Lamotrigine and Cardiac Arrhythmias: A Target Trial Approach.

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 2 datasets: (1) 2009-2018 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: 3,038; levetiracetam: 37,516) from Medicare and 13,098 (lamotrigine: 8,694; levetiracetam: 4,404) from CPRD. In Medicare, the median (interquartile range) age was 61 (44-74) years and 60% were female in the lamotrigine group vs 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 vs 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 vs levetiracetam was 0.73 (95% 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%) vs 2.3% (95% CI 2.1%-2.4%) for Medicare and 0.2% (95% CI 0.1%-0.4%) vs 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.