Valproate therapy for prevention of posttraumatic seizures: a randomized trial

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Object. Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention 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 hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of 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 valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate 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 treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-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 treatment groups, but there was a trend toward a higher mortality rate in patients 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 incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients.

Conclusions. Valproate therapy shows no benefit over short-term phenytoin therapy 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 higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.

Article Information

Address reprint requests to: Nancy R. Temkin, Ph.D., Department of Neurological Surgery, University of Washington, Box 359924, Harborview Medical Center, 325 9th Avenue, Seattle, Washington 98104–2499. email: temkin@biostat.washington.edu.

© AANS, except where prohibited by US copyright law.

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Figures

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    Study schema. AST = aspartate aminotransferase; coag. = coagulation; PRN = pro re nata (as needed).

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    Graphs displaying average (avg.) serum levels of drugs in patients continuing on their assigned treatment. The average value observed in an individual over the period indicated is summarized. The shaded boxes extend from the 25th to the 75th percentile. Upper: Graph depicting phenytoin levels. Lower: Graph depicting valproate levels. The two subgroups of patients receiving valproate therapy are combined.

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    Graph showing the Kaplan—Meier estimate of cumulative late seizure rates in patients assigned to the three treatment arms of the study. The differences are not significant (p = 0.19).

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    Graph showing the Kaplan—Meier estimate of cumulative mortality rates in patients assigned to the three treatment arms of the study. The difference between the phenytoin group and the combined valproate groups is not significant (p = 0.07).

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