- Study Supports Trend Over Dobutamine but Does Not Meet 25 Percent Target for Mortality Reduction -
Results from SURVIVE (Survival Of Patients With Acute Heart Failure In Need Of Intravenous Inotropic Support), a 1,327-patient mortality trial conducted in patients with acute decompensated heart failure (ADHF), showed that levosimendan (Simdax®, outside the United States) resulted in statistically non-significant but consistently lower mortality compared with dobutamine through six months of follow up after randomisation to a single infusion of study drug, with the greatest reductions during the first two weeks following treatment. The study did not meet its primary endpoint of a statistically significant reduction in 180-day all-cause mortality. The data were presented today at the late-breaking clinical trials session of the American Heart Association 2005 annual meeting.
"SURVIVE is the first study to examine mortality for an extended period following treatment of ADHF, and studies the most critically ill of these patients," said Alexandre Mebazaa, M.D., Ph.D., professor and director, Department of Anesthesia and Critical Care Medicine, Lariboisiere Hospital, Paris, France, and SURVIVE principal investigator. "Although the study did not discern a difference in long-term outcome between levosimendan and dobutamine, earlier timepoints, closer to actual drug administration, appear to favor levosimendan."
SURVIVE Study Design and Results
SURVIVE was a prospective, double-blind, randomized, controlled trial of intravenous (I.V.) therapy in 1,327 patients hospitalized for ADHF. The primary endpoint of SURVIVE was all-cause mortality at 180 days, and the study was designed to demonstrate a 25 percent reduction in mortality for levosimendan compared with dobutamine, following a single intravenous infusion. SURVIVE was conducted in Austria, Finland, France, Germany, Israel, Latvia, Poland, Russia, and the United Kingdom.
Patients included in the SURVIVE trial were hospitalized for ADHF and had a left ventricular ejection fraction (a measure of the heart's pumping ability) of 30 percent or less within the previous 12 months before trial initiation. Patients had to require I.V. inotropic therapy because of an insufficient response to I.V. diuretics and/or vasodilators. Patients were randomized to either dobutamine (minimum dose 5 mcg/kg/min) or levosimendan bolus (12 mcg/kg) followed by a stepped dose regimen of levosimendan
(0.1 - 0.2 mcg/kg/min). Levosimendan was dosed for a maximum of 24 hours, while dobutamine could be dosed longer than 24 hours at a physician's discretion. Both treatment groups also received standard of care. During the six-month duration of the study, patients who were re-hospitalized for heart failure were allowed to receive additional treatment of the same study medication.
(0.1 - 0.2 mcg/kg/min). Levosimendan was dosed for a maximum of 24 hours, while dobutamine could be dosed longer than 24 hours at a physician's discretion. Both treatment groups also received standard of care. During the six-month duration of the study, patients who were re-hospitalized for heart failure were allowed to receive additional treatment of the same study medication.
At five days, two weeks, one month, and six months following the study drug infusion, mortality in the levosimendan group was reduced by 27 percent, 14 percent, 13 percent, and 6.4 percent, respectively, compared to the dobutamine group. These differences did not reach statistical significance.
A secondary endpoint of BNP (B-Type natriuretic peptide) was significantly reduced in the levosimendan arm compared to the dobutamine arm. High BNP is a marker of impaired cardiac function.
In SURVIVE, the most common treatment-emergent cardiovascular adverse events reported within 31 days after treatment among levosimendan vs. dobutamine-treated patients, respectively, were atrial fibrillation (9.1 percent vs. 6.1 percent), cardiac failure (12.3 percent vs. 17.0 percent), hypotension (15.5 percent vs. 13.9 percent), and ventricular tachycardia (7.9 percent vs. 7.3 percent).
About Levosimendan
Levosimendan is an investigational intravenous (I.V.) agent for ADHF that is currently approved in more than 40 countries outside the United States under the brand names Simdax®. Levosimendan has a unique, dual mechanism of action: calcium sensitization, which improves cardiac contractility without additional oxygen consumption; and potassium ATP channel opening, which results in vasodilation, improving blood flow to vital organs. Both mechanisms ultimately allow for greater blood circulation from the heart to vital organs and tissues during an acute episode of heart failure.
The originator of levosimendan is Orion Corporation, Finland (www.orion.fi). Abbott Laboratories (www.abbott.com) and Orion have been partners for i.v. levosimendan since 1998. In April 2004, Abbott received the rights for the further development of injectable levosimendan and nearly all global rights to market the i.v. product, excluding the Nordic countries.
Heart Failure Background/Public Health Implications
Heart failure is a chronic condition resulting from weakened heart function that impairs the ability of the heart to pump blood throughout the body. This impairs the function of vital organs and diminishes patients' capacity to perform everyday tasks. In acute decompensated heart failure (ADHF), patients have a sudden deterioration in heart function resulting in symptoms that require urgent medical treatment and often hospitalization.
According to the American Heart Association, heart failure is the one of the most common causes of hospitalization for patients over 65 years of age in the Western world. In the United States, approximately five million Americans have been diagnosed with heart failure and approximately 550,000 new cases are diagnosed annually. There are 3.5 million annual hospital discharges with primary and secondary diagnoses of heart failure and approximately 6.9 million discharges worldwide.
First-year mortality rate for ADHF patients is up to 40 percent to 50 percent. Costs associated with heart failure are more than $27 billion annually in the United States.
Indications and Important Safety Information - Levosimendan (Simdax®)
Outside the U.S., Simdax® (levosimendan) is indicated as add-on therapy for the short-term treatment of acutely decompensated severe chronic heart failure when there is a need for inotropic support and conventional therapy has not proven sufficient.
Levosimendan should not be used in patients with marked mechanical obstructions affecting ventricular filling or outflow of both; or in those patients with severe kidney or liver impairment, severe hypotension and tachycardia, a history of Torsades de Pointes, or known hypersensitivity to levosimendan.
In current labeling for countries where levosimendan is approved, the most common adverse events seen in clinical trials were headache, hypotension, tachycardia, myocardial ischemia, atrial fibrillation, extrasystole, ventricular tachycardia, and palpitations.
About Orion
www.orion.fi
Orion (OMX: ORNAS, ORNBS), the originator of levosimendan, is one of the leading healthcare companies in the Nordic area of Europe. At the heart of the Orion Group is Orion Pharma, a research and development-orientated pharmaceutical division. Orion Pharma focuses on three therapy areas: CNS therapies, cardiology and critical care, and hormonal therapies.
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