On a DOAC, levetiracetam was linked to twice the clot risk of lamotrigine or lacosamide

Design

Retrospective target-trial emulation with propensity matching

Population

9,529 adults with epilepsy starting antiseizure monotherapy on a DOAC

Primary outcome

Thromboembolism, major bleeding, all-cause mortality

Effect

Levetiracetam vs lamotrigine/lacosamide: thromboembolism HR 1.98 (1.37-2.87)

A JAMA Neurology study, published on 1 October 2026, emulated target trials in an international electronic record network. It followed 9,529 adults with epilepsy, mean age 63, who started antiseizure monotherapy while taking a direct oral anticoagulant, and compared each drug group with lamotrigine or lacosamide using propensity matching.

Levetiracetam was associated with higher thromboembolic risk (HR 1.98, 95% CI 1.37 to 2.87) and higher mortality (HR 1.60, 1.23 to 2.08), with similar bleeding. Strong enzyme inducers such as carbamazepine and phenytoin were associated with more thromboembolism (HR 1.55) but less major bleeding (HR 0.62), consistent with lower DOAC levels. Valproate was associated with higher mortality (HR 1.49) and intracranial bleeding (HR 3.01). The authors estimate about 28% of thromboembolic events might have been avoided with lamotrigine or lacosamide. In patients on warfarin, risks were near null.

The levetiracetam signal is notable because it is often chosen precisely for its lack of interactions; a possible effect on P-glycoprotein has been proposed but is not established. This is observational evidence and does not prove cause, but it is a reason to think about the antiseizure drug when a patient starts a DOAC.

• Consider lamotrigine or lacosamide when choosing an antiseizure drug for a patient on a DOAC.
• Avoid strong enzyme inducers with DOACs where possible; they lower anticoagulant levels.
• Review an existing antiseizure drug when a DOAC is started for atrial fibrillation or thrombosis.
• Do not switch a well-controlled patient abruptly on this evidence alone; discuss risks and options.
• Involve the prescriber of the anticoagulant in the decision.

Why it matters

Levetiracetam is often picked as the 'interaction-free' option, and this challenges that assumption in anticoagulated patients.

Don't overread it

Observational record data — it cannot show that levetiracetam causes clots, and the mechanism is unproven.

The statistics, in plain English

A hazard ratio of 1.98 means about twice the rate of thromboembolic events, with an interval of 1.37 to 2.87 that stays clear of 1. Propensity matching balances measured factors only, so unmeasured differences between patients could explain part of it.

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