Epistemis

Rivaroxaban / Apixaban

  • Direct Acting Oral Anticoagulants (DOACs)

Direct Factor Xa Inhibitors (e.g. *Xarelto*, *Eliquis*).

Mechanism

Mechanism of Action

Rivaroxaban and Apixaban are small hydrophobic synthetic molecules that act as reversible, competitive and highly selective inhibitors of the active center of Factor Xa (both free and integrated into the prothrombinase complex).

Molecular Mechanism of Direct Factor Xa Inhibitors

1. Factor Xa is the convergence enzyme of the intrinsic and extrinsic coagulation pathways. It binds to Factor Va, anionic phospholipids and calcium to form the prothrombinase complex, which converts Factor II (Prothrombin) to Factor IIa (Thrombin) through proteolytic cleavage.
2. A single milligram of Factor Xa is capable of catalyzing the generation of more than 1,000 milligrams of thrombin in seconds (enzymatic amplification).
3. Rivaroxaban and Apixaban directly penetrate the S1 and S4 specificity pocket of the active Factor Xa molecule.
4. This binding blocks the interaction of Factor Xa with its substrate (prothrombin), stopping the coagulation cascade before the polymerization of fibrinogen to fibrin. They do not require a plasma cofactor such as AT-III to exert their action.

Pharmacokinetics

Comparative Pharmacokinetics

PK parameterRivaroxabanApixaban
Bioavailability (F)80% to 100% (10 mg dose). For doses of 20 mg it drops to 66%, requiring mandatory administration with food to optimize gastric absorption.Approximately 50%. It is not altered by food intake.
Protein BindingVery high (~92% to 95%, mainly albumin).High (~87%).
Hepatic Metabolism~66% of the total dose is metabolized in the liver by the isoenzymes CYP3A4, CYP3A5 and CYP2C8 to inactive metabolites.~25% metabolized by CYP3A4/3A5 a polar metabolites.
ExcretionDual route: 33% is excreted via the kidneys as active unchanged drug; 33% via the kidney as inactive metabolites; 33% bile-fecal route.Mainly biliary and fecal (~75%); unaltered direct renal excretion of only 27%.
Half-life (t1/2)5 to 9 hours in young people; 11 to 13 hours in the elderly due to physiological renal decline.8 to 15 hours (average 12 hours) with recommended dosing every 12 hours.

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): Co-administered with ASA in the prevention of atherothrombotic events in patients with chronic coronary artery disease (CAD) or symptomatic peripheral arterial disease (PAD) at high risk of events.

Dosage and Settings

Rivaroxaban

  • Stroke prevention in AF: 20 mg orally once a day with dinner. Renal adjustment: Reduce to 15 mg once daily if CrCl is between 15 and 49 mL/min. Contraindicated if it is less than 15 mL/min.
  • Acute DVT/PE Treatment: 15 mg twice daily orally (with food) for the first 21 days; followed by 20 mg once daily for the long-term maintenance phase.

Apixaban

  • Stroke prevention in AF: 5 mg orally twice a day. 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. Body weight 60 kg.
    3. Serum creatinine 1.5 mg/dL (133 µmol/L).
  • Treatment of DVT/PE: 10 mg twice daily orally for 7 days; followed by 5 mg twice daily orally long-term.

Pregnancy and Breastfeeding

FDA Category C. There is a lack of sufficient studies in pregnant women. They cross the placenta and are associated with the risk of fetal hemorrhage and reproductive toxicity. Its use is contraindicated during pregnancy. It is not recommended during breastfeeding; Animal data show high excretion in breast milk.

Security

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 (ADR)

  • 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).

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

PreviousWarfarin Sodium / Acenocoumarol
System
Hematology
Cluster
Direct Acting Oral Anticoagulants (DOACs)
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