Arrhythmia and Survival Outcomes Among Black Patients and White Patients With a Primary Prevention Defibrillator.

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.

Association of device detected atrial and ventricular tachyarrhythmia with adverse events in patients with an implantable cardioverter-defibrillator.

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.

Genetic variant annotation scores in congenital long QT syndrome.

BACKGROUND: Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact. METHODS: We evaluated 2025 patients with unique mutations for LQT1-LQT3. A patient-specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen-2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life-threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C-index. RESULTS: A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen-2. However, none of the genetic scores correlated with the risk of CE (Harrell's C-index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen-2 = 0.52) or LTE (Harrell's C-index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen-2 = 0.52). In contrast, high-risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p < .001) and LTE (HR = 1.89, p < .001). CONCLUSION: In congenital LQTS patients, well-established algorithms (CADD, SIFT, REVEL, and PolyPhen-2) were able to identify the majority of the causal variants as pathogenic. However, the scores did not predict clinical outcomes. These results indicate that mutation location/functional assays are essential for accurate interpretation of the risk associated with LQTS mutations.

Confirm Rx insertable cardiac monitor for primary atrial fibrillation detection in high-risk heart failure patients (Confirm-AF trial).

BACKGROUND: Patients with heart failure (HF) represent a large population of patients who are at high risk for complications related to undiagnosed atrial fibrillation (AF). However, currently there are limited modalities available for early AF detection in this high-risk population. An implantable cardiac monitor (ICM) is inserted subcutaneously and can provide long-term arrhythmia information via remote monitoring. METHODS AND RESULTS: Confirm-AF is a prospective randomized, nonblinded, two arm, multicenter clinical trial to be performed in the United States, enrolling 477 patients with a history of HF hospitalization and left ventricular ejection fraction >35% from 30 medical sites. Patients will be randomized in a 2:1 fashion to undergo ICM implant with remote monitoring and symptom-triggered mobile app transmissions versus (vs.) Non-ICM management and follow-up. The primary objective of this trial is to compare the time to first detection of AF lasting > 5 min using an Abbott ICM compared to non-ICM monitoring in symptomatic HF patients. This article describes the design and analytic plan for the Confirm-AF trial. CONCLUSIONS: The Confirm-AF trial seeks to accurately define the burden of AF in high-risk HF patients with LVEF > 35% using an Abbott ICM. A finding showing significantly higher incidence of AF along with improved clinical outcomes with ICM monitoring is expected to have substantial clinical implications and may change the method of monitoring high-risk HF patients.

Insertable cardiac monitor-guided early intervention to reduce atrial fibrillation burden following catheter ablation: Study design and clinical protocol (ICM-REDUCE-AF trial).

BACKGROUND: Percutaneous catheter ablation (CA) to achieve pulmonary vein isolation is an effective treatment for drug-refractory paroxysmal and persistent atrial fibrillation (AF). However, recurrence rates after a single AF ablation procedure remain elevated. Conventional management after CA ablation has mostly been based on clinical AF recurrence. However, continuous recordings with insertable cardiac monitors (ICMs) and patient-triggered mobile app transmissions post-CA can now be used to detect early recurrences of subclinical AF (SCAF). We hypothesize that early intervention following CA based on personalized ICM data can prevent the substrate progression that promotes the onset and maintenance of atrial arrhythmias. METHODS: This is a randomized, double-blind (to SCAF data), single-tertiary center clinical trial in which 120 patients with drug-refractory paroxysmal or persistent AF are planned to undergo CA with an ICM. Randomization will be to an intervention arm (n = 60) consisting of ICM-guided early intervention based on SCAF and patient-triggered mobile app transmissions versus a control arm (n = 60) consisting of a standard intervention protocol based on clinical AF recurrence validated by the ICM. Primary endpoint is AF burden, which will be assessed from ICMs at 15 months post-AF ablation. Secondary endpoints include healthcare utilization, functional capacity, and quality of life. CONCLUSION: We believe that ICM-guided early intervention will provide a novel, personalized approach to post-AF ablation management that will result in a significant reduction in AF burden, healthcare utilization, and improvements in functional capacity and quality of life.

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.

Outcomes Associated with Introduction of the 5th Generation High-Sensitivity Cardiac Troponin in Patients Presenting with Cardiovascular Disorders.

BACKGROUND: The new high-sensitivity cardiac troponin T (hs-cTnT) is now widely used in the United States. OBJECTIVES: We aimed to examine outcomes associated with the introduction of the new 5th generation hs-cTnT assay among patients presenting to the emergency department (ED) with cardiovascular (CV) disorders. METHODS: The study comprised 5377 patients presenting to the ED with CV disorders between January and September 2018. Outcomes included rates of direct ED discharge, cardiac testing/procedures, and mortality. CV indications for troponin testing were categorized as rule-out acute coronary syndrome (RO-ACS) and other-CV (O-CV). RESULTS: Mean age was 62 ± 17 years, and 47% were female. Demographics and medical history did not differ significantly between the troponin groups. The use of hs-cTnT was associated with increased rates of direct discharge from the ED in the RO-ACS (48% vs. 37%; p < 0.01), but not in the O-CV (25% vs. 25%) cohort. Cardiac tests/procedures were more often performed after hs-cTnT vs. cTnT testing in both cohorts (45% vs. 41% for RO-ACS, and 33% vs. 28% for O-CV; p < 0.05 for both). Multivariate analysis demonstrated that hs-cTnT was not associated with a significant increase in postdischarge mortality in both cohorts (RO-ACS: hazard ratio = 1.47 [p = 0.13], O-CV: hazard ratio = 0.97 [p = 0.87]). CONCLUSIONS: Among patients with RO-ACS, hs-cTnT implementation resulted in increased rates of direct home discharge from the ED, without a significant increase in postdischarge mortality. Among patients presenting with O-CV indication, hs-cTnT implementation resulted in increased rates of cardiac testing procedures without an effect of ED discharge rates or long-term mortality.

Risk factors for ventricular tachyarrhythmic events in patients without left bundle branch block who receive cardiac resynchronization therapy.

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.

The role and outcomes of new supraventricular tachycardia among patients with mild heart failure.

INTRODUCTION: We aimed to assess the predictors of new supraventricular tachycardia (SVT) and the association of new SVT with subsequent clinical outcomes among mild heart failure (HF) patients. METHODS AND RESULTS: The study population comprised patients enrolled in MADIT-CRT, after exclusion of patients with atrial arrhythmias before enrollment (N = 325). Multivariate analysis was used to identify predictors of new-onset SVT and the association of time-dependent development of SVT with subsequent ventricular tachyarrhythmic events (VTEs), HF-hospitalizations, and death. SVT burden was categorized into three groups based on the number of episodes per patient; (a) Low <10, (b) Intermediate ≥10 but <20, and (c) High ≥20. During mean follow up of 3.4 ± 1.1 years, 41(3%) subjects developed new SVT. African American race, diastolic blood pressure (DBP) >80 mmHg and prior non sustained ventricular arrhythmia were independent predictors for SVT. Multivariate analysis showed that the development of time-dependent SVT was associated with a >4-fold increased risk for VTEs (HR = 4.3; 95% CI: 1.6-11.7; P = .004) and with a >6-fold increased risk for all-cause mortality (HR = 6.5; 95% CI: 2.3-18.7; P < .001), but not with HF hospitalizations (HR = 2.2; 95% CI: 0.7-7.2; P = .17). Intermediate, and high SVT-burden were each independent risk factors for death when compared with Low burden (HR = 9.1; P = .03, and HR = 19.4; P < .001; respectively). CONCLUSIONS: In patients with mild HF, the development of new-onset SVT after device implantation is related to distinct baseline clinical and epidemiologic characteristics and is associated with a significant increase in subsequent adverse outcomes, including VTEs and death.

Competing risk analysis of ventricular arrhythmia events in heart failure patients with moderately compromised renal dysfunction.

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.

Circadian variation and seasonal distribution of implantable defibrillator detected new onset atrial fibrillation.

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.

CIED malfunction in patients receiving radiation is a rare event that could be detected by remote monitoring.

INTRODUCTION: An increasing number of patients with cardiac devices require radiation therapy for treatment of a variety of cancers. This study aimed to identify the incidence and predictors of cardiac implantable electronic devices (CIED) malfunction in a real-world population that has received radiation therapy. METHODS: This retrospective cohort study included 109 adult patients who received radiation therapy at the University of Rochester Medical Center, Radiation Oncology Department, between 2000 and 2015. Sixty patients had pacemakers and 49 had automatic implantable cardioverter defibrillators. Subjects received either high energy (16 MV) and/or low energy (6 MV) photon beams with or without electron beams (6-16 MeV). We included interrogations done from first day of radiation and up to 3 months' postradiation therapy. Outcomes analyzed were device-related malfunctions and device-related clinical events. Fisher's exact, Wilcoxon, and Kruskall-Wallis tests were used for bivariate analysis. Logistic regression with robust adjustment was used for multivariate analysis. RESULTS: We identified six device-related malfunctions. All events were minor and included partial settings reset leading to loss of historical data, pacing thresholds changes, lead impedance changes, and LV output increase. Two patients had device-related clinical events, including dyspnea and diaphragmatic-stimulation. In bivariate analysis, CIED malfunction was associated with CIED duration in situ. In multivariate analysis, there was no significant statistical association between adverse events and beam energy type, CIED location, or dose of radiation delivered to the target. CONCLUSIONS: CIED malfunctions are uncommon in real-world patients and associated with minor clinical events. In our cohort, remote CIED monitoring would have identified all events.

Postimplantation ventricular ectopic burden and clinical outcomes in cardiac resynchronization therapy-defibrillator patients: a MADIT-CRT substudy.

BACKGROUND: Frequent ventricular ectopy on preimplantation Holter has been associated with attenuated benefit from cardiac resynchronization therapy (CRT). However, it is unclear whether ectopic burden measured post-CRT implantation can be utilized to evaluate long-term prognosis. We aimed to describe the association between post-CRT implantation ectopic burden and subsequent risk of clinical outcomes. METHODS: At the 12-month follow-up visit, 24-hour Holter recordings were performed in 698 CRT-D patients from the MADIT-CRT study. The mean number of ventricular premature complexes (VPCs/hour) was calculated. High ectopic burden was defined as >10 VPCs/hour and low burden as ≤10 VPCs/hour. Multivariate Cox proportional hazards models were utilized to assess the association between 12-month ectopic burden and the risk of the end points of heart failure (HF) or death and ventricular tachyarrhythmias (VT/VF). RESULTS: At 12 months, 282 (40%) patients presented with low ectopic burden and 416 (60%) patients presented with high ectopic burden. The 3-year risk of HF/death and VT/VF was lower in patients with a low burden (7% and 8%) and significantly higher (25% and 24%) in patients with high burden. In multivariate analyses, patients with a high ectopic burden had approximately threefold increased risk of both HF/death (HR=2.76 [1.62-4.70], p < .001) and VT/VF (HR=2.79 [1.69-4.58], p < .001). CONCLUSION: In CRT-D patients with mild heart failure, high ectopic burden at 12-month follow-up was associated with a high 3-year risk of HF/death and VT/VF and threefold increased risk as compared to patients with low burden. Ectopic burden at 12 months may be a valuable approach for evaluating long-term prognosis.

Effect of Significant Weight Change on Inappropriate Implantable Cardioverter-Defibrillator Therapy.

BACKGROUND: Weight loss has been associated with adverse outcomes among heart failure (HF) patients, including those receiving cardiac resynchronization therapy with defibrillator (CRT-D). The effect of significant weight change on inappropriate implantable cardioverter-defibrillator (ICD) therapy among CRT-D patients is not well understood. METHODS: We evaluated the impact of significant weight change at 1 year on subsequent inappropriate ICD therapy during follow-up among 993 CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. Patients were divided into three subgroups based on weight change at 1 year after enrollment: weight loss (weight loss ≥ 5%), weight gain (weight gain ≥ 5%), and stable weight (weight loss and weight gain < 5%). The primary end point was inappropriate ICD therapy. Secondary end point included inappropriate ICD therapy related to supraventricular arrhythmias (SVAs). RESULTS: There were 102 (10.3%) patients who experienced weight loss, 689 (69.4%) whose weight was stable, and 202 (20.3%) who gained weight at 1 year. Patients with weight loss had increased risk of subsequent inappropriate ICD therapy relative to patients with stable weight (hazard ratio [HR] = 2.35, 95% confidence interval [CI]: 1.39-3.98, P = 0.001) or weight gain (HR = 2.27, 95% CI: 1.18-4.38, P = 0.014). Furthermore, patients losing weight were at greater risk of subsequent inappropriate ICD therapy related to SVAs when compared to patients with stable weight (HR = 2.16, 95% CI: 1.18-3.95, P = 0.013) or weight gain (HR = 2.02, 95% CI: 0.95-4.29, P = 0.068). CONCLUSION: In mild HF patients receiving CRT-D, significant weight loss at 1 year is associated with increased risk of subsequent inappropriate ICD therapy, including risk related to SVAs.

Validation of an automatic diagnosis of strict left bundle branch block criteria using 12-lead electrocardiograms.

AIMS: Strict left bundle branch block (LBBB) criteria were recently proposed to identify LBBB patients to benefit most from cardiac resynchronization therapy (CRT). The aim of our study was to automate identification of strict LBBB in order to facilitate its broader application. METHODS: We developed a series of algorithms to automatically detect and measure parameters required for strict LBBB criteria and proposed a definition of QRS notch detection. The algorithms were developed using training (n = 20) and validation (n = 592) sets consisting of signal-averaged 12-lead ECGs (1,000 Hz sampling) recorded from 612 LBBB patients from Multicenter Automatic Defibrillator Implantation Trial-CRT. Four trained clinicians independently performed adjudication on 148 different ECGs for comparing automatic and manually adjudicated results, in addition to 13 ECGs for evaluation of intraobserver variability and 32 ECGs for interobserver variability. We assessed the performance of the automated algorithms using manually adjudicated ECGs as references. RESULTS: Overall sensitivity and specificity for detecting strict LBBB were 95% and 86%, respectively. The mean absolute deviation (MAD) of QRS duration and notch/slur locations for the automated method versus the manual method was below 1 ms, and MAD values were lower than 2 ms for interobserver and intraobserver variability. Sensitivity and specificity for detecting notch and slur locations were 87% and 96% for notches and 78% and 90% for slurs using the automatic method. In addition 95% and 93% agreements for notches and 90% and 88% agreements for slurs were reached for intra- and interobserver. CONCLUSION: The proposed algorithms automatically measure QRS features for the diagnosis of strict LBBB. Our study shows good performance in reference to manual results.

The Burden and Morphology of Premature Ventricular Contractions and their Impact on Clinical Outcomes in Patients Receiving Biventricular Pacing in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT).

INTRODUCTION: Premature ventricular contractions (PVCs) frequently occur in patients with left ventricular dysfunction. However, there are limited data regarding the burden and morphologic characteristics of PVCs in patients receiving cardiac resynchronization therapy. METHODS AND RESULTS: Patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) with >5000 PVCs on a predevice implant 12-lead, 24-hour Holter were identified. The putative PVC site of origin for the most dominant PVC was characterized and their effects on clinical outcomes were evaluated. A total of 146 patients were identified to have >5000 PVCs on Holter of which 75 (51%) had PVCs originating from a non-outflow tract site. Other sites included the left ventricular outflow tract (LVOT), right ventricular outflow tract (RVOT), and the sinus of Valsalva. In multivariate analysis, the risk for HF/Deatd was similar in patients with Outflow tract PVCs when compared to patients with Non-outflow tract PVCs (HR 1.4, 95% CI 0.7-2.8, P = 0.3). The degree of echocardiographic reverse remodeling was similar in patients with outflow tract versus Non-outflow tract PVCs. One-third of patients with nonischemic cardiomyopathy were found to have PVCs originating from the RVOT. CONCLUSIONS: In patients with mild symptoms of heart failure, there is no difference in the risk of HF or death in patients with outflow versus non-outflow tract PVCs. One-third of patients with NICM have frequent PVCs originating from the RVOT.

The impact of nonsustained ventricular tachycardia on reverse remodeling, heart failure, and treated ventricular tachyarrhythmias in MADIT-CRT.

INTRODUCTION: This study determined whether the presence of nonsustained ventricular tachycardia (NSVT) was predictive of clinical events in MADIT-CRT (multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy) patients treated with CRT-defibrillator. METHODS AND RESULTS: We analyzed 24-hour Holters for the presence of NSVT. Patients were then stratified by the etiology (ischemic or nonischemic) of cardiomyopathy. The impact of NSVT on heart failure events (HF), implantable cardioverter-defibrillator (ICD) therapy for rapid ventricular tachycardia (VT) or fibrillation (VF), and reverse remodeling was determined. At least a single episode of NSVT was recorded in 483 (49%) patients. These patients had a higher burden of premature ventricular contractions, lower percentage of biventricular (BiV) pacing, and significantly less reduction in left ventricular end-diastolic and end-systolic volumes. The risk of HF was significantly greater in patients with nonischemic cardiomyopathy and NSVT (hazard ratio [HR] 2.89; 95% confidence interval [CI]: 1.49-5.61; P = 0.002). The risk of rapid VT/VF was significantly greater (in both ischemic and nonischemic patients) when NSVT was observed (HR 2.06; 95% CI: 1.30-3.26; P = 0.002 in ischemic patients; HR 3.09; 95% CI: 1.80-5.28; P < 0.001 in nonischemic patients). CONCLUSIONS: MADIT-CRT patients with NSVT had a high burden of ventricular ectopy, lower percentage of BiV pacing, and less reverse remodeling. These patients had an increase in HF (in nonischemic cardiomyopathy patients) and rapid VT/VF ICD therapies (in ischemic and nonischemic patients). These findings may have implications for the management of nonsustained ventricular ectopy in CRT patients.

The effect of weight loss on clinical outcomes in patients implanted with a cardiac resynchronization therapy device-A MADIT-CRT substudy.

BACKGROUND: There are no data regarding the effect of weight loss on clinical outcomes in patients undergoing cardiac resynchronization therapy. This study was designed to evaluate the effect of weight loss on clinical outcomes in patients implanted with a cardiac resynchronization therapy with defibrillator (CRT-D). METHODS AND RESULTS: The risk of heart failure (HF) or death, and of death alone, was compared between patients with and without weight loss of ≥2 kg or more at 1 year in the CRT-D arm of the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Weight loss was observed in 170 of 994 patients (17%) implanted with a CRT-D. Multivariate analysis showed a significant increase in the risk of HF or death among patients with weight loss compared with those without weight loss (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.26-2.63; P = .001). Weight loss was associated with a 79% increase in the risk of all-cause mortality (HR 1.79, 95% CI 1.16-3.34; P = .01). When analyzed in a continuous fashion, each kg of weight loss was associated with a 4% increase in the risk of HF or death (P = .03). In left bundle branch block (LBBB) patients with a CRT-D, weight loss was associated with an especially high risk of HF or death (HR 2.23, 95% CI 1.36-3.65; P = .002) and of death alone (HR 2.33, 95% CI 1.07-5.06; P = .03; interaction P = .26). CONCLUSIONS: In patients with mild symptoms of HF receiving CRT-D, weight loss observed at 1 year is associated with adverse clinical outcomes, especially in those with a LBBB electrocardiographic pattern.

Digoxin and Risk of Ventricular Tachyarrhythmia and Death in ICD Recipients.

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.