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

SPS commentary:

The researchers suggest these data inform discussions about benefit and harm of avoiding valproate in girls and women of child-bearing potential.

A commentary notes that since 1990, many new antiseizure medications have been launched, many of which have been licensed on the basis of evidence from add-on therapy in resistant epilepsies; there have been few head-to-head comparative data in patients who are newly diagnosed. Standard and New Antiepileptic Drugs (SANAD) I, the first SANAD trial, provided the first comprehensive data to address this question; lamotrigine was shown to be superior to carbamazepine, gabapentin, oxcarbazepine, and topiramate in time to treatment failure, and valproate was a clinically and cost-effective alternative to lamotrigine or topiramate. Since these trials were done, other medications have been licensed for use, and levetiracetam has been increasingly considered a safe alternative in the treatment of both focal and generalised epilepsies, despite few head-to-head comparative data. The Lancet, SANAD II—two pragmatic, open-label, randomised trials provide useful data in addressing this issue.

According to the commentary, the fact that in SANAD II, levetiracetam was inferior to valproate in all effectiveness measures provides a dilemma for treating female patients with generalised epilepsy, given valproate's teratogenic potential. The recommended maintenance dose of valproate to adult participants was 1000 mg per day in SANAD I and II, a dose linked to a higher risk of malformations, as well as poor cognitive outcome. It suggests it would have been interesting to compare the efficacy of a lower dose of valproate, associated with less teratogenic risks, with that of levetiracetam. It points out that as the European Medicines Agency, contraindicates valproate in women who are able to have children unless the terms of a special pregnancy prevention programme are followed, female patients with generalised epilepsy are denied the most effective treatment, and it is an open question whether drugs shown to have inferior efficacy could be considered as suitable alternative treatments. It concludes that the new findings do not change the need to make every effort to avoid unnecessary exposure to valproate during pregnancy but female patients should be informed that there is ~ 10% risk of malformations and considerable risk of adverse neurodevelopmental outcomes in children exposed to valproate in utero, and they also have the right to know that treatment alternatives are likely to be less effective.

In the other RCT (n=990), levetiracetam and zonisamide did not meet definition of non-inferiority for time to 12-month remission vs. lamotrigine and was inferior for time to treatment failure, and neither were found to be cost-effective alternatives.