Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits.
BACKGROUND
Apixaban is an oral, direct factor Xa (FXa) inhibitor in late-stage clinical development. This study assessed effects of the direct FXa inhibitors, apixaban and rivaroxaban, vs. the direct thrombin inhibitor, dabigatran, on venous thrombosis (VT), bleeding time (BT) and clotting times in rabbits.


METHODS
We induced the formation of non-occlusive thrombus in VT models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban and dabigatran were infused IV to achieve a stable plasma level. Clotting times, including the activated partial thromboplastin time (aPTT), prothrombin time (PT), modified PT (mPT) and thrombin time (TT), were measured.


RESULTS
Apixaban, rivaroxaban and dabigatran exhibited dose-related efficacy in preventing VT with EC(50) of 65, 33 and 194 nm, respectively. At doses for 80% reduction of control thrombus, apixaban, rivaroxaban and dabigatran prolonged BT by 1.13 +/- 0.02-, 1.9 +/- 0.1-* and 4.4 +/- 0.4-fold*, respectively (*P < 0.05, vs. apixaban). In the treatment model, these inhibitors equally prevented growth of a preformed thrombus. Antithrombotic doses of apixaban and rivaroxaban prolonged aPTT and PT by <3-fold with no effect on TT. Dabigatran was > or = 50-fold more potent in prolonging TT than aPTT and PT. Of the clotting assays studied, apixaban, rivaroxaban and dabigatran responded the best to mPT.


CONCLUSIONS
Comparable antithrombotic efficacy was observed between apixaban, rivaroxaban and dabigatran in the prevention and treatment of VT in rabbits. Apixaban and rivaroxaban exhibited lower BT compared with dabigatran at equivalent antithrombotic doses. The clinical significance of these findings remains to be determined.
Wong
P C
PC
Thrombosis Research, Bristol-Myers Squibb Company, Pennington, NJ 08534, USA. pancras.wong@bms.com
Crain
E J
EJ
Watson
C A
CA
Xin
B
B
D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006470:Hemorrhage; D009025:Morpholines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011728:Pyridones / Q000627:therapeutic use; D011817:Rabbits; D000069552:Rivaroxaban; D013876:Thiophenes / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*; D020246:Venous Thrombosis / Q000188:drug therapy*
D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D011720:Pyrazoles; D011725:Pyridines; D011728:Pyridones; D013876:Thiophenes; C522181:apixaban; D000069552:Rivaroxaban; D013917:Thrombin; D000069604:Dabigatran