Importance of assessing changes in ventricular response to atrial fibrillation during evaluation of new heart failure therapies: Experience from trials of flosequinan

This study evaluated the effects of flosequinan on ventricular rate in patients with congestive heart failure end atrial fibrillation to determine whether this agent has a facilitatory effect on atrioventricular conduction and whether such an effect may be deleterious. Flosequinan is known to have a dose-dependent positive chronotropic effect on the sinus node, but its effect on atrioventricular conduction has not been evaluated. An excessive increase in ventricular rate during the treatment of heart failure could raise a safety concern and counterbalance beneficial responses. Data were analyzed from 338 patients participating in three similarly designed placebo- controlled exercise trials with flosequinan who also underwent ambulatory electrocardiographic monitoring. The effects of two doses of flosequinan on supine, standing, ambulatory, and exercise heart rates and on exercise capacity in patients in sinus rhythm and atrial fibrillation were compared. Flosequinan increased heart rate in a dose-dependent manner, in patients both with sinus rhythm and atrial fibrillation. A 100 mg once daily dose produced significant increases, in both rhythms, ranging from 6 to 11 beats/min, in supine end standing heart rate, ambulatory heart rate, and exercise heart rate. With a dose of 75 mg twice daily, heart rates under these conditions increased by >20 beats/min in flosequinan-treated patients in atrial fibrillation, a change significantly greater than that observed with placebo or flosequinan, 100 mg once daily end also more than in patients in sinus rhythm treated with the same dose. These results indicate that flosequinan facilitates atrioventricular nodal conduction, increasing the ventricular response in atrial fibrillation, especially at higher dosages. This finding could result from a direct drug action, such as phosphodiesterase inhibition, or reflex sympathetic activation. This response is of sufficient magnitude potentially to impair left ventricular function and interfere with clinical benefit. The effect of heart-failure drugs on ventricular responses in atrial fibrillation should be examined to provide insight into potential mechanisms of both action end safety in this common patient group.