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 as add-on treatment with another antiepileptic medication to try to manage drug-resistant epilepsy.

Aim of the review

This review aimed to determine whether brivaracetam is effective and tolerable when used as add-on treatment for people with drug-resistant epilepsy.

Results

We were able to identify six studies that investigated brivaracetam as add-on treatment for drug-resistant epilepsy. These studies included a total of 2411 participants, aged 16 to 80. Most participants 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 more likely to withdraw from studies due to side effects, but they were not actually more likely to experience side effects when compared to people receiving placebo.

Quality of the evidence

Evidence taken from studies examining the effectiveness of brivaracetam was of moderate quality. This means that we can be fairly certain that study findings showing that brivaracetam is effective in reducing the frequency of seizures in drug-resistant epilepsy are accurate. Evidence regarding the tolerability of brivaracetam, for example, the number of people who withdrew from these studies and the number of people who experienced side effects, however, was of low quality. This means that we cannot be sure that trial findings are completely accurate, and that more research is needed to fully investigate the tolerability of brivaracetam. All study participants were adults, and most had focal epilepsy. As a result, the review cannot inform us about how effective brivaracetam is in children or in individuals with other types of epilepsy, for example, generalised epilepsy, which is epilepsy that involves the whole brain.

Evidence is current to October 2018.

Authors' conclusions: 

Brivaracetam, when used as add-on therapy for patients with drug-resistant epilepsy, is effective in reducing seizure frequency and can aid patients in achieving seizure freedom. However, add-on brivaracetam is 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 studies included participants under the age of 16, and all studies were of short duration. Consequently, these findings are mainly applicable to adult patients with drug-resistant focal epilepsy. Future research should thus focus on investigating the tolerability and efficacy of brivaracetam during longer-term follow-up, and should also assess the efficacy and tolerability of add-on brivaracetam in managing other types of seizures and its use in other age groups.

Read the full abstract...
Background: 

Epilepsy is one of the most common neurological disorders. It is estimated that up to 30% of patients 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. This review investigates 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 strategy: 

We searched the following databases on 9 October 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL); Medline (Ovid) 1946 to 8 October 2018; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Originally we also searched SCOPUS as a substitute for Embase, but this is no longer necessary, because randomised and quasi-randomised controlled trials in Embase are now included in CENTRAL.

Selection criteria: 

We sought randomised controlled trials with parallel-group design, recruiting people of any age with drug-resistant epilepsy. We accepted studies with any level of blinding (double-blind, single-blind, or unblind).

Data collection and analysis: 

In accordance with standard methodological procedures expected by the Cochrane Collaboration, 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 (ITT) population for all primary analyses, and we presented results as risk ratios (RRs) with 95% confidence intervals (CIs).

Main results: 

The review included six trials representing 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. All six studies included adult participants between 16 and 80 years old, and 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. One study failed to provide details on the method used for allocation concealment, and one did not report all outcomes prespecified in the trial protocol. One study did not describe how blinding was maintained, and another noted discrepancies in reporting.

Participants receiving brivaracetam add-on were significantly 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-quality evidence). Participants receiving brivaracetam were also significantly more likely to attain seizure freedom (RR 5.89, 95% CI 2.30 to 15.13; 6 studies; moderate-quality evidence). The incidence of treatment withdrawal for any reason (RR 1.27, 95% CI 0.94 to 1.74; 6 studies; low-quality evidence), as well as the risk of participants experiencing one or more adverse events (RR 1.08, 95% CI 1.00 to 1.17; 5 studies; moderate-quality evidence), was not significantly different following treatment with brivaracetam compared to placebo. However, participants receiving brivaracetam did appear to be significantly more likely to withdraw from treatment specifically because of adverse events compared with those receiving placebo (RR 1.54, 95% CI 1.02 to 2.33; 6 studies; low-quality evidence).

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