Abstract: IPD were available for 595 participants out of 1102 eligible individuals, from four out of 11 trials (i.e. 54% of the potential data). For remission outcomes, a HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, a HR greater than 1 indicates an advantage for carbamazepine. Most participants included in analysis (78%) were classified as experiencing focal onset seizures at baseline and only 22% were classified as experiencing generalised onset seizures; the results of this review are therefore mainly applicable to individuals with focal onset seizures. Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 546 participants: 0.94, 95% CI 0.70 to 1.26, moderate-certainty evidence); time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 546 participants: 0.99, 95% CI 0.69 to 1.41, moderate-certainty evidence); both showing no clear difference between the drugs and time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 546 participants: 1.27, 95% CI 0.87 to 1.86, moderate-certainty evidence), showing that treatment failure due to adverse events may occur earlier on carbamazepine than phenytoin, but we cannot rule out a slight advantage to carbamazepine or no difference between the drugs. For our secondary outcomes (pooled HRs adjusted for seizure type), we did not find any clear differences between carbamazepine and phenytoin: time to first seizure post-randomisation (582 participants): 1.15, 95% CI 0.94 to 1.40, moderate-certainty evidence); time to 12-month remission (551 participants): 1.00, 95% CI 0.79 to 1.26, moderate-certainty evidence); and time to six-month remission (551 participants): 0.90, 95% CI 0.73 to 1.12, moderate-certainty evidence). For all outcomes, results for individuals with focal onset seizures were similar to overall results (moderate-certainty evidence), and results for the small subgroup of individuals with generalised onset seizures were imprecise, so we cannot rule out an advantage to either drug, or no difference between drugs (low-certainty evidence). There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to treatment failure'. Heterogeneity was present in analysis of 'time to first seizure' for individuals with generalised onset seizures, which could not be explained by subgroup analysis or sensitivity analyses. Limited information was available about adverse events in the trials and we could not compare the rates of adverse events between carbamazepine and phenytoin. Some adverse events reported on both drugs were abdominal pain, nausea, and vomiting, drowsiness, motor and cognitive disturbances, dysmorphic side effects (such as rash). Moderate-certainty evidence provided by this systematic review does not show any differences between carbamazepine and phenytoin in terms of effectiveness (retention) or efficacy (seizure recurrence and seizure remission) for individuals with focal onset or generalised onset seizures. However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies, which may have had an impact on the results of this review. We therefore do not suggest that results of this review alone should form the basis of a treatment choice for a person with newly-onset seizures. We did not find any evidence to support or refute current treatment policies. We implore that future trials be designed to the highest quality possible, with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Plain-language summary: For this updated review, we looked at the evidence from 11 randomised controlled clinical trials comparing phenytoin and carbamazepine, based on how effective the drugs were at controlling seizures (i.e. whether people went back to having seizures or had long periods of freedom from seizures (remission)), and how tolerable any related side effects of the drugs were. Methods We were able to combine data for 595 people from four of the 11 trials; for the remaining 507 people from seven trials, information was not available to use in this review. The evidence is current to August 2018. Key results This review of trials found no difference between these two drugs for the seizure types studied for the outcomes of treatment failure (withdrawal from treatment for any reason and also withdrawal from treatment due to continuing seizures or due to side effects) and controlling seizures (recurrence of seizures or achievement of a seizure-free period (remission) of six months or 12 months). Three-quarters of the people recruited in the four trials had focal onset seizures and only one quarter of the people recruited in the four trials had generalised onset seizures, so the results of this review mainly apply to people with focal onset seizures and the results are very limited for people with generalised onset seizures. More information is needed for people with generalised onset seizures. Some side effects reported by people taking carbamazepine and people taking phenytoin were abdominal pain, nausea, vomiting, tiredness, motor problems (such as poor co-ordination), cognitive problems (poor memory), rashes and other skin problems. Certainty of the evidence We judged the certainty of the evidence as moderate to low for the evidence of treatment failure, moderate for remission outcomes and low for seizure outcomes, as it is likely that misclassification of seizure type influenced the results of the review. Within two of the trials providing data for this review, the design of the trial meant that the people and treating clinicians knew which medication they were taking. This design may have influenced the results. Some of the trials contributing data to the review had methodological problems, which may have introduced bias and inconsistent results into this review, and some individuals over the age of 30 with newly-diagnosed generalised onset seizures may have had their seizure type wrongly diagnosed. These problems may have affected the results of this review and we judged the certainty of the evidence provided by this review as moderate for people with focal onset seizures and of low certainty for people with generalised onset seizures. We do not suggest using the results of this review alone for making a choice between carbamazepine or phenytoin for the treatment of epilepsy. We suggest that all future trials comparing these drugs or any other antiepileptic drugs should be designed using high-quality methods, and that the seizure types of people included in trials should be classified very carefully to ensure results are also of high quality.