Vernakalant: Conversion of atrial fibrillation in patients with ischemic heart disease

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Abstract

Background

Vernakalant is a novel, relatively atrial-selective antiarrhythmic drug. This analysis assessed the efficacy and safety of intravenous vernakalant for the rapid conversion of atrial fibrillation (AF) to sinus rhythm in patients with a history of ischemic heart disease (IHD).

Methods

The presence of IHD was extracted from the medical history of patients from four randomized placebo-controlled studies and one open label study. The efficacy analysis included patients with recent onset AF (consistent with the European labeled indication), while the safety analysis included all patients with AF or atrial flutter (AFL) (3 h to 45 days duration) who were exposed to study drug.

Results

A total of 1052 adult patients were enrolled and treated; 274 patients (91 placebo, 183 vernakalant) with a history of IHD and 778 patients (224 placebo, 554 vernakalant) without IHD. Conversion of AF to sinus rhythm was not influenced by IHD. In patients with recent onset AF, the placebo-subtracted conversion rate with vernakalant was 45.7% in the IHD group and 47.3% in the non-IHD group. In the 24 h following treatment, the rate of treatment-emergent serious adverse events and discontinuations due to adverse events was similar in both the IHD and non-IHD groups, and there was no case of torsades de pointes, ventricular fibrillation, or death in patients with IHD.

Conclusions

Vernakalant was safe and well tolerated in AF/AFL patients with a history of IHD, and was significantly more effective than placebo for the acute conversion of AF regardless of IHD status.

Introduction

Cardioversion of AF is a frequent procedure performed in cardiology and emergency departments. Early conversion of AF to sinus rhythm (SR) improves symptoms, prevents the detrimental effects of prolonged AF, and avoids hospitalization [1], [2]. Although electrical cardioversion is highly effective, it requires sedation or anesthesia [3]. Currently available antiarrhythmic agents for pharmacological cardioversion of AF are only moderately effective and may be limited in use by delayed onset of action, as well as proarrhythmic risk which becomes more evident when used in patients with underlying heart disease [3], [4], [5]. There is a need for a safe and effective antiarrhythmic agent for the acute conversion of AF that can be used in a broad patient population, including those with IHD.

Vernakalant is a novel antiarrhythmic agent that acts by blocking early-activating potassium channels combined with concentration-, voltage-, and frequency-dependent blockade of sodium channels [6]. Vernakalant demonstrates preferential effects for atrial tissue (particularly during AF) and has limited actions on ventricular tissue, as it has been shown to selectively prolong the atrial refractory period and rate-dependently slow atrial conduction without affecting ventricular refractoriness [6], [7], [8]. Although vernakalant causes minor blockade of the rapidly activating delayed rectifier current IKr, the late sodium channel block associated with vernakalant offsets the inhibition of IKr, reducing the risk of QT prolongation [6]. Intravenous vernakalant was well tolerated in placebo-controlled clinical trials [9], [10], [11], [12] and rapidly and effectively converted recent onset AF (> 3 h to ≤ 7 days duration); however, there was lower efficacy in longer duration AF and a lack of efficacy in atrial flutter (AFL).

There are limited data available on the efficacy and safety of antiarrhythmic agents in patients who have IHD. This analysis was conducted to assess the efficacy and safety of intravenous vernakalant for the rapid conversion of AF to SR in patients with a history of IHD.

Section snippets

Patient population

Data from the Atrial arrhythmia Conversion Trial I (ACT I) [10], ACT II [9], ACT III [12], ACT IV [13], and Scene 2 (unpublished) clinical studies were combined. These were multicenter, randomized, double-blind, placebo-controlled, parallel group studies, with the exception of ACT IV, which was an open label, single arm study. These studies were designed to assess the efficacy and safety of vernakalant injection in patients with AF or AFL of > 3 h to ≤ 45 days duration (ACT I, ACT III, ACT IV, and

Study Population

The 5 clinical studies included in this analysis were conducted from August 2003 to February 2007. The efficacy population consisted of 707 patients, of which 188 patients (64 placebo, 124 vernakalant) had a history of IHD and 519 patients (145 placebo, 374 vernakalant) did not have IHD (Table 1). The pooled safety population consisted of 1052 patients, of which 274 patients (91 placebo, 183 vernakalant) had a history of IHD and 778 patients (224 placebo, 554 vernakalant) did not have IHD (

Efficacy and safety

In this post-hoc analysis, the safety and efficacy of vernakalant injection were not influenced by a history of IHD. Conversion rates were higher in AF patients who received vernakalant compared to placebo, both in those patients with and those without IHD; the treatment difference did not significantly differ between the IHD group and the non-IHD group. In the ACT II study alone, however, higher efficacy was observed in the IHD group compared to the non-IHD group (which was essentially

Conclusions

This analysis demonstrates that vernakalant injection is effective for the acute conversion of AF to SR, and is safe and well tolerated, in AF/AFL patients with IHD. Vernakalant provides an effective therapeutic alternative for the conversion of AF, with an acceptable safety profile in patients with a history of IHD.

Acknowledgments

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology, and thank Anjie Moore for assistance in preparing the manuscript.

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