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)

Apixaban (ELIQUIS)

Indications

  • Primary and secondary stroke prevention in non-valvular atrial fibrillation (NVAF) AVERROES and ARISTOTLE trials
  • Treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) AMPLIFY trial
  • VTE prevention in the knee and hip surgery

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 coagulation factors present in the plasma
Indirect anticoagulants
They affect coagulation factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs are bound to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs act through the activation of antithrombin
  • vitamin K antagonists (VKAs)
    • warfarin (coumadin)
  • xabans (free and clot-bound factor Xa inhibitors)
    • apixaban
    • rivaroxaban
    • edoxaban
    • betrixaban
  • hirudin (direct thrombin inhibitor – DTI)

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

→ monitoring of patients treated with DOACs

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
  • 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)

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