Factor Xa inhibitors

Introduction
Factor Xa inhibitors are a class of anticoagulant medications that selectively inhibit Factor Xa, a critical serine protease in the coagulation cascade responsible for converting prothrombin (Factor II) to thrombin (Factor IIa). By targeting this central enzyme, Factor Xa inhibitors prevent the formation of fibrin clots and are widely used in the prevention and treatment of venous thromboembolism (VTE), stroke prevention in non-valvular atrial fibrillation, and the management of deep vein thrombosis (DVT) and pulmonary embolism (PE).

These agents are a subset of direct oral anticoagulants (DOACs), also known as non-vitamin K oral anticoagulants (NOACs), or selective Factor Xa inhibitors, and they have largely replaced warfarin for many indications due to their predictable pharmacokinetics, fixed dosing, and lack of need for routine INR monitoring.

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1. Drugs in the Factor Xa Inhibitor Class

Drug Name	Brand Name	Route
Rivaroxaban	Xarelto	Oral
Apixaban	Eliquis	Oral
Edoxaban	Savaysa, Lixiana	Oral
Betrixaban	Bevyxxa (withdrawn in U.S. 2020)	Oral
Fondaparinux	Arixtra	Subcutaneous (indirect, via antithrombin III)

Note: Fondaparinux is indirect, working through antithrombin III, while the others are direct Factor Xa inhibitors.

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2. Mechanism of Action

Factor Xa inhibitors selectively block the activity of activated Factor X (Factor Xa), thereby:

• Inhibiting the conversion of prothrombin to thrombin

• Preventing thrombin-mediated conversion of fibrinogen to fibrin

• Reducing platelet activation and aggregation indirectly

Unlike warfarin, which inhibits vitamin K-dependent synthesis of multiple clotting factors (II, VII, IX, X), Factor Xa inhibitors act directly on the active site of Factor Xa—either free or within the prothrombinase complex.

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3. Clinical Indications

Approved uses for Factor Xa inhibitors include:

A. Venous Thromboembolism (VTE)

• Treatment of deep vein thrombosis (DVT)

• Treatment of pulmonary embolism (PE)

• Prevention of recurrence of DVT and PE

B. Stroke Prevention in Atrial Fibrillation

• In patients with non-valvular atrial fibrillation

• Not recommended in patients with mechanical heart valves or moderate/severe mitral stenosis

C. Post-Operative Thromboprophylaxis

• Prevention of DVT in patients undergoing hip or knee replacement surgery

  • Rivaroxaban, apixaban, edoxaban approved

D. Extended VTE Prophylaxis in Medically Ill

• Betrixaban (prior to discontinuation) was approved for this

E. Off-label Uses (Under study)

• Cancer-associated thrombosis

• Antiphospholipid syndrome (with caution)

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4. Pharmacokinetics

Parameter	Rivaroxaban	Apixaban	Edoxaban	Fondaparinux
Bioavailability	~80–100% (w/ food)	~50%	~62%	~100% (SC)
Half-life	5–9 hrs (young), 11–13 hrs (elderly)	~12 hrs	10–14 hrs	17–21 hrs
Protein Binding	~92–95%	~87%	~55%	~94%
Metabolism	CYP3A4, P-gp	CYP3A4, P-gp	Minimal CYP, P-gp	Not metabolized
Excretion	66% renal/hepatic	27% renal, 75% fecal	50% renal	~100% renal
Dosing Adjustment	Renal and hepatic impairment	Renal only	Renal only	Renal only

Note: Rivaroxaban must be taken with food when ≥15 mg doses are prescribed to enhance absorption.

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5. Dosing Guidelines (Selected)

Rivaroxaban

• DVT/PE treatment: 15 mg BID x 21 days → 20 mg daily

• Atrial fibrillation: 20 mg daily (15 mg if CrCl 15–50 mL/min)

• Post-hip/knee surgery: 10 mg daily

Apixaban

• DVT/PE: 10 mg BID x 7 days → 5 mg BID

• Atrial fibrillation: 5 mg BID; reduce to 2.5 mg BID if ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL

• Post-op prophylaxis: 2.5 mg BID

Edoxaban

• DVT/PE: 60 mg daily after 5–10 days of parenteral anticoagulant

• Atrial fibrillation: 60 mg daily (avoid if CrCl >95 mL/min)

Fondaparinux

• DVT/PE: 5–10 mg SC daily based on body weight

• Avoid in CrCl <30 mL/min

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6. Advantages Over Warfarin

• Predictable pharmacokinetics → no routine INR monitoring

• Fewer drug–food interactions

• Rapid onset of action

• Shorter half-life → faster reversal

• Fixed dosing

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7. Disadvantages and Limitations

• Cost – more expensive than warfarin

• Renal elimination – not ideal in end-stage renal disease

• No monitoring – disadvantage in overdose or compliance concerns

• Limited data in:

  • Mechanical heart valves

  • Moderate-to-severe mitral stenosis

  • Pregnancy/lactation

  • Pediatrics (except emerging data)

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8. Adverse Effects

A. Bleeding (Most common serious AE)

• GI bleeding (↑ with rivaroxaban)

• Intracranial hemorrhage (less than with warfarin)

• Hematuria, epistaxis

B. Hepatic

• Elevated transaminases

• Rare hepatotoxicity

C. Other

• Anemia

• Hypersensitivity reactions

• Injection site reaction (fondaparinux)

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9. Contraindications

• Active major bleeding

• Hypersensitivity to the drug

• Severe renal impairment (CrCl <15 mL/min for apixaban/rivaroxaban; <30 mL/min for fondaparinux)

• Hepatic disease with coagulopathy

• Pregnancy and breastfeeding (not adequately studied)

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10. Drug Interactions

Interacting Agent	Mechanism	Clinical Effect
CYP3A4 & P-gp inhibitors (ketoconazole, ritonavir, amiodarone)	Reduced clearance	↑ Bleeding risk
CYP3A4 inducers (rifampin, phenytoin, carbamazepine)	Increased clearance	↓ Efficacy
NSAIDs, antiplatelets	Additive bleeding risk	↑ Bleeding
SSRIs/SNRIs	Platelet inhibition	↑ Bleeding
Warfarin	Do not co-administer	↑/↓ INR unpredictably

11. Reversal Agents

Drug	Indication	Reversal Agent
Apixaban, Rivaroxaban	Major bleeding	Andexanet alfa (Andexxa®)
Edoxaban, Fondaparinux	No specific reversal agent	Prothrombin complex concentrate (PCC) or activated charcoal (if recent ingestion)

Andexanet alfa is a recombinant modified human Factor Xa decoy protein that binds and neutralizes Xa inhibitors.

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12. Monitoring Parameters

• Baseline:

  • Renal function (eGFR or CrCl)

  • Hepatic function

  • CBC, hemoglobin/hematocrit

• During therapy:

  • Bleeding symptoms

  • Renal function (especially in elderly)

  • Compliance/adherence

No routine coagulation monitoring (e.g., PT/INR or aPTT) is necessary in most cases.

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13. Comparative Summary

Feature	Apixaban	Rivaroxaban	Edoxaban	Fondaparinux
Renal dosing?	Yes	Yes	Yes	Yes
CYP metabolism	CYP3A4	CYP3A4	Minimal	None
Reversal agent?	Andexanet alfa	Andexanet alfa	Off-label PCC	Off-label PCC
Dosing frequency	Twice daily	Once/twice daily	Once daily	Once daily (SC)
Post-op prophylaxis use?	Yes	Yes	Yes (Japan, Europe)	Yes

14. Special Populations

A. Pregnancy and Lactation

• Not routinely recommended

• Lack of safety data

• Warfarin contraindicated as well → consider LMWH

B. Elderly

• Higher bleeding risk

• Adjust doses accordingly, especially for apixaban

C. Obesity

• Apixaban and rivaroxaban can be used up to 120–150 kg

• Beyond this, consider measuring anti-Xa activity or warfarin

D. Cancer-associated thrombosis

• Apixaban and edoxaban now included as options in guidelines

• Risk of GI bleeding must be balanced