Results from a post-hoc analysis of the data from the ATHENA trial, a double-blind, anti-arrhythmic, morbidity-mortality study that evaluated a new drug, dronedarone (Multaq, Sanofi-Aventis), in patients with atrial fibrillation, show that dronedarone reduces stroke risk.
The analysis was presented at the clinical trial update session of the European Society of Cardiology congress 2008, in Munich, Germany.
Previous results from the ATHENA study have shown that dronedarone on top of standard therapy decreased the combined primary endpoint of the risk of cardiovascular hospitalisations or death from any cause by a statistically significant 24% as compared to placebo. The ATHENA stroke post-hoc analysis on non-pre-specified secondary endpoints showed that dronedarone decreased the risk of stroke (ischaemic or haemorrhagic) compared to placebo by 34% (46 vs. 70 stroke events respectively; p=0.027) over a follow-up averaging 21 months in atrial fibrillation/atrial flutter patients adequately treated by standard therapy, including antithrombotics.
“This reduction occurred in patients who were generally receiving appropriate antithrombotic therapy. The effect was consistent in higher-risk patients with different risk factors,” co-principal investigator Dr Stuart J Connolly, McMaster University, Hamilton, Canada, said when presenting the findings. “No previous antiarrhythmic therapy has been shown to reduce stroke in this way.”
Largely on the strength of ATHENA, one of the largest antiarrhythmic drug trials ever conducted, with 4,628 randomised patients, dronedarone is under review by regulators in both the US and Europe. Observers have noted that the drug has so far shown a fairly benign safety profile, putting it in stark contrast to amiodarone. The two drugs are biochemically similar, but dronedarone lacks its molecular cousin’s iodine component primarily responsible for an infamous array of end-organ toxicities.
As the discussant for Connolly’s presentation, Dr Karl-Heinz Kuck, Asklepios Clinic St Georg, Hamburg, Germany, reviewed a few reservations about dronedarone and ATHENA. The trial, he said, enrolled few patients with heart failure and primarily patients with paroxysmal AF, pointing to the need for studies in broader patient groups, he said. Also, dronedarone’s long-term safety needs exploring, especially given ATHENA’s finding of a somewhat higher incidence of elevated creatinine associated with the drug – although there were few such cases overall.
“When we have all these questions answered, we may know what place there may be for dronedarone for maintaining sinus rhythm and to prevent stroke and for other indications in patients with atrial fibrillation,” Kuck said.
The patients studied in ATHENA were either 75 years of age or older (with or without cardiovascular risk factor) or above 70 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%). Patients were randomised to receive dronedarone 400 mg BID or placebo, with a maximum follow-up of 30 months.
“My personal view is that the stroke reduction by more than 30% is one of the most important findings of this trial,” Kuck said. “I won’t care too much, as a doctor who treats thousands of patients with atrial fibrillation, when the patient comes back to me with a recurrence that might be important to the patient’s quality of life and the economic situation of our healthcare system. But a stroke reduction of 34% is more than important to the patient and also to the healthcare system. It’s a significant benefit for patients with atrial fibrillation.”