A large Danish study of more than 90,000 users of lamotrigine found no associated risk of developing cardiac rhythm and conduction abnormalities in persons without pre-existing cardiac morbidity or an increased risk of death in patients with pre-existing cardiac disease.

Last year, the American health authorities, FDA, warned that the drug lamotrigine could increase the risk of serious cardiac conduction disorder, which may be life-threatening for patients with pre-existing cardiac disease.

Lamotrigine is one of the most common antiseizure drugs in the treatment of epilepsy and depressive episodes in patients with bipolar disease. FDA has issued the warning based on studies of cell cultures, which have shown that lamotrigine may inhibit sodium channels of the heart, which may affect cardiac rhythm.

- It is important to both patients and doctors to know the risks and balance the beneficial effects and the possible side effects of lamotrigine when we talk about treatment of epilepsy and bipolar disorder. To increase our knowledge about the possible side effects shown in cell cultures, we have used Danish registries to study the risk of heart disease and mortality in persons who use lamotrigine, says Jakob Christensen, Consultant at Aarhus University Hospital and Associate professor at Aarhus University. Jakob Christensen is a specialist in both neurology and clinical pharmacology, and he has been working with Danish registries for many years.

Researchers from Aarhus University Hospital and Aarhus University have identified 91,949 persons above 15 years in the Register of Medicinal Product Statistics, who received at least one prescription for lamotrigine between 1997 and 2016. Through the Danish National Patient Registry and the Causes of Death Registry the researchers have identified persons who developed heart disease and persons who died within two years from starting lamotrigine treatment.

-We did not find a significant difference in risk associated with lamotrigine treatment despite access to complete Danish registry data. Our results do not support the FDA warning against use of lamotrigine among persons at risk of cardiac conduction disorder, says Jakob Christensen.

The researchers have made several statistical and control analyses of data.

- The side effects are serious, and we have made many different analyses to be sure we have not missed anything. We found e.g., an increased risk of skin rash, which was expected because it is a well-known side effect of lamotrigine treatment, says Julie Werenberg Dreier, senior researcher at the National Centre for Register-based Research at Aarhus University.

- We also found an increased risk of cardiac arrhythmia with use of another drug where this is also a known side effect. Overall, it seems that with our design and the data available to us, we would be able to identify an increased risk of cardiac arrhythmia also in patients using lamotrigine - if there was a risk.

Observational studies like this study cannot deliver decisive evidence for or against an increased risk in patients with pre-existing heart disease using lamotrigine. The Danish researchers therefore support the FDA wish for more studies on the cardiac risk of several other drugs affecting the cardiac sodium channels in the same way as lamotrigine.


Behind the research result:

Study type: Registry study comprising more than 90,000 new users of lamotrigine above 15 years of age

Collaborators: National Centre for Register-based Research and Centre for Integrated Register-based Research (CIRRAU) at Aarhus University

External funding: The study was supported by The Danish Epilepsy Association, Central Denmark Region and the Novo Nordisk Foundation (NNF16OC0019126)

Conflicts of interest: Jakob Christensen has received a fee for lectures and for being a member of the scientific advisory committee at UCB Nordic and Eisai AB. Jakob Christensen has received travel support from UCB Nordic. The other authors declare no conflicts of interest.

Read the scientific article:

Christensen J, Trabjerg B, Dreier JW. Cardiac Morbidity and Mortality Associated with the Use of Lamotrigine. Epilepsia. 2022 Jun 23. doi: 10.1111/epi.17339. Epub a head of print. PMID: 35735211.

Further information:

Jakob Christensen, Consultant
Department of Neurology, Aarhus University Hospital
and Associate professor at Department of Clinical Medicine, Aarhus University
Tel.: +45 6086 5899, e-mail: jakob@farm.au.dk