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Background: Left atrial appendage (LAA) occlusion provides an alternative to oral anticoagulation for thromboembolic risk reduction in patients with nonvalvular atrial fibrillation. Since regulatory approval in 2015, the WATCHMAN device has been the only LAA closure device available for clinical use in the United States. The PINNACLE FLX study (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the Watchman FLX LAA Closure Technology) evaluated the safety and effectiveness of the next-generation WATCHMAN FLX LAA closure device in patients with nonvalvular atrial fibrillation in whom oral anticoagulation is indicated, but who have an appropriate rationale to seek a nonpharmaceutical alternative. Methods: This was a prospective, nonrandomized, multicenter US Food and Drug Administration study. The primary safety end point was the occurrence of one of the following events within 7 days after the procedure or by hospital discharge, whichever was later: death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery. The primary effectiveness end point was the incidence of effective LAA closure (peri-device flow ≤5 mm), as assessed by the echocardiography core laboratory at 12-month follow-up. Results: A total of 400 patients were enrolled. The mean age was 73.8±8.6 years and the mean CHA 2 DS 2 -VASc score was 4.2±1.5. The incidence of the primary safety end point was 0.5% with a 1-sided 95% upper CI of 1.6%, meeting the performance goal of 4.2% ( P P Conclusions: LAA closure with this next-generation LAA closure device was associated with a low incidence of adverse events and a high incidence of anatomic closure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02702271.

Background There is a paucity of interventional research that systematically assesses the role of exercise intensity and cardiorespiratory fitness, and their relationship with executive function in older adults. To address this limitation, we have examined the effect of a systematically manipulated exercise intervention on executive function. Methods Ninety-nine cognitively normal participants (age = 69.10 ± 5.2 years; n = 54 female) were randomized into either a high-intensity cycle-based exercise, moderate-intensity cycle-based exercise, or no-intervention control group. All participants underwent neuropsychological testing and fitness assessment at baseline (preintervention), 6-month follow-up (postintervention), and 12-month postintervention. Executive function was measured comprehensively, including measures of each subdomain: Shifting, Updating/ Working Memory, Inhibition, Verbal Generativity, and Nonverbal Reasoning. Cardiorespiratory fitness was measured by analysis of peak aerobic capacity; VO2peak. Results First, the exercise intervention was found to increase cardiorespiratory fitness (VO2peak) in the intervention groups, in comparison to the control group (F =10.40, p≤0.01). However, the authors failed to find mean differences in executive function scores between the high-intensity, moderate intensity, or inactive control group. On the basis of change scores, cardiorespiratory fitness was found to associate positively with the executive function (EF) subdomains of Updating/Working Memory (β = 0.37, p = 0.01, r = 0.34) and Verbal Generativity (β = 0.30, p = 0.03, r = 0.28) for intervention, but not control participants. Conclusion At the aggregate level, the authors failed to find evidence that 6-months of high-intensity aerobic exercise improves EF in older adults. However, it remains possible that individual differences in experimentally induced changes in cardiorespiratory fitness may be associated with changes in Updating/ Working Memory and Verbal Generativity.

Objective:Exercise has been found to be important in maintaining neurocognitive health. However, the effect of exercise intensity level remains relatively underexplored. Thus, to test the hypothesis that self-paced high-intensity exercise and cardiorespiratory fitness (peak aerobic capacity; VO2peak) increase grey matter (GM) volume, we examined the effect of a 6-month exercise intervention on frontal lobe GM regions that support the executive functions in older adults.Methods:Ninety-eight cognitively normal participants (age = 69.06 ± 5.2 years; n = 54 female) were randomised into either a self-paced high- or moderate-intensity cycle-based exercise intervention group, or a no-intervention control group. Participants underwent magnetic resonance imaging and fitness assessment pre-intervention, immediately post-intervention, and 12-months post-intervention.Results:The intervention was found to increase fitness in the exercise groups, as compared with the control group (F = 9.88, p = β = 0.29, p = 0.036, r = 0.27), right supplementary motor area (β = 0.30, p = 0.031, r = 0.29), and both right (β = 0.32, p = 0.034, r = 0.30) and left gyrus rectus (β = 0.30, p = 0.037, r = 0.29) for intervention, but not control participants. No differences in volume were observed across groups.Conclusions:At an aggregate level, six months of self-paced high- or moderate-intensity exercise did not increase frontal GM volume. However, experimentally-induced changes in individual cardiorespiratory fitness was positively associated with frontal GM volume in our sample of older adults. These results provide evidence of individual variability in exercise-induced fitness on brain structure.

BACKGROUND: Physical inactivity has been consistently linked to increased risk of cognitive decline; however, studies examining the impact of exercise interventions on cognition have produced inconsistent findings. Some observational studies suggest exercise intensity may be important for inducing cognitive improvements; however, this has yet to be thoroughly examined in older adult cohorts. The objective of the current study was to evaluate the effect of systematically manipulated high-intensity and moderate-intensity exercise interventions on cognition. In addition, we investigated individual variability in exercise response by examining effects of relevant genetic factors and changes in cardiorespiratory fitness on cognitive change.METHODS: This multi-arm randomised clinical trial investigated the effects of 6-months of high-intensity exercise and moderate-intensity exercise, compared with an inactive control, on cognition. Outcome measures were assessed at pre- (baseline), post- (6 months), and 12-months post-intervention. Ninety-nine cognitively normal men and women (aged 60 – 80 years) were enrolled from October 2016 to November 2017. Participants that were allocated to an exercise group (i.e., high-intensity or moderate-intensity) engaged in cycle-based exercise two times per week for 6 months. Cognition was assessed using a comprehensive neuropsychological test battery. Cardiorespiratory fitness was evaluated by a graded exercise test. Apolipoprotein e4 genotype and brain-derived neurotrophic factor Val66Met carriage were identified.RESULTS: There was a dose-dependent effect of exercise intensity on cardiorespiratory fitness; whereby the high-intensity group experienced greater increases in fitness than the moderate-intensity and control groups. However, there was no direct effect of exercise on cognition. We observed an association between changes in global cognition and executive function and changes in cardiorespiratory fitness from pre- to post-intervention: this relationship was strongest in brain-derived neurotrophic factor non-Met carriers.CONCLUSIONS We did not observe a direct effect of exercise on cognition. Nevertheless, our data suggests genetics may moderate the relationship between fitness and cognitive change following exercise, and this should be examined further in larger trials.TRIAL REGISTRATION: This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000643370). Registered 3rd May 2017 - retrospectively registered. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372780

Introduction Leg order during sequential single-leg cycling (i.e., exercising both legs independently within a single session) may affect local muscular responses potentially influencing adaptations. This study examined the cardiovascular and skeletal muscle hemodynamic responses during double-leg and sequential single-leg cycling. Methods Ten young healthy adults (28 ± 6 yr) completed six 1-min double-leg intervals interspersed with 1 min of passive recovery and, on a separate occasion, 12 (six with one leg followed by six with the other leg) 1-min single-leg intervals interspersed with 1 min of passive recovery. Oxygen consumption, heart rate, blood pressure, muscle oxygenation, muscle blood volume, and power output were measured throughout each session. Results Oxygen consumption, heart rate, and power output were not different between sets of single-leg intervals, but the average of both sets was lower than the double-leg intervals. Mean arterial pressure was higher during double-leg compared with sequential single-leg intervals (115 ± 9 vs 104 ± 9 mm Hg, P < 0.05) and higher during the initial compared with second set of single-leg intervals (108 ± 10 vs 101 ± 10 mm Hg, P < 0.05). The increase in muscle blood volume from baseline was similar between the active single leg and the double leg (267 ± 150 vs 214 ± 169 μM·cm, P = 0.26). The pattern of change in muscle blood volume from the initial to second set of intervals was significantly different (P < 0.05) when the leg was active in the initial (−52.3% ± 111.6%) compared with second set (65.1% ± 152.9%). Conclusions These data indicate that the order in which each leg performs sequential single-leg cycling influences the local hemodynamic responses, with the inactive muscle influencing the stimulus experienced by the contralateral leg.

Aims Long-term results from catheter ablation therapy for atrial fibrillation (AF) remain uncertain and clinical practice guidelines recommend continuation of long-term oral anticoagulation in patients with a high stroke risk. Left atrial appendage closure (LAAC) with Watchman has emerged as an alternative to long-term anticoagulation for patients accepting of the procedural risks. We report on the initial results of combining catheter ablation procedures for AF and LAAC in a multicentre registry. Methods and results Data were pooled from two prospective, real-world Watchman LAAC registries running in parallel in Europe/Middle-East/Russia (EWOLUTION) and Asia/Australia (WASP) between 2013 and 2015. Of the 1140 patients, 139 subjects at 10 centres underwent a concomitant AF ablation and LAAC procedure. The mean CHA2DS2-VASc score was 3.4 ± 1.4 and HAS-BLED score 1.5 ± 0.9. Successful Watchman implantation was achieved in 100% of patients. The overall 30-day serious adverse event (SAE) rate was 8.7%, with the device and/or procedure-related SAE rate of 1.4%. One pericardial effusion required percutaneous drainage, but there were no strokes, device embolization, or deaths at 30 days. The 30-day bleeding SAE rate was 2.9% with 55% of patients prescribed NOAC and 38% taking warfarin post-procedure. Conclusion The outcomes from these international, multicentre registries support the feasibility and safety of performing combined procedures of ablation and Watchman LAAC for patients with non-valvular AF and high stroke risk. Further data are needed on long-term outcomes for the hybrid technique on all-cause stroke and mortality.

Background The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial demonstrated that left atrial appendage closure (LAAC) with the Watchman device (Boston Scientific, St. Paul, Minnesota) was equivalent to warfarin for preventing stroke in atrial fibrillation, but had a high rate of complications. In a second randomized trial, PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy), the complication rate was low. The warfarin cohort experienced an unexpectedly low ischemic stroke rate, rendering the efficacy endpoints inconclusive. However, these outcomes were based on relatively few patients followed for a relatively short time. Objectives The final results of the PREVAIL trial, both alone and as part of a patient-level meta-analysis with the PROTECT AF trial, are reported with patients in both trials followed for 5 years. Methods PREVAIL and PROTECT AF are prospective randomized clinical trials with patients randomized 2:1 to LAAC or warfarin; together, they enrolled 1,114 patients for 4,343 patient-years. Analyses are by intention-to-treat, and rates are events per 100 patient-years. Results For the PREVAIL trial, the first composite coprimary endpoint of stroke, systemic embolism (SE), or cardiovascular/unexplained death did not achieve noninferiority (posterior probability for noninferiority = 88.4%), whereas the second coprimary endpoint of post-procedure ischemic stroke/SE did achieve noninferiority (posterior probability for noninferiority = 97.5%); the warfarin arm maintained an unusually low ischemic stroke rate (0.73%). In the meta-analysis, the composite endpoint was similar between groups (hazard ratio [HR]: 0.820; p = 0.27), as were all-stroke/SE (HR: 0.961; p = 0.87). The ischemic stroke/SE rate was numerically higher with LAAC, but this difference did not reach statistical significance (HR: 1.71; p = 0.080). However, differences in hemorrhagic stroke, disabling/fatal stroke, cardiovascular/unexplained death, all-cause death, and post-procedure bleeding favored LAAC (HR: 0.20; p = 0.0022; HR: 0.45; p = 0.03; HR: 0.59; p = 0.027; HR: 0.73; p = 0.035; HR: 0.48; p = 0.0003, respectively). Conclusions These 5-year outcomes of the PREVAIL trial, combined with the 5-year outcomes of the PROTECT AF trial, demonstrate that LAAC with Watchman provides stroke prevention in nonvalvular atrial fibrillation comparable to warfarin, with additional reductions in major bleeding, particularly hemorrhagic stroke, and mortality. (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation; NCT00129545; and Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy; NCT01182441)

Background Left atrial appendage closure (LAAC) was approved by the U.S. Food and Drug Administration (FDA) as a stroke prevention alternative to warfarin for patients with nonvalvular atrial fibrillation. However, clinical decision-making is confounded by the fact that although LAAC attenuates the anticoagulant-related lifetime risk of bleeding, implantation is associated with upfront complications. Thus, enthusiasm for LAAC as a treatment option has been appropriately tempered, particularly as the therapy is introduced beyond the clinical trial sites into general clinical practice. Objectives This study evaluated the acute procedural performance and complication rates for all cases performed in the United States since FDA approval. Methods In the absence of a formal national clinical registry since regulatory approval in March 2015, we obtained procedural data on implantation procedures. Every LAAC procedure requires the presence of a manufacturer clinical specialist and for procedural parameter and periprocedural complication data to be collected using a standardized process and forms. Results In 3,822 consecutive cases, implantation was successful in 3,653 (95.6%), with a median procedure time of 50 min (range 10 to 210 min). Implanting physicians performing these procedures (n = 382) included 71% new, nonclinical trial implanters, who performed 50% of the procedures. Procedural complication rates included 39 pericardial tamponades (1.02%) (24 treated percutaneously, 12 surgically, and 3 fatal); 3 procedure-related strokes (0.078%); 9 device embolizations (0.24%) (6 requiring surgical removal); and 3 procedure-related deaths (0.078%). Conclusions Despite a large fraction of previously inexperienced operators, in the real-world post-FDA approval experience of LAAC, procedural success was high and complication rates were low.

Background Long-term data on the safety and efficacy of left atrial appendage closure (LAAC) for stroke prevention in patients with nonvalvular atrial fibrillation remain limited. Objectives The purpose of this study was to evaluate 4.5- to 5-year data in 2 U.S. Food and Drug Association LAAC mandated registries (CAP [Continued Access to PROTECT-AF] and CAP2 [Continued Access to PREVAIL]) for safety and efficacy. Methods Two registries of patients implanted with LAAC devices provide the largest source of follow-up data. Both accompanied their respective randomized clinical trials, PROTECT-AF (Watchman Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device In Patients with Atrial Fibrillation versus Long Term Warfarin Therapy), which used the same endpoints (primary efficacy of composite of stroke, systemic embolism, cardiovascular/unexplained death, and safety). Results CAP included 566 patients with an average follow-up of 50.1 months (2,293 patient-years), and CAP2 included 578 patients with an average follow-up of 50.3 months (2,227 patient-years). CAP2 patients were significantly older and had higher CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) scores (4.51 vs. 3.88; p Conclusions These registries, which contain the longest and largest follow-up data of patients with the Watchman device, support LAAC as a safe and effective therapy for long-term anticoagulation in patients with nonvalvular atrial fibrillation, and document the lowest rate of hemorrhagic stroke identified in this population.

Introduction Regular exercise can reduce the risk of developing cardiovascular disease through risk factor modification, with high-intensity exercise and more recently small muscle mass training providing alternatives to moderate-intensity exercise. Methods This study randomly assigned 53 healthy middle-age adults (age, 62 ± 6 yr) to complete 24 sessions (8 wk; 3 d·wk−1) of exercise training, using either high-intensity double-leg cycling (n = 17; HITDL), high-intensity single-leg cycling (n = 18; HITSL), or moderate-intensity double-leg cycling (n = 18; MCTDL). Biomarkers of cardiovascular risk (total cholesterol, triglycerides, HDL-c, LDL-c, apo-B48, and glucose), anthropometry measures (body mass, body mass index, waist circumference, and waist-to-hip ratio), resting blood pressure, and aerobic capacity were assessed pre- and postintervention. Results Total work completed was greater (P < 0.01) in MCTDL (5938 ± 1462 kJ) compared with the HITDL (3462 ± 1063 kJ) and HITSL (4423 ± 1875 kJ). Pre- to posttraining differences were observed for waist-to-hip ratio (0.84 ± 0.09 vs 0.83 ± 0.09; P < 0.01), resting systolic blood pressure (129 ± 11 vs 124 ± 12 mm Hg; P < 0.01), total cholesterol (5.87 ± 1.17 vs 5.55 ± 0.98 mmol·L−1; P < 0.01), and LDL-c (3.70 ± 1.04 vs 3.44 ± 0.84 mmol·L−1; P < 0.01), with no differences between conditions. In addition, aerobic capacity increased after training (22.3 ± 6.4 vs 24.9 ± 7.6 mL·kg−1·min−1; P < 0.01), with no differences between conditions. Conclusion These findings suggest that all three modes of exercise can be prescribed to achieve cardiovascular risk reduction in an aging population.

This study examined the acute performance, cardiovascular and local muscular responses to perceived exertion-based high-intensity interval exercise using either double- or single-leg cycling. Fifteen healthy middle-aged adults completed, on separate occasions, ten 30-s double-leg intervals interspersed with 60 s passive recovery and twenty (ten with each leg) 30-s single-leg intervals interspersed with 60 s passive recovery. Impedance cardiography, blood pressure, muscle oxygenation and total haemoglobin content (near-infrared spectroscopy), oxygen consumption and power output were measured throughout each session. Normalised to the lean mass used during each trial, single-leg cycling resulted in lower power output (single-leg: 8.92 ± 1.74 W kg

Background Left atrial appendage closure is a non-pharmacological alternative for stroke prevention in high-risk non-valvular atrial fibrillation patients, but has not been widely studied in Asian patients. The prospective WASP registry assessed real-world outcomes for patients undergoing WATCHMAN implant in the Asia-Pacific region. Methods Data were collected from consecutive patients across 9 centres. Major endpoints included procedural success, safety and long-term outcomes including occurrence of bleeding, stroke/transient ischaemic attack/systemic embolism and all-cause mortality. Results Subjects (n = 201) had a mean age of 70.8 ± 9.4 years, high stroke risk (CHA2DS2-VASc: 3.9 ± 1.7), elevated bleeding risk (HAS-BLED: 2.1 ± 1.2) with 53% patients from Asian countries. Successful implantation occurred in 98.5% of patients; 7-day device/procedure-related SAE rate was 3.0%. After 2 years of follow-up, the rates of ischaemic stroke/TIA/SE and major bleeding were 1.9 and 2.2 per 100-PY, respectively, representing relative reductions of 77% and 49% versus expected rates per risk scores. The relative risk reductions versus expected rates were more pronounced in Asians vs. Non-Asians (89% vs 62%; 77% vs 14%). Other significant findings included larger mean LAA ostium diameter for Asians vs. Non-Asians (23.4 ± 4.1 mm vs. 21.2 ± 3.2 mm, p, Graphical abstract Unlabelled Image

Background: In patients with atrial fibrillation, left atrial appendage closure with the Watchman device prevents thromboembolism from the left atrial appendage; however, thrombus may form on the left atrial face of the device, and then potentially embolize. Herein, we studied the incidence, predictors, and clinical outcome of device-related thrombus (DRT) using a large series of clinical trial cohorts of patients undergoing Watchman implantation. Methods: We studied the device arms of 4 prospective Food and Drug Administration trials: PROTECT-AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) (n=463); PREVAIL (Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) (n=269); CAP (Continued Access to PROTECT AF registry) (n=566); and CAP2 (Continued Access to PREVAIL registry) (n=578). Surveillance transesophageal echocardiographs were performed at 45 days and 12 months in all patients, and also at 6 months in the randomized control trials. We assessed both the incidence of DRT during these transesophageal echocardiographs (and other unscheduled transesophageal echocardiographs), and clinical outcomes of postprocedure stroke or systemic embolism (SSE) and adjusted for CHA 2 DS 2 -VASC and HAS-BLED scores. Results: Of 1739 patients who received an implant (7159 patient-years follow-up; CHA 2 DS 2 -VASc=4.0), DRT was seen in 65 patients (3.74%). The rates of SSE with and without DRT were 7.46 and 1.78 per 100 patient-years (adjusted rate ratio, 3.55; 95% confidence interval [CI], 2.18–5.79; P P P =0.007), permanent atrial fibrillation (OR, 2.24; 95% CI, 1.19–4.20; P =0.012); vascular disease (OR, 2.06; 95% CI, 1.08–3.91; P =0.028); left atrial appendage diameter (OR, 1.06 per mm increase; 95% CI, 1.01–1.12; P =0.019); left ventricular ejection fraction (OR, 0.96 per 1% increase; 95% CI, 0.94–0.99; P =0.009). DRT and SSE both occurred in 17 of 65 patients (26.2%). Of the 19 SSE events in these patients with DRT, 9 of 19 (47.4%) and 12 of 19 (63.2%) occurred within 1 and 6 months of DRT detection. Conversely, after left atrial appendage closure, most SSEs (123/142, 86.62%) occurred in patients without DRT. Conclusions: After left atrial appendage closure with Watchman, DRT (≈3.7%) is not frequent but, when present, is associated with a higher rate of stroke and systemic embolism.

Objectives The purpose of this study was to compare the relative risk of major bleeding with left atrial appendage (LAA) closure compared with long-term warfarin therapy. Background LAA closure is an alternative approach to chronic oral anticoagulation for the prevention of thromboembolism in patients with atrial fibrillation (AF). Methods We conducted a pooled, patient-level analysis of the 2 randomized clinical trials that compared WATCHMAN (Boston Scientific, Natick, Massachusetts) LAA closure with long-term warfarin therapy in AF. Results A total of 1,114 patients were included, with a median follow-up of 3.1 years. The overall rate of major bleeding from randomization to the end of follow-up was similar between treatment groups (3.5 events vs. 3.6 events per 100 patient-years; rate ratio [RR]: 0.96; 95% confidence interval [CI]: 0.66 to 1.40; p = 0.84). LAA closure significantly reduced bleeding >7 days post-randomization (1.8 events vs. 3.6 events per 100 patient-years; RR: 0.49; 95% CI: 0.32 to 0.75; p = 0.001), with the difference emerging 6 months after randomization (1.0 events vs. 3.5 events per 100 patient-years; RR: 0.28; 95% CI: 0.16 to 0.49; p Conclusions There was no difference in the overall rate of major bleeding in patients assigned to LAA closure compared with extended warfarin therapy over 3 years of follow-up. However, LAA closure significantly reduced bleeding beyond the procedural period, particularly once adjunctive pharmacotherapy was discontinued. The favorable effect of LAA closure on long-term bleeding should be considered when selecting a stroke prevention strategy for patients with nonvalvular AF. (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation; NCT00129545 ; and Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy [PREVAIL]; NCT01182441 )

Introduction Inconsistent results from previous studies of exercise and cognitive function suggest that rigorously designed randomized controlled trials are urgently needed. Here, we describe the design of the Intense Physical Activity and Cognition (IPAC) study, which will assess the impact of a 6-month high-intensity exercise intervention on cognitive function and biomarkers of dementia risk, compared with a 6-month moderate-intensity exercise intervention and control group (no study-related exercise). Methods One-hundred and five cognitively healthy men and women aged between 60 and 80 years are randomized into a high-intensity exercise, moderate-intensity exercise, or control group. Individuals randomized to an exercise intervention undertake 6 months of cycle-based exercise twice a week, at 50 minutes per session. All participants undergo comprehensive neuropsychological testing, blood sampling, brain magnetic resonance imaging, fitness testing, and a body composition scan at baseline, 6 months (immediately after intervention), and 18 months (12 months after intervention). Discussion The IPAC study takes a multidisciplinary approach to investigating the role of exercise in maintaining a healthy brain throughout aging. Rigorous monitoring of exertion and adherence throughout the intervention, combined with repeated measures of fitness, is vital in ensuring an optimum exercise dose is reached. Results from the IPAC study will be used to inform a large-scale multicentre randomized controlled trial, with the ultimate aim of pinpointing the frequency, duration, and intensity of exercise that provides the most benefit to the brain, in terms of enhancing cognitive function and reducing dementia risk in older adults.

Long-term follow up of NVAF patients (pts) undergoing left atrial appendage occlusion (LAAO) for stroke prevention remains of significant interest. For LAAO with the Watchman™ (St. Paul, MN) device, the Continued Access to PROTECT AF Registry (CAP) is the largest U.S. registry with the longest

Left atrial appendage closure with the WATCHMAN device is an alternative to anticoagulation for stroke prevention in selected patients with atrial fibrillation (AF). LA device-related thrombus (DRT) is poorly defined and understood. We aimed to (1) develop consensus echocardiographic diagnostic criteria for DRT; (2) estimate the incidence of DRT; and (3) determine clinical event rates in patients with DRT. In phase 1 (training), a training manual was developed and reviewed by 3 echocardiographers with left atrial appendage closure device experience. All available transesophageal (TEE) studies in the WATCHMAN left atrial appendage system for embolic protection in patients with atrial fibrillation (PROTECT-AF) trial patients with suspected DRT were reviewed in 2 subsequent phases. In phase 2 (primary blind read), each reviewer independently scored each study for DRT, and final echo criteria were developed. Unanimously scored studies were considered adjudicated, whereas all others were reevaluated by all reviewers in phase 3 (group adjudication read). DRT was suspected in 35 of 485 patients by the site investigator, the echocardiography core laboratory, or both; 93 of the individual TEE studies were available for review. In phase 2, 3 readers agreed on 67 (72%) of time points. Based on phases 1 and 2, 5 DRT criteria were developed. In phase 3, studies without agreement in phase 2 were adjudicated using these criteria. Overall, at least 1 TEE was DRT positive in 27 (5.7%) PROTECT-AF patients. Stroke, peripheral embolism, or cardiac/unexplained death occurred in subjects with DRT at a rate of 3.4 per 100 patient-years follow-up. In conclusion, DRT were identified on at least 1 TEE in 27 PROTECT-AF patients, indicating a DRT incidence of 5.7%. Primary efficacy events in patients with DRT occurred at a rate of 3.4 per 100 patient-years follow-up, intermediate in frequency between event rates previously reported for the overall device and warfarin arms in PROTECT-AF.

Atrial fibrillation (AF) is one of the most common arrhythmias seen in clinical cardiology practice. Patients with non-valvular AF have an approximately 5-fold increase in the risk of stroke, with an exponential increase with advancing age. Cardioembolic strokes carry a high mortality risk. Although the potential of warfarin to reduce systemic embolization in AF patients is well established, its use is difficult due to narrow therapeutic windows and additional complications (e.g. increased risk of bleeding), especially for aging patients. Therefore, alternative means of treatment to reduce stroke risk in these patients are needed. The left atrial appendage is the major source of thrombus formation in patients with non-valvular AF. The WATCHMAN device (Boston Scientific, MA) is a percutaneous left atrial appendage closure device which has been tested prospectively in multiple randomized trials. It offers a new stroke risk reduction option for high-risk patients with non-valvular atrial fibrillation who are seeking an alternative to long-term warfarin therapy. Based on the robust WATCHMAN clinical program which consists of numerous studies, with more than 2,400 patients and nearly 6,000 patient-years of follow-up, the WATCHMAN LAAC Device is approved by FDA. In this article we reviewed the preclinical studies and clinical trials, as well as the next generation of the device.

The purpose of this study was to compare the relative risk of major bleeding with left atrial appendage (LAA) closure compared with long-term warfarin therapy.LAA closure is an alternative approach to chronic oral anticoagulation for the prevention of thromboembolism in patients with atrial fibrillation (AF).We conducted a pooled, patient-level analysis of the 2 randomized clinical trials that compared WATCHMAN (Boston Scientific, Natick, Massachusetts) LAA closure with long-term warfarin therapy in AF.A total of 1,114 patients were included, with a median follow-up of 3.1 years. The overall rate of major bleeding from randomization to the end of follow-up was similar between treatment groups (3.5 events vs. 3.6 events per 100 patient-years; rate ratio [RR]: 0.96; 95% confidence interval [CI]: 0.66 to 1.40; p = 0.84). LAA closure significantly reduced bleeding7 days post-randomization (1.8 events vs. 3.6 events per 100 patient-years; RR: 0.49; 95% CI: 0.32 to 0.75; p = 0.001), with the difference emerging 6 months after randomization (1.0 events vs. 3.5 events per 100 patient-years; RR: 0.28; 95% CI: 0.16 to 0.49; p0.001), when patients assigned to LAA closure were able to discontinue adjunctive oral anticoagulation and antiplatelet therapy. The reduction in bleeding with LAA closure was directionally consistent across all patient subgroups.There was no difference in the overall rate of major bleeding in patients assigned to LAA closure compared with extended warfarin therapy over 3 years of follow-up. However, LAA closure significantly reduced bleeding beyond the procedural period, particularly once adjunctive pharmacotherapy was discontinued. The favorable effect of LAA closure on long-term bleeding should be considered when selecting a stroke prevention strategy for patients with nonvalvular AF. (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation; NCT00129545; and Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy [PREVAIL]; NCT01182441).

This study examined physiological and perceptual responses to matched work high-intensity interval training using all-out and 2 even-paced methodologies. 15 trained male cyclists performed 3 interval sessions of three 3-min efforts with 3 min of active recovery between efforts. The initial interval session was completed using all-out pacing, with the following 2 sessions being completed with computer- and athlete-controlled pacing in a randomised and semi-counterbalanced manner. Computer- and athlete-controlled intervals were completed at the mean power from the corresponding interval during the all-out trial. Oxygen consumption and ratings of perceived exertion were recorded during each effort. 20 min following each session, participants completed a 4-km time trial and provided sessional rating of perceived exertion. Oxygen consumption was greater during all-out (54.1±6.6 ml.kg(-1).min(-1); p

Importance While effective in preventing stroke in patients with atrial fibrillation (AF), warfarin is limited by a narrow therapeutic profile, a need for lifelong coagulation monitoring, and multiple drug and diet interactions. Objective To determine whether a local strategy of mechanical left atrial appendage (LAA) closure was noninferior to warfarin. Design, Setting, and Participants PROTECT AF was a multicenter, randomized (2:1), unblinded, Bayesian-designed study conducted at 59 hospitals of 707 patients with nonvalvular AF and at least 1 additional stroke risk factor (CHADS2score ≥1). Enrollment occurred between February 2005 and June 2008 and included 4-year follow-up through October 2012. Noninferiority required a posterior probability greater than 97.5% and superiority a probability of 95% or greater; the noninferiority margin was a rate ratio of 2.0 comparing event rates between treatment groups. Interventions Left atrial appendage closure with the device (n = 463) or warfarin (n = 244; target international normalized ratio, 2-3). Main Outcomes and Measures A composite efficacy end point including stroke, systemic embolism, and cardiovascular/unexplained death, analyzed by intention-to-treat. Results At a mean (SD) follow-up of 3.8 (1.7) years (2621 patient-years), there were 39 events among 463 patients (8.4%) in the device group for a primary event rate of 2.3 events per 100 patient-years, compared with 34 events among 244 patients (13.9%) for a primary event rate of 3.8 events per 100 patient-years with warfarin (rate ratio, 0.60; 95% credible interval, 0.41-1.05), meeting prespecified criteria for both noninferiority (posterior probability, >99.9%) and superiority (posterior probability, 96.0%). Patients in the device group demonstrated lower rates of both cardiovascular mortality (1.0 events per 100 patient-years for the device group [17/463 patients, 3.7%] vs 2.4 events per 100 patient-years with warfarin [22/244 patients, 9.0%]; hazard ratio [HR], 0.40; 95% CI, 0.21-0.75;P = .005) and all-cause mortality (3.2 events per 100 patient-years for the device group [57/466 patients, 12.3%] vs 4.8 events per 100 patient-years with warfarin [44/244 patients, 18.0%]; HR, 0.66; 95% CI, 0.45-0.98;P = .04). Conclusions and Relevance After 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality. Trial Registration clinicaltrials.gov Identifier:NCT00129545

Identify which populations of patients may warrant further attention when providing palliative care to HF patients. Original Research Background: National guidelines recommend integrating palliative care into Heart Failure (HF) treatment. Few studies examine whether HF patients receive palliative care. Research Objectives: Methods: Patients diagnosed with NYHA class II-III HF were surveyed about whether they had discussed with their clinician what to expect in the future regarding their HF, prognosis, advanced care planning, and their surrogate choice, and if they had not, whether they wanted to have these conversations. Results: Participants (n=102) were on average 53 years old, had HF for 7 years, were 66% male, and had either Class II (57%) or Class III (43%) HF. Most participants reported having had discussions with their provider about what to expect in the future regarding HF (76.5%), prognosis (68.0%), and their surrogate choice (63.4%). Half discussed advanced care planning (46.5%). Of those who reported not having these conversations, most wanted to discuss what to expect in the future with respect to HF (81.5%), prognosis (76.3%), and advanced care planning (56.4%). HF class was not associated with having had or desiring to have discussions on any issue. Men were more likely than women to report discussions about future expectations of HF (83.6% vs. 62.9%; p=0.02), prognosis (78.5% vs. 48.6% p=0.002), and advanced care planning (56.1% vs. 28.6%; p=0.008). Conclusions: Most participants discussed palliative care issues with providers, and most of those who did not wanted to. Our data cannot explain why women are less likely to report these discussions but suggest that clinicians be mindful of this disparity.

To the Editor: Emergency department (ED) use has been affected by insurance patterns over time and will likely be further affected by health reform’s expansions of coverage. Because of their disproportionate use of the ED, uninsured patients are often impugned as high, and frequently inappropriate, ED users.1,2 However, recent studies have shown that insured patients can be more frequent utilizers than the uninsured, particularly those with insurance like Medicaid that still leaves them with difficulties in accessing primary care.2-4 We therefore sought to describe recent trends in the association between insurance coverage and ED use in California for non-elderly adult patients, who have experienced the greatest changes in insurance coverage in recent years and are likely to see the biggest shifts as the result of health reform. Previous studies have considered trends in ED use, but predate the recent economic downturn and related insurance changes.2,5

Patients (Pts) with chronic kidney disease (CKD) and atrial fibrillation have a greater risk of stroke and death than those with normal renal function and are at higher risk for bleeding with oral anticoagulants (OAC). We analyzed the efficacy of left atrial appendage closure (LAAC) with WATCHMAN

Left atrial appendage closure (LAAC) with the Watchman Device (Boston Scientific, MN) is an alternative to warfarin for stroke risk reduction in high risk non-valvular atrial fibrillation (NVAF) patients. This analysis presents the most updated clinical event rates over the longest course of

The Watchman™ (Boston Scientific Corporation, MA) device for left atrial appendage occlusion for stroke prevention in nonvalvular atrial fibrillation was FDA approved in March of 2015. We now provide the first report of the post-approval experience with the device in the United States. Each

WATCHMAN left atrial appendage (LAA) closure is a novel approach to preventing stroke in patients with atrial fibrillation (AF) that could reduce the longer-term risk of bleeding compared with anticoagulation. We compared the temporal incidence of major bleeding beyond the immediate procedural

The PhysioFlow bioimpedance cardiography device provides key measures of central systolic and diastolic and peripheral vascular function. Many of these variables have not been assessed for intrarater reliability and agreement during rest, submaximal exercise and high-intensity interval exercise. Twenty healthy adults (age: 26±4 years) completed two identical trials beginning with five minutes of rest followed by two 5-minute submaximal cycling bouts at 50% and 70% of peak power output. Subjects then completed ten 30-second cycling intervals at 90% of peak power output interspersed with 60 s of passive recovery. Bioimpedance cardiography (PhysioFlow; Manatec Biomedical, France) monitored heart rate, stroke volume, cardiac output, stroke volume index, cardiac index, ventricular ejection time, contractility index, ejection fraction, left cardiac work index, end diastolic volume, early diastolic filling ratio, systemic vascular resistance and systemic vascular resistance index continuously throughout both trials. Intraclass correlation coefficients (ICC), standard errors of measurement and minimal detectable differences were calculated for all variables. Heart rate, stroke volume, cardiac output, left cardiac work index and end diastolic volume demonstrated a good level of reliability (ICC>.75) at rest, during submaximal exercise and high-intensity interval exercise. All other variables demonstrated inconsistent reliability across activity types and intensities. When using the PhysioFlow device, heart rate, stroke volume, cardiac output, left cardiac work index and end diastolic volume were deemed acceptable for use regardless of exercise type (continuous vs. interval) or intensity (low, moderate, or high). However, other variables measured by this device appear less reliable.