The RAFT Trial: Efficacy and Safety of Sustained-Release Propafenone (Propafenone SR) for Patients with Atrial Fibrillation

In this interview, Dr. James Reiffel discusses the recent findings of the Rythmol Atrial Fibrillation Trial (RAFT). The RAFT trial studied a new sustained-release formation of propafenone (propafenone SR), and found that the frequency of symptomatic arrhythmia recurrence in atrial fibrillation patients was significantly reduced with all three twice-daily propafenone SR doses tested. Dr. Reiffel is a Professor of Clinical Medicine at the Columbia University College of Physicians and Surgeons, as well as an Attending Physician at the Columbia University Medical Center Campus, The New York Presbyterian Hospital. He is also the Director of Electrocardiography at the Columbia Presbyterian Medical Center and a Staff Electrophysiologist in the Division of Cardiology/Department of Medicine. Dr. Reiffel has published over 200 papers related to cardiac dysrhythmias, and has been an invited lecturer at several hundred programs and institutions worldwide. His current research interests include the optimum management of patients with atrial fibrillation and flutter, studies in cardiac repolarization as they relate to dysrhythmias and gender differences in proarrhythmic risk, and the development of new antiarrhythmic pharmaceuticals.

Can you describe the RAFT Trial for us? The RAFT Trial was a prospective, multicenter (United States), randomized, double-blind, placebo-controlled trial in 523 patients that assessed the efficacy and safety of sustained-release propafenone for the prevention of symptomatic recurrences of AF. Propafenone SR was dosed at 225, 325, and 425 mg bid up to 39 weeks (Slide 1).

How large was the RAFT trial? Why is this significant? RAFT enrolled 523 patients, which is almost 10-fold larger than the pivotal trials employed for the approval process of flecainide for atrial fibrillation management approximately a decade ago. The significance of this is that one can have more confidence in the results of a contemporary trial with regards to efficacy and safety when the magnitude of the observations is greater.

What was the major observation in RAFT? Propafenone SR significantly lengthened the time to the first symptomatic atrial arrhythmia recurrence at all three doses, compared with placebo, as approximately 70% of the patients on 425 mg bid were free of recurrent atrial fibrillation. The median time to recurrence was 41 days in the placebo group, > 300 days in the propafenone 425 mg group, 291 days in the propafenone 325 mg group, and 112 days in the 225 mg group. (Slide 2, 3)

Were the observations in RAFT confirmed in the second pivotal trial, ERAFT? Yes, the ERAFT (European Rythmol SR Atrial Fibrillation Trial) Study had qualitatively similar observations with the 325 and 425 mg bid doses (225 mg bid was not used in ERAFT).

What other results were noted in RAFT? In RAFT, the subpopulation analyses based upon the variables of age (Were there any side effects with the active drug in RAFT? In both RAFT and ERAFT, the most common side effects were those previously seen with immediate release propafenone: dizziness, visual, and other CNS symptoms; gastrointestinal; altered taste, altered ECG parameters. The discontinuation rate for all adverse events was comparable to placebo in both the 225 mg and 325 mg formulations and higher in the 425 mg formulation. Discontinuation due to severe adverse events was less than placebo in all formulations.

How will the RAFT trial findings affect clinical practice? RAFT and ERAFT led to the FDA approval of sustained-release propafenone (Rythmol SR) to prolong the time to the recurrence of symptomatic AF in patients without structural heart disease. The sustained-release formulation has been shown to provide more stable serum concentrations of the drug, with fewer peaks and troughs, which may lead to fewer adverse effects and fewer breakthrough episodes. A bid formulation should provide greater convenience for patients, thus allowing for greater compliance and therapeutic benefit.

What proportion of AF patients might be affected by the RAFT findings? Of the estimated 2.3 million atrial fibrillation patients, according to published sources, approximately 35% have been found to have lone AF, and up to 35% have associated hypertension. Thus, up to 70% of AF patients who require an antiarrhythmic drug (AAD) might be candidates for sustained-release propafenone as an initial antiarrhythmic drug choice. Antiarrhythmic drug therapy for the maintenance of sinus rhythm in AF patients is only appropriate for those patients whose quality of life is inadequate with rate control alone, and perhaps for those of younger age with a lesser degree of symptoms in whom a class IC agent can be used (no structural heart disease or uncomplicated hypertension), or possibly in those whom anticoagulation therapy is not feasible.

Why were the doses in RAFT different than the standard dosing of propafenone immediate release for atrial fibrillation? With a sustained-release version of a drug with significant first-pass metabolism, higher daily doses of the drug are required than with immediate release versions due to more continuous availability of the compound to hepatic metabolism. Therefore, the dosing equivalency is not a 1:1 mg conversion. According to the study authors and based upon pharmacokinetic comparative data, 325 mg bid of the SR formulation of propafenone is similar to 150 mg tid of the immediate release formulation, and 425 mg bid of the SR preparation is similar to a slightly less than 225 mg tid of the IR preparation. In RAFT, a lower dose was also used in order to assess for the FDA a minimum effective dose. As the 225 mg bid dose was found to prevent about 50% of symptomatic events over the 300-day study, far superior to placebo, this was indicated to be the initiating dose. Therefore, the message is that for those patients initiating therapy, 225 mg may be reasonable with subsequent titration upwards as needed. Titration is easy after five days of therapy. For those patients switching from the immediate release of propafenone, they should consider the findings in the studies and the relative dosity in formulation noted above.

Should the results of RAFT change the drug approach to AF management? The AHA/ACC/ESC guidelines are quite clear that for patients with no or minimal structural heart disease (as defined by LVH).