Prior history of atrial fibrillation and arrhythmic outcomes: Data from the WEARIT-II prospective registry.

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.

[History of surgical treatment of cardiac arrhythmias in Germany : Surgical treatment of ventricular tachycardia and supraventricular tachycardia, especially pre-excitation syndromes (WPW)]. / Geschichte der chirurgischen Behandlung von Herzrhythmusstörungen in Deutschland : Chirurgische Therapie ventrikulärer Tachykardien sowie supraventrikulärer Tachykardien, insbesondere Präexzitationssyndromen (WPW).

The history of surgical treatment of ventricular tachycardias (VT) is short, lasting from 1978 until 1993. "Indirect procedures" with infarct scar resection were performed without electrophysiologic studies, whereas "direct procedures" consisted of either complete endocardial incisions ("encircling endocardial ventriculotomy") or large endocardial resections ("endocardial peel-off" technique) after precise epicardial and endocardial mapping procedures. In Germany, the first to report on intra-operative electrophysiologic mapping for VT treatment were Ostermeyer, Breithardt and Seipel in 1979. In 1981, the Hannover group (Frank, Klein) published their first results of surgical treatment of VT. In 1984, Ostermeyer et al. demonstrated that a partial endocardial incision resulted in more beneficial results with less myocardial damage (8% versus 46%) than applying a complete encircling incision. In 1987, the Düsseldorf group reported treatment results of 93 patients. After 5 years, 77% had no VT recurrence, while total mortality after 1 year was 11% and after 5 years 30%. In 1992, the Hannover group reported results of 147 patients after endocardial resection for VT. Total mortality after 3 years was 27%; recurrence of VT events occurred in 18% of the surviving cohort.The history of surgical procedures for supraventricular tachycardia (SVT), in particular Wolff-Parkinson-White (WPW) syndrome, is even shorter than that of surgery for VT. As early as 1969, Sealy, Gallagher and Cox reported the first cases of surgical intervention for WPW syndrome via endocardial access in cardioplegic arrest. In 1984, Guiraudon and Klein reported on a new procedure with epicardial access to the accessory bundle without cardioplegia in laterally localised conduction pathways. In Germany, too, the groups in Düsseldorf (Ostermeyer, Seipel, Breithardt, Borggrefe) from 1980 and the Hannover group (Frank, Klein and Kallfelz) from 1981 performed surgical procedures for WPW syndrome. In 1987, Borggrefe reported on 18 patients with WPW syndrome and atrial fibrillation who had undergone surgery. After 2 years, 14 of 18 patients had no recurrences of tachycardia; in 1989, Frank, Klein and Kallfelz (Hannover) reported on 10 children (2-14 years) operated on using the cryoablation technique. Between 1984 and 1992, a total of 120 patients with SVT, mostly WPW syndrome, were operated on in Hannover; after 42 months, 12 patients had a recurrence of SVT. Two patients died during the reoperation.

[Short history of the DC-Catheter-Ablation]. / Kurze Geschichte der Katheterablation mit DC-Schocks.

Direct current (DC) catheter ablation in 5 patients aiming to interrupt rapid atrioventricular (AV) conduction with atrial fibrillation and subsequent pacemaker implantation was first published by M. M. Scheinman et al. (San Francisco, CA, USA) in 1982. In Germany, L. Seipel, G. Breithardt, and M. Borggrefe reported their first experience with DC catheter ablation in 1984, followed by the group in Bonn (M. Manz and B. Lüderitz) in 1985. The first international DC catheter ablation registry, which also included four German centers, reported DC catheter ablation results of 127 patients in 24 centers in 1984. Complete AV block was achieved in 71% patients. In 1992, the Hannover group (H­J. Trappe, H. Klein and J. Huang) reported results of DC catheter ablation of AV conduction performed between 1983 and 1990 in 100 patients (86% with rapid atrial fibrillation, 14% with AV-node reentry tachycardias). The first successful DC catheter ablation in a patient with Wolff-Parkinson-White (WPW) syndrome was reported in 1985 by F. Morady et al. (San Francisco, CA, USA). In 1987, M. Borggrefe et al. were the first to report a switch from DC catheter ablation to a high-frequency (HF) catheter ablation procedure in a patient with WPW syndrome. The use of DC catheter ablation to treat ventricular tachycardia (VT) was described by G. O. Hartzler (Kansas City, MO, USA) in 3 patients in 1983. M. Borggrefe et al. (1989) reported on 24 patients who underwent DC catheter ablation for VT. Of those, 17 patients did not have VT recurrence within the following 14 months. In 1994, the Hannover group (H-J Trappe, H. Klein) published their 5­year long-term results of DC catheter ablation of VT in 51 patients. VT recurrence occurred in 57% patients and overall mortality was also high (16%). A comparison of DC catheter ablation with HF catheter ablation for recurrent VT was reported in 1994 by G. Gonska et al. (Göttingen, Germany). After 2 years follow-up, success rates were not found to be significantly different.

[History of the implantable cardioverter-defibrillator in Germany]. / Die Geschichte des implantierbaren Kardioverter-Defibrillators in Deutschland.

The implantable cardioverter-defibrillator (ICD) was a breakthrough in the prevention of sudden cardiac death. After years of technical development in the USA, Michel Mirowski succeeded in proving reliable automatic defibrillation of ventricular tachyarrhythmias through initial human implantations in 1980, despite many obstacles. Nearly 4 years later, the first patients received ICDs at multiple centers in Germany. Subsequently, outside the USA, Germany became the country with highest implantation rates. The absolute number of implantations remained small as long as implantations required epicardial defibrillation electrodes and therefore thoracotomy by cardiac surgeons. Pacemaker-like implantation using a transvenous defibrillation electrode with a pectoral ICD became feasible in the early 1990s pushing implantation rates to the next level. Technical advancements were accompanied by clinical research in Germany, and often, the first-in-human studies were conducted in Germany. In 1991, the first guidelines for indications were established in the USA and Germany. Several randomized studies on indications were published between 1996 and 2009, mostly led by American teams with German participation, but also under German leadership (CASH, CAT, DINAMIT, IRIS). The DANISH study in 2016 questioned the results of these long-standing studies. Instead of providing ICDs to patients using a broad indication, future efforts aim to identify patients who, despite optimal medical therapy, cardiac resynchronization therapy (CRT), and/or catheter ablation, need protection against sudden cardiac death. Risk scores incorporating myocardial scars in magnetic resonance imaging (MRI) and genetic information are expected to contribute to more individualized and effective indications.

Upgrade of right ventricular pacing to cardiac resynchronization therapy in heart failure: a randomized trial.

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.

Sex Differences in the Risk of First and Recurrent Ventricular Tachyarrhythmias Among Patients Receiving an Implantable Cardioverter-Defibrillator for Primary Prevention.

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.

Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure.

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.

Comparison of Frequency of Ventricular Tachyarrhythmia in Men-Versus-Women in Patients with Implantable Cardioverter-Defibrillator for Primary Prevention.

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.

Survival After Implantable Cardioverter-Defibrillator Shocks.

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.

Predicted benefit of an implantable cardioverter-defibrillator: the MADIT-ICD benefit score.

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.

Protected risk stratification with the wearable cardioverter-defibrillator: results from the WEARIT-II-EUROPE registry.

BACKGROUND: The prospective WEARIT-II-EUROPE registry aimed to assess the value of the wearable cardioverter-defibrillator (WCD) prior to potential ICD implantation in patients with heart failure and reduced ejection fraction considered at risk of sudden arrhythmic death. METHODS AND RESULTS: 781 patients (77% men; mean age 59.3 ± 13.4 years) with heart failure and reduced left ventricular ejection fraction (LVEF) were consecutively enrolled. All patients received a WCD. Follow-up time for all patients was 12 months. Mean baseline LVEF was 26.9%. Mean WCD wearing time was 75 ± 47.7 days, mean daily WCD use 20.3 ± 4.6 h. WCD shocks terminated 13 VT/VF events in ten patients (1.3%). Two patients died during WCD prescription of non-arrhythmic cause. Mean LVEF increased from 26.9 to 36.3% at the end of WCD prescription (p < 0.01). After WCD use, ICDs were implanted in only 289 patients (37%). Forty patients (5.1%) died during follow-up. Five patients (1.7%) died with ICDs implanted, 33 patients (7%) had no ICD (no information on ICD in two patients). The majority of patients (75%) with the follow-up of 12 months after WCD prescription died from heart failure (15 patients) and non-cardiac death (15 patients). Only three patients (7%) died suddenly. In seven patients, the cause of death remained unknown. CONCLUSIONS: Mortality after WCD prescription was mainly driven by heart failure and non-cardiovascular death. In patients with HFrEF and a potential risk of sudden arrhythmic death, WCD protected observation of LVEF progression and appraisal of competing risks of potential non-arrhythmic death may enable improved selection for beneficial ICD implantation.

Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM-HF, INOVATE-HF, and NECTAR-HF.

AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation. METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's unpaired t-test, and differences in changes of mean values using two-sample t-tests. Guideline-directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM-HF. In INOVATE-HF, VNS was aimed at peripheral neural targets, using closed-loop delivery that required synchronization of VNS to R-wave sensing by an intracardiac lead. Pulse frequency was low (1-2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR-HF and ANTHEM-HF used open-loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR-HF, VNS delivery at 20 Hz caused off-target effects that limited VNS up-titration in a majority of patients. In ANTHEM-HF, VNS delivery at 10 Hz allowed up-titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM-HF. When ANTHEM-HF and NECTAR-HF were compared, greater improvements from baseline were observed in ANTHEM-HF in standard deviation in normal-to-normal R-R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE-HF, greater improvement in 6-min walk distance was observed in ANTHEM-HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04). CONCLUSIONS: In this post-hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

FXD-CSD-GUI: a graphical user interface for the X-ray-diffraction-based determination of crystallite size distributions.

Bragg intensities can be used to analyse crystal size distributions in a method called FXD-CSD, which is based on the fast measurement of many Bragg spots using two-dimensional detectors. This work presents the Python-based software and its graphical user interface FXD-CSD-GUI. The GUI enables user-friendly data handling and processing and provides both graphical and numerical crystal size distribution results.

Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design.

BACKGROUND: The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function. METHODS: The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point-reduction in the composite of cardiovascular death or first HF hospitalization-and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score). CONCLUSIONS: Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.