Apixaban

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Continuing Education Activity

Apixaban is a novel oral anticoagulant (NOAC) approved by the US Food and Drug Administration (FDA) in 2012 for use in patients with non-valvular atrial fibrillation to reduce the risk of stroke and blood clots. Later, in 2014, it was approved to treat deep venous thrombosis (DVT) and pulmonary embolism (PE). In 2014, it was also approved for use to reduce the risk of blood clots (DVT and PE) in patients following knee and hip replacement surgery. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, monitoring, and toxicity of apixaban.

Objectives:

  • Identify the appropriate indications for apixaban.
  • Summarize the mechanism of action of apixaban.
  • Describe the potential adverse event profile of apixaban.
  • Review interprofessional team strategies for improving care coordination and communication to enhance patient outcomes and minimize adverse events with apixaban.

Indications

Apixaban is a novel oral anticoagulant (NOAC) that was approved by the US Food and Drug Administration (FDA) in 2012 for use in patients with non-valvular atrial fibrillation to reduce the risk of stroke and blood clots. [1][2][3]  Later, in 2014, it was approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). In 2014, it was also approved for use to reduce the risk of blood clots (DVT and PE) in patients following knee and hip replacement surgery.[4][5]

Mechanism of Action

The clotting cascade is a complex process involving multiple factors acting in three defined phases: initiation, propagation, and fibrin formation.

Initiation

This step occurs when the vascular endothelium and the clotting factors are disturbed.

Propagation

This step involves the production of large amounts of thrombin at the site of injury.

Fibrin Formation

Thrombin acts on fibrinogen to form fibrin. 

The coagulation proteins form the basic components of the coagulation system. They lead to a complex interplay of reactions resulting in the conversion of plasma soluble fibrinogen to insoluble fibrin strands. There are two main pathways to the clotting cascade: the intrinsic pathway and the extrinsic pathway. External trauma activates the extrinsic pathway and causes blood loss from the vascular system, and it is faster than the intrinsic pathway and involves factor VII. Trauma inside the vascular system activates platelets via exposed endothelium, chemicals, or collagen, which can initiate the intrinsic pathway. It involves factors XII, XI, IX, and VIII. Both pathways share a common ending where they activate factor X to Xa, which activates prothrombin (II) to thrombin (IIa), thereby forming a stable clot.

Apixaban is a highly selective direct factor Xa inhibitor, blocking the propagation phase of the coagulation cascade. It exerts its effect on both free and clot-bound factor Xa. Factor Xa is a catalyst for the conversion of prothrombin to thrombin, which is the final step in the coagulation cascade leading to fibrin and clot formation.[6] Other direct factor Xa inhibitors include rivaroxaban and edoxaban.

Apixaban exerts no effect on platelet aggregation.

Administration

Apixaban is available in the oral formulation as 2.5 mg and 5 mg tablets. Dosing depends on the indication for treatment, the age of the patient, serum creatinine, and body weight.

Patients with deep vein thrombosis and pulmonary embolism are required to take 10 mg twice daily for seven days, followed by 5 mg twice daily. For patients with non-valvular atrial fibrillation, the recommended dose is 5 mg twice daily.

In the EU, it currently has approval as a prophylactic agent following hip and knee replacement surgery; it is not FDA-approved for this indication at the time of this writing.[7]

In patients with 2 out of 3 of the following, the dose of 5 mg should be reduced to 2.5 mg daily.

  • Age 80 years or older
  • Serum creatinine greater than or equal to 1.5 mg/dl
  • Bodyweight less than or equal to 60 kg

Apixaban can be administered without regard to meals. Its elimination occurs via urine and feces. Biliary and direct intestinal excretion contributes to its elimination in the feces. Usually, 27% of the drug is cleared by the renal route.

Dosing in Renal Impairment

As mentioned above, the recommended dose for patients with at least 2 of the following should be reduced from 5 mg to 2.5 mg daily.[8][9][8]

  • Age 80 years or older
  • Serum creatinine greater than or equal to 1.5 mg/dl
  • Bodyweight less than or equal to 60 kg

Clinical efficacy and safety studies with apixaban did not include patients with end-stage renal disease (ESRD) on dialysis. It is thereby not recommended in the drug label as a proven anticoagulant of choice in patients with ESRD. An alternate anticoagulant like warfarin should be considered in patients with ESRD.

Dosing in Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dose adjustment required.

Moderate hepatic impairment (Child-Pugh class B): Limited clinical experience in patients with moderate hepatic impairment; hence, any dosing adjustment has yet to be established.

Severe hepatic impairment (Child-Pugh class C): Apixaban is not recommended.

Adverse Effects

Being an anticoagulant, the most common adverse effect of apixaban is bleeding (1% to 10%). The risk of major bleeding is 3% or less, and clinically relevant nonmajor bleeding is 2% to 4%. Other less common adverse effects include nausea (3%), gingival hemorrhage (1% or less), hematuria (2% or less), hypermenorrhea (1%), anemia (3%), bruise (1% to 2%), hematoma (1% to 2%), postprocedural hemorrhage (1% or less), rectal hemorrhage (1% or less), increased serum transaminases (1% or less), epistaxis (4% or less), hemoptysis (1% or less). In rare instances (less than 1%), it can cause a hypersensitivity reaction.

Contraindications

Active pathological bleeding and severe hypersensitivity reaction to apixaban, for example, an anaphylactic reaction, are the contraindications to the use of apixaban.

Monitoring

Unlike warfarin, apixaban does not need monitoring of the patient's international normalized ratio (INR), thereby offering an advantage.[10] Patients on warfarin are required to get their INR checked every week, two weeks, or four weeks depending on the control; whereas, apixaban patients do not need any blood draws; this improves patient adherence.[11][12]

The most significant adverse effect is bleeding. Therefore, concomitant use of drugs affecting hemostasis, including antiplatelets, other anticoagulants, thrombolytic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), SSRIs, and SNRIs, should be judicious.

Its elimination half-life is about 12 hours (8 to 15 hours).

Before a patient undergoes elective surgery or an invasive procedure, the drug should be held for 48 hours if the procedure is a moderate-high risk with clinically significant bleeding. For procedures with a low risk of bleeding, it should be held 24 hours prior to the procedure. Bridging anticoagulation 24 to 48 hours after is not usually recommended.[13] Furthermore, the drug must be restarted following surgical or other procedures after establishing adequate hemostasis.

Toxicity

In May 2018, the FDA approved the first antidote for the reversal of factor Xa inhibitors called andexanet alfa. Andexanet alfa is a biologic agent, a modified recombinant derivative of factor Xa that acts as a decoy receptor. It has a higher affinity for factor Xa inhibitor than natural Xa, and consequently, the inhibitor binds to the drug rather than to natural Xa itself. It received the US Orphan Drug and FDA Breakthrough Therapy designations. There is limited real-world data on the use of this antidote due to its recent approval. Further research will result in knowing its efficacy and safety profile in the future.[14]

Prothrombin complex concentrates (PCCs) are a mixture of factor II, IX, and X. Some versions also include factor VII. It has been known since the 1960s and has been shown to reverse laboratory measures and bleeding from factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban in healthy volunteers, animal models, and in vitro studies of healthy donor blood. One institution instituted a protocol of administering 4-factor PCC for patients with rivaroxaban-associated or apixaban-associated bleeding requiring immediate reversal. However, whether this strategy results in clinical improvements for such patients has yet to be determined.[14]

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members, including clinicians (MDs, DOs, PAs, NPs), specialists (cardiologists, internists, hospitalists, hematologists, and others), primary care providers, nursing staff, and pharmacists, who treat patients with atrial fibrillation should be well informed regarding pharmacotherapy with apixaban. This novel oral anticoagulant was approved by the US Food and Drug Administration in 2012 for use in patients with non-valvular atrial fibrillation to reduce the risk of stroke and blood clots. Later, in 2014, it was approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). In 2014, it was also approved for use to reduce the risk of blood clots (DVT and PE) in patients following knee and hip replacement surgery.[15] The drug is relatively safe and, unlike warfarin, does not need INR monitoring. However, ongoing close monitoring of patients taking apixaban is necessary to prevent bleeding; to this end, all providers, including clinicians, nurses, and pharmacists, should counsel the patient so they are aware of the early signs of potential bleeding that could lead to more severe events. The interprofessional team needs to work as a cohesive unit to ensure that apixaban treatment is safe and effective for their patients, resulting in optimal patient outcomes with minimal adverse events. [Level 5]


Article Details

Article Author

Akanksha Agrawal

Article Author

Connor Kerndt

Article Editor:

Biagio Manna

Updated:

10/7/2021 8:54:44 AM

PubMed Link:

Apixaban

References

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