Use of levetiracetam or zonisamide as first-line treatments in newly diagnosed focal epilepsy, or levetiracetam for newly diagnosed generalised epilepsy, is not supported by the results of two parallel, randomised, unblinded controlled trials.
The SANAD II trials, published in Health Technology Assessment on 17 December 2021 and funded by the National Institute for Health Research, looked at the use of two newer anti-seizure medicines, levetiracetam and zonisamide, and whether they should be used as first-line treatments. The trials recruited 1,510 people, male and female, in the UK aged ≥5 years with newly diagnosed epilepsy between April 2013 and June 2017: of these, 990 participants had focal epilepsy and 520 had generalised or unclassified epilepsy.
In one trial, participants with focal epilepsy were started on levetiracetam, zonisamide or lamotrigine. In the other trial, participants with generalised or unclassified epilepsy were started on levetiracetam or valproate.
For the focal epilepsy trial, levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat (ITT) analysis of time to 12-month remission (hazard ratio [HR] versus lamotrigine 1.18, 97.5% confidence interval (CI) 0.95–1.47), but zonisamide did meet the criteria (HR vs. lamotrigine 1.03, 97.5% CI 0.83–1.28). The per protocol (PP) analysis, which accounted for treatment failure, found both levetiracetam and zonisamide to be inferior to lamotrigine.
Secondary outcomes of the focal epilepsy trial also suggested that treatment failure owing to adverse reactions was significantly more likely with levetiracetam and zonisamide compared with lamotrigine. Adverse reactions, including psychiatric disorders and gastrointestinal problems, were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide.
Cost-effectiveness analyses showed that neither levetiracetam nor zonisamide offered value for money for the NHS compared with lamotrigine.
The authors concluded that lamotrigine should remain a first-line standard treatment for focal epilepsy and that neither levetiracetam nor zonisamide should be used as routine first-line anti-seizure medicines.
For the generalised and unclassifiable epilepsy trial, levetiracetam did not meet the criteria for non-inferiority in the primary ITT analysis of time to 12-month remission (HR 1.19, 95% CI 0.96–1.47). The PP analysis found valproate to be superior to levetiracetam.
Adverse reactions were reported by 37% of participants starting valproate and 42% of participants starting levetiracetam.
The cost-effectiveness analyses found that levetiracetam is not good value for money for the NHS when compared with valproate.
The authors conclude that the findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy.
“For women of childbearing potential, these results inform discussions about benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate,” they add.
National Institute for Health and Care Excellence guidance, which was updated in May 2021, recommends lamotrigine for first-line treatment of focal epilepsy in females of childbearing potential, and lamotrigine or carbamazepine for males, as well as females not of childbearing age or potential.