Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials

Abstract

Background: Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area.

Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130).

Findings: A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400 mg/d was top-ranked, followed by RTG 1200 mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100 mg/d leading, followed by CNB 400 mg/d. Regarding tolerability, LCM 600 mg/d had the lowest ranking, followed by CNB 400 mg/d. For the safety outcome of AEs, ESL 1200 mg/d was ranked lowest, followed by CNB 400 mg/d. Regarding SAEs, LCM 400 mg/d was ranked lowest, followed by RTG 1200 mg/d.

Interpretation: ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS.

Funding: None.

Keywords: Antiseizure medications; Epilepsy; Focal seizures; Network meta-analysis; Seizure.

Fig. 1

Search process.

Fig. 2

Network map for all outcomes. Considering each ASM as a separate node: a, network map for seizure response; b, network map for seizure freedom; c, network map for tolerability; d, network map for AEs; e, network map for SAEs; Considering different dosage as separate nodes: f, network map for seizure response; g, network map for seizure freedom; h, network map for tolerability; i, network map for AEs; j, network map for SAEs. Each node represents an intervention, and the size of the node is proportional to the number of patients assigned to the intervention. The lines indicate direct comparisons between nodes, and the size of the line is proportional to the number of trials comparing each pair of nodes. PBO, Placebo; RUF, Rufinamide; BRV, Brivaracetam; CNB, Cenobamate; ESL, Eslicarbazepine; LCM, Lacosamide; RTG, Retigabine; PER, Perampanel; AEs, adverse effects; SAEs, serious adverse events.

Fig. 3

Results of network meta-analysis considering each ASM as a separate node. a, Forest plot between ASMs and placebo for the efficacy, tolerability and safety outcomes; b. the SUCRA values of all ASMs for all outcomes. PBO, Placebo; RUF, Rufinamide; BRV, Brivaracetam; CNB, Cenobamate; ESL, Eslicarbazepine; LCM, Lacosamide; RTG, Retigabine; PER, Perampanel; AEs, adverse effects; SAEs, serious adverse events; RR, risk ratio; CI, credible interval; SUCRA, the surface under the cumulative ranking curve.

Fig. 4

Results of network meta-analysis considering each dosage as a separate node. a, Forest plot between ASMs with different dosages and placebo for the efficacy, tolerability and safety outcomes; b. the SUCRA values of all ASMs with different dosages for all outcomes. PBO, Placebo; RUF, Rufinamide; BRV, Brivaracetam; CNB, Cenobamate; ESL, Eslicarbazepine; LCM, Lacosamide; RTG, Retigabine; PER, Perampanel; AEs, adverse effects; SAEs, serious adverse events; RR, risk ratio; CI, credible interval; SUCRA, the surface under the cumulative ranking curve.