Direct oral anticoagulants

Direct oral anticoagulants (DOACs) are commonly used anticoagulants. As the name suggests, they act directly on one of the clotting factors and because they’re taken orally (except argatroban).

DOACs are mostly used as safer and non-inferior alternatives to warfarin.

They are also called novel oral anticoagulants (NOACs), although they were introduced in 2008, so this name is no longer fitting.

Compounds

• Direct thrombin inhibitors
  • Dabigatran (Pradaxa®)
  • Argatroban
    • (NB! Not taken orally, so not technically a DOAC)
• Direct factor X inhibitors
  • Apixaban (Eliquis®)
  • Rivaroxaban (Xarelto®)
  • Edoxaban (Lixiana®)
• Antidotes
  • Idarucizumab (antidote to dabigatran)
  • Andexanet (antidote to apixaban and rivaroxaban)

Indications

DOACs can be used for most indications for anticoagulants, including stroke prevention in atrial fibrillation and prevention and treatment of venous thromboembolism.

Mechanism of action

These drugs bind to and inhibit certain clotting factors directly. Dabigatran and argatroban bind to and inhibit thrombin (factor IIa). Rivaroxaban, apixaban, edoxaban are factor Xa inhibitors.

Idarucizumab is a monoclonal antibody which binds to and inactivates dabigatran. Andexanet is a modified recombinant factor Xa. Apixaban and rivaroxaban bind to andexanet with the same affinity as factor Xa, which frees up endogenous factor Xa.

Pharmacokinetics

DOACs are excreted renally, and so require dose adjustment in mild forms of kidney failure and possibly being contraindicated in severe forms. Dabigatran is renally excreted to a much larger degree than the factor Xa inhibitors.

However, they’re also metabolised by the liver and so are also contraindicated in severe liver failure.

Contraindications

• Pregnancy
• Mechanical prosthetic heart valve
• Severe kidney failure
• Severe liver failure
• Extremes of body weight (very high or very low)
  • Requires dose adjustment in some DOACs and is contraindicated for others

Reversal

Idarucizumab and andexanet can be used to reverse their effect, but are not readily available and are quite expensive. They're mostly reserved for life-threatening haemorrhage. Transfusion of fresh frozen plasma (FFP) can also reverse their effect in theory, but the clinical value of doing this is uncertain.

Monitoring

There is no routine monitoring of DOAC efficacy, as they have a predictable dose-effect relationship. Many labs can measure the serum level of the specific DOAC or the anti-factor Xa assay (a different assay from the one used for UFH/LMWH), but this does not correlate with therapeutic efficacy, only drug absorption. As such, monitoring is rarely indicated.

Advantages of DOACs vs VKAs

• Don’t require regular monitoring
• Lower bleeding risk

Disadvantages of DOACs vs VKAs

• Reversing their effect requires antidotes which are very expensive and not readily available
• More expensive