XXXIII Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia

Ponencias 27 Introduction Four direct oral anticoagulants (DOACs) are currently approved for clinical use in different indications including venous thromboem- bolism (VTE) prevention in patients undergoing major orthopedic surgery; acute phase treatment and secondary prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE); stroke prevention in patients with non-valvular atrial fibrillation (SPAF); and the treat- ment of acute coronary syndromes. The uptake of the DOACs in clin- ical practice has been particularly fast, especially in some countries where these agents are now more prescribed than vitamin K antago- nists (VKAs), in particular for SPAF and for the treatment of DVT. The DOACs have clear practical advantages over VKAs, including the administration in fixed dose regimens without the need for routine laboratory monitoring, the reduced number of drug-drug interactions and the limited food-drug interactions, and their fast onset and offset of action. In addition, the DOACs have gained a great interest among physicians and also patients thanks to the results of phase III ran- domized clinical trials consistently showing a favorable safety profile both in SPAF, with a 52% lower risk of intracranial haemorrhage in comparison to VKAs (1), and in VTE treatment, with a statistical- ly significant 39% reduction in major bleeding rates in comparison to VKAs (2). These findings have been confirmed by a number of post-marketing observational studies (3-11). A pooled analysis of safety outcomes among the more than 100,000 patients enrolled in phase III clinical trials found that, compared to warfarin, the risk of fatal bleeding was 50% lower among DOAC-treated patients than in patients treated with standard anticoagulation (12). Despite these advantages, after the approval of the DOACs there was a clear need to define optimal strategies tomanage patients requir- ing urgent invasive procedures and patients presenting with bleeding complications. There was in particular the impression that the lack of an antidote could represent a major limitation in the use of these novel agents. As of today, there is still no high-quality evidence on which to base recommendations for DOACs reversal when required. Their relatively short half-life certainly offers an advantage in non-urgent situations, when withholding DOACs is usually sufficient to allow an adequate management of the patients. However, severe liver or renal impairment affect excretion andmay result in substantial prolongation of the half-lives and need to be taken into account. In the need for urgent reversal, a number of strategies have been proposed, including the administration of activated charcoal if the DOACs were ingested within 2 hours or the use of nonspecific rever- sal agents that promote the formation of fibrin, such as prothrombin complex concentrate (PCC), activated PCC (aPCC), and recombinant factor VIIa (13). Unfortunately, current evidence on the efficacy of these agents is based on animal models and studies in healthy volun- teers using laboratory end-points and these pro-haemostatic agents produce a risk of thrombosis. For this reason, the addition of PCC or aPCC to the best supportive therapy is suggested only for patients with severe or life-threatening DOAC-associated bleeding (14,15). To obviate the need for non-specific intervention and to reduce the risk of side effects in several clinical settings including life-threaten- ing bleeding, urgent interventions, or major trauma, specific reversal agents have been developed. Specific reversal agents three reversal agents are currently under development, idaruci- zumab, andexanet alfa, and ciraparantag. Idarucizumab, the reversal agent that is specific for the direct thrombin inhibitor dabigatran, is licensed in Europe, the United States, Canada, and several other coun- tries worldwide. The approval by the Food and Drug Administration (FDA) in the United States of a specific reversal agent of factor Xa directed agents, andexanet alfa, is expected soon. Finally, the universal reversal agent ciraparantag is in earlier clinical development. Idarucizumab Idarucizumab is a monoclonal antibody fragment. Its affinity with dabigatran is 350-fold higher than with thrombin, thus allowing rapid and almost irreversible neutralization of both free and thrombin-bound drug 16 . The half-life of this reversal agent, which is mainly excreted via the kidneys, is about 45 minutes in subjects with normal renal function (16). No procoagulant effects after the administration of idarucizumab have so far been reported (17-18). Idarucizumab is currently assessed in a phase III trial, REVERSE- AD, which is actively enrolling two prospective cohorts of dabiga- tran-treated patients requiring urgent reversal (19). In the first cohort, adult patients presenting with overt, uncontrollable, or life-threatening bleeding are eligible if they require a reversal agent in the opinion of the investigator; in the second cohort, adult patients requiring surgery or other invasive procedures that can not be delayed for at least 8 hours. All patients receive 5 g of intravenous idarucizumab administered as two bolus infusions no more than 15 minutes apart, each containing 2.5 g of the reversal agent. The primary end-point of the study is the maximum percentage reversal of the anticoagulant effect of dabigatran on the basis of the measurement of the dilute thrombin time or ecarin clotting time at any point from the end of the first infusion to 4 hours after the second infusion. Clinical outcomes include the severity of bleeding and haemodynamic stability for the Reversal of direct-acting oral anticoagulants: notes on the consensus of the Anticoagulation Education Task Force W. Ageno Department of Medicine and Surgery. Università dell`Insubria. Varese, Italia