Andrew Brenyo

Cardiac Resynchronization Therapy Reduces Left Atrial Volume and the Risk of Atrial Tachyarrhythmias in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)

OBJECTIVES We hypothesized that reductions in left atrial volume (LAV) with a cardiac resynchronization therapy-defibrillator (CRT-D) would translate into a subsequent reduction in the risk of atrial tachyarrhythmias (AT). BACKGROUND There is limited information regarding the effect of CRT-D on the risk of AT. METHODS Percent reduction in LAV at 1 year following CRT-D implantation (pre-specified as low [lowest quartile: <20% reduction in LAV] and high [≥20% reduction in LAV] response to CRT-D) were related to the risk of subsequent AT (comprising atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachyarrhythmias) among patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). RESULTS The cumulative probability of AT 2.5 years after assessment of echocardiographic response was lowest among high LAV responders to CRT-D (3%) and significantly higher among both low LAV responders to CRT-D (9%) and implantable cardioverter-defibrillator-only patients (7%; p = 0.03 for the difference among the 3 groups). Consistently, multivariate analysis showed that high LAV responders to CRT-D experienced a significant 53% (p = 0.01) reduction in the risk of subsequent AT as compared with implantable cardioverter-defibrillator-only patients, whereas low LAV responders did not derive a significant risk reduction with CRT-D therapy (hazard ratio [HR]: 1.05 [95% confidence interval (CI): 0.54 to 2.00]; p = 0.89). Patients who developed in-trial AT experienced significant increases in the risk for both the combined endpoint of heart failure or death (HR: 2.28 [95% CI: 1.45 to 3.59]; p < 0.001) and the separate occurrence of all-cause mortality (HR: 1.89 [95% CI: 1.08 to 3.62]; p = 0.01). CONCLUSIONS In the MADIT-CRT study, favorable reverse remodeling of the left atrium with CRT-D therapy was associated with a significant reduction in risk of subsequent AT. (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

PR Interval Identifies Clinical Response in Patients With Non–Left Bundle Branch Block A Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy Substudy

Background —In MADIT-CRT, patients with non-LBBB (including RBBB, IVCD) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR-interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results —Non-LBBB patients (n=537, 30%) were divided in two groups based on their baseline PR-interval as normal (including minimally prolonged) PR (PR < 230 ms), and prolonged PR (PR ≥ 230 ms). The primary end point was heart failure (HF) or death. Separate secondary end points included HF events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to ICD therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR-interval, CRT-D treatment was associated with a 73% reduction in the risk of HF/Death (HR=0.27, 95% CI: 0.13-0.57, p<0.001) and 81% decrease in the risk of all-cause mortality (HR=0.19, 95% CI: 0.13-0.57, p<0.001) compared to ICD therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend towards an increased risk of HF/Death (HR=1.45, 95% CI: 0.96-2.19, p=0.078, interaction p-value<0.001) and more than a 2-fold higher mortality (HR=2.14, 95% CI: 1.12-4.09, p=0.022, interaction p-value<0.001) compared to ICD therapy. Conclusions —The data support the use of CRT-D in MADIT-CRT, non-LBBB patients with a prolonged PR-interval. In non-LBBB patients with a normal PR-interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration —http://clinicaltrials.gov; Unique Identifier: [NCT00180271][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcircae%2Fearly%2F2014%2F06%2F24%2FCIRCEP.113.001299.atomBackground—In Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT), patients with non–left bundle branch block (LBBB; including right bundle branch block, intraventricular conduction delay) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results—Non-LBBB patients (n=537; 30%) were divided into 2 groups based on their baseline PR interval as normal (including minimally prolonged) PR (PR <230 ms) and prolonged PR (PR ≥230 ms). The primary end point was heart failure or death. Separate secondary end points included heart failure events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to implantable cardioverter defibrillator therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR interval, CRT-D treatment was associated with a 73% reduction in the risk of heart failure/death (hazard ratio, 0.27; 95% confidence interval, 0.13–0.57; P<0.001) and 81% decrease in the risk of all-cause mortality (hazard ratio, 0.19; 95% confidence interval, 0.13–0.57; P<0.001) compared with implantable cardioverter defibrillator therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend toward an increased risk of heart failure/death (hazard ratio, 1.45; 95% confidence interval, 0.96–2.19; P=0.078; interaction P<0.001) and a more than 2-fold higher mortality (hazard ratio, 2.14; 95% confidence interval, 1.12–4.09; P=0.022; interaction P<0.001) compared with implantable cardioverter defibrillator therapy. Conclusions—The data support the use of CRT-D in MADIT-CRT non-LBBB patients with a prolonged PR interval. In non-LBBB patients with a normal PR interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration—http://clinicaltrials.gov; Unique Identifier: NCT00180271.

PR-Interval Identifies Clinical Response in Patients with Non-LBBB: A MADIT-CRT Sub-Study

Background —In MADIT-CRT, patients with non-LBBB (including RBBB, IVCD) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR-interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results —Non-LBBB patients (n=537, 30%) were divided in two groups based on their baseline PR-interval as normal (including minimally prolonged) PR (PR < 230 ms), and prolonged PR (PR ≥ 230 ms). The primary end point was heart failure (HF) or death. Separate secondary end points included HF events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to ICD therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR-interval, CRT-D treatment was associated with a 73% reduction in the risk of HF/Death (HR=0.27, 95% CI: 0.13-0.57, p<0.001) and 81% decrease in the risk of all-cause mortality (HR=0.19, 95% CI: 0.13-0.57, p<0.001) compared to ICD therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend towards an increased risk of HF/Death (HR=1.45, 95% CI: 0.96-2.19, p=0.078, interaction p-value<0.001) and more than a 2-fold higher mortality (HR=2.14, 95% CI: 1.12-4.09, p=0.022, interaction p-value<0.001) compared to ICD therapy. Conclusions —The data support the use of CRT-D in MADIT-CRT, non-LBBB patients with a prolonged PR-interval. In non-LBBB patients with a normal PR-interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration —http://clinicaltrials.gov; Unique Identifier: [NCT00180271][1] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00180271&atom=%2Fcircae%2Fearly%2F2014%2F06%2F24%2FCIRCEP.113.001299.atomBackground—In Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT), patients with non–left bundle branch block (LBBB; including right bundle branch block, intraventricular conduction delay) did not have clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D). We hypothesized that baseline PR interval modulates clinical response to CRT-D therapy in patients with non-LBBB. Methods and Results—Non-LBBB patients (n=537; 30%) were divided into 2 groups based on their baseline PR interval as normal (including minimally prolonged) PR (PR <230 ms) and prolonged PR (PR ≥230 ms). The primary end point was heart failure or death. Separate secondary end points included heart failure events and all-cause mortality. Cox proportional hazards regression models were used to compare risk of end point events by CRT-D to implantable cardioverter defibrillator therapy in the PR subgroups. There were 96 patients (22%) with a prolonged PR and 438 patients (78%) with a normal PR interval. In non-LBBB patients with a prolonged PR interval, CRT-D treatment was associated with a 73% reduction in the risk of heart failure/death (hazard ratio, 0.27; 95% confidence interval, 0.13–0.57; P<0.001) and 81% decrease in the risk of all-cause mortality (hazard ratio, 0.19; 95% confidence interval, 0.13–0.57; P<0.001) compared with implantable cardioverter defibrillator therapy. In non-LBBB patients with normal PR, CRT-D therapy was associated with a trend toward an increased risk of heart failure/death (hazard ratio, 1.45; 95% confidence interval, 0.96–2.19; P=0.078; interaction P<0.001) and a more than 2-fold higher mortality (hazard ratio, 2.14; 95% confidence interval, 1.12–4.09; P=0.022; interaction P<0.001) compared with implantable cardioverter defibrillator therapy. Conclusions—The data support the use of CRT-D in MADIT-CRT non-LBBB patients with a prolonged PR interval. In non-LBBB patients with a normal PR interval, implantation of a CRT-D may be deleterious. Clinical Trial Registration—http://clinicaltrials.gov; Unique Identifier: NCT00180271.

The association between biventricular pacing and cardiac resynchronization therapy-defibrillator efficacy when compared with implantable cardioverter defibrillator on outcomes and reverse remodelling

AIMS Previous studies on biventricular (BIV) pacing and cardiac resynchronization therapy-defibrillator (CRT-D) efficacy have used arbitrarily chosen BIV pacing percentages, and no study has employed implantable cardioverter defibrillator (ICD) patients as a control group. METHODS AND RESULTS Using Kaplan-Meier plots, we estimated the threshold of BIV pacing percentage needed for CRT-D to be superior to ICD on the end-point of heart failure (HF) or death in 1219 left bundle branch block (LBBB) patients in the MADIT-CRT trial. Patients were censored at the time of crossover. In multivariable Cox analyses, no difference was seen in the risk of HF/death between ICD and CRT-D patients with BIV pacing ≤90% [HR = 0.78 (0.47-1.30), P = 0.344], and with increasing BIV pacing the risk of HF/death was decreased [CRT-D BIV 91-96% vs. ICD: HR = 0.63 (0.42-0.94), P = 0.024 and CRT-D BIV ≥97% vs. ICD: HR = 0.32 (0.23-0.44), P < 0.001]. The risk of death alone was reduced by 52% in CRT-D patients with BIV ≥97% (HR = 0.48, P < 0.016), when compared with ICD patients. Within the CRT-D group, for every 1 percentage point increase in BIV pacing, the risk of HF/death and death alone significantly decreased by 6 and 10%, respectively. Increasing BIV pacing percentage was associated with significant reductions in left ventricular volume. CONCLUSION In patients with LBBB, who were in sinus rhythm at enrolment, BIV pacing exceeding 90% was associated with a benefit of CRT-D in HF/death when compared with ICD patients. Furthermore, BIV pacing ≥97% was associated with an even further reduction in HF/death, a significant 52% reduction in death alone, and increased reverse remodelling. Clinical trials.gov identifier: NCT00180271.

Wearable Defibrillator in Congenital Structural Heart Disease and Inherited Arrhythmias

Patients with congenital structural heart disease (CSHD) and inherited arrhythmias (IAs) are at high risk of ventricular tachyarrhythmias and sudden cardiac death. The present study was designed to evaluate the short- and long-term outcomes of patients with CSHD and IA who received a wearable cardioverter-defibrillator (WCD) for the prevention of sudden cardiac death. The study population included 162 patients with CSHD (n = 43) and IA (n = 119) who were prospectively followed up in a nationwide registry from 2005 to 2010. The mortality rates were compared using Kaplan-Meier survival analysis. The mean age of the study patients was 38 ± 27 years. The patients with CSHD had a greater frequency of left ventricular dysfunction (ejection fraction <30%) than did the patients with IA (37% vs 5%, respectively; p = 0.002). The predominant indication for WCD was pending genetic testing in the IA group and transplant listing in the CSHD group. Compliance with the WCD was similar in the 2 groups (91%). WCD shocks successfully terminated 3 ventricular tachyarrhythmias in the patients with IA during a median follow-up of 29 days of therapy (corresponding to 23 appropriate WCD shocks per 100 patient-years). No arrhythmias occurred in the patients with CSHD during a median follow-up of 27 days. No patients died while actively wearing the WCD. At 1 year of follow-up, the survival rates were significantly lower among the patients with CSHD (87%) than among the patients with IA (97%, p = 0.02). In conclusion, our data suggest that the WCD can be safely used in high-risk adult patients with IA and CSHD. Patients with IA showed a greater rate of ventricular tachyarrhythmias during therapy but significantly lower long-term mortality rates.

Predictors of Spontaneous Reverse Remodeling in Mild Heart Failure Patients With Left Ventricular Dysfunction

Background—There are limited data regarding factors associated with spontaneous left ventricular reverse remodeling (S-LVRR) among mildly symptomatic heart failure (HF) patients and its prognostic implications on clinical outcomes. Methods and Results—Best subsets logistic regression analysis was used to identify factors associated with S-LVRR (defined as ≥15% reduction in left ventricular end-systolic volume at 1-year of follow-up) among 612 patients treated with internal cardioverter defibrillator–only therapy in Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) and to create a score for the prediction of S-LVRR. Cox proportional hazards regression modeling was used to assess the clinical outcome of all internal cardioverter defibrillator–only patients (n=714) with a high S-LVRR score. S-LVRR occurred in 25% of internal cardioverter defibrillator–only patients. Predictors of S-LVRR included systolic blood pressure≥140 mm Hg, serum creatinine<1.0 mg/dL, QRS 130 to 160 ms, and nonischemic cardiomyopathy. Multivariate analysis showed that each 1-point increment in S-LVRR score (range, 0–7) was associated with an 11% (P=0.019) reduction in the risk of HF or death. Treatment with cardiac resynchronization therapy was associated with a significant reduction in the risk of HF or death only among internal cardioverter defibrillator–treated patients with a low (Q1–3) S-LVRR score (hazard ratio=0.55; P<0.001), but not among those with a higher (Q4) score (hazard ratio=1.06; P=0.72). Conclusions—Our data suggest that approximately one quarter of mild HF patients eligible for biventricular pacing experience S-LVRR. Combined assessment of clinical factors associated with S-LVRR can be used to identify mild HF patients with a low risk for clinical events without cardiac resynchronization therapy intervention. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Review of Complementary and Alternative Medical Treatment of Arrhythmias

Complementary and alternative medical (CAM) therapies are commonly used by patients for the treatment of medical conditions spanning the full spectrum of severity and chronicity. The use of alternative remedies, both herbal and others, for conditions lacking effective medical treatment, is on the increase. Included within this categorization, arrhythmic disease-absent effective catheter-based therapy or with medical therapy limited by the toxicities of contemporary antiarrhythmic agents is frequently managed by patients with CAM therapies without their practitioners knowledge and in the face of potential herb-drug toxicities. This study reviews 9 CAM therapies: 7 individual herbal therapies along with acupuncture and yoga that have been studied and reported as having an antiarrhythmic effect. The primary focuses are the proposed antiarrhythmic mechanism of each CAM agent along with interactions between the CAM therapies and commonly prescribed medical therapy for arrhythmia patients. We stress persistent vigilance on the part of the provider in discussing the use of herbal or other CAM agents within the arrhythmia population.

Sex-related differences in patients' responses to heart failure therapy

Men and women with heart failure display important differences in clinical characteristics that might affect their responses to pharmacological and nonpharmacological therapies. In women, heart failure is associated with a higher frequency of hypertension, nonischemic cardiomyopathy and left bundle branch block than in men. Subgroup analyses of data from randomized clinical trials suggest that these differences result in a differential response to heart failure therapies, including a somewhat better response to β-blockers, a worse prognosis with digoxin therapy, and a lower survival benefit with implantable cardioverter-defibrillators in women. Importantly, female patients with heart failure also derive significantly greater improvements in cardiac volumes from cardiac resynchronization therapy than do male patients, and this treatment is associated with reduced risks of all-cause mortality and heart failure events among women with mild symptoms. These data suggest that sex-related differences might exist in response to both medical and device therapies for patients with heart failure.

Genetics of Sudden Cardiac Death

Advances in genetic testing technology have led to a proliferation of new genetic tests and accelerated developments in the field of cardiovascular genetic medicine. These advances enhance presymptomatic diagnosis and can establish a definitive molecular diagnosis for symptomatic patients at risk for sudden cardiac death. Most importantly, genotype-phenotype correlations can add important information for predicting outcome and selecting treatment for patients with inherited arrhythmic disorders. This paper reviews the current data regarding genotype-phenotype correlations and the role of clinical genetic testing in diagnosis, prognosis, and management of inheritable disorders leading to sudden cardiac death.

Atrioventricular delay programming and the benefit of cardiac resynchronization therapy in MADIT-CRT

BACKGROUND The optimal atrioventricular pacing delay (AVD) in cardiac resynchronization therapy (CRT) remains to be determined. OBJECTIVE To determine whether programming CRT devices to short AVD (S-AVD) will improve clinical response secondary to greater reductions in dyssynchrony. METHODS The study population comprised 1235 patients with left bundle branch block enrolled in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy (MADIT-CRT). We assessed the relationship between AVD and outcomes. Patients programmed to S-AVD (median value of <120 ms; n = 337) vs long AVD (L-AVD; ≥120 ms; n = 390) were assessed for the end points of heart failure (HF) or death, death alone, and echocardiographic response to the CRT at 1-year follow-up. Outcomes were also compared to the left bundle branch block implantable cardioverter-defibrillator-only group (n = 508). RESULTS Multivariate analysis showed that patients programmed to S-AVD experienced a significant 33% (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.44-0.85; P = .037) reduction in the risk of HF or death and a 47% (HR 0.53; 95% CI 0.29-0.94; P = .031) reduction in death alone as compared with those programmed to L-AVD. Patients with CRT-programmed S-AVD and L-AVD experienced 63% (HR 0.37; 95% CI 0.26-0.53; P < .001) and 46% (HR 0.54; 95% CI 0.31-0.96; P < .001) reduction, respectively, in the risk of HF or death compared to patients with implantable cardioverter-defibrillator alone. At 1 year of follow-up, S-AVD vs L-AVD was associated with a greater reduction in left ventricular end-systolic volume (34.2% vs 30.8%; P = .002) along with a significantly greater improvement in dyssynchrony (22.3% vs 9.4%; P = .036). CONCLUSIONS Our findings indicate that in MADIT-CRT programming, the CRT AVD <120 ms was associated with a greater clinical and echocardiographic response to CRT.