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

Phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset (simple partial, complex partial and secondary generalized tonic-clonic seizures) seizures whilst valproate is more effective in generalized onset seizures (generalized tonic-clonic seizures, absence, myoclonus) although there is no evidence from randomized controlled trials to support this belief. The use of individual patient data meta-analysis enabled us to examine time to event outcomes which are important in epilepsy monotherapy trials, and also to examine treatment-covariate interactions.

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

Our search strategy included: (i) the Cochrane Epilepsy Group trial register, (ii) MEDLINE 1966-2000, (iii) hand-searching relevant journals, (iv) the pharmaceutical industry, and (v) researchers in the field.

Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenytoin monotherapy with valproate monotherapy.

This was an individual patient data review. Outcomes were time to (i) withdrawal of allocated treatment, (ii) 12 month remission, (iii) six month remission, and (iv) first seizure post randomization. Data were analysed using stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. A test for interaction between treatment and seizure type (partial onset versus generalized onset) was also undertaken for each outcome.

Data were available for 669 subjects from five trials, representing 60% of the subjects recruited into the eleven trials that met our inclusion criteria. One important limitation of these data is that in four of the five trials, for patients classified as having generalized onset seizures, tonic-clonic seizures were the only seizure types recorded at follow up, despite the fact that some patients will have been experiencing other generalized seizure types such as absence or myoclonus. Their results for the generalized seizures therefore relate only to generalized onset tonic-clonic seizures. The main overall results were as follows (HR(95% CI), HR>1 indicates a clinical advantage for phenytoin for both remission outcomes and a clinical advantage for valproate for the outcomes time to withdrawal and time to first seizure) (i) time to withdrawal of allocated treatment 1.10(0.79-1.54), (ii) time to 12 month remission 1.04(0.78-1.38), (iii) time to six month remission 0.89(0.71-1.11), and (iv) time to first seizure 0.92(0.74-1.14). The results suggest no overall difference between drugs for these outcomes. The test for an interaction between treatment and seizure type (generalized versus partial onset) was non significant for all outcomes.

We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. As generalized seizures such as absence and myoclonus were counted in only one trial, results do not address the treatment of these seizure types. We found no unequivocal evidence to overthrow or support the policy of using valproate in generalized onset tonic-clonic seizures and phenytoin in partial onset seizures.