Abstract
Background
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.
Objectives
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).
Search methods
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.
Selection criteria
Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures comparing monotherapy with either carbamazepine or lamotrigine.
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 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.
Main results
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.
Authors’ conclusions
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.
Plain language summary
Lamotrigine versus carbamazepine monotherapy (single drug treatment) for epilepsy
This is an updated version of the original Cochrane review published in Issue 1, 2006 of the Cochrane Database of Systematic Reviews.
Background
Epilepsy is a common neurological disorder in which abnormal electrical discharges from the brain cause recurrent seizures. We studied two types of epileptic seizures 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 (also known as focal 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). Partial seizures may become generalised (secondary generalisation) and move from one part of the brain throughout the brain. For around 70% of people with epilepsy, a single antiepileptic drug can control generalised onset or partial onset seizures.
This review applies to people with partial seizures (with or without secondary generalisation) and people with generalised tonic-clonic seizures, a specific generalised seizure type. This review does not apply to people with other generalised seizure types such as absence seizures or myoclonic seizures as the recommended treatments for these seizure types are different.
Objective
Carbamazepine and lamotrigine are first-choice treatments for individuals with recently diagnosed epilepsy. The aim of this review was to compare how effective these drugs are at controlling seizures, to find out if they are associated with side effects that may result in individuals stopping the drug and to inform a choice between these drugs.
Methods
The last search for trials was in October 2016. We assessed the evidence from 13 randomised controlled trials comparing lamotrigine with carbamazepine. We were able to combine data for 2572 people from nine of the 13 trials; for the remaining 822 people from four trials, data were not available to use in this review.
Results
The results of the review suggest that people are more likely to withdraw earlier from carbamazepine than lamotrigine treatment. The most common drug-related reason for withdrawal was adverse events: 51% of total withdrawals in participants on carbamazepine and 36% of total withdrawals in participants on lamotrigine. The second most common drug-related cause for withdrawal was seizure recurrence: 56 of 683 total withdrawals (8%) on carbamazepine and 93 of 610 total withdrawals (15%) on lamotrigine.
The results also suggest that recurrence of seizures after starting treatment with lamotrigine may happen earlier than treatment with carbamazepine and seizure freedom for a period of six months may occur earlier on carbamazepine than lamotrigine. The majority of the people included in the 13 trials (88%) experienced partial seizures, so the results of this review apply mainly to people with this seizure type.
The most common side effects reported by participants during the trials were dizziness, fatigue, gastrointestinal problems, headaches and skin problems. These side effects were reported a similar number of times by people taking lamotrigine or carbamazepine.
Quality of the evidence
For people with partial onset seizures, we judged the quality of the evidence to be high for the outcomes of seizure recurrence and remission of seizures and we judged the quality of the evidence to be moderate for the outcome of treatment withdrawal. The design of the trials (whether the people and treating clinicians knew which drug they were taking) may have influenced the rates of withdrawal from treatments. Up to 50% of people in the trials used in our results may have been wrongly classified as having generalised seizures; for people with generalised onset seizures, we judged the quality of the evidence to be moderate for the outcomes of seizure recurrence and remission of seizures and low quality for the outcome of treatment withdrawal.
Conclusions
For people with partial onset seizures, lamotrigine and carbamazepine are effective treatments and a choice between these two treatments must be made carefully. More information is needed for people with generalised onset seizures. We recommend that all future trials comparing these drugs, or any other antiepileptic drugs, should be designed using high-quality methods. Seizure types of people included in trials should also be classified very carefully to ensure that the results are also of high quality.
