Skip to main content
SpringerLink
Log in

Efficacy and safety of antiepileptic drugs for refractory partial-onset epilepsy: a network meta-analysis

  • Review
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

The optimal combination of antiepileptic drugs (AEDs) for the treatment of refractory partial-onset epilepsy is a perpetual point of debate. While several network meta-analyses (NMAs) have been published, conclusions remain controversial, especially since newer AEDs have been introduced. In our review, we included the newer AEDs to evaluate the comparative efficacy and safety of AEDs for the treatment of refractory partial-onset epilepsy. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (Cochrane Library 2017, Issue 1) from their inception to February 18, 2017. The risk of bias in the included randomized controlled trials (RCTs) was evaluated according to the Cochrane Collaboration’s risk of bias tool. An NMA was performed with a Bayesian random-effects model, and we used the surface under the cumulative ranking curve to detect the optimal AEDs. Seventy-six RCTs with 17 AEDs and 20,711 patients were included in the NMAs, which showed that Brivaracetam (BRV), Levetiracetam (LEV), Oxcarbazepine (OXC), Topiramate, Vigabatrin (VGB), and Valproate (VPA) had a greater likelihood of allowing patients to achieve seizure freedom. We also found that LEV was associated with a lower withdrawal rate due to adverse effects than Lacosamide, Eslicarbazepine acetate, OXC, Pregabalin, and Retigabine. LEV, VGB, VPA, and BRV emerged as the agents with the best combination of properties when considering the efficacy and safety outcomes based on the full double-blind treatment period. However, it is critical to perform RCTs and to obtain prospective data from representative cohort studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE (2015) Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med 162:46–54

    Article  PubMed  Google Scholar 

  2. Beyenburg S, Stavem K, Schmidt D (2010) Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 51:7–26

    Article  CAS  PubMed  Google Scholar 

  3. Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82

    Article  CAS  PubMed  Google Scholar 

  4. Bodalia PN, Grosso AM, Sofat R, Macallister RJ, Smeeth L, Dhillon S, Casas JP, Wonderling D, Hingorani AD (2013) Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials. Br J Clin Pharmacol 76:649–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brooks SP, Gelman Andrew (1998) General methods for monitoring convergence of iterative simulations. J Comput Graph Stat 7:434–455

    Google Scholar 

  6. Bucher HC, Guyatt GH, Griffith LE, Walter SD (1997) The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 50:683–691

    Article  CAS  PubMed  Google Scholar 

  7. Tassinari CA, Michelucci R, Chauvel P, Chodkiewicz J, Shorvon S, Henriksen O, Dam M, Reife R, Pledger G, Karim R (1996) Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia 37:763–768

    Article  CAS  PubMed  Google Scholar 

  8. Campos MS, Ayres LR, Morelo MR, Marques FA, Pereira LR (2016) Efficacy and tolerability of antiepileptic drugs in patients with focal epilepsy: systematic review and network meta-analyses. Pharmacotherapy 36:1255–1271

    Article  CAS  PubMed  Google Scholar 

  9. Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD (1995) Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet (London, England) 346:140–144

    Article  CAS  Google Scholar 

  10. Costa J, Fareleira F, Ascencao R, Borges M, Sampaio C, Vaz-Carneiro A (2011) Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia 52:1280–1291

    Article  PubMed  Google Scholar 

  11. Devinsky O (1999) Patients with refractory seizures. N Engl J Med 340:1565–1570

    Article  CAS  PubMed  Google Scholar 

  12. Dias S, Welton NJ, Caldwell DM, Ades AE (2010) Checking consistency in mixed treatment comparison meta-analysis. Stat Med 29:932–944

    Article  CAS  PubMed  Google Scholar 

  13. Emilio Russo RCMM (2017) The preclinical discovery and development of brivaracetam for the treatment of focal epilepsy. Expert Opin Drug Discov. doi:10.1080/17460441.2017.1366985

    Google Scholar 

  14. Forsgren L, Beghi E, Oun A, Sillanpaa M (2005) The epidemiology of epilepsy in Europe—a systematic review. Eur J Neurol 12:245–253

    Article  CAS  PubMed  Google Scholar 

  15. Hemming K, Maguire MJ, Hutton JL, Marson AG (2013) Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev. doi:10.1002/14651858

    PubMed  Google Scholar 

  16. Higgins JP, Whitehead A (1996) Borrowing strength from external trials in a meta-analysis. Stat Med 15:2733–2749

    Article  CAS  PubMed  Google Scholar 

  17. Higgins JPTTS (2014) Cochrane handbook for systematic reviews of interventions, version 5.1.0 (updated March 2011). The Cochrane Collaboration 2011. Accessed 20 Jan 2014

  18. Johannessen Landmark C, Johannessen SI (2008) Pharmacological management of epilepsy: recent advances and future prospects. Drugs 68:1925–1939

    Article  PubMed  Google Scholar 

  19. Kaminski RM, Matagne A, Leclercq K, Gillard M, Michel P, Kenda B, Talaga P, Klitgaard H (2008) SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 54:715–720

    Article  CAS  PubMed  Google Scholar 

  20. Khan N, Shah D, Tongbram V, Verdian L, Hawkins N (2013) The efficacy and tolerability of perampanel and other recently approved anti-epileptic drugs for the treatment of refractory partial onset seizure: a systematic review and Bayesian network meta-analysis. Curr Med Res Opin 29:1001–1013

    Article  CAS  PubMed  Google Scholar 

  21. Klein P, Schiemann J, Sperling MR, Whitesides J, Liang W, Stalvey T, Brandt C, Kwan P (2015) A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia 56:1890–1898

    Article  CAS  PubMed  Google Scholar 

  22. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshe SL, Perucca E, Wiebe S, French J (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE commission on therapeutic strategies. Epilepsia 51:1069–1077

    Article  CAS  PubMed  Google Scholar 

  23. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382:951–962

    Article  CAS  PubMed  Google Scholar 

  24. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet (London, England) 382:951–962

    Article  CAS  Google Scholar 

  25. Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23:3105–3124

    Article  CAS  PubMed  Google Scholar 

  26. Luoni C, Bisulli F, Canevini MP, De Sarro G, Fattore C, Galimberti CA, Gatti G, La Neve A, Muscas G, Specchio LM, Striano S, Perucca E (2011) Determinants of health-related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia 52:2181–2191

    Article  PubMed  Google Scholar 

  27. Martyn-St James M, Glanville J, McCool R, Duffy S, Cooper J, Hugel P, Lane PW (2012) The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: a systematic review and indirect comparison. Seizure 21:665–678

    Article  PubMed  Google Scholar 

  28. Matagne A, Margineanu DG, Kenda B, Michel P, Klitgaard H (2008) Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. Br J Pharmacol 154:1662–1671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S (2014) Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia 55:47–56

    Article  CAS  PubMed  Google Scholar 

  30. Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64:163–171

    Article  PubMed  Google Scholar 

  31. Salanti G, Marinho V, Higgins JP (2009) A case study of multiple-treatments meta-analysis demonstrates that covariates should be considered. J Clin Epidemiol 62:857–864

    Article  PubMed  Google Scholar 

  32. Sankaraneni R, Lachhwani D (2015) Antiepileptic drugs—a review. Pediatr Ann 44:e36–e42

    Article  PubMed  Google Scholar 

  33. Shi LL, Dong J, Ni H, Geng J, Wu T (2017) Felbamate as an add-on therapy for refractory partial epilepsy. Cochrane Database Syst Rev 7:CD008295

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology of the Affiliated Hospital of Qing Dao University, 16 Jiangsu Rd, Shinan, Qingdao, Shandong, China

    Qingting Hu, Wenhui Teng, Fangfang Hao & Naidong Wang

  2. Department of Pharmacology, Qing Dao University School of Pharmacy, Qingdao, China

    Fang Zhang, Jing Zhang & Mingxiao Yin

Authors
  1. Qingting Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenhui Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fangfang Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingxiao Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naidong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naidong Wang.

Ethics declarations

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Funding source

This study was financially supported by Grants from the Natural Science Foundation of Shandong Province of China, no. ZR2016 HM 46, Innovation and Entrepreneurship Training Program of undergraduate student in Qingdao University. No. 201611065160.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Q., Zhang, F., Teng, W. et al. Efficacy and safety of antiepileptic drugs for refractory partial-onset epilepsy: a network meta-analysis. J Neurol 265, 1–11 (2018). https://doi.org/10.1007/s00415-017-8621-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-017-8621-x

Keywords

Search

Navigation