Valproate therapy for prevention of posttraumatic seizures: a randomized trial

Object. Seizures frequently accompany moderate to severe traumatic brain in jury. Phenytoin and carbamazepine are effective in preventing early, but no t late, posttraumatic seizures. In this study the authors compare the safet y and effectiveness of valproate with those of short-term phenytoin for pre vention of seizures following traumatic brain injury. Methods. The study was a randomized, double-blind, single-center, parallel- group clinical trial. Treatment began within 24 hours of injury. One hundre d thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a I-month course o f valproate, and 127 were assigned to receive a 6-month course of valproate . The cases were followed for up to 2 years. The rates of early seizures were low and similar when using either valproat e or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valpr oate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7-13.3). The rates of late seizures did not differ among tr eatment groups (15% in patients receiving the 1-week course of phenytoin, 1 6% in patients receiving the I-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8-2 .4). The rates of mortality were not significantly different between treatm ent groups, but there was a trend toward a higher mortality rate in patient s treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9-4.1). The incide nce of serious adverse events: including coagulation problems and liver abn ormalities, was similar in phenytoin- and valproate-treated patients. Conclusions. Valproate therapy shows no benefit over short-term phenytoin t herapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate -treated patients. The lack of additional benefit and the potentially highe r mortality rate suggest that valproate should not be routinely used for th e prevention of posttraumatic seizures.