New anticoagulants have many advantages over warfarin, but as yet there are no specific antidotes to counteract their blood-thinning effects
For many years, the only anticoagulant drug that was orally available was the vitamin K antagonist warfarin. However, the landscape has changed dramatically in recent years, with a variety of oral anticoagulants reaching the market, including the direct thrombin inhibitor dabigatran etexilate, and the direct factor Xa inhibitors apixaban and rivaroxaban.
These drugs have many advantages over warfarin, not least that their pharmacokinetics are much more predictable than they are for the notoriously difficult warfarin, and routine coagulation monitoring is not required.
However, if a patient experiences a life-threatening haemorrhagic event or has non-elective major surgery while taking one of these drugs, they are put at additional risk because of the blood-thinning properties of the drug. Whereas a dose of vitamin K is sufficient to reverse the effects of warfarin, there are no easy antidotes to the new breed of drugs. Therefore several specific antidotes are under development, including idarucizumab.
Idarucizumab is a humanised antibody fragment being developed by Boehringer Ingelheim to reverse the effects of its anticoagulant drug dabigatran etexilate. Rather than having activity at a target within the body, idarucizumab specifically binds to and inhibits dabigatran, thus preventing its thrombin inhibition activity.1
Unusually, the company has submitted the drug for approval on the strength of Phase I results. A study in healthy volunteers first looked at the ability of dabigatran to inhibit fibrin formation in blood at a non-penetrating wound by measuring the amount of fibrinopeptide A (FPA) that was produced.2 They then tested whether idarucizumab was able to restore fibrin formation at the site of the wound.
Subjects were given 220mg doses of dabigatran etexilate for four days, with FPA levels assessed before treatment started, and on both the third and fourth days at 2.5 and 6 hours after the morning dose. On the fourth day, the volunteers were given 1, 2 or 4g of idarucizumab via infusion or placebo two hours after the morning dose, and incisions made in the forearm with a scalpel. Blood was collected from the wound, and FPA levels, ecarin clotting time (ECT) and diluted thrombin time (dTT) measured.
Both the antibody fragment and the drug were well tolerated, and dabigatran caused almost complete inhibition of FPA. Fibrin formation returned in a significant and dose-dependent manner with increasing doses of idaracizumab to 24, 45 and 63% of pre-dabigatran levels respectively. Anticoagulation, as measured by ECT and dTT, was significantly prolonged by dabigatran, but this returned to the levels seen in the control after both 2g and 4g doses of idaracizumab. No clinically relevant side-effects were observed.
A Phase III trial is now under way to investigate its effectiveness in clinical settings. It will look at the effects of idaracizumab in patients being treated with dabigatran etexilate who are in need of emergency surgery, or who have an uncontrolled or life-threatening bleeding event.
1. M. Honickel et al. Thromb. Haemost. 2015, 113, epub ahead of print
2. J. van Ryn et al. Amer. Heart Assn Sci. Sessions 2014 (Chicago, 15-19 November), Abst. 33249