Axel Bauer1, Mathias Klemm2, Konstantinos D Rizas2, Wolfgang Hamm2, Lukas von Stülpnagel3, Michael Dommasch4, Alexander Steger4, Andrezej Lubinski5, Panagiota Flevari6, Markus Harden7, Tim Friede7, Stefan Kääb2, Bela Merkely8, Christian Sticherling9, Rik Willems10, Heikki Huikuri11, Marek Malik12, Georg Schmidt4, Markus Zabel13. 1. Medizinische Klinik und Poliklinik I, Munich University Clinic, Munich, Germany; University Hospital for Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria; German Center for Cardiovascular Research partner site, Munich Heart Alliance, Munich, Germany. Electronic address: axel.bauer@i-med.ac.at. 2. Medizinische Klinik und Poliklinik I, Munich University Clinic, Munich, Germany; German Center for Cardiovascular Research partner site, Munich Heart Alliance, Munich, Germany. 3. Medizinische Klinik und Poliklinik I, Munich University Clinic, Munich, Germany; German Center for Cardiovascular Research partner site, Munich Heart Alliance, Munich, Germany; Department of Electrical and Computer Engineering, Technical University of Munich, Munich, Germany. 4. German Center for Cardiovascular Research partner site, Munich Heart Alliance, Munich, Germany; Klinikum rechts der Isar, Medizinische Klinik und Poliklinik I, Technical University of Munich, Munich, Germany. 5. Department of Cardiology, Medical University of Lodz Hospital, Lodz, Poland. 6. Second Department of Cardiology, Attikon University Hospital, Athens, Greece. 7. Department of Medical Statistics, Heart Center University Medical Center Göttingen, Göttingen, Germany; German Center for Cardiovascular Research partner site Göttingen, Göttingen, Germany. 8. Department of Cardiology, Semmelweis University Heart Center, Budapest, Hungary. 9. University Hospital, University of Basel, Basel, Switzerland. 10. University Hospitals of Leuven, Leuven, Belgium. 11. Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland. 12. Heart and Lung Institute, Imperial College London, London, UK. 13. Department of Cardiology and Pneumology, Heart Center University Medical Center Göttingen, Göttingen, Germany; German Center for Cardiovascular Research partner site Göttingen, Göttingen, Germany.
Abstract
BACKGROUND: A small proportion of patients undergoing primary prophylactic implantation of implantable cardioverter defibrillators (ICDs) experiences malignant arrhythmias. We postulated that periodic repolarisation dynamics, a novel marker of sympathetic-activity-associated repolarisation instability, could be used to identify electrically vulnerable patients who would benefit from prophylactic implantation of ICDs by way of a reduction in mortality. METHODS: We did a prespecified substudy of EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD), a prospective, investigator-initiated, non-randomised, controlled cohort study done at 44 centres in 15 EU countries. Patients aged 18 years or older with ischaemic or non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (≤35%) were eligible for inclusion if they met guideline-based criteria for primary prophylactic implantation of ICDs. Periodic repolarisation dynamics from 24-h Holter recordings were assessed blindly in patients the day before ICD implantation or on the day of study enrolment in patients who were conservatively managed. The primary endpoint was all-cause mortality. Propensity scoring and multivariable models were used to assess the interaction between periodic repolarisation dynamics and the treatment effect of ICDs on mortality. FINDINGS: Between May 12, 2014, and Sept 7, 2018, 1371 patients were enrolled in our study. 968 of these patients underwent ICD implantation, and 403 were treated conservatively. During follow-up (median 2·7 years [IQR 2·0-3·3] in the ICD group and 1·2 years [0·8-2·7] in the control group), 138 (14%) patients died in the ICD group and 64 (16%) patients died in the control group. We noted a 43% reduction in mortality in the ICD group compared with the control group (adjusted hazard ratio [HR] 0·57 [95% CI 0·41-0·79]; p=0·0008). Periodic repolarisation dynamics significantly predicted the treatment effect of ICDs on mortality (adjusted p=0·0307). The mortality benefits associated with ICD implantation were greater in patients with periodic repolarisation dynamics of 7·5 deg or higher (n=199; adjusted HR 0·25 [95% CI 0·13-0·47] for the ICD group vs the control group; p<0·0001) than in those with periodic repolarisation dynamics less than 7·5 deg (n=1166; adjusted HR 0·69 [95% CI 0·47-1·00]; p=0·0492; pinteraction=0·0056). The number needed to treat was 18·3 (95% CI 10·6-4895·3) in patients with periodic repolarisation dynamics less than 7·5 deg and 3·1 (2·6-4·8) in those with periodic repolarisation dynamics of 7·5 deg or higher. INTERPRETATION: Periodic repolarisation dynamics predict mortality reductions associated with prophylactic implantation of ICDs in contemporarily treated patients with ischaemic or non-ischaemic cardiomyopathy. Periodic repolarisation dynamics could help to guide treatment decisions about prophylactic ICD implantation. FUNDING: The European Community's 7th Framework Programme.
BACKGROUND: A small proportion of patients undergoing primary prophylactic implantation of implantable cardioverter defibrillators (ICDs) experiences malignant arrhythmias. We postulated that periodic repolarisation dynamics, a novel marker of sympathetic-activity-associated repolarisation instability, could be used to identify electrically vulnerable patients who would benefit from prophylactic implantation of ICDs by way of a reduction in mortality. METHODS: We did a prespecified substudy of EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD), a prospective, investigator-initiated, non-randomised, controlled cohort study done at 44 centres in 15 EU countries. Patients aged 18 years or older with ischaemic or non-ischaemic cardiomyopathy and reduced left ventricular ejection fraction (≤35%) were eligible for inclusion if they met guideline-based criteria for primary prophylactic implantation of ICDs. Periodic repolarisation dynamics from 24-h Holter recordings were assessed blindly in patients the day before ICD implantation or on the day of study enrolment in patients who were conservatively managed. The primary endpoint was all-cause mortality. Propensity scoring and multivariable models were used to assess the interaction between periodic repolarisation dynamics and the treatment effect of ICDs on mortality. FINDINGS: Between May 12, 2014, and Sept 7, 2018, 1371 patients were enrolled in our study. 968 of these patients underwent ICD implantation, and 403 were treated conservatively. During follow-up (median 2·7 years [IQR 2·0-3·3] in the ICD group and 1·2 years [0·8-2·7] in the control group), 138 (14%) patientsdied in the ICD group and 64 (16%) patientsdied in the control group. We noted a 43% reduction in mortality in the ICD group compared with the control group (adjusted hazard ratio [HR] 0·57 [95% CI 0·41-0·79]; p=0·0008). Periodic repolarisation dynamics significantly predicted the treatment effect of ICDs on mortality (adjusted p=0·0307). The mortality benefits associated with ICD implantation were greater in patients with periodic repolarisation dynamics of 7·5 deg or higher (n=199; adjusted HR 0·25 [95% CI 0·13-0·47] for the ICD group vs the control group; p<0·0001) than in those with periodic repolarisation dynamics less than 7·5 deg (n=1166; adjusted HR 0·69 [95% CI 0·47-1·00]; p=0·0492; pinteraction=0·0056). The number needed to treat was 18·3 (95% CI 10·6-4895·3) in patients with periodic repolarisation dynamics less than 7·5 deg and 3·1 (2·6-4·8) in those with periodic repolarisation dynamics of 7·5 deg or higher. INTERPRETATION: Periodic repolarisation dynamics predict mortality reductions associated with prophylactic implantation of ICDs in contemporarily treated patients with ischaemic or non-ischaemic cardiomyopathy. Periodic repolarisation dynamics could help to guide treatment decisions about prophylactic ICD implantation. FUNDING: The European Community's 7th Framework Programme.
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