Abstract
W. S. Terman, C. B. Josephson, P. Goyal, A. Gonzalez-Izquierdo, J. Morrison, S. Denaxas, and S. Wiebe. Neurology. 2025 Jul 8;105(1):e213640. doi: 10.1212/WNL.0000000000213640. Epub 2025 Jun 11.
G. Y. F. Ho, D. B. Horton, P. J. Patel, T. Gerhard, and C. V. Dave. Neurology. 2025 Jul 8;105(1):e213643. doi: 10.1212/WNL.0000000000213643. Epub 2025 Jun 11.
Commentary
Lamotrigine is a widely used antiseizure medication with a favorable safety profile and effectiveness in various seizure syndromes, including focal and generalized epilepsies. This agent is well tolerated across the age spectrum and is often preferred for women of childbearing potential because of its reassuring data in pregnancy. In addition to good tolerability, lamotrigine has few clinically relevant drug–drug interactions, does not induce hepatic enzymes or require routine laboratory safety monitoring. These advantages have been recently hindered by concerns that lamotrigine can provoke cardiac arrhythmia. 1 Lamotrigine blocks voltage-gated sodium channels, which explains much of its antiseizure action, and exhibits class IB antiarrhythmic activity at therapeutic concentrations. 2 However, at high concentrations or under certain predisposing conditions, lamotrigine was shown to slow ventricular conduction and promote reentrant arrhythmias in experimental models. 3 Further, rare case reports described QRS widening, QTc prolongation, cardiac arrhythmias, and sudden cardiac death in patients with high risks or those with polypharmacy. 4 Collectively, these findings raised concern about cardiac safety and prompted a regulatory warning in 2020 indicating that lamotrigine may increase the risk of sudden cardiac death through QRS prolongation in susceptible individuals.1,5 However, clinical evidence to date has been mixed: some early observational and randomized studies do not show a clear increase in risk, while a smaller cohort study suggested a possible risk.6–8 These conflicting findings leave clinicians uncertain, prompting calls for more definitive evidence, particularly in patients with pre-existing cardiac disease and those taking other sodium-channel blockers.
To address this gap, two large epidemiologic studies using real-world data have recently been undertaken at US academic centers.9,10 In the first study, Terman and colleagues examined patients with newly initiated lamotrigine for seizure indications and compared them with new users of levetiracetam, a drug not thought to affect cardiac conduction. 9 They used two complementary datasets: US Medicare claims and the UK CALIBER, a data platform combining the national health records from outpatient and inpatient encounters, together capturing more than 50 000 individuals taking one of these agents for the first time. The investigators methodically characterized demographics, structural epilepsy etiologies, mood comorbidities, cardiovascular risk factors, and concomitant use of sodium channel-blocking drugs, as well as socioeconomic factors that could influence adherence. Using standardized adjustment of these covariates within Cox proportional hazards models, they estimated hazard ratios (HRs) and standardized cumulative incidence rates (IRs) for ventricular tachycardia (VT), ventricular fibrillation (VF), and cardiac death in the intention-to-treat and per-protocol analyses. They found that across approximately 2 years of follow-up, the absolute risk of ventricular arrhythmias was low, and the cumulative incidence of ventricular arrhythmia did not differ between lamotrigine and levetiracetam users. In fact, lamotrigine users had lower all-cause death rates, which could have been due to better adherence to this medication compared to levetiracetam and overall improvement in seizure-related mortality. Sensitivity analyses that reintroduced patients with baseline cardiac conduction diseases still did not show an increase in fatal arrhythmia or cardiac deaths with lamotrigine.
Ho and colleagues extended this work by focusing specifically on older adults with epilepsy in a large Medicare cohort and examining the risks of VT, VF, or flutter and sudden cardiac death. 10 The authors compared new lamotrigine users with new levetiracetam users and excluded individuals with prior emergency or inpatient diagnoses of ventricular arrhythmia or sudden cardiac arrest. Unlike the investigators in the first study, 9 they did not limit the analysis to monotherapy with lamotrigine, which provides a more practical view of real-world prescribing where polytherapy is common. As in the first study, lamotrigine users tended to be younger and had fewer cardiovascular comorbidities. Therefore, the investigators applied inverse probability of treatment, aiming to balance the clinical characteristics of cohorts taking lamotrigine and levetiracetam. They used several baseline covariates, such as age, cardiac disease burden, and concomitant administration of sodium channel-blocking agents. The authors estimated adjusted IR and HR ratios for ventricular arrhythmia and sudden cardiac death using Cox models. The results again showed no evidence that lamotrigine increased the risk of serious ventricular arrhythmias or cardiac death compared with levetiracetam (HR 0.84, 95% confidence interval (CI), 0.67-1.06). Further, lamotrigine users had a significantly lower risk of fatal arrhythmia or sudden death if they had pre-existing arrhythmias or used other antiarrhythmic medications.
Taken collectively, these two large, methodologically complementary studies deliver a consistent message that lamotrigine, when prescribed for epilepsy, does not increase cardiac risk. The studies focused on new lamotrigine users and adjusted for a rich set of confounders; they examined outcomes in overall cohorts as well as in clinically important subgroups. The consistency of findings across diverse populations, using multiple analytic approaches, strengthens the conclusion that the 2020 regulatory warning may overstate the cardiac risk in patients with epilepsy, including those already receiving treatment for arrhythmia. At the same time, important caveats remain. Both studies rely on administrative data and therefore capture arrhythmias that lead to hospital encounters, while out-of-hospital sudden deaths may have been missed. Further, information on family history, baseline electrocardiogram (ECG) features, and detailed seizure history was limited, likely leading to some residual confounding. Importantly, the 2-year follow-up period may be insufficient, and existing studies may not fully capture long-term cardiac risks, potentially leading to an underestimation of such risks in lamotrigine users.
For clinicians, this combined evidence is highly relevant to everyday epilepsy practice. For most patients with epilepsy, particularly those who are elderly or frail, lamotrigine remains a reasonable and often very effective treatment option. The finding of no increase in serious ventricular arrhythmias and cardiac death is especially reassuring. Reasonable precautions still include attention to concurrent use of sodium channel blockers or agents known to prolong QT interval, as well as consideration of a baseline ECG in patients with known structural heart disease. Future work should integrate population-based data with systematic ECG phenotyping and mechanistic cardiac studies to identify additional subgroups that may be more vulnerable.
