Elsevier

Heart Rhythm

Volume 7, Issue 9, September 2010, Pages 1273-1279
Heart Rhythm

Focus issue: Atrial fibrillation
Experimental
Acute dronedarone is inferior to amiodarone in terminating and preventing atrial fibrillation in canine atria

https://doi.org/10.1016/j.hrthm.2010.05.019Get rights and content

Background

Dronedarone is approved by the U.S. Food and Drug Administration for the treatment of patients with atrial fibrillation (AF) as a safe alternative to amiodarone. There are no full-length published reports describing the effectiveness of acute dronedarone use against AF in experimental or clinical studies.

Objective

The purpose of this study was to determine the effect of acute dronedarone and amiodarone on electrophysiological parameters, and their anti-AF efficacy in canine isolated arterially perfused right atria.

Methods

Transmembrane action potentials and pseudoelectrocardiograms were recorded. Acetylcholine (ACh, 1.0 μM) was used to induce persistent AF.

Results

Amiodarone-induced changes were much more pronounced than those of dronedarone on (1) action potential duration (ΔAPD90, +51 ± 17 ms vs. 4 ± 6 ms, P >.01), (2) effective refractory period (ΔERP, +84 ± 23 ms vs. 18 ± 9 ms, P <.001), (3) diastolic threshold of excitation (ΔDTE, +0.32 ± 0.11 mA vs. 0.03 ± 0.02 mA, P <.001), and (4) Vmax (ΔVmax, −43 ± 14% vs. −11 ± 4%, P <.01, n = 5 to 6; all recorded at 10 μM, cycle length = 500 ms). Persistent AF was induced in 10 of 10 atria exposed to ACh alone; subsequent addition of dronedarone or amiodarone terminated AF in 1 of 7 and 4 of 5 atria, respectively. Persistent ACh-mediated AF was induced in 5 of 6 and 0 of 5 atria pretreated with dronedarone and amiodarone, respectively.

Conclusion

The electrophysiological effects and anti-AF efficacy of acute dronedarone are much weaker than those of amiodarone in a canine model of AF. The efficacy of acute dronedarone to prevent induction of acetylcholine-mediated AF as well as to terminate persistent AF in canine right atria is relatively poor. Our data suggest that acute dronedarone is a poor substitute for amiodarone for acute cardioversion of AF or prevention of AF recurrence.

Introduction

Currently available drugs for rhythm control of atrial fibrillation (AF) are far from optimal from the standpoint of efficacy and safety.1, 2 Amiodarone remains the most effective anti-AF agent for the long-term maintenance of sinus rhythm, but its long-term use is often associated with extracardiac toxicity. Dronedarone is an amiodarone derivative that lacks the iodine moiety that is believed to be responsible for the toxicity of amiodarone. Available data indicate that long-term use of dronedarone is generally safer than that of amiodarone, but that its efficacy to maintain sinus rhythm is considerably lower than that of amiodarone.3, 4

Although several clinical trials report an anti-AF effect of dronedarone for long-term maintenance of sinus rhythm,5, 6 there are no full-length articles evaluating the effectiveness of acute dronedarone against AF in experimental or clinical studies. The main objective of the current study was to directly compare the acute electrophysiological effects of dronedarone and amiodarone and their anti-AF potency in a canine model of AF.

Section snippets

Methods

Dogs weighing 20 to 25 kg were anticoagulated with heparin (200 IU/kg) and anesthetized with pentobarbital sodium (35 mg/kg intravenously). The chest was opened via a left thoracotomy, and the heart excised, placed in a cardioplegic solution consisting of cold (4°C) Tyrode solution containing 8.5 mM [K+]0, and transported to a dissection tray. Three-fourths of both ventricles were quickly removed. The ostium of the right coronary artery was cannulated with polyethylene tubing (inside diameter

Electrophysiological effects of dronedarone versus amiodarone

Amiodarone but not dronedarone prolonged APD90 (Figure 1). Dronedarone and amiodarone caused no significant change in APD70 (−Δ2 ± 5 and +Δ3 ± 7, respectively), but both abbreviated the APD50 (−Δ24 ± 8 and −Δ21 ± 9 ms, respectively; both P <.05 vs. control, n = 5–6, in Crista terminalis (CT), 10 μM; CL = 500 ms). Both drugs prolonged ERP, but amiodarone prolonged it to a much greater extent than dronedarone (Figure 1). The greater prolongation of ERP by amiodarone was largely due to a much

Discussion

The main results of the present study are that electrophysiological effects and anti-AF efficacy of acute dronedarone are much weaker than those of amiodarone in coronary-perfused canine right atria.

Study limitations

Our experiments were conducted in isolated Tyrode-perfused canine atrial preparations, lacking exogenous autonomic influences, hormones, and other blood-related factors, which may modify pharmacological in vivo responses. Another important limitation is that we used nonremodeled atria, whereas clinical AF is commonly associated with structural and electrical abnormalities, which may also significantly modify atrial electrophysiological responses to AADs as well as alter anti-AF actions.

Conclusion

This is the first full-length report that compares the anti-AF efficacy of acute dronedarone and amiodarone in either experimental or clinical studies. The results of this study clearly indicate that the acute electrophysiological effects and anti-AF potency of dronedarone are much weaker than those of acute amiodarone.

Acknowledgments

The authors acknowledge the expert technical assistance of Judy Hefferon and Robert Goodrow.

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    Supported by grant HL-47678 from NHLBI (CA), grants from Gilead Sciences, Inc., and the New York State and Florida Grand Lodges of Free and Accepted Masons. Dr. Antzelevitch received research support and is a consultant to Gilead Sciences. Dr. Belardinelli is an employee of Gilead Sciences, Inc.

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