Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review
Abstract
Background
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, the majority of which may be able to achieve remission with a single antiepileptic drug (AED).
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 AED for an individual is based on the highest‐quality evidence available regarding the potential benefits and harms of various treatments. It is also important to compare the efficacy and tolerability of AEDs appropriate to given seizure types.
Topiramate and carbamazepine are commonly used AEDs. Performing a synthesis of the evidence from existing trials will increase the precision of results of outcomes relating to efficacy and tolerability, and may help inform a choice between the two drugs.
Objectives
To assess the effects of topiramate monotherapy versus carbamazepine monotherapy for epilepsy 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
We searched the Cochrane Epilepsy Group Specialized Register (14 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (14 April 2016) and MEDLINE (Ovid, 1946 to 14 April 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 with or without other generalised seizure types with a comparison of monotherapy with either topiramate or carbamazepine.
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 6‐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), and used the generic inverse variance method to obtain the overall pooled HRs and 95% CIs.
Main results
IPD were available for 1151 of 1239 eligible individuals from two of three eligible studies (93% of the potential data). A small proportion of individuals recruited into these trials had 'unclassified seizures;' for analysis purposes, these individuals are grouped with those with generalised onset seizures. 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 topiramate.
The main overall results, given as pooled HR adjusted for seizure type (95% CI) were: for time to withdrawal of allocated treatment 1.16 (0.98 to 1.38); time to first seizure 1.11 (0.96 to 1.29); and time to 6‐month remission 0.88 (0.76 to 1.01). There were no statistically significant differences between the drugs. A statistically significant advantage for carbamazepine was shown for time to 12‐month remission: 0.84 (0.71 to 1.00).
The results of this review are applicable mainly to individuals with partial‐onset seizures; 85% of included individuals experienced seizures of this type at baseline. For individuals with partial‐onset seizures, a statistically significant advantage for carbamazepine was shown for time to withdrawal of allocated treatment (HR 1.20, 95% CI 1.00 to 1.45) and time to 12‐month remission (HR 0.84, 95% CI 0.71 to 1.00). No statistically significant differences were apparent between the drugs for other outcomes and for the limited number of individuals with generalised‐onset tonic‐clonic seizures with or without other generalised seizure types or unclassified seizures.
The most commonly reported adverse events with both drugs were drowsiness or fatigue, ‘pins and needles’ (tingling sensation), headache, gastrointestinal disturbance and anxiety or depression The rate of adverse events was similar across the two drugs.
We judged the methodological quality of the included trials generally to be good; however, there was some evidence that the open‐label design of the larger of the two trials may have influenced the withdrawal rate from the trial. Hence, we judged 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 evidence from this review to be high for individuals with partial‐onset seizures and moderate for individuals with generalised‐onset or unclassified seizures.
Authors' conclusions
For individuals with partial‐onset seizures, there is evidence that carbamazepine is less likely to be withdrawn and that 12‐month remission will be achieved earlier than with topiramate. No differences were found between the drugs in terms of the outcomes measured in the review for individuals with generalised tonic‐clonic seizures with or without other seizure types or unclassified epilepsy; however, we encourage caution in the interpretation of these results due to the small numbers of participants with these seizure types.
We recommend that future trials should be designed to the highest quality possible and take into consideration masking, choice of population, classification of seizure type, duration of follow‐up, choice of outcomes and analysis, and presentation of results.
PICOs
Plain language summary
Topiramate versus carbamazepine as single drug treatment for epilepsy
Background
Epilepsy is a common disorder of the nervous system in which abnormal electrical discharges from the brain cause recurrent seizures (physical convulsions or thought disturbances or a combination of these symptoms). 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 the same part of the brain. Partial‐onset seizures may become generalised (secondary generalisation) and move from one part of the brain to throughout the brain. Up to 70% of individuals with active epilepsy have the potential to go into long‐term remission shortly after starting drug therapy and around 70% of these individuals can achieve seizure freedom using a single antiepileptic drug.
This review applies to people with partial‐onset seizures (with or without secondary generalisation) and people with tonic‐clonic seizures, a specific type of generalised‐onset seizure, as the recommended treatments for these seizure types are similar.
Objective
Topiramate and carbamazepine are commonly used treatments for individuals with epilepsy. The aim of this review was to compare how effective these drugs are at controlling recently diagnosed seizures, whether they are associated with side effects that may result in individuals stopping the drug and to inform a choice between these drugs.
Methods
We searched for trials published April 2016. We assessed the evidence from three clinical trials that compared topiramate with carbamazepine. We were able to combine data for 1151 people from two trials; we were not able to use the data from the remaining trial, which included 88 participants.
Results
Most (85%) of the people included in the two trials experienced partial seizures, so the results of this review apply mainly to people with this seizure type. Many of the remaining 15% of people experienced a seizure type which was difficult to classify as partial or generalised (unclassified seizures). Considering only people with partial seizures, the results showed that those taking carbamazepine were more likely to take their treatment for longer and to achieve a remission of 12 months duration earlier than those taking topiramate. No differences were found between the drugs in individuals with generalised‐onset or unclassified epilepsy.
The most common side effects reported by the participants during the trials were fatigue, ‘pins and needles’ (tingling sensation), headache, gastrointestinal problems and anxiety or depression. These side effects were reported a similar number of times by people taking topiramate or carbamazepine.
Quality of the evidence
For people with partial‐onset seizures, we judged the quality of the evidence to be moderate to high. The design of the trials (whether the people and treating clinicians knew which drug they were taking) may have influenced the how long a participant stayed on their treatment. For the small number of people with generalised‐onset or unclassified seizures, we judged the quality of the evidence to be low to moderate.
Conclusions
Carbamazepine is currently recommended by experts for the treatment of individuals who are newly diagnosed with partial‐onset seizures and the results of this review do not provide any evidence to contradict this. More information is needed for people with generalised‐onset or unclassified seizures. We recommend that all future trials comparing these drugs, or any other antiepileptic drugs, should be designed using high‐quality methods, and the types of seizure of the people included in any trials should be classified very carefully to ensure that the results are also of high quality.
