Sanofi-aventis announced that findings from the landmark ATHENA study showed that Multaq (dronedarone), a potential therapy for the treatment of patients with atrial fibrillation or atrial flutter, decreased the risk of cardiovascular hospitalisations or death from any cause by a statistically significant 24 per cent (p=0.00000002), meeting the study's primary endpoint.
The ATHENA results will be presented at the late breaking clinical trial session of Heart Rhythm 2008, the Heart Rhythm Society's 29th Annual Scientific Sessions in San Francisco, USA, a company press release stated.
For the first time in twenty years of clinical drug trials in atrial fibrillation, an investigational medicine, Multaq, showed a significant decrease in the risk of cardiovascular death by 30 per cent (p=0.03) on top of standard therapy, including rate control and antithrombotic drugs, in patients with atrial fibrillation or atrial flutter. Multaq also significantly decreased the risk of arrhythmic death by 45 per cent (p=0.01) and there were numerically fewer deaths (16 per cent) from any cause in the dronedarone group compared to placebo (p=0.17). First cardiovascular hospitalisation was reduced by 25 per cent (p=0.000000009) in the dronedarone group.
"The ATHENA results have the potential to change the face of atrial fibrillation management. For atrial fibrillation patients, who together with their physicians struggle on a daily basis to manage the dramatic consequences of this complex disease, Multaq carries hope for patients" said Marc Cluzel, sanofi-aventis senior vice president, R&D. "This milestone is indicative of sanofi-aventis' commitment to bringing innovative therapies to market, and of our ongoing commitment to provide patients, physicians and public health stakeholders with breakthrough medicines in those therapeutic areas where there are major healthcare needs and limited solutions".
Atrial fibrillation is a major cause of hospitalisation and mortality and affects about 2.5 million people in the United States, as well as 4.5 million people in the European Union and is emerging as a growing public health concern due to an aging population. Patients suffering from atrial fibrillation have twice the risk of death, an increased risk of stroke and cardiovascular complications, including congestive heart failure. Furthermore atrial fibrillation considerably impairs patients' lives, mainly because of their inability to perform normal daily activities due to complaints of palpitations, chest pain, dyspnoea, fatigue or light-headedness, without consideration of the cumbersome and sometime serious constraints imposed by current therapies of atrial fibrillation.
"In atrial fibrillation where treatment morbidity-mortality benefit still needed to be demonstrated, ATHENA is a unique trial using clinically relevant outcomes such as cardiovascular hospitalisation or death as the primary endpoint. In this regard, the trial has clearly achieved these safety and efficacy endpoints," said Dr Stefan H. Hohnloser, J.W. from the Goethe University, Division of Clinical Electrophysiology, Frankfurt, Germany, who served as co-principal investigator of the ATHENA study. "As a consequence, dronedarone is the first safe treatment for atrial fibrillation, which has been demonstrated to reduce cardiovascular hospitalisation or mortality in patients with AF" he added.
The most frequently reported adverse events of Multaq vs. placebo in the ATHENA trial were gastro-intestinal effects (26 per cent vs. 22 per cent), skin disorders (10 per cent vs. 8 per cent, mainly rash) and increased blood creatinine (4.7 per cent vs. 1 per cent). The mechanism of blood creatinine increase (inhibition of creatinine secretion at the renal tubular level) is well defined. Compared to placebo, Multaq showed a low risk of pro-arrhythmia and no excess of hospitalisations for congestive heart failure. There was a similar rate of study drug discontinuation between the 2 study groups.
"ATHENA is truly a landmark trial, that marks a paradigm change for the management of atrial fibrillation," said Dr Christopher Cannon, a Senior Investigator in the TIMI Study Group at Brigham and Women's Hospital, who was not involved in the study. "Atrial fibrillation is a very common disease, and our prior treatment options have been focused only on symptom relief and a hope to not do harm, which has been the problem with prior antiarrhythmic drugs. Now, with a highly significant reduction in death or hospitalisation, as well as a 45 per cent reduction in arrhythmic death or 30 per cent cardiovascular death, dronedarone may become a first line treatment of atrial fibrillation".
ATHENA, the largest double blind randomised study in patients with atrial fibrillation, was conducted in more than 550 sites in 37 countries and enrolled a total of 4,628 patients. The landmark ATHENA trial is the first morbidity-mortality study as part of the Multaq phase III clinical development program, which also included five other multinational clinical studies, an initial study, ANDROMEDA, conducted in patients with severe congestive heart failure and a recent decompensation, and a total of 4 international studies in atrial fibrillation: EURIDIS/ADONIS, ERATO, and the ongoing DIONYSOS trial.
Based upon this new clinical data, sanofi-aventis plans to submit a registration dossier to the European Medicines Agency (EMEA), and a new drug application (NDA) to the US Food and Drug Administration (FDA) during the 3rd quarter of 2008. About Atrial Fibrillation / Flutter Atrial fibrillation is a major cause of hospitalisation and mortality and affects about 2.5 million people in the USA and 4.5 million people in the European Union. The Atrial Fibrillation Foundation expects the number of patients with AF to double in the next 20 years. Without appropriate management, atrial fibrillation can lead to serious complications, such as stroke and congestive heart failure.
AF is a condition in which the upper chambers of the heart beat in an uncoordinated and disorganised fashion, resulting in an irregular and fast heart rhythm (i.e. an irregular heartbeat). Atrial flutter is an abnormal fast heart rhythm that occurs in the atria of the heart. This rhythm occurs often in individuals with other heart conditions (e.g. pericarditis, coronary artery disease, and cardiomyopathy). Atrial flutter frequently degenerates to atrial fibrillation. However, it may persist for months to years. When blood is not completely pumped out of the heart's chambers, it can pool and clot. If a blood clot forms in the atria, it can exit the heart and block an artery in the brain, resulting in a stroke. Consequently, about 15 percent of all strokes result from atrial fibrillation.
The landmark ATHENA study is a randomised, placebo controlled, international multi-center study that evaluated for the first time a treatment on top of standard background therapy for the management of patients with atrial fibrillation in reducing morbidity and mortality by preventing cardiovascular hospitalisations or death from any cause. The study included 4,628 patients, which make it the largest ever outcome study of an anti-arrhythmic treatment for atrial fibrillation.
The ATHENA study objectives were to show a potential benefit of Multaq on the primary composite endpoint of all-cause mortality combined with cardiovascular hospitalisation as compared to placebo. The pre-specified secondary endpoints were death from any cause, cardiovascular death and hospitalisation for cardiovascular reasons. The pre-specified safety endpoint was the incidence of treatment emergent adverse events (time of observation for treatment emergent adverse events) including: all adverse events, serious adverse events, adverse events leading to study drug discontinuation.
The atrial fibrillation or atrial flutter patients studied were either 75 years of age or over (with or without cardiovascular risk factor) or were below 75 years of age with at least one additional cardiovascular risk factor (hypertension, diabetes, previous cerebrovascular event, left atrium size greater than 50 mm or left ventricular ejection fraction lower than 40 percent). Patients suffering from decompensated heart failure were excluded from the study. Patients were randomised to receive Multaq 400 mg BID or placebo, with a maximum follow-up of 30 months.