ADD-ONS / MEDICATION / ANTICOAGULANTS
Apixaban (Eliquis)
Created 21/10/2022, last revision 25/10/2022
Apixaban (ELIQUIS) is an oral anticoagulant drug used to treat and prevent VTE and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. It is used as an alternative to warfarin, which does not require laboratory monitoring or dietary restrictions. Apixaban belongs to a group of drugs called direct oral anticoagulants (DOACs)
Contraindications
- hypersensitivity to apixaban or any of the excipients
- pregnancy and breastfeeding (not recommended)
- severe renal impairment → use Cockcroft-Gault formula!
- contraindicated with CrCl <15 mL/min (0.25 mL/s)
- clinically significant active bleeding
- lesions or conditions considered a significant risk factor for major bleeding
- current or recent gastrointestinal ulcerations, presence of malignant tumors
- a recent brain or spinal injury
- a recent surgical procedure in the brain, spine, or eye
- recent intracranial hemorrhage, known presence or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or severe
intraspinal or intracerebral vascular anomalies
- spontaneous or pharmacological (concomitant anticoagulants) disorders of hemostasis
- liver disease
- all DOACs are contraindicated in patients with liver disease associated with coagulopathy and clinically apparent risk of bleeding
- use with caution in patients with mild-moderate hepatopathy (Child-Pugh A/B)
- no dosage adjustment is necessary for patients with mild hepatic impairment
- concomitant therapy (especially potent P-glycoprotein inhibitors)
- ketoconazole, itraconazole
- macrolides
- mechanical heart valve requiring VKAs
Mechanism of action
- direct, competitive, highly selective inhibitor of activated factor Xa (fXa)
- free Xa, bound in a prothrombinase complex with cofactor V and incorporated into the fibrin network of the coagulum, is inhibited ⇒ sufficient blockade of the fibrin-bound factor is ensured, in contrast to indirect fXa inhibitors, and secondary activation of coagulation after thrombus breakdown does not occur
- unlike indirect factor Xa inhibitors (heparin, LMWH), the effect is not dependent on the presence of antithrombin III
- up to 5% of the population with thrombotic complications have insufficient antithrombin levels
- the anticoagulant effect is directly proportional to the apixaban plasma levels and lasts only for this period
| Direct anticoagulants They inactivate the clotting factors present in the plasma |
Indirect anticoagulants They affect clotting factors by reducing their liver production |
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| Direct thrombin/factor Xa inhibitors These drugs bind to thrombin/factor Xa and thereby block their function |
Indirect thrombin/factor Xa inhibitors These drugs activate antithrombin |
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Pharmacokinetics and pharmacodynamics
Absorption and onset of action
- active drug with an easy absorption
- due to low affinity for the P-glycoprotein transporter, apixaban has a bioavailability of 50-80%
- rapid onset of action (30-60 min), maximum concentration within 2-4 hours, half-life ~ 13 hours – administered twice daily
- low inter-individual and intra-individual variability of effect due to reliable bioavailability, low variability of biotransformation and bioelimination
- little impact of renal or hepatic failure
- minimal risk of food or drug interactions
Elimination
- 2/3 by the liver, 1/3 by the kidney
- apixaban is always partially degraded by CYP3A4/5
- can therefore be administered to patients with mild-moderate renal insufficiency (up to 60% of Afib patients enrolled in the ARISTOTLE study had mild or moderate renal insufficiency)
- in patients with renal failure, exposure to apixaban is increased by approx. 1/4
Apixaban is the substrate of two efflux pumps, P-gp and BCRP. The activity of both systems determines the bioavailability and bioelimination. Apixaban is also a substrate of CYP isoenzymes (mainly CYP3A4), which influence its transformation to inactive metabolites. Inhibition of P-gp increases bioavailability and slows the elimination into the bile; blockade of CYP3A4 slows inactivation and transformation. Many drugs are significant inhibitors of both CYP3A4 and P-gp. Clinically important inhibitors of both systems include azole-type antifungals, antiretrovirals, and the macrolides
Interactions
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Dosing
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- used orally with or without food twice daily (every 12 hours).
- the tablet may be crushed and mixed with water or apple juice if needed
Monitoring
- clinical monitoring usual for all anticoagulated patients
- specific laboratory monitoring can be done in selected cases
Complications, adverse events
Bleeding
- in the AVERROES trial, long-term treatment with 10 mg of apixaban daily resulted in clinically significant bleeding and major bleeding in 4-5% of patients per year
- intracranial bleeding accounted for 0.5% of these
- bleeding was most commonly: epistaxis, gastrointestinal bleeding, hematuria or bleeding at the surgical site, puncture, or catheter site
- the incidence of bleeding is lower compared to warfarin (relative decrease of 50%) [Agnelli, 2013]
Other adverse events
- anemia (1%) – often as a result of bleeding
- GIT disorders (nausea)
- asymptomatic elevation of liver enzymes
- the elevation is usually mild and transient
- the elevation is usually mild and transient
- mild transient thrombocytopenia
- other adverse effects are minor and rare
Overdose
- if the agent was administered within the past 2 hours consider activated oral charcoal (recommendation with unproven clinical benefit)
- there is no hard evidence regarding the antifibrinolytics (tranexamic acid, aminocaproic acid) or systemic hemostatic agents (desmopressin, aprotinin)
- the antidote is still somewhat a theoretical possibility (price, availability) → andexanet alfa
- andexanet alfa (sold under the trade name Andexxa) is an antidote for the medications rivaroxaban and apixaban when the reversal of anticoagulation is needed. It has not been found to be useful for other factor Xa inhibitors
- both antidote and substitution therapy should be reserved for severe bleeding or urgent surgery (↑ risk of VTE)
