SURVIVE in print: No short- or long-term survival benefit from levosimendan in acute heart failure

May 09, 2007

Chicago, IL - On paper, levosimendan (Simdax, Orion Pharma) seemed like it might make an effective and safer substitute for inotropic agents in the setting of acute decompensated heart failure (ADHF), and early clinical trials suggested it had promise. But in a randomized mortality trial comparing levosimendan with dobutamine, one- and six-month outcomes—which also included various objective and subjective measures of heart-failure severity—were about the same with both drugs[1].

These results from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) were published in the May 2, 2007 issue of the Journal of the American Medical Association. Preliminary findings that were essentially the same had been reported at the American Heart Association 2005 Scientific Sessions and covered by heart wire at the time.

SURVIVE, conducted in eight European countries and Israel, "is the first prospective, randomized trial to monitor long-term survival in patients with ADHF," according to the authors, led by Dr Alexandre Mebazaa (Lariboisiere Hospital, Paris, France).

Abbott Laboratories, which licenses intravenous levosimendan from Orion Pharma and holds marketing rights, announced to Orion in late April that it was halting the drug's development in the US "because it would not be commercially reasonable," according to an Orion press release[2].

SURVIVE randomized 1327 patients hospitalized with ADHF to receive levosimendan or dobutamine, double-blind and with double placebos. All patients entered with an LVEF <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 per minute. Dobutamine was initiated at >5 µg/kg per minute and increased incrementally to a maximum of 40 µg/kg per minute 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 two 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.

Short- and long-term outcomes in the SURVIVE trial

End point Levosimendan, n=664 Dobutamine, n=663 p
Dyspnea at 24 h, >mild improvement (%) 82 83 0.96
All-cause mortality at 31 days (%) 12 14 0.29
All-cause mortality at 180 days (%)* 26 28 0.40
Cardiovascular mortality at 180 days (%) 24 26 0.33
Mean out-of-hospital days alive at 180 days 120.2 116.6 0.30
*Primary end point

Decreases in brain-type natriuretic peptide (BNP) levels at 24 hours through day 5 were more pronounced in the levosimendan group (p<0.001 for all time points), a significant difference that appeared unrelated to clinical responses. There were no significant differences in patient 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.

During the first month, levosimendan-treated patients experienced significantly more headache, hypokalemia, premature ventricular contractions, and atrial fibrillation than the dobutamine group.

The Orion statement said that intravenous levosimendan "will remain available in the markets where it already has been approved. The product has marketing authorizations or submitted applications in more than 40 countries."

The SURVIVE trial was funded by Abbott and Orion Pharma. Disclosures for the individual coauthors are included in the report.


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