Background
Methods
Results and discussion
About apixaban
Laboratory measurement of apixaban
Interactions with other medications
Starting apixaban
Switching from warfarin to apixaban
Switching from low molecular weight heparin (LMWH) to apixaban
Switching from apixaban
Apixaban to warfarin
Apixaban to low molecular weight heparin (LMWH)
Bleeding management in patients receiving apixaban
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Establish the primary source of bleeding wherever possible, and secure haemostasis with local measures.
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Most cases of minor bleeding will resolve after cessation of drug, standard supportive treatment, including transfusion, mechanical compression and other local measures.
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If bleeding occurs within 6 hours of last apixaban dose, activated charcoal may reduce apixaban absorption, and hence anticoagulant effect [17]. This should also be considered soon after overdose or accidental ingestion.
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A specific antidote for apixaban is not currently available [5]. Two synthetic molecules are currently in early clinical trials for apixaban reversal. Andexanet alpha (PRT064445) is a truncated form of enzymatically inactive factor Xa, which can dose-dependently reverse the inhibitory activity and correct the prolongation of ex vivo clotting times by apixaban and other factor Xa inhibitors [18]. Another synthetic small molecule, aripazine (PER977), appears to have broad activity against the NOACs, reversing the anticoagulant activity of dabigatran, rivaroxaban, apixaban and edoxaban in rat bleeding models [19].
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Apixaban is highly (~87%) protein bound, and hence not expected to be dialyzable [5]. Based on studies of other factor Xa inhibitors in healthy volunteers, prothrombin complex concentrates (PCC) may reverse the anticoagulant effect, however the effect of PCC on clinical bleeding is not proven [20]. When apixaban (200 ng/ml) was added in vitro to blood from healthy donors, PCC and activated PCC were more effective at improving thrombin generation than recombinant FVIIa (rFVIIa) [21].
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There is no clinical evidence examining the use of rFVIIa or bypassing agents (FEIBA) in bleeding patients receiving apixaban. In a rabbit model of apixaban-induced bleeding, neither rFVIIa nor PCC reduced blood loss from a standardised hepatosplenic injury, although rFVIIa did reverse prolongation of the prothrombin time and shortened skin bleeding time [22]. When apixaban (200 ng/ml) was added in vitro to blood from healthy donors, rFVIIa was more effective than PCC in restoring clotting times and thromboelastography parameters [21]. In animal, in vitro and healthy volunteer studies, these agents have partially reversed the anticoagulant effect of apixaban and other factor Xa inhibitors [23‐26]. These agents can be considered for life-threatening bleeding, but carry a proven risk of thrombosis.
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There is no evidence to support the use of FFP, other than for volume replacement in case of major bleeding.
Peri-operative management in patients receiving apixaban
Advice for assessing peri-procedural dosing
High bleeding risk
Low bleeding risk
Minimal bleeding risk
Re-commencing apixaban after surgery
Neuraxial anaesthesia
Conclusions
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Apixaban is a direct FXa inhibitor indicated in Australia for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective total hip or total knee replacement surgery (2.5 mg BID) and for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke (5 mg BID or 2.5 mg BID if ≥2 of the following; ≤60 kg, ≥80 years, serum creatinine level ≥133 um/L) [5].
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In the ARISTOTLE study of apixaban in patients with atrial fibrillation, annual major bleeding events for apixaban compared to warfarin were 2.13% per year versus 3.09% per year (p < 0.001). Intracranial haemorrhage events were 0.33% per year for apixaban, compared to 0.80% per year for warfarin (p < 0.001) [3].
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There is no standardised assay currently commercially available in Australia to measure apixaban effect. As apixaban minimally prolongs PT or aPTT, these clotting tests are not recommended to assess the pharmacodynamic effects of apixaban [5]. A chromogenic anti Xa assay or dilute PT assay may be useful, where knowledge of apixaban exposure is required [10‐12].
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Apixaban is contraindicated in patients who are receiving concomitant treatment with strong inhibitors of both CYP3A4 and P-gp, however no dose adjustment for apixaban is required when co-administered with less potent inhibitors. No dose adjustment for apixaban is required during concomitant therapy with strong CYP3A4 and P-gp inducers, however they may lead to reduced apixaban plasma concentrations [5].
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Apixaban is not expected to be dialyzable, however prothrombin complex concentrates (PCC) may reverse the anticoagulant effect and recombinant FVIIa or bypassing agents (FEIBA) can be considered for life-threatening bleeding. FFP will not reverse apixaban effect but can be used as volume replacement in case of major bleeding.
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Planning for elective surgery or invasive procedures should involve balancing the intervention-associated bleeding risk and thrombotic risk associated with anticoagulant interruption in each individual.