Association between proactive esophageal cooling and increased lab throughput.

INTRODUCTION: Proactive esophageal cooling has been FDA cleared to reduce the likelihood of ablation-related esophageal injury resulting from radiofrequency (RF) cardiac ablation procedures. Data suggest that procedure times for RF pulmonary vein isolation (PVI) also decrease when proactive esophageal cooling is employed instead of luminal esophageal temperature (LET) monitoring. Reduced procedure times may allow increased electrophysiology (EP) lab throughput. We aimed to quantify the change in EP lab throughput of PVI cases after the introduction of proactive esophageal cooling. METHODS: EP lab throughput data were obtained from three EP groups. We then compared EP lab throughput over equal time frames at each site before (pre-adoption) and after (post-adoption) the adoption of proactive esophageal cooling. RESULTS: Over the time frame of the study, a total of 2498 PVIs were performed over a combined 74 months, with cooling adopted in September 2021, November 2021, and March 2022 at each respective site. In the pre-adoption time frame, 1026 PVIs were performed using a combination of LET monitoring with the addition of esophageal deviation when deemed necessary by the operator. In the post-adoption time frame, 1472 PVIs were performed using exclusively proactive esophageal cooling, representing a mean 43% increase in throughput (p < .0001), despite the loss of two operators during the post-adoption time frame. CONCLUSION: Adoption of proactive esophageal cooling during PVI ablation procedures is associated with a significant increase in EP lab throughput, even after a reduction in total number of operating physicians in the post-adoption group.

Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation.

BACKGROUND: Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit. METHODS: We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason). RESULTS: We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group. CONCLUSIONS: Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).

Atrioesophageal Fistula Rates Before and After Adoption of Active Esophageal Cooling During Atrial Fibrillation Ablation.

BACKGROUND: Active esophageal cooling reduces the incidence of endoscopically identified severe esophageal lesions during radiofrequency (RF) catheter ablation of the left atrium for the treatment of atrial fibrillation. A formal analysis of the atrioesophageal fistula (AEF) rate with active esophageal cooling has not previously been performed. OBJECTIVES: The authors aimed to compare AEF rates before and after the adoption of active esophageal cooling. METHODS: This institutional review board (IRB)-approved study was a prospective analysis of retrospective data, designed before collecting and analyzing the real-world data. The number of AEFs occurring in equivalent time frames before and after adoption of cooling using a dedicated esophageal cooling device (ensoETM, Attune Medical) were quantified across 25 prespecified hospital systems. AEF rates were then compared using generalized estimating equations robust to cluster correlation. RESULTS: A total of 14,224 patients received active esophageal cooling during RF ablation across the 25 hospital systems, which included a total of 30 separate hospitals. In the time frames before adoption of active cooling, a total of 10,962 patients received primarily luminal esophageal temperature (LET) monitoring during their RF ablations. In the preadoption cohort, a total of 16 AEFs occurred, for an AEF rate of 0.146%, in line with other published estimates for procedures using LET monitoring. In the postadoption cohort, no AEFs were found in the prespecified sites, yielding an AEF rate of 0% (P < 0.0001). CONCLUSIONS: Adoption of active esophageal cooling during RF ablation of the left atrium for the treatment of atrial fibrillation was associated with a significant reduction in AEF rate.

Evaluation of Safety Outcomes of Undiluted Levetiracetam Intravenous Push Compared to Intravenous Piggyback.

BACKGROUND: Breakthrough seizures and status epilepticus require urgent management. Administration of intravenous push (IVP) levetiracetam has been demonstrated to be safe as compared to intravenous piggyback (IVPB). This transition can potentially offer faster time to administration and reduced drug and material cost. The objective of this study was to observe safety of administration in patients receiving levetiracetam via IVP compared to IVPB in acute care settings. METHODS: This is a multi-center, observational, retrospective cohort study of 1214 adult patients who received levetiracetam pre- and post-implementation of IVP over a 6 month timespan. Primary outcome was time from order verification to administration of urgent first-time doses. Secondary outcomes included time to administration of loading doses and cost. Safety outcome was infusion site related reactions. RESULTS: Time from order verification to administration of urgent first-time doses pre- and post-implementation of IVP administration was reduced from 61 minutes to 47 minutes (P=0.0002). Infusion site related reactions were observed in 6 out of 5432 doses in the IVPB arm and in 5 out of 4700 doses in the IVP arm (P=1). Total estimated cost was $76,171.96 for the 5449 IVPB total doses and $11,484.33 for the 4721 IVP total doses. CONCLUSIONS: Transition from IVPB to IVP administration reduced time from order verification to administration of urgent first-time doses with both administrations having similar incidence of infusion site related reactions. Cost savings and improved workflow were observed. Levetiracetam administered via IVP may be considered as a safe alternative method of administration in the acute care setting.

Accessibility and use of novel methods for predicting physical activity and energy expenditure using accelerometry: a scoping review.

Use of raw acceleration data and/or 'novel' analytic approaches like machine learning for physical activity measurement will not be widely implemented if methods are not accessible to researchers.Objective: This scoping review characterizes the validation approach, accessibility and use of novel analytic techniques for classifying energy expenditure and/or physical activity intensity using raw or count-based accelerometer data.Approach: Three databases were searched for articles published between January 2000 and February 2021. Use of each method was coded from a list of citing articles compiled from Google Scholar. Authors' provision of access to the model (e.g., by request, sample code) was recorded.Main Results: Studies (N = 168) included adults (n = 143), and/or children (n = 38). Model use ranged from 0 to 27 uses/year (average 0.83) with 101 models that have never been used. Approximately half of uses occurred in a free-living setting (52%) and/or by other authors (56%). Over half of included articles (n = 107) did not provide complete access to their model. Sixty-one articles provided access to their method by including equations, coefficients, cut-points, or decision trees in the paper (n = 48) and/or by providing access to code (n = 13).Significance: The proliferation of approaches for analyzing accelerometer data outpaces the use of these models in practice. As less than half of the developed models are made accessible, it is unsurprising that so many models are not used by other researchers. We encourage researchers to make their models available and accessible for better harmonization of methods and improved capabilities for device-based physical activity measurement.

Step Monitor Accuracy During PostStroke Physical Therapy and Simulated Activities.

Introduction/Purpose: The amount of stepping activity during rehabilitation post-stroke can predict walking outcomes, although the most accurate methods to evaluate stepping activity are uncertain with conflicting findings on available stepping monitors during walking assessments. Rehabilitation sessions also include non-stepping activities and the ability of activity monitors to differentiate these activities from stepping is unclear. The objective of this study was to examine the accuracy of different activity monitors worn by individuals post-stroke with variable walking speeds during clinical physical therapy (PT) and research interventions focused on walking. Methods: In Part I, 28 participants post-stroke wore a StepWatch, ActiGraph with and without a Low Frequency Extension (LFE) filter, and Fitbit on paretic and non-paretic distal shanks at or above the ankle during clinical PT or research interventions with steps simultaneously hand counted. Mean absolute percent errors were compared between limbs and tasks performed. In Part II, 12 healthy adults completed 8 walking and 9 non-walking tasks observed during clinical PT or research. Data were descriptively analyzed and used to assist interpretation of Part I results. Results: Part I results indicate most devices did not demonstrate an optimal limb configuration during research sessions focused on walking, with larger errors during clinical PT on the non-paretic limb. Using the limb that minimized errors for each device, the StepWatch had smaller errors than the ActiGraph and Fitbit (p<0.01), particularly in those who walked < 0.8 m/s. Conversely, errors from the ActiGraph-LFE demonstrated inconsistent differences in step counts between Fitbit and ActiGraph. Part II results indicate that errors observed during different stepping and non-stepping activities were often device-specific, with non-stepping tasks frequently detected as stepping. Conclusions: The StepWatch and ActiGraph-LFE had smaller errors than the Fitbit or ActiGraph, with greater errors in those walking at slower speeds. Inclusion of non-stepping activities affected step counts and should be considered when measuring stepping activity in individuals post-stroke to predict locomotor outcomes following rehabilitation.

Interaction between the BDNF rs11030101 genotype and job stress on cognitive empathy.

BACKGROUND: Empathy refers to an individual's ability to experience the emotional and cognitive processes of another person during social interactions. Although many studies have examined the effects of genetic variation on emotional empathy, little is currently known about whether genetic factors may influence cognitive empathy. This study investigated the relationship between BDNF rs11030101 genotype, job stress, and empathy, especially cognitive empathy, in a Chinese Han population. METHODS: A cross-sectional design was used and 340 participants were recruited from a university in Beijing. Interpersonal Reactivity Index (IRI) was used to measure empathy. Job stress was measured using House and Rizzo's Job Stress Scale. The BDNF rs11030101 was genotyped in all participants. RESULTS: Gender and age were associated with various IRI subscales (p < 0.001). After controlling for gender, age and education level, BDNF rs11030101 genotype had no main effect on all empathy subscales (p > 0.05). Job stress was negatively associated with Perspective Taking (p = 0.006) and positively associated with Personal Distress (p < 0.001). In addition, the BDNF rs11030101 genotype modulated the relationship between job stress and Fantasy (p = 0.013), indicating that T allele carriers had higher Fantasy scores at higher job stress and lower Fantasy scores at lower job stress than AA homozygotes. This interaction was only present in women. LIMITATIONS: The sample size and single-nucleotide polymorphism are limited, and the cross-sectional design should be improved. CONCLUSIONS: Female university faculty with the BDNF rs11030101 T allele may utilize higher emotional job demands, thereby fostering their cognitive empathy.

Nonparametric estimation of recursive point processes with application to mumps in Pennsylvania.

The self-exciting Hawkes point process model (Hawkes, 1971) has been used to describe and forecast communicable diseases. A variant of the Hawkes model, called the recursive model, was proposed by Schoenberg et al. (2019) and has been shown to fit well to various epidemic disease datasets. Unlike the Hawkes model, the recursive model allows the productivity to vary as the overall rate of incidence of the disease varies. Here, we extend the data-driven nonparametric expectation-maximization method of Marsan and Lengliné (2008) in order to fit the recursive model without assuming a particular functional form for the productivity. The nonparametric recursive model is trained to fit to weekly reported cases of mumps in Pennsylvania during the January 1970-September 1990 time frame and then assessed using one week forecasts for the October 1990-December 2001 time period. Both its training and predictive ability are evaluated compared to that of other candidate models, such as Hawkes and SVEILR (susceptible, vaccinated, exposed, infected, lightly infected, recovered) compartmental models.

Expanding Advocacy to the Grassroots Level: The New York State Model.

New York State has achieved pharmacy practice advancement legislation more slowly than other states. Despite the benefits of pharmacy advocacy in shaping legislation, in New York State advocacy activities have generally been limited to once per year during Lobby Day. Implementation of a grassroots advocacy infrastructure has been able to organize and sustain legislative engagement among members of our professional organization, with more than 100 legislative visits completed since creation of the Grassroots Advocacy Committee. A committee with infrastructure including a buddy system and legislative visit tracking process and educational programs, such as simulation training, have reduced the perceived burdens of participation. Other pharmacy organizations who have identified advocacy as a priority can utilize these tools to organize their members to support legislative goals.

Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth.

Targeting protein-protein interactions (PPIs) is a promising approach in the development of drugs for many indications. 14-3-3 proteins are a family of phosphoprotein-binding molecules with critical functions in dozens of cell signaling networks. 14-3-3s are abundant in the central nervous system, and the small molecule fusicoccin-A (FC-A), a tool compound that can be used to manipulate 14-3-3 PPIs, enhances neurite outgrowth in cultured neurons. New semisynthetic FC-A derivatives with improved binding affinity for 14-3-3 complexes have recently been developed. Here, we use a series of screens that identify these compounds as potent inducers of neurite outgrowth through a polypharmacological mechanism. Using proteomics and X-ray crystallography, we discover that these compounds extensively regulate the 14-3-3 interactome by stabilizing specific PPIs, while disrupting others. These results provide new insights into the development of drugs to target 14-3-3 PPIs, a potential therapeutic strategy for CNS diseases.

Use of consumer monitors for estimating energy expenditure in youth.

The purpose of this study was to compare energy expenditure (EE) estimates from 5 consumer physical activity monitors (PAMs) to indirect calorimetry in a sample of youth. Eighty-nine youth (mean (SD); age, 12.3 (3.4) years; 50% female) performed 16 semi-structured activities. Activities were performed in duplicate across 2 visits. Participants wore a Cosmed K4b2 (criterion for EE), an Apple Watch 2 (left wrist), Mymo Tracker (right hip), and Misfit Shine 2 devices (right hip; right shoe). Participants were randomized to wear a Samsung Gear Fit 2 or a Fitbit Charge 2 on the right wrist. Oxygen consumption was converted to EE by subtracting estimated basal EE (Schofield's equation) from the measured gross EE. EE from each visit was summed across the 2 visit days for comparison with the total EE recorded from the PAMs. All consumer PAMs estimated gross EE, except for the Apple Watch 2 (net Active EE). Paired t tests were used to assess differences between estimated (PAM) and measured (K4b2) EE. Mean absolute percent error (MAPE) was used to assess individual-level error. The Mymo Tracker was not significantly different from measured EE and was within 15.9 kcal of measured kilocalories (p = 0.764). Mean percent errors ranged from 3.5% (Mymo Tracker) to 48.2% (Apple Watch 2). MAPE ranged from 16.8% (Misfit Shine 2 - right hip) to 49.9% (Mymo Tracker). Novelty Only the Mymo Tracker was not significantly different from measured EE but had the greatest individual error. The Misfit Shine 2 - right hip had the lowest individual error. Caution is warranted when using consumer PAMs in youth for tracking EE.

Accuracy of the Cosmed K5 portable calorimeter.

PURPOSE: The purpose of this study was to assess the accuracy of the Cosmed K5 portable metabolic system dynamic mixing chamber (MC) and breath-by-breath (BxB) modes against the criterion Douglas bag (DB) method. METHODS: Fifteen participants (mean age±SD, 30.6±7.4 yrs) had their metabolic variables measured at rest and during cycling at 50, 100, 150, 200, and 250W. During each stage, participants were connected to the first respiratory gas collection method (randomized) for the first four minutes to reach steady state, followed by 3-min (or 5-min for DB) collection periods for the resting condition, and 2-min collection periods for all cycling intensities. Collection periods for the second and third methods were preceded by a washout of 1-3 min. Repeated measures ANOVAs were used to compare metabolic variables measured by each method, for seated rest and each cycling work rate. RESULTS: For ventilation (VE) and oxygen uptake (VO2), the K5 MC and BxB modes were within 2.1 l/min (VE) and 0.08 l/min (VO2) of the DB (p≥0.05). Compared to DB values, carbon dioxide production (VCO2) was significantly underestimated by the K5 BxB mode at work rates ≥150W by 0.12-0.31 l/min (p<0.05). K5 MC and BxB respiratory exchange ratio values were significantly lower than DB at cycling work rates ≥100W by 0.03-0.08 (p<0.05). CONCLUSION: Compared to the DB method, the K5 MC and BxB modes are acceptable for measuring VE and VO2 across a wide range of cycling intensities. Both K5 modes provided comparable values to each other.

Implanted Monitor Alerting to Reduce Treatment Delay in Patients With Acute Coronary Syndrome Events.

BACKGROUND: Increased pre-hospital delay during acute coronary syndrome (ACS) events contributes to worse outcome. OBJECTIVES: The purpose of this study was to assess the effectiveness of an implanted cardiac monitor with real-time alarms for abnormal ST-segment shifts to reduce pre-hospital delay during ACS events. METHODS: In the ALERTS (AngeLmed Early Recognition and Treatment of STEMI) pivotal study, subjects at high risk for recurrent ACS events (n = 907) were randomized to control (Alarms OFF) or treatment groups for 6 months, after which alarms were activated in all subjects (Alarms ON). Emergency department (ED) visits with standard-of-care cardiac test results were independently adjudicated as true- or false-positive ACS events. Alarm-to-door (A2D) and symptom-to-door (S2D) times were calculated for true-positive ACS ED visits triggered by 3 possible prompts: alarm only, alarms + symptoms, or symptoms only. RESULTS: The Alarms ON group showed reduced delays, with 55% (95% confidence interval [CI]: 46% to 63%) of ED visits for ACS events <2 h compared with 10% (95% CI: 2% to 27%) in the Alarms OFF group (p < 0.0001). Results were similar when restricted to myocardial infarction (MI) events. Median pre-hospital delay for MI was 12.7 h for Alarms OFF and 1.6 h in Alarms ON subjects (p < 0.0089). Median A2D delay was 1.4 h for asymptomatic MI. Median S2D delay for symptoms-only MI (no alarm) in Alarms ON was 4.3 h. CONCLUSIONS: Intracardiac monitoring with real-time alarms for ST-segment shift that exceeds a subject's self-normative ischemia threshold level significantly reduced the proportion of pre-hospital delays >2 h for ACS events, including asymptomatic MI, compared with symptoms-only ED visits in Alarms OFF. (AngeLmed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).

Components of Radiologic Progressive Disease Defined by RECIST 1.1 in Patients with Metastatic Clear Cell Renal Cell Carcinoma.

Background Progression-free survival (PFS) determined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) is the reference standard to assess efficacy of treatments in patients with clear cell renal cell carcinoma. Purpose To assess the most common components of radiologic progressive disease as defined by RECIST 1.1 in patients with clear cell renal cell carcinoma and how the progression events impact PFS. Materials and Methods This secondary analysis of the phase III METEOR trial conducted between 2013 and 2014 included patients with metastatic clear cell renal cell carcinoma, with at least one target lesion at baseline and one follow-up time point, who were determined according to RECIST 1.1 to have progressive disease. A chest, abdominal, and pelvic scan were acquired at each time point. Kruskal-Wallis analysis was used to test differences in median PFS among the RECIST 1.1 progression events. The Holm-Bonferroni method was used to compare the median PFS of the progression events for the family-wise error rate of 5% to adjust P values for multiple comparisons. Results Of the 395 patients (296 men, 98 women, and one patient with sex not reported; mean age, 61 years ± 10), 73 (18.5%) had progression due to non-target disease, 105 (26.6%) had new lesions, and 126 (31.9%) had progression of target lesions (defined by an increase in the sum of diameters). Patients with progression of non-target disease and those with new lesions had shorter PFS than patients with progression defined by the target lesions (median PFS, 2.8 months [95% confidence interval {CI}: 1.9 months, 3.7 months] and 3.6 months [95% CI: 3.3 months, 3.7 months] vs 5.4 months [95% CI: 5.0 months, 5.5 months], respectively [P < .01]). Conclusion The most common causes for radiologic progression of renal cell carcinoma were based on non-target disease and new lesions rather than change in target lesions, despite this being considered uncommon in the Response Evaluation Criteria in Solid Tumors version 1.1 literature. © RSNA, 2019 See also the editorial by Kuhl in this issue.

Domain agnostic online semantic segmentation for multi-dimensional time series.

Unsupervised semantic segmentation in the time series domain is a much studied problem due to its potential to detect unexpected regularities and regimes in poorly understood data. However, the current techniques have several shortcomings, which have limited the adoption of time series semantic segmentation beyond academic settings for four primary reasons. First, most methods require setting/learning many parameters and thus may have problems generalizing to novel situations. Second, most methods implicitly assume that all the data is segmentable and have difficulty when that assumption is unwarranted. Thirdly, many algorithms are only defined for the single dimensional case, despite the ubiquity of multi-dimensional data. Finally, most research efforts have been confined to the batch case, but online segmentation is clearly more useful and actionable. To address these issues, we present a multi-dimensional algorithm, which is domain agnostic, has only one, easily-determined parameter, and can handle data streaming at a high rate. In this context, we test the algorithm on the largest and most diverse collection of time series datasets ever considered for this task and demonstrate the algorithm's superiority over current solutions.

Implantable Cardiac Alert System for Early Recognition of ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Symptoms remain a poor prompt for acute coronary syndromes (ACS). Timely restoration of perfusion in ST-segment elevation myocardial infarction is associated with improved left ventricular function and survival. OBJECTIVES: This report details the results of ALERTS (AngelMed for Early Recognition and Treatment of STEMI), a multicenter, randomized trial of an implantable cardiac monitor that alerts patients with rapidly progressive ST-segment deviation. METHODS: High-risk ACS subjects (N = 907) were randomized to a control (alarms deactivated) or treatment group for 6 months, after which alarms were activated in all subjects. The primary safety endpoint was absence of system-related complications (>90%). The composite primary efficacy endpoint was cardiac/unexplained death, new Q-wave myocardial infarction, or detection to presentation time >2 h. RESULTS: Safety was met with 96.7% freedom from system-related complications (n = 30). The efficacy endpoint for a confirmed occlusive event within 7 days was not significantly reduced in the treatment compared with control group (16 of 423 [3.8%] vs. 21 of 428 [4.9%], posterior probability = 0.786). Within a 90-day window, alarms significantly decreased detection to arrival time at a medical facility (51 min vs. 30.6 h; Pr [pt < pc] >0.999). In an expanded analysis using data after the randomized period, positive predictive value was higher (25.8% vs. 18.2%) and false positive rate significantly lower in the ALARMS ON group (0.164 vs. 0.678 false positives per patient-year; p < 0.001). CONCLUSIONS: The implantable cardiac system detects early ST-segment deviation and alerts patients of a potential occlusive event. Although the trial did not meet its pre-specified primary efficacy endpoint, results suggest that the device may be beneficial among high-risk subjects in potentially identifying asymptomatic events. (AngelMed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).

A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation.

OBJECTIVES: This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. BACKGROUND: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. METHODS: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. RESULTS: The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CONCLUSIONS: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172).