Direct and specific inhibition of factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral factor Xa inhibitors promise efficacy comparable to standard therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral, direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n = 12) received a single, 60 mg dose of DU-176b. Antithrombotic effects were assessed by comparing ex-vivo thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with factor Xa activity, thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the thrombus was 28% and 21% smaller versus baseline, respectively (p < 0.05). Under arterial condition, the reduction was 26% and 17% (p < 0.05). Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma drug concentrations (R2 = 0.79 and 0.78). Direct and specific inhibition of factor Xa by DU-176b significantly reduced ex-vivo thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.

Background: Dilated cardiomyopathy is associated with increased risk of major cardiovascular events. Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging is a unique tissue-based marker that, in single-center studies, suggests strong prognostic value. We retrospectively studied associations between LGE presence and adverse cardiovascular events in patients with dilated cardiomyopathy in a multicenter setting as part of an emerging global consortium (MINICOR [Multi-Modal International Cardiovascular Outcomes Registry]). Methods: Consecutive patients with dilated cardiomyopathy referred for cardiac magnetic resonance (2000–2017) at 12 institutions in 4 countries were studied. Using multivariable Cox proportional hazard and semiparametric Fine and Gray models, we evaluated the association between LGE and the composite primary end point of all-cause mortality, heart transplantation, or left ventricular assist device implant and a secondary arrhythmic end point of sudden cardiac death or appropriate implantable cardioverter-defibrillator shock. Results: We studied 1672 patients, mean age 56±14 years (29% female), left ventricular ejection fraction 33±11%, and 25% having New York Heart Association class III to IV; 650 patients (39%) had LGE. During 2.3 years (interquartile range, 1.0–4.3) follow-up, 160 patients experienced the primary end point, and 88 experienced the arrhythmic end point. In multivariable analyses, LGE was associated with 1.5-fold (hazard ratio, 1.45 [95% CI, 1.03–2.04]) risk of the primary end point and 1.8-fold (hazard ratio, 1.82 [95% CI, 1.20–3.06]) risk of the arrhythmic end point. Primary end point risk was increased in patients with multiple LGE patterns, although arrhythmic risk was higher among patients receiving primary prevention implantable cardioverter-defibrillator and widening QRS. Conclusions: In this large multinational study of patients with dilated cardiomyopathy, the presence of LGE showed strong prognostic value for identification of high-risk patients. Randomized controlled trials evaluating LGE-based care management strategies are warranted.

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Background: There is increasing evidence that right ventricular ejection fraction (RVEF) may provide incremental value to left ventricular (LV) ejection fraction for the prediction of major adverse cardiovascular events. To date, generalizable utility for RVEF quantification in patients with cardiovascular disease has not been established. Using a large prospective clinical outcomes registry, we investigated the prognostic value of RVEF for the prediction of major adverse cardiovascular events- and heart failure-related outcomes. Methods: Seven thousand one hundred thirty-one consecutive patients with known or suspected cardiovascular disease undergoing cardiovascular magnetic resonance imaging were prospectively enrolled. Multichamber volumetric quantification was performed by standardized operational procedures. Patients were followed for the primary composite outcome of all-cause death, survived cardiac arrest, admission for heart failure, need for transplantation or LV assist device, acute coronary syndrome, need for revascularization, stroke, or transient ischemic attack. A secondary, heart failure focused outcome of heart failure admission, need for transplantation/LV assist device or death was also studied. Results: Mean age was 54±15 years. The mean LV ejection fraction was 55±14% (range 6%–90%) with a mean RVEF of 54±10% (range 9%–87%). At a median follow-up of 908 days, 870 (12%) patients experienced the primary composite outcome and 524 (7%) the secondary outcome. Each 10% drop in RVEF was associated with a 1.3-fold increased risk of the primary outcome ( P <0.001) and 1.5-fold increased risk of the secondary outcome ( P <0.001). RVEF was an independent predictor following comprehensive covariate adjustment, inclusive of LV ejection fraction. Patients with an RVEF<40% experienced a 3.1-fold risk of the primary outcome ( P <0.001) with a 1-year cumulative event rate of 22% versus 7% above this cutoff. Conclusions: RVEF is a powerful and independent predictor of major adverse cardiac events with broad generalizability across patients with known or suspected cardiovascular disease. These findings support migration towards biventricular phenotyping for the classification of risk in clinical practice. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04367220.