title: Apixaban Versus Warfarin for Mechanical Heart Valve Thromboprophylaxis in a Swine Aortic Heterotopic Valve Model.
abstract: 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 to 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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lester
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Coleman
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Diaz
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Tatum O
authors.initials: TO
authors.lastname: Jackson
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Hawley
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Mathues
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Grant
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ramacciotti
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Frost
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Wakefield
authors.affiliation: From the Unit for Laboratory Animal Medicine (P.A.L., D.D.M.) and Conrad Jobst Vascular Research Laboratories (P.A.L., D.M.C., J.A.D., T.O.J., A.E.H., A.R.M., B.T.G., T.W.W., D.D.M.), University of Michigan, Ann Arbor; and Global Clinical Research, Research & Development (R.M.K., E.R.) and Exploratory Clinical and Translational Research (C.E.F., Y.S.), Bristol-Myers Squibb Company, Princeton, NJ. ddmyers@med.umich.edu.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Myers
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001021:Aortic Valve / Q000601:surgery*; D001777:Blood Coagulation / Q000187:drug effects*; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation / Q000009:adverse effects* / Q000295:instrumentation*; D006470:Hemorrhage / Q000139:chemically induced; D019934:International Normalized Ratio; D023421:Models, Animal; D011474:Prosthesis Design; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D034421:Sus scrofa; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D014859:Warfarin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin
keywords: anticoagulant; aortic valve; atrial fibrillation; embolism; pharmacokinetics