TY - JOUR
T1 - Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia
AU - Bergeman, Auke T.
AU - Lieve, Krystien V. V.
AU - Kallas, Dania
AU - Bos, J. Martijn
AU - Rosés I Noguer, Ferran
AU - Denjoy, Isabelle
AU - Zorio, Esther
AU - Kammeraad, Janneke A. E.
AU - Peltenburg, Puck J.
AU - Tobert, Katie
AU - Aiba, Takeshi
AU - Atallah, Joseph
AU - Drago, Fabrizio
AU - Batra, Anjan S.
AU - Brugada, Ramon
AU - Borggrefe, Martin
AU - Clur, Sally-Ann B.
AU - Cox, Moniek G. P. J.
AU - Davis, Andrew
AU - Dhillon, Santokh
AU - Etheridge, Susan P.
AU - Fischbach, Peter
AU - Franciosi, Sonia
AU - Haugaa, Kristina
AU - Horie, Minoru
AU - Johnsrude, Christopher
AU - Kane, Austin M.
AU - Krause, Ulrich
AU - Kwok, Sit-Yee
AU - Lapage, Martin J.
AU - Ohno, Seiko
AU - Probst, Vincent
AU - Roberts, Jason D.
AU - Robyns, Tomas
AU - Sacher, Frederic
AU - Semsarian, Christopher
AU - Skinner, Jonathan R.
AU - Swan, Heikki
AU - Tavacova, Terezia
AU - Tisma-Dupanovic, Svjetlana
AU - Tfelt-Hansen, Jacob
AU - Yap, Sing-Chien
AU - Kannankeril, Prince J.
AU - Leenhardt, Antoine
AU - Till, Janice
AU - Sanatani, Shubhayan
AU - Tanck, Michael W. T.
AU - Ackerman, Michael J.
AU - Wilde, Arthur A. M.
AU - van der Werf, Christian
N1 - Funding Information: A.A.W. was funded by Predict-2, EU E-rare grant (Transnational Research Projects on Rare Diseases 2015, Improving CPVT). S.S. was funded by the Heart and Stroke Foundation (grant G-19-0024239). M.J.A. was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. A.L. was funded by a grant from Programme Hospitalier de Recherche Clinique–PHRC 2014 (Ministère de la Santé N° AOR 04070). C.S. is the recipient of a National Health and Medical Research Council Practitioner Fellowship (No.1154992) and was supported by a New South Wales Health Cardiovascular Disease Clinician Scientist Grant. S.O. was funded by AMED (JP18ek0109202] and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K09689). J.T.H. was funded by the John and Birthe Meyer Family Foundation. K.H.H. was funded by the Norwegian Research Council (ProCardio No.309762, GENE POSITIVE No. 288438, and EMPATHY No. 298736). E.Z. was funded by Mécanismes Proarythmiques Dépendant du Sodium et du Calcium, Agènce Nationale de la Recherche (ANR-19-CE14-0031-001). Funding Information: A.W. is a consultant for ARMGO and LQT Therapeutics. S.S. is a consultant for Cardurion. M.J.A. is a consultant for Abbott, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. M.J.A. and the Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, Thryv Therapeutics, and Pfizer. However, none of these entities were involved in this study. S.P.E. is a consultant for UptoDate and has a relationship with Pfizer. S.C.Y. is a consultant for Boston Scientific and has received research grants from Medtronic and Biotronik. The other authors report no conflicts. Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/12/19
Y1 - 2023/12/19
N2 - BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.
AB - BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.
KW - catecholaminergic polymorphic ventricular tachycardia
KW - sudden cardiac death
KW - ventricular arrhythmias
UR - http://www.scopus.com/inward/record.url?scp=85180080164&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/CIRCULATIONAHA.123.064786
DO - https://doi.org/10.1161/CIRCULATIONAHA.123.064786
M3 - Article
C2 - 37886885
SN - 0009-7322
VL - 148
SP - 2029
EP - 2037
JO - Circulation
JF - Circulation
IS - 25
ER -