Cardiac Risk Warning for Lamotrigine Challenged

Real-world data from two new studies showed no increased risk for cardiac issues in older adults with epilepsy taking the antiseizure medication (ASM) lamotrigine (Lamictal) vs levetiracetam. The findings add to growing evidence that may eventually lead the FDA to reconsider its current cardiac safety warning, researchers said.

The FDA added the cardiac warning label in 2020 based on in vitro studies and case reports of arrhythmias in some patients with underlying heart disease who were taking the drug.

However, as reported by Medscape Medical News at that time, several groups challenged the severity of the warning — particularly given that clinicians had been prescribing lamotrigine for three decades without the widespread evidence of such risks.

The first new cohort study used data from US Medicare claims and UK claims for more than 53,00 total patients. Its findings showed no difference in new diagnoses of ventricular tachycardia/ventricular fibrillation (VT/VF) between patients initiating the use of lamotrigine and those initiating the use of levetiracetam.

Results from the second cohort study, which used Medicare data of nearly 12,000 new lamotrigine users and nearly 150,000 new levetiracetam users, showed no significant between-group differences in incidence of ventricular arrhythmia and sudden cardiac arrest (VA/SCA).

The study was prompted by the FDA’s safety warning, which was based on limited evidence, lead author Gloria Y.F. Ho, PhD, told Medscape Medical News.

“Our study was done in people, had a comparator, and also looked at several subgroups. And we did not find an increased risk” for cardiac outcomes, said Ho, visiting scholar at the Center for Pharmacoepidemiology and Treatment Science at Rutgers University, New Brunswick, New Jersey.

The findings for both studies were published online on June 11 in Neurology.

Closing the Evidence Gap

Lamictal accounts for “about 10% of all antiseizure medication use,” the investigators noted in a press release. It remains first-line therapy for certain forms of epilepsy, according to the American Epilepsy Society (AES) and the American Academy of Neurology.

The drug inhibits voltage-gated sodium channels, which is a mechanism also implicated in regulating cardiomyocyte excitability.

In October 2020, the FDA updated the lamotrigine label to warn about its potential to prolong QT interval, induce new arrhythmias, and slow ventricular conduction in patients with structural or functional heart disease on the basis of an in vitro electrophysiologic study and some case reports.

In addition, rodent studies have shown prolonged QT interval time with high-dose lamotrigine vs placebo or a low dose of the drug.

“However, it is uncertain whether these findings are applicable to human physiology,” Ho and colleagues wrote. They added that other studies have often been underpowered to detect rare outcome risks.

“In such instances, real-world data sources can help provide valuable insights to fill this gap,” they noted.

Class III Evidence

In the first study, led by Samuel W. Terman, MD, from the Department of Clinical Neurosciences at the University of Calgary, Calgary, Alberta, Canada, participants were included if they had filled their first ASM prescription following a first seizure or epilepsy diagnosis, with no prescriptions for this drug class in the previous year.

The full patient population included 40,554 patients from Medicare (3038 lamotrigine users and 37,516 levetiracetam users) and 13,098 patients from the UK Clinical Practice Research Datalink (CPRD; 8694 lamotrigine users and 4404 levetiracetam users).

In the Medicare group, the median age of those receiving lamotrigine vs levetiracetam was 61 vs 74 years. In the CPRD group, the median age was 34 vs 48 years.

The adjusted hazard ratio (HR) for VT/VF was 0.73 for lamotrigine vs levetiracetam in the Medicare dataset and 0.75 for lamotrigine vs levetiracetam in the CPRD dataset. The cumulative incidences were 1.7% vs 2.3% and 0.2% vs 0.3%, respectively.

In addition, lamotrigine showed a “slightly, but nonsignificantly, lower 2-year absolute difference” in cumulative VT/VF incidence in both datasets, the researchers wrote.

Sensitivity analyses assessing such things as atrial or any arrhythmias and existing cardiovascular diagnoses showed similar results.

“This study provides class III evidence that lamotrigine did not significantly increase the 2-year cumulative incidence of VT/VF in adult patients with epilepsy,” the investigators wrote. They added that the findings “do not support concerns regarding lamotrigine increasing arrhythmias.”

No Risk in Patients With Heart Disease

Using 2007-2019 data of Medicare-insured patients with epilepsy and aged at least 65 years, Ho and her team assessed 11,786 new users of lamotrigine (mean age, 74 years; 64% women) and 147,130 new users of levetiracetam (mean age, 77 years; 60% women).

Results showed similar incidence of VA/SCA between the two treatment groups (7 vs 8.2 per 1000 person-years; P =.15) and a nonsignificantly higher adjusted HR of 0.84 for the lamotrigine vs levetiracetam groups (P =.13). The HRs for VA and SCA individually were similar at 0.86 and 0.83, respectively.

Secondary analyses showed no increased risk for VA/SCA in lamotrigine vs levetiracetam users with a baseline history of cardiac conditions, such as heart disease or heart failure.

However, lamotrigine users with a baseline history of arrhythmias had a significantly reduced risk for VA/SCA (HR, 0.51) and for the use of any antiarrhythmic drugs (HR, 0.67).

The investigators noted that although “it has been postulated that lamotrigine increases the risk for VA/SCA because of its pharmacodynamic properties,” this assertion was based on studies that did not include older at-risk adults, including those with a history of heart disease. The new findings “do not support” the current FDA warning label, they added.

“Lamotrigine is a very common and effective drug. Because of the FDA warning, it may limit its use in people who could benefit from it. Because they have a history of heart disease, they may not be able to get the prescription and this could affect the clinical management of epilepsy,” Ho said.

Still, she recommended that clinicians evaluate patients on a case by case basis. “At the end of the day, people in this age group may have other comorbidities and may be taking other medications. So I cannot just say, ‘This is safe. Go ahead and use it,’” she said.

Ho also noted that the findings may not be generalizable to younger patients because they used Medicare data of individuals older than 65 years or generalizable to those without epilepsy because the drug is also prescribed as a mood stabilizer for bipolar disorder.

Two Studies, Same Conclusion

In an accompanying editorial, Leah J. Blank, MD/MPH, assistant professor of neurology at the Icahn School of Medicine at Mount Sinai, New York City, noted that both groups of investigators used real-world data and advanced analysis techniques to answer safety questions surrounding the drug.

Although Blank pointed out both studies were observational and retrospective in nature, she wrote that the researchers accounted for all of that in their measures.

“Together, these data suggest that lamotrigine likely is safe in clinical practice and can continue to be used as an effective and well tolerated antiseizure medication,” Blank wrote.

She also told Medscape Medical News that she prescribes the medication in her own practice.

“The studies were important because lamotrigine is an excellent antiseizure medication and it appears to be very well tolerated. Patients tend to like it and do well on it,” said Blank.

“It’s reassuring that two different groups, using slightly different methods, came to the same conclusion that there is not an increased risk for cardiac events in people taking lamotrigine,” she said.

Blank said it is worth noting that the human data do not support the FDA warning label.

Asked whether it would be taking the new findings into consideration regarding its safety warning, a spokesperson for the FDA told Medscape Medical News that, in general, it does not comment on specific studies.

Rather, the organization “evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

In addition, a representative for the AES told Medscape Medical News that the organization is not currently working on a statement based on these studies at this time.

Although the first study’s investigators reported having “no financial disclosures or competing interests relevant to the study,” Terman reported having received support from Xenon Pharmaceutical and Jazz Pharmaceutical in the past for unrelated activities. The second study’s investigators and Blank reported having no relevant financial relationships.