Factor Xa Inhibitors

Factor Xa inhibitors block the enzyme at the junction of the intrinsic and extrinsic pathways, reducing thrombin generation. Direct inhibitors act on factor Xa without a cofactor, and indirect inhibitors act through antithrombin. They treat and prevent thrombosis, with predictable response and little or no monitoring.

Members. Direct oral: rivaroxaban, apixaban, edoxaban. Indirect parenteral: fondaparinux (synthetic pentasaccharide), and danaparoid. Heparins also have anti-Xa effect.

Mechanism. Direct inhibitors bind the active site of free, clot-bound and prothrombinase-bound factor Xa. Fondaparinux binds antithrombin and increases its inhibition of factor Xa about 300-fold, with no effect on thrombin.

Pharmacokinetics. Direct oral inhibitors peak 1 to 4 hours with half-life 9 to 14 hours. Fondaparinux is fully bioavailable subcutaneously, with half-life 17 to 21 hours and renal clearance, so it is given once daily and accumulates in renal impairment.

• Rivaroxaban, apixaban, edoxaban: oral; dosed by indication, with the main atrial fibrillation doses given below.
• Fondaparinux: subcutaneous once daily; no heparin-induced thrombocytopenia; no specific reversal.
• Danaparoid: heparinoid used in heparin-induced thrombocytopenia where available.

• Fondaparinux prophylaxis: 2.5 mg subcutaneously daily.
• Fondaparinux treatment of venous thromboembolism: 5 mg (under 50 kg), 7.5 mg (50 to 100 kg) or 10 mg (over 100 kg) once daily, with warfarin overlap.
• Fondaparinux in non-ST-elevation acute coronary syndrome: 2.5 mg once daily for up to 8 days, with unfractionated heparin added during percutaneous coronary intervention to prevent catheter thrombosis.
• Heparin-induced thrombocytopenia: fondaparinux 5 to 10 mg daily or apixaban or rivaroxaban in stable patients.
• Oral inhibitors: apixaban 5 mg twice daily (2.5 mg if two of: age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over) in atrial fibrillation; rivaroxaban 20 mg daily with food in atrial fibrillation; edoxaban 60 mg daily.
• Selection: apixaban in older adults and gastrointestinal bleeding risk. Fondaparinux in heparin-induced thrombocytopenia and non-ST-elevation acute coronary syndrome. Do not use a direct oral inhibitor with a mechanical valve or moderate to severe mitral stenosis.

Contraindications. Active bleeding, creatinine clearance under 30 mL/min (fondaparinux; under 15 mL/min for direct oral inhibitors), weight under 50 kg for prophylactic fondaparinux (relative), and acute bacterial endocarditis.

Adverse effects. Bleeding, anaemia, injection site reaction, thrombocytopenia (rare), and liver enzyme rise.

Reversal. Andexanet alfa for apixaban and rivaroxaban where available, or four-factor prothrombin complex concentrate 25 to 50 units/kg. Fondaparinux has no antidote, and recombinant factor VIIa has been used in life-threatening bleeding. Haemodialysis does not remove factor Xa inhibitors.

Interactions. Strong CYP3A4 and P-glycoprotein inhibitors (ritonavir, ketoconazole) and inducers (rifampicin, carbamazepine, phenytoin) change oral inhibitor levels. Antiplatelet drugs and NSAIDs raise bleeding.

Monitoring. Kidney function, haemoglobin, platelets and adherence. Anti-Xa calibrated to the specific drug where levels are needed. Prothrombin time is an unreliable gauge.

Referral and escalation. Life-threatening bleeding, thrombosis despite treatment, or renal deterioration needs urgent review.

Special groups. Pregnancy: fondaparinux in heparin-induced thrombocytopenia only. Renal impairment: avoid fondaparinux below 30 mL/min. Older adults and low weight: reduce doses and monitor. Obesity: usual doses for apixaban and rivaroxaban.