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Amiodarone plus Flecainide combination therapy in patients with Amiodarone refractory paroxysmal atrial fibrillation
4262
Letters to the Editor
Amiodarone plus Flecainide combination therapy in patients with Amiodarone refractory paroxysmal atrial fibrillation Darren R. Kagal ⁎, Eugene Crystal, Ilan Lashevsky, Irving Tiong, Ching Lau, Atilio Costa Vitali, David Newman Sunnybrook Health Sciences Centre, Toronto, ON, Canada University of Toronto, Toronto, ON, Canada
a r t i c l e
i n f o
Article history: Received 9 April 2013 Accepted 13 April 2013 Available online 13 May 2013 Keywords: Atrial fibrillation Antiarrhythmic therapy Rhythm control Amiodarone Flecainide
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 combination was 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%
⁎ Corresponding author at: Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada. Tel.: +1 416 398 2220; fax: +1 647 776 7730. E-mail address: [email protected] (D.R. Kagal).
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, and one patient had a history of rate-related non-dilated cardiomyopathy. The average body surface area corrected left atrial volume index was 38 +/− 11 mL/m2. Nine patients (33%), received their combination therapy after a PVI. Eight patients (30%) had a history of cavotricuspid isthmus ablation for atrial flutter. Sixteen patients (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.
Table 1 Baseline demographics. Mean Baseline demographics Age Male Female Hypertension Diabetes Sleep apnea Prior PVI A flutter ablation AF related hospitalization
65 +/− 10 years 23 (85%) 4 (15%) 17 (63%) 4 (17%) 3 (11%) 9 (33%) 8 (30%) 9 (33%)
Echocardiographic findings Normal EF Grade 2 LV (tachycardia-mediated) Grade 3–4 LV Left ventricular hypertrophy Significant LA dilatation (LA volume index N 40 mL/m2)
25 (93%) 2 (7%) 0 5 (19%) 10 (37%)
Medications Beta blockers Calcium channel blockers Digoxin
16 (59%) 1 (4%) 2 (7%)
Letters to the Editor
4263
1 Upper 95% CI
0.9 0.8 0.7
% Success 0.6 0.5 0.4 Lower 95% CI
0.3 0.2 N:
0 27
6 20
12 16
18 13
24 11
30
Duration of follow-up (months) Fig. 1. Kaplan–Meier curve of efficacy of drug combination over time. Kaplan–Meier curve and 95% confidence intervals of the combination of Flecainide and Amiodarone in PAF patients who had not been refractory to Amiodarone alone. N represents the number of patients improving with combination Amiodarone and Flecainide throughout the follow up period. Success is defined as an aggregate of patient and physician satisfaction with the combination. Patients were censured when the drug combination was stopped for toxicity, inefficacy or post pulmonary venous isolation (PVI). See text for further discussion.
The combination of Amiodarone and Flecainide was relatively safe. There were no deaths or arrhythmia induced syncope reported. Overall, 37% of patients had to discontinue their medications due to adverse effects. Although the rate of adverse events was not trivial, the indication for combination therapy was not to avoid adverse effects of Amiodarone. There is only one case series that was published that included patients with this combination of antiarrhythmic therapy for the goal of pharmaco-conversion. Igrashi et al observed 51 patients with persistent AF awaiting PVI, and treated them with combination of Amiodarone and Flecainide. Sixty-five percent of patients spontaneously reverted to normal sinus rhythm [1]. This study, with a goal of pharmaconversion,
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.154
differed from our study population, as it included patients with persistent atrial fibrillation. However, it did demonstrate an overall acceptable and similar safety profile. In a highly selected PAF cohort, the combination of Amiodarone and Flecainide may prove beneficial. This novel observation warrants further study.
Reference [1] Igarashi M, Tada H, Segikuchi H, et al. Effect of restoration of sinus rhythm by extensive antiarrhythmic drugs in predicting results of catheter ablation of persistent atrial fibrillation. Am J Cardiol 2010;106:62–8.
Letters to the Editor
Amiodarone plus Flecainide combination therapy in patients with Amiodarone refractory paroxysmal atrial fibrillation Darren R. Kagal ⁎, Eugene Crystal, Ilan Lashevsky, Irving Tiong, Ching Lau, Atilio Costa Vitali, David Newman Sunnybrook Health Sciences Centre, Toronto, ON, Canada University of Toronto, Toronto, ON, Canada
a r t i c l e
i n f o
Article history: Received 9 April 2013 Accepted 13 April 2013 Available online 13 May 2013 Keywords: Atrial fibrillation Antiarrhythmic therapy Rhythm control Amiodarone Flecainide
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 combination was 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%
⁎ Corresponding author at: Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, Ontario M4N 3M5, Canada. Tel.: +1 416 398 2220; fax: +1 647 776 7730. E-mail address: [email protected] (D.R. Kagal).
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, and one patient had a history of rate-related non-dilated cardiomyopathy. The average body surface area corrected left atrial volume index was 38 +/− 11 mL/m2. Nine patients (33%), received their combination therapy after a PVI. Eight patients (30%) had a history of cavotricuspid isthmus ablation for atrial flutter. Sixteen patients (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.
Table 1 Baseline demographics. Mean Baseline demographics Age Male Female Hypertension Diabetes Sleep apnea Prior PVI A flutter ablation AF related hospitalization
65 +/− 10 years 23 (85%) 4 (15%) 17 (63%) 4 (17%) 3 (11%) 9 (33%) 8 (30%) 9 (33%)
Echocardiographic findings Normal EF Grade 2 LV (tachycardia-mediated) Grade 3–4 LV Left ventricular hypertrophy Significant LA dilatation (LA volume index N 40 mL/m2)
25 (93%) 2 (7%) 0 5 (19%) 10 (37%)
Medications Beta blockers Calcium channel blockers Digoxin
16 (59%) 1 (4%) 2 (7%)
Letters to the Editor
4263
1 Upper 95% CI
0.9 0.8 0.7
% Success 0.6 0.5 0.4 Lower 95% CI
0.3 0.2 N:
0 27
6 20
12 16
18 13
24 11
30
Duration of follow-up (months) Fig. 1. Kaplan–Meier curve of efficacy of drug combination over time. Kaplan–Meier curve and 95% confidence intervals of the combination of Flecainide and Amiodarone in PAF patients who had not been refractory to Amiodarone alone. N represents the number of patients improving with combination Amiodarone and Flecainide throughout the follow up period. Success is defined as an aggregate of patient and physician satisfaction with the combination. Patients were censured when the drug combination was stopped for toxicity, inefficacy or post pulmonary venous isolation (PVI). See text for further discussion.
The combination of Amiodarone and Flecainide was relatively safe. There were no deaths or arrhythmia induced syncope reported. Overall, 37% of patients had to discontinue their medications due to adverse effects. Although the rate of adverse events was not trivial, the indication for combination therapy was not to avoid adverse effects of Amiodarone. There is only one case series that was published that included patients with this combination of antiarrhythmic therapy for the goal of pharmaco-conversion. Igrashi et al observed 51 patients with persistent AF awaiting PVI, and treated them with combination of Amiodarone and Flecainide. Sixty-five percent of patients spontaneously reverted to normal sinus rhythm [1]. This study, with a goal of pharmaconversion,
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.04.154
differed from our study population, as it included patients with persistent atrial fibrillation. However, it did demonstrate an overall acceptable and similar safety profile. In a highly selected PAF cohort, the combination of Amiodarone and Flecainide may prove beneficial. This novel observation warrants further study.
Reference [1] Igarashi M, Tada H, Segikuchi H, et al. Effect of restoration of sinus rhythm by extensive antiarrhythmic drugs in predicting results of catheter ablation of persistent atrial fibrillation. Am J Cardiol 2010;106:62–8.