- Email: [email protected]
Beta-blockers in the treatment of catecholaminergic polymorphic ventricular tachycardia
EDITORIAL COMMENTARY
Beta-blockers in the treatment of catecholaminergic polymorphic ventricular tachycardia Christian van der Werf, MD, PhD, Krystien V. Lieve, MD From the AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary inherited arrhythmia syndrome with bidirectional or polymorphic ventricular arrhythmias and associated symptoms under conditions of increased sympathetic activity as its signature feature.1 Ever since CPVT was first described, the typical circumstances of exercise of emotion during occurrence of symptoms2,3 and the efficacy of beta-blocker therapy have been recognized.4 Today, beta-blockers are the mainstay of therapy for patients with clinical manifestations of CPVT.5 However, arrhythmic event rates in these patients on beta-blocker therapy are substantial,6,7 which underscores the importance of effective second-line therapeutic options such as flecainide8 and left cardiac sympathetic denervation.9 Betablockers probably also are protective in carriers of a familial CPVT-causing mutation with no signs of CPVT (concealed mutation carriers),10 although the natural history of these individuals and the efficacy of beta-blockers on their prognosis have not been studied. Multiple factors affect an eventual favorable response to beta-blockers. The most important factors are nonadherence and the type and dosage of beta-blocker. For example, in a recently published large cohort of 226 children with CPVT, 82 arrhythmic events occurred in children on beta-blocker monotherapy or a beta-blocker combined with a calcium channel blocker or flecainide.6 Poor adherence contributed to 48% of these events. In addition to the general major public health problem of medication nonadherence, the adverse effects of beta-blocker therapy in children or young adults with CPVT often have a significantly impact on patient quality of life and reinforce nonadherence or require dose adjustment or beta-blocker discontinuation. In our patient population of CPVT patients who were identified through cascade screening, significant adverse effects were reported in 29%.10 Adverse events led to discontinuation of initial
Address reprint requests and correspondence: Dr. Christian van der Werf, AMC Heart Center, Department of Cardiology, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
therapy with beta-blockers in 8% of patients in the aforementioned pediatric cohort.6 With regard to the type of beta-blocker, the well-known differences in the pharmacodynamics and pharmacokinetics of the various beta-blockers (including their β1 selectivity, half-life, and lipophilicity) are obviously relevant. In addition, the sodium channel and cardiac ryanodine receptor channel–inhibiting properties reported for propranolol11 and carvedilol,12 respectively, could theoretically contribute further to the antiarrhythmic efficacy of these beta-blockers in treatment of CPVT. Prospective studies comparing the efficacy of different beta-blockers in patients with CPVT have not been performed. Although a prospective study on the short-term efficacy (assessed by the exercise-induced ventricular arrhythmia burden) of different beta-blockers seems feasible, a prospective (preferably randomized) comparison of their efficacy in preventing arrhythmic events in the long term is a undertaking that probably will never be performed. Therefore, this important and clinically relevant information must be derived from retrospective analyses in available cohorts. In this issue of HeartRhythm, Leren et al13 compared the ventricular arrhythmia burden during exercise testing in 34 CPVT patients treated with the nonselective beta-blocker nadolol and β1-selective (cardioselective) beta-blockers, mostly metoprolol SR. After 2009, when data on possible lower arrhythmic event rates with nadolol in patients with CPVT were published,14 the authors cleverly took advantage of a local policy that prevented the immediate initiation of nadolol to test the ventricular arrhythmia burden in patients while undergoing treatment with a β1-selective beta-blocker. Overall, nadolol was associated with a significant reduction of the ventricular arrhythmia burden compared to β1-selective beta-blockers and no therapy. For example, significant ventricular arrhythmias (ie, 410 ventricular extrasystoles) or more complex ventricular arrhythmias were absent in 59% of patients on nadolol, 7% of patients on a β1-selective beta-blocker, and 12% of untreated patients. Compared with β1-selective beta-blockers, nadolol was associated with a lower maximal heart rate, thereby reducing the ventricular arrhythmic window (ie, range of heart rate http://dx.doi.org/10.1016/j.hrthm.2015.10.027
2 during which ventricular arrhythmias occur). Holter recordings also showed less severe ventricular arrhythmias in patients treated with nadolol compared with β1-selective beta-blockers and untreated patients, whereas the incidence of ventricular extrasystoles was similar. The numbers of patients and arrhythmic events were too small to draw any meaningful conclusions on this end-point. The authors also performed several interesting subanalyses, but the following observations were based on a very small number of patients. First, in patients who received equivalent dosages of nadolol and metoprolol SR, nadolol was associated with a lower maximal heart rate and less severe ventricular arrhythmias. Second, nadolol was associated with less severe ventricular arrhythmias in patients who reached a similar maximal heart rate on nadolol and β1selective beta-blockers. This finding suggests that the stronger negative chronotropic effect of nadolol as well as other (unknown) mechanisms play a role in the associated reduced ventricular arrhythmia burden. Although these observations certainly are relevant, it must be recognized that the efficacy was assessed by analyzing only 1 exercise test per patient per medication. The ventricular arrhythmia burden on exercise testing in patients with CPVT may show intraindividual variations despite unchanged therapy8 and is not perfectly predictive of arrhythmic events,14 although it is frequently used to guide therapy in clinical practice in the absence of better predictors. The moderate predictive value was also visible in this study in which β1-selective beta-blockers did not significantly change the ventricular arrhythmia burden compared with no therapy. This unexpected finding is not in agreement with previous experiences,14 including our own in the Netherlands (where nadolol is not available)10 and current recommendations to treat CPVT patients with any kind of betablocker,5 although the use of nonselective beta-blockers is advised. The results of this study are in accordance with the important 2009 study by Hayashi et al14 on risk factors for arrhythmic events in CPVT and the efficacy of beta-blockers. In their series, the use of (unspecified) beta-blockers other than nadolol was an independent predictor for arrhythmia events. In contrast, in the large pediatric series by Roston et al,6 the type of beta-blocker did not influence the likelihood of arrhythmic events. In conclusion, there is mounting evidence that nadolol is more effective in CPVT than other, particularly β1-selective, beta-blockers. This may be explained at least in part by the
Heart Rhythm, Vol 0, No 0, Month 2015 typically required once-daily dosing, which may result in improved adherence and an increased negative chronotropic effect. The study by Leren et al further supports current recommendations to consider nadolol a first-choice betablocker for treatment of CPVT. Data on the second-best choice beta-blocker are lacking because other unselective beta-blockers such as propranolol and carvedilol have not been compared to other beta-blockers in CPVT. Hence, use of a low threshold for adding flecainide in patients with persistent symptoms or significant ventricular arrhythmias is still highly recommended.
References 1. Van der Werf C, Wilde AAM. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart 2013;99:497–504. 2. Horan M, Venables AW. Paroxysmal tachycardia with episodic unconsciousness. Arch Dis Child 1962;37:82–85. 3. Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using His bundle electrography. Br Heart J 1975;37:339–344. 4. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512–1519. 5. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:1932–1963. 6. Roston TM, Vinocur JM, Maginot KR, et al. Catecholaminergic polymorphic ventricular tachycardia in children: an analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 2015;8:633–642. 7. Van der Werf C, Zwinderman AH, Wilde AAM. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14:175–183. 8. Van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244–2254. 9. De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation 2015;131:2185–2193. 10. Van der Werf C, Nederend I, Hofman N, et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol 2012;5:748–756. 11. Bankston JR, Kass RS. Molecular determinants of local anesthetic action of betablocking drugs: implications for therapeutic management of long QT syndrome variant 3. J Mol Cell Cardiol 2010;48:246–253. 12. Zhou Q, Xiao J, Jiang D, Wang R, et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2þ release. Nat Med 2011;17: 1003–1009. 13. Leren IS, Saberniak J, Majid E, Haland TF, Edvardsen T, Haugaa KH. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia Heart Rhythm 2015. Epub ahead of print. 14. Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff J-M, Klug D, Hayashi M, Takatsuki S, Villain E, Kamblock J, Messali A, Guicheney P, Lunardi J, Leenhardt A. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119: 2426–2434.
Beta-blockers in the treatment of catecholaminergic polymorphic ventricular tachycardia Christian van der Werf, MD, PhD, Krystien V. Lieve, MD From the AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary inherited arrhythmia syndrome with bidirectional or polymorphic ventricular arrhythmias and associated symptoms under conditions of increased sympathetic activity as its signature feature.1 Ever since CPVT was first described, the typical circumstances of exercise of emotion during occurrence of symptoms2,3 and the efficacy of beta-blocker therapy have been recognized.4 Today, beta-blockers are the mainstay of therapy for patients with clinical manifestations of CPVT.5 However, arrhythmic event rates in these patients on beta-blocker therapy are substantial,6,7 which underscores the importance of effective second-line therapeutic options such as flecainide8 and left cardiac sympathetic denervation.9 Betablockers probably also are protective in carriers of a familial CPVT-causing mutation with no signs of CPVT (concealed mutation carriers),10 although the natural history of these individuals and the efficacy of beta-blockers on their prognosis have not been studied. Multiple factors affect an eventual favorable response to beta-blockers. The most important factors are nonadherence and the type and dosage of beta-blocker. For example, in a recently published large cohort of 226 children with CPVT, 82 arrhythmic events occurred in children on beta-blocker monotherapy or a beta-blocker combined with a calcium channel blocker or flecainide.6 Poor adherence contributed to 48% of these events. In addition to the general major public health problem of medication nonadherence, the adverse effects of beta-blocker therapy in children or young adults with CPVT often have a significantly impact on patient quality of life and reinforce nonadherence or require dose adjustment or beta-blocker discontinuation. In our patient population of CPVT patients who were identified through cascade screening, significant adverse effects were reported in 29%.10 Adverse events led to discontinuation of initial
Address reprint requests and correspondence: Dr. Christian van der Werf, AMC Heart Center, Department of Cardiology, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail address: [email protected].
1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.
therapy with beta-blockers in 8% of patients in the aforementioned pediatric cohort.6 With regard to the type of beta-blocker, the well-known differences in the pharmacodynamics and pharmacokinetics of the various beta-blockers (including their β1 selectivity, half-life, and lipophilicity) are obviously relevant. In addition, the sodium channel and cardiac ryanodine receptor channel–inhibiting properties reported for propranolol11 and carvedilol,12 respectively, could theoretically contribute further to the antiarrhythmic efficacy of these beta-blockers in treatment of CPVT. Prospective studies comparing the efficacy of different beta-blockers in patients with CPVT have not been performed. Although a prospective study on the short-term efficacy (assessed by the exercise-induced ventricular arrhythmia burden) of different beta-blockers seems feasible, a prospective (preferably randomized) comparison of their efficacy in preventing arrhythmic events in the long term is a undertaking that probably will never be performed. Therefore, this important and clinically relevant information must be derived from retrospective analyses in available cohorts. In this issue of HeartRhythm, Leren et al13 compared the ventricular arrhythmia burden during exercise testing in 34 CPVT patients treated with the nonselective beta-blocker nadolol and β1-selective (cardioselective) beta-blockers, mostly metoprolol SR. After 2009, when data on possible lower arrhythmic event rates with nadolol in patients with CPVT were published,14 the authors cleverly took advantage of a local policy that prevented the immediate initiation of nadolol to test the ventricular arrhythmia burden in patients while undergoing treatment with a β1-selective beta-blocker. Overall, nadolol was associated with a significant reduction of the ventricular arrhythmia burden compared to β1-selective beta-blockers and no therapy. For example, significant ventricular arrhythmias (ie, 410 ventricular extrasystoles) or more complex ventricular arrhythmias were absent in 59% of patients on nadolol, 7% of patients on a β1-selective beta-blocker, and 12% of untreated patients. Compared with β1-selective beta-blockers, nadolol was associated with a lower maximal heart rate, thereby reducing the ventricular arrhythmic window (ie, range of heart rate http://dx.doi.org/10.1016/j.hrthm.2015.10.027
2 during which ventricular arrhythmias occur). Holter recordings also showed less severe ventricular arrhythmias in patients treated with nadolol compared with β1-selective beta-blockers and untreated patients, whereas the incidence of ventricular extrasystoles was similar. The numbers of patients and arrhythmic events were too small to draw any meaningful conclusions on this end-point. The authors also performed several interesting subanalyses, but the following observations were based on a very small number of patients. First, in patients who received equivalent dosages of nadolol and metoprolol SR, nadolol was associated with a lower maximal heart rate and less severe ventricular arrhythmias. Second, nadolol was associated with less severe ventricular arrhythmias in patients who reached a similar maximal heart rate on nadolol and β1selective beta-blockers. This finding suggests that the stronger negative chronotropic effect of nadolol as well as other (unknown) mechanisms play a role in the associated reduced ventricular arrhythmia burden. Although these observations certainly are relevant, it must be recognized that the efficacy was assessed by analyzing only 1 exercise test per patient per medication. The ventricular arrhythmia burden on exercise testing in patients with CPVT may show intraindividual variations despite unchanged therapy8 and is not perfectly predictive of arrhythmic events,14 although it is frequently used to guide therapy in clinical practice in the absence of better predictors. The moderate predictive value was also visible in this study in which β1-selective beta-blockers did not significantly change the ventricular arrhythmia burden compared with no therapy. This unexpected finding is not in agreement with previous experiences,14 including our own in the Netherlands (where nadolol is not available)10 and current recommendations to treat CPVT patients with any kind of betablocker,5 although the use of nonselective beta-blockers is advised. The results of this study are in accordance with the important 2009 study by Hayashi et al14 on risk factors for arrhythmic events in CPVT and the efficacy of beta-blockers. In their series, the use of (unspecified) beta-blockers other than nadolol was an independent predictor for arrhythmia events. In contrast, in the large pediatric series by Roston et al,6 the type of beta-blocker did not influence the likelihood of arrhythmic events. In conclusion, there is mounting evidence that nadolol is more effective in CPVT than other, particularly β1-selective, beta-blockers. This may be explained at least in part by the
Heart Rhythm, Vol 0, No 0, Month 2015 typically required once-daily dosing, which may result in improved adherence and an increased negative chronotropic effect. The study by Leren et al further supports current recommendations to consider nadolol a first-choice betablocker for treatment of CPVT. Data on the second-best choice beta-blocker are lacking because other unselective beta-blockers such as propranolol and carvedilol have not been compared to other beta-blockers in CPVT. Hence, use of a low threshold for adding flecainide in patients with persistent symptoms or significant ventricular arrhythmias is still highly recommended.
References 1. Van der Werf C, Wilde AAM. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart 2013;99:497–504. 2. Horan M, Venables AW. Paroxysmal tachycardia with episodic unconsciousness. Arch Dis Child 1962;37:82–85. 3. Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using His bundle electrography. Br Heart J 1975;37:339–344. 4. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512–1519. 5. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 2013;10:1932–1963. 6. Roston TM, Vinocur JM, Maginot KR, et al. Catecholaminergic polymorphic ventricular tachycardia in children: an analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 2015;8:633–642. 7. Van der Werf C, Zwinderman AH, Wilde AAM. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14:175–183. 8. Van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244–2254. 9. De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation 2015;131:2185–2193. 10. Van der Werf C, Nederend I, Hofman N, et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol 2012;5:748–756. 11. Bankston JR, Kass RS. Molecular determinants of local anesthetic action of betablocking drugs: implications for therapeutic management of long QT syndrome variant 3. J Mol Cell Cardiol 2010;48:246–253. 12. Zhou Q, Xiao J, Jiang D, Wang R, et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2þ release. Nat Med 2011;17: 1003–1009. 13. Leren IS, Saberniak J, Majid E, Haland TF, Edvardsen T, Haugaa KH. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia Heart Rhythm 2015. Epub ahead of print. 14. Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff J-M, Klug D, Hayashi M, Takatsuki S, Villain E, Kamblock J, Messali A, Guicheney P, Lunardi J, Leenhardt A. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119: 2426–2434.