|The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: a systematic review and indirect comparison
|Martyn-St James M, Glanville J, McCool R, Duffy S, Cooper J, Hugel P, Lane PW
This review concluded that retigabine provided similar risks and benefits, compared with the other selected anti-epileptic drugs, as additional therapy, for patients with partial-onset seizures, with or without secondary generalisation, but the limitations of the analyses should be considered. These conclusions appear to be reliable.
To evaluate the efficacy and tolerability of retigabine, compared with selected anti-epileptic drugs.
Eighteen electronic databases (including MEDLINE, EMBASE, DARE, and HTA database), trial registries, guideline collections, or regulatory authority records, were searched, without language restrictions, up to June 2010. Unpublished data were provided by the manufacturer of retigabine (GlaxoSmithKline).
Parallel or crossover randomised controlled trials of additional anti-epileptic drug therapy were eligible for inclusion if they were of adults (18 years old or older), with partial-onset epileptic seizures, who had failed to respond adequately to previous anti-epileptic drugs. The treatment had to be at target dose (maintenance phase) for eight weeks or more, and the prospective baseline period had to be four weeks or more. Trials had to report the change in seizure frequency and treatment withdrawal, as outcomes. The selected anti-epileptic drugs for comparison were eslicarbazepine acetate, lacosamide, tiagabine, zonisamide and pregabalin.
All the included trials were placebo controlled and most evaluated more than one dose of retigabine. The authors did not state how many reviewers selected the trials.
Assessment of study quality
The quality of the included trials was assessed for appropriateness of randomisation, concealment of treatment allocation, comparability of groups at baseline, blinding procedures, unexpected imbalances in drop-outs, reporting of measured outcomes, and inclusion of an intent-to-treat analysis.
The authors did not state how many reviewers performed the assessment.
The proportions of responders (defined as patients with 50% or greater reduction in seizure frequency), seizure-free patients, withdrawals, and patients reporting anti-epileptic drug-related adverse events (ataxia, dizziness, fatigue, nausea, or somnolence), were extracted from each study to calculate odds ratios and related 95% confidence intervals.
One reviewer extracted the data, and they were checked by a second reviewer.
Methods of synthesis
Pooled odds ratios and relative risks were calculated for the drug to placebo comparisons, using both fixed-effect and random-effects models; only odds ratios were presented. Statistical heterogeneity was assessed using Cochran's Q and Ι². Publication bias was investigated by funnel plot inspection.
A hierarchical Bayesian network meta-analysis was used to compare the anti-epileptic drugs indirectly with each other, using a fixed-effect logistic regression model. The results were presented as mean odds ratios and 95% credible intervals.
Where the trials had multiple treatment arms, evaluating different drug doses, compared with placebo, the results of the different treatment arms were combined to create a pooled comparison of the drug versus placebo. Additional analyses were undertaken to consider clinically relevant dose ranges.
Results of the review
Twenty trials met the inclusion criteria. Three assessed retigabine (1,242 patients), three assessed eslicarbazepine acetate (1,050 patients), three assessed lacosamide (1,308 patients), three assessed tiagabine (769 patients), and three assessed zonisamide (642 patients). The other five assessed pregabalin (1,487 patients). The double-blind period (following baseline, titration, and maintenance periods) ranged from 12 to 24 weeks.
In the network meta-analysis, retigabine was no better and no worse than the other anti-epileptic drugs for responder rate, during the maintenance period; seizure freedom, during maintenance and double-blind periods; withdrawals due to adverse events; and incidences of ataxia, dizziness, fatigue and nausea.
Retigabine was associated with a lower responder rate than pregabalin, during the double-blind period (OR 0.65, CrI 0.41 to 0.96), a higher withdrawal rate, for any reason, than eslicarbazepine acetate (OR 1.91, CrI 1.18 to 2.89), and a higher incidence of somnolence than tiagabine (OR 2.38, CrI 1.03 to 7.14).
The funnel plot inspection was not informative as there were too few trials.
Retigabine provided similar risks and benefits, compared with the other selected anti-epileptic drugs, as additional therapy, for patients with partial-onset seizures, with or without secondary generalisation, but the limitations of the analyses should be considered.
This review appeared to be carefully conducted, with comprehensive searches for relevant evidence and largely reproducible methods for selecting, assessing and combining the retrieved data. The authors pointed out several limitations to their analysis, which were statistical heterogeneity was present for some comparisons; where it was not present, the trials varied in their dosing schedules and participants (age, gender, severity, or concomitant treatment); only a few trials were available for each drug; publication bias could not be excluded for the non-retigabine evidence; most trials had short treatment periods; and not all anti-epileptic drugs were compared. Trial quality was assessed, but the results were not incorporated in the synthesis.
The authors conclusions that retigabine was similar to the other included anti-epileptic drugs, but the limitations should be considered, appear to be reliable.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that their indirect comparisons should be considered with the direct evidence, and that head-to-head randomised controlled trials, should compare different anti-epileptic drugs for specific patient populations.
Funded by GlaxoSmithKline, manufacturer of retigabine.
Martyn-St James M, Glanville J, McCool R, Duffy S, Cooper J, Hugel P, Lane PW. The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: a systematic review and indirect comparison. Seizure 2012; 21(9): 665-678
Subject indexing assigned by CRD
Humans; Anticonvulsants; Carbamates; Phenylenediamines; Epilepsies, Partial; Epilepsy
Date bibliographic record published
Date abstract record published
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.