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Tolerability of new antiepileptic drugs: a network meta-analysis

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Abstract

Objective

The objective of this study was to perform a comparative assessment of tolerability of all licensed new antiepileptic drugs (AEDs) through a network meta-analysis (NMA) including all placebo-controlled double-blind clinical trials (RCTs) in all conditions in which these drugs have been tested.

Methods

NMA with a frequentist approach was used to compare proportions of patients withdrawing because of adverse events (AEs). Analyses were conducted for all therapeutic doses pooled and specifically for high therapeutic doses. Patients treated with non-therapeutic doses of each drug were excluded.

Results

A total of 195 RCTs were included in the current analysis, comprising a total of 28,013 patients treated with AEDs and 17,908 patients treated with placebo. RCTs included in the analysis were 8 for brivaracetam; 5 for eslicarbazepine; 22 for gabapentin; 7 for lacosamide; 14 for levetiracetam; 14 for lamotrigine; 6 for oxcarbazepine; 9 for perampanel; 50 for pregabalin; 5 for tiagabine; 36 for topiramate; 7 for zonisamide; 4 for gabapentin-extended formulation (ER); 2 each for levetiracetam-ER, lamotrigine-ER, and topiramate-ER; and 1 each for oxcarbazepine-ER and pregabalin-ER. Brivaracetam, gabapentin, gabapentin-ER, and levetiracetam had a significantly lower withdrawal rate compared to several other AEDs, while eslicarbazepine, lacosamide, oxcarbazepine, and topiramate had a higher withdrawal rate. Perampanel, lamotrigine, pregabalin, tiagabine, and zonisamide showed an intermediate pattern of tolerability. Additional analysis has been conducted through selection of highly recommended doses for each drug. This analysis has roughly confirmed results of head to head comparisons of the all-dose analysis, with some exceptions. A further analysis has been conducted after exclusion of RCTs in which patients were allocated to the therapeutic dose of the experimental drug without titration, and it failed to show clinically important differences.

Significance

Relevant differences in short-term tolerability of AEDs have been observed between AEDs. Brivaracetam, gabapentin, and levetiracetam show the best tolerability profile while other AEDs are at higher risk for intolerable adverse effects.

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Contributions of authors

GZ proposed the project, wrote the protocol, carried out the review, and wrote the article. FG and UB made all analyses. VF performed literature search. GZ, FG, FSG, VF, and SG extracted data for a subset of included articles, cross-checked the results, and assessed eligibility and risk of bias. All authors commented on or edited sections of the article.

Author information

Authors and Affiliations

  1. Department of Medicine, Unit of Neurology, Florence Health Authority, Florence, Italy

    Gaetano Zaccara & Fabio Giovannelli

  2. Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Florence, Italy

    Fabio Giovannelli

  3. Section of Neurology, Pisa University Hospital, Pisa, Italy

    Filippo Sean Giorgi

  4. Department of Internal Medicine and Therapeutics, Division of Clinical and Experimental Pharmacology, University of Pavia, Pavia, Italy

    Valentina Franco

  5. Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy

    Sara Gasparini

  6. School of Clinical Science, Bristol Heart Institute, University of Bristol, Bristol, UK

    Umberto Benedetto

Authors
  1. Gaetano Zaccara
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  2. Fabio Giovannelli
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  3. Filippo Sean Giorgi
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  4. Valentina Franco
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  5. Sara Gasparini
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  6. Umberto Benedetto
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Corresponding author

Correspondence to Fabio Giovannelli.

Ethics declarations

Ethics statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Disclosure

GZ has received speaker’s or consultancy fees from EISAI, Jansen-Cilag, Sanofi-Aventis, and UCB Pharma. FG, FSG, and SG report no disclosures. VF is a former employee of Eisai s.r.l., Italy.

Funding

The authors received no funding for this study.

Electronic supplementary material

Additional Supporting Information may be found in the online version of this article:

ESM 1

PRISMA checklist (DOCX 19 kb)

ESM 2

Inclusion and exclusion criteria and therapeutic doses included in the analysis for each AED (DOCX 21 kb)

ESM 3

Flow charts and references of the identified studies (DOC 195 kb)

ESM 4

Main features of the 196 RCTs included in the analysis (XLS 75 kb)

ESM 5

Diseases explored and main conditions in which they were grouped (DOC 30 kb)

ESM 6

Risk of bias of the included studies (DOCX 23 kb)

ESM 7

Results of main findings (PPTX 133 kb)

ESM 8

Results of secondary analyses (PPTX 390 kb)

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Zaccara, G., Giovannelli, F., Giorgi, F.S. et al. Tolerability of new antiepileptic drugs: a network meta-analysis. Eur J Clin Pharmacol 73, 811–817 (2017). https://doi.org/10.1007/s00228-017-2245-z

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  • DOI: https://doi.org/10.1007/s00228-017-2245-z

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