Abstract

The use of vitamin K antagonists in the prevention of arterial thrombosis is hampered by many limitations, such as a narrow therapeutic window, frequent monitoring and drug and food interactions. Dabigatran is a potent, direct thrombin inhibitor that effectively inhibits venous thrombosis in several animal models. It can be given orally as the prodrug, dabigatran etexilate, and is rapidly converted by ubiquitous esterases to the active principle dabigatran during absorption. It has no drug-drug or food interaction potential and therefore does not need monitoring.

The objective of this study was to investigate the antithrombotic and anticoagulant effects of dabigatran in an arterial thrombosis model that measures cyclic flow (Folt’s model) in injured arteries of pigs.

Domestic pigs (15–18g) were anesthetized, ventilated and monitored during the entire procedure (n=4–6 /treatment group). Acute compression damage and stenosis of the right carotid artery resulted in thrombus formation as measured using a Doppler flow probe. Mechanical embolization of the clot restored flow through the vessel until a new thrombus reoccluded the vessel a few min later. Subsequent thrombosis and embolization created a reproducible pattern of flow reduction in the vessel. Dabigatran was given i.v. in doses of 0.1–3 mg/kg either before injury (prevention) or after injury (treatment) was induced. The frequency of recurrent thrombosis was measured in 20 min intervals over the first hour and in 30 min intervals over the 2nd hr post-injury. Antithrombotic effectiveness was measured as the reduction in closure frequency during each interval. Anticoagulant effects were monitored as the aPTT.

In placebo-treated animals there were ~10 closures per interval (9.81± 0.92) after injury. When dabigatran was given prior to vessel damage, there was a dose-dependent inhibition of cyclic closure, 94% with 1 mg/kg i.v. in the first 20 min interval. There was still a 66% reduction in cyclic closures in the final 30 min interval 1.5–2 hrs after injury. Baseline aPTT values of 14.7 ± 0.5 s were elevated in a dose-dependent manner to peak levels of 31.7, 42.7 and 71.8 s 5 min after dosing with 0.1, 0.3 and 1.0 mg/kg, respectively.

Dosing dabigatran post-vessel injury also resulted in a dose-dependent inhibition of cyclic closure. In placebo-treated animals there were a constant ~15 closures per interval (15.2 ± 0.3). There was a dose-dependent inhibition in the frequency of arterial closure, with an 84% reduction in the first 20 min after an i.v. dose of 3 mg/kg. Interestingly, the reduction in cyclic closure frequency was maintained over the entire 2 hr period after a single bolus dose and between 90–120 min post dosing, cyclic closure was also inhibited by 84% with the 3 mg/kg dose. These antithrombotic effects were associated with a dose-dependent elevation in the aPTT from 14.2 s with placebo, to a 5 min peak level of 29.2, 60.7 and 218.1 s, respectively with 0.1, 1 and 3 mg/kg.

These results indicate that dabigatran is effective in the prevention and treatment of arterial thrombosis in this model. A single bolus dose administered just after injury was sufficient to dampen the thrombogenic response of the damaged arterial wall for up to 2 hrs post injury, illustrating the potential benefit from inhibition of clot-bound thrombin. Thus dabigatran may be an effective alternative to current anticoagulant therapy in arterial indications.

Disclosures: All authors are or were employees of Boehringer Ingelheim when the study was performed.

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