Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: the SURVIVE Randomized Trial

Abstract

Context. Because acute decompensated heart failure (HF) causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival. Objective. To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. Methods. The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial that compared the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated HF who required inotropic support. The trial was conducted at 75 centers in 9 countries, and patients were randomized between March 2003 and December 2004. Interventions. Intravenous levosimendan (n=664) or intravenous dobutamine (n=663). Main Outcome Measure. All-cause mortality at 180 days. Results. All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74–1.13; P=.40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group. Conclusions. Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes.—Mebazaa A, Nieminen MS, Packer M, et al, for the SURVIVE Investigators. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007;297(17):1883–1891. Comment. The SURVIVE study was an eagerly awaited trial, at least for the HF community. Its preliminary findings were presented at the American Heart Association 2005 scientific sessions; however, its full results have only been recently published. Levosimendan has been touted as an effective and safer substitute for inotropic agents in the setting of acute decompensated HF. Early clinical trials suggested that levosimendan can be an exciting choice for the treatment of acute decompensation of HF; however, this needed validation by a large clinical trial. This led to the SURVIVE study, which is the first prospective, randomized trial to monitor long-term survival in patients with acute decompensated HF. SURVIVE randomized 1327 patients hospitalized with acute decompensated HF to receive levosimendan or dobutamine, double-blind and with double placebos. All patients entered with a left ventricular ejection fraction ≤30% and had been judged to need inotropic therapy after not responding to vasodilators or diuretics. Levosimendan was given as a 12-µg/kg loading dose followed by a 24-hour infusion of 0.1- to 0.2-µg/kg/min. Dobutamine was initiated at ≥5 µg/kg/min and increased incrementally to a maximum of 40 µg/kg/min at the physicians' discretion and was given for at least 24 hours. All-cause mortality at 180 days, the primary end point, was similar in the 2 groups: 26% for patients who had received levosimendan and 28% for those in the dobutamine group. No patient subgroup that appeared to gain any special benefit from either drug was identified. Decreases in brain-type natriuretic peptide levels at 24 hours through day 5 were more pronounced in the levosimendan group (P<.001 for all time points), a significant difference that appeared unrelated to clinical responses. There were no significant differences in dyspnea and global assessment at 24 hours, 31-day all-cause mortality, cardiovascular mortality, and number of out-of-hospital days alive over 180 days—all secondary end points. At this point, one could suggest that this drug may be used as an alternative to dobutamine. This recommendation, however, may not be the right choice at this time as we look at the side-effect profile of the drug. Certainly there is no excess mortality; however, during the first month, levosimendan-treated patients experienced significantly more headache, hypokalemia, premature ventricular contractions, and atrial fibrillation than the dobutamine group. Conclusions. In a randomized mortality trial comparing levosimendan with dobutamine, 1- and 6-month outcomes, which also included various objective and subjective measures of HF severity, were about the same with both drugs. Essentially, levosimendan did not reduce all-cause mortality at 180 days or affect any secondary clinical outcomes.