Background: About 50 persons in 100,000 have epilepsy. In 30 to 40 percent of cases, seizures are generalized. This form of epilepsy usually begins at an early age and has a genetic predisposition, but it does not have obvious causative factors. Valproate (Depacon) currently is recommended as a first-line therapy for patients with generalized seizures, although there is little evidence from randomized controlled trials to support its use. With alternative drugs now available, the Standard and New Antiepileptic Drug study was conducted in the United Kingdom to compare the efficacy, tolerability, quality of life, and economic impacts of valproate, lamotrigine (Lamictal), and topiramate (Topamax) in patients with generalized seizures.

The Study: Patients attending specialized outpatient hospital clinics were eligible if they had at least two unprovoked epileptic seizures within one year before the start of the study and were eligible for valproate therapy. Patients were excluded if they had any progressive neurologic condition or contraindication to any of the study medications.

Following a detailed demographic and medical history, including data on personal and family history of seizures, patients who were classified as having generalized or unclassified seizures were randomly allocated to receive one of the three study medications (i.e., valproate, lamotrigine, or topiramate). The treating physician managed the dosage of the study medication to establish the minimal effective dose for each patient.

The two primary outcomes measured were time to a one-year remission of seizure and time to treatment failure, which was defined as discontinuation of medication because of inadequate control of seizures or intolerable adverse effects, or the addition of another antiseizure agent. Secondary outcomes assessed included time to first seizure, time to achieve a two-year remission, adverse events, quality-of-life measures, and cost-effectiveness.

The 238 patients assigned to valproate were comparable with the 239 patients in the lamotrigine group and the 239 patients in the topiramate group. The mean age of the participants was 22 years, and the average age at first seizure was 18 years. About 25 percent of patients had unclassified seizures, and 88 percent had never been treated for seizures.

Results: Follow-up was achieved for the equivalent of 2,333 patient-years. For time to treatment failure, valproate was significantly better than topiramate or lamotrigine. Early treatment failures were attributed to adverse effects, whereas later treatment failures generally reflected inadequate control of seizures. Clinically significant adverse events were reported by 36 percent of patients receiving valproate, 37 percent of those receiving lamotrigine, and 45 percent of those receiving topiramate. Lethargy or fatigue was the most prevalent adverse event and was reported by 20 percent of the patients in the topiramate group, 12 percent of those taking valproate, and 9 percent of patients receiving lamotrigine.

Overall, more than 80 percent of patients achieved remission of seizure at one year. Valproatewasstatisticallysuperiortolamotrigine. The effectiveness of topiramate was intermediate between the two other drugs, but the difference between valproate and topiramate did not achieve statistical significance.

Only 165 patients completed the questionnaires on cost and quality of life, but the available data indicated that topiramate was less expensive and more effective than lamotrigine. Valproate performed best on cost-per-seizure-avoided and on quality-of-life measures.

Conclusion: Valproate should remain as the first-line therapy for patients with generalized or difficult-to-classify seizures. Because this was a heterogeneous group of patients, individual patients may achieve better results with one of the other agents. In particular, consideration must be given for women of childbearing age and the potential adverse effects of valproate during pregnancy.

editor's note: In a companion article,¹ the authors report on comparisons of therapy for partial onset seizures in 1,721 patients. They compared carbamazepine (Tegretol), gabapentin (Neurontin), lamotrigine, oxcar-bazepine (Trileptal), and topiramate. For time to treatment failure for patients with partial seizures, lamotrigine performed significantly better than the other medications, although the difference between lamotrigine and oxcarbazepine did not reach statistical significance. For time to 12-month remission, carbamazepine was considered the best medication overall. However, the authors conclude that lamotrigine had the best overall clinical performance compared with the other study medications, and it is a cost-effective alternative to carbamazepine for partial onset seizures.—a.d.w.