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NEUROCRITICAL CARE PHARMACY Idarucizumab for Rapid Reversal of Dabigatran Anticoagulation By Kent Owusu, PharmD, BCPS and David Reardon, PharmD, BCPS The vitamin K antagonist (VKA) warfarin In patients receiving dabigatran, idarucizumab (Praxbind®) has been the standard oral anticoagulant has been shown to be effective at complete, immediate, and (OAC) for several decades, but recently sustained reversal of the anticoagulant effects. Idarucizumab is the availability of target-specific oral a monoclonal antibody fragment (Fab) that was approved by anticoagulants (TSOACs) has provided the FDA in October 2015 for reversal of the anticoagulant effects alternative options for patients for whom of dabigatran in patients who need emergency surgery/urgent VKA may not be a viable option. High intra- procedures and in life-threatening or uncontrolled bleeding. patient pharmacodynamic variability due The monoclonal antibody binds both free and thrombin-bound to drug-drug and drug-food interactions, dabigatran with an affinity 350 times higher than dabigatran’s Kent Owusu, variability in dose response, delayed onset affinity for thrombin. This binding effectively neutralizes and offset of action, narrow therapeutic dabigatran from circulation and inhibits its ability to act as an PharmD, BCPS window, and requirement of frequent anticoagulant. monitoring of INR with subsequent dose adjustments present challenges with Pollack and colleagues evaluated the clinical efficacy of the use of VKA therapy. The predictable idarucizumab in a prospective cohort study of 90 patients pharmacokinetics and wide therapeutic who were receiving dabigatran, 51 of whom had a serious window highlight the TSOACs as attractive bleeding event and 39 of whom required an urgent procedure. alternatives. Idarucizumab 5 g, based on dabigatran levels in patients in the 99th percentile in the Randomized Evaluation of Long-Term The lack of a reversal agent for the TSOACs in Anticoagulation Therapy trial, was administered as two 2.5 g the setting of serious bleeding or in the event infusions no more than 15 minutes apart. The primary endpoint of necessary surgical intervention has raised was the maximum percentage reversal within four hours of David Reardon, concerns about prescribing the TSOACs. idarucizumab administration based on the dTT and ECT. The PharmD, BCPS While the reported risk of intracranial secondary endpoint evaluated restoration of hemostasis. hemorrhage with the TSOACs is generally lower than VKA, bleeding remains a clinically relevant side In patients with an elevated dTT or ECT at baseline, the maximum effect. Until recently, management of bleeding in TSOAC-treated percentage reversal with idarucizumab was 100%. In patients patients consisted primarily of supportive care, administration of who presented with serious bleeding and could be assessed, coagulation factors, dialysis, and surgical intervention. Dabigran hemostasis was restored at a median of 11.4 hours. Normal etexilate (DE) (Pradaxa®) is currently the only TSOAC with a intraoperative hemostasis was reported in 33 of the evaluable reversal agent commercially available. 36 patients requiring an urgent procedure. Mildly abnormal hemostasis was reported in two patients and moderately abnormal DE is currently approved by the U.S. FDA for prevention hemostasis in one patient. The authors of the study concluded and treatment of venous thromboembolism, prevention of that idarucizumab completely reversed the anticoagulant effects of postoperative deep vein thrombosis after hip repair, and for dabigatran within minutes of administration. the prevention of stroke in patients with non-valvular atrial fibrillation. Upon in vivo bioactivation to active dabigatran, DE is Due to the short half-life of dabigatran, clinical assessment a specific, reversible, direct thrombin inhibitor that inhibits both of the patient is required to determine appropriate care. If a free and fibrin-bound thrombin. patient presents with non-life-threatening hemorrhage or is in need of non-urgent surgery, discontinuation of dabigatran and In comparative studies in patients with well managed VKA (target administration of appropriate supportive care is usually sufficient. INR 2-3; median time in therapeutic range 64%), DE showed In cases of life-threatening bleeding or in patients where surgery a decrease in the rate of stroke or systemic embolism by 34% cannot be delayed more than eight hours, the administration of and intracranial hemorrhage by 60%. A recent publication on idarucizumab is clinically indicated. national trends in oral anticoagulant use in the U.S. reported a 17% rate of DE prescribing for patients with non-valvular atrial Clinicians must also realize the importance of supportive care, fibrillation. With this level of DE prescribing, the introduction of even in the setting of idarucizumab administration. Reversal of a reversal agent is very timely. the anticoagulant effect of dabigatran happens within minutes of idarucizumab administration but does not necessarily correlate Unlike patients treated with VKA, the INR is relatively insensitive with restoration of hemostasis which may take several hours. to dabigatran-induced anticoagulation. The ecarin clotting time Patients should be managed appropriately for any ongoing (ECT) provides a quantitative dose response to dabigatran and bleeding according to local or institutional guidelines. the activated partial thromboplastin time (aPTT) provides an estimate of effect. ECT is currently not commercially available in Kent Owusu, PharmD and David Reardon, PharmD are clinical the U.S. and aPTT only provides an approximate assessment of pharmacists at Yale-New Haven Hospital and members of the NCS dabigatran effect. Pharmacy Committee. They are invited guest writers for Currents. Owing to the mechanism of action of dabigatran, the thrombin time (TT) appeared to be a reasonable assessment although coagulation assessments have shown the TT to be too sensitive to give interpretable information. The development of the diluted thrombin time (dTT) therefore provides a viable option for coagulation assessment of dabigatran, although there are no reported cut-offs for which surgical intervention may be safely performed. 22


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