(197) The Risk of Hypokalemia in Patients Treated with Levetiracetam: A Comparative Cohort Study

Background: Although levetiracetam is an effective anticonvulsant drug with a positive benefit-risk profile, multiple cases of hypokalemia have been reported, following levetiracetam use, which may lead to serious cardiovascular complications, muscle weakness, Ileus disease, or renal failure. However, establishing causal relationship between levetiracetam and hypokalemia based on case reports might confounded by other therapies or comorbidities.

Objectives: To investigate the possible causal association between the use of levetiracetam and the development of hypokalemia using an active comparator approach. Considering the potential influence of class effects and if patients with drugs or conditions commonly associated with levetiracetam developed hypokalemia.

Methods: This was a retrospective cohort study using Real-world Evidence Research Network at Saudi Food and Drug Authority (SFDA) between 2016 and 2022. The cohort comprised adults (≥ 18 years old) who initiated either levetiracetam or carbamazepine (active comparator) and had no history of hypokalemia during the six months prior to initiation of either drugs. The index date was the first levetiracetam or carbamazepine prescription’s date. Patients were followed until end of 2022, end of follow-up period (i.e. 6-months), death, loss of follow-up, or occurrence of hypokalemia. Study outcome definition was as ascertained based on diagnostic code (E87.6) or by serum potassium level (levels below 3.5 mmol/L). To control the measurable confounding factors, we employed a stabilized inverse probability of treatment weighting (IPTW) estimation in a Cox proportional hazards model.

Results: A total of 8,982 patients entered the study cohort, and their baseline characteristics were comparable between the two groups after IPTW adjustment. The incidence rate of hypokalemia was 303 cases per 10,000 patient-years in levetiracetam-exposed cohort compared to 57 cases per 10,000 patient-years among carbamazepine users. Patients exposed to levetiracetam had a higher hazard of hypokalemia, with an adjusted hazard ratio (HR) of 1.99 (95% confidence interval [CI], 0.88-4.49). By restricting hypokalemia definition to cases of moderate to severe hypokalemia we observed an adjusted HR of 2.17 (95% CI, 0.93-5.03). The different modeling assumptions in the sensitivity analysis yielded comparable results to the main analysis.

Conclusions: Our study found that risk of hypokalemia with levetiracetam cannot be ruled given the wide confidence intervals. Further studies with a larger sample size and different data source are needed to confirm our findings.