EXPLANATION


Rivaroxaban is a direct Factor Xa inhibitor that is FDA approved for anticoagulation in children over two years of age after the Fontan operation. The brand name of rivaroxaban is Xarelto®. It is currently the only direct oral anticoagulant (DOAC) that is FDA approved for this indication in the pediatric patient population. Routine blood tests to monitor anticoagulation and dietary restrictions are not required with the use of rivaroxaban, unlike warfarin anticoagulation. Other direct Factor Xa inhibitors include apixaban, enoxaparin, and edoxaban.


Andexanet alfa (andexanet) is a reversal agent that neutralizes the anticoagulant effects of both direct and indirect factor Xa inhibitors. Andexanet is a catalytically inactive, recombinant modified human factor Xa protein that binds with high affinity to the active site of factor Xa (FXa) inhibitor thereby preventing FXa inhibitor from binding to Factor Xa and thus antagonizing its anticoagulant effect as assessed by measurement of thrombin generation and anti-factor Xa activity. Andexanet antagonizes the anticoagulant activity of apixaban, rivaroxaban, edoxaban, and enoxaparin. Andexanet was FDA approved in 2018, under its Accelerated Approval Program, for the reversal of life-threatening bleeding or uncontrolled bleeding in patients treated with apixaban or rivaroxaban. In the patient described in the question stem, andexanet administration would rapidly reverse systemic anticoagulation.


The side effect profile of andexanet alfa is most notable for venous and arterial thrombotic events. In fact, a 2020 meta-analysis of 16 prospective and retrospective studies enrolling patients treated with specific antidotes (idarucizumab and andexanet alfa) for anticoagulation reversal demonstrated a pooled incidence of 5.5% for thrombotic events. A systematic review of the studies on the safety and efficacy of nonvitamin K oral anticoagulants (NOACs) in adult patients with congenital heart disease (CHD) revealed a low annual incidence of thromboembolic events (0.98%) and major bleeding events (1.74%). Although the most common indication for anticoagulation in the adult patient population with congenital heart disease was atrial fibrillation in this study, the majority of both thromboembolic (3.13%) and hemorrhagic (3.17%) events occurred in patients with the Fontan palliation.


Idarucizumab is a monoclonal antibody fragment used to reverse the effects of dabigatran, a direct thrombin inhibitor. It binds to dabigatran with 350 times greater affinity than thrombin. Idarucizumab would not be effective in reversing the anticoagulant effects of rivaroxaban in this patient.


Vitamin K is utilized for the reversal of coumadin anticoagulation. It would be expected to significantly lower the international normalized ratio (INR) in a 24 to 48 hour time period. It is not utilized as the sole reversal agent in the setting of a life-threatening hemorrhage due to coumadin anticoagulation but is administered concomitantly with fresh frozen plasma or prothrombin complex concentrates.


Platelet transfusion could be indicated in the setting of traumatic intracranial hemorrhage, especially to reverse the effects of antiplatelet medications or in the setting of thrombocytopenia. It would not be the first-line intervention in this patient treated with rivaroxaban.


In the setting of an intracranial hemorrhage in a patient treated with rivaroxaban, Andexanet alfa is the best initial treatment option.


REFERENCES


Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413-2424. doi:10.1056/NEJMoa1510991


Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2019;380(14):1326-1335. doi:10.1056/NEJMoa1814051


Stalikas N, Doundoulakis I, Karagiannidis E, et al. Non-Vitamin K Oral Anticoagulants in Adults with Congenital Heart Disease: A Systematic Review. J Clin Med. 2020;9(6):1794. Published 2020 Jun 9. doi:10.3390/jcm9061794


Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373(6):511-520. doi:10.1056/NEJMoa1502000


Rodrigues AO, David C, Ferreira JJ, Pinto FJ, Costa J, Caldeira D. The incidence of thrombotic events with idarucizumab and andexanet alfa: A systematic review and meta-analysis. Thromb Res. 2020;196:291-296. doi:10.1016/j.thromres.2020.09.003