DVT and stroke prevention - dabigatran etexilate
The protease thrombin regulates fibrin clot formation and induces platelet activation and aggregation. It is an excellent target for both antithrombotic and anticoagulant drugs. It can be inhibited either directly or indirectly via the suppression of precursor proteins, but this can cause bleeding and dosage variability between patients.
The protease thrombin regulates fibrin clot formation and induces platelet activation and aggregation. It is an excellent target for both antithrombotic and anticoagulant drugs. It can be inhibited either directly or indirectly via the suppression of precursor proteins, but this can cause bleeding and dosage variability between patients.
A new direct thrombin inhibitor, dabigatran, is being developed by Boehringer Ingelheim, along with the double prodrug derivative dabigatran etexilate.1 The latter was given to 289 patients in a multicentre open label dose escalating study after hip replacement surgery.2 They were given oral doses ranging from 12.5 to 300mg twice a day, or 150 or 300mg once a day for six to 10 days. Some minor dose-related bleeding was seen, and the likelihood of developing DVT, with an overall incidence of 12%, was not related to the dose administered.
Its safety and efficacy were compared with enoxaparin in nearly 2,000 patients undergoing knee or hip replacement.3 Subjects were given 50, 150 or 225mg of dabigatran etexilate orally twice a day, or 300mg once a day, for six to 10 days, starting one to four hours after surgery, or 40mg subcutaneous doses of enoxaparin once a day, starting 12 hours before surgery. Those given 50mg doses had a significantly lower incidence of major bleeding than those on enoxaparin - 0.3% compared with 2%. Those given the higher dose once a day, however, had a bleeding rate of nearly 5%. Venous thromboembolism rates were also lower in those given dabigatran etexilate.
It has also been investigated in patients with atrial fibrillation on stable warfarin who also had other risk factors for developing thromboembolism.4 In the randomised dose finding trial, patients were given 50, 150 or 300mg dabigatran etexilate twice a day for 12 weeks, either in combination with or without aspirin or warfarin. The 150mg dose had the same anticoagulant effect as the higher dose with warfarin. Doses of 200-300mg a day were therefore recommended for use in Phase III trials.