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    Cardiac Matters

    Reversal Agents for Direct-Acting Oral Anticoagulants

    There has been increasing interest and research over the past few years on reversal agents for direct-acting oral anticoagulants (DOACs).

    Idarucizumab (Praxbind), a humanized monoclonal antibody fragment for the reversal of dabigatran (Pradaxa) in life-threatening bleeding or emergency procedures, was the first targeted DOAC reversal agent, and was approved in 2015.1

    The RE-VERSE AD study is an on-going multinational study designed to prove idarucizumab efficacy and safety. An interim analysis was published in 2015 that included 51 patients with serious bleeding and 39 patients who needed an urgent procedure while on dabigatran. The primary endpoint was the maximum percentage reversal (based on dilute thrombin time or ecarin clotting time) of the effect of the anticoagulant 4 hours after idarucizumab administration. The median maximum percentage reversal was 100% (95% CI, 100 to 100).2 An updated analysis of the study was published in 2016 with 123 patients total. This analysis found complete reversal of dabigatran in more than 89% of the patients at the end of idarucizumab administration, with a median time for hemostasis achieved in 9.8 hours in those with serious bleeding and mean time to surgery of 1.7 hours in those requiring emergent procedures. Of the 123 patients, 26 died due to the emergent situation or other comorbid conditions.3

    Read more Cardiac Matters

    Idarucizumab is dosed at 5 grams (administered as two 2.5 gram vials) as an IV infusion. As with reversal of any anticoagulation, there is risk of thromboembolism. The molecule has strong affinity for dabigatran with no known affects to reverse other anticoagulants.1

    There is on-going research for another reversal agent, andexanet alfa, which works on factor Xa inhibitors. This experimental therapy works by mimicking the protein structure of factor Xa to attract binding of factor Xa inhibitors such as apixaban and rivaroxaban. Once bound to andexanet alfa, the factor Xa inhibitors can no longer exert their anticoagulant effect on endogenous factor Xa in the blood. While structurally similar to factor Xa, andexanet alfa is catalytically inactive and does not promote clotting.

    ANNEXA-A and ANNEXA-R are two parallel, randomized, placebo-controlled trials designed to evaluate the reversal abilities of andexanet alfa on apixiban and rivaroxaban. Anti-factor Xa activity, a measure of anticoagulation with factor Xa inhibitors, was decreased by more than 90% in the active arms of both studies vs placebo (p < 0.001 for both trials). The effects of the active arms were sustained with the bolus plus a 2-hour infusion of andexanet alfa. No serious adverse effects were reported among the 101 patients treated with andexanet alfa. The most common side effects of active treatment were flushing, feeling hot, constipation, dysgeusia, and urticaria.4

    Related article: Anakinra for RA and Refractory Idiopathic Recurrent Pericarditis

    These two agents are promising antidotes, since the traditional treatment for bleeding due to DOACs includes therapy with multiple blood products and/or non-specific clotting factors.5 Future research examining clinical outcomes will help to further elucidate the role of these new and upcoming therapies.  


    References
    1. Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2015.
    2. Pollack CV Jr, Reilly PA, Eikelboom J et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015; 373:511-20.
    3. Pollack CV, Reilly P, Eikelboom J, et al. Idarucizumab for reversal of the anticoagulant effects of dabigatran in patients in an emergency setting of major bleeding, urgent surgery, or interventions. J Am Coll Cardiol. 2016; 67(13 Suppl):664.
    4. Siegal DM, Curnutte JT, Connolly, SJ et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413-24.
    5. Raval AN, Cigarroa JE, Chung MK, et al. Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association. Circulation. 2017;135:e604-e633.

    Germin Fahim, Pharm.D., BCPS
    Germin Fahim, Pharm.D., BCPS is Clinical Assistant Professor at Ernest Mario School of Pharmacy at Rutgers University ,and Clinical ...

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