Amiodarone vs Bepridil in Achieving Conversion to Sinus Rhythm
This study was designed as a prospective, randomised, open label trial. Patients who met our criteria for participation were enrolled in this study from July 2008 to July 2010. Persistent AF was defined as non-self-terminating AF requiring pharmacological or electrical conversion for restoration of sinus rhythm. When AF persisted for more than 1 month, its duration was determined precisely based on symptoms and repeated ECGs.
Forty patients with persistent AF were enrolled in this study and randomly assigned into two groups (amiodarone: (A) or bepridil: (B)). Patients were excluded from the study when the AF persisted for more than 2 years, when direct current (DC) cardioversion was attempted more than twice on the separate occasion at least 2 months interval or when the QT interval on the baseline ECG was already longer than 0.5 s.
Group A received a starting dose of 400 mg/day in the first week followed by a dose of 200 mg/day thereafter. This administration protocol was based on previous studies in which even a low dose (200 mg/day) conferred therapeutic effects, particularly for Japanese patients. The dose for group B started at 150 mg/day for the first 2 weeks and was then adjusted to between 100 mg and 200 mg/day according to the age, gender, body weight, renal function and QT interval. All patients received anticoagulation therapy with warfarin, with appropriate control by international normalised ratio testing. Digitalis, β-blockers or calcium antagonists for rate control were accepted, when necessary. Digitalis was used for either of two purposes, namely, for acute rate control in patients with relatively depressed LV function or as a treatment for intolerable hypotension induced by β-blocker or verapamil. Most of these patients were taken off the digitalis once their heart rate was controlled. To avoid the proarrhythmic effects of both drugs by using digitalis concomitantly, special care was taken to measure serum K and blood concentration of digitalis. The effects of pharmacological conversion and subsequent maintenance of sinus rhythm after administration of each drug were evaluated. DC cardioversion was performed if sinus rhythm was not restored within 3 months after medications were commenced. When pharmacological conversion was achieved, it was maintained for at least a year unless obvious adverse complications were recognised.
A standard 12 leads ECG was recorded before and after the administration of each drug. The ECG parameters of heart rate, QRS duration, QT interval and QTc were measured at baseline, 1 week, 2 weeks and once monthly during the follow-up period. In consideration of the pharmacodynamics, the bepridil group was followed up weekly during the first month. The QT interval was measured manually from the lead with the longest interval. QTc was measured by dividing the QT interval by the square root of the averaged RR with the minimum difference interval. During AF, these indices were calculated by averaging 10 stable beats obtained from the baseline ECG. Restoration to sinus rhythm was judged from the symptoms and the periodic ECG recordings. To monitor for recurrence of AF, a Holter ECG was recorded at 1 month after sinus conversion and thereafter at 2–3-month intervals. Blood examinations were performed to assess thyroid function, KL-6, and other routine laboratory parameters. The serum concentration of each drug was also checked at the appropriate times. The incidence of adverse complications was compared between the two groups. Adverse events were classified as either major or minor. An event was major if it required both withdrawal of the drug and subsequent treatment of some form. An event was minor if it required either reduction or careful follow-up without treatment. Adverse side effects were evaluated by routine and regular follow-up methods.
The primary end point in both groups was the sinus rhythm conversion rate. Secondary end points were recurrent AF after pharmacological or electrical cardioversion, hospitalisation for cardiovascular events, or adverse complications.
Continuous variables are presented as mean ± SD and compared using the Student t test. Categorical variables were compared using the Fisher's exact test. Data were analysed by the χ test, when appropriate. A p value of <0.05 was considered statistically significant. All analysis was conducted by STATISTICA V.6 (StatSoft, Tulsa).
The institutional ethical committee of our hospital approved the study and all of the patients gave their written informed consent.
Methods
This study was designed as a prospective, randomised, open label trial. Patients who met our criteria for participation were enrolled in this study from July 2008 to July 2010. Persistent AF was defined as non-self-terminating AF requiring pharmacological or electrical conversion for restoration of sinus rhythm. When AF persisted for more than 1 month, its duration was determined precisely based on symptoms and repeated ECGs.
Patient's Population and Study Protocol
Forty patients with persistent AF were enrolled in this study and randomly assigned into two groups (amiodarone: (A) or bepridil: (B)). Patients were excluded from the study when the AF persisted for more than 2 years, when direct current (DC) cardioversion was attempted more than twice on the separate occasion at least 2 months interval or when the QT interval on the baseline ECG was already longer than 0.5 s.
Group A received a starting dose of 400 mg/day in the first week followed by a dose of 200 mg/day thereafter. This administration protocol was based on previous studies in which even a low dose (200 mg/day) conferred therapeutic effects, particularly for Japanese patients. The dose for group B started at 150 mg/day for the first 2 weeks and was then adjusted to between 100 mg and 200 mg/day according to the age, gender, body weight, renal function and QT interval. All patients received anticoagulation therapy with warfarin, with appropriate control by international normalised ratio testing. Digitalis, β-blockers or calcium antagonists for rate control were accepted, when necessary. Digitalis was used for either of two purposes, namely, for acute rate control in patients with relatively depressed LV function or as a treatment for intolerable hypotension induced by β-blocker or verapamil. Most of these patients were taken off the digitalis once their heart rate was controlled. To avoid the proarrhythmic effects of both drugs by using digitalis concomitantly, special care was taken to measure serum K and blood concentration of digitalis. The effects of pharmacological conversion and subsequent maintenance of sinus rhythm after administration of each drug were evaluated. DC cardioversion was performed if sinus rhythm was not restored within 3 months after medications were commenced. When pharmacological conversion was achieved, it was maintained for at least a year unless obvious adverse complications were recognised.
Follow-up Schedule
A standard 12 leads ECG was recorded before and after the administration of each drug. The ECG parameters of heart rate, QRS duration, QT interval and QTc were measured at baseline, 1 week, 2 weeks and once monthly during the follow-up period. In consideration of the pharmacodynamics, the bepridil group was followed up weekly during the first month. The QT interval was measured manually from the lead with the longest interval. QTc was measured by dividing the QT interval by the square root of the averaged RR with the minimum difference interval. During AF, these indices were calculated by averaging 10 stable beats obtained from the baseline ECG. Restoration to sinus rhythm was judged from the symptoms and the periodic ECG recordings. To monitor for recurrence of AF, a Holter ECG was recorded at 1 month after sinus conversion and thereafter at 2–3-month intervals. Blood examinations were performed to assess thyroid function, KL-6, and other routine laboratory parameters. The serum concentration of each drug was also checked at the appropriate times. The incidence of adverse complications was compared between the two groups. Adverse events were classified as either major or minor. An event was major if it required both withdrawal of the drug and subsequent treatment of some form. An event was minor if it required either reduction or careful follow-up without treatment. Adverse side effects were evaluated by routine and regular follow-up methods.
End Points
The primary end point in both groups was the sinus rhythm conversion rate. Secondary end points were recurrent AF after pharmacological or electrical cardioversion, hospitalisation for cardiovascular events, or adverse complications.
Statistical Analysis
Continuous variables are presented as mean ± SD and compared using the Student t test. Categorical variables were compared using the Fisher's exact test. Data were analysed by the χ test, when appropriate. A p value of <0.05 was considered statistically significant. All analysis was conducted by STATISTICA V.6 (StatSoft, Tulsa).
Ethical Status
The institutional ethical committee of our hospital approved the study and all of the patients gave their written informed consent.
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