Bronislava Polonsky

Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure

BACKGROUND The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone. METHODS We evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis. RESULTS At 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval [CI], 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundle-branch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P=0.04; P<0.001 for interaction of treatment with QRS morphologic findings). CONCLUSIONS Our findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271, NCT01294449, and NCT02060110.).

Efficacy of Antiarrhythmic Drugs in Arrhythmogenic Right Ventricular Cardiomyopathy: A Report From the North American ARVC Registry

OBJECTIVES This study sought to examine the efficacy of empiric antiarrhythmic drugs in a rigorously characterized cohort of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. BACKGROUND Antiarrhythmic drugs are important in protecting against ventricular arrhythmias in ARVC, but no studies have provided data in a group rigorously screened for the disease. METHODS Antiarrhythmic medicines were examined in all subjects with implantable cardioverter-defibrillators (ICDs) enrolled in the North American ARVC Registry. A Cox proportional hazards model was used to account for time on each drug, and a hierarchical analysis was performed for repeated measures within individuals. RESULTS Ninety-five patients were studied, with a mean follow-up of 480 +/- 389 days. Fifty-eight (61%) received beta-blockers, and these medicines were not associated with an increased or decreased risk of ventricular arrhythmias. Sotalol was associated with a greater risk of any clinically relevant ventricular arrhythmia as defined by sustained ventricular tachycardia or ICD therapy (hazard ratio [HR]: 2.55, 95% confidence interval [CI]: 1.02 to 6.39, p = 0.045), but this was not statistically significant after adjusting for potential confounders. An increased risk of any ICD shock and first clinically relevant ventricular arrhythmia while on sotalol remained significant after multivariable adjustment. Those on amiodarone (n = 10) had a significantly lower risk of any clinically relevant ventricular arrhythmia (HR: 0.25, 95% CI: 0.07 to 0.95, p = 0.041), a finding that remained significant after multivariable adjustment. CONCLUSIONS In a cohort of well-characterized ARVC subjects, neither beta-blockers nor sotalol seemed to be protective. Evidence from a small number of patients suggests that amiodarone has superior efficacy in preventing ventricular arrhythmias.

Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy

AIMS It has been proposed that competitive sport increases the risk of ventricular tachyarrhythmias (VTA) and death in patients with arrhythmogenic right-ventricular cardiomyopathy (ARVC). However, it is unknown whether this only applies to competitive sport or if recreational sports activity also increases the risk of VTA/death. METHODS AND RESULTS Probands diagnosed with ARVC according to the 2010 task force criteria for ARVC (n = 108) were included in the current analysis. At the time of enrolment, study participants were questioned about exercise level prior to and after ARVC diagnosis, within three categories of sports participation: competitive (n = 41), recreational (n = 48), and inactive (n = 19). Competitive sport was associated with a significantly higher risk of VTA/death when compared with both recreational sport [HR = 1.99 (1.21-3.28), P = 0.007] and inactive patients [HR = 2.05 (1.07-3.91), P = 0.030]. No increased risk of VTA/death was associated with recreational sport when compared with patients who were inactive [HR = 1.03 (0.54-1.97), P = 0.930]. Symptoms developed at an earlier age in patients who participated in competitive sport (30 ± 12 years), when compared with patients who participated in recreational sport (38 ± 17 years) (P = 0.015) and inactive patients (41 ± 11 years) (P = 0.002). No difference in age at first symptom was seen between patients who participated in recreational sport and inactive patients (P = 0.651). CONCLUSION Competitive sport was associated with a two-fold increased risk of VTA/death, and earlier presentation of symptoms, when compared with inactive patients, and to patients who participated in recreational sport. When compared with inactive patients, recreational sport was not associated with earlier onset of symptoms or increased risk of VTA/death. ClinicalTrials.gov Identifier: NCT00024505.

Efficacy of different beta-blockers in the treatment of long QT syndrome.

BACKGROUND In LQTS, β-blocker therapy is effective in reducing the risk of cardiac events (syncope, aborted cardiac arrest, sudden cardiac death). Limited studies have compared the efficacy of different β-blockers. OBJECTIVES The goal of this study was to compare the efficacy of different β-blockers in long QT syndrome (LQTS) and in genotype-positive patients with LQT1 and LQT2. METHODS The study included 1,530 patients from the Rochester, New York-based LQTS Registry who were prescribed common β-blockers (atenolol, metoprolol, propranolol, or nadolol). Time-dependent Cox regression analyses were used to compare the efficacy of different β-blockers with the risk of cardiac events in LQTS. RESULTS Relative to being off β-blockers, the hazard ratios and 95% confidence intervals (CIs) for first cardiac events for atenolol, metoprolol, propranolol, and nadolol were 0.71 (0.50 to 1.01), 0.70 (0.43 to 1.15) 0.65 (0.46 to 0.90), and 0.51 (0.35 to 0.74), respectively. In LQT1, the risk reduction for first cardiac events was similar among the 4 β-blockers, but in LQT2, nadolol provided the only significant risk reduction (hazard ratio: 0.40 [0.16 to 0.98]). Among patients who had a prior cardiac event while taking β-blockers, efficacy for recurrent events differed by drug (p = 0.004), and propranolol was the least effective compared with the other β-blockers. CONCLUSIONS Although the 4 β-blockers are equally effective in reducing the risk of a first cardiac event in LQTS, their efficacy differed by genotype; nadolol was the only β-blocker associated with a significant risk reduction in patients with LQT2. Patients experiencing cardiac events during β-blocker therapy are at high risk for subsequent cardiac events, and propranolol is the least effective drug in this high-risk group.

Ventricular arrhythmias in the North American multidisciplinary study of ARVC: predictors, characteristics, and treatment.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with sudden cardiac death. However, the selection of patients for implanted cardioverter-defibrillators (ICDs), as well as programming of the ICD, is unclear. OBJECTIVES The objective of this study was to identify predictors, characteristics, and treatment of ventricular arrhythmias in patients with ARVC. METHODS The Multidisciplinary Study of Right Ventricular Cardiomyopathy established the North American ARVC Registry and enrolled patients with a diagnosis of ARVC. Patients were followed prospectively. RESULTS Of 137 patients enrolled, 108 received ICDs. Forty-eight patients had 502 sustained episodes of ventricular arrhythmias, including 489 that were monomorphic and 13 that were polymorphic. In the patients with ICDs, independent predictors of ventricular arrhythmias in follow-up included spontaneous sustained ventricular arrhythmias before ICD implantation and T-wave inversions inferiorly. The only independent predictor for life-threatening arrhythmias, defined as sustained ventricular tachycardia (VT) ≥240 beats/min or ventricular fibrillation, was a younger age at enrollment. Anti-tachycardia pacing (ATP), independent of the cycle length of the VT, was successful in terminating 92% of VT episodes. CONCLUSIONS In the North American ARVC Registry, the majority of ventricular arrhythmias in follow-up are monomorphic. Risk factors for ventricular arrhythmias were spontaneous ventricular arrhythmias before enrollment and a younger age at ICD implantation. ATP is highly successful in terminating VT, and all ICDs should be programmed for ATP, even for rapid VT.

Clinical Aspects of Type 3 Long QT Syndrome: An International Multicenter Study

Background: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of &bgr;-blocker therapy has not been studied previously in a large LQT3 population. Methods: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. Results: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome–related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent &bgr;-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × &bgr;-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). Conclusions: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, &bgr;-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.Background: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population. Methods: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. Results: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome–related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females ( P =0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction ( P =0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events ( P <0.02). Conclusions: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events. # Clinical Perspective {#article-title-37}

Association between myocardial substrate, implantable cardioverter defibrillator shocks and mortality in MADIT-CRT

OBJECTIVE The aim of the present study was to assess a possible association between myocardial substrate, implantable cardioverter defibrillator (ICD) shocks, and subsequent mortality. METHODS Within the multicentre automatic defibrillator implantation trial-cardiac resynchronization therapy (MADIT-CRT) population (n = 1790), we investigated the association between myocardial substrate, ICD shocks and subsequent mortality using multivariate Cox regression analyses and landmark analyses at 1-year follow-up. RESULTS The 4-year cumulative probability of ICD shocks was 13% for appropriate shock and 6% for inappropriate shock. Compared with patients who never received ICD therapy, patients who received appropriate shock had an increased risk of mortality [HR = 2.3 (1.47-3.54), P < 0.001], which remained increased after adjusting for echocardiographic remodelling at 1 year (HR = 2.8, P = 0.001). Appropriate anti-tachycardia pacing (ATP) only was not associated with increased mortality (P = 0.42). We were not able to show an association between inappropriate shocks (P = 0.53), or inappropriate ATP (P = 0.10) and increased mortality. Advanced myocardial structural disease, i.e. higher baseline echocardiographic volumes and lack of remodelling at 1 year, was present in patients who received appropriate shocks but not in patients who received inappropriate shocks or no shocks. CONCLUSION In the MADIT-CRT study, receiving appropriate ICD shocks was associated with an increased risk of subsequent mortality. This association was not evident for appropriate ATP only. These findings, along with advanced cardiac structural disease in the patients who received appropriate shocks, suggest that the compromised myocardium is a contributing factor to the increased mortality associated with appropriate ICD shock therapy. Clinical trials.gov identifier: NCT00180271.

Impact of the right ventricular lead position on clinical outcome and on the incidence of ventricular tachyarrhythmias in patients with CRT-D

BACKGROUND Data on the impact of right ventricular (RV) lead location on clinical outcome and ventricular tachyarrhythmias in cardiac resynchronization therapy with defibrillator (CRT-D) patients are limited. OBJECTIVE To evaluate the impact of different RV lead locations on clinical outcome in CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial. METHODS We investigated 742 of 1089 CRT-D patients (68%) with adjudicated RV lead location enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial to evaluate the impact of RV lead location on cardiac events. The primary end point was heart failure or death; secondary end points included ventricular tachycardia (VT), ventricular fibrillation (VF), or death and VT or VF alone. RESULTS Eighty-six patients had the RV lead positioned at the RV septal or right ventricular outflow tract region, combined as nonapical RV group, and 656 patients had apical RV lead location. There was no difference in the primary end point in patients with nonapical RV lead location versus those with apical RV lead location (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.54-1.80; P = .983). Echocardiographic response to CRT-D was comparable across RV lead location groups (P > .05 for left ventricular end-diastolic volume, left ventricular end-systolic volume, and left atrial volume percent change). However, nonapical RV lead location was associated with significantly higher risk of VT/VF/death (HR 2.45; 95% CI 1.36-4.41; P = .003) and VT/VF alone (HR 2.52; 95% CI 1.36-4.65; P = .002), predominantly in the first year after device implantation. Results were consistent in patients with left bundle branch block. CONCLUSIONS In CRT-D patients, there is no benefit of nonapical RV lead location in clinical outcome or echocardiographic response. Moreover, nonapical RV lead location is associated with an increased risk of ventricular tachyarrhythmias, particularly in the first year after device implantation.

Clinical Impact, Safety, and Efficacy of Single‐ versus Dual‐Coil ICD Leads in MADIT‐CRT

Current data on efficacy, safety and impact on clinical outcome of single‐ versus dual‐coil implantable cardioverter‐defibrillator (ICD) leads are limited and contradictory.

Effect on Cardiac Function of Cardiac Resynchronization Therapy in Patients With Right Bundle Branch Block (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT] Trial)

Cardiac resynchronization therapy (CRT) is effective for the treatment of patients with heart failure and a wide QRS duration, particularly left bundle branch block. However, subjects with right bundle branch block (RBBB) do not appear to benefit from CRT. The aim of this study was to determine whether patients with specific RBBB conduction patterns responded to CRT in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial. In the present post hoc analysis, patients with RBBB who received CRT with an implantable cardioverter defibrillator (n = 132) were divided into 2 groups according to the baseline QRS morphology in the inferior and high lateral leads: group 1: left anterior fascicular block (LAFB) pattern (n = 80; 60.6%); and group 2: non-LAFB pattern (n = 52; 39.4%). Subjects with RBBB who received an implantable cardioverter defibrillator served as the control group (n = 87). The primary end point was echocardiographic response to CRT, defined as percent change in left ventricular (LV) and left atrial volumes from baseline to 1 year. The secondary end point was heart failure or death. The non-LAFB group demonstrated a significantly larger percent reduction in LV end-diastolic volume, LV end-systolic volume, and left atrial volume compared to controls (-11%, p <0.0001; -17%, p <0.0001; -15%, p <0.0001, respectively) and LAFB (-5%, p = 0.028; -7%, p = 0.019; -6%; p = 0.022; respectively) by multivariate analysis. No difference was found in the 3-year crude event rates for death or heart failure among the LAFB (22%), non-LAFB (21%), or ICD-only (20%) groups (p = NS). In conclusion, conduction patterns influence echocardiographic response to CRT in patients with RBBB, with favorable reductions in the LV and left atrial volumes in those without an LAFB conduction pattern. This echocardiographic benefit did not translate into a reduction in heart failure or death during a 3-year follow-up period.