• Rebecca Bresnahan, Mariangela Panebianco, and Anthony G Marson.
• Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Lower Lane, Liverpool, UK, L9 7LJ.
• Cochrane Db Syst Rev. 2019 Mar 28; 3: CD011501.

BackgroundEpilepsy 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.ObjectivesTo evaluate the efficacy and tolerability of brivaracetam when used as add-on treatment for people with drug-resistant epilepsy.Search MethodsWe 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 CriteriaWe 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 AnalysisIn 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 ResultsThe 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).Authors' ConclusionsBrivaracetam, 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.

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