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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis

S Beyenburg, K Stavem, and D Schmidt.

Review published: 2010.

Link to full article: [Journal publisher]

CRD summary

This review concluded that the placebo-corrected efficacy of adjunctive anti-epileptic drugs for refractory epilepsy (in terms of seizure-free and 50% reductions in seizure outcomes) was very small. Although the authors' conclusions were consistent with the evidence presented, they should be interpreted with caution given the potential for bias.

Authors' objectives

To determine the placebo-corrected efficacy of adjunctive anti-epileptic drugs in patients with refractory epilepsy.


PubMed, EMBASE, Index Medicus and the Cochrane Library were searched, up to December 2008, for studies published in English. Search terms were available in an online appendix (see URL for Additional Data). Reference lists of retrieved papers, bibliographies of reviews and book chapters were handsearched. Experts were contacted for unpublished trials.

Study selection

Double-blind randomised placebo-controlled trials or randomised controlled trials ((RCTs) with a double-blind placebo-controlled phase that compared adjunctive anti-epileptic drugs with placebo controls in patients with refractory epilepsy were eligible for inclusion. Eligible trials had to reported seizure-free outcome and/or 50% seizure reduction, and had to include at least 20 patients. Trials in abstract format were excluded.

Refractory epilepsy was defined as when one or several anti-epileptic drugs had failed to control seizures.

Most included trials were of patients with focal epilepsy, but some were of patients with generalised epilepsy, with or without myoclonic seizures, or tonic-clonic seizures and Lennox-Gastaut syndrome. One trial was of older patients with epilepsy and intellectual disability. The mean age of included patients ranged between 8.4 and 41.2 years; ages ranged from 2 to 77 years (where reported).

The anti-epileptic drugs assessed were varied and included eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, pregabalin, retigabine, rufinamide, tiagabine, topiramate, vigabatrin, and zonisamide. The dose of anti-epileptic drugs varied across included trials; the treatment duration was mostly around 12 weeks, but ranged from four to 36 weeks. A small number of trials used a cross-over design.

Two reviewers independently applied the inclusion criteria and selected studies.

Assessment of study quality

It appeared that quality was not formally assessed, but all of the included trials were double-blind placebo controlled trials.

Data extraction

The difference between pre- and post-intervention seizure-free outcome and 50% seizure reduction were extracted to calculate risk difference (RD) with 95% confidence intervals (CIs)

Two reviewers independently extracted the data and resolved disagreements by discussion.

Methods of synthesis

Risk difference and 95% confidence intervals were pooled using a random-effects model with inverse variance weighting component, although the weighting of the trials was not reported in the review. Heterogeneity between trials was assessed by the Q and I2 statistics.

The impact of date of trial publication, age at randomisation, treatment dose and trial population (adults versus children, and only patients with focal epilepsy) on the main outcomes was assessed by sensitivity analysis and meta-regression.

Publication bias was assessed by a funnel plot and Egger’s test.

Results of the review

Fifty-four trials (n=11,106 patients), published in 55 articles, met the inclusion criteria. All the trials were placebo-controlled double blinded. Most of the trial used intention-to-treat analysis. Six publications were based on data from children, 46 used data from adults, and three publications involved combined datasets from children and adults.

For patient with refractory epilepsy who received adjunctive anti-epileptic drugs, the seizure-free rate was 8.2% (range 0 to 35%) compared with placebo (2.1%, range 0 to 17%). In terms of weighted risk difference, there was statistically significant seizure-free outcomes with adjunctive anti-epileptic drugs compared with placebo (RD 0.06, 95% CI 0.04 to 0.08; 30 trials; n=6,554 patients), but heterogeneity was significant (I2=74%).

Adjunctive anti-epileptic drugs led to 35% (range 14 to 60%) of patients with a 50% reduction in seizure rate versus 15% (range 0 to 39%) of patients on placebos. In the weighted-pooled analysis, adjunctive anti-epileptic drugs led to a statistically significant 50% reduction in seizure rate compared with placebo (RD 0.21, 95% CI 0.19 to 0.24; 54 trials, n=11,106 patients), but heterogeneity was significant (I2=57%).

Sensitivity analyses did not change the results of seizure-free and 50% seizure reduction. Meta-regression analyses also showed no difference in effect between year of publication (before 2001 versus 2001 and later) on seizure-free (p=0.60) or 50% seizure reduction (p=0.62).

There was evidence of publication bias for trials involving adults only, but not for trials of children only.

Authors' conclusions

The placebo-corrected efficacy of adjunctive treatment with anti-epileptic drugs in terms of seizure free and 50% seizure reduction in refractory epilepsy was very small.

CRD commentary

This review addressed a well-defined question in terms of participants, interventions, outcomes, and study design. The search included appropriate databases. Attempts were made to retrieve unpublished studies. However, given that the search was restricted to English, the potential for language bias could not be ruled out. Publication bias could not be ruled for a subgroup of studies involving adults only. Two reviewers independently selected studies and extracted data to minimise bias and errors during the review process.

The quality of the included trials was unclear, as no formal assessment was undertaken. The characteristics of the individual trials were presented, although the type of placebos used in the trials was unclear. Potential sources of heterogeneity were explored and evidence of significant statistical heterogeneity was found. The authors discussed potential factors that could influence validity and generalisability of the results in detail. Sensitivity and subgroup analyses demonstrated that the results were robust to changes in the factors considered.

Although the authors' conclusions were consistent with the evidence presented, they should be interpreted with caution given the concerns regarding the potential for bias.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that promising strategies for developing more effective anti-epileptic drugs may include: overcoming the blood brain barrier to allow the crossing of large anti-epileptic drug molecules; finding new targets to regulate drug resistance in epilepsy; and overcoming increased efflux transport of anti-epileptic drugs from the epileptogenic brain area in refractory epilepsy through co-administration of suitable p-glycoprotein inhibitors.


Not stated.

Bibliographic details

Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 2010; 51(1): 7-26. [PubMed: 19744114]

Indexing Status

Subject indexing assigned by NLM


Adult; Anticonvulsants /therapeutic use; Child; Drug Resistance; Epilepsy /drug therapy; Female; Humans; Male; Placebos; Randomized Controlled Trials as Topic /statistics & numerical data; Treatment Outcome



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 19744114


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