DOACs

Mechanism of Action

DOACs have a novel mode of action, and are widely used for the treatment and prevention of DVT, and stroke prevention in atrial fibrillation. Anticoagulants target thrombi in the veins. In contrast, thrombi in faster flowing arteries are mainly composed of platelets, making antiplatelet medication would be more effective. 

DOACs do not require routine INR monitoring, offering greater convenience. However easily accessible monitoring can be advantageous in certain circumstances where monitoring for efficacy and toxicity is required. Anti-xa levels can be monitored with Xa inhibitors however this is not routine practice. 

Four DOACs currently available:

• Factor Xa inhibitors: apixaban, rivaroxaban, edoxaban
  • Reversibly inhibit factor xa, which inhibits thrombin generation and thrombus development.
• Direct thrombin inhibitor: dabigatran
  • Reversibly inhibits free thrombin, fibrin bound thrombin and thrombin-induced platelet aggregation. 

Created in BioRender. Boucher, M. (2025) https://BioRender.com/w7hteoo

Fig 1: the clotting cascade and actions of anticoagulants

Apixaban

Apixaban can be taken with or without food, this does not impact on efficacy. Apixaban is a CYP3A4 substrate and P-gp transporter substrate, leading to several drug interactions.

Interactions

• Avoid strong CYP3A4 and P-gp inhibitors such as ketoconazole, itraconazole, voriconazole, posaconazole and HIV protease inhibitors e.g. rivonavir (risk of increased levels of apixaban)
• With strong CYP3A4 and P-gp inducers (such as phenytoin, carbamazepine, phenobarbital or st john’s wort) – risk of subtherapeutic levels of apixaban, cautiously use in prophylactic therapy i.e. stroke prevention in AF, avoid if using for treatment of DVT

Special populations

• Higher exposure found in elderly, lower body weights and renal impairment: dose adjustment often required

Rivaroxaban

Rivaroxaban 15mg and 20mg doses should be taken with food, as this has been shown to increase absorption. Like apixaban, rivaroxaban is a CYP3A4 and P-gp transporter substrate

Interactions

• Avoid strong inhibitors of CYP3A4 and P-gp (e.g. ketoconazole, itraconazole, voriconazole and HIV protease inhibitors). Risk of increasing rivaroxaban plasma levels. 
• Caution with drugs which strongly inhibit either CYP3A4 or P-gp (e.g. clarithromycin) or moderate inhibitors of CYP3A4 (e.g. fluconazole) – risk of increasing rivaroxaban plasma levels – may only be clinically significant in high risk patients e.g. in renal impairment. 
• Avoid strong CYP3A4 inducers (e.g. rifampicin) unless the patient is closely observed for signs and symptoms of thrombosis

Special populations

Rivaroxaban has increased plasma levels in renal impairment therefore dose adjustment is advised.

Edoxoban

Edoxaban can be taken with or without food and there is currently no reversal agent. Edoxaban is a P-gp transporter substrate leading to some clinically significant drug interactions.

Interactions

• Increased plasma levels with  P-gp inhibitors (e.g. ciclosporin*, erythromycin*, ketoconazole*, verapamil) 
• Reduced plasma levels with P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital and st john’s wort) 

*when edoxaban is concomitantly administered with these medications, a dose reduction for edoxaban is recommended by the manufacturer. 

Special populations

Increased edoxaban exposure in low body weight (≤60kg) and renal impairment: dose adjustment required 

Dabigatran 

Dabigatran is a potent, competitive, reversible direct thrombin inhibitor. Thrombin enables the conversion of fibrinogen into fibrin in the coagulation cascade, so its inhibition prevents thrombus development.  

Dabigatran is a prodrug (dabigatran etexilate) and is converted to active dabigatran. Food delays absorption by 2 hours but does not affect the bioavailability, therefore no recommendation is made upon taking dabigatran in relation to food. Dabigatran is a P-gp substrate leading to several clinical significant drug interactions. 

Interactions

• Dose reduction advised with mild-moderate P-gp inhibitors
• Avoid with strong P-gp inhibitors (e.g., ketoconazole, dronedarone, ciclosporin, itraconazole, glecaprevir/pibrentasvir): increased exposure of dabigatran expected 
• Avoid with P-gp inducers (e.g., rifampicin, st john’s wort, carbamazepine, phenytoin or ritonavir): expected to reduce efficacy of dabigatran.

Special populations

Higher exposure in elderly patients (75 years old) and renal impairment: dose adjustment advised 

Reversal

Apixaban and rivaroxaban

Rivaroxaban and apixaban can be reversed by the same agent, andexanet alfa (Ondexxya▼), which has the followng mechanism of action:

• Binding and sequestering of the factor xa inhibitor
• Inhibits tissue factor pathway inhibitor which can increase tissue factor initiated thrombin generation, leading to a procoagulant effect

Dabigatran

Idarucizumab neutralises the anticoagulant effect of dabigatran by binding to dabigatran with very high affinity (approximately 300-fold more potent than the binding affinity of dabigatran for thrombin). 

Edoxaban

There is currently no reversal agent for edoxaban

Summary Table

References

1. SPC Apixaban https://www.medicines.org.uk/emc/product/2878/smpc accessed 9/9/24
2. SPC Rivaroxaban Xarelto 20mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 9/9/24
3. SPC edoxaban Lixiana 15mg Film-Coated Tablets – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 9/9/24
4. SPC Dabigatran Dabigatran Etexilate 110 mg hard capsules – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 9/9/24
5. Spc Praxbind 2.5 g/50 mL solution for injection/infusion – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 9/9/24