XXXIII Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia

XXXIII Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia 28 first cohort, and haemostasis during the procedure for the second cohort. In an interim analysis of the first 90 patients enrolled in the study (51 in the first cohort and 39 in the second cohort) (20), the median maximum percentage reversal of anticoagulant activity was 100% and, after the target dose was administered, complete reversal was evident at 4 hours. At 12 hours and 24 hours, the dilute thrombin time was below the upper limit of the normal in 90% of patients with bleeding who could be evaluated and 81% of those who underwent urgent procedures. The median reported time to cessation of bleed- ing among patients who required reversal because of major bleeding was 11.4 hours. Among patients who underwent a procedure, nor- mal intraoperative haemostasis was reported in 92%, and mildly or moderately abnormal haemostasis was reported in 5.5% and 2.8% of patients, respectively. Thrombotic events occurred in five patients, one within 72 hours of idarucizumab administration and 4 later. None was receiving antithrombotic therapy when these events occurred. No serious adverse reactions were seen in these studies, nor were anti- drug antibodies detected. Andexanet alfa Andexanet alfa is a recombinant modified human factor Xa vari- ant (21). It acts as a decoy for the oral factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, but also low molecular weight heparins and fondaparinux), thus binds and sequestering them within the vascular space and restoring factor Xa activity (22). Andexanet alfa has half- life of approximately 1 hour. In studies conducted in volunteers, an intravenous andexanet bolus of 400 mg rapidly, but transiently, reversed 94% of the anti-fac- tor Xa activity of apixaban and 800 mg reversed 92% of rivaroxaban (23). Lower doses of andexanet were needed to reverse apixaban than rivaroxaban because drug concentrations are lower with twice daily dosing. The administration of a bolus followed by a 2-hour intrave- nous infusion of andexanet at a dose of 4 and 8 mg/min for apixaban and rivaroxaban, respectively, resulted in a more sustained reversal (23). No serious adverse events or thrombotic events were observed. The efficacy and safety of andexanet alfa is currently assessed by an ongoing phase III prospective cohort study. In this study, patients with major bleeding within 18 hours after the administration of a fac- tor Xa inhibitor receive a bolus of andexanet alfa followed by a 2-hour infusion of the drug. The doses used in the study are a bolus of 400 mg and an infusion of 480 mg in patients who had taken apixaban or rivaroxaban more than 7 hours before the administration of andexanet alfa; a bolus of 800mg and an infusion of 960mg for patients who had taken enoxaparin, edoxaban, or rivaroxaban 7 hours or less before the administration of andexanet alfa. The two primary outcomes of this study are the percent change in the anti-factor Xa activity and the rate of excellent or good hemostatic efficacy 12 hours after the infusion of andexanet alfa (24). A preliminary report of the first 67 patients, in most cases with gastrointestinal or intracranial bleeding, was recent- ly published (24). After the administration of the bolus, the median anti-factor Xa activity was decreased by 89% in patients treated with rivaroxaban and by 93% in patients receiving apixaban. The effect was sustained during the infusion, while a relative decrease frombase- line of 39% in patients treated with rivaroxaban and 30% in patients receiving apixaban was detected 4 hours after the end of the infusion. Clinical haemostasis 12 hours after the infusion was excellent or good in 37 of 47 patients in the efficacy population and thrombotic events occurred in 12 of 67 patients during the 30-day follow-up. Ciraparantag Ciraparantag is a small, synthetic, positively charged molecule that binds to unfractionated heparin, low molecular weight hepa- rin, rivaroxaban, apixaban, edoxaban, and dabigatran via hydrogen bonds (25). In healthy volunteers treated with edoxaban, an intrave- nous bolus of ciraparantag shortened the whole blood clotting time to within 10% of baseline in a dose-dependent manner (26). In another study, ciraparantag completely reversed the whole blood clotting time induced by enoxaparin in a dose relatedmanner (27). No procoagulant or side effects were detected in doses up to 300 mg.Additional studies in healthy volunteers are underway. Indications for the administration of reversal agents and recommendations from the anticoagulation education task force The management of anticoagulant-associated bleeding depends on the severity of bleeding and is firstly based on general measures, which include fluid resuscitation, red blood cell transfusion and, most importantly, the diagnosis and treatment of the bleeding site. The reversibility of the anticoagulant drug with blood products and drug-specific reversal agents, when available, represent important, additional specific interventions. To optimize the use of reversal strategies in each hospital, the implementation of local protocols that include all necessary actions and define the role of all specialists to be involved is required. To provide some guidance on how to develop such protocols, we recently organized a meeting aimed at discussing the current status of anticoagulation reversal and the possible changes in the manage- ment of bleeding associated with DOACs. At this meeting, different medical professional societies, patient groups, and healthcare provid- ers were invited. This task force produced a white paper containing some recommendations on who qualifies for treatment with a reversal agent and how to manage access to these agents (28). In particu- lar, we recommended the development of local protocols to identify key stakeholders involved in anticoagulant reversal; define logistic matters, such as drug storage; and define which patients should be candidate to receive reversal agents (28). It was suggested that a mul- tidisciplinary team should be nominated, with the inclusion of experts in emergency care and bleeding management, as well as pharmacists and administrators and that some clear guidance to which situations warrant prompt use of reversal agents should also be given. The task force approved the guidance document produced by the Internation- al Society on Thrombosis and Haemostasis, which recommended the use of reversal agents in patients with life-threatening bleeding; bleeding in a closed space or critical organ; persistent major bleeding despite local measures or risk of recurrent bleeding because of delayed DOAC clearance or DOAC overdose; need for urgent intervention that is associated with high risk of bleeding; and emergency surgery or intervention in patients at high risk for bleeding (29). Finally, it was suggested that education of patients about DOACs by healthcare pro-