Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial

The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart disease (VHD) is of substantial interest.This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin.Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards.After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio [HR]: 1.40; 95% confidence interval [CI]:1.26 to 1.56; p 0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p 0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction [pThe presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391)

Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF‐TIMI48 Trial

Background: We studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation (AF). Methods and Results: ENGAGE AF‐TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved high‐dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower‐dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS 2Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HR adj]=1.46; 95% CI, 1.27–1.67, P<0.001). SAPT did not alter the relative efficacy of edoxaban compared to warfarin in preventing stroke or systemic embolic events (SEEs): edoxaban versus warfarin without SAPT, hazard ratio (HR adj for HDER)=0.94; (95% CI: 0.77–1.15) with SAPT, HR adj=0.70 (95% CI: 0.50–0.98), P interaction (P int)=0.14. (HR adj for LDER versus warfarin without SAPT=1.19 (95% CI 0.99–1.43) With SAPT, 1.03 (95% CI, 0.76–1.39) P int=0.42. Major bleeding was lower with edoxaban than warfarin both without SAPT, HR adj for HDER=0.80 (95% CI, 0.68–0.95), and with SAPT, HR adj=0.82 (95% CI, 0.65–1.03; P int=0.91). For LDER without SAPT (HR adj=0.56 [95% CI 0.46–0.67]) and with SAPT (HR adj=0.51 [95% CI 0.39–0.66]). Conclusions: Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT. Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT. Clinical Trial Registration URL: http://www.clinicaltrials.gov/. Unique identifier: NCT00781391

Variability of Individual Platelet Reactivity Over Time in Patients Treated With Clopidogrel Insights From the ELEVATE–TIMI 56 Trial

AbstractBackgroundThe degree of antiplatelet response to clopidogrel has been associated with clinical outcomes. Studies have investigated whether adjustment of antiplatelet therapies based on a single platelet function test is beneficial.ObjectivesThe aim of the study was to test the stability of platelet reactivity measurements over time among patients treated with standard and double doses of clopidogrel.MethodsThe ELEVATE–TIMI 56 (Escalating Clopidogrel by Involving a Genetic Strategy–Thrombolysis In Myocardial Infarction 56) investigators genotyped 333 patients with coronary artery disease and randomized them to various clopidogrel regimens. Patients with at least 2 platelet function results on the same maintenance dose of clopidogrel (75 mg or 150 mg) were analyzed. Platelet aggregation was measured using P2Y12 reaction units (PRU).ResultsIn total, the mean platelet reactivity and the total number of nonresponders (PRU ≥230) with clopidogrel did not change between 2 periods for the 75-mg (22.4% vs. 21.9%; p = 0.86) and 150-mg doses of clopidogrel (11.5% vs. 11.5%; p = 1.00). In contrast, when evaluating each patient individually, 15.7% of patients taking clopidogrel 75 mg and 11.4% of patients taking 150 mg had a change in their responder status when tested at 2 different time points (p < 0.001). Despite being treated with the same dose of clopidogrel, >40% of patients had a change in PRU >40 on serial sampling, which approximates the average PRU difference caused by increasing the clopidogrel dose from 75 mg to 150 mg.ConclusionsMeasurements of platelet reactivity vary over time in a significant proportion of patients. Thus, treatment adjustment according to platelet function testing at a single time point might not be sufficient for guiding antiplatelet therapy in clinical or research settings. (Escalating Clopidogrel by Involving a Genetic Strategy–Thrombolysis In Myocardial Infarction 56 [ELEVATE–TIMI 56]; NCT01235351

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease

BACKGROUND –: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality with a known genetic contribution. We tested the performance of a genetic risk score (GRS) for its ability to predict VTE in three cohorts of patients with cardiometabolic disease. METHODS –: We included patients from the FOURIER, PEGASUS-TIMI 54, and SAVOR-TIMI 53 trials (history of atherosclerosis, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE GRS based on 297 SNPs with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared to available clinical risk factors (age, obesity, smoking, history of heart failure, diabetes) and common monogenic mutations. RESULTS –: A total of 29,663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (p-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI 1.23–2.89, p=0.004) and 2.70-fold (95% CI 1.81–4.06, p<0.0001) higher risk of VTE compared to patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the GRS was associated with a 47% (95% CI 29–68) increased risk of VTE (p<0.0001). CONCLUSIONS –: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia

New approaches to the study of human brain networks underlying spatial attention and related processes

Cognitive processes, such as spatial attention, are thought to rely on extended networks in the human brain. Both clinical data from lesioned patients and fMRI data acquired when healthy subjects perform particular cognitive tasks typically implicate a wide expanse of potentially contributing areas, rather than just a single brain area. Conversely, evidence from more targeted interventions, such as transcranial magnetic stimulation (TMS) or invasive microstimulation of the brain, or selective study of patients with highly focal brain damage, can sometimes indicate that a single brain area may make a key contribution to a particular cognitive process. But this in turn raises questions about how such a brain area may interface with other interconnected areas within a more extended network to support cognitive processes. Here, we provide a brief overview of new approaches that seek to characterise the causal role of particular brain areas within networks of several interacting areas, by measuring the effects of manipulations for a targeted area on function in remote interconnected areas. In human participants, these approaches include concurrent TMS-fMRI and TMS-EEG, as well as combination of the focal lesion method in selected patients with fMRI and/or EEG measures of the functional impact from the lesion on interconnected intact brain areas. Such approaches shed new light on how frontal cortex and parietal cortex modulate sensory areas in the service of attention and cognition, for the normal and damaged human brain