Authors: Pollack CV Jr et al., N Engl J Med 2015 Jun 22
Idarucizumab immediately reversed dabigatran-induced increases in clotting variables without causing serious adverse events.
Dabigatran is a direct thrombin inhibitor that is approved for the prevention of stroke in atrial fibrillation and for the treatment of venous thromboembolism. Bleeding is usually managed by discontinuing the drug or, if severe, by giving a prothrombin complex concentrate. However, a specific antidote would be required if more urgent reversal of the drug were needed.
Now, researchers have developed a monoclonal antibody fragment, idarucizumab, which tightly binds to dabigatran and nullifies its anticoagulant activity. The agent has now been evaluated in two studies: a randomized, placebo-controlled, double-blind, proof-of-concept phase 1 study in healthy male volunteers, and a prospective cohort trial in patients requiring urgent reversal because of bleeding or need for a surgical procedure.
In the first study, conducted by the drug manufacturer, participants were given dabigatran for 4 days and then intravenous doses of idarucizumab, ranging from 1 to 5 g. Coagulation variables (thrombin times, ecarin clotting time, activated clotting time, and partial thromboplastin time) were all prolonged on day 3 of dabigatran dosing, and mild bleeding was observed in four participants (3 with hematuria and 1 with epistaxis). Infusion of idarucizumab resulted in an immediate and complete reversal of the dabigatran-induced increases in clotting tests, which was maintained for at least 72 hours with all but the 1 g dose of idarucizumab. The antidote was well-tolerated; no serious or severe adverse events were observed.
The second study included 90 patients who were being treated with dabigatran, 51 with bleeding (intracranial, 18; gastrointestinal, 20), and 39 requiring urgent interventions. The median time since the last dose of dabigatran was 15.4 hours, and the dose of idarucizumab used for reversal was 5 g. After infusion of the antidote, the dilute thrombin time was normalized in more than 90% of patients, and the concentration of unbound dabigatran was <20 ng/mL at 24 hours in 79%. In the patients with hemorrhage, the median time for bleeding cessation was 11.4 hours, and in those undergoing surgery, normal intraoperative hemostasis was reported in 92%. In the 72 hours following administration of idarucizumab, only one patient had a thrombotic event.
The safety and specificity of idarucizumab in reversing the anticoagulant effects of dabigatran are well documented in these studies of healthy volunteers, bleeding patients, and those undergoing surgery. The introduction of this and other antidotes to the new oral anticoagulants is an important step in the development of these agents, and it raises the question of whether every patient starting on one of these drugs should receive a vial containing the specific antidote in case bleeding occurs and the reversal agent might not be immediately available.