Rivaroxaban / Apixaban

Mechanism

Mechanism of Action

Rivaroxaban and apixaban are small synthetic molecules acting as reversible, competitive and selective inhibitors of the active site of Factor Xa (both free and integrated into the prothrombinase complex)..

Molecular Mechanism of Direct Factor Xa Inhibitors

1. Factor Xa connects the intrinsic and extrinsic coagulation pathways. It assembles with factor Va, anionic phospholipids and calcium to form the prothrombinase, which converts factor II (prothrombin) into factor IIa (thrombin) by proteolysis.
2. One milligram of factor Xa can catalyse production of more than 1,000 milligrams of thrombin within seconds (enzymatic amplification).
3. Rivaroxaban and apixaban bind directly to the S1 and S4 specificity pockets of active factor Xa.
4. This blocks factor Xa's interaction with prothrombin and interrupts coagulation before fibrinogen polymerization. They do not require a plasma cofactor such as AT-III.

Pharmacokinetics

Comparative Pharmacokinetics

Indicators and dose

Indications

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation with one or more risk factors (CHA2DS2-VASc scale).
• Treatment of acute DVT and PE, and secondary prevention of recurrence.
• VTE prophylaxis after hip or knee replacement surgery.
• Rivaroxaban (low dose 2.5 mg): Combined with aspirin to prevent atherothrombotic events in selected patients with chronic coronary artery disease or symptomatic peripheral artery disease at high event risk.

Dosage and Adjustments

Rivaroxaban

• Prevention of Stroke in AF: 20 mg orally once daily with the evening meal. Kidney adjustment: Reduce to 15 mg once daily when CrCl_Cr is 15–49 mL/min. Not recommended below 15 mL/min under European product information.
• Acute DVT/PE Treatment: 15 mg orally twice daily with food for the first 21 days, then 20 mg once daily for maintenance.

Apixaban

• Prevention of Stroke in AF: 5 mg orally twice daily. Dose adjustment to 2.5 mg twice daily if the patient meets at least two of the following three criteria:
  1. Age ≥ 80 years.
  2. Peso corporal ≤ 60 kg.
  3. Serum creatinine ≥ 1.5 mg/dL (133 µmol/L).
• Treatment of DVT/PE: 10 mg orally twice daily for 7 days, then 5 mg orally twice daily.

Pregnancy and Breastfeeding

FDA Category C. Insufficient studies in pregnant patients. They cross the placenta and are associated with fetal bleeding and reproductive toxicity risks. Its use is contraindicated during pregnancy. Not recommended during breastfeeding; animal data show substantial milk transfer.

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Contraindications

• Clinically significant active bleeding from any location.
• Organic injury or pathology with serious risk of major bleeding (e.g., active or recent gastrointestinal ulcer, neoplasms with high risk of bleeding, recent brain or spinal surgery).
• Coexistence with any other anticoagulant agent (except during the transition of the therapeutic regimen).
• Hepatopathy associated with clinically relevant coagulopathy and significant bleeding risk (Child-Pugh class B and C).
• End-stage renal failure (creatinine clearance < 15 mL/min or patients undergoing chronic dialysis).
• Wearers of mechanical heart valve prostheses.

Adverse effects (ADRs)

• Hemorrhage: Main ADR (epistaxis, hematuria, gastrointestinal bleeding, menorrhagia). The overall risk of intracranial hemorrhage is statistically lower compared to adjusted VKAs (~50% reduction in phase III clinical trials).
• Anemia: Consequent to chronic subclinical blood loss.
• Elevation of liver enzymes: Transient and usually reversible increase in transaminases.
• Hypersensitivity reactions: Pruritus, rash, urticaria and, rarely, anaphylaxis.

Interactions

Both drugs are substrates of P-glycoprotein (P-Gp) and cytochrome CYP3A4. Therefore:

• Increased effect and bleeding risk: Coadministration with strong combined inhibitors of CYP3A4 and P-Gp (such as Ketoconazole, Itraconazole, Voriconazole, Ritonavir).
• Decreased effect and risk of therapeutic failure (Thrombosis): Coadministration with potent combined inducers of CYP3A4 and P-Gp (Rifampicin, Phenytoin, Carbamazepine, Phenobarbital, St. John's Wort).