Apixaban


Article Author:
Akanksha Agrawal


Article Editor:
Biagio Manna


Editors In Chief:
Russell McAllister
Jason Widrich
Daniel Sizemore


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Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
3/8/2019 8:19:37 AM

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 3 defined phases: initiation, propagation, and fibrin formation. 

Initiation

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

Propagation

This 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 soluble fibrinogen to insoluble fibrin strands. There are 2 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. It is faster than the intrinsic pathway and involves factor VII. Trauma inside the vascular system caused by platelets, exposed endothelium, chemicals, or collagen activates 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 to thrombin, thereby forming a stable clot. Apixaban is a direct factor Xa inhibitor, blocking the propagation phase of the coagulation cascade. Other direct factor Xa inhibitors include rivaroxaban and edoxaban.

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 7 days, followed by 5 mg twice daily. For patients with non-valvular atrial fibrillation, the recommended dose is 5 mg twice daily. As a prophylactic agent post hip and knee replacement surgery, a dose of 2.5 mg twice daily starting 12 to 24 hours postoperatively for a total duration of 35 and 12 days respectively is recommended.

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
  • Body weight less than or equal to 60 kg

It can be administered without regard to the meal. 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, 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
  • Body weight 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, dosing adjustment cannot be provided.

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). Rarely (less than 1%), it can cause a hypersensitivity reaction.

Contraindications

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

Monitoring

Unlike warfarin, apixaban does not need monitoring of patients' international normalized ratio (INR), thereby offering an advantage. Patients on warfarin are required to get their INR checked every week, 2 weeks, or 4 weeks depending on the control; whereas, apixaban patients do not need any blood draws. This improves patient compliance.[6][7]

The major 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. [8]Furthermore, the drug must be restarted following surgical or other procedures once adequate hemostasis is established.

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, 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 future.

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.

Enhancing Healthcare Team Outcomes

Healthcare workers including nurse practitioners, internists, cardiologist and the primary care provider who treat patients with atrial fibrillation should be aware of apixiban. 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.[9]The drug is relatively safe and unlike warfarin does not need INR monitoring.


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Apixaban - Questions

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Which of the following anticoagulants is FDA approved for the treatment of deep venous thrombosis and pulmonary embolism?



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A 58-year-old man with a past medical history of atrial fibrillation, diabetes mellitus, and hypertension is scheduled to have elective cholecystectomy. The patient is on Apixaban. How long before the surgery should the patient stop taking his apixaban?



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An 81-year-old man with the diagnosis of non-valvular atrial fibrillation is to be started on anticoagulation. His body weight is 75 kg, and laboratory work is remarkable for blood urea nitrogen of 25 mg/dl and creatinine of 1.7 mg/dL. After extensive discussion with him, it has been decided to start him on apixaban. On what dose should he be started?



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A 65-year-old man is scheduled for an outpatient screening colonoscopy. His past medical history is notable for an unprovoked pulmonary embolism five years ago. He is on apixaban for anticoagulation. He is otherwise healthy and denies any history of bleeding. Laboratory studies show normal complete blood count. His serum creatinine level is 0.9 mg/dL. What is the most appropriate plan for this patient's anticoagulation before undergoing colonoscopy?



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Which of the following oral anticoagulant is a factor Xa inhibitor?



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Apixaban - References

References

Skelley JW,Thomason AR,Hammond LN, Extended-Duration Use of Direct Oral Anticoagulants to Prevent VTE in Acutely III Medical Patients. The Senior care pharmacist. 2019 Feb 1;     [PubMed]
Powell J,Taylor J,Garland SG, Andexanet alfa: A Novel Factor Xa Inhibitor Reversal Agent. The Annals of pharmacotherapy. 2019 Feb 27;     [PubMed]
Knotts TL,Mousa SA, Anticoagulation in Venous Thromboembolism Prophylaxis in Medically Ill Patients: Potential Impact of NOACs. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019 Feb 27;     [PubMed]
Weitz JI,Chan NC, Long-Term Management of Venous Thromboembolism: Lessons from EINSTEIN CHOICE and Other Extension Trials. Thrombosis and haemostasis. 2019 Feb 26;     [PubMed]
Young M, Atrial Fibrillation. Critical care nursing clinics of North America. 2019 Mar;     [PubMed]
Kajy M,Shokr M,Ramappa P, Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: Systematic Review of Current Literature. American journal of therapeutics. 2019 Jan 29;     [PubMed]
Gressenberger P, Reversal strategies in patients treated with direct oral anticoagulants. VASA. Zeitschrift fur Gefasskrankheiten. 2019 Feb 5;     [PubMed]
Kaye AD,Manchikanti L,Novitch MB,Mungrue IN,Anwar M,Jones MR,Helander EM,Cornett EM,Eng MR,Grider JS,Harned ME,Benyamin RM,Swicegood JR,Simopoulos TT,Abdi S,Urman RD,Deer TR,Bakhit C,Sanapati M,Atluri S,Pasupuleti R,Soin A,Diwan S,Vallejo R,Candido KD,Knezevic NN,Beall D,Albers SL,Latchaw RE,Prabhakar H,Hirsch JA, Responsible, Safe, and Effective Use of Antithrombotics and Anticoagulants in Patients Undergoing Interventional Techniques: American Society of Interventional Pain Physicians (ASIPP) Guidelines. Pain physician. 2019 Jan;     [PubMed]
Coleman CI,Briere JB,Fauchier L,Levy P,Bowrin K,Toumi M,Millier A,Taieb V,Wu O, Meta-analysis of real-world evidence comparing non-vitamin K antagonist oral anticoagulants with vitamin K antagonists for the treatment of patients with non-valvular atrial fibrillation. Journal of market access     [PubMed]

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