Oral Anticoagulants

Vitamin K antagonists

Vitamin K antagonists include warfarin, acenocoumarol and phenindione. Warfarin is the most commonly used vitamin K antagonist therefore will be focused on in this article. 

Warfarin

Mechanism of action

Warfarin inhibits the enzyme vitamin K epoxide reductase, reducing the regeneration of vitamin K1. Vitamin K1 is responsible for synthesising vitamin K dependent clotting factors II, VII, IX, X, therefore warfarin decreases clotting ability. Vitamin K1 also synthesises anticoagulant proteins C and S.

After taking a vitamin K antagonist, it takes 48-72 hours for it to take effect; this is due to the half lives of the vitamin K dependent clotting factors:

• Factor II: ~60 hours
• Factor VII: 4–6 hours
• Factor IX: 24 hours
• Factor X: 48–72 hours

At the start of treatment with warfarin there can be a prothrombotic effect (especially in patients with a protein C and S deficiency) because proteins C and S have shorter half-lives (8 hours and 30 hours respectively). The prothrombotic effect lasts until the vitamin K dependent clotting factors have circulated out of the body. 

For this reason, patients who are at high risk thrombosis will receive bridging therapy often with low molecular weight heparin (LMWH) until the international normalised ratio (INR) is within a therapeutic range. 

Monitoring 

Warfarin has a narrow therapeutic window/index, requiring monitoring with the international normalised ratio (INR). The dose of warfarin is usually adjusted based on the INR.

• An INR measures how long it takes for your blood to clot
• A normal INR = 1
• Common targets:
  • INR 2.5 (range 2–3) for AF, DVT, or PE
  • Higher or variable targets for mechanical prosthetic heart valves
• INR below range → risk of thrombosis
• INR above range → risk of bleeding

Interactions

Warfarin is a mixture of enantiomers: 

• R-warfarin is metabolised by CYP1A2 and CYP3A4
• S-warfarin is metabolised by CYP2C9 

Reversal 

Warfarin’s effect can be reversed with vitamin K (oral/IM depending on urgency). Patients should be counselled on consuming a similar amount of vitamin K daily through diet e.g. liver, broccoli, brussels sprouts and green leafy vegetables, to avoid INR fluctuations.

Direct oral anticoagulants (DOACs)

DOACs have a novel mode of action, and are widely used for the treatment and prevention of DVT, and stroke prevention in atrial fibrillation. They 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. 

Apixaban 

• Taken with or without food, this does not impact on efficacy
• Pharmacokinetics: CYP3A4 substrate and P-gp transporter substrate
• 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. 
• Pharmacokinetics: CYP3A4 substrate 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: increased plasma levels in renal impairment, dose adjustment is advised.

Reversal (apixaban and rivaroxaban)

• Rivaroxaban and apixaban can be reversed by the same agent, andexanet alfa (Ondexxya▼). 
• Mechanism: 
  • Binding and sequestering the factor xa inhibitor
  • Inhibits tissue factor pathway inhibitor which can increase tissue factor initiated thrombin generation, leading to a procoagulant effect

Edoxoban

• Edoxaban can be taken with or without food. 
• There is currently no reversal agent for edoxaban
• Pharmacokinetics: P-gp transporter substrate
• 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 exposure in low body weight (≤60kg) and renal impairment: dose adjustment required 

Dabigatran 

• Prodrug (dabigatran etexilate) converted to active dabigatran. 
• Mechanism: potent, competitive, reversible direct thrombin inhibitor. Thrombin enables the conversion of fibrinogen into fibrin in the coagulation cascade, so its inhibition prevents thrombus development.  
• Administration: Food delays absorption by 2 hours but not affect the bioavailability
• Pharmacokinetics: Dabigatran is a P-gp substrate
• 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: 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). 

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