Arrhythmias and conduction disturbances
Usefulness of Vernakalant Hydrochloride Injection for Rapid Conversion of Atrial Fibrillation

https://doi.org/10.1016/j.amjcard.2010.06.054Get rights and content

The objective of the present study was to assess the safety and effectiveness of vernakalant hydrochloride injection (RSD1235), a novel antiarrhythmic drug, for the conversion of atrial fibrillation (AF) or atrial flutter to sinus rhythm (SR). Patients with either AF or atrial flutter were randomized in a 1:1 ratio to receive vernakalant (n = 138) or placebo (n = 138) and were stratified by an arrhythmia duration of >3 hours to ≤7 days (short duration) and 8 to ≤45 days (long duration). The first infusion of placebo or vernakalant (3 mg/kg) was given for 10 minutes followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later if the arrhythmia had not terminated. A total of 265 patients were randomized and received treatment. The primary end point was conversion of AF to SR for ≥1 minute within 90 minutes of the start of the drug infusion in the short-duration AF group. Of the 86 patients receiving vernakalant in the short-duration AF group, 44 (51.2%) demonstrated conversion to SR compared to 3 (3.6%) of the 84 in the placebo group (p <0.0001). The median interval to conversion of short-duration AF to SR in the responders given vernakalant was 8 minutes. Of the entire AF population (short- and long-duration AF), 47 (39.8%) of the 118 vernakalant patients experienced conversion of AF to SR compared to 4 (3.3%) of the 121 placebo patients (p <0.0001). Transient dysgeusia and sneezing were the most common adverse events in the vernakalant patients. One vernakalant patient who had severe aortic stenosis experienced hypotension and ventricular fibrillation and died. In conclusion, vernakalant demonstrated a rapid and high rate of conversion for short-duration AF and was well tolerated.

Section snippets

Methods

The present study was a prospective, randomized, double-blind, placebo-controlled international trial conducted from June 27, 2004 to August 1, 2005. The institutional or regional review board at each site approved the protocol, and the patients gave written informed consent before starting the study procedures. An unblinded independent data safety monitoring board was used throughout the trial. The sponsors and members of the steering committee had full access to the data. The sponsor

Results

The disposition of the 276 study patients is depicted in Figure 2. No patient had previously participated in a vernakalant study, including ACT I. The baseline demographics and baseline medical therapies are listed in Table 1. The treatment groups were relatively well-balanced. Of the 86 vernakalant patients in the primary efficacy group, 44 (51.2%) demonstrated conversion to SR for ≥1 minute within 90 minutes of infusion (primary efficacy end point) compared to 3 (3.6%) of the 84 placebo

Discussion

In the present study, vernakalant was effective in converting short-duration AF (51.2% compared to 3.6% of placebo patients). However, vernakalant was ineffective for AFL.

The results of the present study are consistent with those of the ACT-I.5 For patients with short-duration AF, conversion to SR with vernakalant was rapid. From the initiation of the infusion, the median interval to conversion in the present trial (8 minutes) was similar to that in ACT I (11 minutes).5 In both the present

Acknowledgment

We thank the nurse coordinators at the participating sites for their cooperation with the present study, and Therese Kitt, MD, Bruce McNutt, MD, Bo Yan, PhD, and Jimmy Wang, PhD, of Astellas Pharma US, Inc. (Deerfield, Illinois), Greg Beatch, PhD, Garth Dickinson, MD, Sheila Grant, BS, MBA, and Brian Mangal, MS, of Cardiome Pharma, Corp. (Vancouver, Canada), and David S. Berger, PhD, who served as a medical writer, and Kara L. Guarini, PhD, from JL Shapiro Associates, Inc (Edison, New Jersey).

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    Vernakalant targets multiple ion channels, including the atrial selective acetylcholine-activated potassium current (IK,Ach) and was approved for pharmacological cardioversion by the European Medicines Agency in 2010. In clinical trials, vernakalant converted 51% of patients with short duration atrial fibrillation (3 h to 7 days) with a median time to conversion of 10 min.15,16 The initial dose is 3 mg/kg dose over 10 min and a second infusion of 2 mg/kg can be given if atrial fibrillation persists after 10 min.

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This study was sponsored by Astellas Pharma US, Inc., Deerfield, Illinois and Cardiome Pharma Corp., Vancouver, British Columbia, Canada.

Drs. Pratt, Roy, and Wyse have previously received consulting fees from Cardiome or Astellas.

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ACT-III Investigators are listed in the Appendix

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