Abstract
Background
This is an updated version of the Cochrane Review previously published in 2019.
Epilepsy is one of the most common neurological disorders. It is estimated that up to 30% of individuals with epilepsy continue to have epileptic seizures despite treatment with an antiepileptic drug. These patients are classified as drug‐resistant and require treatment with a combination of multiple antiepileptic drugs. Brivaracetam is a third‐generation antiepileptic drug that is a high‐affinity ligand for synaptic vesicle protein 2A. In this review we investigated the use of brivaracetam as add‐on therapy for epilepsy.
Objectives
To evaluate the efficacy and tolerability of brivaracetam when used as add‐on treatment for people with drug‐resistant epilepsy.
Search methods
For the latest update we searched the following databases on 7 September 2021: the Cochrane Register of Studies (CRS Web); MEDLINE (Ovid) 1946 to 3 September 2021. CRS Web includes randomised controlled trials (RCTs) and quasi‐RCTs from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Cochrane Epilepsy.
Selection criteria
We searched for parallel‐group RCTs that recruited people of any age with drug‐resistant epilepsy. We accepted studies with any level of blinding (double‐blind, single‐blind, or unblinded).
Data collection and analysis
In accordance with standard Cochrane methodological procedures, two review authors independently assessed trials for inclusion before evaluating trial quality and extracting relevant data. The primary outcome to be assessed was 50% or greater reduction in seizure frequency. Secondary outcomes were: seizure freedom, treatment withdrawal for any reason, treatment withdrawal due to adverse events, the proportion of participants who experienced any adverse events, and drug interactions. We used an intention‐to‐treat population for all primary analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs).
Main results
We did not identify any new studies for this update, therefore the results and conclusions of the review are unchanged.
The previous review included six studies involving a total of 2411 participants. Only one study included participants with both focal and generalised onset seizures; the other five trials included participants with focal onset seizures only. Study participants were aged 16 to 80 years. Treatment periods ranged from 7 to 16 weeks. We judged two studies to have low risk of bias and four to have unclear risk of bias. Details on the method used for allocation concealment and how blinding was maintained were insufficient in one study each. One study did not report all outcomes prespecified in the trial protocol, and there were discrepancies in reporting in a further study.
Participants receiving brivaracetam add‐on were more likely to experience a 50% or greater reduction in seizure frequency than those receiving placebo (RR 1.81, 95% CI 1.53 to 2.14; 6 studies; moderate‐certainty evidence). Participants receiving brivaracetam were more likely to attain seizure freedom; however, the evidence is of low certainty (RR 5.89, 95% CI 2.30 to 15.13; 6 studies). The incidence of treatment withdrawal for any reason was slightly greater for participants receiving brivaracetam compared to those receiving placebo (RR 1.27, 95% CI 0.94 to 1.74; 6 studies; low‐certainty evidence). The risk of participants experiencing one or more adverse events did not differ significantly following treatment with brivaracetam compared to placebo (RR 1.08, 95% CI 1.00 to 1.17; 5 studies; moderate‐certainty evidence). However, participants receiving brivaracetam did appear to be more likely to withdraw from treatment due to adverse events compared with those receiving placebo (RR 1.54, 95% CI 1.02 to 2.33; 6 studies; low‐certainty evidence).
Authors’ conclusions
When used as add‐on therapy for individuals with drug‐resistant epilepsy, brivaracetam may be effective in reducing seizure frequency and may aid patients in achieving seizure freedom. However, add‐on brivaracetam is probably associated with a greater proportion of treatment withdrawals due to adverse events compared with placebo. It is important to note that only one of the eligible studies included participants with generalised epilepsy. None of the included studies involved participants under the age of 16, and all studies were of short duration. Consequently, the findings of this review are mainly applicable to adult patients with drug‐resistant focal epilepsy. Future research should focus on investigating the tolerability and efficacy of brivaracetam during longer‐term follow‐up, as well as assess the efficacy and tolerability of add‐on brivaracetam in managing other types of seizures and in other age groups.
PICOs
Population (12)
Intervention (3)
Comparison (3)
Outcome (3)
The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses . PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome
Plain language summary
Brivaracetam add‐on therapy for drug‐resistant epilepsy
Background
Epilepsy is a disorder characterised by multiple seizures. Most people can control their epilepsy with a single antiepileptic drug; however, some people require multiple antiepileptic drugs. These people are said to have drug‐resistant epilepsy. Brivaracetam is an antiepileptic drug that can be taken with another antiepileptic medication to try to manage drug‐resistant epilepsy.
Aim of the review
We aimed to determine whether brivaracetam is effective and tolerable when used as add‐on treatment for people with drug‐resistant epilepsy. For this update, we did not identify any new studies to add, therefore our conclusions remain unchanged.
Results
We identified six studies (2411 participants) that investigated brivaracetam as add‐on treatment for drug‐resistant epilepsy. Study participants were aged 16 to 80, and most had focal epilepsy (i.e. epilepsy that originates in one area of the brain). People who received brivaracetam in addition to their normal antiepileptic medication were almost twice as likely to experience a 50% or greater reduction in the frequency of their seizures compared to people who were given placebo (i.e. a fake, inactive drug that should not affect epilepsy). People who received brivaracetam were also nearly six times more likely to achieve freedom from all seizures than those receiving placebo. People who received brivaracetam were not more likely to experience side effects compared to people receiving placebo; however, they were more likely to withdraw from study due to side effects.
Certainty of the evidence
The evidence for freedom from all seizures was of low certainty and the evidence for 50% or greater reduction in the seizure frequency was of moderate certainty. This means that when brivaracetam is used as an add‐on for adults with drug‐resistant focal epilepsy, people may be more likely to become free from all seizures than people given placebo and that brivaracetam is probably effective at reducing seizure frequency. The evidence for the proportion of people who experienced any side effects was of moderate certainty so is likely to be accurate. We did not investigate the number of people who experienced individual adverse events. This should be investigated in future reviews.
The evidence for this review was taken from randomised controlled trials that only studied adults and mainly studied people with drug‐resistant focal epilepsy, and not with generalised epilepsy.
This review shows that overall brivaracetam is a fairly tolerable and effective drug for use specifically in adults with drug‐resistant focal epilepsy. All study participants were adults, and most had focal epilepsy. Therefore, we do not know the effectiveness of brivaracetam in children or in people with other types of epilepsy, such as generalised epilepsy (i.e. epilepsy that involves the whole brain).
The evidence is current to 7 September 2021.
