Lamotrigine Not Associated with Increased Cardiac Events, Contrary to FDA Concerns

Among older adults treated for epilepsy, the risk for ventricular arrhythmia and sudden cardiac arrest is not elevated with the use of lamotrigine compared with levetiracetam, according to results published in Neurology.

Lamotrigine has been subject to cardiac safety concerns due to its sodium channel–blocking mechanism, which can influence cardiac conduction. In 2020, the US Food and Drug Administration issued a label warning regarding potential proarrhythmic effects of the drug in patients with structural heart conditions. To further investigate this potential risk, researchers analyzed real-world outcomes among older patients with epilepsy to determine whether initiation of lamotrigine was associated with elevated rates of ventricular arrhythmia and sudden cardiac arrest compared with levetiracetam, a commonly prescribed antiseizure medication without known cardiac conduction effects.

The researchers utilized Medicare claims data from 2007 to 2019, identifying patients aged 65 years and older with a diagnosis of epilepsy. From this cohort, 11,786 were new users of lamotrigine and 147,130 were new users of levetiracetam. Lamotrigine users were younger than levetiracetam users (median [IQR] age, 74 [69-81] vs 77 [71-84] years) and had fewer comorbidities, including:

• Heart failure (24.0% vs 35.3%)
• Arrhythmia (32.1% vs 44.7%)
• Stroke (43.6% vs 60.7%)
• Hypertension (83.5% vs 91.0%)
• Dementia (51.2% vs 58.3%)
• QT-prolonging medication use (61.7% vs 57.8%)

Over a median follow-up of 160 days, lamotrigine users had a slightly lower rate of ventricular arrhythmia and sudden cardiac arrest than levetiracetam users at 7.0 vs 8.2 per 1000 person years (adjusted hazard ratio [aHR], 0.84; 95% CI, 0.67-1.06).

Stratified by treatment duration, there were no significant differences in risk for ventricular arrhythmia and sudden cardiac arrest between cohorts, with similar rates in the first 180 days (aHR, 0.81; 95% CI, 0.60-1.10) and beyond 180 days (aHR, 0.88; 95% CI, 0.63-1.25). However, there was a significantly reduced risk for ventricular arrhythmia and sudden cardiac arrest among lamotrigine users with a history of arrhythmia (aHR, 0.51; 95% CI, 0.32-0.80) or those using antiarrhythmic medications (aHR, 0.67; 95% CI, 0.50-0.91).

Study limitations include the inability to capture out-of-hospital cardiac arrests and lack of electrocardiogram data to evaluate direct electrophysiologic effects.

“These findings do not support the FDA safety warning about lamotrigine use in people with a history of structural or functional heart disease,” the study authors concluded.