Clinical Predictors of Time-to-First Appropriate Implantable Cardioverter-Defibrillator Discharge in High-Risk Patients with Brugada Syndrome Implanted Prophylactically: Analysis of 246 Patients

Anat Milman ¹ Antoine Andorin ² Jean-Baptiste Gourraud ² Frederic Sacher ³ Philippe Mabo ⁴ Sung-Hwan Kim ⁵ Shingo Maeda ⁶ Yoshihide Takahashi ⁶ Tsukasa Kamakura ⁷ Takeshi Aiba ⁷ Giulio Conte ⁸ Eran Leshem ^1,9 Michael Rahkovich ^1,10 Yuka Mizusawa ¹¹ Pieter Postema ¹¹ Elena Arbelo ¹² Zhengrong Huang ¹³ Isabelle Denjoy ¹⁴ Carla Giustetto ¹⁶ Carlo Napolitano ¹⁷ Aviram Hochstadt ¹⁹ Yoav Michowitz ¹ Ramon Brugada ²⁰ Jean Champagne ²¹ Leonardo Calo ²² Jacob Tfelt-Hansen ²³ Silvia Priori ^17,18 Masahiko Takagi ²⁴ Christian Veltmann ²⁵ Pietro Delise ²⁶ Domenico Corrado ²⁷ Elijah Behr ²⁸ Fiorenzo Gaita ¹⁶ Gan-Xin Yan ²⁹ Josep Brugada ¹² Antoine Leenhardt ^14,15 Arthur Wilde ¹¹ Pedro Brugada ⁸ Kengo Kusano ⁷ Kenzo Hirao ⁶ Gi-Byoung Nam ³⁰ Vincent Probst ² Bernard Belhassen ¹

¹Department of Cardiology, Tel Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv University
²Service de Cardiologie, L'institut du Thorax, CHU de Nantes
³Service de Cardiologie, LIRYC Institute, INSERM 1045, Bordeaux University Hospital
⁴Cardiology and Vascular Disease Division, Rennes University Health Centre, 35033 Rennes Cedex
⁵Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea
⁶Heart Rhythm Center, Tokyo Medical and Dental University
⁷Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
⁸Heart Rhythm Management Center, UZ-VUB
⁹CardioVascular Institute, Beth Israel Deaconess Medical Center
¹⁰Arrhythmia Services, Sunnybrook Health Sciences Centre
¹¹Department of clinical and experimental Cardiology, Heart Center AMC, University of Amsterdam
¹²Cardiovascular Institute, Hospital Clínic Pediatric Arrhythmia Unit, Hospital Sant Joan de Déu University of Barcelona
¹³Department of Cardiology, The First Affiliated Hospital of Xiamen University
¹⁴Service de Cardiologie et CNMR Maladies Cardiaques Héréditaires Rares, Hôpital Bichat
¹⁵Service de Cardiologie, Université Paris Diderot, Sorbonne
¹⁶Division of Cardiology, University of Torino, Department of Medical Sciences, Città della Salute e della Scienza Hospital
¹⁷Molecular Cardiology, Istituti Clinici Scientifici Maugeri IRCCS
¹⁸Department of Molecular Medicin, University of Pavia
¹⁹Department of Internal Medicine J,, Tel-Aviv Medical Center
²⁰Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona-IdIBGi
²¹Division of Cardiology, Quebec Heart and Lung Institute
²²Division of Cardiology, Policlinico Casilino
²³The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, and Department of Medicine and Surgery, University of Copenhagen
²⁴Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine
²⁵Rhythmology and Electrophysiology, Department of Cardiology, Hannover Medical School
²⁶Division of Cardiology, Hospital of Peschiera del Garda
²⁷Department of Cardiac, Thoracic and Vascular Sciences, University of Padova
²⁸Cardiovascular Sciences, St. George's University of London
²⁹Heart Center, Lankenau Medical Center
³⁰Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine

Background:
Present guidelines recommend prophylactic implantation of a cardioverter-defibrillator (ICD) in high-risk patients with Brugada syndrome (BrS). We sought to determine predictors of time-to-first appropriate ICD discharge in a large cohort of patients.

Methods:
Information on 246 BrS patients was gathered from a multicenter survey (n=21) involving 10 Western (177 patients) and 3 Asian (69 patients) countries. There were 224 males (91%), aged 1 to 73 (mean 43.4±13.2) years at ICD implantation. All patients received primary prophylactic ICD that delivered ≥ 1 appropriate discharges. Only time-to-first appropriate ICD discharge was analyzed using Kaplan Meier curves regarding patients’ characteristics. Cox regression was performed on time-to-first arrhythmic event with the above parameters to diminish group effects. Also, logistic regression models were utilized to identify which parameters predict time to arrhythmia < 5 years.

Results:
The median time-to-first appropriate discharge was 24 months (IQR 0-51.60). A shorter median time-to-shock was observed in patients of Asian ethnicity (HR 1.99, p<0.001), those with syncope (HR=1.34, p=0.026) and those with a class IIa indication for ICD (syncope and spontaneous type 1 BrS ECG) compared with class IIb indication (inducible VF on EPS) (HR=1.40, p=0.006). A longer median time-to-shock was associated with a positive family history of sudden cardiac death (HR 0.76, p=0.013). Cox regression revealed a shorter time-to-ICD discharge in Asians ((HR 3.12, P<0.001) while a longer time-to-ICD discharge was observed in patients with positive EPS (HR=0.65, p=0.05).

In 203 patients (82.5%), appropriate therapy was delivered during first 5 years. The only factor associated with this time delivery was Asian ethnicity (OR 0.345; p=0.023).

Conclusions:
Most patients (82.5%) with ICD implanted for primary prevention and having an appropriate therapy, experienced first appropriate therapy during the first 5 years after implantation. Asian descent correlates with shorter time to ICD therapy, while positive EPS with a longer time.