebo. There was a significant reduction in BNP in the levosimendan group compared to the dobutamine group. While BNP is a marker, this study raises questions as to whether BNP is a surrogate endpoint given that the treatment was not associated with reduced mortality.There was a significant reduction in BNP in the levosimendan group compared to the dobutamine group. While BNP is a marker, this study raises questions as to whether BNP is a surrogate endpoint given that the treatment was not associated with reduced mortality.

www. Clinical trial results.org SURVIVE-W: Summary Among patients with acute heart failure in need of intravenous inotropic support, treatment with levosimendan did not significantly reduce all-cause mortality compared with treatment with dobutamine There was no difference in all-cause mortality at 31 days or at 5 days though in the subgroup of patients with a history of heart failure, mortality did trend lower at 5 days BNP at 24 hours was significantly lower (p=<0.001) in the levosimendan group compared with the dobutamine group. BNP dropped by almost 50% after the infusion and stayed low for at least five days There were no differences in hypotension or ventricular tachycardia. However, atrial fibrillation occurred more often in the levosimendan group (9% vs 6%) while cardiac failure occurred less often in the levosimendan group (12% vs 17%) Among patients with acute heart failure in need of intravenous inotropic support, treatment with levosimendan did not significantly reduce all-cause mortality compared with treatment with dobutamine There was no difference in all-cause mortality at 31 days or at 5 days though in the subgroup of patients with a history of heart failure, mortality did trend lower at 5 days BNP at 24 hours was significantly lower (p=<0.001) in the levosimendan group compared with the dobutamine group. BNP dropped by almost 50% after the infusion and stayed low for at least five days There were no differences in hypotension or ventricular tachycardia. However, atrial fibrillation occurred more often in the levosimendan group (9% vs 6%) while cardiac failure occurred less often in the levosimendan group (12% vs 17%) ESC 2005