Comparing Efficacy and Costs of Levetiracetam and Valproate for Epilepsy

3d illustration of nerve cells.
Investigators sought to compare the long-term clinical and cost effectiveness of levetiracetam vs valproate in patients with newly diagnosed generalized or unclassifiable epilepsy.

In patients with epilepsy, levetiracetam, which has been recommended as an alternative to valproate especially for girls and women who can become pregnant, was not clinically effective or cost-effective, according to study findings published in The Lancet.

The Standard and New Antiepileptic Drug (SANAD) II trial, an open-label, phase 4 randomized controlled trial, is the first randomized controlled trial to investigate these 2 measures for patients with newly diagnosed generalized or unclassified epilepsy.

The study researchers performed the trial through UK National Health Service centers. They included adult and pediatric patients (aged at least 5 years) who had a history of at least 2 epileptic seizures and who had never been treated with an antiseizure medication.

The 520 patients had a median age of 13.9 years, and most were men or boys (65%). Most patients had generalized epilepsy (n=397), including 104 with childhood absence epilepsy. The other patients had unclassifiable epilepsies.

The study researchers randomly assigned the patients 1:1 to either the valproate or levetiracetam cohort and followed up with them for 2 years. The recommended daily dosages for patients aged 5 to 12 years was 25 mg/kg of valproate or 40 mg/kg of levetiracetam. The recommended daily dosage for patients older than 12 years of age was 500 mg 2 times daily for valproate or levetiracetam.

Findings indicated that levetiracetam did not meet their noninferiority definition for time to 12-month remission from seizures (hazard ratio [HR], 1.19; 95% CI, 0.96-1.47; noninferiority margin, 1.314).

There was a 9% higher immediate 12-month remission rate with valproate (26% vs 36%). Median time to achieve 12-month remission was shorter for valproate (445 days; 95% CI, 406-531) than for levetiracetam (636 days; 95% CI, 553-728) and per-protocol analysis showed enhanced remission with valproate as compared with levetiracetam.

The same was true for time to 24-month remission, with a difference of 12%, and time to first seizure (HR, 0.82; 95% CI, 0.67-1.00). The study researchers also found that levetiracetam was more likely to exhibit inadequate seizure control (HR, 0.43; 95% CI, 0.30-0.63).

Unadjusted total costs were higher by £61 for participants who took levetiracetam. Adjusted total costs were £104 higher for levetiracetam. Quality-adjusted life-years (QALYs) were higher for valproate (1.637 QALYs; 95% CI, 1.565-1.673) compared with levetiracetam (1.603 QALYs; 95% CI, 1.500-1.631) in the base-case analysis.

Limitations of the study included the fact that some seizures may not have been reported, the open-label nature of the trial, possible misclassification of patients, and the small number of participants classified with a specific generalized epilepsy syndrome.

”Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate,” concluded the study researchers.

Disclosure: Some study authors declared affiliations the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Marson A, Burnside G, Appleton R, et al. The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1375-1386. doi:10.1016/S0140-6736(21)00246-4