Abstract
Background
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). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013.
Objectives
To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types).
Search methods
We searched the Cochrane Epilepsy Group’s Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
Selection criteria
Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy.
Data collection and analysis
This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI.
Main results
IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to partial onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (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 valproate.
The main overall results (pooled HR adjusted for seizure type) were time to: (a) withdrawal of allocated treatment 1.09 (95% CI 0.76 to 1.55); (b) achieve 12-month remission 0.98 (95% CI 0.78 to 1.23); (c) achieve six-month remission 0.95 (95% CI 0.78 to 1.15); and (d) first seizure 0.93 (95% CI 0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. We did not find any statistical interaction between treatment and seizure type (partial versus generalised).
Authors’ conclusions
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
Plain language summary
Phenytoin versus valproate monotherapy(single drug treatment) for partial onset seizures and generalised onset tonic-clonic seizures
Background
Epilepsy is a disorder in which recurrent seizures are caused by abnormal electrical discharges from the brain. We studied two seizure types in this review: generalised onset seizures in which electrical discharges begin in one part of the brain and move throughout the brain; and partial onset seizures in which the seizure is generated in and affects one part of the brain (the whole hemisphere of the brain or part of a lobe of the brain). Most seizures can be controlled by a single antiepileptic drug. Worldwide, phenytoin and valproate are commonly used antiepileptic drugs.
Objective
Phenytoin and valproate are commonly used treatments for individuals with epilepsy. The aim of this review was to compare how effective these drugs are at controlling seizures and whether individuals choose to withdraw from these treatments, to inform a choice between these drugs.
Methods
The last search for trials for this review was 19th May 2015. We assessed the evidence from 11 randomised controlled clinical trials comparing phenytoin to valproate and we were able to combine data for 699 people from 5 of the 11 trials; for the remaining 450 people from 6 trials, data were not available to use in this review.
Key Results
This review of trials found no difference between these two drugs for the seizure types studied for the outcomes of withdrawal from treatment and controlling seizures. The review also found no evidence to support or refute the policy of using valproate for generalised onset tonic-clonic seizures and phenytoin for partial onset seizures. However, up to 49% of people within the trials classified as having generalised seizures may have had their seizure type wrongly diagnosed, and this misclassification may have influenced the results of this review. We were unable to address the issue of preferring valproate for generalised onset seizure types other than tonic-clonic.
Quality of the evidence
We judged the quality of the evidence as moderate for the evidence of withdrawal from treatment and low to very low for seizure outcomes as it is likely that misclassification of seizure type influenced the results of the review.
Conclusions
Phenytoin and valproate are commonly used treatments for individuals with epilepsy, but we found no difference between these treatments for the outcomes of this review or between seizure types. More information is needed as it is likely that misclassification of seizure type influenced the results of the review.
