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.


OBJECTIVE
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.


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.


METHODS
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.


METHODS
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.


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.


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.
Department of Biostatistics, The University of Liverpool, Duncan Building, Daulby Street, Liverpool, UK, L69 3GA.
Sarah J
SJ
Nolan
Anthony G
AG
Marson
Jennifer
J
Weston
Catrin
C
Tudur Smith
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002220:Carbamazepine / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004828:Epilepsies, Partial / Q000188:drug therapy*; D004829:Epilepsy, Generalized / Q000188:drug therapy*; D006801:Humans; D060828:Induction Chemotherapy; D010672:Phenytoin / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D028761:Withholding Treatment
D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin