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Valproate (Depakene) emerged as the best first-line choice for generalized epilepsy in a pragmatic study and lamotrigine (Lamictal) as the best first-line treatment for focal epilepsy, British researchers said.

The conclusions came from the phase IV open-label Standard and New Antiepileptic Drugs () study with two parts: a randomized trial of levetiracetam (Keppra) and valproate in newly diagnosed generalized epilepsy patients, and a randomized trial of levetiracetam, lamotrigine, and zonisamide (Zonegran) in newly diagnosed focal epilepsy patients. Results were published in separate papers in The Lancet.

In , levetiracetam did not meet non-inferiority criteria compared with valproate in intention-to-treat analysis of time to 12-month remission (HR 1.19, 95% CI 0.96-1.47; non-inferiority margin 1.329), reported Anthony Marson, MD, of University of Liverpool in England, and co-authors. Treatment failure due to inadequate seizure control was more likely with levetiracetam, and a per-protocol analysis that took treatment failure into account found valproate to be superior (HR 1.68, 95% CI 1.30–2.15). Cost-effectiveness based on differences in costs and quality-adjusted life years found valproate to be superior.

Among , levetiracetam did not meet non-inferiority criteria for 12-month remission compared with lamotrigine in intention-to-treat analysis (HR 1.18, 97.5% CI 0.95-1.47, non-inferiority margin 1.314), but zonisamide did (HR 1.03, 97.5% 0.83–1.28). Per-protocol analysis showed 12-month remission was superior with lamotrigine than either levetiracetam (HR 1.32, 97.5% CI 1.05-1.66) or zonisamide (HR 1.37, 97.5% 1.08–1.73). Lamotrigine was superior to both drugs in cost-utility analyses.

"The available evidence now identifies valproate as more clinically and cost effective than both lamotrigine and levetiracetam," Marson said in a statement. "Levetiracetam has been widely adopted in the U.K. and worldwide as a first-line treatment for focal epilepsy, but this should no longer be the case as it is neither clinically nor cost effective compared to lamotrigine," he added.

The results update , which were published in 2007. Adult and pediatric patients 5 and older were included in SANAD II. Participants subsequently diagnosed as not having epilepsy were excluded from per-protocol analyses.

"The fact that in SANAD II, levetiracetam was inferior to valproate in all effectiveness measures provides a dilemma for treating female patients with generalized epilepsy, given valproate's teratogenic potential," noted J. Helen Cross, PhD, of University College London in England, and Torbjorn Tomson, MD, PhD, of Karolinska University in Stockholm, in an .

In the U.S., the that children born to pregnant women using valproate may have impaired cognitive development and has cautioned women of childbearing age about valproate use during pregnancy due to known risks of birth defects.

The SANAD II results do not change the need to avoid unnecessary exposure to valproate during pregnancy, Cross and Tomson emphasized. "Female patients should be informed that there is approximately a 10% risk of malformations and considerable risk of adverse neurodevelopmental outcomes in children exposed to valproate in utero," they wrote. "However, they also have the right to know that treatment alternatives are likely to be less effective."

The SANAD II generalized epilepsy study included 520 people with two or more generalized or unclassifiable seizures recruited from April 2013 to August 2016 and randomized 1:1 to either levetiracetam or valproate. Most were male (65%) and median age was 13.9 years. For participants 12 and older, advised maintenance doses were 500 mg twice per day for levetiracetam and valproate; for children 5–12, advised daily doses were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. Adverse reactions were reported by 37% of people assigned to valproate and 42% assigned to levetiracetam. There were two deaths that were unrelated to trial treatments. No pregnancies occurred in participants taking valproate.

In the SANAD II focal epilepsy trial, 990 people who had two or more focal seizures were recruited between May 2013 and June 2017 and randomized 1:1:1 to lamotrigine, levetiracetam, or zonisamide. Mean age was 39.3 and 57% were men. For participants 12 or older, advised daily doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children between 5 and 12, advised doses were lamotrigine 1.5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2.5 mg/kg twice per day. Adverse reactions were reported by 33% of participants who started lamotrigine, 44% participants who started levetiracetam, and 45% participants who started zonisamide. There were 37 deaths during the trial.

"In the focal epilepsy study, low numbers of children (155 [16%] of 990 total participants) were recruited, probably related to the fact zonisamide is not licensed in this age group," the editorialists noted.

"It also needs to be acknowledged that other seizure medications have now been licensed, specifically for patients with focal seizures, that were not included in the studies," they added. "Nonetheless, the pragmatic design of the studies provides useful data for treatment choice."

The studies had several limitations, Marston and co-authors said. Seizure reports were collected through diaries and clinic visits, and some seizures may have been missed. Clinicians involved with SANAD II chose and adjusted doses according to their usual practice, and newer drugs were not assessed.