Amiodarone plus Flecainide combination therapy in patients with Amiodarone refractory paroxysmal atrial fibrillation

Abstract

Anti-arrhythmic drug therapy is often prescribed for patients with symptomatic recurrent paroxysmal atrial fibrillation (PAF). Current recommendations advocate therapy for a rhythm control strategy to be based on patient preference. Antiarrhythmic drug therapy for this goal may be used as sole therapy or as an adjunct before or after ablation procedure(s). We hypothesized that combining Flecainide, a Class Ic antiarrhythmic, to Amiodarone therapy may be tolerated, safe and improve symptoms in selected patients who desire a rhythm control effort despite established inefficacy of Amiodarone. Patients in a community based arrhythmia clinic were prospectively screened and included in this study. Consecutive patients were enrolled from January 2002 to December 2010. Biochemically and clinically euthyroid patients on Amiodarone with recurrent symptomatic documented PAF were identified. Eligible patients had to have demonstrated failed monotherapy with any anti-arrhythmic agent, including Amiodarone for at least four months of stable dosing with Amiodarone. Patients required no or minimal coronary disease, no significant left ventricular dysfunction in sinus rhythm, and no metabolic cause for recurrence. Patients were closely followed every 3–6 months with an echocardiogram, Holter monitor, and exercise stress echo. Indications for starting combination of Amiodarone and Flecainide were patients' pending pulmonary venous isolation ablation, patients' post pulmonary venous isolation with recurrent symptoms, or patients with refractory PAF despite being on other antiarrhythmic medications. All patients were on Amiodarone for variable periods of time prior to addition of Flecainide. Flecainide was started at 25 mg twice a day, and titrated up to 50 mg bid if tolerated. Serial ECG and QTc intervals were assessed. The primary outcome was an aggregate of overall physician and patient perceived satisfaction with clinically improved rhythm control compared to pre-combination therapy. Patients were censured from follow up if the drug combinationwas stopped for reasons of: inefficacy, toxicity, or after a three month blanking period post pulmonary vein isolation (PVI). In total, 27 patients were enrolled into the study. The average age was 65 +/− 10 years old. Eighty-two percent of patients were male. Fifteen percent had a history of diabetes, 63% had hypertension, 44% had dyslipidemia, and 11% had a history of coronary artery disease. Other baseline demographics can be found in Table 1. Twenty four patients had normal LV ejection fraction. Three patients (11%) had mild LV dysfunction (grade 2 LV) and five (19%) had left ventricular hypertrophy. One patient had hypertrophic non-obstructive cardiomyopathy, andonepatienthadahistoryof rate-relatednon-dilated cardiomyopathy. The average body surface area corrected left atrial volume index was 38 +/− 11 mL/m. Nine patients (33%), received their combination therapy after a PVI. Eight patients (30%) had a history of cavotricuspid isthmus ablation for atrial flutter. Sixteenpatients (59%)were on beta blockers. Two patients were on Digoxin and one patient was on a calcium channel blocker. Nineteen (70%) patients were on angiotensin converting enzyme inhibitors or angiotensin receptor blockers. The average dosage of Amiodarone was 179 +/− 50 mg/day. The average daily dose of Flecainide was 122 +/− 65 mg/day. Eighteen of the patients (67%) had symptomatic improvement with combination therapy. Approximately, 75% of patients had symptomatic improvement by one year. Sixty percent of patients had symptomatic improvement at two years. The average duration of combination therapy follow up was 17 +/− 15 months. Of the patients who had symptomatic improvement, two patients discontinued Amiodarone due to significant liver enzyme rise. One patient discontinued combination due to ventricular tachycardia originating from the aortic cusp, requiring catheter ablation. Two patients required a permanent pacemaker implantation due to significant bradycardia. One patient discontinued Amiodarone due to corneal irritation. Another patient discontinued Amiodarone due to extrapyramidal side effects. One patient discontinued therapy due to drug-induced hypothyroidism. Fig. 1 demonstrates the Kaplan–Meier curve of efficacy of drug combination over time.