Impact of High-Voltage Device Implantation in Elderly Japanese Patients With Heart Failure as Primary Prevention　- Post Hoc Analysis of HINODE.

BACKGROUND: Despite an increased incidence of chronic heart failure (HF) and sudden cardiac death (SCD), the use of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) is much lower in Japan than in Western countries. The HF Indication and SCD Prevention Trial Japan (HINODE) prospectively assessed the mortality rate, appropriately treated ventricular arrhythmias (VA), and HF in Japanese patients with a higher risk of HF.Methods and Results: HINODE consisted of ICD, CRT-defibrillator (CRT-D), pacing, and non-device treatment cohorts. This subanalysis evaluated the impact of the implantation of high-voltage devices (HVD; ICD and CRT-D) in 171 Japanese patients. We compared all-cause mortality, VA, and HF events between elderly (age >70 years at study enrollment) and non-elderly HVD recipients. The estimated survival rate through 24 months in the HVD cohort was 85.8% (97.5% lower control limit 77.6%). The risk of all-cause mortality was increased for the elderly vs. non-elderly (hazard ratio [HR] 2.82; 95% confidence interval [CI] 1.01-7.91; P=0.039), but did not differ after excluding ICD patients with CRT-D indication (HR 2.32; 95% CI 0.79-6.78; P=0.11). There were no differences in VA and HF event-free rates between elderly and non-elderly HVD recipients (P=0.73 and P=0.55, respectively). CONCLUSIONS: Although elderly patients may have a higher risk of mortality in general, the benefit of HVD therapy in this group is comparable to that in non-elderly patients.

Association of interventricular activation delay with clinical outcomes in cardiac resynchronization therapy.

BACKGROUND: Pacing at sites of longest interventricular delay has been associated with greater reverse remodeling in cardiac resynchronization therapy (CRT). However, the effects of pacing at such sites on clinical outcomes is less well studied. OBJECTIVE: The purpose of this study was to assess the association between interventricular delay and clinical outcomes in CRT patients implanted with quadripolar left ventricular (LV) leads. METHODS: RALLY-X4 was a registry study of the Acuity X4 quadripolar LV leads. Interventricular delay was measured during unpaced basal rhythm from the right ventricular (RV) lead to the LV lead electrode (E1 to E4) chosen for CRT pacing. Patients were stratified by median RV-LV delay (80 ms) into short and long delay groups; they also were analyzed by multivariable modeling. The primary composite outcome measure was all-cause mortality and heart failure hospitalization (HFH) at 18 months. RESULTS: A total of 581 patients had complete RV-LV delay data. Mean LV ejection fraction was 27%, and 73% had typical left bundle branch block. Predictors of long RV-LV delay included female sex, left bundle branch block, and QRS duration >150 ms. Survival free of the primary outcome at 18-month follow-up was 87% in the long activation delay group compared with 77% in the short delay group (P = .0042). Multivariate analysis showed that RV-LV delay was an independent predictor of survival free of HFH (P = .028). CONCLUSION: Among CRT patients with quadripolar LV pacing leads, longer baseline interventricular activation delay was significantly associated with the composite endpoint of all-cause mortality and HFH.

Primary results from the Japanese Heart Failure and Sudden Cardiac Death Prevention Trial (HINODE).

AIMS: The HINODE study aimed to analyse rates of mortality, appropriately treated ventricular arrhythmias (VA), and heart failure in Japanese patients and compared with those in Western patients. METHODS AND RESULTS: After treatment decisions following contemporary practice in Japan, patients were prospectively enrolled into four cohorts: (i) internal cardioverter-defibrillator (ICD), (ii) cardiac resynchronization therapy (CRT) defibrillator (CRT-D), (iii) standard medical therapy ('non-device': ND), or (iv) pacing (indicated for CRT; received pacemaker or CRT pacing). Cohorts 1-3 required a left ventricular ejection fraction ≤35%, a history of heart failure, and a need for primary prevention of sudden cardiac death based on two to five previously identified risk factors. Endpoint outcomes were adjudicated by the independent committees. ICD and CRT-D cohorts, considered as high-voltage (HV) cohorts, were pooled for Kaplan-Meier analysis and propensity-matched to Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) arm B and C patients. The study enrolled 354 patients followed for 19.6 ± 6.5 months, with a minimum of 12 months. Propensity-matched HV cohorts showed comparable VA (P = 0.61) and mortality rates (P = 0.29) for HINODE and MADIT-RIT. The ND cohort presented a high crossover rate to ICD therapy (6.1%, n = 7/115), and the CRT-D cohort showed elevated mortality rates. The pacing cohort revealed that patients implanted with pacemakers had higher mortality (26.0%) than those with CRT-Pacing (8.4%, P = 0.05). CONCLUSIONS: The mortality and VA event rates of landmark trials are applicable to patients with primary prevention in Japan. Patients who did not receive guideline-indicated CRT devices had poor outcomes.

Rationale and design of the HINODE study: Heart failure indication and sudden cardiac death prevention trial Japan.

BACKGROUND: Randomized trials in Western countries have provided evidence that prophylactic implantable cardioverter-defibrillator (ICD) therapy reduces mortality in heart failure (HF) patients with reduced left ventricular ejection fraction. However, the risk of life-threatening ventricular arrhythmias in Japanese HF patients sharing similar risk factors is still unknown. METHODS: The Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan trial (NCT03185832) is a prospective, multicenter registry designed to collect data on ventricular arrhythmia, HF events, and mortality in Japanese HF patients. Japanese patients with HF and 2-5 predefined risk factors who were indicated for cardiac device implantation based on European Society of Cardiology guidelines were enrolled in four treatment arms: implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy defibrillator (CRT-D), HF pacing (PA; Pacemaker and cardiac resynchronization pacemaker), and nondevice (ND) cohorts and followed for a minimum of 12 months. Since it is anticipated that some baseline patient characteristics and risk factors will differ significantly from those reported in predominantly Western populations, event rates will be compared to a propensity-matched population from the MADIT RIT trial. Primary endpoints are composite rates of first appropriately treated ventricular arrhythmias (VA) or/and life-threatening VA symptoms for the ICD and CRT-D cohorts. For nondevice and PA cohorts, the primary outcome is all-cause mortality. CONCLUSIONS: The Heart Failure Indication and Sudden Cardiac Death Prevention Trial Japan is a large prospective multicenter registry with defined device treatment cohorts and will provide data for risk stratification for cardiovascular events in Japanese HF patients.

Effect of lead design and pacing vector on electrical parameters of quadripolar coronary sinus leads: The RALLY-X4 study.

BACKGROUND: Various lead designs have been developed to accommodate different coronary sinus anatomies. Our objectives were to compare electrical parameters of straight and spiral left ventricular leads, to evaluate capture thresholds and impedances using different pacing vectors, and to study evolution of thresholds over time. METHODS: The RALLY-X4 study enrolled patients implanted with a lead from the Acuity X4 family (straight, spiral short, or spiral long). Electrical parameters (including capture thresholds from all 17 vectors) were measured at baseline and follow-up. RESULTS: Data from 795 patients who were successfully implanted were analyzed. Straight and spiral leads had similar proportions of patients with thresholds <2.5 V/0.4 ms using the distal electrode (61-65% of patients) or from at least one of the proximal (E2-E4) electrodes (81-83% of patients). Unipolar vectors had significantly lower thresholds and impedances than bipolar vectors, with similar measurements compared to extended bipolar configurations. Capture thresholds increased with more proximal electrodes for all leads. Over a mean follow-up of 1 year, a slight decrease in capture thresholds was observed. CONCLUSION: Straight and spiral quadripolar leads allow to obtain clinically acceptable capture thresholds from at least one of the proximal electrodes in >80% of patients. Pacing vectors significantly affect electrical parameters, with higher thresholds in more proximal electrodes and lower thresholds with unipolar and extended bipolar configurations. Capture thresholds slightly decreased over a mean follow-up of 1 year.

Multicenter automatic defibrillator implantation trial: reduce inappropriate therapy (MADIT-RIT): background, rationale, and clinical protocol.

The implantable cardioverter defibrillator (ICD) is highly effective in reducing mortality due to cardiac arrhythmias in high-risk cardiac patients. However, inappropriate therapies caused predominantly by supraventricular tachyarrhythmias (SVTs) remain a significant side effect of ICD therapy despite medical treatment, affecting 8-40% of patients. The MADIT-RIT is a global, prospective, randomized, nonblinded, three-arm, multicenter clinical investigation to be performed in the Unites States, Europe, Canada, Israel and Japan, and will utilize approximately 90 centers with plan to enroll 1500 patients programmed to three treatment arms. The objective of the MADIT-RIT trial is to determine if dual-chamber ICD or CRT-D devices with high rate cutoff (MADIT-RIT-Arm B) and/or long delay in combination with detection enhancements (MADIT-RIT-Arm C) are associated with fewer patients experiencing inappropriate therapies than standard programming (MADIT-RIT-Arm A) during postimplant follow-up of patients with indication for primary prevention device therapy. This paper describes design and analytic plan for the MADIT-RIT trial.

Treatment of atrial fibrillation with an implantable atrial defibrillator--long term results.

OBJECTIVES: To evaluate the long-term outcome with an implantable atrial defibrillator (IAD) in patients with recurrent atrial fibrillation (AF). BACKGROUND: Maintenance of sinus rhythm using repeated internal cardioversion shocks has been shown to be effective and safe in short-term studies but long term follow-up is unknown. METHODS: Since 1995, 136 patients (30 women) with symptomatic, drug-refractory atrial fibrillation were implanted with an IAD (METRIX, InControl). This analysis was performed after a median of 40 (range 7-66) months after implantation. RESULTS: In 26 patients, the programmed mode was not documented during last follow-up, four patients had died. Of the remaining 106 patients (mean age 58+/-10, range 34 - 79 years), 39 were actively delivering therapy with the device, in 14 patients the device was used to monitor the arrhythmia but no shocks were delivered, and in 53 patients it was turned off or explanted. Increases in defibrillation thresholds (n=7), patient intolerance of multiple cardioversion shocks (n=15), and significant bradycardia requiring dual-chamber pacing (n=12) were the main reasons for discontinuation of therapy in addition to battery depletion (n=19). After explantation, efforts to maintain sinus rhythm were continued in 17 patients whereas rate control was attempted in 36 patients. CONCLUSIONS: A strategy of maintaining sinus rhythm long-term with an IAD is feasible in a proportion of patients. However, patient selection is critical, and technical improvements (i.e. higher shock energies, dual-chamber pacing and additional preventive and anti-tachycardia pacing algorithms) are required to increase the number of patients having long term benefit, and frequent arrhythmia recurrences and patient intolerance to repeated cardioversion shocks remain a major limitation.