Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

Abstract

To cite this article: Wong PC, Watson CA, Crain EJ. Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008; 6: 1736-41.Summary. 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 kgwas 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.

Inhibition of Factor XIa Reduces the Frequency of Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

“…In addition, our current data appear to be more sensitive in prolongation of bleeding time in response to 3 mg/kg/h apixaban treatment (i.e., 993 6 141 seconds; Fig. 5) versus that of previously reported at ∼300 seconds for 2.1 mg/kg/h apixaban (Wong et al, 2008b). The reason for this difference is unknown.…”

“…Integrated carotid blood flow over 60 minutes was measured by area under the curve (AUC), calculated by the trapezoidal rule, and expressed as the percentage of control blood flow as described previously elsewhere (Wong et al, 2008b). At end of study (i.e., 60 minutes after FeCl 3 injury), the wet thrombus weight was measured using a balance with a detection limit of 0.001 mg (Mettler Toledo Excellence Plus XP Series Analytical Balances; MettlerToledo, Columbus, OH).…”

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

“…Since rabbit platelets appear to be resistant to aspirin, the rabbit model might not be the best one to assess efficacy and/or safety for the aspirin and apixaban drug combination. In contrast to aspirin, the ED 50 value for clopidogrel on arterial thrombosis appeared to be more potent (about 3-fold) than those from a rabbit model of electrically induced carotid artery thrombosis (ED 50 5 0.8 mg/kg/d, PO) (Wong et al, 2008b).…”

“…The carotid blood flow was monitored for 60 minutes from the application of FeCl 3 (as time zero). Integrated carotid blood flow over 60 minutes was measured by area under the curve (AUC) calculated by the trapezoidal rule, and expressed as percent of control blood flow as described previously (Wong et al, 2008b). At the end of study (i.e., 60 minutes after FeCl 3 injury), a section of vessel at the injury site (∼20 mm long) was cut and the thrombus was pushed out using a blunt forceps to a parafilm with a drop of saline.…”

Novel Oral Anticoagulants

“…Apixaban in combination with acetylsalicylic acid or acetylsalicylic acid plus clopidogrel demonstrated enhanced antithrombotic efficacy without excessive increases in bleeding time and will be investigated further in clinical trials. 76 Preliminary in vitro studies indicate that metabolic drug-drug interaction potential between apixaban and coadministered cytochrome P450 substrates or inhibitors is minimal, indicating that dose adjustments may not be required. 77 Although routine monitoring is not required, there are limited data available regarding effective methods of monitoring the effect of apixaban should this be required.…”