In July 2009, Multaq®, an antiarrhythmic drug developed by sanofi-aventis, was approved by the U.S. Food and Drug Administration for patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL). In this interview, we speak with Gerald V. Naccarelli, MD about Multaq®. Dr. Naccarelli is the Bernard Trabin Chair in Cardiology, Professor of Medicine, and Chief of the Division of Cardiology at Penn State Heart & Vascular Institute. He was also an investigator in the ATHENA trial. Tell us about the development of Multaq®, including clinical experience in the ATHENA trial. How did Multaq® come to market? Multaq®’s clinical development took almost a decade and hundreds of millions of dollars in cost. Following the phase IIa dosing trial DAFNE, the drug demonstrated rated control efficacy in ERATO and the ability to significantly suppress AF in ADONIS and EURIDIS. Safety concerns in severe heart failure were noted in ANDROMEDA, which led to the pivotal trial ATHENA. In ATHENA, a total of 4,628 patients were randomized to dronedarone 400 mg twice daily versus placebo. This was the largest trial ever done in AF (even larger than AFFIRM). ATHENA demonstrated that Multaq® met the study’s primary composite endpoint of reducing cardiovascular hospitalizations and death (the drug reduced this endpoint by 24% compared to placebo and this was highly statistically significant). The majority of the benefit came from reducing cardiovascular hospitalizations. This study also gave a safety signal to the FDA related to a neutral effect on mortality in an appropriate patient population since patients with severe congestive heart failure (CHF), who were enrolled in ANDROMEDA, were excluded from ATHENA. What population of patients is Multaq® approved for? Multaq® is a multichannel blocker having effects on all four Vaughan Williams classes. The drug has a similar chemical structure to amiodarone (benzofuran derivative) without the iodine moieties that minimize any thyroid toxicity. Multaq® is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter, with a recent episode of AF/AFL and associated cardiovascular risk factors: • Age >70 • Hypertension • Diabetes • Prior cerebrovascular accident • Left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] What specific benefits does Multaq® offer patients? Multaq® offers a safe antiarrhythmic that has efficacy in treating atrial fibrillation and can be initiated as an outpatient. The unique benefit is that Multaq® was demonstrated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter and associated cardiovascular risk factors. This is the first antiarrhythmic drug to demonstrate this kind of benefit in AF patients. What patients are contraindicated from taking Multaq®? Multaq® is contraindicated in patients with NYHA Class IV heart failure or NYHA Class II-III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given Multaq® had a greater than two-fold increase in mortality. Such patients should not be given Multaq®. Multaq® is also contraindicated in patients with the following conditions: • Second- or third-degree atrioventicular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) • Bradycardia How will the approval of Multaq® affect the management and treatment of patients with atrial fibrillation and atrial flutter? The addition of Multaq® to our treatment of AF patients will allow more outpatient-initiated treatment of AF without hospitalizations necessary to initiate sotalol and dofetilide. In addition, dronedarone will often be used more front line than amiodarone, and thus minimize a patient’s exposure to the toxicity of amiodarone. In addition, based on the ATHENA trial, the drug will decrease CV hospitalizations by 24% and reduce the cost of taking care of AF patients. Discuss the launch of the mPACT Multaq® Partnership for Appropriate Care and Treatment and the Risk Evaluation and Mitigation Strategy (REMS). What is the purpose of these initiatives? Sanofi-aventis initiated the mPACT Partnership. This program was developed to assist healthcare professionals with identification of appropriate patients and to ensure safe use of Multaq® while minimizing risk. The risk mitigation program consists of a communication plan for healthcare professionals, a medication guide for patients and post-marketing surveillance. How does Multaq® compare with other pharmacological agents on the market today? Based on studies, Multaq® appears to be effective in suppressing AF and maintaining sinus rhythm in about 50% of patients. This is comparable to flecainide, propafenone, sotalol and dofetilide, but not as effective as amiodarone. Except for patients with severe heart failure, dronedarone will be used in patients with and without structural heart disease, while class IC agents are limited to patients without significant structural heart disease. Dronedarone can be initiated as an outpatient and has rate control properties similar to sotalol and amiodarone. Its unique efficacy is in reducing cardiovascular hospitalizations, and none of the other drugs or even catheter ablation have demonstrated this endpoint. What is significant about the approval of Multaq®? Multaq®’s approval is significant because it is the first antiarrhythmic for AF in almost 10 years. The drug is now also approved in Canada and soon in Europe. In addition to the drug offering an alternative to other therapies, the reduction in cardiovascular hospitalization will result in patient and physician satisfaction and a decrease in unnecessary hospitalization, thus reducing cost. The drug’s approval also gives encouragement to the pharmaceutical industry that a drug can get approved for AF, and many companies are now lining up to offer us other novel therapies for our patients. Is there anything else you'd like to add? We will continue to learn about the safety and efficacy of Multaq® as the drug is used commercially and more phase IV studies are performed. As cardiologists, we are quite happy to be able to offer our AF patients some new treatment options.