Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review

Sarah J Nevitt, Catrin Tudur Smith, Jennifer Weston, Anthony G Marson

This is an updated version of the original Cochrane review published in Issue 1, 2006 of the Cochrane Database of Systematic Reviews.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 to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy.The correct choice of first-line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments. It is also important that the effectiveness and tolerability of AEDs appropriate to given seizure types are compared to one another.Carbamazepine or lamotrigine are first-line recommended treatments for new onset partial seizures and as a first- or second-line treatment for generalised tonic-clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs. To review the time to withdrawal, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic-clonic seizures (with or without other generalised seizure types). The first searches for this review were run in 1997. For the most recent update we searched the Cochrane Epilepsy Group Specialized Register (17 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 17 October 2016) and MEDLINE (Ovid, 1946 to 17 October 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators. Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures comparing monotherapy with either carbamazepine or lamotrigine. 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 first seizure post-randomisation, time to six-month, 12-month and 24-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. We included 13 studies in this review. Individual participant data were available for 2572 participants out of 3394 eligible individuals from nine out of 13 trials: 78% of the potential data. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine and for first seizure and withdrawal outcomes a HR < 1 indicated an advantage for lamotrigine.The main overall results (pooled HR adjusted for seizure type) were: time to withdrawal of allocated treatment (HR 0.72, 95% CI 0.63 to 0.82), time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and time to six-month remission (HR 0.84, 95% CI 0.74 to 0.94), showing a significant advantage for lamotrigine compared to carbamazepine for withdrawal but a significant advantage for carbamazepine compared to lamotrigine for first seizure and six-month remission. We found no difference between the drugs for time to 12-month remission (HR 0.91, 95% CI 0.77 to 1.07) or time to 24-month remission (HR 1.00, 95% CI 0.80 to 1.25), however only two trials followed up participants for more than one year so the evidence is limited.The results of this review are applicable mainly to individuals with partial onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures.The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs.The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open-label treatment may have influenced the withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with partial onset seizures and moderate for individuals with generalised onset seizures. Lamotrigine was significantly less likely to be withdrawn than carbamazepine but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. A choice between these first-line treatments must be made with careful consideration. We recommend that future trials should 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.