Abstracts

Lamotrigine (LTG) is a commonly prescribed anti-seizure medication that has indications in many other diseases, such as bipolar disorder, major depressive disorder, migraine prophylaxis, and neuropathic pain. It is a frequently used medication due to its efficacy with low rates of serious adverse events and its perceived safety during pregnancy. It is a class 1B antiarrhythmic that reduces the late sodium current. In October 2020 and March 2021, the U.S. Food and Drug Administration (FDA) announced a warning of arrhythmias associated with lamotrigine, particularly in patients with structural and functional heart disease. The warning was based on in vitro results from a single study, which has not been validated in clinical trials. This study assesses the changes in cardiac ECG metrics when people with and without cardiovascular disease are on vs. off lamotrigine.

Data retrieval was performed using SlicerDicer, a feature of the EPIC electronic medical record system. The study cohort consists of 237 people with an ECG off and on lamotrigine, stratified by history of cardiovascular disease (CVD, N=97). The last ECG before starting LTG and the first ECG after starting LTG ( >5-days post-prescription, average 11 months) were used for analysis. Cardiac electrical conduction (PR interval, QRS duration) and repolarization (QT_c interval) measures were collected from the ECG. The percent change in ECG metrics on vs. off lamotrigine was calculated, and 1-sample Wilcoxon signed-rank tests were conducted within each group.

In the whole cohort, the PR interval was 3.3% longer on vs. off lamotrigine (p< 0.001, Fig.1). This was seen in both the CVD and No-CVD groups. There was no significant change in the QRS duration or QT_c interval in the overall cohort, or when stratifying for CVD. Three percent of subjects (7:237) had normal PR when off, but pathologically prolonged PR ( >200ms) while on LTG, with an average PR increase of 17%. Conversely, 2.5% of subjects (6:237) had pathological PR prolongation off LTG, but normal PR intervals on lamotrigine, with an average PR decrease of 16% on lamotrigine. Twelve subjects had PR prolongation both off and on lamotrigine, with an average PR increase of 4%.

In line with the FDA warning that lamotrigine can have off-target cardiac effects, LTG leads to a significant increase in the PR interval, which was seen in both people with and without CVD. Yet, only 3% developed pathological PR prolongation when on LTG, and there was no change in QRS or QT_c duration.