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Efficacy and Safety of Five Broad-Spectrum Antiseizure Medications for Adjunctive Treatment of Refractory Epilepsy: A Systematic Review and Network Meta-analysis

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Abstract

Background

Overall, up to one-third of epilepsy patients have drug-resistant epilepsy. However, there was previously no meta-analysis to support the guidelines for broad-spectrum antiseizure medication selection for the adjunctive treatment of refractory epilepsy. In the present meta-analysis, we assessed the efficacy and safety of three second-generation broad-spectrum antiseizure medications, lamotrigine (LTG), levetiracetam (LEV), and topiramate (TPM), and two third-generation broad-spectrum antiseizure medications, perampanel (PER) and lacosamide (LCM), for the adjunctive treatment of refractory epilepsy.

Methods

We systematically searched PubMed, Embase, and CENTRAL from inception to July 15, 2022. The studies included in the meta-analysis were required to meet the following criteria: (1) be randomized, double-blind clinical trials; (2) include patients aged >2 years with a clinical diagnosis of drug-resistant epilepsy; (3) have at least 8 weeks for the treatment period excluding the titration phase; and (4) report the outcomes of seizure response, seizure freedom and the withdrawal rate due to treatment-emergent adverse effects. Data were extracted, and the risk of bias for each study was assessed by two authors independently using RoB2 tools. We performed the network meta-analysis for each outcome through a group of programs in the mvmeta and network packages in Stata. Relative odds ratios with 95% confidence intervals were calculated as the result of the analyses. The surface under the cumulative ranking curve (SUCRA) and mean ranks were used to rank these treatments.

Results

Forty-two randomized controlled trials (RCTs) (LTG-placebo: n = 6, LEV-placebo: n = 13, TPM-placebo: n = 9, PER-placebo: n = 6, LCM-placebo: n = 7, LEV-TPM: n = 1) with 10257 participants (LTG = 569, LEV = 1626, TPM = 701, PER = 1734, LCM = 1908, placebo = 3719) were included. Levetiracetam had subequal efficacy in 50 % seizure frequency reduction to TPM [odds ratio (OR) 1.00, 95% confidence interval (CI) 0.73–1.38], and LEV had a higher rate of ≥ 50% seizure frequency reduction than LCM (OR 1.49, 95% CI 1.11–2.01) and PER (OR 1.68, 95% CI 1.24–2.29). Levetiracetam was also related to a higher proportion of seizure freedom participants than TPM (OR 1.87, 95% CI 1.20–2.89), PER (OR 2.23, 95% CI 1.12–4.43), and LCM (OR 2.97, 95% CI 1.46–6.05). In addition, LEV was associated with a lower risk of experiencing at least one treatment-emergent adverse event (TEAE) than PER (OR 0.63, 95% CI 0.46–0.85) and TPM (OR 0.51, 95 % CI 0.36–0.72) and a lower proportion of patients experiencing TEAEs leading to discontinuation than PER (OR 0.51, 95% CI 0.27–0.97) and TPM (OR 0.50, 95 % CI 0.27–0.93).

Conclusions

Third-generation drugs (PER and LCM) had no advantages in terms of efficacy and safety for adjunctive treatment of refractory epilepsy compared with several second-generation drugs (LEV and LTG). Levetiracetam was the priority choice for adjunctive treatment of refractory epilepsy. Perampanel and LCM had no advantages in terms of efficacy and safety among the five drugs.

Registration

PROSPERO registration number, CRD42022344153; last edited on December 23, 2022.

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Acknowledgements

The authors thank Professor Yong Liu for his help in the network meta-analysis.

Author information

Author notes

  1. Hecheng Wang and Haoran Wang contributed equally to this work.

Authors and Affiliations

  1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Pan**, 124221, China

    Hecheng Wang, Haoran Wang, **g Zhao, Xuewen Niu, Lei Zhu, **aomin Ma, Yu Zong & Yanshuo Han

  2. Department of Neurology, Dalian Municipal Central Hospital, Central Hospital of Dalian University of Technology, Dalian, China

    Yi Liu

  3. Department of Psychiatry, Sheng**g Hospital of China Medical University, Shenyang, China

    Yinglin Huang

  4. School of Basic Medical Sciences, **nxiang Medical University, **nxiang, 453003, China

    Wei Zhang

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  8. Yu Zong
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  9. Yinglin Huang
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  10. Wei Zhang
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  11. Yanshuo Han
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Corresponding authors

Correspondence to Wei Zhang or Yanshuo Han.

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Funding

This work was financially supported by the Natural Science Foundation of Henan (222300420515), the Natural Science Foundation of Liaoning Province (2023-MS-096), and Fundamental Research Funds for the Central Universities (nos. DUT21RC(4)003 and DUT22YG107).

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None of the authors has any conflict of interest to disclose.

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Author contributions

H-CW, H-RW, WZ and Y-SH contributed to the concept of the study and the study design. X-WN, X-MM, LZ, JZ contributed to the data search. H-CW, H-RW, YL, contributed to the data selection and data extraction. YZ, Y-LH and H-RW contributed to the quality assessment. H-RW and H-CW performed the statistical analysis. All authors contributed to the interpretation of the data. WZ and Y-SH supervised the work. H-CW, H-RW and Y-S H drafted the manuscript. All authors reviewed and approved the final manuscript.

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Wang, H., Wang, H., Liu, Y. et al. Efficacy and Safety of Five Broad-Spectrum Antiseizure Medications for Adjunctive Treatment of Refractory Epilepsy: A Systematic Review and Network Meta-analysis. CNS Drugs 37, 883–913 (2023). https://doi.org/10.1007/s40263-023-01029-0

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