Ranolazine, an antianginal agent with antiarrhythmic properties, prevents atrial fibrillation (AF) in patients with acute coronary syndrome. In experimental models, the combination of ranolazine and amiodarone has marked synergistic effects that potently suppress AF. Currently, the clinical effect of the ranolazine–amiodarone combination for the conversion of AF is unknown. This prospective randomized pilot study compared the safety and efficacy of ranolazine plus amiodarone versus amiodarone alone for the conversion of recent-onset AF. We enrolled 51 consecutive patients with AF (<48-hour duration) eligible for pharmacologic cardioversion. Patients (33 men, 63 ± 8 years of age) were randomized to intravenous amiodarone for 24 hours (group A, n = 26) or to intravenous amiodarone plus oral ranolazine 1,500 mg at time of randomization (group A + R, n = 25). The 2 groups were well balanced with respect to clinical characteristics and left atrial diameter. Conversion within 24 hours (primary end point) was achieved in 22 patients (88%) in group A + R versus 17 patients (65%) in group A (p = 0.056). Time to conversion was shorter in group A + R than in group A (9.8 ± 4.1 vs 14.6 ± 5.3 hours, p = 0.002). According to Cox regression analysis, left atrial diameter and A + R treatment were the only independent predictors of time to conversion (hazard ratio 5.35, 95% confidence interval 2.37 to 12.11, p <0.001; hazard ratio 0.81, 95% confidence interval 0.74 to 0.88, p <0.001, respectively). There were no proarrhythmic events in either group. In conclusion, addition of ranolazine to standard amiodarone therapy is equally safe and appears to be more effective compared to amiodarone alone for conversion of recent-onset AF.
The efficacy and safety of currently available drugs for conversion of atrial fibrillation (AF), the most commonly encountered arrhythmia, remain suboptimal. Amiodarone is widely used for this purpose but is limited by its delayed onset of action and by a conversion rate that is lower than other antiarrhythmics. Ranolazine is an antianginal agent with increasingly appreciated antiarrhythmic properties affecting ventricular and supraventricular arrhythmias. In clinical studies, ranolazine has prevented the occurrence of AF in patients with acute coronary syndrome or after coronary bypass surgery. In experimental models, ranolazine has potently augmented the AF-suppressing effects of amiodarone and of the amiodarone-derivative dronedarone by an atrium-selective inhibition of sodium channels. Despite compelling preclinical evidence indicating a synergistic action of ranolazine and amiodarone in suppressing AF, the clinical effect of ranolazine when added to standard amiodarone treatment for the conversion of AF is currently unknown. The purpose of this randomized pilot study was to compare the safety and efficacy of ranolazine added to amiodarone versus amiodarone alone for the conversion of recent-onset AF.
Methods
All consecutive adult patients with symptomatic recent-onset AF (<48-hour duration) who presented from January 2011 to December 2011 and were suitable for pharmacologic cardioversion were prospectively screened for study participation. We excluded patients with cardiogenic shock; acute coronary syndrome; atrial flutter; symptomatic bradycardia; corrected QT (QTc) interval >440 ms; cardiac surgery within 30 days before enrollment; pacemaker; hepatic, renal, or thyroid disorders; uncorrected electrolyte imbalance; previous exposure to ranolazine; or those taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir). Patients who had taken class I or III antiarrhythmic drug in the preceding 24 hours were also excluded. The study protocol was approved by the institutional ethics committee, and all study participants provided informed consent.
Patients were randomized to intravenous amiodarone (loading dose 5 mg/kg in 1 hour followed by 50 mg/hour for 24 hours or until cardioversion if achieved in <24 hours; group A) or to intravenous amiodarone at the same dosage plus ranolazine 1,500 mg given orally once at time of randomization (group A + R). The 24-hour efficacy evaluation period is consistent with vast evidence from previous studies that have tested intravenous amiodarone. Amiodarone infusion was discontinued if any of the following was observed: QTc interval >550 ms; heart rate <40 beats/min or symptomatic bradycardia; systolic blood pressure <80 mm Hg not responding to intravenous fluid administration; or intolerable side effects. All patients were kept in the coronary care unit for 24 hours under continuous electrocardiographic and blood pressure monitoring and then remained for ≥1 day in the cardiology department. If the patient was still in AF after 24 hours, electrical cardioversion was attempted directly or after 4 weeks of anticoagulation treatment, as appropriate. QT interval was measured at baseline, at the time of AF conversion (if achieved), and at 24 hours and was corrected for heart rate (QTc interval) using the Bazett formula. Transthoracic echocardiography was performed in all patients by an investigator blinded to study intervention.
The study’s primary end point was prespecified as the proportion of patients with conversion of AF to sinus rhythm (SR) within 24 hours. Secondary end points were time to AF conversion and occurrence of proarrhythmic events, which were defined as new onset of sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes. An exploratory end point assessed AF conversion from 6 to 24 hours because AF conversion within 6 hours of amiodarone infusion is similar to the rate of placebo-related spontaneous conversion and because ranolazine reaches peak plasma concentration within 5 hours after oral administration.
Statistical analyses were performed with IBM SPSS Statistics 20.0 (IBM Corp., Armonk, New York). Continuous variables are summarized as mean ± SD and categorical variables as absolute number and percentage. Variables were compared by Student’s t test or paired-samples t test, as appropriate (continuous factors) or by chi-square test (categorical factors). Time to AF conversion was evaluated with Kaplan–Meier analysis. Log-rank test was used to compare cumulative progression curves of conversion of AF to SR in the 2 groups. A multivariable Cox proportional hazards model evaluated the association between treatment group and time to conversion, controlling for potential confounders such as age, left atrial (LA) diameter, left ventricular ejection fraction, presence of hypertension or coronary artery disease, a history of paroxysmal AF, and concurrent use of β blockers or calcium channel blockers. Proportional hazards assumption was evaluated for all variables using graphic tests and Schoenfeld residuals. Findings were considered statistically significant at the 0.05 level.
Results
During the study period, 51 of 153 consecutive patients with AF were enrolled and randomly allocated to group A (n = 26) or group A + R (n = 25). Demographic and baseline clinical characteristics are presented in Table 1 . The 2 groups were well balanced with respect to clinical characteristics, LA diameter, and left ventricular ejection fraction.
| Variable | Group A | Group A + R | p Value |
|---|---|---|---|
| (n = 26) | (n = 25) | ||
| Age (years) | 62 ± 8 | 64 ± 7 | 0.6 |
| Men | 18 (69%) | 15 (60%) | 0.49 |
| Type of atrial fibrillation | |||
| First episode | 9 (35%) | 7 (28%) | 0.61 |
| Previous episodes | 17 (65%) | 18 (72%) | 0.61 |
| Lone atrial fibrillation | 4 (15%) | 5 (20%) | 0.67 |
| Underlying cardiovascular disease ⁎ | 22 (85%) | 20 (80%) | 0.67 |
| Hypertension | 20 (77%) | 17 (68%) | 0.47 |
| Ischemic heart disease | 7 (27%) | 5 (20%) | 0.56 |
| Left atrial diameter (mm) | 4.3 ± 0.5 | 4.5 ± 0.5 | 0.58 |
| Left ventricular ejection fraction (%) | 58 ± 7 | 55 ± 9 | 0.44 |
| Corrected QT interval (ms) | 410 ± 20 | 406 ± 13 | 0.41 |
| Medications | |||
| β Blockers | 16 (61%) | 12 (48%) | 0.33 |
| Calcium channel blockers | 4 (15%) | 6 (24%) | 0.44 |
| Digoxin | 3 (12%) | 4 (16%) | 0.69 |
| Statins | 16 (61%) | 13 (52) | 0.49 |
| Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers | 8 (31%) | 12 (48%) | 0.21 |
⁎ Patients may have had ≥1 condition listed under the cardiovascular disease category.
Conversion of AF to SR within 24 hours was achieved in 39 patients (22 in group A + R, 88%, vs 17 in group A, 65%, p = 0.056). Cumulative conversion progression in the 2 treatment groups is presented in Figure 1 . During 24 hours after randomization, the conversion rate was higher in group A + R compared to group A (p = 0.002, log-rank test). During the 6- to 24-hour interval, i.e., after a 6-hour blanking period, the conversion rate in group A + R versus group A remained significantly higher (p = 0.003, log-rank test; Figure 2 ). Compared to group A, mean time to conversion was shorter in group A + R (14.6 ± 5.3 vs 9.8 ± 4.1 hours, respectively, p = 0.002). Median time to conversion was 18 hours for group A versus 10 hours for group A + R. According to multivariate Cox regression analysis, A + R treatment and LA diameter were independently associated with time to AF conversion (hazard ratio 0.81, 95% confidence interval 0.74 to 0.88, p <0.001; hazard ratio 5.35, 95% confidence interval 2.37 to 12.11, p <0.001, respectively).
QTc interval increased from baseline to 24 hours in the 2 groups (group A: 410 ± 20 to 428 ± 21 ms, p <0.001; group A + R: 406 ± 13 to 426 ± 17 ms, p <0.001). There was no difference in QTc interval at 24 hours (p = 0.66) or in QTc lengthening from baseline to 24 hours between groups A and A + R (17 ± 5 vs 19 ± 6 ms, p = 0.19). In patients who met the primary end point, QTc interval at time of conversion did not differ between groups A and A + R (432 ± 24 vs 429 ± 19 ms, p = 0.44). No patient required amiodarone discontinuation owing to excessive QTc prolongation (prespecified as QTc interval >550 ms).
One patient in group A had an allergic reaction that required permanent discontinuation of amiodarone infusion; the patient had an uneventful recovery. Systolic blood pressure temporarily decreased <90 mm Hg in 6 patients in group A and in 8 patients in group A + R, but all responded well to intravenous administration of fluids with no need for additional treatment. There were no proarrhythmic events throughout the study period in either treatment group.
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