Direct oral anticoagulant agents are now routinely used for the prevention of stroke in nonvalvular atrial fibrillation
Rivaroxaban, apixaban and dabigatran are now commonly used as alternatives to vitamin K antagonist therapy (e.g., warfarin) for patients with atrial fibrillation, and for the treatment and prevention of venous thromboembolism. Dabigatran is a direct thrombin inhibitor, whereas apixaban and rivaroxaban are direct inhibitors of factor Xa.1
Risk of bleeding with direct oral anticoagulants is lower than with vitamin K antagonists, but varies by site
In a meta-analysis, fewer incidents of major bleeding were reported with direct oral anticoagulants than with vitamin K antagonists. Specifically, fewer intracranial bleeds occurred, but the incidence of gastrointestinal bleeding was higher.1
Direct oral anticoagulants are characterized by rapid onset of action and short half-lives2
Depending on the anticoagulant, the onset of action varies from 1.5 to 4 hours, with a half-life between 5 and 17 hours (Appendix 1, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.150604/-/DC1). Dabigatran tends to have a shorter onset of action and longer half-life, compared with rivaroxaban and apixaban. Drug interactions can occur with all three drugs.
Direct oral anticoagulants variably affect standard clot-based assays
All three drugs cause variable test results. This may depend on the instrument and reagents used. The results may not have linear correlation to plasma concentrations of the drugs. The activated partial thromboplastin time is more sensitive to dabigatran, but a normal result does not preclude the ongoing presence of drug and concordant bleeding risk. A normal thrombin time, however, rules out the presence of dabigatran. The prothrombin time (PT) is more sensitive to factor Xa inhibitors. Depending on the reagent used, PT may be normal even with therapeutic concentrations of factor Xa inhibitors. In general, the international normalized ratio is not helpful.3
Idarucizumab has recently been approved by the US Food and Drug Administration to reverse the activity of dabigatran
Idarucizumab is a humanized monoclonal antibody against dabigatran. Now in phase 3 clinical trials, andexanet is a recombinant factor Xa derivative designed to competitively counteract apixaban and rivaroxaban. Current strategies are largely extrapolated from bleeding in other settings (Box 1).4
Potential management strategies for bleeding caused by direct oral anticoagulants and warfarin
| Agent | Strategy |
|---|---|
| Warfarin | Vitamin K, PCC, FP, TXA |
| Dabigatran | Activated charcoal, hemodialysis, aPCC, TXA or idarucizumab |
| Rivaroxaban | PCC, TXA |
| Apixaban | PCC, TXA |
Note: aPCC = activated prothrombin concentrates, FP = frozen plasma, PCC = prothrombin complex concentrates, TXA = tranexamic acid.
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Footnotes
Competing interests: Alun Ackery and Michelle Sholzberg received personal fees from Boehringer Ingelheim to attend a regional advisory board meeting to discuss the development of an antidote to dabigatran. No other competing interests were declared.
This article has been peer reviewed.
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- Direct oral anticoagulant agents are now routinely used for the prevention of stroke in nonvalvular atrial fibrillation
- Risk of bleeding with direct oral anticoagulants is lower than with vitamin K antagonists, but varies by site
- Direct oral anticoagulants are characterized by rapid onset of action and short half-lives2
- Direct oral anticoagulants variably affect standard clot-based assays
- Idarucizumab has recently been approved by the US Food and Drug Administration to reverse the activity of dabigatran
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