Prospective observational study of implantable cardioverter-defibrillators in primary prevention of sudden cardiac death: study design and cohort description

BACKGROUND: Primary-prevention implantable cardioverter-defibrillators (ICDs) reduce total mortality in patients with severe left ventricular systolic function. However, only a minority of patients benefit from these devices. We designed the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD) to identify risk factors and enhance our understanding of the biological mechanisms that predispose to arrhythmic death in patients undergoing ICD implantation for primary prevention of sudden death. METHODS AND RESULTS: This is a multicenter prospective cohort study with a target enrollment of 1200 patients. The primary end point is ICD shocks for adjudicated ventricular tachyarrhythmias. The secondary end point is total mortality. All patients undergo a comprehensive evaluation including history and physical examination, signal-averaged electrocardiograms, and blood sampling for genomic, proteomic, and metabolomic analyses. Patients are evaluated every 6 months and after every known ICD shock for additional electrocardiographic and blood sampling. As of December 2011, a total of 1177 patients have been enrolled with more nonwhite and female patients compared to previous randomized trials. A total of 143 patients have reached the primary end point, whereas a total of 260 patients died over an average follow-up of 59 months. The PROSE-ICD study represents a real-world cohort of individuals with systolic heart failure receiving primary-prevention ICDs. CONCLUSIONS: Extensive electrophysiological and structural phenotyping as well as the availability of serial DNA and serum samples will be important resources for evaluating novel metrics for risk stratification and identifying patients at risk for arrhythmic sudden death. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ Unique Identifier: NCT00733590.This work was supported in part by the Donald W. Reynolds Cardiovascular Foundation and NIH R01 HL091062 (to G.F.T.).S

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

The benefit of upgrading chronically right ventricle–paced heart failure patients to resynchronization therapy demonstrated by strain rate imaging

RV pacing induces conduction delay (CD), mechanical dyssynchrony, and increased morbidity in patients with HF. CRT improves HF symptoms and survival, but sparse data exist on its direct effect on chronically RV-paced HF patients. To assess the benefit of cardiac resynchronization therapy (CRT) in chronically right ventricle (RV)–paced heart failure (HF) patients. We studied 12 consecutive patients with class III HF who had a previously implanted pacemaker or implantable cardioverter-defibrillator. These individuals were chronically RV paced and referred for upgrade to a biventricular device by their primary cardiologists. Tissue Doppler and strain rate imaging (TDI and SRI, respectively) were performed immediately before each upgrade and 4–6 weeks afterward to quantify changes in regional wall motion and synchrony with CRT. CRT significantly reduced the mean QRS duration (205 ms to 156 ms; P<.0001), and it increased the ejection fraction (30.7%±5.1% to 35.8%±5.1%; P<.01). Left ventricular end-systolic and end-diastolic dimensions were also significantly reduced. Clinically, patients improved by an average of one New York Heart Association (NYHA) functional class after upgrade ( P = .006). The parameter exhibiting greatest improvement was the coefficient of variation (CoV: standard deviation/mean) of time to peak systolic strain rate, a marker of ventricular dyssynchrony, which decreased from 34.3%±13.0% to 19.0%±6.6% ( P<.01). Reduction in CoV of time to peak systolic strain rate was maximally seen in the midventricle (38.2%±19.6% to 16.5%±9.7%; P<.01). Upgrading chronically RV-paced HF patients to CRT improves global and regional systolic function. TDI and SRI provide compelling evidence that this benefit parallels that seen in HF patients with CD unrelated to RV pacing, which implies that biventricular pacing synchronizes mechanical activation in different myocardial regions in patients upgraded from RV pacing as well

Preclinical safety and electrical performance of novel atrial leadless pacemaker with dual-helix fixation

Background: Complications associated with transvenous pacemakers, specifically those involving the lead or subcutaneous pocket, may be avoided with leadless pacemakers (LPs). The safety and efficacy of single-chamber right ventricular LPs have been demonstrated, but their right atrium (RA) use poses new design constraints. Objectives: The purpose of this study was to evaluate the implant success, electrical performance, and safety of a novel RA LP design in benchtop and preclinical studies. Methods: A new LP was designed with a dual-helix fixation mechanism specific to the RA anatomy. A 12-week preclinical ovine study was conducted to evaluate implant success, electrical performance, mechanical stability, and safety in vivo, with supporting benchtop measurements to quantify the mechanical forces needed for device retrieval and dislodgment. Results: LPs were successfully implanted in all 10 ovine subjects with no complications. The pacing capture threshold improved significantly over time from implant to week 12 (1.1 ± 0.7 V vs 0.4 ± 0.2 V, P =.008). Sensing amplitudes and pacing impedances were stable from implant to week 12 (4.8 ± 1.8 mV vs 6.0 ± 1.9 mV, P =.160; and 393 ± 77 Ω vs 398 ± 65 Ω, P =.922, respectively). Gross pathology and microscopic histology revealed no adverse interactions and no evidence of device dislodgment or clinically significant myocardial perforation. Benchtop ex vivo porcine atrial tissue measurements revealed greater pull forces required to dislodge the LP vs transvenous active fixation lead (0.42 ± 0.18 lbf vs 0.29 ± 0.08 lbf, P =.020), and greater rotational forces required for deliberate extraction (0.28 ± 0.04 lbf vs 0.14 ± 0.07 lbf, P <.001). Conclusion: The novel atrial LP demonstrated successful implantation, with acceptable electrical performance, mechanical stability, and safety in a 12-week preclinical study

Clinical and serum-based markers are associated with death within 1 year of de novo implant in primary prevention ICD recipients

Implantable cardioverter-defibrillator (ICD) implantation is contraindicated in those with <1-year life expectancy. The aim of this study was to develop a risk prediction score for 1-year mortality in patients with primary prevention ICDs and to determine the incremental improvement in discrimination when serum-based biomarkers are added to traditional clinical variables. We analyzed data from the Prospective Observational Study of Implantable Cardioverter-Defibrillators, a large prospective observational study of patients undergoing primary prevention ICD implantation who were extensively phenotyped for clinical and serum-based biomarkers. We identified variables predicting 1-year mortality and synthesized them into a comprehensive risk scoring construct using backward selection. Of 1189 patients deemed by their treating physicians as having a reasonable 1-year life expectancy, 62 (5.2%) patients died within 1 year of ICD implantation. The risk score, composed of 6 clinical factors (age ≥75 years, New York Heart Association class III/IV, atrial fibrillation, estimated glomerular filtration rate <30 mL/min/1.73 m(2), diabetes, and use of diuretics), had good discrimination (area under the curve 0.77) for 1-year mortality. Addition of 3 biomarkers (tumor necrosis factor α receptor II, pro-brain natriuretic peptide, and cardiac troponin T) further improved model discrimination to 0.82. Patients with 0-1, 2-3, 4-6, or 7-9 risk factors had 1-year mortality rates of 0.8%, 2.7%, 16.1%, and 46.2%, respectively. Individuals with more comorbidities and elevation of specific serum biomarkers were at increased risk of all-cause mortality despite being deemed as having a reasonable 1-year life expectancy. A simple risk score composed of readily available clinical data and serum biomarkers may better identify patients at high risk of early mortality and improve patient selection and counseling for primary prevention ICD therap