News:Dronedarone (Multaq®) a Promising New Drug for the Management of Patients with Atrial Fibrillation or Flutter

May 15, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

Atrial fibrillation is one of the major causes for frequent hospitalization and mortality affecting over 2 million people in the United States. Various therapeutic agents have been studied for the management of patients with atrial fibrillation. Beta blockers and amiodarone are commonly used agents but are associated with high recurrence rates and adverse events. Without appropriate therapy, disabling stroke and congestive cardiac failure are adverse consequences of uncontrolled atrial fibrillation or flutter.

Dronedarone (Multaq®) manufactured by Sanofi-aventis is a new multi-channel blocker that affects the calcium, potassium and sodium channels and has anti-adrenergic properties. Unlike amiodarone, this drug does not contain iodine radical and hence does not result in adverse effects on thyroid and lung functions.

The ATHENA study (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) is a randomized, placebo-controlled international multi-center study that evaluated the effect of dronedarone in addition to standard background therapy for the management of patients with atrial fibrillation or flutter in reducing morbidity and mortality in terms of reductions in cardiovascular hospitalizations or death from any cause. Patients were randomized to receive dronedarone 400mg twice a day or a placebo and were followed up for 30 months. Patients were enrolled from 550 sites in 37 countries.

This study consisted of a total of 4,628 patients who were ≥75 years with or without cardiovascular risk factor or <75 years with at least one additional cardiovascular risk factor such as hypertension, diabetes, previous cerebrovascular event, left atrial size >50mm or left ventricular ejection fraction <40%. Patients with decompensated congestive heart failure were excluded from the study.

The primary endpoint of this trial consisted of a composite of all-cause mortality combined with cardiovascular hospitalizations. The pre-specified secondary endpoints consisted of death from any cause, cardiovascular death and hospitalization for cardiovascular reasons. The pre-specified safety endpoint consisted of adverse events associated with the drug including all adverse events, serious adverse events and adverse events leading to study drug discontinuation.

In the ATHENA trial, dronedarone met the study’s primary endpoint reducing the risk of cardiovascular hospitalization or death from any cause by 25% (p=0.00000002). Furthermore, this study demonstrated a significant reduction in the risk of cardiovascular death by 30% with dronedarone compared with placebo (p=0.03) when administered together with standard rate control agents and antithrombotic agents among patients with atrial fibrillation or flutter. Likewise, this drug resulted in a significant reduction in the risk of arrhythmic death by 45% (p=0.01). Although there was a 16% reduction in death from any cause this was not significant with dronedarone compared with placebo (p=0.17). Dronedarone was also associated with a significant reduction (25%) in first cardiovascular hospitalization (p=0.000000009) compared with placebo treatment.

Adverse events such as gastro-intestinal effects (26% vs. 22%), skin rash (10% vs. 8%) and increased serum creatinine (4.7% vs. 1%) were observed among patients who received dronedarone and placebo respectively. Dronedarone is known to inhibit renal tubular excretion of creatinine. But there were no increased pro-arrhythmic effects or increase in hospitalization for congestive heart failure associated with dronedarone compared with placebo therapy. Similar rates of drug discontinuation were observed between the two groups.

Given the striking results in the ATHENA trial, dronedarone appears to be a promising agent in the management of patients with atrial fibrillation or flutter in addition to standard rate control and antithrombotic agents. Furthermore, this agent might be favored over amiodarone given its lack of interaction with thyroid and lung functions.

Source

 * 1) Heart Rhythm Society Meeting, San Francisco 2008
 * 2) Press release Sanofi-aventis

Reference

 * 1) Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with atrial fibrillation/atrial flutter. Hohnloser SH, Connolly SJ, Crijns HJ, Page RL, Seiz W, Torp-Petersen C. J Cardiovasc Electrophysiol. 2008 Jan;19(1):69-73. Epub 2007 Nov 21.