Prevalence, Timing, and Impact of Early Recurrence of Atrial Tachyarrhythmias after Pulsed Field Ablation: A Secondary Analysis of the PULSED AF Trial.

BACKGROUND: Early recurrence of atrial tachyarrhythmias (ERATs) within three months following thermal ablation for atrial fibrillation (AF) is common and often considered transient. Pulsed field ablation (PFA) is a non-thermal energy source in which ERAT is not well described. OBJECTIVE: To analyze ERAT in AF patients undergoing PFA in the PULSED AF trial. METHODS: This analysis included 294 patients (154 paroxysmal, 140 persistent AF) that had ≥10 rhythm assessments during the 90-day blanking period. ERAT was defined as any instance of ≥30s of AF, atrial flutter, or atrial tachycardia on trans-telephonic monitoring (weekly and symptomatic) or ≥10s on ECG (at 3 months), both within 90 days. Late recurrence of atrial tachyarrhythmias (LRATs) was defined as observed atrial tachyarrhythmias between 90 days and 12 months. RESULTS: The overall prevalence of ERAT was 27.1% in paroxysmal and 31.6% in persistent AF patients. In patients with ERAT, 73% had ERAT onset within the first month post-procedure. Presence of ERAT was associated with LRAT in paroxysmal (HR 6.4 (95% c.i. 3.6-11.3)) and persistent (HR 3.8 (95% c.i. 2.2-6.6)) AF patients. Yet, in 29.4% of paroxysmal and 34.3% of persistent AF patients with ERAT, LRAT was not observed. LRAT was positively correlated with the number of ERAT observations. CONCLUSION: ERAT post PFA predicted LRAT in paroxysmal and persistent AF patients. However, the concept of a blanking period post PFA is still valid as approximately 1/3 of patients with ERAT did not continue on to LRAT during follow-up and may not need re-ablation.

Influence of monitoring and atrial arrhythmia burden on quality of life and health care utilization in patients undergoing pulsed field ablation: A secondary analysis of the PULSED AF trial.

BACKGROUND: Freedom from atrial arrhythmia (AA) recurrence ≥30 seconds after pulsed field ablation (PFA) in patients with atrial fibrillation (AF) was reported in PULSED AF (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF; ClinialTrials.gov Identifier: NCT04198701). AA burden may be a more clinically meaningful endpoint. OBJECTIVE: The purpose of this study was to determine the influence of monitoring strategies on AA detection and AA burden association with quality of life (QoL) and health care utilization (HCU) after PFA. METHODS: Patients underwent 24-hour Holter monitoring at 6 and 12 months and weekly, and symptomatic transtelephonic monitoring (TTM). AA burden post-blanking was calculated as the greater of (1) percentage of AA on total Holter time; or (2) percentage of weeks with ≥1 TTM with AA out of all weeks with ≥1 TTM. RESULTS: Freedom from all AAs varied by >20% when differing monitoring strategies were used. PFA resulted in zero burden in 69.4% of paroxysmal atrial fibrillation (PAF) and 62.2% of persistent atrial fibrillation (PsAF) patients. Median burden was low (<9%). Most PAF and PsAF patients had ≤1 week of AA detection on TTM (82.6% and 75.4%) and <30 minutes of AA per day of Holter monitoring (96.5% and 89.6%), respectively. Only PAF patients with <10% AA burden averaged a clinically meaningful (>19 point) QoL improvement. PsAF patients experienced clinically meaningful QoL improvements irrespective of burden. Repeat ablations and cardioversions significantly increased with higher AA burden (P <.01). CONCLUSION: The ≥30-second AA endpoint is dependent on the monitoring protocol used. PFA resulted in low AA burden for most patients, which was associated with clinically relevant improvement in QoL and reduced AA-related HCU.

Pulsed Field Ablation for the Treatment of Atrial Fibrillation: PULSED AF Pivotal Trial.

BACKGROUND: Pulsed field ablation uses electrical pulses to cause nonthermal irreversible electroporation and induce cardiac cell death. Pulsed field ablation may have effectiveness comparable to traditional catheter ablation while preventing thermally mediated complications. METHODS: The PULSED AF pivotal study (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF) was a prospective, global, multicenter, nonrandomized, paired single-arm study in which patients with paroxysmal (n=150) or persistent (n=150) symptomatic atrial fibrillation (AF) refractory to class I or III antiarrhythmic drugs were treated with pulsed field ablation. All patients were monitored for 1 year using weekly and symptomatic transtelephonic monitoring; 3-, 6-, and 12-month ECGs; and 6- and 12-month 24-hour Holter monitoring. The primary effectiveness end point was freedom from a composite of acute procedural failure, arrhythmia recurrence, or antiarrhythmic escalation through 12 months, excluding a 3-month blanking period to allow recovery from the procedure. The primary safety end point was freedom from a composite of serious procedure- and device-related adverse events. Kaplan-Meier methods were used to evaluate the primary end points. RESULTS: Pulsed field ablation was shown to be effective at 1 year in 66.2% (95% CI, 57.9 to 73.2) of patients with paroxysmal AF and 55.1% (95% CI, 46.7 to 62.7) of patients with persistent AF. The primary safety end point occurred in 1 patient (0.7%; 95% CI, 0.1 to 4.6) in both the paroxysmal and persistent AF cohorts. CONCLUSIONS: PULSED AF demonstrated a low rate of primary safety adverse events (0.7%) and provided effectiveness consistent with established ablation technologies using a novel irreversible electroporation energy to treat patients with AF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04198701.

Cardioverter-defibrillator reduces mortality risk in eligible ischemic and non-ischemic cardiomyopathy patients: Sub-analysis of the multi-center Improve SCA study.

BACKGROUND & OBJECTIVE: Despite the burden of sudden cardiac arrest (SCA) worldwide, implantable cardioverter-defibrillators (ICDs) are underutilized, particularly in Asia, Latin America, Eastern Europe, the Middle East, and Africa. The Improve SCA trial demonstrated that primary prevention (PP) patients in these regions benefit from an ICD or a cardiac resynchronization therapy defibrillator (CRT-D). We aimed to compare the rate of device therapy and mortality among ischemic and non-ischemic cardiomyopathy (ICM and NICM) PP patients who met guideline indications for ICD therapy and had an ICD/CRT-D implanted. METHODS: Improve SCA was a prospective, non-randomized, non-blinded multicenter trial that enrolled patients from the above-mentioned regions. All-cause mortality and device therapy were examined by cardiomyopathy (ICM vs NICM) and implantation status. Cox proportional hazards methods were used, adjusting for factors affecting mortality risk. RESULTS: Of 1848 PP NICM patients, 1007 (54.5%) received ICD/CRT-D, while 303 of 581 (52.1%) PP ICM patients received an ICD/CRT-D. The all-cause mortality rate at 3 years for NICM patients with and without an ICD/CRT-D was 13.1% and 18.3%, respectively (HR 0.51, 95% CI 0.38-0.68, p < 0.001). Similarly, all-cause mortality at 3 years in ICM patients was 13.8% in those with a device and 19.9% in those without an ICD/CRT-D (HR 0.54, 95% CI 0.33-.0.88, p = 0.011). The time to first device therapy, time to first shock, and time to first antitachycardia pacing (ATP) therapy were not significantly different between groups (p ≥ 0.263). CONCLUSIONS: In this large data set of patients with a guideline-based PP ICD indication, defibrillator device implantation conferred a significant mortality benefit in both NICM and ICM patients. The rate of appropriate device therapy was also similar in both groups. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02099721.

Association of left ventricular remodeling with cardiac resynchronization therapy outcomes.

BACKGROUND: Cardiac resynchronization therapy (CRT) response stratified by left ventricular (LV) remodeling revealed differing mortality profiles for distinct patient cohorts. Measuring functional end points, as well as mortality, may better assess CRT efficacy and inform patient management. However, the association between LV remodeling and functional outcomes after CRT is not well understood. OBJECTIVE: The purpose of this study was to evaluate long-term CRT outcomes by extent of LV remodeling. METHODS: REsynchronization reVErses Remodeling in Systolic Left vEntricular dysfunction (ClinicalTrials.gov identifier NCT00271154) was a prospective, double-blind, randomized trial of CRT. Subjects were classified on the basis of LV end-systolic volume (LVESV) change from baseline to 6 months post-CRT: worsened (increase), stabilized (0%-≤15% reduction), responder (>15%-<30% reduction), and super-responder (≥30% reduction). Subjects were evaluated annually for 5 years. RESULTS: The analyses included 353 subjects randomized to CRT-ON arm. All-cause mortality was higher in the worsened group than in the other 3 response groups (29.8% vs 8.0%; P < .0001), with no difference in survival among those groups (P = .87). A significant interaction between the LVESV group and time was observed for health status and quality of life (P = .02 for both). The interaction was not significant for 6-minute hall walk (P = .79); however, super-responders had increased walk distance compared with the other 3 response groups (P = .03). CONCLUSION: Preventing further increase in LVESV with CRT was associated with reduced mortality, whereas functional measure improvement was associated with LV remodeling magnitude. These results support the consideration of functional and mortality end points to assess CRT efficacy and provide further evidence that the dichotomous "responder and nonresponder" classification should be modified.

The mortality analysis of primary prevention patients receiving a cardiac resynchronization defibrillator (CRT-D) or implantable cardioverter-defibrillator (ICD) according to guideline indications in the improve SCA study.

BACKGROUND: In primary prevention (PP) patients the utilization of implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy-defibrillators (CRT-D) remains low in many geographies, despite the proven mortality benefit. PURPOSE: The objective of this analysis was to examine the mortality benefit in PP patients by guideline-indicated device type: ICD and CRT-D. METHODS: Improve sudden cardiac arrest was a prospective, nonrandomized, nonblinded multicenter trial that enrolled patients from regions where ICD utilization is low. PP patient's CRT-D or ICD eligibility was based upon the 2008 ACC/AHA/HRS and 2006 ESC guidelines. Mortality was assessed according to guideline-indicated device type comparing implanted and nonimplanted patients. Cox proportional hazards methods were used, adjusting for known factors affecting mortality risk. RESULTS: Among 2618 PP patients followed for a mean of 20.8 ± 10.8 months, 1073 were indicated for a CRT-D, and 1545 were indicated for an ICD. PP CRT-D-indicated patients who received CRT-D therapy had a 58% risk reduction in mortality compared with those without implant (adjusted hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.28-0.61, p < .0001). PP patients with an ICD indication had a 43% risk reduction in mortality with an ICD implant compared with no implant (adjusted HR: 0.57, 95% CI: 0.41-0.81, p = .002). CONCLUSIONS: This analysis confirms the mortality benefit of adherence to guideline-indicated implantable defibrillation therapy for PP patients in geographies where ICD therapy was underutilized. These results affirm that medical practice should follow clinical guidelines when choosing therapy for PP patients who meet the respective defibrillator device implant indication.

Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation.

BACKGROUND: In patients with symptomatic paroxysmal atrial fibrillation that has not responded to medication, catheter ablation is more effective than antiarrhythmic drug therapy for maintaining sinus rhythm. However, the safety and efficacy of cryoballoon ablation as initial first-line therapy have not been established. METHODS: We performed a multicenter trial in which patients 18 to 80 years of age who had paroxysmal atrial fibrillation for which they had not previously received rhythm-control therapy were randomly assigned (1:1) to receive treatment with antiarrhythmic drugs (class I or III agents) or pulmonary vein isolation with a cryoballoon. Arrhythmia monitoring included 12-lead electrocardiography conducted at baseline and at 1, 3, 6, and 12 months; patient-activated telephone monitoring conducted weekly and when symptoms were present during months 3 through 12; and 24-hour ambulatory monitoring conducted at 6 and 12 months. The primary efficacy end point was treatment success (defined as freedom from initial failure of the procedure or atrial arrhythmia recurrence after a 90-day blanking period to allow recovery from the procedure or drug dose adjustment, evaluated in a Kaplan-Meier analysis). The primary safety end point was assessed in the ablation group only and was a composite of several procedure-related and cryoballoon system-related serious adverse events. RESULTS: Of the 203 participants who underwent randomization and received treatment, 104 underwent ablation, and 99 initially received drug therapy. In the ablation group, initial success of the procedure was achieved in 97% of patients. The Kaplan-Meier estimate of the percentage of patients with treatment success at 12 months was 74.6% (95% confidence interval [CI], 65.0 to 82.0) in the ablation group and 45.0% (95% CI, 34.6 to 54.7) in the drug-therapy group (P<0.001 by log-rank test). Two primary safety end-point events occurred in the ablation group (Kaplan-Meier estimate of the percentage of patients with an event within 12 months, 1.9%; 95% CI, 0.5 to 7.5). CONCLUSIONS: Cryoballoon ablation as initial therapy was superior to drug therapy for the prevention of atrial arrhythmia recurrence in patients with paroxysmal atrial fibrillation. Serious procedure-related adverse events were uncommon. (Supported by Medtronic; STOP AF First ClinicalTrials.gov number, NCT03118518.).

Utilization of implantable cardioverter-defibrillators for the prevention of sudden cardiac death in emerging countries: Improve SCA clinical trial.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are underutilized in Asia, Latin America, Eastern Europe, the Middle East, and Africa. The Improve SCA Study is the largest prospective study to evaluate the benefit of ICD therapy in underrepresented geographies. This analysis reports the primary objective of the study. OBJECTIVES: The objectives of this study was to determine whether patients with primary prevention (PP) indications with specific risk factors (1.5PP: syncope, nonsustained ventricular tachycardia, premature ventricular contractions >10/h, and low ventricular ejection fraction <25%) are at a similar risk of life-threatening arrhythmias as patients with secondary prevention (SP) indications and to evaluate all-cause mortality rates in 1.5PP patients with and without devices. METHODS: A total of 3889 patients were included in the analysis to evaluate ventricular tachycardia or fibrillation therapy and mortality rates. Patients were stratified as SP (n = 1193) and patients with PP indications. The PP cohort was divided into 1.5PP patients (n = 1913) and those without any 1.5PP criteria (n = 783). The decision to undergo ICD implantation was left to the patient and/or physician. The Cox proportional hazards model was used to compute hazard ratios. RESULTS: Patients had predominantly nonischemic cardiomyopathy. The rate of ventricular tachycardia or fibrillation in 1.5PP patients was not equivalent (within 30%) to that in patients with SP indications (hazard ratio 0.47; 95% confidence interval 0.38-0.57) but was higher than that in PP patients without any 1.5PP criteria (hazard ratio 0.67; 95% confidence interval 0.46-0.97) (P = .03). There was a 49% relative risk reduction in all-cause mortality in ICD implanted 1.5PP patients. In addition, the number needed to treat to save 1 life over 3 years was 10.0 in the 1.5PP cohort vs 40.0 in PP patients without any 1.5PP criteria. CONCLUSION: These data corroborate the mortality benefit of ICD therapy and support extension to a selected PP population from underrepresented geographies.

Design of a "Lean" Case Report Form for Heart Failure Therapeutic Development.

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.

Adaptive cardiac resynchronization therapy is associated with decreased risk of incident atrial fibrillation compared to standard biventricular pacing: A real-world analysis of 37,450 patients followed by remote monitoring.

BACKGROUND: The AdaptivCRT algorithm (aCRT) automatically adjusts atrioventricular delays each minute to achieve ventricular fusion through left ventricular (LV) or biventricular (BiV) pacing. aCRT is associated with superior clinical outcomes compared to standard BiV pacing, but the association of aCRT and subsequent atrial fibrillation (AF) in a real-world population has not been fully evaluated. OBJECTIVE: The purpose of this study was to investigate the incidence of AF ≥48 hours with aCRT vs standard BiV pacing after implant. METHODS: Patients implanted with a cardiac resynchronization therapy (CRT) device between 2013 and 2016 were studied via the de-identified Medtronic CareLink database. For univariate and multivariate survival analyses, Kaplan-Meier and Cox proportional hazards were used, respectively. RESULTS: Of 37,450 patients (mean age 69.1 ± 11.0 years; 67.9% male) followed for a mean 15.5 ± 9.1 months, 9.7% (n = 3647) developed ≥48 hours of AF. In univariate analysis, compared with standard BiV pacing, the aCRT BiV and LV mode was associated with a 54% lower risk of ≥48 hours of AF (P <.001) at 2 years, which persisted after multivariate adjustment (hazard ratio 0.53; 95% confidence interval 0.49-0.57; P <.001), even when stratified by sensed PR interval ≤200 ms and >200 ms. Higher percentages of LV-only pacing with aCRT were associated with lower incidence of AF (comparing >92% LV-only pacing vs 0%-5% LV-only pacing: HR 0.05; 95% CI 0.04-0.06; P <.001). CONCLUSION: In a large, real-world population of CRT recipients, aCRT pacing compared to standard BiV pacing was associated with a lower incidence of AF in patients with both long and short PR intervals. A higher percentage of LV-only pacing during aCRT was also associated with lower incidence of AF.

Improving the utilization of implantable cardioverter defibrillators for sudden cardiac arrest prevention (Improve SCA) in developing countries: Clinical characteristics and reasons for implantation refusal.

BACKGROUND: Despite available evidence that implantable cardioverter defibrillators (ICDs) reduce all-cause mortality among patients at risk for sudden cardiac death, utilization of ICDs is low especially in developing countries. OBJECTIVE: To summarize reasons for ICD or cardiac resynchronization therapy defibrillator implant refusal by patients at risk for sudden cardiac arrest (Improve SCA) in developing countries. METHODS: Primary prevention (PP) and secondary prevention (SP) patients from countries where ICD use is low were enrolled. PP patients with additional risk factors (syncope, ejection fraction < 25%, nonsustained ventricular tachycardia [NSVT], or frequent premature ventricular complexes) were further categorized as "1.5 PP patients." Candidates who declined implantation were asked for reasons for refusal. Baseline factors that may have influenced the implant decision were examined using logistic regression. RESULTS: Among 3892 patients, the implant refusal rate was 46.5% among PP patients (n = 2700), and 10.3% among SP patients (n = 1192). The most common refusal reason was inability to pay for the device (53.8%), followed by not believing in the benefits of the ICD (19.4%). Among PP ICD candidates, those with no syncope, no NSVT, no premature ventricular contractions, shorter QRS duration, no atrial arrhythmias, and no left bundle branch block were more likely to refuse implant. Among SP candidates, a history of cardiovascular surgery and no sinus node dysfunction were significant predictors of ICD refusal. Additionally, countries had significant differences in patient refusal rates among PP and SP groups. CONCLUSION: Implant refusal among PP patients is high in many countries. Increased reimbursement and better awareness of the benefits of an ICD could increase their utilization.

Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: Results of the Adaptive Cardiac Resynchronization Therapy Trial.

BACKGROUND: Data from randomized trials have suggested a modest or no effect of conventional cardiac resynchronization therapy (convCRT) on the incidence of atrial fibrillation (AF). AdaptivCRT (aCRT, Medtronic, Mounds View, MN) is a recently described algorithm for synchronized left ventricular (LV) pacing and continuous optimization of cardiac resynchronization therapy (CRT). OBJECTIVE: We compared the long-term effects of aCRT with convCRT pacing on the incidence of AF. METHODS: The Adaptive CRT trial randomized CRT-defibrillator (CRT-D)-indicated patients (2:1) to receive either aCRT or convCRT pacing. The aCRT algorithm evaluates intrinsic conduction every minute, providing LV-only pacing during normal atrioventricular (AV) conduction and AV and ventriculoventricular timing adjustments during prolonged AV conduction. The primary outcome of this subanalysis was an episode of AF >48 consecutive hours as detected by device diagnostics. RESULTS: Over a follow-up period with a mean and standard deviation of 20.2 ± 5.9 months, 8.7% of patients with aCRT and 16.2% with convCRT experienced the primary outcome (hazard ratio [HR] = 0.54; 95% confidence interval [CI] = 0.31-0.93; P = .03). In patients with prolonged baseline AV, the incidence of the primary outcome was 12.8% in patients randomized to aCRT compared with 27.4% in convCRT patients (HR = 0.45; 95% CI = 0.24-0.85; P = .01). Also, patients with AF episodes adjudicated as clinical adverse events were less common with aCRT (4.3%) than with convCRT (12.7%) (HR = 0.39; 95% CI = 0.19-0.79; P = .01). CONCLUSION: Patients receiving aCRT had a reduced risk of AF compared with those receiving convCRT. Most of the reduction in AF occurred in subgroups with prolonged AV conduction at baseline and with significant left atrial reverse remodeling.

Adaptive CRT in patients with normal AV conduction and left bundle branch block: Does QRS duration matter?

BACKGROUND: Adaptive cardiac resynchronization therapy (aCRT) is a dynamic optimization algorithm which paces only the left ventricle (LV) when atrio-ventricular (AV) conduction is normal, thus reducing right ventricular (RV) pacing. However, the impact of QRS duration on aCRT efficacy remains uncertain. We examined whether QRS duration impacts aCRT effectiveness in patients with left bundle branch block (LBBB) and preserved AV conduction. METHODS: Randomized patients in the Adaptive CRT trial, which enrolled NYHA III/IV patients, were used in this analysis. Patients were randomized to receive aCRT or echo-optimized bi-ventricular CRT (control arm). Endpoints for this analysis were clinical composite score (CCS) at 6months post-implant and time to first heart failure (HF) hospitalization or death. RESULTS: Among the 199 patients with LBBB and normal AV intervals at baseline, 80 patients (40%) had a baseline moderately wide QRS of 120-150ms. In this subgroup, a greater proportion of aCRT patients had an improved CCS (79% vs. 50%) at 6months compared to the control group (p=0.03). There was also a trend toward a lower risk of death or HF hospitalization (hazard ratio: 0.53; 95% CI: 0.24-1.15; p=0.10) in the moderately wide QRS subgroup with aCRT compared to the control arm. In the wide QRS subgroup, the efficacy was comparable in both treatment arms. CONCLUSION: Adaptive CRT was associated with improved patient outcomes over echo-optimized bi-ventricular CRT in patients with preserved AV conduction, LBBB, and moderately wide QRS. The adaptive cardiac resynchronization therapy trial (ClinicalTrials.gov Identifier: NCT00980057) was sponsored by Medtronic plc, Mounds View, MN.

Left Ventricular Architecture, Long-Term Reverse Remodeling, and Clinical Outcome in Mild Heart Failure With Cardiac Resynchronization: Results From the REVERSE Trial.

OBJECTIVES: This study sought to determine the effects of abnormal left ventricular (LV) architecture on cardiac remodeling and clinical outcomes in mild heart failure (HF). BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment for HF that improves survival in part by favorably remodeling LV architecture. LV shape is a dynamic component of LV architecture on which contractile function depends. METHODS: Transthoracic 2-dimensional echocardiography was used to quantify changes in LV architecture over 5 years of follow-up of patients with mild HF from the REVERSE study. REVERSE was a prospective study of patients with large hearts (LV end-diastolic dimension ≥55 mm), LV ejection fraction <40%, and QRS duration >120 ms randomly assigned to CRT-ON (n = 419) and CRT-OFF (n = 191). CRT-OFF patients were excluded from this analysis. LV dimensions, volumes, mass index, and LV ejection fraction were calculated. LV architecture was assessed using the sphericity index, as follows: (LV end-diastolic volume)/(4/3 × π × r3) × 100%. RESULTS: LV architecture improved over time and demonstrated significant associations between LV shape, age, sex, and echocardiography metrics. Changes in LV architecture were strongly correlated with changes in LV end-systolic volume index and LV end-diastolic volume index (both p < 0.0001). Sphericity index emerged as a predictor of death and HF hospitalization in spite of the low adverse event rate. A decrease in LV end-systolic volume index >15% occurred in more than two-thirds of patients, which indicates considerable reverse remodeling. CONCLUSIONS: We demonstrated that change in LV architecture in patients with mild HF with CRT is associated with structural and functional remodeling. Mean LV filling pressure was elevated, and the inability to lower it was an additional predictor of HF hospitalization or death. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154).

The Impact of the PR Interval in Patients Receiving Cardiac Resynchronization Therapy: Results From the REVERSE Study.

OBJECTIVES: This study sought to evaluate the impact of baseline PR interval on cardiac resynchronization therapy (CRT) outcomes in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) study. BACKGROUND: The baseline electrocardiogram has important prognostic value to determine response to CRT. Specifically, QRS duration and morphology are strong predictors of response and outcomes; however, the prognostic importance of the PR interval is less clear. METHODS: REVERSE was a double-blinded, randomized study of CRT in mild heart failure (HF). The primary endpoint was the analysis of patients in sinus rhythm (n = 582) of the time-to-first HF hospitalization or death during the 2-year randomized period of the trial. In addition, the long-term impact of PR interval was assessed in the cohort actively on CRT during the pre-planned 5-year follow-up. Subjects were analyzed by PR interval, grouped by the median (180 ms) in 20-ms bins or as a continuous variable depending on the analysis performed. Secondary endpoints included the clinical composite score and echocardiographic measures of reverse remodeling. RESULTS: During the randomized phase of the study, CRT had similar effectiveness for both PR <180 ms (hazard ratio [HR]: 0.34) and PR >180 ms (HR: 0.57) subgroups (interaction p = 0.33). Similar results were observed when PR interval was grouped in 20-ms bins or treated as a continuous variable. In multivariable analysis of the long-term follow-up, left bundle branch block morphology, New York Heart Association functional class, HF etiology, and QRS duration, but not PR interval, predicted HF hospitalization or death. CONCLUSIONS: Baseline PR interval does not affect clinical outcomes or reverse remodeling with CRT in mild HF. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154).

Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial.

BACKGROUND: The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion. METHODS: A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature. RESULTS: Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions. CONCLUSIONS: The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Impact of magnetic resonance imaging on ventricular tachyarrhythmia sensing: Results of the Evera MRI Study.

BACKGROUND: Studies have shown that magnetic resonance imaging (MRI) conditional pacemakers experience no significant effect from MRI on device function, sensing, or pacing. More recently, similar safety outcomes were demonstrated with MRI conditional defibrillators (implantable cardioverter-defibrillator [ICD]), but the impact on ventricular arrhythmias has not been assessed. OBJECTIVE: The purpose of this study was to assess the effect of MRI on ICD sensing and treatment of ventricular tachyarrhythmias. METHODS: The Evera MRI Study was a worldwide trial of 156 patients implanted with an ICD designed to be MRI conditional. Device-detected spontaneous and induced ventricular tachycardia/ventricular fibrillation (VT/VF) episodes occurring before and after whole body MRI were evaluated by a blinded episode review committee. Detection delay was computed as the sum of RR intervals of undersensed beats. A ≥5-second delay in detection due to undersensing was prospectively defined as clinically significant. RESULTS: Post-MRI, there were 22 polymorphic VT/VF episodes in 21 patients, with 16 of these patients having 17 VT/VF episodes pre-MRI. Therapy was successful for all episodes, with no failures to treat or terminate arrhythmias. The mean detection delay due to undersensing pre- and post-MRI was 0.60 ± 0.59 and 0.33 ± 0.63 seconds, respectively (P = .17). The maximum detection delay was 2.19 seconds pre-MRI and 2.87 seconds post-MRI. Of the 17 pre-MRI episodes, 14 (82%) had some detection delay as compared with 11 of 22 (50%) post-MRI episodes (P = .03); no detection delay was clinically significant. CONCLUSION: Detection and treatment of VT/VF was excellent, with no detection delays or significant impact of MRI observed.

Effects of Cardiac Resynchronization Therapy on Cardiac Remodeling and Contractile Function: Results From Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE).

BACKGROUND: Cardiac resynchronization therapy results in improved ejection fraction in patients with heart failure. We sought to determine whether these effects were mediated by changes in contractility, afterload, or volumes. METHODS AND RESULTS: In 610 patients with New York Heart Association class I/II heart failure from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study, we performed detailed quantitative echocardiography assessment prior to and following cardiac resynchronization therapy. We derived measures of contractility (the slope [end-systolic elastance] and the volume intercept of the end-systolic pressure-volume relationship, stroke work, and preload recruitable stroke work), measures of arterial load and ventricular-arterial coupling, and measures of chamber size (volume intercept, end-systolic and end-diastolic volumes). At 6 and 12 months, cardiac resynchronization therapy was associated with a reduction in the volume intercept and end-systolic and end-diastolic volumes (P<0.01). There were no consistent effects on end-systolic elastance, stroke work, preload recruitable stroke work, or ventricular-arterial coupling. In the active cardiac resynchronization therapy population, baseline measures of arterial load were associated with the clinical composite score (odds ratio 1.30, 95% CI 1.04 to 1.63, P=0.02). The volume intercept was associated with mortality (hazard ratio 1.90, 95% CI 1.01 to 3.59, P=0.047) and more modestly with the combined end point of mortality or heart failure hospitalization (hazard ratio 1.48, 95% CI 0.8 to 2.25, P=0.06). In contrast, end-systolic elastance, stroke work, preload recruitable stroke work, and ventricular-arterial coupling were not associated with any outcomes. CONCLUSION: In patients with NYHA Class I/II heart failure, cardiac resynchronization therapy exerts favorable changes in left ventricular end-systolic and end-diastolic volumes and the volume intercept. The volume intercept may be useful to gain insight into prognosis in heart failure. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00271154.

Improve the prevention of sudden cardiac arrest in emerging countries: the Improve SCA clinical study design.

AIMS: This study aims to demonstrate that primary prevention (PP) patients with one or more additional risk factors are at a similar risk of life-threatening ventricular arrhythmias when compared with secondary prevention (SP) patients, and would receive similar benefit from an implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy-defibrillator (CRT-D) implant. The study evaluates the benefits of therapy for high-risk patients in countries where defibrillation therapy for PP of SCA is underutilized. METHODS: Enrolment will consist of 4800 ICD-eligible patients from Asia, Latin America, Eastern Europe, the Middle East, and Africa. Upon enrolment, patients will be categorized as SP or PP. Primary prevention patients will be assessed for additional risk factors: syncope/pre-syncope, non-sustained ventricular tachycardia, frequent premature ventricular contractions, and low left ventricular ejection fraction. Those PP patients with one or more risk factors will be categorized as '1.5' patients. Implant of an ICD/CRT-D will be left to the patient and/or physician's discretion. The primary endpoint will compare the appropriate ICD therapy rate between SP and 1.5 patients. The secondary endpoint compares mortality between 1.5 implanted and non-implanted patients. CONCLUSION: The Improve SCA study will investigate a subset of PP patients, believed to be at similar risk of life-threatening ventricular arrhythmias as SP patients. Results may help clinicians identify and refer the highest risk PP patients for ICDs, help local societies expand guidelines to include PP of SCA utilizing ICDs, and provide additional geographical-relevant evidence to allow patients to make an informed decision whether to receive an ICD. TRIAL REGISTRATION: NCT02099721.

Full-Body MRI in Patients With an Implantable Cardioverter-Defibrillator: Primary Results of a Randomized Study.

BACKGROUND: Magnetic resonance imaging (MRI) of patients with conventional implantable cardioverter-defibrillators (ICD) is contraindicated. OBJECTIVES: This multicenter, randomized trial evaluated safety and efficacy of a novel ICD system specially designed for full-body MRI without restrictions on heart rate or pacing dependency. The primary safety objective was >90% freedom from MRI-related events composite endpoint within 30 days post-MRI. The primary efficacy endpoints were ventricular pacing capture threshold and ventricular sensing amplitude. METHODS: Subjects received either a single- or dual-chamber ICD. In a 2:1 randomization, subjects either underwent MRI at 1.5-T of the chest, cervical, and head regions to maximize radiofrequency exposure up to 2 W/kg specific absorption rate and gradient field exposure to 200 T/m/s per axis (MRI group, n = 175), or they underwent a 1-h waiting period without MRI (control group, n = 88). A subset of MRI patients underwent ventricular fibrillation induction testing post-MRI to characterize defibrillation function. RESULTS: In 42 centers, 275 patients were enrolled (76% male, age 60.4 ± 13.8 years). The safety endpoint was met with 100% freedom from the composite endpoint (p < 0.0001). Both efficacy endpoints were met with minimal differences in the proportion of MRI and control patients who demonstrated a ≤0.5 V increase in ventricular pacing capture threshold (100% MRI vs. 98.8% control, noninferiority p < 0.0001) or a ≤50% decrease in R-wave amplitude (99.3% MRI vs. 98.8% control, noninferiority p = 0.0001). A total of 34 ventricular tachyarrhythmia/ventricular fibrillation episodes (20 induced; 14 spontaneous) occurred in 24 subjects post-MRI, with no observed effect on sensing, detection, or treatment. CONCLUSIONS: This is the first randomized clinical study of an ICD system designed for full-body MRI at 1.5-T. These data support that the system is safe and the MRI scan does not adversely affect electrical performance or efficacy. (Confirmatory Clinical Trial of the Evera MRI System for Conditionally-Safe MRI Access; NCT02117414).