title: Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits.
abstract: BACKGROUND
  Optimal treatment of arterial thrombosis may include a combination of antiplatelet and anticoagulant drugs. We evaluated apixaban, a direct and highly selective factor Xa inhibitor, in combination with clinically relevant doses of aspirin and/or clopidogrel for prevention of arterial thrombosis in rabbits.
  
  
  METHODS
  Studies were conducted in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time (BT). Apixaban 0.04 and 0.3 mg kg(-1) h(-1) or aspirin 1 mg kg(-1) h(-1) was infused intravenous (i.v.) continuously from 1 h before artery injury or cuticle bleed until the end of the experiment. Clopidogrel at 3 mg kg(-1) was dosed orally once daily for three days, with the last dose given 2 h before injury.
  
  
  RESULTS
  Control thrombus weight and BT averaged 8.6 +/- 0.9 mg and 181 +/- 12 s, respectively (n = 6 per group). Effective doses of apixaban that reduced thrombus weight by 20 and 50% (ED(20) and ED(50)) were 0.04 and 0.3 mg kg(-1) h(-1) i.v., respectively. Addition of aspirin to apixaban ED(20) and ED(50) significantly reduced the thrombus weight from 7.4 +/- 0.5 to 5.3 +/- 0.3 and 3.6 +/- 0.3 mg, respectively, with no significant increases in BT (190 +/- 7 s vs.181 +/- 9 and 225 +/- 11 s, respectively). Addition of aspirin and apixaban (ED(20) dose) to clopidogrel produced a further significant reduction in thrombus weight from 5.3 +/- 0.3 to 0.7 +/- 0.1 mg. This combination of clopidogrel and aspirin with apixaban (ED(20) dose) produced a significant but moderate BT increase of 2.1 times control.
  
  
  CONCLUSIONS
  The combination of apixaban and aspirin or apixaban, aspirin and clopidogrel can reduce formation of occlusive arterial thrombosis without excessive increases in BT in rabbits.
authors.affiliation: Thrombosis Research, Bristol-Myers Squibb Company, Pennington, NJ 08534, USA. pancras.wong@bms.com
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: C A
authors.initials: CA
authors.lastname: Watson
authors.forename: E J
authors.initials: EJ
authors.lastname: Crain
mesh_terms: D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D000077144:Clopidogrel; D004359:Drug Therapy, Combination; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin