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An elevated white blood cell (WBC) count is associated with an increased risk of ischemic events among acute coronary syndrome (ACS) patients, but the association between WBC count and bleeding in ACS patients is not well established. The aim of this analysis was to assess and compare the association between WBC count and the occurrence of short- and long-term bleeding and ischemic events. This was a post hoc analysis of the ATLAS ACS2-TIMI 51 trial. A subset of patients had a WBC count measurement at baseline (n = 14,231, 91.6%). Univariate and multivariable Cox proportional hazard models were constructed to determine if there is an association between WBC count at baseline and a composite outcome of Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeds at 30 days and 1 year. Variables with a p0.2 in the univariate analysis were included as potential parameters in the backward selection process A similar multivariable model was constructed to assess the association between WBC count and a composite ischemic endpoint of cardiovascular death, myocardial infarction and stroke. An increased risk of bleeding per a 1 × 10

Background The identification of acutely ill patients at high risk for venous thromboembolism (VTE) may be determined clinically or by use of integer‐based scoring systems. These scores demonstrated modest performance in external data sets. Objectives To evaluate the performance of machine learning models compared to the IMPROVE score. Methods The APEX trial randomized 7513 acutely medically ill patients to extended duration betrixaban vs. enoxaparin. Including 68 variables, a super learner model (ML) was built to predict VTE by combining estimates from 5 families of candidate models. A “reduced” model (rML) was also developed using 16 variables that were thought, a priori, to be associated with VTE. The IMPROVE score was calculated for each patient. Model performance was assessed by discrimination and calibration to predict a composite VTE end point. The frequency of predicted risks of VTE were plotted and divided into tertiles. VTE risks were compared across tertiles. Results The ML and rML algorithms outperformed the IMPROVE score in predicting VTE (c‐statistic: 0.69, 0.68 and 0.59, respectively). The Hosmer‐Lemeshow goodness‐of‐fit P‐value was 0.06 for ML, 0.44 for rML, and

BACKGROUND Extended-duration thromboprophylaxis with betrixaban reduces the risk of venous thromboembolism (VTE) without increasing major bleeding rates in acutely ill medical patients as compared to standard duration enoxaparin. We aimed to assess the risk-benefit of betrixaban in patients aged ≥ 80 years enrolled in the APEX trial. METHODS APEX was a randomized, double-blind trial in which patients hospitalized for acute medical illnesses received enoxaparin 40 mg qd for 10 ± 4 days or oral betrixaban 80 mg qd for 35 to 42 days. The primary efficacy outcome was VTE, the principal safety outcome was major bleeding. Net clinical benefit (NCB) was defined by the occurrence of VTE or major bleeding. RESULTS Of 7513 patients enrolled in the APEX trial, 2781 (37%) were aged ≥ 80 years. In this subgroup, VTE or major bleeding occurred in 7.0% of betrixaban patients and in 8.4% of enoxaparin patients, for a relative risk in the NCB of 0.82 (95% confidence interval 0.62-1.10). The relative risk reduction obtained with betrixaban was similar between those aged ≥ 80 years and patients younger than 80 years (5.0% and 6.7%, respectively, NCB 0.75, 0.58-0.96, P = .024), with no significant interaction across age groups (P = .33). CONCLUSIONS Event rates were higher in medically ill patients aged ≥ 80 years enrolled in the APEX study than in patients younger than 80 years. The predefined NCB was reduced with extended betrixaban therapy in both groups with no signs of age-related interactions. However, the primary efficacy endpoint was not achieved with betrixaban for patients 80 years of age or older.

Acutely ill medical patients with cancer are at increased risk of venous thromboembolism (VTE). Thromboprophylaxis is recommended in the presence of cancer, but its safety is not known. The aim of this study was to assess the efficacy and safety of extended prophylaxis with betrixaban in cancer patients enrolled in the APEX trial. APEX was a randomized, double-blind trial comparing oral betrixaban 80 mg qd administered for 35-42 days with subcutaneous enoxaparin 40 mg qd administered for 10 ± 4 days. Patients with acute medical illness and a history of cancer or active cancer were eligible for inclusion. Primary efficacy outcome was VTE (composite of symptomatic VTE and asymptomatic proximal deep vein thrombosis); primary safety outcome was major bleeding. Of 7513 patients enrolled in the APEX trial, 959 patients (12.8%), 499 randomized to betrixaban and 460 to enoxaparin, had cancer. The primary efficacy outcome occurred in 5.7% of cancer patients treated with betrixaban and in 6.2% treated with enoxaparin (p = 0.95). No significant interaction according to the presence or absence of cancer was observed (p = 0.36). Major bleeding events occurred in 0.8% of patients in the betrixaban group and in 0% in the enoxaparin group (p = 0.13), with no significant interaction (p = 0.07). The composite of major and clinically relevant non-major bleeds was similar between the two groups (2.9% and 2.0%, respectively, RR 1.43, 95% CI 0.63-3.27). Betrixaban was similarly effective in the reduction of VTE among subjects with and without cancer. The incidence of major bleeding was similarly low.

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 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 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)

International audience; BACKGROUND:CSL112 (apolipoprotein A-I [human]) is a plasma-derived apolipoprotein A-I developed for early reduction of cardiovascular risk following an acute myocardial infarction (AMI). The safety of CSL112 among AMI subjects with moderate, stage 3 chronic kidney disease (CKD) is unknown.METHODS:CSL112_2001, a multicenter, placebo-controlled, parallel-group, double-blind, randomized phase 2 trial, enrolled patients with moderate CKD within 7 days following AMI. Enrollment was stratified on the basis of estimated glomerular filtration rate and presence of diabetes requiring treatment. Patients were randomized in a 2:1 ratio to receive 4 weekly infusions of CSL112 6 g or placebo. The co-primary safety end points were renal serious adverse events (SAEs) and acute kidney injury, defined as an increase ≥26.5 μmol/L in baseline serum creatinine for more than 24 hours, during the treatment period.RESULTS:A total of 83 patients were randomized (55 CSL112 vs 28 placebo). No increase in renal SAEs was observed in the CSL112 group compared with placebo (CSL112 = 1 [1.9%], placebo = 4 [14.3%]). Similarly, no increase in acute kidney injury events was observed (CSL112 = 2 [4.0%], placebo = 4 [14.3%]). Rates of other SAEs were similar between groups. CSL112 administration resulted in increases in ApoA-I and cholesterol efflux similar to those observed in patients with AMI and normal renal function or stage 2 CKD enrolled in the ApoA-I Event Reducing in Ischemic Syndromes I trial.CONCLUSIONS:These results demonstrate the acceptable safety of the 6-g dose of CSL112 among AMI subjects with moderate stage 3 CKD and support inclusion of these patients in a phase 3 cardiovascular outcomes trial powered to assess efficacy.

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.

Objective This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans. Methods Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates. Results Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily. Conclusion This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.

INTRODUCTION Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients. Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population. Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.

Among hospitalized medically ill patients who are at risk of venous thromboembolism (VTE), pharmacological thromboprophylaxis is recommended during the period of immobilization or acute hospital stay.1 However, the risk of VTE extends beyond the standard 10- to 14-day course of anticoagulation and persists for weeks to months after hospital discharge. About half of VTE events occur after the period of index hospitalization and may require rehospitalization.2 Rehospitalization is an end point that adversely affects the morbidity and quality of life of patients and can be a major driver of healthcare costs. Indeed, a goal of patient-centered care is to be both alive and free of hospitalization. The APEX trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial; ClinicalTrials.gov: NCT01583218) was a double-blind randomized clinical trial that compared extended-duration (35–42 days) betrixaban with standard-duration (10±4 days) enoxaparin among acutely ill hospitalized medical patients at increased risk of VTE. A reduction in VTE by extended-duration betrixaban compared with standard-duration enoxaparin has been demonstrated,3 but the impact of extended thromboprophylaxis with betrixaban on the risk of rehospitalization associated with VTE has not been studied. It was hypothesized that betrixaban would reduce VTE-related rehospitalization. The APEX trial randomized 7513 patients to either extended-duration betrixaban or standard-duration enoxaparin for VTE prophylaxis. The full-dose regimen (betrixaban 80 mg daily) was administered to patients who had a creatinine clearance of ≥30 mL/min and were not administered a strong P-glycoprotein inhibitor. VTE-related rehospitalization was …

Contains fulltext : 196178.pdf (Publisher’s version ) (Closed access) Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12 months: (1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (N = 696); (2) rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) (N = 706); and (3) dose-adjusted warfarin plus DAPT (N = 697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49-0.85], p < 0.001, NNT = 11; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48-0.80], p < 0.001, NNT = 10). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49-0.89], p < 0.001, NNT = 14; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48-0.85], p = 0.002, NNT = 13). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10-11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13-14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01830543 (PIONEER AF-PCI).

Background Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial. Methods Hospitalized acutely medically ill subjects (n = 7,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement. Results For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban (p Conclusion Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.

Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35-42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06-5.30, p 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38-0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64-0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41-0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36-0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis.http://www.clinicaltrials.gov , Unique identifier: NCT01583218.

Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep-vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42-0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate.

Background Prior randomized controlled trials (RCT) evaluating the optimal antithrombotic therapies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not been powered to evaluate ischemic outcomes. We compared double therapy with oral anticoagulation (OAC) and a P2Y12 inhibitor to triple therapy with an OAC + dual antiplatelet therapy in patients with AF requiring PCI. Methods Using PRISMA guidelines, we searched for RCTs including patients with AF as an indication for OAC and undergoing PCI or medical management of acute coronary syndrome. The results were pooled using fixed-effects and random-effects models to estimate the overall effect of double therapy versus triple therapy on ischemic and bleeding outcomes. Results We identified four RCTs, comprising 10,238 patients (5,498 double therapy, 4,740 triple therapy). Trial-reported major adverse cardiovascular events were similar between double therapy and triple therapy (fixed effect model OR 1.09, 95% CI 0.94-1.26). However, stent thrombosis (61/5,496 double therapy vs. 33/4738 triple therapy; fixed effect model OR 1.57, 95% CI 1.02-2.40; number needed to treat with triple therapy = 242) favored triple therapy. Bleeding outcomes were less frequent with double therapy (746/5470 vs. 950/4710; fixed effect model OR 0.59, 95% CI 0.53-0.65; number needed to harm with triple therapy = 16), but with significant heterogeneity (Q = 8.33, p = .04; I2 = 64%), as were intracranial hemorrhages (19/5470 vs. 30/4710; fixed effect model OR 0.54, 95% CI 0.31-0.96). Conclusions Double therapy in patients with AF requiring OAC following PCI or Acute coronary syndrome has a significantly better safety profile than triple therapy but may be associated with a modest increased risk of stent thrombosis.

International audience; PURPOSE OF REVIEW:The last 40 years of clinical research in interventional cardiology were extraordinarily innovative. This article will review the most promising up and coming interventional cardiovascular therapies, with a primary focus on the treatment of coronary artery disease.RECENT FINDINGS:From the first stent, to the first transcatheter aortic valve implantation (TAVI), and the left appendage closure technique, percutaneous interventions revolutionized the treatment of multiple diseases and dramatically improved the prognosis of many patients. While these advances have decreased the risk of mortality in some patients (such as ST-elevation myocardial infarction), 15% of acute coronary syndrome (ACS) patients still experience recurrent ischemic events within the first year, challenging us to develop new pharmaceutical targets and new devices. The continued emergence of data supporting inflammation as a risk factor and pharmacologic target as well as data supporting the importance of cholesterol efflux have identified novel therapeutic targets that may play a major role in the improvement of prognosis of patients with coronary artery disease. In addition, novel medical devices are being developed to allow even earlier detection of acute cardiac events and to support high-risk percutaneous coronary interventions. Advances in computing and the ability to analyze large datasets will allow us to use artificial intelligence to augment the clinician patient experience, both in and out of the catheterization laboratory, with live procedural guidance as well as pre- and post-operative prognostication tools.

Prevalence of nine chronic medical conditions in the population-based Ft. Devens Cohort (FDC) of GW veterans were compared with the population-based 2013&ndash, 2014 National Health and Nutrition Examination Survey (NHANES) cohort. Excess prevalence was calculated as the difference in prevalence estimates from the Ft. Devens and NHANES cohorts, and confidence intervals and p-values are based on the standard errors for the two prevalence estimates. FDC males were at increased risk for reporting seven chronic medical conditions compared with NHANES males. FDC females were at decreased risk for high blood pressure and increased risk for diabetes when compared with NHANES females. FDC veterans reporting war-related chemical weapons exposure showed higher risk of high blood pressure, diabetes, arthritis and chronic bronchitis while those reporting taking anti-nerve gas pills had increased risk of heart attack and diabetes. GW veterans are at higher risk of chronic conditions than the general population and these risks are associated with self-reported toxicant exposures.

Background A residual risk of ischemic events following an acute coronary syndrome (ACS) remains despite antiplatelet therapy. The addition of an antithrombin as part of a “dual pathway” approach may further improve outcomes as thrombin generation persists for several months post‐ACS. The present study evaluates the safety and efficacy of “dual pathway” therapy (rivaroxaban plus aspirin) as compared with aspirin monotherapy among post‐ACS patients. Methods and Results A total of 1477 patients were analyzed in a pooled analysis of subsets of the ATLAS ACS‐TIMI (Anti‐Xa Therapy to Lower cardiovascular events in addition to Aspirin with or without thienopyridine therapy in Subjects with Acute Coronary Syndrome – Thrombolysis in Myocardial Infarction) 46 and ATLAS ACS 2‐TIMI 51 trials including post‐ACS patients receiving aspirin monotherapy and randomized to either rivaroxaban 2.5 mg BID or rivaroxaban 5 mg BID or placebo. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or stroke (ischemic, hemorrhagic, or of uncertain cause). The primary safety end point was TIMI‐non‐coronary artery bypass (CABG) major bleeding. The combined rivaroxaban group (2.5 or 5 mg BID) among stabilized post‐ACS patients on a background of aspirin monotherapy was associated with a significant reduction in the primary end point as compared with placebo (hazard ratio=0.65, 95% CI=0.45–0.92, P=0.016). Although the combined rivaroxaban dose groups were associated with higher rates of non‐CABG TIMI major bleeding, the 2.5 mg dose group was not, and the overall number of patients experiencing a non‐CABG TIMI major bleeding event was low (1.5%). Conclusions Among patients in the immediate post‐ACS period, a “dual pathway” approach using aspirin and low‐dose rivaroxaban may reduce the risk of secondary atherothrombotic events, but increase bleeding risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00402597; NCT00809965., See Editorial by Harrison and Newby

Background: Among atrial fibrillation patients undergoing percutaneous coronary intervention enrolled in PIONEER AF-PCI (An Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention), it is unclear if the observed reduction in bleeding events with rivaroxaban regimens is consistent across a range of the international normalized ratio (INR) among subjects administrated Vitamin K antagonist (VKA)-triple therapy. This analysis compares the occurrence of clinically significant bleeding between rivaroxaban and VKA strategies, according to INR stability of subjects administrated VKA. Methods and Results: A total of 2124 atrial fibrillation patients undergoing percutaneous coronary intervention were randomized to 3 groups: rivaroxaban 15 mg od plus a P2Y 12 inhibitor (group 1, n=709); rivaroxaban 2.5 mg bid plus dual antiplatelet therapy (group 2, n=709); and warfarin plus dual antiplatelet therapy (group 3, n=706). Subjects assigned to the VKA group were stratified according to time in therapeutic range and time spent with an INR >3. Kaplan-Meier estimates were calculated for clinically significant bleeding through 1 year and hazard ratios were derived using Cox Proportional Hazards models. Among group 3, 93.4% of the participants had a time in therapeutic range available (mean time in therapeutic range=65.0±24.8%). Both groups 1 and 2 were associated with a reduction in clinically significant bleeding compared with subjects in group 3, regardless of the time in therapeutic range (hazard ratio ranges=0.53–0.71 and 0.57–0.76; respectively, P 3 (hazard ratio ranges=0.59–0.67 and 0.42–0.69; P Conclusions: Among atrial fibrillation patients undergoing percutaneous coronary intervention, rivaroxaban-based therapy was superior to warfarin plus dual antiplatelet therapy in lowering bleeding outcomes regardless of the INR stability. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01830543.

OBJECTIVE Comprehensive review of the use of computerized treatment as a rehabilitation tool for attention and executive function in adults (aged 18 years or older) who suffered an acquired brain injury. DESIGN Systematic review of empirical research. MAIN MEASURES Two reviewers independently assessed articles using the methodological quality criteria of Cicerone et al. Data extracted included sample size, diagnosis, intervention information, treatment schedule, assessment methods, and outcome measures. RESULTS A literature review (PubMed, EMBASE, Ovid, Cochrane, PsychINFO, CINAHL) generated a total of 4931 publications. Twenty-eight studies using computerized cognitive interventions targeting attention and executive functions were included in this review. In 23 studies, significant improvements in attention and executive function subsequent to training were reported; in the remaining 5, promising trends were observed. CONCLUSIONS Preliminary evidence suggests improvements in cognitive function following computerized rehabilitation for acquired brain injury populations including traumatic brain injury and stroke. Further studies are needed to address methodological issues (eg, small sample size, inadequate control groups) and to inform development of guidelines and standardized protocols.

BACKGROUND: Traumatic brain injury (TBI) was not considered to be common in the 1990-1991 Gulf War (GW). Therefore, the relationship between TBI and chronic health symptoms experienced by GW veterans is unknown. Health symptoms reported by veterans deployed more recently to this region (Operations Enduring and Iraqi Freedom) are similar to those of GW veterans and have been primarily attributed to TBI. OBJECTIVE: To examine the relationships among self-reported TBI, health symptoms, chronic multisymptom illness (CMI), and health-related quality of life among GW veterans. PARTICIPANTS: Participants included 1 274 GW veterans from the Devens Cohort Study, 156 of whom self-reported a history of TBI (12.2% of the sample). DESIGN: Cross-sectional retrospective analysis of existing survey data. MAIN MEASURES: A 52-item health symptom checklist and the RAND 36-Item Health short Form Survey. RESULTS: Self-reported TBI in GW Veterans is related to increased rates of health symptoms, CMI, and poorer health-related quality of life. CONCLUSIONS: Gulf War veterans' self-reported exposure to TBI is related to increased rates of chronic health symptoms and CMI, which interfere with everyday activities of daily living. Language: en

Aim Asymptomatic deep vein thrombosis (DVT) diagnosed with compression ultrasound (CUS) is a common endpoint in trials assessing the efficacy of anticoagulants to prevent venous thromboembolism (VTE), but the relationship of asymptomatic thrombus to mortality remains uncertain. Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). Asymptomatic DVT was assessed once with CUS between day 32 and 47, and mortality was assessed through 77 days. Results A total of 309 asymptomatic DVTs were detected through CUS. Of these, 133 (4.27%) subjects were in the betrixaban group, and 176 (5.55%) subjects were in the enoxaparin group (relative risk = 0.77, 95% confidence interval [CI] = 0.62–0.97, p = 0.025, number needed to treat = 79). With respect to all-cause mortality due to cardiovascular diseases, non-cardiovascular diseases and unknown causes, the number of the deaths was 5 (1.67%), 4 (1.34%) and 1 (0.33%) in the asymptomatic DVT group and 25 (0.42%), 33 (0.56%) and 11 (0.19%) in the no DVT group, respectively. Subjects with an asymptomatic DVT had an almost threefold increase in the risk of all-cause mortality compared with subjects without DVT (hazard ratio = 2.87, 95% CI = 1.48–5.57, p = 0.001). A positive linear trend was observed between greater thrombus burden and mortality during the follow-up (p = 0.019). Conclusion Asymptomatic DVT was associated with approximately threefold increased risk of short-term all-cause mortality in patients hospitalized with an acute medical illness within the prior 77 days. A positive linear trend was observed between greater thrombus burden and mortality during the follow-up.

Among acute coronary syndrome (ACS) and stable coronary artery disease patients, the effect of a loading dose of statin, prior to revascularization, has been assessed in several observational studies and randomized controlled trials (1-3). A high dose of statin before percutaneous or surgical revascularization was associated with a decreased risk of periprocedural myocardial infarction (MI), contrast induced—acute kidney injury and, finally, improved clinical outcomes (4,5). The underlying mechanism was hypothesized to be related to the complex pleiotropic effects of statins which improve endothelial function, stabilize the atherosclerotic plaque, and decrease the vascular inflammation (6).

Background Net clinical outcome analyses of acute coronary syndrome (ACS) mingle fatal or irreversible events with survivable or reversible events that vary significantly in clinical impact. Objectives A comparison of efficacy and safety limited to fatal or irreversible ischemic and adverse or seriously harmful events is one way to assess net clinical outcome and risk-benefit overall, given the fact that these events have a similar clinical impact. Methods In the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction) trial of rivaroxaban in the secondary prevention of events among patients with ACS treated with aspirin plus clopidogrel or ticlopidine (clopidogrel/ticlopidine) or aspirin alone, fatal and irreversible efficacy events including nonbleeding cardiovascular death, myocardial infarction, and ischemic stroke were compared to fatal or irreversible safety events, including fatal and intracranial bleeding. Results Rivaroxaban, 2.5 mg orally twice per day, in patients treated with aspirin and clopidogrel/ticlopidine was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: −11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. Taken together, there would be 105 (95% CI: 6 to 204) fatal or irreversible events prevented per 10,000 patient-years of exposure to rivaroxaban compared with placebo, with 11 (10 of 115) fatal or irreversible ischemic events prevented for each fatal or irreversible seriously harmful event caused. If only nonbleeding cardiovascular death is included as a fatal or irreversible event, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking 2.5 mg orally twice per day. Conclusions Both fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy. Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or irreversible events. (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction [ATLAS ACS 2-TIMI 51]; NCT00809965 )

ObjectivesAcross diverse groups of Gulf War (GW) veterans, reports of musculoskeletal pain, cognitive dysfunction, unexplained fatigue, chronic diarrhoea, rashes and respiratory problems are common. GW illness is a condition resulting from GW service in veterans who report a combination of these symptoms. This study integrated the GW literature using meta-analytical methods to characterise the most frequently reported symptoms occurring among veterans who deployed to the 1990–1991 GW and to better understand the magnitude of ill health among GW-deployed veterans compared with non-deployed GW-era veterans.DesignMeta-analysis.MethodsLiterature databases were searched for peer-reviewed studies published from January 1990 to May 2017 reporting health symptom frequencies in GW-deployed veterans and GW-era control veterans. Self-reported health symptom data were extracted from 21 published studies. A binomial-normal meta-analytical model was used to determine pooled prevalence of individual symptoms in GW-deployed veterans and GW-era control veterans and to calculate combined ORs of health symptoms comparing GW-deployed veterans and GW-era control veterans.ResultsGW-deployed veterans had higher odds of reporting all 56 analysed symptoms compared with GW-era controls. Odds of reporting irritability (OR 3.21, 95% CI 2.28 to 4.52), feeling detached (OR 3.59, 95% CI 1.83 to 7.03), muscle weakness (OR 3.19, 95% CI 2.73 to 3.74), diarrhoea (OR 3.24, 95% CI 2.51 to 4.17) and rash (OR 3.18, 95% CI 2.47 to 4.09) were more than three times higher among GW-deployed veterans compared with GW-era controls.ConclusionsThe higher odds of reporting mood-cognition, fatigue, musculoskeletal, gastrointestinal and dermatological symptoms among GW-deployed veterans compared with GW-era controls indicates these symptoms are important when assessing GW veteran health status.

Background Approximately 15%-30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data. Methods The APEX trial randomized 7,513 acutely medically ill hospitalized patients to thromboprophylaxis with either betrixaban for 35-42 days or enoxaparin for 6-14 days. A modified intent-to-treat (mITT) analysis was performed and included all subjects administered study drug, irrespective of CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and venous thromboembolism (VTE)–related mortality). Results In the mITT population, betrixaban significantly reduced the primary end point (which included both symptomatic and CUS events) (165 [4.4%] vs 223 [6.0%]; relative risk = 0.75; 95% CI 0.61-0.91; P = .003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63). Betrixaban also reduced symptomatic VTE through day 42 (35 [1.28%] vs 54 [1.88%], hazard ratio [HR] = 0.65; 95% CI 0.42-0.99; P = .044; ARR = 0.6%; NNT=167) as well as through day 77 (37 [1.02%] vs 67 [1.89%]; HR= 0.55; 95% CI 0.37-0.83; P = .003; ARR = 0.87%; NNT=115) as well as the individual end point of nonfatal pulmonary embolism (9 [0.25%] vs 20 [0.55%]; HR= 0.45; 95% CI 0.21-0.99; P = .041; ARR = 0.30%; NNT=334). On an “as-treated” basis, 80 mg of betrixaban reduced VTE-related mortality through day 77 (10 [0.34%] vs. 22 [0.79%]; HR=0.46; 95% CI 0.22-0.96; P = .035; ARR = 0.45%; NNT=223). Conclusion In an mITT analysis of all patients administered study drug, extended-duration betrixaban reduced the primary end point as well as symptomatic events. In an as-treated analysis, 80 mg of betrixaban reduced VTE-related death.

Recent research demonstrated a relation between traumatic brain injury (TBI), health symptoms and diagnosis of Gulf War Illness (GWI) in Gulf War Veterans, but no study has examined the impact of multiple mild TBIs (mTBIs). A total of 229 male Gulf War Veterans from the Ft Devens Cohort were categorized by a number of mTBIs reported. One-way ANOVA and chi-square test of independence were used to test for differences in total reported health symptoms and diagnosis of chronic multisymptom illness (CMI) or Kansas GWI criteria, two of the most common case definitions of GWI. A total of 72 veterans reported no mTBIs (31.4%), 26 reported one mTBI (11.4%), 25 reported two mTBIs (10.9%), and 106 veterans reported sustaining three or more mTBIs (46.3%). Veterans reporting two or more mTBIs (p < 0.01) or three or more mTBIs (p < 0.001) endorsed significantly higher rates of health symptoms than Veterans reporting no mTBIs. Significantly higher rates of CMI (p = 0.035) and Kansas GWI criteria (p < 0.001) were seen in the three or more mTBI group. Results suggest two mTBIs increase risk of health symptoms, but three mTBIs may be the threshold needed to sustain chronic symptom reporting needed for a formal diagnosis. These findings highlight the importance of implementing policies and procedures monitoring head injuries in military personnel.

This invited paper reviews our research with scalp application of red/near-infrared (NIR) light-emitting diodes (LED) to improve cognition in chronic, traumatic brain injury 1. Application of red/NIR light improves mitochondrial function (especially hypoxic/compromised cells) promoting increased ATP, important for cellular metabolism. Nitric oxide is released locally, increasing regional cerebral blood flow. Eleven chronic, mTBI participants with closed-head injury and cognitive dysfunction received 18 outpatient treatments (MWF, 6 Wks) starting at 10 Mo. to 8 Yr. post-mTBI (MVA, sports-related, IED blast injury). LED therapy is non-invasive, painless, non-thermal (FDA-cleared, non-significant risk device). Each LED cluster head (2.1" diameter, 500mW, 22.2mW/cm2) was applied 10 min (13J/cm2) to 11 scalp placements: midline, from front-to-back hairline; and bilaterally on dorsolateral prefrontal cortex, temporal, and parietal areas. Testing performed pre- and post-LED (+1 Wk, 1 and 2 Mo post- 18th treatment) showed significant linear trend for LED effect over time, on improved executive function and verbal memory. Fewer PTSD symptoms were reported. New studies at VA Boston include TBI patients treated with transcranial LED (26J/cm2); or treated with only intranasal red, 633nm and NIR, 810nm diodes placed into the nostrils (25 min, 6.5mW, 11.4J/cm2). Intranasal LEDs are hypothesized to deliver photons to hippocampus. Results are similar to Naeser et al. (2014). Actigraphy sleep data show increased sleep time (average, +1 Hr/night) post-18th transcranial or intranasal LED treatment. LED treatments may be self-administered at home (Naeser et al., 2011). A shamcontrolled study with Gulf War Illness Veterans is underway.

the use of computerized treatment programs as a rehabilitation tool in ABI. We conducted a systematic review of empirical research on computerized cognitive rehabilitation for attention and executive function after ABI. Design: Systematic Review. Data Sources: A literature search of Pubmed and PsychINFO was conducted using the key terms: computerized cognitive rehabilitation, traumatic brain injury (TBI), stroke, ABI, and executive functioning. Study Selection: Studies reporting on cognitive outcomes following computerized rehabilitation in adult participants with an ABI of any severity were included. Data Extraction: Articles were independently assessed by two reviewers, using Cicerone et al criteria. Data collected included sample size, diagnosis, intervention info, treatment schedule, assessment methods, and results. Data Synthesis: The initial searches yielded a total of 1075 hits; reduced to 121 after title review, which was further reduced to 27 once doubles were eliminated and abstracts were reviewed. Fourteen met inclusion criteria after being read. Nine studies met criteria for Class I, two met criteria for Class II, and three met Class III evidence criteria. There is evidence of improvement in executive functioning in ABI following computerized treatment. Studies were more commonly conducted in stroke patients. TBI studies often included smaller sample sizes and less adequate control groups. Conclusions: The evidence indicates improvements in executive functioning following computerized cognitive rehabilitation training. Additional studies are needed, especially in TBI.