Risk of Ventricular Arrhythmia and Sudden Cardiac Arrest Among Older Patients Using Lamotrigine for Epilepsy

Lamotrigine, an antiseizure medication, blocks the activation of voltage-gated sodium channels and reduces the excitability of cardiomyocytes in vitro. Based on concerns for QT prolongation and case reports of arrhythmias among lamotrigine users, the US Food and Drug Administration placed a safety warning on lamotrigine's label in 2020. However, limited evidence exists on the cardiac risk of lamotrigine in patients with epilepsy. This study assessed whether lamotrigine users with epilepsy had an increased risk of ventricular arrhythmia and sudden cardiac arrest (VA/SCA) compared with users of levetiracetam.

This was a retrospective cohort study among Medicare-insured individuals aged 65 years or older with epilepsy (2007-2019). We identified new users of lamotrigine and levetiracetam without inpatient or emergency VA/SCA diagnosis in the 12-month continuous enrollment baseline period before initiation of treatment. Using inverse probability of treatment weighting derived from propensity scores based on baseline covariates, we compared adjusted incidence rates of inpatient or emergency VA/SCA events in lamotrigine vs levetiracetam users and estimated adjusted hazard ratios (HRs) with 95% CIs using Cox proportional hazard regression.

The study cohort (mean age 77.6 years and 60.5% female) consisted of 11,786 new lamotrigine users and 147,130 new levetiracetam users. At baseline, lamotrigine users were younger and less likely to have cardiovascular and noncardiovascular comorbidities than the levetiracetam users. The incidence and HR of VA/SCA were not statistically higher among lamotrigine users (7.0 vs 8.2 per 1,000 person-years for the lamotrigine and levetiracetam users, respectively; HR 0.84, 95% CI 0.67-1.06). Secondary analyses stratified by baseline cardiac abnormalities showed significantly reduced risk among lamotrigine users in subgroups with baseline arrhythmia (HR 0.51, 95% CI 0.32-0.80) or use of antiarrhythmic drugs (HR 0.67, 95% CI 0.50-0.91).

In older adults with epilepsy, lamotrigine was not associated with an increased risk of VA/SCA compared with levetiracetam, including among those with underlying heart disease. Our findings do not support the reported cardiac risks associated with lamotrigine or the recent changes to its safety label.