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Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. BACKGROUND: This is an update of a Cochrane Review first published in 2002 and last updated in 2017. This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons.Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for focal onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment, due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials; however, the confidence intervals generated by these trials are wide, and therefore, synthesising the data of the individual trials may show differences in efficacy. OBJECTIVES: To review the time to treatment failure, remission and first seizure with carbamazepine compared with phenytoin when used as monotherapy in people with focal onset seizures (simple or complex focal and secondarily generalised), or generalised onset tonic-clonic seizures (with or without other generalised seizure types). SEARCH METHODS: For the latest update, we searched the following databases on 13 August 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy's Specialised Register and CENTRAL; MEDLINE; the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov); and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. SELECTION CRITERIA: Randomised controlled trials comparing monotherapy with either carbamazepine or phenytoin in children or adults with focal onset seizures or generalised onset (tonic-clonic) seizures. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure. Our secondary outcomes were time to first seizure post-randomisation, time to six-month remission, time to 12-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs), with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: 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). AUTHORS' CONCLUSIONS: 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.

Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 2, 2002 and its subsequent updates in 2010 and 2015.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, although the confidence intervals generated by these studies are wide. Differences in efficacy may therefore be shown by synthesising the data of the individual trials. OBJECTIVES: To review the time to withdrawal, six- and 12-month remission, and first seizure with carbamazepine compared to phenytoin, used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures), or generalised tonic-clonic seizures, with or without other generalised seizure types. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (1st November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1st November 2016), MEDLINE (Ovid, 1946 to 1 November 2016), ClinicalTrials.gov (1 November 2016), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP, 1st November 2016). Previously we also searched SCOPUS (1823 to 16th September 2014) as an alternative to Embase, but this is no longer necessary, because randomised and quasi-randomised controlled trials in Embase are now included in CENTRAL. 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, comparing carbamazepine monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This is an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment, and our secondary outcomes were time to six-month remission, time to 12-month remission, and time to 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 595 participants out of 1192 eligible individuals, from four out of 12 trials (i.e. 50% of the potential data). For remission outcomes, HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, HR greater than 1 indicates an advantage for carbamazepine. The methodological quality of the four studies providing IPD was generally good and we rated it at low risk of bias overall in the analyses.The main overall results (pooled HR adjusted for seizure type) were time to withdrawal of allocated treatment: 1.04 (95% CI 0.78 to 1.39; three trials, 546 participants); time to 12-month remission: 1.01 (95% CI 0.78 to 1.31; three trials, 551 participants); time to six-month remission: 1.11 (95% CI 0.89 to 1.37; three trials, 551 participants); and time to first seizure: 0.85 (95% CI 0.70 to 1.04; four trials, 582 participants). The results suggest no overall statistically significant difference between the drugs for these outcomes. There is some evidence of an advantage for phenytoin for individuals with generalised onset seizures for our primary outcome (time to withdrawal of allocated treatment): pooled HR 0.42 (95% CI 0.18 to 0.96; two trials, 118 participants); and a statistical interaction between treatment effect and epilepsy type (partial versus generalised) for this outcome (P = 0.02). However, misclassification of seizure type for up to 48 individuals (32% of those with generalised epilepsy) may have confounded the results of this review. Despite concerns over side effects leading to the withdrawal of phenytoin as a first-line treatment in the USA and Europe, we found no evidence that phenytoin is more likely to be associated with serious side effects than carbamazepine; 26 individuals withdrew from 290 randomised (9%) to carbamazepine due to adverse effects, compared to 12 out of 299 (4%) randomised to phenytoin from four studies conducted in the USA and Europe (risk ratio (RR) 1.42, 95% CI 1.13 to 1.80, P = 0.014). We rated the quality of the evidence as low to moderate according to GRADE criteria, due to imprecision and potential misclassification of seizure type. AUTHORS' CONCLUSIONS: We have not found evidence for a statistically significant difference between carbamazepine and phenytoin for the efficacy outcomes examined in this review, but CIs are wide and we cannot exclude the possibility of important differences. There is no evidence in this review that phenytoin is more strongly associated with serious adverse events than carbamazepine. There is some evidence that people with generalised seizures may be less likely to withdraw early from phenytoin than from carbamazepine, but misclassification of seizure type may have impacted upon our results. We recommend caution when interpreting the results of this review, and do not recommend that our results alone should be used in choosing between carbamazepine and phenytoin. We recommend that future trials should be designed to the highest quality possible, with considerations of allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.

Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. BACKGROUND: This is an updated version of the original Cochrane review published in Issue 2, 2002 and its subsequent update in 2010.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first line treatment due to concerns over adverse events associated with its use, however the drug is still commonly used in low- to middle-income countries due to it's low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, however the confidence intervals generated by these studies are wide. Therefore, differences in efficacy may be shown by synthesising the data of the individual trials. OBJECTIVES: To review the time to withdrawal, six- and 12-month remission, and first seizure of carbamazepine compared to phenytoin when used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures) or generalised tonic-clonic seizures, with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (16 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 8), MEDLINE (1946 to 16 September 2014), SCOPUS (1823 to 16 September 2014), ClinicalTrials.gov (16 September 2014), and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP (18 September 2014). 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 carbamazepine monotherapy versus phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment, and our secondary outcomes were time to 12-month remission, time to six-month remission and time to 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 595 participants out of 1192 eligible individuals, from four out of 12 trials (i.e. 50% of the potential data). For remission outcomes, HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, HR > 1 indicates an advantage for carbamazepine. Methodological quality of the four studies providing IPD was generally good and we rated it at low risk of bias overall in the analyses.The main overall results (pooled HR adjusted for seizure type) were time to withdrawal of allocated treatment: 1.04 (95% CI 0.78 to 1.39); time to 12-month remission: 1.01 (95% CI 0.78 to 1.31); time to six-month remission: 1.11 (95% CI 0.81 to 1.37); and time to first seizure: 0.85 (95% CI 0.70 to 1.04). The results suggest no overall statistically significant difference between the drugs for these outcomes. There is some evidence of an advantage for phenytoin for individuals with generalised onset seizures for our primary outcome (time to withdrawal of allocated treatment): pooled HR 0.42 (95% CI 0.18 to 0.96); and a statistical interaction between treatment effect and epilepsy type (partial versus generalised) for this outcome (P = 0.02), however misclassification of seizure type for up to 48 individuals (32% of those with generalised epilepsy) may have confounded the results of this review. Despite concerns over side effects leading to the withdrawal of phenytoin as first line treatment in the USA and Europe, we found no evidence that phenytoin is more likely to be associated with serious side effects than carbamazepine; 26 individuals withdrew from 290 randomised (9%) to carbamazepine due to adverse effects compared to 12 out of 299 (4%) randomised to phenytoin from four studies conducted in the USA and Europe (risk ratio (RR) 1.42, 95% CI 1.13 to 1.80, P = 0.014). We rated the quality of the evidence as low - moderate according to GRADE criteria, due to imprecision and potential misclassification of seizure type. AUTHORS' CONCLUSIONS: We have not found evidence that a statistically significant difference exists between carbamazepine and phenytoin for the efficacy outcomes examined in this review, however, CIs are wide and the possibility of important differences existing has not been excluded. There is no evidence in this review that phenytoin is more strongly associated with serious adverse events than carbamazepine. There is some evidence that participants with generalised seizures may be less likely to withdraw early from phenytoin than carbamazepine, but misclassification of seizure type may have impacted upon the results of this review. We recommend caution when interpreting the results of this review, and do not recommend that the results of this review alone should be used in choosing between carbamazepine and phenytoin. We recommend that future trials should be designed to the highest quality possible with considerations on allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.