Effects of dronedarone and amiodarone on atrial fibrillatory rate in patients with persistent atrial fibrillation

Abstract

Current guidelines for the management of atrial fibrillation (AF) recommend dronedarone for the prevention of recurring AF [1]. Especially in patients with structural heart disease, e.g. hypertension with left ventricular hypertrophy, dronedarone is a welcome alternative to amiodarone due to its favorable safety profile. However, the antiarrhythmic efficacy of dronedarone is lower than that of amiodarone as exemplified in the DIONYSOS trial [2]. This observation is supported by experimental studies showing much weaker atrial electrophysiologic effects and anti-AF efficacy of dronedarone compared with amiodarone in a canine AF model [3]. However, there is a lack of studies investigating specific antiarrhythmic effects of amiodarone and dronedarone in human AF that are, moreover, restricted to in-vitro experiments of human atrial myocytes [4]. Consequently, we applied time–frequency analysis to the surface ECG for determination of atrial fibrillatory rate (AFR) as a measure of atrial refractoriness for in-vivo monitoring of amiodarone and dronedarone effects in patients with persistent AF. In patients with persistent AFN7 days but b1 year, 2-minute 12 lead ECG recordings were made at baseline and after 3 days of antiarrhythmic drug treatment with all subjects relaxed in a supine position after a 5-minute equilibration period. Dronedarone (2×400 mg/day) or amiodarone (1,200 mg/day loading dose) was initiated prior to external electrical cardioversion on an inpatient basis under continuous electrocardiographic monitoring. All patients were adequately anticoagulated using either oral anticoagulation therapy with an international normalized ratio between 2 and 3 or weight-adapted low molecular weight heparin following exclusion of left atrial thrombus formation by transesophageal echocardiography. Twenty-one consecutive patients treated with dronedarone were prospectively included in our AF registry and matched for age and genderwith 20patientswhowere treatedwith amiodarone. The clinical characteristics of the study population are summarized in Table 1 and showed no difference between the two groups. All patients provided informed consent for study participation, i.e. acquisition and analysis of baseline and on-treatment ECG for evaluation of drug effects. Time–frequency analysis was performed a posteriori on ECG lead V1 as described previously (Fig. 1) [5]. Briefly, after analog-to-digital conversion (1,000 Hz, 12 bit, 0.05–300 Hz) and high-pass filtering to remove baseline wander, QRST complexes were subtracted using spatiotemporal QRST cancelation (Fig. 1, top). One frequency estimate of the atrial signal was obtained every second from overlapping 2.5-second windows by short-term Fourier transform (segment-wise Fast Fourier transform). Thus, this instantaneous signal was represented in a spectral profile. Subsequently, the frequency of the atrial signal was trended as a function of time and mean atrial frequency determined. Frequencies were converted to AFR with its unit fibrillations per minute (fpm; AFR=frequency∗60). All continuous variables are presented as mean±one standard deviation. ECG parameters before and after drug administration were compared using Student's t-test for paired data. Differences in ECG parameter changes between dronedarone and amiodarone were evaluated using t-test for unpaired data. A p valueb .05 was considered statistically significant. The authors of this manuscript certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. At baseline, mean AFR measured 396±44 fpm in the dronedarone group, comparable to 410±32 fpm in the amiodarone group. AFR was reduced by 25±23 fpm with dronedarone (pb .001 for on-treatment vs. baseline) and by 70±29 fpm with amiodarone (pb .001 for on-treatment vs. baseline). The amiodarone-induced AFR reduction was significantly higher than the AFR reduction with dronedarone (pb .001 for amiodarone vs. dronedarone; Fig. 2, left). Ventricular rate at baseline showed no difference between the dronedarone and the amiodarone group. Both drugs slowed ventricular rate significantly; dronedarone by 18±19 beats per minute (bpm, pb .001 for on-treatment vs. baseline) and amiodarone by 9±12 bpm, (p=.002 for on-treatment vs. baseline). There was a trend for greater magnitude of ventricular rate slowingwith dronedarone comparedwith amiodarone (p=.086; Fig. 2, right). Class I and III antiarrhythmic drugs have been shown to increase atrial cycle length (decrease AFR) which coincides with increased refractoriness and decreased conduction velocity [6]. Previous studies [5,7–9] have subsequently demonstrated a substantial AFR