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Direct acting oral anticoagulants and risk of recurrent thrombotic events
Medicines Safety Update
Health professionals are advised that the Product Information (PI) documents for direct acting oral anticoagulants (DOACs) registered in Australia are being updated to include new information about increased risk of recurrent thrombotic events in patients diagnosed with antiphospholipid syndrome (APS).
The DOACs marketed in Australia are apixaban (brand name Eliquis), dabigatran etexilate (Pradaxa) and rivaroxaban (Xarelto).
DOACs are indicated in adults for:
- the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip or total knee replacement surgery
- prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke
- treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE.
Additionally, rivaroxaban in combination with aspirin is indicated for:
- the prevention of major cardiovascular events (composite of stroke, myocardial infarction and cardiovascular death) in patients with coronary artery disease and/or peripheral artery disease.
A clinical trial (TRAPS study1) has shown an increase in the risk of recurrent thrombotic events with rivaroxaban compared to warfarin in patients with APS, a history of thrombosis and a high risk of recurrent thrombotic events (patients who are triple positive for lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies). While there are currently no completed controlled trials relating to this issue for the other two DOACs marketed in Australia, these medicines may be associated with a similar risk.
The final results from an investigator-led randomised controlled trial comparing apixaban and warfarin for secondary prevention of thromboembolism in patients with APS (ASTRO-APS), recently closed due to lack of enrolment, are not yet available.
A review by the European Medicines Agency (EMA) found that the use of DOACs in patients with APS could be associated with increased rates of recurrent thrombotic events compared with treatment with a vitamin K antagonist. The level of evidence for increased risk of recurrent thrombotic events in patients differs between agents, but there is insufficient evidence that any DOAC offers sufficient protection in patients with APS, particularly high risk patients, such as those who are triple positive for lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies.
The TGA has investigated this safety issue and is working with sponsors to update the PI documents for apixaban, dabigatran etexilate and rivaroxaban to reflect current evidence. The Australian sponsors of these medicines have recently sent a joint Dear Health Care Professional letter relating to this matter. A similar action was taken in Europe.
Information for health professionals
DOACs are not recommended in patients with APS, particularly high-risk patients (patients who are triple positive for lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies).
Identify patients you may have that are diagnosed with APS and are receiving treatment with a DOAC. Review whether continued treatment is appropriate, particularly in high-risk patients. If appropriate, consider changing to alternative therapy.
It is recommended that you encourage patients to discuss with you any issues or concerns they have about their treatment.
Please continue to report any suspected adverse events relating to DOACs to the TGA, including any thrombotic events thought to be related to treatment failure or lack of efficacy.
- Pengo V, Dena G, Zoppellaro G et al Rivaroxaban vs warfarin in high risk patients with antiphospholipid syndrome - Blood Journal - July 2018
What to report? You don't need to be certain, just suspicious!
The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.
We particularly request reports of:
- all suspected reactions to new medicines
- all suspected medicines interactions
- suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
Reports may be submitted:
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
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Medicines Safety Update is written by staff from the Pharmacovigilance and Special Access Branch.
Acting Editor: Dr Grant Pegg
Deputy Editor: Mr Michael Pittman
Contributor: Mr Andrew Case