Lamotrigine is associated with a nonpathological increase in cardiac electrical conduction in people with and without heart disease

Objective The US Food and Drug Administration (FDA) issued a warning that lamotrigine slows cardiac conduction, leading to arrhythmias in people with heart disease (HD). This is the first study to investigate the within‐person changes in electrocardiographic (ECG) metrics and prevalence of ECG abnormalities when on versus off lamotrigine, in people with and without a history of HD. Methods The cohort includes 237 people with ECG both on and off lamotrigine, stratified by a history of HD ( n = 97). The within‐person percent change in heart rate and ECG metrics (PR, QRS, and heart rate‐corrected QT [QT c ] intervals) on versus off lamotrigine is compared within and between groups. Linear mixed effect regression models with adjustments for covariates assess the association between within‐subject changes in ECG metrics and pathologies when on versus off lamotrigine. Results PR interval (atrioventricular conduction) is significantly longer on‐ versus off lamotrigine (mean = 3.1% increase). There is a significant increase in the PR within the no HD (3.5%), all HD (2.8%), and structural HD groups (4.1%) when on versus off lamotrigine, but there is no difference between groups. Regression models confirm that lamotrigine is associated with an increase in PR interval in the overall cohort, as well as those with and without HD. Lamotrigine is not associated with an increased prevalence of clinically pathological PR, QRS, or QT c prolongation, or abnormal ECG interpretations. Subanalysis in people with lamotrigine serum levels in the therapeutic range indicate that each 1‐μg/mL increase in concentration is associated with a 2.3% increase in PR interval. Significance Lamotrigine leads to an increase in PR interval in the general population and people with HD (population in FDA warning). However, lamotrigine is not associated with increased odds of PR prolongation or any ECG abnormalities. Despite in vitro data predicting cardiac ECG abnormalities, particularly in people with HD, lamotrigine is not associated with the development of pathological ECG findings.