Rivaroxaban and Apixaban

Mechanism

Pharmacological Class and Group

Antithrombotics, prophylactics and anticoagulants of the class of Direct Oral Anticoagulants (DOACs) and Selective Inhibitors of Activated Factor Xa.

Mechanism of Action

The coagulation cascade converges on the common pathway with the activation of Factor X to Factor Xa. Factor

Molecular Mechanism of Direct Inhibition of Factor Xa

1. Direct, competitive and highly reversible inhibition of Factor Xa: Rivaroxaban and apixaban bind directly and selectively to the active site S1 and S4 of circulating free Factor

ACOD Xa Active Factor Xa ↓ Thrombin Generation Blocking Fibrin Synthesis

2. Buffer effect without cofactor: Unlike low molecular weight heparins (which require the presence of antithrombin III to exert their action), DOAC Xa act directly and autonomously on the target enzyme, achieving a predictable anticoagulant response independent of the circulating levels of plasma cofactors.

3. No need for routine monitoring: They present a wide therapeutic range with stable baseline response profiles, eliminating the need for continuous monitoring of prothrombin time (as occurs with Vitamin K antagonists such as warfarin).

Pharmacokinetics

High Resolution Pharmacokinetics

Indicators and dose

Clinical Indications and Uses

• Prevention of Stroke and Systemic Embolism in Non-Valvular Atrial Fibrillation: First-line, demonstrating better or equal efficacy than warfarin with substantially lower rates of intracranial hemorrhage (ROCKET-AF trials for rivaroxaban and ARISTOTLE for apixaban).
• Treatment and Secondary Prevention of Deep Vein Thrombosis (DVT) and Pulmonary Thromboembolism (PTE): Effective and safe therapeutic scheme for initial outpatient management.
• DVT/PTE prophylaxis after Major Orthopedic Surgery: Indicated after elective hip or knee replacements.

Dosage and Clinical Adjustment

Rivaroxaban:

• Prevention of Stroke in AF: 20 mg once a day orally, mandatory administered with dinner to ensure absorption.
• Renal Adjustment in AF: If the eGFR is 15 to 50 mL/min/1.73 m², the dose must be reduced to 15 mg once a day with food. Contraindicated if it is less than 15 mL/min or on maintenance dialysis.

Apixaban:

• Stroke prevention in AF: 5 mg twice a day orally continuously.
• AF Reduction Dose Adjustment (To 2.5 mg twice daily): Mandatory if the patient concurrently meets a minimum of two of the following three clinical exclusion criteria:

ABC Criteria for Apixaban Reduction in AF

To ensure safe anticoagulation and prevent severe bleeding in frail patients, reduce the apixaban dose to 2.5 mg twice daily only if at least two of the following conditions are present:

Age 80 years or Weight 60 kg or Serum creatinine 1.5 mg/dL

This dose adjustment clearly reduces the risk of major bleeding in the elderly without significantly compromising the protective efficacy against systemic cerebral embolism.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Active clinical bleeding of a severe range or pathology of high active bleeding risk.
• Terminal Stage Renal Failure (eGFR < 15 mL/min/1.73 m² or dialysis): Its use is not generally recommended in terminal stages of loss of glomerular filtration (although apixaban has guidelines for exceptional use at reduced doses in some countries).
• Valvular Atrial Fibrillation (Moderate-Severe Mitral Stenosis or Mechanical Cardiac Prosthesis): The use of DOACs in these patients is associated with catastrophic rates of thrombosis and stroke compared to VKAs.

Relative Contraindications

• Moderate to advanced renal failure with eGFR between 15 and 30 mL/min/1.73 m² (requires mandatory dose reduction).
• Moderate hepatic insufficiency (Child-Pugh Class B) or previous underlying coagulopathy.

Adverse Effects and Toxicity

• Systemic Hemorrhage (main ADR): Major bleeding from the digestive or urinary tract or deep hematomas.
• Anemia secondary to occult bleeding: Requires serial hemoglobin determinations in medical check-ups.
• Moderate thrombocytopenia: Uncommon.

Antidete Alert: Acute Reversal of Anticoagulation by Xa Inhibitors

In the case of severe, imminently life-threatening bleeding (such as active intracranial hemorrhage) or unscheduled emergency surgery, anticoagulation with rivaroxaban or apixaban can be immediately reversed using its specific antidote of choice:

Life Bleeding by DOAC Xa Administer Andexanet Alfa (Xa Recombinant Decoy)

Andexanet alfa is a modified recombinant molecule of human Factor Xa that lacks biological catalytic activity but retains intact binding affinity for Factor Xa inhibitors. It acts as a molecular decoy, binding and neutralizing free rivaroxaban or apixaban in plasma, immediately restoring normal hemostasis.

Relevant Drug Interactions

• Potent Dual Inhibitors of CYP3A4 and P-Glycoprotein (Ketoconazole, Itraconazole, Ritonavir): They critically increase the systemic exposure of DOACs Xa, doubling the risk of major spontaneous bleeding. Their joint use is contraindicated.
• Potent Dual Inducers of CYP3A4 and G-gp (Rifampicin, Carbamazepine, Phenytoin): They drastically accelerate the clearance of DOACs, decreasing their effectiveness by up to 50% and severely increasing the risk of ischemic strokes.