Levetiracetam Compared with Valproate for Generalized and Unclassifiable Epilepsy

June 2022

The first-line treatment for generalized and unclassifiable epilepsy is valproate. The teratogenicity of valproate, however, makes treatment decisions complex for women and girls of childbearing age. Approximately 10% of fetuses exposed to valproate have major malformations and one-third have IQ deficits. Alternatives to valproate are needed, but as yet no other therapies have shown noninferiority in head-to-head randomized clinical trials. Levetiracetam is becoming more commonly used as an alternative to valproate, but evidence that levetiracetam is as effective as a monotherapy is lacking.

The SANAD II (Standard and New Antiepileptic Drugs) trials are head-to-head comparisons to assess noninferiority and cost-effectiveness among common therapies for epilepsy. In this report, the investigators asked whether levetiracetam was as clinically effective and cost-effective as valproate for newly diagnosed generalized epilepsy and unclassifiable epilepsy.

The study was a phase 4 open-label, randomized controlled trial that was also designed to test superiority. It included 520 participants aged ≥5 years who had experienced at least 2 generalized or unclassifiable seizures. The median age was 13.9 years, and 76% of participants received a diagnosis of generalized epilepsy. Participants were randomly assigned to receive valproate or levetiracetam and were followed for at least 2 years by the National Health Service in the United Kingdom. The primary outcome was the time from the start of therapy to the end of a 12-month period without a seizure (12-month remission).

The investigators found that levetiracetam did not reach the threshold of noninferiority for time to 12-month remission. The median time to 12-month remission for valproate was 445 days, whereas it was 636 days for levetiracetam. Valproate was also superior to levetiracetam for time to 24-month remission, time to first seizure, and time to treatment failure for any reason.

In a subgroup analysis, however, no significant difference in time to 12-month remission was found between valproate and levetiracetam for patients with unclassifiable epilepsy or absence epilepsy. Because of this result, the investigators suggested that future studies should separate generalized and unclassifiable epilepsy groups.

Valproate was also more cost-effective than levetiracetam. In addition, more patients taking levetiracetam had psychiatric symptoms compared with patients taking valproate. Approximately 4% of each group experienced severe adverse reactions.

The SANAD II investigators stated that these results demonstrated that men with generalized epilepsy should take valproate over levetiracetam as a first-line therapy. For women, the choice remains complex. “Regulators, guideline developers, clinicians, and patient groups should now consider the benefit-to-risk ratio of each treatment. Some women might prefer a drug with greater efficacy notwithstanding the risk of teratogenicity, while others might prefer one that is safer in pregnancy despite lower efficacy,” the investigators stated.


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.

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