Association of Ventricular Arrhythmias with Lamotrigine: An Observational Cohort Study

Whether lamotrigine (LTG) is associated with ventricular tachycardia (VT) in bipolar disorder (BPD), partial seizures (PSZ) and generalized tonic-clonic seizures (GTSZ) with and without structural heart disease (SHD) remains controversial. A mechanistic rational for LTG-induced re-entrant cardiac arrhythmias has recently been elucidated, leading to a real-world comparative cohort observational study being warranted.

A retrospective observational comparative safety study was performed using a large healthcare claims database of adult participants analyzing the one-year cumulative VT. Analytic cohort included adult participants diagnosed with bipolar I disorder (BPD), partial seizures (PSZ) or generalized tonic-clonic seizures (GTSZ). Participants were free from supraventricular or ventricular arrhythmias during the 6-month baseline period before the index LTG or CTR date. Exposure to LTG versus commonly prescribed alternative agents were the control comparators (CTR). One-year cumulative ventricular tachycardia (VT) incidence was calculated separately for GTSZ, PSZ and BPD using Kaplan-Meier estimator, with participants being censored at last enrollment, treatment switching or discontinuation. The VT association hazard ratios (HR) for LTG versus CTR was adjusted for baseline characteristics.

The analytic cohort included 153,852 LTG and 213,593 CTR for BPD, 10,275 LTG and 24,971 CTR for PSZ, and 5,860 LTG and 17,506 CTR for GTSZ. Baseline cardiovascular risk profiles were higher among CTR than LTG across the three sub-analytic cohorts. The 1-year VT cumulative incidence from LTG or CTR free from was 0.79% vs 0.68% in BPD, 0.76% vs 0.58% in PSZ, and 0.93% vs 0.40% in GTSZ cohorts, The adjusted HR [95% CI] estimates were 1.326 [1.122-1.568, p<0.01], 1.403 [0.920-2.138, p=0.11], and 1.180 [0.607-2.295, p=0.63].

In adult participants, LTG has a strong association to increase VT risk compared to commonly prescribed alternatives.

Question: Does lamotrigine investigated in a real-world database increase the risk of ventricular tachycardia in patients with epilepsy or bipolar disease? Findings: The lamotrigine-ventricular tachycardia association was statistically significant in adult bipolar disease participants. Although limited statistical significance, the positive association is ubiquitous across epileptic conditions. Structural heart disease has a notable increased effect on the incidence on the onset of ventricular tachycardia. Meaning: Caution should be exercised in the use of lamotrigine in adult bipolar disease patients to avoid ventricular tachycardia.