What are Direct Oral Anticoagulants (DOACs)?

Direct Oral Anticoagulants (DOACs)

Direct oral anticoagulants (DOACs) are a class of medications that directly inhibit specific coagulation factors, including oral direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban), representing the current standard of care for the prevention and treatment of common thrombotic disorders. 1

Types and Mechanisms of Action

DOACs can be classified based on their specific targets in the coagulation cascade:

• Factor Xa inhibitors:

  • Apixaban
  • Edoxaban
  • Rivaroxaban
  • These directly inhibit activated factor Xa 1

• Direct thrombin inhibitors:

  • Dabigatran - prevents activation of factor II reversibly 1

Clinical Applications

DOACs are widely used for:

1. Stroke prevention in non-valvular atrial fibrillation 1
2. Treatment and prevention of venous thromboembolism (VTE) 1
3. Prevention of VTE after orthopedic procedures (particularly hip and knee arthroplasty) 1

Advantages Over Traditional Anticoagulants

DOACs offer several benefits compared to vitamin K antagonists (VKAs) like warfarin:

• Fixed dosing without need for routine monitoring 1
• Limited dietary interactions 1
• Faster onset and offset of action 1
• Lower risk of intracranial hemorrhage 1
• More predictable pharmacokinetics 1

Important Considerations and Limitations

Contraindications

• Mechanical heart valves: DOACs are contraindicated in patients with mechanical prosthetic valves 2
• Triple-positive antiphospholipid syndrome: Not recommended due to increased rates of recurrent thrombotic events compared to vitamin K antagonist therapy 2, 3
• Severe renal impairment: Use with caution or avoid depending on the specific DOAC and degree of impairment 2, 3

Drug-Drug Interactions

Drug interactions are an important consideration with DOACs:

• P-glycoprotein (P-gp) interactions: All DOACs are substrates of P-gp and may interact with strong inducers or inhibitors of this drug transporter 1
• CYP3A4 interactions: Rivaroxaban and apixaban are particularly susceptible to drugs altering cytochrome P450 isoenzyme activities 1, 4
• Combined inhibitors: Avoid concomitant use of DOACs with drugs that are known combined P-gp and strong CYP3A4 inhibitors/inducers 3

Management of Bleeding

In case of major bleeding, specific reversal agents are available:

• Idarucizumab (Praxbind): Specific reversal agent for dabigatran 1, 5
• Andexanet alfa: Specific reversal agent for factor Xa inhibitors (particularly rivaroxaban and apixaban) 1, 5
• Prothrombin Complex Concentrates (PCCs): Non-specific reversal agent when specific antidotes are unavailable 5

Monitoring

Unlike warfarin, routine coagulation monitoring is generally not required for DOACs. However, in specific situations, testing may be helpful:

• Conventional tests (PT/INR, aPTT) have limited utility for monitoring DOAC effect 5, 6
• Specialized tests may be used in specific situations:
  • Calibrated chromogenic anti-FXa assays for factor Xa inhibitors
  • Diluted thrombin time or ecarin clot time for dabigatran 5, 6

Perioperative Management

For patients requiring procedures:

• Minimal bleeding risk procedures: DOACs may be continued or discontinued only on the day of procedure 7
• Low to moderate bleeding risk: Discontinue DOACs 1 day before and restart 1 day after 7
• High bleeding risk: Discontinue DOACs 2 days before and restart 2 days after 7

Future Developments

The next generation of anticoagulants targeting factors XI/XIa and XII/XIIa are currently under investigation. These emerging medications are expected to have different risk-benefit profiles compared to current DOACs 1.