Predictors of short-term clinical response to cardiac resynchronization therapy

Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with symptomatic heart failure and QRS prolongation but there is uncertainty about which patient characteristics predict short-term clinical response. Methods and results: In an individual patient meta-analysis of three double-blind, randomized trials, clinical composite score (CCS) at 6 months was compared in patients assigned to CRT programmed on or off. Treatment–covariate interactions were assessed to measure likelihood of improved CCS at 6 months. MIRACLE, MIRACLE ICD, and REVERSE trials contributed data for this analysis (n = 1591). Multivariable modelling identified QRS duration and left ventricular ejection fraction (LVEF) as predictors of CRT clinical response (P < 0.05). The odds ratio for a better CCS at 6 months increased by 3.7% for every 1% decrease in LVEF for patients assigned to CRT-on compared to CRT-off, and was greatest when QRS duration was between 160 and 180 ms. Conclusions: In symptomatic chronic heart failure patients (NYHA class II–IV), longer QRS duration and lower LVEF independently predict early clinical response to CRT

Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer

A Leadless Ventricular Pacemaker Providing Atrioventricular Synchronous Pacing in the Real-World Setting: 12-Month Results from the Micra AV Post-Approval Registry.

BACKGROUND Advances in leadless pacemaker technology have enabled accelerometer-based atrioventricular (AV) synchronous pacing by sensing atrial mechanical contraction. OBJECTIVES To report performance of the Micra AV leadless pacemaker from the worldwide Micra AV post-approval registry (PAR) through 12-months. METHODS The Micra AV PAR is a prospective single-arm observational registry designed to assess safety and effectiveness of Micra AV in a real-world setting. For the present interim analysis, major complications and system revisions through 12-months were summarized and compared to a historical cohort of 2,667 transvenous dual-chamber pacing patients. RESULTS The device was successfully implanted in 796 of 801 patients (99.4%) at 97 centers in 19 countries. Micra AV patients were older (74.1 vs. 71.1 years, P90%. CONCLUSIONS The Micra AV leadless pacemaker was implanted with a high rate of success in patients with multiple co-morbidities, with a significantly lower rate of complications and system revisions through 12-months compared to a historical cohort of patients with transvenous dual-chamber pacemakers

Inappropriate shocks in single-chamber and subcutaneous implantable cardioverter-defibrillators: a systematic review and meta-analysis

Aims: Single-chamber (VR-ICD) and subcutaneous (S-ICD) implantable cardioverter-defibrillators are effective to protect patients against sudden death but expose them to higher risk of inappropriate shock (IS). We sought to quantify the annual rate and influencing factors of ISs in VR- and S-ICDs from the literature. Methods and results: PubMed, Embase, and Cochrane Library were searched for full text articles with IS rates. Poisson distribution estimated proportion of patients with ISs; rates were annualized based on follow-up duration. Random effects meta-analysis accounted for study-to-study variation. Out of 3264 articles, 16 qualified for the meta-analysis. Across studies, 6.4% [95% confidence interval (CI) 5.1-7.9%] of patients received an IS per year. Meta-regression analyses demonstrated that IS rates were lower in more recent studies [rate ratio (RR) per year: 0.93, 95% CI: 0.87-0.98; P = 0.01] and trended lower in studies with longer follow-up (RR per year: 0.78, 95% CI: 0.60-1.01; P = 0.06). Use of S-ICDs (RR: 1.81, 95% CI: 0.86-3.81; P = 0.12) and ventricular tachycardia zone programmed on (RR: 1.13, 95% CI: 0.65-1.97; P = 0.66) were not associated with a significantly increased change in risk. The IS rate observed in one of the more recent studies was significantly lower than predicted after accounting for covariates (RR: 0.29, 95% CI: 0.14-0.60; P < 0.001). Conclusions: A comprehensive review of the literature shows that 6.4% of patients with ICDs experienced their first IS annually. One of the 16 studies was better than predicted with the lowest reported rate (1.9%) and could not be explained by timing of the study or other covariates

SVT discrimination algorithms significantly reduce the rate of inappropriate therapy in the setting of modern day delayed high-rate detection programming

BACKGROUND Contemporary ICD programming involving delayed high-rate detection and use of SVT discriminators has significantly reduced the rate of inappropriate shocks. The extent to which SVT algorithms alone reduce inappropriate therapies is poorly understood. METHODS AND RESULTS PainFree SST enrolled 2,770 patients with a single or dual-chamber ICD or cardiac resynchronization defibrillator. Patients were followed for 22±9 months with SVT discriminators on in 96% of patients. Sustained ventricular tachyarrhythmias and SVT episodes were adjudicated by an independent physician committee. For this analysis, all episodes were subjected to post-processing computer simulation with SVT discriminators off with and without delayed high-rate detection criteria (VF zone only, 30/40@320ms). There were 3,282 adjudicated SVT episodes of which 115 resulted in an ICD shock and 113 received only ATP (2-year inappropriate shock and therapy rates of 3.1% and 4.1%). Therapy was appropriately withheld for the remaining 3,054 SVT episodes. With both SVT discriminators and delayed high-rate detection simulated off, the 2-year inappropriate therapy rate would have been 22.9% (Hazard Ratio [HR]=6.24, 95% confidence interval [CI]: 5.20-7.49). With SVT discriminators simulated off and delayed high-rate detection simulated on in all patients, the 2-year rate would have been 6.4% (HR=1.63, CI: 1.44-1.85). CONCLUSIONS Use of SVT discriminators has a significant role in reducing the rate of inappropriate ICD therapy even in the setting of delayed high-rate detection settings. Deactivating SVT discriminators would have resulted in an overall increase in the inappropriate ICD therapy rate by 63% and 524% with and without delayed high-rate detection programming, respectively. This article is protected by copyright. All rights reserved

Economic implications of adding a novel algorithm to optimize cardiac resynchronization therapy: rationale and design of economic analysis for the AdaptResponse trial

International audienceAims Although cardiac resynchronization therapy (CRT) has proven beneficial in several randomized trials, a subset of patients have limited clinical improvement. The AdaptivCRT algorithm provides automated selection between synchronized left ventricular or biventricular pacing with optimization of atrioventricular delays. The rationale and design of the economic analysis of the AdaptResponse clinical trial are described. Rationale The costs associated with HF hospitalization are substantial and are compounded by a high rate of readmission. HF hospitalization payments range from $1,001 for Greece to$12,235 for US private insurance. When examining the breakdown of HF-related costs, it is clear that approximately 55% of the hospitalization costs are directly attributable to length of stay. Notably, the mean costs of a CRT patient in need of a HF-related hospitalization are currently estimated to be an average of $10,679. Methods The economic analysis of the AdaptResponse trial has two main objectives. The hospital provider objective seeks to test the hypothesis that AdaptivCRT reduces the incidence of all-cause re-admissions after a heart failure admission within 30 days of the index event. A negative binomial regression model will be used to estimate and compare the number of readmissions after an index HF hospitalization. The payer economic objective will assess cost-effectiveness of CRT devices with the AdaptivCRT algorithm relative to traditional CRT programming. This analysis will be conducted from a U.S. payer perspective. A decision analytic model comprised of a 6-month decision tree and a Markov model for long term extrapolation will be used to evaluate lifetime costs and benefits. Conclusion AdaptivCRT may offer improvements over traditional device programming in patient outcomes. How the data from AdaptResponse will be used to demonstrate if these clinical benefits translate into substantial economic gains is herein described

Comparison of ICD shock rates in Japanese and non-Japanese patients in the PainFree SST study

BACKGROUND The PainFree Smart Shock Technology (SST) study showed a low implantable cardioverter-defibrillator (ICD) inappropriate shock rate. However, the majority of patients were from Western countries with patient characteristics different from those in Japan. ICD shock rates using the novel SST algorithms in Japanese patients are still unknown. METHODS All 2,770 patients in the PainFree SST study (Japan [JPN]: N = 181, other geographies [OJPN]: N = 2,589) were included in this analysis. RESULTS Japanese patients had higher average left ventricular ejection fraction (P < 0.0001), higher prevalence of secondary prevention indications (P < 0.0001), nonischemic cardiomyopathy (P < 0.0001), and permanent atrial fibrillation (P < 0.0001). The appropriate shock rate at 12 months was not different between JPN and OJPN: 6.4% and 6.3%, respectively (P = 0.95). The inappropriate shock rate at 12 months was significantly higher in Japanese patients (2.9% vs 1.7%, P = 0.017). However, after propensity score matching to adjust for the difference in baseline characteristics, the difference in inappropriate shock rate was not statistically significant (P = 0.51). CONCLUSIONS There was no difference in the appropriate shock rate between Japan and other geographies. The inappropriate shock rate in Japan was low, although it was slightly higher compared to other geographies due to baseline characteristics, including a higher prevalence of permanent AF. There was not a statistically significant difference after adjusting for baseline characteristics

Updated performance of the Micra transcatheter pacemaker in the real-world setting : A comparison to the investigational study and a transvenous historical control

Early results of the Micra Investigational Device Exemption (IDE) study and Micra Post-Approval Registry (PAR) demonstrated excellent safety and efficacy performance; however, intermediate-term results across a large patient population in the real-world setting have not been evaluated. We report updated performance of the Micra transcatheter pacemaker from a worldwide PAR and compare it with the IDE study as well as a transvenous historical control. The safety objective of the analysis was system- or procedure-related major complications through 12 months postimplantation. We compared the major complication rate with that of the 726 patients from the IDE and with a reference data set of 2667 patients with transvenous pacemakers by using a Fine-Gray competing risk model. The Micra device was successfully implanted in 1801 of 1817 patients (99.1%). The mean follow-up period was 6.8 ± 6.9 months. Through 12 months, the major complication rate was 2.7% (95% confidence interval [CI] 2.0%-3.7%). The risk of major complications for Micra PAR patients was 63% lower than that for patients with transvenous pacemakers through 12 months postimplantation (hazard ratio 0.37; 95% CI 0.27-0.52; P <.001). The major complication rate trended lower in the PAR than in the IDE study (hazard ratio 0.71; 95% CI 0.44-1.1; P =.160), driven by the lower pericardial effusion rate in the PAR. There were 3 cases of infection associated with the procedure, but none required device removal and there were no battery or telemetry issues. Pacing thresholds were low and stable through 12 months postimplantation. Performance of the Micra transcatheter pacemaker in international clinical practice remains consistent with previously reported data. Major complications were infrequent and occurred 63% less often compared to transvenous systems. Micra Transcatheter Pacing System Post-Approval Registry ClinicalTrials.gov identifier: NCT02536118; Micra Transcatheter Pacing Study ClinicalTrials.gov identifier: NCT02004873

IRS proteins regulate TGFβ2 mRNA expression and breast cancer cell motility.

<p>(A) Expression of TGFβ1 and TGFβ2 by qPCR in T47D-YA-IRS-1 (#10 and #20) and T47D-YA-IRS-2 (#1 and #6). (B) IGF-induced TGFβ2 expression in MCF10A, MCF-7L, MCF-7 ATCC, MDA-231 and F11 cells. For A & B, all cells were exposed to 5nm IGF-I for 4 hours prior to harvesting mRNA. Gene expression was normalized to RPLP0 and is presented as fold-change of treatment (black bars) vs. serum-free (white bars) conditions. (C) TGFβ2 expression was assessed by qPCR in an IRS-gene deletion mouse models (left) and IRS-overexpressing SH-EP neuroblastoma cells (right). (D) IRS-1, IRS-2 and TGFβ2 expression in a panel of patient breast tumors. Arrows indicate invasive breast carcinoma. Yellow bars signify high gene expression, blue bars signify low gene expression. E) pSMAD2 was examined by immunoblot at the indicated time points in MCF-7 cells. (F) Cell motility was examined by modified Boyden chamber assay. MCF-7 cells were incubated in the presence of neutralizing antibodies to either TGFβ1 or TGFβ2 and IGF-induced motility assessed. Error bars represent standard deviation and all results are representative of at least three independent replicates.</p