Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures

This is an updated version of the previously published Cochrane review (Issue 4, 2009)Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures with or without other generalised seizure types.

To review the best evidence comparing phenytoin and valproate when used as monotherapy in individuals with partial onset seizures or generalised onset tonic-clonic seizures with or without other generalised seizure types.

We searched the Cochrane Epilepsy Group's Specialised Register (19 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, The Cochrane Library, January 2013), MEDLINE (1946 to 18 February 2013), SCOPUS (19 February 2013), ClinicalTrials.gov (19 February 2013), and WHO International Clinical Trials Registry Platform ICTRP (19 February 2013). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.

Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy.

This was an individual patient data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI.

Individual patient data were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to generalised tonic-clonic seizures, but not absence or myoclonus seizure types. For remission outcomes, HR > 1 indicates an advantage for phenytoin and for first seizure and withdrawal outcomes HR > 1 indicates an advantage for valproateThe main overall results (pooled HR adjusted for seizure type, 95% CI) were time to (a) withdrawal of allocated treatment 1.09 (0.76 to 1.55); (b) 12-month remission 0.98 (0.78 to 1.23); (c) six-month remission 0.95 (0.78 to 1.15) and (d) first seizure 0.93 (0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. No statistical interaction between treatment and seizure type (partial versus generalised) was found, but misclassification of seizure type may have confounded the results of this review.

We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.