Reversing factor Xa inhibitors – clinical utility of andexanet alfa

Abstract

Approximately half of patients started on an oral anticoagulant in the USA now receive one of the newer direct oral anticoagulants (DOACs). Although there is an approved reversal agent for the direct thrombin inhibitor dabigatran, a specific reversal agent for the anti-factor Xa (FXa) DOACs has yet to be licensed. Unlike the strategy to reverse the only oral direct thrombin inhibitor with idarucizumab, which is a humanized monoclonal antibody fragment, a different approach is necessary to design a single agent that can reverse multiple anti-FXa medications. Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, such as apixaban, edoxaban and rivaroxaban, and indirect FXa inhibitors such as low-molecular-weight heparins. This narrative reviews the development of andexanet alfa and explores its basic science, pharmacokinetics/pharmacodynamics, animal models, and human studies.

Andexanet Alfa: First Global Approval

“…Andexanet alfa is a genetically modified variant of human factor Xa protein that is catalytically inactive but retains the structural similarity to that of endogenous factor Xa [2, 7–9]. The modifications mean that andexanet alfa is unable to cleave and activate prothrombin and cannot assemble into the prothrombinase complex [2, 7–9].…”

“…The modifications mean that andexanet alfa is unable to cleave and activate prothrombin and cannot assemble into the prothrombinase complex [2, 7–9]. Andexanet alfa binds to apixaban, betrixaban, edoxaban and rivaroxaban with high affinity (0.53–1.53 nmol/L), similar to that seen with endogenous factor Xa [24, 25].…”

“…Andexanet alfa binds to apixaban, betrixaban, edoxaban and rivaroxaban with high affinity (0.53–1.53 nmol/L), similar to that seen with endogenous factor Xa [24, 25]. Consequently, andexanet alfa sequesters factor Xa inhibitors, leading to reversing the anticoagulant effects of factor Xa inhibitors and restoring the activity of endogenous factor Xa [2, 7, 8]. …”

“…apixaban, edoxaban, rivaroxaban and betrixaban (which was approved in the USA in June 2017 [1])] or indirect (e.g. fondaparinux and the low-molecular-weight-heparin enoxaparin) factor Xa inhibitors [2] are effective anticoagulants for the treatment and prevention of thromboembolism, and stroke prevention in atrial fibrillation [3]. Although these agents show a better bleeding risk profile compared with that of vitamin K antagonists (e.g.…”

Approaches to the prevention and therapy of ibrutinib-associated bleeding in adult patients

“…Как известно, апиксабан и ривароксабан также частично метаболизируются спомощьюцитохромаCYP3A,втовремякакдабигатран и эндоксабан -нет [40]. Таким образом, присовместномиспользованииибрутинибаиDOAC необходимоучитыватьизменениеметаболизмаданныхпрепаратов,особенноеслипациентужеполучает препараты, ингибирующие активность CYP3A, напримеразолы.Сдругойстороны,существуетан-тидотпротивингибиторовХ-фактора-андаксанет альфа,способныйвосстановитьактивностьХ-факторазасчитанныеминуты [41].Вслучаенеобходимостиназначенияантикоагулянтнойтерапиипациентам, получающим ибрутиниб, рекомендовано рассмотреть возможность отмены ингибитора Btk насрокантикоагулянтнойтерапииилиназначения альтернативнойтерапии,еслирискипоосновному заболеваниювслучаеотменыилизаменыпрепарата непревышаютрискигеморрагическихосложнений. Привыборепрепаратадляантикоагулянтнойтерапии предпочтение должно отдаваться DOAC, аневарфарину [36].Чтокасаетсяривароксабана,то, сучетомбольшейчастотыгеморрагическихосложнений,посравнениюсапиксабаномиэдоксабаном прииспользованиивысокихдоз(20мг / сут)рацио-нальноуменьшитьдозудо10мг / сутилиотказаться в пользу другого препарата этой же группы [42].…”