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 heartwire 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.

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.

Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine
for patients with acute decompensated heart failure. The SURVIVE
randomized trial. JAMA 2007; 297:1883-1891.
Orion Pharma. Orion's partner discontinues development of
levosimendan (Simdax) in the US [press release]. April 25, 2007.
Available at:
http://www.orion.fi/english/investors/stockreleases.shtml/a04?26492.