Clinical and Electrophysiologic Effects of Calcium Channel Blockers in Patients Receiving Ibutilide

Mark A. Wood, MD, David M. Gilligan, MD, Chris Brown-Mahoney, PhD, Fatemeh Nematzadeh, MD, Bruce S. Stambler, MD, Kenneth A. Ellenbogen, MD


Am Heart J. 2002;143(1) 

In This Article

Abstract and Introduction

Background: Ibutilide is indicated for the acute termination of atrial fibrillation and atrial flutter. Recent work concludes that ibutilide activates a late inward sodium current that is blocked by nifedipine. Because calcium channel blockers are commonly used in patients with atrial fibrillation, it is important to exclude an antagonistic effect on ibutilide in the clinical setting.
Methods: We performed a retrospective electrocardiographic (ECG) review of patients enrolled in 3 clinical trials of ibutilide (2 atrial fibrillation conversion protocols and 1 ventricular tachycardia suppression protocol) to determine clinical efficacy and ECG effects of ibutilide in patients receiving and not receiving calcium channel blockers. Calcium channel blockers were administered as clinically indicated. A meta-analysis of the effects of calcium channel blockers on the conversion efficacy of atrial fibrillation and atrial flutter by ibutilide was also performed for studies in the literature.
Results: One hundred thirty patients were included in the ECG analysis (106 from atrial fibrillation protocols and 24 from the ventricular tachycardia protocol). Sixty-eight of the 130 patients were taking calcium channel blockers at the time of ibutilide administration. There were no differences in the QT or QTc intervals, conversion rate for atrial fibrillation or atrial flutter, or suppression of ventricular tachycardia between patients taking and not taking calcium channel blockers. In the meta-analysis of 4 studies, there was no difference in the conversion rates between patients taking (52%, n = 221) and not taking (45%, n = 402) calcium channel blockers (P = .09).
Conclusions: In the clinical setting, the concomitant use of calcium channel blockers does not alter the ECG effects or efficacy of ibutilide for the treatment of atrial or ventricular arrhythmias.

Ibutilide fumarate (Corvert, Pharmacia and Upjohn, Kalamazoo, Mich) is the only Food and Drug Administration-approved intravenous antiarrhythmic agent for the termination of atrial fibrillation and flutter.[1] Despite its prominent status in the management of these arrhythmias, ibutilide's mechanism of action is still undetermined. Studies by Lee and Lee[2] and Lee et al[3] concluded that ibutilide exerts class III antiarrhythmic effects by activating a late inward sodium current during the plateau of the cardiac action potential. These effects have been reported in guinea pig ventricular myocytes and human atrial myocytes.[2,4] In human atrial myocytes, the prolongation of action potential duration and enhanced inward current are both reversed by the L-type calcium channel blocker nifedipine. Lee and Lee[4] proposed that the L-type calcium channel is a possible mediator of the late current enhanced by ibutilide. The role of this inward current is debated and has not been verified by other laboratories.[5,6,7] Nevertheless, the inward current has been widely accepted to contribute to ibutilide's mechanism of action.[8,9,10]

In the clinical setting, calcium channel blockers are commonly used in patients with atrial fibrillation and flutter. The L-type calcium channel blocker diltiazem is the agent of choice for heart rate control in these disorders.[11] Calcium channel blockers are also used for treatment of myocardial ischemia and hypertension, both of which are prevalent in patients with atrial arrhythmias. Because calcium channel blockers are used in up to 46% of patients receiving ibutlide in the clinical setting, it is important to exclude an antagonistic action of calcium channel blockers on the clinical effects of ibutilide.[12] The purpose of this study was to examine the effects of concomitant calcium channel blocker use on the clinical and electrocardiographic (ECG) response to ibutilide. If the electrophysiologic effects of ibutilide are mediated by a nifedipine-sensitive channel, the simultaneous use of L-type calcium channel blockers may attenuate the clinical response to ibutilide.