Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation

Abstract

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary–perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms ( P <0.05 for both). Flecainide increased the effective refractory period in atria by 27% ( P <0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria ( P <0.01) but by only 7% ( P <0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and T peak -T end intervals by 25 and 55%, respectively ( P <0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects ( P <0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT–mediated ventricular proarrhythmia.