The new oral anticoagulants (NOAC’s) either directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban and edoxaban). These direct oral anticoagulants have several advantages over vitamin K antagonists; they have a wider therapeutic window, quick onset of action, do not require regular blood coagulation monitoring, and have a shorter half lives. Warfarin (vitamin K antagonist) demands constant monitoring of the international normalized ratio (INR) that in turn compels dose adjustment. The new oral anticoagulants have proven to be viable alternatives to a vitamin K antagonist in industry sponsored randomized trials involving thousands of patients. The NOAC’s when compared to warfarin providing good anticoagulation (INR between 2and 3, 60% of the time) were found to be non-inferior and in some cases superior in patients with non-valvular atrial fibrillation. Intracranial and fatal bleeds were lowered by 50% with the NOAC’s and major bleeding by 28% as compared to warfarin.
Clinicians however have been diffident administering NOAC’s because of no reliable anti-dote in the event of a bleed. Bleeding on warfarin is managed by stopping it, or if need be injecting vitamin K. Fresh frozen plasma and prothrombin complex too may be used to reverse bleeds with warfarin, but almost 10% such patients hospitalized die within 3 months. Death can be as high as 50% in the event of intracranial hemorrhage.
Now for the first time, the New England Journal of Medicine has published a pilot trial (REVERSE-AD) of 90 patients (on dabigatran) given 5 grams of an intravenous monoclonal antibody to reverse serious bleeding or the need for emergency surgery. The monoclonal antibody administered in the observational study has been given the tongue-twisting name of idarucizumab. The multicenter observational trial analyzed a single 5-g dose of idarucizumab in patients on dabigatran needing reversal. More than 90% of patients achieved normal hemostasis with idarucuzimab. The development of an antidote capable of effectively neutralizing the anticoagulant effect of dabigatran is a welcome advancement in the management of patients of atrial fibrillation. The idarucuzimab trial tried to determine the safety and efficacy of 5 g the intravenous drug while reversing the anticoagulant effects of dabigatran in patients who had serious bleeds or needed an urgent procedure. The effect of neutralizing effect was observed in minutes. There is also obviously great need for an antidote for the direct Xa inhibitors.
Idarucizumab binds dabigatran with an affinity that is 350 times as high as that seen with thrombin. The monoclonal antibody is injected intravenously as two 50-ml bolus infusions, each containing 2.5 g of idarucuzimab, less than 15 minutes apart.
Dabigatran is used to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation; for treatment of deep vein thrombosis and pulmonary embolism in patients who have been treated with parenteral anticoagulants for 5-10 days; to reduce risk of recurrence of deep vein thrombosis and pulmonary embolism in patients previously treated.
Idarucizumab is yet to be made available in India. Boehringer Ingelheim has applied for marketing of idarucizumab for rapid reversal of dabigatran (Pradaxa) bleeds to the European Medicines Agency, and the US FDA