- Abbott to Complete Data Analyses and Discuss Results with Regulatory Agencies -
Results from the REVIVE II (Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy) trial showed that patients with acute decompensated heart failure (ADHF) who received a single infusion of levosimendan (Simdax®, outside the United States), together with standard therapy, significantly outperformed patients who received standard therapy alone, in the pre-specified primary endpoint (p = 0.015), a composite of clinical signs and symptoms of ADHF over five days as assessed by patients and their physicians.
More patients improved, and fewer patients worsened, when treated with levosimendan. Levosimendan patients also had a reduced average length of initial hospital stay. Data from REVIVE II were presented today at the American Heart Association annual meeting in the late-breaking clinical trial session.
REVIVE II Study Design and Study Results
REVIVE II is the first large, prospective, randomized, double-blind, controlled trial to evaluate the effects of levosimendan plus standard therapy compared to standard therapy alone over the clinical course of ADHF. Standard therapy consisted of physician-selected drugs used in ADHF (e.g., diuretics, vasodilators, and inotropes). REVIVE II was designed to reflect prevailing clinical practice where multiple agents are used in combination to treat ADHF. A patient's clinical course over five days was determined by a composite of the patient's self assessment of symptoms, together with a physician's assessment of the occurrence of clinical deterioration. Six hundred patients in the United States, Australia and Israel were studied.
Patients included in the trial had been hospitalized for ADHF with dyspnea (shortness of breath) at rest despite treatment with IV diuretics, and with left ventricular ejection fraction (a measure of the heart's pumping ability) of 35 percent or less that was measured within the last year. Patients were randomized to receive either a levosimendan bolus (6-12 mcg/kg) followed by a stepped dose regimen of levosimendan (0.1 - 0.2 mcg/kg/min) for 24 hours plus standard therapy, or a placebo infusion for 24 hours plus standard therapy.
More patients receiving levosimendan plus standard therapy improved compared with those receiving standard therapy alone (19.4 percent vs. 14.6 percent, respectively), a 33 percent relative increase. Fewer patients receiving levosimedan plus standard therapy worsened compared with patients receiving standard therapy alone (19.4 percent vs. 27.2 percent, respectively), a 29 percent relative decrease. One of the measures of worsening was the need for rescue therapy. Fewer patients receiving levosimendan plus standard therapy required rescue therapy (15.1 percent) versus standard therapy alone (26.2 percent), a 42 percent relative decrease. The percentage of patients who did not meet the criteria for improvement or worsening was comparable in the two groups (61 percent for levosimendan plus standard therapy vs. 58 percent for standard therapy alone).
BNP (B-Type natriuretic peptide) was one of several secondary endpoints evaluated. High BNP is a marker of impaired cardiac function. There was a statistically significant decrease in BNP in the levosimendan plus standard therapy arm compared to the standard therapy arm at 24 hours (p < 0.001). This effect was sustained at five days (p = 0.002).
Patients receiving levosimendan plus standard therapy also experienced a shorter average hospital stay than patients receiving standard therapy (7.0 days vs. 8.9 days, respectively, p = 0.001).
REVIVE II was not primarily designed to assess mortality. A secondary endpoint was mortality at 90 days for which there was no statistically significant difference between treatment arms, although there were a greater number of deaths in the levosimendan arm (levosimendan 45 vs. standard therapy/placebo 35).
The most common treatment-emergent cardiovascular adverse events in REVIVE II were hypotension (50 percent vs. 36 percent); ventricular tachycardia (25 percent vs. 17 percent); cardiac failure (23 percent vs. 27 percent); and atrial fibrillation (8 percent vs. 2 percent) in the levosimendan plus standard therapy arm vs. the standard therapy alone arm, respectively.
REVIVE II confirms the results of the REVIVE I trial, which was a 100-patient pilot study of the same design conducted in the same patient population with a similar endpoint.
"In REVIVE II we developed a novel endpoint which we believe represents the best current measure of the clinical course of patients with ADHF and were able to show that levosimendan favorably affected this endpoint," said Milton Packer, M.D., director, Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas, and REVIVE II primary investigator. "Results of the REVIVE II study should be interpreted in the context of the severity of ADHF and limited research and treatment innovations available to patients."
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 name 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., Simcdax® (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.
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.
Jukka Viinanen Jari Karlson
President and CEO CFO
Contact Persons in Orion Corporation:
Aino Takala, MD, PhD, Head of Strategic Planning, Orion Pharma, phone +358 50 429 4503
Jukka Viinanen, President and CEO, Orion Corporation, phone +358 10 429 3710
Orionintie 1 A, 02200 Espoo