Because of the risk of bleeding and challenges associated with warfarin management, oral alternatives to vitamin K antagonists for mechanical valve anticoagulation are needed. Objective-Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives

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... o warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy. Approach and Results-A well-documented heterotopic aortic valve porcine model was used to test the hypothesis that apixaban has comparable efficacy to warfarin for thromboprophylaxis of mechanical heart valves. Sixteen swine were implanted with a bileaflet mechanical aortic valve that bypassed the ligated descending thoracic aorta. Animals were randomized to 4 groups: control (no anticoagulation; n=4), apixaban oral 1 mg/kg twice a day (n=5), warfarin oral 0.04 to 0.08 mg/kg daily (international normalized ratio 2-3; n=3), and apixaban infusion (n=4). Postmortem valve thrombus was measured 30 days post-surgery for control-oral groups and 14 days post-surgery for the apixaban infusion group. Control thrombus weight (mean) was significantly different (1422.9 mg) compared with apixaban oral (357.5 mg), warfarin (247.1 mg), and apixiban 14-day infusion (61.1 mg; P<0.05). Conclusions-Apixaban is a promising candidate and may be a useful alternative to warfarin for thromboprophylaxis of mechanical heart valves. Unlike warfarin, no adverse bleeding events were observed in any apixaban groups. Visual Overview-An online visual overview is available for this article. (Arterioscler Thromb Vasc Biol. 2017;37:942-948. The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/University of Michigan (NIH-NCI P30CA046592) for assistance with pharmacokinetic assays and Terry Majors for assistance with coagulation analysis. Dr Thomas R. Meier for assistance with development of a swine jacketed-tether infusion system. Lorie Gavulic for her medical illustrations. Finally, we would like to thank the Unit for Laboratory Animal Medicine Animal Care Supervisors, Scot A. Pittman and Michael J Ream and Veterinary Technicians, Lisa A. Burlingame and Laura B. Durham for their expert technical assistance and supportive veterinary care during the course of this study. Sources of Funding This research was supported with funding from Bristol-Myers Squibb and the Conrad Jobst Foundation through an industry-academic alliance with the University of Michigan. Bristol-Myers Squibb colleagues were not involved in either data collection or analysis. Highlights • Despite small sample size, apixaban demonstrated similar significant reductions in mechanical valve thrombus weights, as oral warfarin, in swine implanted with a heterotopic mechanical heart valve. Compared with warfarin, swine in the apixaban groups showed no evidence of bleeding complications. • Apixaban is a promising candidate and may be a useful alternative to warfarin for thromboprophylaxis of mechanical heart valves. • Human plasma concentrations from apixaban clinical trials were used to develop a novel targeted infusion model for swine based on comparable pharmacokinetic parameters. Additional dose-response studies are warranted to fully elucidate the thromboprophylaxis efficacy of apixaban.