Lamotrigine and Cardiac Arrhythmias. A Target Trial Approach

W. S. Terman, C. B. Josephson, P. Goyal, A. Gonzalez-Izquierdo, J. Morrison, S. Denaxas, and S. Wiebe. Neurology. 2025 Jul 8;105(1):e213640. doi: 10.1212/WNL.0000000000213640. Epub 2025 Jun 11.

Background and objectives: While lamotrigine is an effective, well-tolerated antiseizure medication (ASM), a recent warning raised the possibility of ventricular arrhythmias. We compared arrhythmia incidence between patients newly treated for seizures with lamotrigine and those with levetiracetam (presumed cardiac-inert control). Methods: We included patients whose first ASM prescription fill was after the first seizure or epilepsy ICD code in the study period, with no ASM in the previous year. We conducted retrospective cohort studies to emulate a target trial using two datasets: (1) 2009 to 2018 Medicare claims (United States) and (2) Clinical Practice Research Datalink (CPRD), a population-based cohort (United Kingdom). We examined cumulative incidence curves for ventricular tachycardia or fibrillation (VT/VF) from Cox proportional hazard models. Results: We included 40 554 patients (lamotrigine: 3038; levetiracetam: 37 516) from Medicare and 13 098 (lamotrigine: 8694; levetiracetam: 4404) from CPRD. In Medicare, the median (interquartile range) age was 61 (44-74) years and 60% were female in the lamotrigine group versus 74 (65-82) years and 57% female in the levetiracetam group. In CPRD, the median (interquartile range) age was 34 (23-53) years and 63% were female in the lamotrigine group versus 48 (29-66) years and 50% female in the levetiracetam group. After adjusting for demographics, comorbidities, and medication use, the hazard ratio for VT/VF comparing patients whose first ASM was lamotrigine versus levetiracetam was 0.73 (95% confidence interval (CI) 0.50-1.08) for Medicare and 0.75 (95% CI 0.35-1.59) for CPRD, with a 2-year cumulative incidence of 1.7% (95% CI 1.0%-2.3%) versus 2.3% (95% CI 2.1%-2.4%) for Medicare and 0.2% (95% CI 0.1%-0.4%) versus 0.3% (95% CI 0.2%-0.6%) for CPRD. In both datasets, lamotrigine showed a slightly but nonsignificantly lower 2-year absolute difference in cumulative incidence of VT/VF compared with levetiracetam (Medicare: −0.6%, 95% CI −1.2% to 0.0%; CPRD: −0.1%, 95% CI −0.3% to 0.1%). Numerous sensitivity analyses modifying the outcome (atrial arrhythmias or any arrhythmias), censorship procedure (further censoring patients on discontinuing their initial ASM akin to a “per-protocol” analysis), or population (patients with existing cardiovascular diagnoses) found similar results. Discussion: These data do not support concerns regarding lamotrigine increasing arrhythmias. Limitations include possible residual confounding and lack of generalizability to other populations. Classification of evidence: This study provides Class III evidence that lamotrigine compared with levetiracetam did not significantly increase the 2-year cumulative incidence of VT/VF in adult patients with epilepsy.

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

G. Y. F. Ho, D. B. Horton, P. J. Patel, T. Gerhard, and C. V. Dave. Neurology. 2025 Jul 8;105(1):e213643. doi: 10.1212/WNL.0000000000213643. Epub 2025 Jun 11.

Background and objectives: 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. Methods: 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 versus levetiracetam users and estimated adjusted hazard ratios (HRs) with 95% confidence intervals (Cis) using Cox proportional hazard regression. Results: 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 1000 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). Discussion: 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.