PO-01-148 COMBINATION OF FLECAINIDE AND IBUTILIDE FOR EFFECTIVE AND SAFE MANAGEMENT OF ATRIAL FIBRILLATION

Abstract

There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). To investigate a novel pharmacological approach for rhythm control management of AF. We studied the effectiveness of clinically relevant concentrations of flecainide (1.5 μM) and ibutilide (20 nM), alone and in combination, to prevent the induction of AF and to cardiovert persistent AF, defined here as AF lasting > 1 hr, using canine isolated coronary-perfused right atrial preparations. In addition, we examined the safety of the flecainide and ibutilide (50 nM) combination using canine left ventricular (LV) wedge preparations. Persistent AF could be induced in 100% of preparations following exposure to acetylcholine (0.5 μM; n=5). Persistent AF remained inducible in 60% of atria in the presence of ibutilide alone and in 20% of preparations in the presence of flecainide alone, but in 0% of preparations in the presence of the combination of ibutilide and flecainide (n=5 per group). When used alone, flecainide and ibutilide cardioverted persistent AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination (n=5 per group). Ibutilide prolonged both atrial and ventricular effective refractory period (ERP; by 15 and 8%, respectively; p<0.05 for both; Cycle length [CL] = 500 ms; n=5 for each). Flecainide significantly prolonged ERP in atria (by 27%; p<0.001) but not in ventricles (2% increase) due to atrial predominant induction of post-repolarization refractoriness. The combination of the two drugs prolonged ERP by 42% in atria (p<0.001 vs. control and 0<0.05 vs. flecainide alone) but by only 7% in ventricles (p<0.05; n=5, CL=500 ms). In separate experiments involving LV wedge preparations, risk factors for Torsade de Pointes were accentuated by ibutilide (50 nM) and slowed pacing (CL= 2000 ms; n=5). Under these conditions, ibutilide induced significant prolongation of QT and Tpeak /Tend intervals (by 25 and 55%, respectively; p<0.01 for both; n=5). Further addition of flecainide (1.5 μM) partially reversed these effects leading to an increase of these parameters by only 15 and 19%, respectively; p<0.05, combination vs. ibutilide; n=5). Torsade de Pointes was never observed with the drug combination. Our experimental data indicate that a combination of flecainide and ibutilide significantly improves pharmacological cardioversion of AF as well as prevention of AF with very little or no risk of long QT-mediated ventricular proarrhythmia.