- Email: [email protected]
Antiarrhythmic drug treatment after cardioversion of atrial fibrillation
Correspondence
Paulus Kirchhof and colleagues (July 21, p 238)1 present the results of the Flec-SL study in which shortterm (4-week) antiarrhythmic drug treatment with flecainide after cardioversion was less effective than was long-term (6-month) treatment for recurrent atrial fibrillation (AF). First, Kirchhof and colleagues state that, although not non-inferior, shortterm treatment with flecainide had about 80% of the 6-month effect of long-term treatment and thereby prevented most AF recurrences. Indeed, several studies have shown that most recurrences of AF occur within 1 month after cardioversion,2 which accounts for this important short-term effect. Second, only 2·1% of the study population received verapamil. We are disappointed that concomitant use of verapamil was not required in this study, because a combination of flecainide and verapamil has been shown to significantly reduce AF recurrences compared with flecainide alone.3 We therefore believe that patients did not receive optimum treatment in this study. Moreover, combination therapy with upstream therapy such as angiotensin-receptor blockers or angiotensin-convertingenzyme inhibitors might have further improved effectiveness of rhythm control by flecainide.4 Kirchhof and colleagues mention that upstream treatment did not affect AF recurrence, but the study design was not suitable to investigate this issue. Third, on the basis of the short-term effectiveness of flecainide, Kirchhof and colleagues advocate that repeated cardioversions during short-term antiarrhythmic drug treatment could be useful in patients with infrequent AF recurrences. However, compared with continuous antiarrhythmic drug treatment, episodic treatment with www.thelancet.com Vol 380 October 27, 2012
antiarrhythmic drugs might actually lead to more adverse events.5 We declare that we have no conflicts of interest.
Marcelle D Smit, Marjolein L Moes, *Isabelle C Van Gelder [email protected] Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, Netherlands 1
2
3
4
5
Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet 2012; 380: 238–46. Tieleman RG, Van Gelder IC, Crijns HJ, et al. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillationinduced electrical remodeling of the atria? J Am Coll Cardiol 1998; 31: 167–73. De Simone A, De Pasquale M, De Matteis C, et al. Verapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24: 1425–29. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002; 106: 331–36. Ahmed S, Rienstra M, Crijns HJ, et al. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation: a randomized trial. JAMA 2008; 300: 1784–92.
We wish to congratulate the authors of the Flec-SL trial1 on this excellent work which will have a substantial effect on practice. The Flec-SL trial shows that flecainide seems to be safe in the management of atrial fibrillation (AF). This finding contrasts with that seen in patients with ventricular ectopy after myocardial infarction in the Cardiac Arrhythmia Suppression Trial.2 Also, in an observational cohort study,3 an increased incidence of sudden cardiac death or proarrhythmic events was found in patients with AF who started flecainide treatment. The safety of flecainide therefore remains an important issue. Flecainide is metabolised via the polymorphic CYP2D6 enzyme, and CYP2D6 genotype, sex, and age (possibly owing to age-dependent decline of renal function and of metabolic shift from CYP2D6 to CYP1A24) are suggested to be risk
factors for concentration-dependent adverse effects. In Japanese patients with supraventricular tachyarrhythmia, flecainide pharmacokinetics differed between CYP2D6 genotypes,5 and drug interactions between flecainide and CYP2D6 inhibitors have been reported. Thus, it would be interesting to know whether in Flec-SL patients who had adverse events there was any link to unusual flecainide concentrations in serum or the above risk factors (eg, CYP2D6 genotype, CYP2D6-inhibiting comedication, and renal impairment).
Science Photo Library
Antiarrhythmic drug treatment after cardioversion of atrial fibrillation
We declare that we have no conflicts of interest.
*Matthias Schwab, Klaus Moerike [email protected] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany (MS); and Department of Clinical Pharmacology, University Hospital Tiibingen, Tiibingen, Germany (KM, MS) 1
2
3
4
5
Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet 2012; 380: 238–46. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781–88. Almroth H, Andersson T, Fengsrud E, et al. The safety of flecainide treatment of atrial fibrillation: long-term incidence of sudden cardiac death and proarrhythmic events. J Intern Med 2011; 270: 281–90. Doki K, Homma M, Kuga K, Aonuma K, Kohda Y. Effects of CYP2D6 genotypes on agerelated change of flecainide metabolism: involvement of CYP1A2-mediated metabolism. Br J Clin Pharmacol 2009; 68: 89–96. Doki K, Homma M, Kuga K, et al. Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol 2006; 62: 919–26.
Paulus Kirchhof and colleagues1 have done a thorough job of assessing the short-term and long-term use of flecainide after cardioversion. However, a few interesting points arise from the analysis which we feel might be pertinent. The presence of chronic obstructive pulmonary disease (COPD) is an important predictor of maintenance of normal sinus rhythm after cardioversion.2 It would be interesting to know whether Kirchhof and
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1467
Correspondence
colleagues have made an attempt to assess the prevalence of COPD and its correlation with clinical outcomes in various subgroups. Furthermore, because women are reported to have an increased risk of recurrence after cardioversion,3 did Kirchhof and colleagues make an attempt to study the benefits of antiarrhythmic therapy with flecainide in women and compare them with those in men? Kirchhof and colleagues speculate that focal firing from the pulmonary veins could be one of the possible explanations for the noted clinical benefits of flecainide. It would be interesting to know whether catheter ablation was attempted in patients for whom antiarrhythmic therapy failed and whether focal firing or other electrophysiological mechanisms were noted in these patients. We declare that we have no conflicts of interest.
Ajay Vallakati, *Abhishek Sharma, Dhanunjaya Lakkireddy [email protected] KU Cardiovascular Research Institute, University of Kansas Hospital & Medical Center, KS, USA (AV, DL); and Maimonides Medical Center, Brooklyn, NY 11219, USA (AS) 1
2
3
Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet 2012; 380: 238–46. Gurevitz OT, Varadachari CJ, Ammash NM, et al. The effect of patient sex on recurrence of atrial fibrillation following successful direct current cardioversion. Am Heart J 2006; 152: e9–13. Okçün B, Yigit Z, Küçükoglu MS, et al. Predictors for maintenance of sinus rhythm after cardioversion in patients with nonvalvular atrial fibrillation. Echocardiography 2002; 19: 351–57.
Authors’ reply We appreciate the thoughtful comments of the correspondents, and would like to briefly provide our view on the different topics. Although verapamil or β blockers might have a true antiarrhythmic effect after cardioversion, the data are ambiguous. Furthermore, pathophysiological insights suggest that mere inhibition of the L-type calcium channel is unlikely 1468
to prevent atrial fibrillation (AF).1 In addition to the studies mentioned, the PAFAC trial2 compared a combination of verapamil and quinidine with d,lsotalol, which combines β blockade and potassium channel inhibition, for prevention of AF after cardioversion. There was no difference in effectiveness, but the verapamil-quinidine combination caused numerically less drug-induced proarrhythmia. Consequently, β blockers and verapamil are recommended for rate control rather than for rhythm control. The patients in the Flec-SL trial received adequate rate control therapy (see original table 1), following current and previous AF guidelines.3 Treatment with angiotensinconverting-enzyme inhibitors or sartans, which were given to about half the Flec-SL trial population, is largely ineffective in preventing recurrent AF in patients without structural heart disease.4 Hence, we would be hesitant to conclude that continued upstream treatment would be clinically mandated in the Flec-SL patient population for whom structural heart disease was rare. In the Flec-SL trial, short-term antiarrhythmic drug therapy was not associated with adverse events, and we designed the trial with a view to reducing complications of antiarrhythmic drug therapy. One previous study,5 referred to in the discussion of our paper, reported that episodic treatment with amiodarone increased treatment-related complications compared with long-term amiodarone treatment. Amiodarone, a multichannel blocker with additional rate-controlling effects, has a biological half-life of several months, rendering it unsuitable for episodic or short-term treatment. The available data hence suggest that short-term antiarrhythmic drug therapy would be a valuable treatment option when agents with a suitable pharmacological profile are used. According to the p values of the adequate interaction tests, female
sex did not affect the outcome of the Flec-SL trial, nor did the presence of chronic obstructive pulmonary disease (COPD). Severe COPD was relatively rare in the population studied in FlecSL (4·6%), hence the study does not provide substantial new information on the question of whether COPD affects recurrence of atrial fibrillation. There were only eight catheter ablations done during the study period and their presence did not alter the treatment effect. Unfortunately, we do not have access to CYP2D6 variant data in this population. We declare that we have no conflicts of interest.
*Paulus Kirchhof, Günter Breithardt, Andras Treszl, Karl Wegscheider [email protected] University of Birmingham, Institute for Biomedical Research, Birmingham B15 2TT, UK (PK); Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany (PK, GB); and Department of Medical Biometry and Epidemiology, University of Hamburg, Hamburg, Germany (AT, KW) 1
2
3
4
5
Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011; 91: 265–325. Fetsch T, Bauer P, Engberding R, et al. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 2004; 25: 1385–94. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14: 1385–413. Disertori M, Latini R, Barlera S, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360: 1606–17. Ahmed S, Rienstra M, Crijns HJ, et al. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation: a randomized trial. JAMA 2008; 300: 1784–92.
Reconstructive surgery after female genital mutilation The paper by Pierre Foldès and colleagues (July 14, p 134)1 finds that reconstructive surgery after female genital mutilation seems to be associated with reduced pain and www.thelancet.com Vol 380 October 27, 2012
Paulus Kirchhof and colleagues (July 21, p 238)1 present the results of the Flec-SL study in which shortterm (4-week) antiarrhythmic drug treatment with flecainide after cardioversion was less effective than was long-term (6-month) treatment for recurrent atrial fibrillation (AF). First, Kirchhof and colleagues state that, although not non-inferior, shortterm treatment with flecainide had about 80% of the 6-month effect of long-term treatment and thereby prevented most AF recurrences. Indeed, several studies have shown that most recurrences of AF occur within 1 month after cardioversion,2 which accounts for this important short-term effect. Second, only 2·1% of the study population received verapamil. We are disappointed that concomitant use of verapamil was not required in this study, because a combination of flecainide and verapamil has been shown to significantly reduce AF recurrences compared with flecainide alone.3 We therefore believe that patients did not receive optimum treatment in this study. Moreover, combination therapy with upstream therapy such as angiotensin-receptor blockers or angiotensin-convertingenzyme inhibitors might have further improved effectiveness of rhythm control by flecainide.4 Kirchhof and colleagues mention that upstream treatment did not affect AF recurrence, but the study design was not suitable to investigate this issue. Third, on the basis of the short-term effectiveness of flecainide, Kirchhof and colleagues advocate that repeated cardioversions during short-term antiarrhythmic drug treatment could be useful in patients with infrequent AF recurrences. However, compared with continuous antiarrhythmic drug treatment, episodic treatment with www.thelancet.com Vol 380 October 27, 2012
antiarrhythmic drugs might actually lead to more adverse events.5 We declare that we have no conflicts of interest.
Marcelle D Smit, Marjolein L Moes, *Isabelle C Van Gelder [email protected] Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, Netherlands 1
2
3
4
5
Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet 2012; 380: 238–46. Tieleman RG, Van Gelder IC, Crijns HJ, et al. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillationinduced electrical remodeling of the atria? J Am Coll Cardiol 1998; 31: 167–73. De Simone A, De Pasquale M, De Matteis C, et al. Verapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24: 1425–29. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002; 106: 331–36. Ahmed S, Rienstra M, Crijns HJ, et al. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation: a randomized trial. JAMA 2008; 300: 1784–92.
We wish to congratulate the authors of the Flec-SL trial1 on this excellent work which will have a substantial effect on practice. The Flec-SL trial shows that flecainide seems to be safe in the management of atrial fibrillation (AF). This finding contrasts with that seen in patients with ventricular ectopy after myocardial infarction in the Cardiac Arrhythmia Suppression Trial.2 Also, in an observational cohort study,3 an increased incidence of sudden cardiac death or proarrhythmic events was found in patients with AF who started flecainide treatment. The safety of flecainide therefore remains an important issue. Flecainide is metabolised via the polymorphic CYP2D6 enzyme, and CYP2D6 genotype, sex, and age (possibly owing to age-dependent decline of renal function and of metabolic shift from CYP2D6 to CYP1A24) are suggested to be risk
factors for concentration-dependent adverse effects. In Japanese patients with supraventricular tachyarrhythmia, flecainide pharmacokinetics differed between CYP2D6 genotypes,5 and drug interactions between flecainide and CYP2D6 inhibitors have been reported. Thus, it would be interesting to know whether in Flec-SL patients who had adverse events there was any link to unusual flecainide concentrations in serum or the above risk factors (eg, CYP2D6 genotype, CYP2D6-inhibiting comedication, and renal impairment).
Science Photo Library
Antiarrhythmic drug treatment after cardioversion of atrial fibrillation
We declare that we have no conflicts of interest.
*Matthias Schwab, Klaus Moerike [email protected] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany (MS); and Department of Clinical Pharmacology, University Hospital Tiibingen, Tiibingen, Germany (KM, MS) 1
2
3
4
5
Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet 2012; 380: 238–46. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781–88. Almroth H, Andersson T, Fengsrud E, et al. The safety of flecainide treatment of atrial fibrillation: long-term incidence of sudden cardiac death and proarrhythmic events. J Intern Med 2011; 270: 281–90. Doki K, Homma M, Kuga K, Aonuma K, Kohda Y. Effects of CYP2D6 genotypes on agerelated change of flecainide metabolism: involvement of CYP1A2-mediated metabolism. Br J Clin Pharmacol 2009; 68: 89–96. Doki K, Homma M, Kuga K, et al. Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol 2006; 62: 919–26.
Paulus Kirchhof and colleagues1 have done a thorough job of assessing the short-term and long-term use of flecainide after cardioversion. However, a few interesting points arise from the analysis which we feel might be pertinent. The presence of chronic obstructive pulmonary disease (COPD) is an important predictor of maintenance of normal sinus rhythm after cardioversion.2 It would be interesting to know whether Kirchhof and
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1467
Correspondence
colleagues have made an attempt to assess the prevalence of COPD and its correlation with clinical outcomes in various subgroups. Furthermore, because women are reported to have an increased risk of recurrence after cardioversion,3 did Kirchhof and colleagues make an attempt to study the benefits of antiarrhythmic therapy with flecainide in women and compare them with those in men? Kirchhof and colleagues speculate that focal firing from the pulmonary veins could be one of the possible explanations for the noted clinical benefits of flecainide. It would be interesting to know whether catheter ablation was attempted in patients for whom antiarrhythmic therapy failed and whether focal firing or other electrophysiological mechanisms were noted in these patients. We declare that we have no conflicts of interest.
Ajay Vallakati, *Abhishek Sharma, Dhanunjaya Lakkireddy [email protected] KU Cardiovascular Research Institute, University of Kansas Hospital & Medical Center, KS, USA (AV, DL); and Maimonides Medical Center, Brooklyn, NY 11219, USA (AS) 1
2
3
Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet 2012; 380: 238–46. Gurevitz OT, Varadachari CJ, Ammash NM, et al. The effect of patient sex on recurrence of atrial fibrillation following successful direct current cardioversion. Am Heart J 2006; 152: e9–13. Okçün B, Yigit Z, Küçükoglu MS, et al. Predictors for maintenance of sinus rhythm after cardioversion in patients with nonvalvular atrial fibrillation. Echocardiography 2002; 19: 351–57.
Authors’ reply We appreciate the thoughtful comments of the correspondents, and would like to briefly provide our view on the different topics. Although verapamil or β blockers might have a true antiarrhythmic effect after cardioversion, the data are ambiguous. Furthermore, pathophysiological insights suggest that mere inhibition of the L-type calcium channel is unlikely 1468
to prevent atrial fibrillation (AF).1 In addition to the studies mentioned, the PAFAC trial2 compared a combination of verapamil and quinidine with d,lsotalol, which combines β blockade and potassium channel inhibition, for prevention of AF after cardioversion. There was no difference in effectiveness, but the verapamil-quinidine combination caused numerically less drug-induced proarrhythmia. Consequently, β blockers and verapamil are recommended for rate control rather than for rhythm control. The patients in the Flec-SL trial received adequate rate control therapy (see original table 1), following current and previous AF guidelines.3 Treatment with angiotensinconverting-enzyme inhibitors or sartans, which were given to about half the Flec-SL trial population, is largely ineffective in preventing recurrent AF in patients without structural heart disease.4 Hence, we would be hesitant to conclude that continued upstream treatment would be clinically mandated in the Flec-SL patient population for whom structural heart disease was rare. In the Flec-SL trial, short-term antiarrhythmic drug therapy was not associated with adverse events, and we designed the trial with a view to reducing complications of antiarrhythmic drug therapy. One previous study,5 referred to in the discussion of our paper, reported that episodic treatment with amiodarone increased treatment-related complications compared with long-term amiodarone treatment. Amiodarone, a multichannel blocker with additional rate-controlling effects, has a biological half-life of several months, rendering it unsuitable for episodic or short-term treatment. The available data hence suggest that short-term antiarrhythmic drug therapy would be a valuable treatment option when agents with a suitable pharmacological profile are used. According to the p values of the adequate interaction tests, female
sex did not affect the outcome of the Flec-SL trial, nor did the presence of chronic obstructive pulmonary disease (COPD). Severe COPD was relatively rare in the population studied in FlecSL (4·6%), hence the study does not provide substantial new information on the question of whether COPD affects recurrence of atrial fibrillation. There were only eight catheter ablations done during the study period and their presence did not alter the treatment effect. Unfortunately, we do not have access to CYP2D6 variant data in this population. We declare that we have no conflicts of interest.
*Paulus Kirchhof, Günter Breithardt, Andras Treszl, Karl Wegscheider [email protected] University of Birmingham, Institute for Biomedical Research, Birmingham B15 2TT, UK (PK); Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany (PK, GB); and Department of Medical Biometry and Epidemiology, University of Hamburg, Hamburg, Germany (AT, KW) 1
2
3
4
5
Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev 2011; 91: 265–325. Fetsch T, Bauer P, Engberding R, et al. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 2004; 25: 1385–94. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14: 1385–413. Disertori M, Latini R, Barlera S, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360: 1606–17. Ahmed S, Rienstra M, Crijns HJ, et al. Continuous vs episodic prophylactic treatment with amiodarone for the prevention of atrial fibrillation: a randomized trial. JAMA 2008; 300: 1784–92.
Reconstructive surgery after female genital mutilation The paper by Pierre Foldès and colleagues (July 14, p 134)1 finds that reconstructive surgery after female genital mutilation seems to be associated with reduced pain and www.thelancet.com Vol 380 October 27, 2012