Agent now available for reversing new oral anticoagulant in bleeding patients
The new oral anticoagulants (NOACs) are skyrocketing in popularity, displacing warfarin as first-line anticoagulants for many patients. Dabigatran is a direct thrombin inhibitor used for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism. Dabigatran and other NOACs have several advantages over warfarin. Their pharmacokinetics are simpler, they don't have the pesky food and drug interactions that plague warfarin, they don't require monitoring and frequent dose adjustments, and importantly, they carry a lower risk of major bleeding complications.
However, a major concern is that unlike warfarin, which can be reversed with Prothrombin Complex Concentrates (PCC) or fresh frozen plasma and vitamin K, dabigatran and the other NOACs lacked a dedicated reversal agent. This made emergency physicians and others who anticipate worst-case scenarios somewhat nervous. Although the NOACs are associated with fewer serious bleeding complications than warfarin, life-threatening bleeding can still occur. How should we manage the patient on dabigatran with an intracranial hemorrhage? Or the trauma patient who requires emergent surgery for their liver laceration who happens to be on dabigatran? Alternative reversal methods have been proposed, such as use of three- or four-factor PCC, fresh frozen plasma, or even emergent hemodialysis to remove circulating anticoagulant. However, the efficacy of these methods has been questioned, and safety concerns have been raised regarding thrombotic risk of PCC.
In October 2015 the U.S FDA approved a target-specific reversal agent for dabigatran. Idarucizumab, marketed as Praxbind, is a monoclonal antibody fragment (Fab) that binds directly to dabigatran, neutralizing its activity. It is approved for reversal of anticoagulation in patients on dabigatran requiring emergent or urgent surgery or in patients with life-threatening bleeding. Dabigatran inhibits thrombin, which catalyzes one of the final steps in the clotting cascade. Idarucizumab reverses dabigatran's anticoagulant effects by binding tightly to dabigatran with an affinity 350 times greater than thrombin, thus freeing thrombin's functionality in the clotting cascade.
Studies show that administration of idarucizumab to healthy young volunteers, older volunteers ages 65-80, and volunteers ages 45-80 with mild or moderate renal impairment resulted in complete reversal of dabigatran's anticoagulant effects within minutes without any procoagulant effects. This reversal of anticoagulation lasts 24 hours, which is an advantage over PCC, which has more transient effects. One important caveat is that there must be dabigatran in the bloodstream for idarucizumab to have any effect. Once the dabigatran is cleared by the kidney, idarucizumab will have nothing to bind to and will have no effect. It is recommended to give it if the last dose of dabigatran was in the last 24-48 hours. There may be some benefit of longer time frames in patients with renal failure, who will have a slower clearance rate of the dabigatran. Finally, since it is a monoclonal antibody, it is highly specific for dabigatran. It will not reverse the anticoagulant effects of coumadin, plavix, or other NOACs such as rivaroxaban.
The data on idarucizumab in patients who are actually bleeding or being operated on looks favorable as well. The Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) trial, a large international prospective cohort study of patients on dabigatran who receive idarucizumab either for serious bleeding or prior to an urgent surgical procedure, is still ongoing. A preliminary analysis of the first 90 patients revealed that idarucizumab rapidly and completely restored coagulation parameters in 88-98% of patients who had elevated clotting times at baseline. Among patients who underwent surgery, normal hemostasis was reported in 92%, with mild to moderate impairment in 8%. Only one of 90 patients (1%) had a thrombotic event within 72 hours of administration of idarucizumab. These data mirror the safety and efficacy data on idarucizumab from earlier human and animal studies.
The FDA-approved dose for idarucizumab is 5 mg, which is administered as two separate 2.5 mg IV doses infused over 5 minutes. The second dose should be administered within 15 minutes of the first infusion. There is no dosing change needed for renal or hepatic impairment.
Adverse reactions are rare and include headache (5%) and hypokalemia (7%). There are case reports of serious complications in patients receiving idarucizumab, including acute ischemic stroke, cardiac arrest, NSTEMI, DVT, and PE, but the incidence is thought to be extremely low.
Contraindications include hypersensitivity to idarucizumab or any components of the formulation. Risks/benefits of anticoagulation should be considered before reversing anticoagulation with idarucizumab, since the underlying disease state may predispose to thrombotic events. However, since it is typically reserved for life-threatening bleeds, the scale typically would favor its use. Cost is also a consideration. Not all emergency departments may be able to stock idarucizumab due to the infrequent need for it and its cost.
There are no studies of human or animal models of pregnancy. It is unknown if idarucizumab is excreted in breast milk.
A single 2.5 mg/50 mL dose of idarucizumab costs $2,100, so recommended treatment with two doses costs $4,200. This is slightly cheaper than four-factor PCC, which costs about $5,000 for an 80 kg patient.
Karen Serrano, MD, and Christina Shenvi, MD, are assistant professors of emergency medicine at the University of North Carolina. Shenvi authors RX Pad each month in EPM. A version of this article originally appeared at Emergency Physicians Monthly.
New England Journal of MedicineSource Reference: Connolly SJ, et al. "Dabigatran versus warfarin in patients with atrial fibrillation" N Engl J Med 2009; DOI: 10.1056/NEJMoa0905561
Emergency Medicine JournalSource Reference: Alikhan R, et al. "The acute management of hemorrhage, surgery and overdose in patients receiving dabigatran" Emerg Med J 2014; DOI: 10.1136/emermed-2012-201976.
AnesthesiologySource Reference: Honickel M, et al. "Prothrombin complex concentrate is effective in treating the anticoagulant effects of dabigatran in a porcine polytrauma model" Anesthesiology 2015; DOI: 10.1097/ALN.0000000000000863