Researchers from the University of Liverpool and the University of Zurich have identified a potential safety consideration involving levetiracetam, one of the world's most commonly prescribed antiseizure medications.
Some people with epilepsy also have conditions such as atrial fibrillation, an irregular heart rhythm that increases the risk of stroke and requires treatment with direct oral anticoagulants (DOACs), a widely used class of blood-thinning medicines. As a result, an estimated 6% of people with epilepsy receive concomitant treatment with an antiseizure medication and a DOAC, equivalent to approximately 36,000 of the 600,000 people living with epilepsy in the UK.
A study published in JAMA Neurology found that people with epilepsy taking levetiracetam alongside a DOAC, including medicines such as apixaban and rivaroxaban, had almost twice the risk of stroke, heart attack or other serious blood clots compared with patients taking alternative antiseizure medications.
The international study also found that patients taking levetiracetam had a 60% higher risk of death, although there was no significant difference in the risk of major bleeding.
Some antiseizure medications are already known to reduce the effectiveness of blood thinners by increasing the breakdown of medicines in the liver. However, levetiracetam has generally been considered less likely to interact with other drugs and is frequently prescribed for patients requiring anticoagulation.
To investigate whether this assumption was justified, researchers analysed anonymised electronic health records from 165 healthcare organisations within the international TriNetX network. From more than 2.29 million adults with epilepsy, they identified 9,529 patients who started an antiseizure medication while taking a DOAC.
Dr Gashirai Mbizvo, Senior Clinical Lecturer in Neurology at the University of Liverpool and Consultant Neurologist at The Walton Centre NHS Foundation Trust, said: "Levetiracetam is often favoured in people taking anticoagulants because it has generally been assumed not to interact significantly with these medications.
"Our findings challenge that assumption and suggest that patients taking levetiracetam alongside direct oral anticoagulants may face a substantially higher risk of serious blood clots and death than those taking alternative antiseizure medications.
"Importantly, this study identifies a safety signal rather than proving that levetiracetam directly causes these outcomes. Patients should not stop or change either their antiseizure medication or anticoagulant without medical advice."
The researchers found that levetiracetam, which was taken by the majority (57%) of the study population, was associated with almost twice the risk of stroke, heart attack or other thromboembolic events compared with lamotrigine or lacosamide.
The study also confirmed concerns about older enzyme-inducing antiseizure medications, including carbamazepine and phenytoin, which were associated with a 55% higher risk of blood clots and a 38% lower risk of major bleeding, a pattern consistent with reduced anticoagulant effectiveness.
Professor Marian Galovic, from the University of Zurich, said: "This study demonstrates the value of international collaboration in addressing important questions that cannot easily be answered through conventional clinical trials.
"Further research is now needed to replicate these findings and better understand the mechanisms responsible for the increased risks we observed."
Researchers emphasise that maintaining seizure control remains critically important and that alternative antiseizure medications will not be suitable for every patient.
The Medicines and Healthcare products Regulatory Agency (MHRA) has been notified of the findings.
The paper, 'Safety of Antiseizure Medications During Direct Oral Anticoagulant Therapy in Epilepsy' was published in JAMA Neurology (DOI: 10.1001/jamaneurol.2026.2712).
