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, over-dose management, and toxicity of apixaban. It also highlights the role of interprofessional team members in patient care using apixaban as a treatment option.

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) approved by the US Food and Drug Administration (FDA) in 2012.[1][2]This medication is approved for various indications, as described below.

FDA-approved Indications

• It is indicated in patients with non-valvular atrial fibrillation to reduce the risk of stroke and systemic embolism.[3]
• It is also approved for the treatment of deep vein thrombosis (DVT).[4]
• It is approved for the treatment of pulmonary embolism (PE).[5]
• It is also indicated for the prophylaxis in DVT, which may lead to PE, in patients who may have undergone knee or hip replacement surgery.[6][7]
• It is also approved for reducing the risk of recurrent DVT and PE after initial therapy.[8]

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 converting plasma-soluble fibrinogen to insoluble fibrin strands. There are two main pathways to the clotting cascade: the intrinsic and extrinsic pathways. 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. For antithrombotic activity, it does not need antithrombin III. 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.[9] Other direct factor Xa inhibitors include rivaroxaban and edoxaban.

Apixaban exerts no effect on platelet aggregation.

Pharmacokinetics: It has dose linear pharmacokinetics up to 10mg dose.[10]

Absorption

• Absolute bioavailability: 50% (up to 10 mg dose)
• With Food: No effect on bioavailability in the presence of food
• Peak plasma concentration: 3 to 4 hours

Distribution

• Plasma protein binding: Approximately 87%
• The volume of distribution: Approximately 21 L

Metabolism

• Metabolized mainly via CYP3A4
• 25% of the orally administered dose of apixaban is excreted in urine and feces as metabolites

Elimination

• Eliminated in both urine and feces
• Apparent half-life: 12 hours after oral administration

Administration

Apixaban is available in the oral formulation as 2.5 mg and 5 mg tablets. Dosing depends on the indication for treatment, the patient's age, 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.[11] 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

If the dose is not taken as per schedule, the patient should take the dose as soon as possible within the same day and resume the twice-daily schedule. However, a double dose is not recommended to make up for a missing dose.

Other options for administration: The patients who have difficulty swallowing whole tablets may be able to crush and suspend 2.5 mg and 5 mg of apixaban tablets in water, apple juice, 5% dextrose in water (D5W), or applesauce and administer them orally immediately. These crushed tablets remained stable for up to 4 hours. Alternatively, these tablets may be crushed and suspended in 60 mL of water or D5W for prompt delivery via a nasogastric tube.

Specific Patients Population 

Patient with Hepatic Impairment 

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

Patient with 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 twice daily.[11]

• 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, therefore, not recommended on 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.

Pregnant Women: It is considered a pregnancy category B medicine. There is a limited amount of data available on the use of apixaban tablets in pregnant women and the associated risk of major birth defects, adverse outcomes, or miscarriage. The treatment with the drug may lead to an increased risk of bleeding during pregnancy and delivery.

Breastfeeding Women: There is no data available on the presence of apixaban or its metabolites in human milk. However, apixaban and/or its metabolites were present in the rat milk. Taking apixaban tablets during breastfeeding is not recommended, as human exposure via milk is still unknown.

Pediatric Patients: The safety and efficacy of apixaban tablets are not established in pediatric patients. 

Geriatric Patients: There is no clinically significant difference in the safety and efficacy of apixaban when comparing different age groups.

Adverse Effects

As an anticoagulant, apixaban's most common adverse effect 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), aspartate aminotransferase increased (1% or less), gamma-glutamyltransferase increased (1% or less), epistaxis (4% or less), and hemoptysis (1% or less). In rare instances (less than 1%), it can cause a hypersensitivity reaction.

Drug Interactions

Most apixaban drug interactions are associated with CYP3A4 and P-gp, as apixaban is a substrate for both. The drugs that inhibit CYP3A4 and P-gp may increase the exposure of apixaban and the associated risk of bleeding. On the contrary, drugs that induce CYP3A4 and P-gp may decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events.[12][13]

Coadministration of Apixaban with Combined P-gp Strong CYP3A4 Inhibitors

If patients receive apixaban 5 mg or 10 mg twice daily, it is recommended to decrease the dose of apixaban by 50% for patients who are also receiving P-gp and potent CYP3A4 inhibiting drugs like ritonavir, ketoconazole, and itraconazole. However, If patients receive apixaban 2.5 mg twice daily dose, it is recommended to avoid coadministration for patients who are also receiving P-gp and potent CYP3A4 inhibitors. 

Coadministration of Apixaban with Combined P-gp Strong CYP3A4 Inducers

It is recommended to avoid coadministration of apixaban with other P-gp and strong CYP3A4-inducing drugs like phenytoin, carbamazepine, and rifampin, as these drugs may lead to a decrease in the exposure of apixaban.

Coadministration of Apixaban with other Anticoagulants and Antiplatelet Agents

When apixaban is coadministered with other anticoagulants and antiplatelet agents like heparin, aspirin, and chronic NSAIDs, it may increase the risk of bleeding.

Contraindications

Per the manufacturer's label, active pathological bleeding and severe hypersensitivity reaction to apixaban, for example, an anaphylactic reaction, are the contraindications to using apixaban.

Box Warning

Premature discontinuation of oral anticoagulant medicines, including apixaban, can increase the risk of thrombotic adverse events and spinal/epidural hematoma. Clinicians should monitor patients frequently for signs and symptoms of neurological impairment. Urgent treatment is necessary if neurological compromise is noted.

Monitoring

Unlike warfarin, apixaban does not need monitoring of the patient's international normalized ratio (INR), offering an advantage.[14] Patients on warfarin must get their INR checked every week, two weeks, or four weeks depending on the control, whereas patients using apixaban do not need any blood draws; this improves patient adherence.[15][16]

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.[17] 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; 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 determine its efficacy and safety profile in the future.[18]

Prothrombin complex concentrates (PCCs) are a mixture of factors 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.[18]

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 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.[19] 

Unlike warfarin, the drug is relatively safe and 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. If any team member notices signs of bleeding, they must promptly communicate this to the prescriber for therapeutic intervention. 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]