Search

Introduction: The implantable cardioverter defibrillator reduces mortality among patients with heart failure (HF) due to ischemic heart disease. Clinical trial data have called into question the benefit of an ICD in patients with HF due to nonischemic cardiomyopathy (NICM). We developed a risk stratification score for ventricular tachyarrhythmia (VTA) among patients with NICM receiving a primary prevention ICD., Methods: The study population comprised 1515 patients with NICM who were enrolled in the landmark MADIT trials. Fine and Gray analysis was used to develop a model to predict the occurrence of VTAs and ICD therapies while accounting for the competing risk of non-arrhythmic mortality. External validation was carried out in the RAID Trial population., Results: Four risk factors associated with increased risk for VTA were identified: male sex, left ventricular ejection fraction ≤25%, no indication for cardiac resynchronization therapy with a defibrillator (CRT-D), and Black race. A score was generated based on this model, and patients were stratified into low (N = 390), intermediate (N = 728), and high-risk (N = 387) groups. The 5-year cumulative incidences of VTA were 15%, 24%, and 42%, respectively. Application of score groups for the secondary endpoints of Fast VT or VF and Appropriate ICD Shock revealed similar findings. Recurrent event analysis yielded consistent results. The AUC in the validation cohort for the endpoint of Appropriate ICD Shock was 69.3., Conclusions: Our study shows that patients with NICM can be risk stratified using demographic and clinical variables and may be used when evaluating such patients for a primary prevention ICD., (© 2024 Wiley Periodicals LLC.)

Background: Some studies have shown digoxin use to be associated with adverse outcomes, including increased mortality. There are limited data on whether digoxin use is associated with increased risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in heart failure patients with an implantable cardioverter-defibrillator (ICD)., Objectives: This study sought to assess whether digoxin use is associated with increased risk of VT/VF in patients with heart failure with reduced ejection fraction with a primary prevention ICD in landmark clinical trials., Methods: The study cohort consisted of patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in 4 landmark MADIT trials (Multicenter Automatic Defibrillator Implantation Trials). We employed propensity score quintile stratification for treatment with digoxin as well as additional multivariable adjustment to assess the risk of digoxin vs no-digoxin therapy for the endpoints of first and recurrent VT/VF and all-cause mortality. The proportional hazards regression models for arrhythmia-specific endpoints incorporated adjustments for the competing risk of death., Results: At baseline, 1,155 of 4,499 patients were on digoxin (26%). After propensity score quintile stratification, patients prescribed digoxin were shown to exhibit a statistically significant 48% increased risk of VT/VF (P < 0.001), 42% increased risk of the composite of VT/VF or death (P < 0.001), and a 37% increased risk of all-cause mortality (P = 0.006). Digoxin use was also associated with increased risk of appropriate ICD shocks (HR: 1.91; P < 0.001) and with increased burden of VT/VF events (HR: 1.46; P = 0.001)., Conclusions: Our findings suggests that digoxin use is associated with ventricular tachyarrhythmia and death in heart failure with reduced ejection fraction patients with an ICD., Competing Interests: Funding Support and Author Disclosures The MADIT-RISK study was supported by NIH grant HL077478. Dr Aktas has received research funding from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Heart failure patients with a history of atrial fibrillation (AF) and ventricular tachycardia/ventricular fibrillation (VT/VF) are known to have worse outcomes. However, there are limited data on the temporal relationship between development of these arrhythmias and the risk of subsequent congestive heart failure (CHF) exacerbation and death., Methods: The study cohort comprised 5511 patients implanted with an implantable cardioverter-defibrillator (ICD) in landmark clinical trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, and RAID) who were in sinus rhythm at enrollment. Multivariate cox analysis was performed to evaluate the time-dependent association between development of in-trial device detected AF and VT/VF with subsequent CHF exacerbation and death., Results: Multivariate analysis showed that AF occurrence and VT/VF occurrence were both associated with a similar magnitude of risk for subsequent CHF exacerbation (HR = 1.73 and 1.87 respectively, p < .001 for both). In contrast, only in-trial VT/VF was associated with a significant > two-fold increase in the risk of subsequent mortality (HR = 2.13, p < .001) whereas AF occurrence was not associated with a significant mortality increase after adjustment for in-trial VT/VF (HR = 1.36, p = .096)., Conclusion: Our findings from a large cohort of ICD recipients enrolled in landmark clinical trials show that device detected AF and VT/VF can be used to identify patients with increased risk for CHF exacerbation and mortality. These findings suggest a need for early intervention in CHF patients who develop device-detected atrial and ventricular tachyarrhythmias., (© 2024 Wiley Periodicals LLC.)

Introduction: Wearable cardioverter defibrillator (WCD) is utilized in patients with assumed but not yet confirmed risk for sudden cardiac death (SCD). Many of these patients also present with atrial fibrillation (AF). However, the rate of WCD-detected ventricular or atrial arrhythmia events in this specific high-risk cohort is not well understood., Methods: In WEARIT-II, the cumulative probability of any sustained or nonsustained VT/VF (WCD-treated and nontreated), and atrial/supraventricular arrhythmias during WCD use was assessed using the Kaplan-Meier method by prior AF, with comparisons by the log-rank test. The incidence of ventricular and atrial arrhythmia events were expressed as events per 100 patient-years, and were analyzed by prior AF using negative binomial regression., Results: WEARIT-II enrolled 2000 patients, 557 (28%) of whom had AF before enrollment. Cumulative probability of any sustained or nonsustained WCD-detected VT/VF during WCD use was significantly higher among patients with a history of AF than without AF (6% vs. 3%, p = .001). Similarly, the recurrent rate of any sustained or nonsustained VT/VF was significantly higher in patients with prior AF versus no prior AF (131.5 events per 100 patient-years vs. 22.7 events per 100 patient-years, p = .001). Patients with prior AF also had a significantly higher burden of any WCD-detected atrial arrhythmias/SVT/inappropriate arrhythmias therapy (183.2 events per 100 patient-years vs. 74.8 events per 100 patient-years, p < .001)., Conclusion: Our results demonstrate that patients with a history of AF wearing the WCD for risk assessment have a higher incidence of ventricular arrhythmias that may facilitate the decision making for ICD implantation., (© 2024 Wiley Periodicals LLC.)

Background: Data on the risk of ventricular tachycardia (VT), ventricular fibrillation (VF), and death by sex in patients with prior VT/VF are limited., Objectives: This study aimed to assess sex-related differences in implantable cardioverter-defibrillator (ICD)-treated VT/VF events and death in patients implanted for secondary prevention or primary prevention ICD indications who experienced VT/VF before enrollment in the RAID (Ranolazine Implantable Cardioverter-Defibrillator) trial., Methods: Sex-related differences in the first and recurrent VT/VF requiring antitachycardia pacing or ICD shock and death were evaluated in 714 patients., Results: There were 124 women (17%) and 590 men observed during a mean follow-up of 26.81 ± 14.52 months. Compared to men, women were at a significantly lower risk of VT/VF/death (HR: 0.67; P = 0.029), VT/VF (HR: 0.68; P = 0.049), VT/VF treated with antitachycardia pacing (HR: 0.59; P = 0.019), and VT/VF treated with ICD shock (HR: 0.54; P = 0.035). The risk of recurrent VT/VF was also significantly lower in women (HR: 0.35; P < 0.001). HR for death was similar to the other endpoints (HR: 0.61; P = 0.162). In comparison to men, women presented with faster VT rates (196 ± 32 beats/min vs 177 ± 30 beats/min, respectively; P = 0.002), and faster shock-requiring VT/VF rates (258 ± 56 beats/min vs 227 ± 57 beats/min, respectively; P = 0.30). There was a significant interaction for the risk of VT/VF by race (P = 0.013) with White women having significantly lower risk than White men (HR: 0.36; P < 0.001), whereas Black women had a similar risk to Black men (HR: 1.06; P = 0.851)., Conclusions: Women with a history of prior VT/VF experienced a lower risk recurrent VT/VF requiring ICD therapy when compared to men. Black Women had a risk similar to men, whereas the lower risk for VT/VF in women was observed primarily in White women. (Ranolazine Implantable Cardioverter-Defibrillator Trial; NCT01215253)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants from the National Heart, Lung, and Blood Institute: Clinical Coordination Center (UO1 HL096607) and Data Coordination Center (UO1 HL096610. Study drug and additional financial support for drug distribution was provided by Gilead Sciences (grant IN-US-259-0125). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The current guidelines advocate prophylactic implantable cardioverter-defibrillator (ICD) for all patients with symptomatic heart failure (HF) with low left ventricular ejection fraction. Because many patients will never use their device, a score delineating subgroups with differential ICD benefit is crucial. We aimed to evaluate the MADIT-II-based Risk Stratification Score (MRSS) feasibility to delineate the ICD survival benefit in a nationwide registry of patients with HF with prophylactic ICDs. Accordingly, all Israeli patients with HF with prophylactic ICD/cardiac resynchronization therapy defibrillators were categorized into MRSS-based risk subgroups. The study end points included overall mortality, sustained ventricular arrhythmia (VA), and a competing risk of VA (potential preventable arrhythmic death, where ICD could benefit survival) versus nonarrhythmic death. Potential ICD survival benefit was estimated by the area between these cumulative incidence curves. In 2,177 patients with HF implanted prophylactic device, 189 patients (8.7%) had VA and 316 (14.5%) died during a median follow-up of 2.9 years. The MRSS risk subgroups were significantly associated with overall mortality (p <0.001) and weakly with VA (p = 0.3). The competing risk analysis of VA versus nonarrhythmic death revealed a significantly shorter duration (p <0.001) and smaller magnitude of ICD survival benefit with increased risk subgroups, yielding an estimated 76, 60, 38, and 0 life days gained from prophylactic ICD implant during a 5-year follow-up for the MRSS low-, intermediate-, high-, and very high-risk subgroups, respectively (p for trend <0.05). In conclusion, MRSS use in a nationwide registry of patients with ischemic and nonischemic cardiomyopathy, revealed subgroups with differing ICD survival benefit, suggesting it could help evaluate prophylactic ICD survival benefit., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There are conflicting data on the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the risk of life-threatening ventricular tachyarrhythmia in heart failure patients., Objectives: The authors aimed to assess whether QRS morphology is associated with risk of ventricular arrhythmias in CRT recipients., Methods: The study population comprised 2,862 patients implanted with implantable cardioverter defibrillator (ICD)/CRT-D for primary prevention who were enrolled in 5 landmark primary prevention ICD trials (MADIT-II [Multicenter Automated Defibrillator Implantation Trial], MADIT-CRT [Multicenter Automated Defibrillator Implantation Trial-Cardiac Resynchronization Therapy], MADIT-RIT [Multicenter Automated Defibrillator Implantation Trial-Reduction in Inappropriate Therapy], MADIT-RISK [Multicenter Automated Defibrillator Implantation Trial-RISK], and RAID [Ranolazine in High-Risk Patients With Implanted Cardioverter Defibrillators]). Patients with QRS duration ≥130 ms were divided into 2 groups: those implanted with an ICD only vs CRT-D. The primary endpoint was fast ventricular tachycardia (VT)/ventricular fibrillation (VF) (defined as VT ≥200 beats/min or VF), accounting for the competing risk of death. Secondary endpoints included appropriate shocks, any sustained VT or VF, and the burden of fast VT/VF, assessed in a recurrent event analysis., Results: Among patients with left bundle branch block (n = 1,792), those with CRT-D (n = 1,112) experienced a significant 44% (P < 0.001) reduction in the risk of fast VT/VF compared with ICD-only patients (n = 680), a significantly lower burden of fast VT/VF (HR: 0.55; P = 0.001), with a reduced burden of appropriate shocks (HR: 0.44; P < 0.001). In contrast, among patients with non-left bundle branch block (NLBBB) (N = 1,070), CRT-D was not associated with reduction in fast VT/VF (HR: 1.33; P = 0.195). Furthermore, NLBBB patients with CRT-D experienced a statistically significant increase in the burden of fast VT/VF events compared with ICD-only patients (HR: 1.90; P = 0.013)., Conclusions: Our data suggest a potential proarrhythmic effect of CRT among patients with NLBBB. These data should be considered in patient selection for treatment with CRT., Competing Interests: Funding Support and Author Disclosures The MADIT studies were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center, Rochester, New York. All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: De novo implanted cardiac resynchronization therapy with defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain., Methods: In this multicentre, randomized, controlled trial, 360 symptomatic (New York Heart Association Classes II-IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥ 20%, and a wide paced QRS complex duration ≥ 150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalization, or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalization., Results: Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm vs. 101/128 (78.9%) in the ICD arm (odds ratio 0.11; 95% confidence interval 0.06-0.19; P < .001). All-cause mortality or heart failure hospitalization occurred in 22/215 (10%) in the CRT-D arm vs. 46/145 (32%) in the ICD arm (hazard ratio 0.27; 95% confidence interval 0.16-0.47; P < .001). The incidence of procedure- or device-related complications was similar between the two arms [CRT-D group 25/211 (12.3%) vs. ICD group 11/142 (7.8%)]., Conclusions: In pacemaker or ICD patients with significant RVP burden and reduced ejection fraction, upgrade to CRT-D compared with ICD therapy reduced the combined risk of all-cause mortality, heart failure hospitalization, or absence of reverse remodelling., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Both selective and nonselective beta-blockers are used to treat patients with heart failure (HF). However, the data on the association of beta-blocker type with risk of atrial arrhythmia and ventricular arrhythmia (VA) in HF patients with a primary prevention implantable cardioverter-defibrillator (ICD) are limited., Objectives: This study sought to evaluate the effect of metoprolol vs carvedilol on the risk of atrial tachyarrhythmia (ATA) and VA in HF patients with an ICD., Methods: This study pooled primary prevention ICD recipients from 5 landmark ICD trials (MADIT-II, MADIT-CRT, MADIT-RIT, MADIT-RISK, and RAID). Fine and Gray multivariate regression models, stratified by study, were used to evaluate the risk of ATA, inappropriate ICD shocks, and fast VA (defined as ventricular tachycardia ≥200 beats/min or ventricular fibrillation) by beta-blocker type., Results: Among 4,194 patients, 2,920 (70%) were prescribed carvedilol and 1,274 (30%) metoprolol. The cumulative incidence of ATA at 3.5 years was 11% in patients treated with carvedilol vs 15% in patients taking metoprolol (P = 0.003). Multivariate analysis showed that carvedilol treatment was associated with a 35% reduction in the risk of ATA (HR: 0.65; 95% CI: 0.53-0.81; P < 0.001) when compared to metoprolol, and with a corresponding 35% reduction in the risk of inappropriate ICD shocks (HR: 0.65; 95% CI: 0.47-0.89; P = 0.008). Carvedilol vs metoprolol was also associated with a 16% reduction in the risk of fast VA. However, these findings did not reach statistical significance (HR: 0.84; 95% CI: 0.70-1.02; P = 0.085)., Conclusions: These findings suggests that HF patients with ICDs on carvedilol treatment experience a significantly lower risk of ATA and inappropriate ICD shocks when compared to treatment with metoprolol., Competing Interests: Funding Support and Author Disclosures Each of the MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The MADIT-RISK study was supported by the National Heart, Lung, and Blood Institute grant HL077478. The RAID trial was supported by National Heart, Lung, and Blood Institute grants UO1 HL096607 and UO1 HL096610 and by Gilead Sciences Inc grant IN-US-259-0125. Dr Goldenberg has received research grants from Boston Scientific, ZOLL Medical Corporation, Medtronic, Biosense-Webster, and Biotronik. Dr Kutyifa has received research grants from Boston Scientific, Biotronik, and ZOLL Medical Corporation, and Spire Inc; and has consulting agreements with ZOLL Medical Corporation and Biotronik. Dr Steinberg has received research grants from the National Institutes of Health, Medtronic, AliveCor, and Atricure. Dr Zareba has received research grants from Boston Scientific. Dr Aktas has received research grants from Boston Scientific, Abbott, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra-operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant., Methods: We designed a prospective, multicenter, open-label, randomized-controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra-operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life., Conclusion: The primary aim of this first-ever randomized trial is to assess the efficacy of intra-operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA., (© 2023 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Background: Black Americans have a higher risk of nonischemic cardiomyopathy (NICM) than White Americans. We aimed to evaluate differences in the risk of tachyarrhythmias among patients with an implantable cardioverter-defibrillator (ICD)., Methods: The study population comprised 3895 ICD recipients in the United States enrolled in primary prevention ICD trials. Outcome measures included ventricular tachyarrhythmia (VTA), atrial tachyarrhythmia (ATA), ICD therapies, VTA burden (using Andersen-Gill recurrent event analysis), death, and the predicted benefit of the ICD. All events were adjudicated blindly. Outcomes were compared between self-reported Black patients versus White patients with cardiomyopathy (ischemic and NICM)., Results: Black patients were more likely to be female (35% versus 22%) and younger (57±12 versus 62±12 years) with a higher frequency of comorbidities. In NICM, Black patients had a higher rate of first VTA, fast VTA, ATA, and appropriate and inappropriate ICD therapy (VTA ≥170 bpm, 32% versus 20%; VTA ≥200 bpm, 22% versus 14%; ATA, 25% versus 12%; appropriate therapy, 30% versus 20%; and inappropriate therapy, 25% versus 11%; P <0.001 for all). Multivariable analysis showed that Black patients with NICM experienced a higher risk of all types of arrhythmia or ICD therapy (VTA ≥170 bpm, hazard ratio [HR] 1.71; VTA ≥200 bpm, HR 1.58; ATA, HR 1.87; appropriate therapy, HR 1.62; inappropriate therapy, HR 1.86; P ≤0.01 for all), higher burden of tachyarrhythmias or therapies (VTA, HR 1.84; appropriate therapy, HR 1.84; P <0.001 for both), and a higher risk of death (HR 1.92; P =0.014). In contrast, in ischemic cardiomyopathy, the risk of all types of tachyarrhythmia, ICD therapy, or death was similar between Black patients and White patients. Both Black patients and White patients derived a significant and similar benefit from ICD implantation., Conclusions: Among patients with NICM with an ICD for primary prevention, Black patients compared with White patients had a high risk and burden of VTA, ATA, and ICD therapies with a lower survival rate. Nevertheless, the overall benefit of the ICD was maintained and was similar to that of White patients., Competing Interests: Disclosures Drs Younis, Ali, Ido Goldenberg, and Aktas, and S. McNitt and B. Polonsky, have nothing to declare. Drs Kutyifa, Wazni, Zareba, and Ilan Goldenberg report receiving grants from Boston Scientific.

Background: The benefit of implantable cardioverter-defibrillators (ICDs) in elderly patients is controversial., Objectives: The aims of this study were to evaluate the risk for ventricular tachyarrhythmia (VTA) and ICD shocks by age groups and to assess the competing risk for VTA and death without prior VTA., Methods: The study included 5,170 primary prevention ICD recipients enrolled in 5 landmark ICD trials (MADIT [Multicenter Automatic Defibrillator Implantation Trial] II, MADIT-Risk, MADIT-CRT [MADIT Cardiac Resynchronization Therapy], MADIT-RIT [MADIT Reduce Inappropriate Therapy], and RAID [Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillator]). Fine and Gray regression analysis was used to evaluate the risk for fast VTA (ventricular tachycardia ≥200 beats/min or ventricular fibrillation) vs death without prior fast VTA in 3 prespecified age groups: <65, 65 to <75, and ≥75 years., Results: The cumulative incidence of fast VTA at 3 years was similar for patients <65 years of age and those 65 to <75 years of age (17% vs 15%) and was lowest among patients ≥75 years of age (10%) (P < 0.001). Multivariate Fine and Gray analysis showed a 40% lower risk for fast VTA in patients ≥75 years of age (HR: 0.60; 95% CI: 0.46-0.78; P < 0.001) compared with patients <65 years of age. In patients ≥75 years of age, a risk reversal was observed whereby the risk for death without prior fast VTA exceeded the risk for developing fast VTA. A history of nonsustained ventricular tachycardia, male sex, and the presence of nonischemic cardiomyopathy were identified as predictors of fast VTA in patients ≥75 years of age., Conclusions: Patients ≥75 years of age have a significantly lower risk for VTA and ICD shocks compared with younger patients. Aging is associated with a higher risk for death compared with the risk for fast VTA, the reverse of what is seen in younger patients., Competing Interests: Funding Support and Author Disclosures Each of the MADIT trials was funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center. The MADIT-Risk study was supported by National Heart, Lung, and Blood Institute grant HL077478. The RAID trial was supported by National Heart, Lung, and Blood Institute grants UO1 HL096607 and UO1 HL096610 and by a grant from the Gilead Sciences (IN-US-259-0125). Dr Aktaş has received research grants from Boston Scientific and Medtronic. Dr Kutyifa has received research grants from Boston Scientific, Biotronik, and ZOLL. Dr Steinberg has received research grants from the National Institutes of Health, Medtronic, AliveCor, and Atricure. Dr Zareba has received research grants from Boston Scientific. Dr Rosero has received research grants from Medtronic and Biotronik. Dr Huang has received research grants from Medtronic, Biosense Webster, and Biotronik. Dr Goldenberg has received research grants from Boston Scientific, Zoll, Medtronic, Biosense Webster, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy showed a significant reduction in the risk of inappropriate therapy in patients with a programmed high-rate cutoff ≥200 beats per minute or delayed therapy for events ≥170 beats per minute compared with conventional programming. We aimed to characterize outcomes by left ventricular ejection fraction (LVEF) ranges for patients with high-rate, delayed, or conventional implantable cardioverter-defibrillator programming. We assessed the effect of LVEF (LVEF &lt;15%, LVEF 15% to 25%, LVEF &gt;25%) on the risk of inappropriate conventional implantable cardioverter-defibrillator therapy and death in Multicenter Automatic Defibrillator Implantation Trial - Reduce Inappropriate Therapy. Inappropriate therapies and death were independently evaluated by the adjudication committee. Statistical methods involved Kaplan-Meier time-to-event graphs and Cox proportional hazards regression analyses. The study involved 140 patients (9%) with LVEF 15%, 585 with LVEF 15% to 25% (39%), and 774 with LVEF &gt;25% (52%). High-rate or delayed programming significantly reduced the risk of inappropriate therapy compared with conventional programming in patients with all LVEFs (p &lt;0.001 for all LVEF). Patients with LVEF &lt;15% had an exceptional 97% lower risk of inappropriate therapy, with high-rate programming than conventional programming (hazard ratio 0.028, p = 0.001), without an increase in mortality. High-rate and delayed programming is superior to conventional programming in all LVEF ranges, without adverse effects., Competing Interests: Disclosures Dr. Dauberthas received honoraria for: events committee, data safety monitoring board, bonsulting, advisory boards and/or for lectures from: Abbott, Acutus Medical, Biosense, Biotronik, Boston Scientific, Farapulse, Medtronic, Microport, Phillips, and Vytronus. Dr. Goldenberg has received grants from Boston Scientific, Abbott, and Medtronic. Dr. Kutyifa has received research grants from Boston Scientific, ZOLL Inc., Biotronik, Spire, and National Institutes of Health and received consultant fees from Biotronik, Medtronic, Abbott, and ZOLL Inc. Dr. Zareba received fees from Boston Scientific, LivaNova, and Biotronik and consulting fee from Medtronic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Implantable cardioverter defibrillator therapy is indicated in a subset of patients with heart failure with reduced ejection as primary prevention for sudden cardiac death. The advent of novel medical therapies including mineralocorticoid receptor antagonists, angiotensin receptor blocker/neprilysin inhibitors, and sodium-glucose transporter 2 inhibitor in the past 2 decades has revolutionized heart failure with reduced ejection management. Current guideline-directed medical therapy has reduced all-cause mortality and sudden cardiac death and confers a considerable improvement in left ventricular ejection fraction over a short period of time. However, there is limited evidence at present to suggest whether implantable cardioverter defibrillator therapy continues to have the same benefit in sudden cardiac death prevention at current left ventricular ejection fraction cutoff indications for patients on contemporary guideline-directed medical therapy for heart failure with reduced ejection. In this review, the authors propose in lieu of current evidence that it is reasonable to reevaluate indications for implantable cardioverter defibrillator therapy in patients on contemporary guideline-directed medical therapy for heart failure with reduced ejection.

Current guidelines do not account for possible sex differences in the risk of ventricular tachyarrhythmia (VTA). We sought to identify specific factors associated with increased risk for VTA in women implanted with a primary prevention implantable cardioverter-defibrillator (ICD). Our study cohort consisted of 4,506 patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in the 4 landmark MADIT studies - MADIT-II, MADIT-RISK, MADIT-CRT and MADIT-RIT (1,075 women [24%]). Fine and Gray regression models were used to identify female-specific risk factors for the primary end point of VTA, defined as ICD-recorded, treated, or monitored, sustained ventricular tachycardia ≥170 beats per minute or ventricular fibrillation. At 3.5 years of follow-up, the cumulative incidence of VTA was significantly lower in women than men (17% vs 26%, respectively; p <0.001 for the entire follow-up). Use of amiodarone at enrollment, Black race, and history of previous myocardial infarction without previous revascularization was found to be independent risk factors of VTA in women. Of these factors, only Black race was associated with a statistically significant risk increase in men. At 3.5 years, the cumulative incidence of VTA in women with one or more of these risk factors was 27% compared with 14% in women with none of the risk factors (hazard ratio [confidence interval] = 2.08 [1.49 to 2.91]). In conclusion, our study, comprising 4 landmark ICD clinical trials, shows that sex and race have the potential to be used for improved risk stratification of patients who are candidates for primary prevention ICD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Current guidelines for primary implantable cardioverter-defibrillator (ICD) therapy do not account for sex differences in arrhythmic risk in ICD candidates., Objective: To evaluate the association between sex and risk of ventricular tachyarrhythmia (VTA) and mortality., Design, Setting, and Participants: This cohort study compared differences in the risk of VTA and mortality between 4506 men and women enrolled in the 4 Multicenter Automatic Defibrillator Implantation Trials (MADIT) between July 1, 1997, and December 31, 2011. Data from prospective randomized controlled multicenter studies were analyzed retrospectively. Men and women with an ICD or cardiac resynchronization therapy defibrillator who were enrolled in all MADIT studies were included. Data were analyzed between January 10 and June 10, 2021., Exposures: ICD implant., Main Outcomes and Measures: The primary end point was sustained VTA, defined as ICD-recorded, treated or monitored VTA at least 170/min or ventricular fibrillation. Secondary VTA end points included VTA at least 200/min, appropriate ICD shocks, and appropriate antitachycardia pacing. All end points were included in a first and recurrent event analysis., Results: Of the 4506 study participants, 3431 were men (76%). Mean (SD) age of the cohort was 64 (12) years. For women vs men, the mean (SD) age (64 [12] years vs 64 [11] years) and left ventricular ejection fraction (24% vs 25%) were similar, but women exhibited a higher frequency of nonischemic cardiomyopathy (454 of 1075 women [42%] vs 2535 of 3431 men [74%]). Women had significantly lower 3-year cumulative probability of sustained VTA (16% vs 26%), fast VTA (9% vs 17%), and appropriate ICD shocks (7% vs 15%) compared with men (P < .001 for all). Multivariable analysis showed that female sex was independently associated with at least 40% lower risk of all first and recurrent VTA end points (P < .001 for all), including the primary end point (first event, HR = 60 [95% CI, 50-73], P < .001; recurrent event, HR = 49 [95% CI, 43-55], P < .001), after accounting for the competing risk of all-cause mortality and nonarrhythmic mortality. The lower VTA risk associated with female sex was consistent in risk subsets but was significantly more pronounced in patients with nonischemic cardiomyopathy (female vs male in the ischemic group: hazard ratio, 0.73 [95% CI, 0.56-0.95], P = .02; nonischemic group: hazard ratio, 0.50 [95% CI, 0.38-0.66], P < .001; P = .03 for interaction between female sex and cardiomyopathy)., Conclusions and Relevance: Findings suggest that women display a significantly lower risk of first and recurrent life-threatening VTA events than men, and that it is more pronounced in patients with nonischemic cardiomyopathy, suggesting a need for sex-specific risk assessment for primary prevention ICD therapy.

Background: The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized placebo-controlled trial showed that ranolazine treatment was associated with reduction in recurrent ventricular tachycardia (VT) requiring appropriate implantable cardioverter-defibrillator (ICD) therapy., Objectives: This study aimed to identify groups of patients in whom ranolazine treatment would result in the highest reduction of ventricular tachyarrhythmia (VTA) burden., Methods: Andersen-Gill analyses were performed to identify variables associated with risk for VTA burden among 1,012 patients enrolled in RAID. The primary endpoint was VTA burden defined as VTA episodes requiring appropriate treatment., Results: Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. The effect of ranolazine on VTA burden was seen among patients without concomitant AAD therapy (HR [HR]: 0.68; 95% CI: 0.55-0.84; P < 0.001), whereas no effect was seen among those who are concomitantly treated with other AADs (HR: 1.33; 95% CI: 0.90-1.96; P = 0.16); P = 0.003 for interaction. In patients with cardiac resynchronization therapy (CRT) ICDs, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; 95% CI: 0.47-0.86; P < 0.001), whereas among patients with ICDs without CRT no significant effect was noted (HR: 0.94; 95% CI: 0.74-1.18; P = 0.57); P = 0.047 for interaction., Conclusions: In patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants from the National Heart, Lung, and Blood Institute: Clinical Coordination Center (UO1 HL096607) and Data Coordination Center (UO1 HL096610. Study drug and additional financial support for drug distribution was provided by Gilead Sciences grant number IN-US-259-0125. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the association of cardiomyopathy etiology with the likelihood of ventricular arrhythmias, appropriate implantable cardioverter-defibrillator (ICD) therapy, and mortality., Background: There are conflicting data on the benefit of primary prevention ICD therapy in patients with ischemic versus nonischemic cardiomyopathy (ICM/NICM)., Methods: The study population comprised 4803 patients with ICM (n = 3,106) or NICM (n = 1,697) with a primary prevention ICD enrolled in 5 randomized trials conducted between 1997 and 2017. The primary end point was sustained ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF). Secondary end points included appropriate ICD therapy and all-cause mortality. Differences in cause-specific mortality, including noncardiac, sudden cardiac, and non-sudden cardiac death, were also examined., Results: Patients with ICM were significantly older and had more comorbid conditions, whereas those with NICM had a more advanced heart failure class at enrollment and were more often prescribed medical or cardiac resynchronization therapy for heart failure. Multivariate analysis showed that ICM versus NICM had a similar risk of VT/VF events (HR: 0.98 [95% CI: 0.79-1.20]) and appropriate ICD therapy (HR: 1.03 [95% CI: 0.87-1.22]), whereas the risk of all-cause mortality was 1.8-fold higher among ICM versus NICM patients (HR: 1.84 [95% CI: 1.42-2.38]), dominated by non-sudden cardiac mortality., Conclusions: Combined data from 5 landmark ICD clinical trials show that ICM patients experience a similar risk of life-threatening ventricular arrhythmic events but have an increased risk of all-cause mortality, dominated by non-sudden cardiac death, compared with NICM patients., Competing Interests: Funding Support and Author Disclosures Each of the MADIT trials were funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center, Rochester, NY. The RAID trial was funded by the National Institutes of Health (NIH) grant U01HL096607. Dr Aktas has received research grants from Boston Scientific and Medtronic. Dr Zareba has received research grants from Boston Scientific, LevaNova, Biotronik, and Gilead Sciences; and has been a consultant for Medtronic, Abbott, and Astra-Zeneca. Dr Daubert has received honoraria for serving on events committees, data safety monitoring boards, and advisory boards, as a consultant, and/or for lectures from Abbott, Biosense, Biotronik, Boston Scientific, Farapulse, Medtronic, Microport, Phillips, Vytronus, and Zoll; and has received research grants from Abbott and Medtronic. Dr Huang has received research support from Biosense Webster, Biotronik, and Medtronic; and has received Fellowship Program support from Boston Scientific, Medtronic, Abbott, and Biotronik. Dr Rosero has received research grants from Medtronic, Biotronik, and Spire Inc. Dr Kutyifa has received research grants from Boston Scientific, Biotronik, ZOLL Inc., and Spire Inc.; and has consultant agreements with Zoll Inc. and Biotronik. Dr Goldenberg has received research grants from Boston Scientific, Zoll, Medtronic, Biosense Webster, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not been well studied in patients with long QT syndrome (LQTS)., Objectives: This study aimed to assess the survival benefits of ICDs in the overall LQTS population and in subgroups defined by ICD indications., Methods: This study included 3,035 patients (597 with ICD) from the Rochester LQTS Registry with a QTc ≥470 milliseconds or confirmed LQTS mutation. Using multivariable Cox proportional hazards models, the risk of all-cause mortality, all-cause mortality before age 50 years, and sudden cardiac death (SCD) were estimated as functions of time-dependent ICD therapy. Indication subgroups examined included patients with: 1) nonfatal cardiac arrest; 2) syncope while on beta-blockers; and 3) a QTc ≥500 milliseconds and syncope while off beta-blockers., Results: During the 118,837 person-years of follow-up, 389 patients died (137 before age 50 years, and 116 experienced SCD). In the entire population, patients with ICDs had a lower risk of death (HR: 0.54; 95% CI: 0.34-0.86), death before age 50 years (HR: 0.29; 95% CI: 0.14-0.61), and SCD (HR: 0.22; 95% CI: 0.09-0.55) than patients without ICDs did. Patients with ICDs also had a lower risk of mortality among the 3 indication subgroups (HR: 0.14; 95% CI: 0.06-0.34; HR: 0.27; 95% CI: 0.10-0.72; and HR: 0.42; 95% CI: 0.19-0.96, respectively)., Conclusions: ICD therapy was associated with a lower risk of all-cause mortality, all-cause mortality before age 50 years, and SCD in the LQTS population, as wells as with a lower risk of all-cause mortality in indication subgroups. This study provides evidence supporting ICD implantation in patients with high-risk LQTS., Competing Interests: Funding Support and Author Disclosures The study was performed with support from National Institutes of Health grants HL-33843, HL-51618, and HL-123483. Dr Zareba has received research grant support from Biotronik and LivaNova; and has received consulting honoraria for Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The role of cardiovascular implantable electronic device (CIED)-derived activity to predict implantable cardioverter-defibrillator (ICD) therapy or death is not known., Objective: We aimed to assess CIED-derived activity to predict clinical outcomes., Methods: In 1500 patients enrolled in MADIT-RIT, CIED-derived patient activity was acquired daily, then averaged for the first 30 days following randomization to predict inappropriate/appropriate therapy or death. Kaplan-Meier analysis and Cox proportional regression models were used to evaluate inappropriate/appropriate therapy, heart failure, or death by 30-day CIED-derived patient activity quintiles., Results: There were 1463 patients with CIED activity data (98%). Patients in the highest quintile (Q5) of activity (more active) had the highest rate of inappropriate therapy, 21% at 2 years, as compared to 7%-11% in the other 4 quintiles (P < .001), a 1.75 times higher risk (95% confidence interval [CI]: 1.23-2.50, P = .002). However, patients in the lowest quintile of activity (Q1, 1 hour/day) had the highest risk of mortality, 15% in 2 years, as compared to Q2-3 (1-2 hours/day, 8%-7% mortality), and Q4-5 (>2 hours/day, 2%-3% mortality) (P < .001). Patients with the lowest level of activity (Q1) had a 2.02 times higher risk of mortality (95% CI: 1.21-3.38, P = .007), and they had an 82% higher risk of heart failure hospitalization (95% CI: 1.28-2.57, P = .001)., Conclusions: High CIED-derived 30-day median patient activity predicted inappropriate therapy, while low patient activity predicted mortality and heart failure in ICD and cardiac resynchronization therapy with defibrillator patients enrolled in MADIT-RIT. Device-derived activity assessment could serve as a useful predictor of outcomes., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Cardiac resynchronization therapy (CRT) may be pro-arrhythmic in patients with non-left bundle branch block (non-LBBB). We hypothesized that combined assessment of risk factors (RF) for ventricular tachyarrhythmias (VTAs) can be used to stratify non-LBBB patients for CRT implantation., Methods: The study comprised 412 non-LBBB patients from MADIT-CRT randomized to CRT-D (n = 215) versus ICD only (n = 197). Best-subset regression analysis was performed to identify RF associated with increased VTA risk in CRT-D patients without LBBB. The primary end point was first occurrence of sustained VTA during follow-up. Secondary end points included VTA/death and appropriate shock., Results: Four RFs were associated with increased VTA risk: blood urea nitrogen >25mg/dl, ejection fraction <20%, prior nonsustained VT, and female gender. Among CRT-D patients, 114 (53%) had no RF, while 101 (47%) had ≥1 RF. The 4-year cumulative probability of VTA was higher among those with ≥1 RF compared with those without RF (40% vs. 14%, p < .001). Multivariate analysis showed that in patients without RF, treatment with CRT-D was associated with a 61% reduction in VTA compared with ICD-only therapy (p = .002), whereas among patients with ≥1 RF, treatment with CRT-D was associated with a corresponding 73% (p = .025) risk increase. Consistent results were observed when the secondary end points of VTA/death and appropriate ICD shocks were assessed., Conclusion: Combined assessment of factors associated with increased risk for VTA can be used for improved selection of non-LBBB patients for CRT-D., (© 2021 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Background: There are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality., Objectives: The aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality., Methods: The study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks., Results: When analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratio [HR]: 2.78 and 2.31; p < 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT <200 beats/min (HRs: 2.25 and 2.62; both p < 0.001), whereas appropriate therapy for VT <200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p > 0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HR: all >2.8; p < 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV)., Conclusion: The combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients., Competing Interests: Funding Support and Author Disclosures Each of the MADIT trials was funded by an unrestricted research grant from Boston Scientific to the University of Rochester Medical Center, Rochester, New York. The RAID trial was funded by the National Institutes of Health (grant U01HL096607). Dr. Aktaş has received research grants from Boston Scientific and Medtronic. Dr. Zarebas has received research grants from Boston Scientific. Dr. Kutyifa has received research grants from Boston Scientific, Biotronik, ZOLL, and Spire; and has consultant agreements with Zoll and Biotronik. Dr. Daubert has received honoraria for events committee, data safety monitoring board, consulting, advisory boards and lectures from Abbott, Biosense, Biotronik, Boston Scientific, Farapulse, Medtronic, Microport, Phillips, Vytronus, and Zoll; and has received research grants from Abbott and Medtronic. Dr. Estes has served as a consultant for Boston Scientific (education), Medtronic (independent quality physician panel), and Abbott (education). Dr. Goldenberg has received research grants from Boston Scientific, Zoll, Medtronic, Biosense-Webster, and Biotronik., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks., Methods and Results: The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m., systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability., Conclusions: We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: We aimed to characterize the hourly, daily, and seasonally variations in the detection of new atrial fibrillation (AF) in heart failure patients implanted with a defibrillator., Methods: In 1309 patients enrolled in MADIT-RIT without AF at baseline, atrial arrhythmia data were analyzed from device interrogations. The circadian, weekly, and seasonal distribution of device detected AF was evaluated. The morning period was defined as 06:00-11:59, afternoon as 12:00-16:59, evening as 17:00-22:59, and the nighttime as 23:00-05:59., Results: During 17 months of follow-up, 66 (5%) patients developed new device-detected AF. AF patients were less likely to have ischemic cardiomyopathy and were more likely to have received an implantable cardioverter defibrillator rather than a cardiac resynchronization therapy with defibrillator. The highest number of AF occurred during the evening hours (25 patients [38%]) followed by a second peak in AF detection during the afternoon hours (21 patients [32%]). Importantly during the nighttime, new AF occurred only in three patients (4%). In comparison with the nighttime period, the odds ratio (OR) of developing AF during the evening time period was 8.5-fold higher (95% CI 7.3-9.7, P < .01). Detection of AF during the spring and winter seasons accounted for 67% of all new device-detected AF., Conclusions: There is diurnal and seasonal variation in new onset AF. A double peak in the incidence of AF is observed during the afternoon and evening hours, and during the spring and winter seasons. This information may be useful when deciding when to screen at-risk patients for new AF., (© 2020 Wiley Periodicals LLC.)

Background Sex differences in outcome have been reported in patients with congenital long QT syndrome. We aimed to report on the incidence of time-dependent life-threatening events in male and female patients with long QT syndrome with an implantable cardioverter defibrillator (ICD). Methods and Results A total of 60 patients with long QT syndrome received an ICD for primary or secondary prevention indications. Life-threatening events were evaluated from the date of ICD implant and included ICD shocks for ventricular tachycardia, ventricular fibrillation, or death. ICDs were implanted in 219 women (mean age 38±13 years), 46 girls (12±5 years), 55 men (43±17 years), and 40 boys (11±4 years). Mean follow-up post-ICD implantation was 14±6 years for females and 12±6 years for males. At 15 years of follow-up, the cumulative probability of life-threatening events was 27% in females and 34% in males (log-rank P =0.26 for the overall difference). In the multivariable Cox model, sex was not associated with significant differences in risk first appropriate ICD shock (hazard ratio, 0.83 female versus male; 95% CI, 0.52-1.34; P =0.47). Results were similar when stratified by age and by genotype: long QT syndrome type 1 (LQT1), long QT syndrome type 2 (LQT2), and long QT syndrome type 3 (LQT3). Incidence of inappropriate ICD shocks was higher in males versus females (4.2 versus 2.7 episodes per 100 patient-years; P =0.018), predominantly attributed to atrial fibrillation. The first shock did not terminate ventricular tachycardia/ventricular fibrillation in 48% of females and 62% of males ( P =0.25). Conclusions In patients with long QT syndrome with an ICD, the risk and rate of life-threatening events did not significantly differ between males and females regardless of ICD indications or genotype. In a substantial proportion of patients with long QT syndrome, first shock did not terminate ventricular tachycardia/ventricular fibrillation.

Aims: Patients with impaired renal function were shown to have an attenuated benefit from implantable cardioverter-defibrillator. However, there are limited data on the competing risk of ventricular arrhythmia events and death by renal function in patients without severe disease. Therefore, we aimed to assess the competing risk of ventricular arrhythmia events and death by renal function., Methods and Results: We analysed 1782 patients (99%) enrolled in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) with glomerular filtration rate (GFR) data available. Cumulative incidence function curves were used to display the rate of ventricular tachycardia (VT), ventricular fibrillation (VF), and the competing risk of death without experiencing VT/VF. Multivariable Fine and Gray regression models and recurrent event analysis were performed. There were 355 (20%) patients with GFR < 52 and 1427 with GFR ≥ 52 (lowest quintile). The incidence of non-fatal VT/VF at 4 years was higher in patients with high GFR (26%) as compared to low GFR (16%), whereas rates of death without non-fatal VT/VF were 5% and 20% (P < 0.001). In Fine and Gray models, the low GFR group was 35% less likely to experience VT/VF compared to the high GFR [95% confidence interval (CI) 0.48-0.88, P = 0.005]. In contrast,death without experiencing VT/VF was 3.5-fold higher in the low GFR group (95% CI 2.38-5.12, P-value < 0.001). Recurrent event analysis consistently showed a lower risk of recurrent VT/VF, recurrent anti-tachycardia pacing only, and shock in the low GFR group., Conclusions: We show, in a competing risk model, a lower risk of VT/VF events and a higher risk of mortality without an arrhythmic event in patients with moderate renal dysfunction in MADIT-CRT. These findings can be used for improved selection of patients for defibrillator therapy among CRT candidates., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00180271., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Mild heart failure (HF) patients without left bundle branch block (LBBB) did not derive a significant reduction in risk of a HF event/death in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). However, the efficacy of CRT with a defibrillator (CRT-D) may be modified after the development of the first hospitalization for HF (HHF). We aimed to study the effect of CRT-D on long-term risk of recurrent HHF in patients without LBBB in MADIT-CRT., Methods: Data on recurring HHF were collected for 1818 subjects. The CRT-D versus implantable cardioverter-defibrillator-only risk for first and subsequent HHF was assessed by QRS morphology in on-treatment analysis using Cox proportional hazards regression modeling., Results: During long-term follow-up, 412 patients had ≥1 HHF and 333 had ≥2 HHF. Multivariate analysis revealed that in LBBB patients, CRT-D, compared with implantable cardioverter-defibrillator, was associated with a significant reduction in risk of first and subsequent HHF (first: hazard ratio, 0.41 [95% CI, 0.31-0.54], P <0.001; subsequent: hazard ratio, 0.45 [95% CI, 0.29-0.70], P <0.001). Among patients without LBBB, the benefit of CRT-D was nonsignificant for the first HHF (hazard ratio, 0.96; P =0.808). However, after occurrence of a first HHF, CRT-D therapy was associated with a pronounced 44% reduction in risk of subsequent HHF (hazard ratio, 0.56 [95% CI, 0.32-0.97], P =0.039). Patients without LBBB with ≥1 HHF during the first year of follow-up demonstrated increasing dyssynchrony at 1 year compared with those who had no HHF ( P =0.016)., Conclusions: In MADIT-CRT, we show a beneficial effect of CRT-D in patients without LBBB subsequent to development of a first HHF, possibly due to increased dyssynchrony associated with HF progression. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00180271, NCT01294449, and NCT02060110.

Background: Implantation of the subcutaneous implantable cardioverter-defibrillator (S-ICD) is spreading and has been shown to be safe and effective; however, it does not provide brady-pacing. Currently, data on the need for brady-pacing and cardiac resynchronization therapy (CRT) implantation in patients with ICD indication are limited., Methods: The Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II enrolled post-MI patients with reduced ejection fraction (EF ≤ 35%), randomized to either an implantable cardioverter-defibrillator (ICD) or conventional medical therapy. Kaplan-Meier analyses and multivariate Cox models were performed to assess the incidence and predictors of pacemaker (PM), or CRT implantation in the conventional arm of MADIT-II, after excluding 32 patients (6.5%) with a previously implanted PM., Results: During the median follow-up of 20 months, 24 of 458 patients (5.2%) were implanted with a PM or a CRT (19 PM, 5 CRT). Symptomatic sinus bradycardia was the primary indication for PM implantation (n = 9, 37%), followed by AV block (n = 5, 21%), tachy-brady syndrome (n = 4, 17%), and carotid sinus hypersensitivity (n = 1, 4%). Baseline PR interval >200 ms (HR = 3.07, 95% CI: 1.24-7.57, p = .02), and CABG before enrollment (HR = 6.88, 95% CI: 1.58-29.84, p = .01) predicted subsequent PM/CRT implantation. Patients with PM/CRT implantation had a significantly higher risk for heart failure (HR = 2.67, 95% CI = 1.38-5.14, p = .003), but no increased mortality risk (HR = 1.06, 95% CI = 0.46-2.46, p = .89)., Conclusion: The short-term need for ventricular pacing or CRT implantation in patients with MADIT-II ICD indication was low, especially in those with a normal baseline PR interval, and such patients are appropriate candidates for the subcutaneous ICD., (© 2020 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals, Inc.)

Multiple randomized multicentre clinical trials have established the role of the implantable cardioverter-defibrillator (ICD) as the mainstay in the treatment of ventricular tachyarrhythmias and sudden cardiac death (SCD) prevention. These trials have focused mainly on heart failure patients with advanced left ventricular dysfunction and were mostly conducted two decades ago, whereas a more recent trial has provided conflicting results. Therefore, much remains to be determined on how best to balance the identification of patients at high risk of SCD together with who would benefit most from ICD implantation in a contemporary setting. Implantable cardioverter-defibrillators have also evolved from the simple, defibrillation-only devices implanted surgically to more advanced technologies of multi-chamber devices, with physiologic bradycardic pacing, including cardiac resynchronization therapy, atrial and ventricular therapeutic pacing algorithms, and subcutaneous ICDs. These multiple options necessitate individualized approach to device selection and programming. This review will focus on the current knowledge on selection of patients for ICD treatment, device selection and programming, and future directions of implantable device therapy for SCD prevention., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Atrial tachyarrhythmias (ATAs) are common among heart failure (HF) patients., Objective: The purpose of this study was to assess predictors for the development of new ATA and its components (atrial fibrillation/flutter [AF], supraventricular tachycardia [SVT]), and their association with subsequent clinical outcomes., Methods: We assessed predictors for first and recurrent ATA, AF, and SVT among 1500 patients in MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). We also investigated the association of new ATA, AF, or SVT with subsequent ventricular arrhythmia (VA), adverse events (HF hospitalization, syncope, or death), or death by time-dependent analysis., Results: During 17 months of follow-up, 286 patients (19%) developed new ATA, of whom 92 (6%) had AF and 194 (12%) had SVT. Younger age (≤65 years), diastolic blood pressure ≥72 mm Hg, heart rate ≥63 bpm, absence of diabetes, and prior atrial arrhythmia were independent predictors of ATA. Prior atrial arrhythmia was the only predictor of AF (hazard ratio 3.14; P <.001). New ATA was associated with significantly increased risk for subsequent VA (HR 2.12; P <.001), increased adverse events (HR 1.42; P <.001), and death (HR 1.85; P = .038). New AF and new SVT were both independently associated with >2-fold increased risk for the development of subsequent VA (HR 2.21; P = .012l and HR 2.15; P <.001, respectively) and adverse events., Conclusion: Among MADIT-RIT patients, younger age, absence of diabetes, higher blood pressure, higher heart rate, and prior atrial arrhythmia predicted device-detected ATA. Both AF and SVT were associated with increased risk for subsequent VA and adverse events. Aggressive management should be considered in HF patients who develop new-onset, device-detected ATA to improve clinical outcomes., (Published by Elsevier Inc.)

Aims: To explore the association between resting heart rate (RHR) and ventricular tachyarrhythmias (VTA) events among patients who were enrolled in MADIT-RIT., Methods and Results: Multivariate Cox proportional hazards regression modelling was employed to evaluate the association between baseline RHR [dichotomized at the lower quartile (≤63 b.p.m.) and further assessed as a continuous measure] and the risk for any VTA, fast VTA (>200 b.p.m.), and appropriate implantable cardioverter-defibrillator (ICD) therapy, among 1500 patients who were enrolled in MADIT-RIT. Kaplan-Meier survival analysis showed that at 2 years of follow-up the rate of any VTA was significantly lower among patients with low baseline RHR (≤63 b.p.m.) as compared with faster RHR (11% vs. 19%, respectively; P = 0.001 for the overall difference during follow-up). Similar results were shown for the association with the rate of fast VTA (8% vs. 14%, respectively; P = 0.016), and appropriate ICD therapy (10% vs. 18%, respectively; P = 0.004). Multivariate analysis, after adjustment for medical therapy, showed that low baseline RHR was associated with a significant 45% (P = 0.002) reduction in the VTA risk as compared with faster baseline RHRs. When assessed as a continuous measure, each 10 b.p.m. decrement in RHR was associated with a corresponding 13% (P = 0.014) reduction in the VTA risk., Conclusion: In MADIT-RIT, low RHR was independently associated with a lower risk for life-threatening arrhythmic events. These findings suggest a possible role for RHR for improved selection of candidates for ICD therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: There are limited data regarding factors that identify implantable cardioverter-defibrillator (ICD) patients who will experience either ventricular tachyarrhythmic (VTA) or non-arrhythmic (NA) mortality, and the commonly used clinical classification of sudden cardiac death (SCD) vs. non-sudden cardiac death (NSCD) may not be accurate enough. We aimed to correlate clinical adjudication of mortality events to device interrogation data and to identify risk factors for VTA mortality in Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)., Methods and Results: Of the 746 patients who received an ICD in MADIT-II, 44 died from cardiac causes and had available interrogation data at the time of death. Sudden cardiac death vs. NSCD was defined by an adjudication committee. Ventricular tachyarrhythmic and NA arrhythmic deaths were categorized by the presence or absence of ventricular tachycardia or fibrillation (VT/VF) during the terminal event. Mode of death was found to be inaccurate when validated by device interrogation for VTA events: 50% patients adjudicated as SCD did not have a VTA event at the time of death; and 25% of adjudicated NSCD were found to have VT/VF during the mortality event. Multivariate analysis showed that factors independently associated with VTA mortality included: VT/VF >72 h prior to the mortality event [hazard ratio (HR) 8.0; P < 0.001], hospitalization for heart failure (HR 6.7; P = 0.001), and a history of hypertension (HR 4; P = 0.04)., Conclusion: Current classification of SCD vs. NSCD fails to identify VTA events at the time of death in a significant proportion of patients, and simple clinical parameters can be used to identify ICD recipients with increased risk for VTA mortality., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study assessed the arrhythmic risk of cardiac resynchronization therapy (CRT) patients who improved beyond Heart Rhythm Society/European Society of Cardiology guidelines for an implantable cardioverter-defibrillator (ICD) (ischemic cardiomyopathy: left ventricular ejection fraction [LVEF] >35% or New York Heart Association [NYHA] functional class I and if LVEF was 31% to 35%; nonischemic cardiomyopathy: LVEF >35% or NYHA functional class I and if LVEF was ≤35%)., Background: It is currently unknown whether protection with a defibrillator is still warranted in patients who respond to CRT., Methods: This study compared the risk of ICD therapy for any ventricular tachyarrhythmia (VTA) and for fast VTA (≥200 beats/min) among patients implanted with a CRT with a defibrillator (CRT-D) in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) (N = 734) who improved at 1 year beyond guideline recommendations for primary ICD therapy (group A) with those who remained within guideline recommendations for an ICD at 1 year (group B)., Results: Most patients implanted with a CRT-D device improved at 1 year beyond guideline indications for an ICD (90%). Multivariate analysis showed lower risks for any VTA and fast VTA among group A patients versus group B patients (57% risk reduction; p = 0.0006 and 46% risk reduction; p = 0.068, respectively). However, the 2-year rates of any VTA and fast VTA among CRT patients who improved beyond guidelines indications for an ICD was still substantial (VTA: 13% and 29%, and fast VTA: 7% and 16%, respectively)., Conclusions: Most patients with mild heart failure implanted with a CRT device experience an improvement in left ventricular function and/or NYHA functional class beyond guideline recommendations for primary ICD therapy. However, despite this pronounced CRT response, there remains a substantial VTA risk, and protection with a defibrillator may still be warranted in this population., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The clinical benefit of primary prevention implantable cardioverter-defibrillator (ICD) therapy in asymptomatic patients (New York Heart Association [NYHA] functional class I) with ischemic cardiomyopathy and left ventricular dysfunction is continually disputed., Objective: The purpose of this study was to evaluate the incidence of ventricular arrhythmias, mortality rates, and appropriate device therapies by NYHA class in a prospective national ICD registry., Methods: The study comprised 1670 consecutive patients with ischemic cardiomyopathy who were implanted with a primary prevention ICD and enrolled in the prospective national Israeli ICD Registry from 2010. The risk for clinical and arrhythmic events was assessed by NYHA class., Results: Asymptomatic patients (NYHA I) composed 19% of the study cohort. Comparison according to NYHA class showed that the highest mortality rate was in the NYHA III-IV group vs NYHA I and NYHA II (10.5% vs 5.4% and 5.8%, respectively; log rank P = .003). Conversely, cumulative incidence of appropriate ICD therapies, corrected for death as a competing risk, were higher among patients with NYHA I (11% vs 7%; P = .021). In a multivariate model, NYHA I vs ≥II remained independently associated with a significant 2-fold risk for appropriate ICD therapy (hazard ratio 2.03; 95% confidence interval 1.28-3.24)., Conclusion: Our findings indicate that patients with ischemic cardiomyopathy without heart failure symptoms have a higher risk of appropriate ICD therapy compared with symptomatic patients after adjustment for the competing risk of death, suggesting possible incremental benefit of primary ICD implantation in this population., (Copyright © 2019. Published by Elsevier Inc.)

Background Patients with heart failure and an implantable cardioverter-defibrillator ( ICD ) for primary prevention are at increased mortality risk after receiving shock therapy. We sought to determine the prognostic significance of ICD therapies, both shock and antitachycardia pacing, delivered for different ventricular arrhythmia ( VA ) rates. Methods and Results We evaluated mortality risk among 1790 ICD -implanted patients from MADIT -CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). For the first analysis, patients were divided into mutually exclusive groups by the rate of treated VA only: slow VA (<200 beats per minute) and fast VA (≥200 beats per minute or ventricular fibrillation). In a secondary analysis, both the type of ICD therapy and VA rate were used. The reference group was always patients who had no ICD therapy. ICD therapy for fast VA was associated with increased mortality risk (hazard ratio [ HR] , 2.27; 95% CI , 1.48-3.48; P<0.001). However, mortality risk after ICD therapy for slow VA was similar to the risk related to no ICD therapy ( HR , 1.45; 95% CI , 0.86-2.44; P=0.162). Consistently, shocks ( HR , 2.96; 95% CI , 1.91-4.60; P<0.001) and antitachycardia pacing ( HR , 2.22; 95% CI , 0.96-5.14; P=0.063) for fast VA were both associated with increased mortality risk. Shocks and antitachycardia pacing for slow VA were not significantly associated with increased mortality risk ( HR , 1.43 [95% CI , 0.52-3.92; P=0.489]; and HR , 1.43 [95% CI, 0.80-2.56; P=0.232], respectively). Conclusions In patients with mild heart failure receiving ICD for primary prevention, mortality is associated with the rate of underlying VA rather than the type of therapy. These findings suggest that fast VA is a marker for increased mortality rather than shock therapy directly contributing to increased risk. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00180271.

Aims: Heart failure patients with advanced chronic kidney disease (CKD) may experience an increased rate of non-arrhythmic mortality due to associated comorbidities. We aimed to evaluate the risk of mortality without appropriate implantable cardioverter-defibrillator (ICD) shocks in this high-risk population., Methods and Results: The study population comprised 3542 patients who received an ICD, were enrolled, and prospectively followed-up in the Israeli ICD registry. Study patients were categorized into two groups: those with advanced CKD [defined by a glomerular filtration rate of <30 mL/min/1.73 m2 or being on dialysis at time of implantation (n = 197)], and those without advanced CKD (n = 3344). The primary endpoint was the risk of death without receiving appropriate ICD shock. Kaplan-Meier survival analysis showed that at 5 years of follow-up the rates of death without prior ICD shock were significantly higher in the advanced kidney disease group (46%) compared with the non-advanced CKD group (19%; log-rank P-value <0.001). Consistently, multivariate analysis showed that the risk of death without receiving appropriate ICD shock therapy at 5 years was 2.5-fold (P < 0.001) higher among advanced CKD patients. In contrast, the rate of appropriate ICD shock therapy at 5 years among advanced CKD patients was only 9%, with a very high mortality rate (63%) within 3.5 years subsequent to shock therapy., Conclusion: Nearly one-half of ICD with advanced CKD die within 5 years without receiving an appropriate ICD shock. These findings stress the importance of appropriate patient selection for primary ICD implantation in this high-risk population., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Prospective data regarding the role of implantable cardioverter-defibrillator (ICD) for the primary prevention of sudden cardiac death in patients with long QT syndrome (LQTS) is scarce. Herein, we explore the prospective Rochester LQTS ICD registry to assess the risk for appropriate shock in primary prevention in a real-world setting., Methods and Results: We studied 212 LQTS patients that had ICD implantation for primary prevention. Best-subsets proportional-hazards regression analysis was used to identify clinical variables that were associated with the first appropriate shock. Conditional models of Prentice, Williams, and Peterson were utilized for the analysis of recurrent appropriate shocks. During a median follow-up of 9.2 ± 4.9 years, there were 42 patients who experienced at least one appropriate shock and the cumulative probability of appropriate shock at 8 years was 22%. QTc ≥ 550 ms [hazard ratio (HR) 3.94, confidence interval (CI) 2.08-7.46; P < 0.001) and prior syncope on β-blockers (HR 1.92, CI 1.01-3.65; P = 0.047) were associated with increased risk of appropriate shock. History of syncope while on β-blocker treatment (HR 1.87, CI 1.28-2.72; P = 0.001), QTc 500-549 ms (HR 1.68, CI 1.10-2.81; P = 0.048), and QTc ≥ 550 ms (HR 3.66, CI 2.34-5.72; P < 0.001) were associated with increased risk for recurrent appropriate shocks, while β-blockers were not protective (HR 1.03, CI 0.63-1.68, P = 0.917). LQT2 (HR 2.10, CI 1.22-3.61; P = 0.008) and multiple mutations (HR 2.87, CI 1.49-5.53; P = 0.002) were associated with higher risk for recurrent shocks as compared with LQT1., Conclusion: In this prospective ICD registry, we identified clinical and genetic variables that were associated appropriate shock risk. These data can be used for risk stratification in high-risk patients evaluated for primary prevention with ICD.

Objectives: The authors aimed to evaluate the association of left ventricular (LV) lead location and long-term outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy)., Background: There is limited data on the association of lead location with long-term clinical outcomes in patients with cardiac resynchronization therapy with defibrillator (CRT-D)., Methods: The LV lead location was classified in 797 patients with CRT-D, in 569 patients with left bundle branch block (LBBB), in 228 patients with non-LBBB, and in 505 patients with an implantable cardioverter-defibrillator (ICD) only. Leads were classified into apical (n = 83) and non-apical (n = 486); with the non-apical LV leads further categorized into anterior (n = 99) and posterior/lateral (n = 387) within LBBB. All-cause mortality and heart failure (HF) events were assessed using Kaplan-Meier and Cox analyses., Results: In CRT-D patients with LBBB and posterior/lateral LV lead location, there was an association with a significant reduction in long-term all-cause mortality (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.37 to 0.79; p = 0.001), and HF events (HR: 0.44, 95% CI: 0.33 to 0.60; p < 0.001) compared to an ICD only, accompanied with better LV reverse remodeling. CRT-D patients with LBBB and an anterior LV lead location were shown to be associated with a significant reduction in HF events compared to an ICD only (anterior HR: 0.50, 95% CI: 0.30 to 0.82; p = 0.006); however, no association with mortality reduction was observed from CRT-D versus an ICD only. CRT-D was not associated with improved outcomes in non-LBBB patients, regardless of LV lead location., Conclusions: In mild HF patients with LBBB and an implanted CRT-D, lateral/posterior, and anterior LV lead locations are similarly associated with reduction in the risk of HF or death events compared to ICD alone. Mortality benefit derived from CRT-D is associated only with patients with lateral/posterior LV lead location. An apical LV lead location should be avoided due to the early risk of death whenever possible. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT], NCT00180271; Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy Post Approval Registry [MADIT-CRT-PAR], NCT01294449; and MADIT-CRT Long-Term International Follow-Up Registry - Europe, NCT02060110)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Life expectancy of less than 1 year is usually a contraindication for implantable cardioverter defibrillator (ICD) implantation. The aim was to identify patients at risk of death during the first year after implantation., Methods and Results: Data were derived from a prospective Israeli ICD Registry. Two groups of patients were compared, those who died and those who were alive 1 year after ICD implantation. Factors associated with 1-year mortality were identified on a derivation cohort. A risk score was established and validated. A total of 2617 patients have completed 1 year of follow-up after ICD or cardiac resynchronization therapy defibrillator (CRT-D) implantation. Age greater than 75 years (hazard ratio [HR], 2.7; 95% confidence interval [95% CI], 1.6 to 4.4), atrial fibrillation (AF; HR, 1.9; 95% CI, 1.12 to 3.17), chronic lung disease (HR, 2.0; 95% CI, 1.1 to 3.76), anemia (HR, 2.3; 95% CI, 1.3 to 3.93) and chronic renal failure (CRF; HR, 3.4; 95% CI, 1.74 to 6.6) were independent risk factors for 1-year mortality. We propose a simple AAACC ("triple A double C") score for prediction of 1-year mortality after ICD implantation: Age greater than 75 years (3 points(pts)), anemia (2 pts), AF (1 pt), CRF (3 pts) and chronic lung disease (1 pt). Mortality risk increased with rising number of points (from 1% with 0 pts to 12.5% with >4 pts). The risk score was evaluated with receiver operating characteristic curve and the area under the curve of the validation curve is 0.71 (95% CI, 0.66 to 0.76)., Conclusions: Age greater than 75, AF, chronic lung disease, anemia, and CRF were independent risk factors for 1-year mortality. AAACC risk score identifies patients at high risk of death during 1 year after ICD implantation., (© 2018 Wiley Periodicals, Inc.)

The ACC/AHA/HRS (American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society) guidelines recommend implantable cardioverter-defibrillator (ICD) therapy primary prevention in all patients with severely reduced left ventricular ejection fraction (≤30%) regardless of New York Heart Association (NYHA) functional class, whereas recent European guidelines limit the indication to those with symptomatic heart failure (NYHA ≥ II). We therefore aimed to evaluate the long-term survival benefit of primary ICD therapy among postmyocardial infarction patients with and without heart failure (HF) symptoms who were enrolled in MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II). We classified 1,164 MADIT-II patient groups according to the baseline NYHA class (NYHA I [n = 442], NYHA II [n = 425], and NYHA III [n = 297]); patients with NYHA IV were excluded. Multivariate Cox proportional hazards regression modeling was performed to compare the mortality reduction with ICD versus non-ICD therapy during 8 years of follow-up between the 3 NYHA groups. The median (interquartile range) follow-up time was 7.6 (3.5 to 9) years. At 8 years of follow-up, the cumulative probability of mortality in the non-ICD treatment arm was 57% for NYHA I, 57% for NYHA II, and 76% for NYHA III (p <0.001). Multivariate models demonstrated similar long-term mortality risk reduction with ICD compared with the non-ICD treatment arm regardless of HF symptoms: NYHA I (HR = 0.63, 0.46 to 0.85, p = 0.003), NYHA II (HR = 0.68, 0.50 to 0.93, p = 0.017), and NYHA III (HR = 0.68, 0.50 to 0.94, p = 0.018); p for NYHA class by treatment arm interaction >0.10. In conclusion, primary ICD therapy provides consistent long-term survival benefit among patients with previous myocardial infarction and severe left ventricular dysfunction, regardless of HF symptoms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is an effective treatment for heart failure (HF); however, a third of patients are non-responders. The development of quadripolar left ventricular (LV) lead was shown, mainly in single manufactures' registry, to improve LV remodeling and overall mortality. However, limited reports exist on the impact of quadripolar LV leads on HF hospitalization rates in real-life cohorts. We evaluated the clinical outcomes associated with quadripolar LV leads in a large nation-wide registry including all patients implanted with a cardiac resynchronization therapy with defibrillator (CRT-D)., Methods: Between July 2010 and October 2016, 2913 consecutive patients were implanted with a CRT-D and all were prospectively enrolled in the Israeli ICD Registry. Quadripolar LV leads were implanted in 973 (33.4%) patients during this period, and their clinical outcomes were compared to CRT-D recipients implanted with a bipolar LV lead. Primary endpoint was HF hospitalization rate., Results: Quadripolar leads were implanted more in patients with non-ischemic cardiomyopathy and for primary prevention indication and less in post-infarction patients and for secondary prevention of sudden death. Longer QRS duration was observed with quadripolar leads (147 ± 23 vs 143 ± 25; p < 0.001). Outcome event rate for 100 patient years revealed no difference in HF hospitalization rates between bipolar and quadripolar LV leads. Quadripolar lead implant led to lower cardiac mortality, with no influence on overall mortality. Multivariate analysis revealed no significant differences in study endpoints between bipolar and quadripolar LV leads., Conclusion: In a large real-life registry, implantation of quadripolar LV leads in patients with CRT-D did not influence HF hospitalization rates.

Anemia was shown to be associated with increased risk for adverse events in patients with heart failure (HF). However, there are limited data on the association between anemia and the risk for ventricular arrhythmias (VAs) in patients with an implantable cardioverter defibrillator (ICD). The present study population comprised 2,352 patients who were enrolled and prospectively followed up in the Israeli ICD Registry. The risk for a first appropriate ICD shock for VA was assessed by the presence of anemia, categorized at the lower tertile of hemoglobin distribution (≤12 g/dL [n = 753]). Patients who had anemia displayed higher risk clinical characteristics including older age, more advanced HF symptoms, and atrial fibrillation (p <0.01 for all). Kaplan-Meier survival analysis showed that at 2.5 years of follow-up the rate of appropriate shocks was significantly higher in patients with low (11%) versus high (6%) hemoglobin (log-rank p <0.005). Multivariate analysis showed that anemia was independently associated with a significant 56% increased risk for first appropriate ICD shock (p <0.026). When hemoglobin was assessed as a continuous measure, each 1 g/dL reduction in hemoglobin was independently associated with a significant 8% increased risk for first appropriate shock (p <0.03). Anemia was also associated with increased risk for all-cause mortality (hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.4 to 2.27], p <0.001), HF hospitalizations or death (HR 1.78, 95% CI 1.48 to 1.13, p <0.001), but not with inappropriate ICD shocks (HR 1.24, 95% CI 0.70 to 2.21, p = 0.47). In conclusion, our findings suggest that the presence of anemia in patients with ICD is associated with increased risk for VA during long-term follow-up., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: There is lack of conclusive evidence from randomized clinical trials on the efficacy and safety of upgrade to cardiac resynchronization therapy (CRT) in patients with implanted pacemakers (PM) or defibrillators (ICD) with reduced left ventricular ejection fraction (LVEF) and chronic heart failure (HF). The BUDAPEST-CRT Upgrade Study was designed to compare the efficacy and safety of CRT upgrade from conventional PM or ICD therapy in patients with intermittent or permanent right ventricular (RV) septal/apical pacing, reduced LVEF, and symptomatic HF., Methods and Results: The BUDAPEST-CRT study is a prospective, randomized, multicentre, investigator-sponsored clinical trial. A total of 360 subjects will be enrolled with LVEF ≤ 35%, NYHA functional classes II-IVa, paced QRS ≥ 150 ms, and a RV pacing ≥ 20%. Patients will be followed for 12 months. Randomization is performed in a 3:2 ratio (CRT-D vs. ICD). The primary composite endpoint is all-cause mortality, a first HF event, or less than 15% reduction in left ventricular (LV) end-systolic volume at 12 months. Secondary endpoints are all-cause mortality, all-cause mortality or HF event, and LV volume reduction at 12 months. Tertiary endpoints include changes in quality of life, NYHA functional class, 6 min walk test, natriuretic peptides, and safety outcomes., Conclusion: The results of our prospective, randomized, multicentre clinical trial will provide important information on the role of cardiac resynchronization therapy with defibrillator (CRT-D) upgrade in patients with symptomatic HF, reduced LVEF, and wide-paced QRS with intermittent or permanent RV pacing., Clinical Trials.gov Identifier: NCT02270840., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: The aim of this study was to evaluate the effects of fish oils, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on ventricular tachyarrhythmic episodes (VTEs) in implantable cardioverter defibrillator (ICD) recipients with ischemic cardiomyopathy., Methods: One hundred five ICD recipients with ischemic cardiomyopathy received 3.6 g of EPA and DHA and placebo for 6 months, each at a random order, with a 4-month washout period between treatments. Eighty-seven patients completed the 16-month study protocol. The primary end point was any VTE (including sustained and non-sustained ventricular tachycardias at a rate of >150 bpm) as recorded by the ICDs. Secondary end points included device therapy (anti-tachycardia pacing (ATP) or shocks)., Results: During treatment with fish oils, there was a significant increase in EPA and DHA concentrations in red blood cells (RBCs) and subcutaneous fat tissue. Among 87 patients who completed the study protocol, the mean number of VTEs was significantly lower during treatment with fish oil (1.7) vs. placebo (5.6; p = 0.035). Appropriate device therapy for VTE occurred in 18 (21%) patients. Fish oil therapy was associated with a trend toward fewer VTEs terminated with ATP (2.8 ± 13.7 vs. 0.5 ± 2.1, respectively; p = 0.077). VTE terminated by ICD shocks, however, was rare, and rates were similar between both groups (0.11 ± 0.6 vs. 0.10 ± 0.4, p = not significant, respectively)., Conclusions: Our data suggest that fish oil therapy may be associated with a reduction in the frequency of VTE in ICD recipients with ischemic cardiomyopathy.

Aims: Dual-coil leads were traditionally considered standard of care due to lower defibrillation thresholds (DFT). Higher complication rates during extraction with parallel progression in implantable cardioverter defibrillator (ICD) technology raised questions on dual coil necessity. Prior substudies found no significant outcome difference between dual and single coils, although using higher rates of DFT testing then currently practiced. We evaluated the temporal trends in implantation rates of single- vs. dual-coil leads and determined the associated adverse clinical outcomes, using a contemporary nation-wide ICD registry., Methods and Results: Between July 2010 and March 2015, 6343 consecutive ICD (n = 3998) or CRT-D (n = 2345) implantation patients were prospectively enrolled in the Israeli ICD Registry. A follow-up of at least 1 year of 2285 patients was available for outcome analysis. The primary endpoint was all-cause mortality. Single-coil leads were implanted in 32% of our cohort, 36% among ICD recipients, and 26% among CRT-D recipients. Secondary prevention indication was associated with an increased rate of dual-coil implantation. A significant decline in dual-coil leads with reciprocal incline of single coils was observed, despite low rates of DFT testing (11.6%) during implantation, which also declined from 31 to 2%. In the multivariate Cox model analysis, dual- vs. single-coil lead implantation was not associated with an increased risk of mortality [hazard ratio (HR) = 1.23; P= 0.33], heart failure hospitalization (HR = 1.34; P=0.13), appropriate (HR = 1.25; P= 0.33), or inappropriate ICD therapy (HR = 2.07; P= 0.12)., Conclusion: Real-life rates of single-coil lead implantation are rising while adding no additional risk. These results of single-coil safety are reassuring and obtained, despite low and contemporary rates of DFT testing., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: Cardiac resynchronization therapy (CRT) with a defibrillator (CRT-D) has downsides of high cost and inappropriate shocks compared to CRT without a defibrillator (CRT-P). Recent data suggest that the survival benefit of implantable cardioverter defibrillator (ICD) therapy is attenuated in the older age group. We hypothesized that, among octogenarians eligible for cardiac resynchronization therapy, CRT-P confers similar morbidity and mortality benefits as CRT-D., Methods and Results: We compared morbidity and mortality outcomes between consecutive octogenarian patients eligible for CRT therapy who underwent CRT-P implantation at Barzilai MC (n = 142) vs. those implanted with CRT-D for primary prevention indication who were prospectively enrolled in the Israeli ICD Registry (n = 104). Among the 246 study patients, mean age was 84 ± 3 years, 74% were males, and 66% had ischaemic cardiomyopathy. Kaplan-Meier survival analysis showed that at 5 years of follow-up the rate of all-cause mortality was 43% in CRT-P vs. 57% in the CRT-D group [log-rank P = 0.13; adjusted hazard ratio (HR) = 0.79, 95% CI 0.46-1.35, P = 0.37]. Kaplan-Meier analysis also showed no significant difference in the rates of the combined endpoint of heart failure or death (46 vs. 60%, respectively, log-rank P = 0.36; adjusted HR was 0.85, 95% CI 0.51-1.44, P = 0.55). A Cox proportional hazard with competing risk model showed that re-hospitalizations for cardiac cause were not different for the two groups (adjusted HR 1.35, 95% CI 0.7-2.6, P = 0.37)., Conclusion: Our data suggest that, in octogenarians with systolic heart failure, CRT-P therapy is associated with similar morbidity and mortality outcomes as CRT-D therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Patients with diabetes mellitus, prior myocardial infarction, older age, and a relatively preserved left ventricular ejection fraction remain at risk for sudden cardiac death that is potentially amenable by the subcutaneous implantable cardioverter defibrillator with a good risk-benefit profile. The launched MADIT S-ICD study is designed to test the hypothesis that post-myocardial infarction diabetes patients with relatively preserved ejection fraction of 36%-50% will have a survival benefit from a subcutaneous implantable cardioverter defibrillator., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: There are limited data regarding the effect of diabetes mellitus (DM) on the risks of both appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy. The present study was designed to compare the outcome of appropriate and inappropriate ICD therapy in patients with or without DM., Methods and Results: The risk of a first appropriate ICD therapy for ventricular tachyarrhythmias (including anti tachycardia pacing and shock) was compared between 764 DM and 1346 non-DM patients enrolled in the national Israeli ICD registry. We also compared the risks of inappropriate ICD therapy, and death or cardiac hospitalization between diabetic and non-diabetic patients. Diabetic patients were older, were more likely to have ischemic cardiomyopathy, lower ejection fraction, atrial fibrillation, and other co-morbidities. The 3-year cumulative incidence of appropriate ICD therapy was similar in the DM and non-DM groups (12 and 13%, respectively, p = 0.983). Multivariate analysis showed that DM did not affect the risk of appropriate ICD therapy (HR = 1.07, 95% CI 0.78-1.47, p = 0.694) or inappropriate therapy (HR = 0.72, 95% CI 0.42-1.23, p = 0.232). However, DM was associated with a 31% increased risk for death or cardiac hospitalization (p = 0.005). Results were similar in subgroup analyses including ICD and defibrillators with cardiac resynchronization therapy function recipients, primary or secondary prevention indication for an ICD., Conclusions: Despite a significant excess of cardiac hospitalizations and mortality in the diabetic population, there was no difference in the rate of ICD treatments, suggesting that the outcome difference is not related to arrhythmias.