ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes
Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al.;
Commented by , 27 Sep 2006
Background
Over the years, many trials have addressed the comparative value of different antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy, and there is a need for the available evidence to be critically assessed.
Aim
To assess which AEDs have the best evidence for efficacy or effectiveness as initial monotherapy in newly diagnosed epilepsy.
Methods
- A 10-member subcommission of the International League against Epilepsy (ILAE) conducted a structured review of the literature from 1940 to July 2005.
- Studies were rated based on quality of evidence. Class I studies were double-blind randomised controlled trials (RCT) with >48-week duration without forced exit criteria, information on >24-week seizure freedom or >48-week retention (effectiveness), and either demonstration of superiority or 80% power to detect a <20% relative difference in efficacy/effectiveness versus an adequate comparator.
Class II studies met class I criteria except for having 24 to 47-week duration and power only to exclude a 21-30% relative difference. Class III studies included other RCTs, and class IV other forms of evidence, including expert opinion.
- Quality of evidence was used to determine the strength of the level of recommendation.
Results
- A total of 50 RCTs and 7 metanalyses contributed to the assessment. Only 4 RCTs met class I evidence criteria and 2 met class II criteria; the remaining 44 were rated as class III.
- AEDs with level A or B efficacy/effectiveness evidence as initial monotherapy were only identified for partial seizures in adults (level A, carbamazepine and phenytoin; level B: valproate); partial seizures in children (level A, oxcarbazepine) and partial seizures in the elderly (level A, gabapentin and lamotrigine).
- Two seizure types (generalized tonic-clonic seizures, absence seizures) and two epilepsy syndromes (rolandic epilepsy and juvenile myoclonic epilepsy) had no AEDs with level A or B efficacy/effectiveness evidence as initial monotherapy.
Professor Perucca's comments
In recent years, there has been an explosion of guidelines in every area of medicine. Guidelines for the initial treatment of the epilepsies have been produced by governmental agencies (ref. 1, ref. 2, ref. 3, ref. 4), professional organizations (ref. 5), scientific societies (ref. 6), as well as formulary committees and a myriad of groups sponsored by industry and others (ref. 7).
Guidelines serve different scopes: some provide guidance based on regulatory-type evidence, others address needs that are not covered by regulators, others again are bent on fostering or discouraging the use of more expensive medicines or treatments (ref. 7, ref. 8). Because different guidelines use different methodology, it is no surprise that they often produce diverging recommendations.
The ILAE Guidelines are the latest newcomer. Given the ILAE role in epileptology (96 chapters and 15,000 professional members worldwide) these guidelines are likely to be broadly disseminated. An accompanying editorial called them the "mother of all … guidelines " and "… without question superior to any previous guideline in this area and… as definitive statement as possible based on the evidence from clinical trials" (ref. 7).
In fact, the reader expecting to find in these guidelines therapeutic algorithms will be disappointed. The use of the term "guidelines" for this work is probably misleading – the document is just a rigorous assessment of the quality of the evidence supporting the use of various AEDs in newly diagnosed epilepsy.
The AEDs which are given the highest grade in this document are not necessarily those with the best efficacy and effectiveness – they are simply those with the best evidence for efficacy and effectiveness.
The major usefulness of the work is in highlighting the paucity of well designed trials in this area: out of 50 RCTs, only 6 provided Class I or II evidence based on a reasonable set of criteria. The biggest deficiencies include lack of blinding, insufficient duration of follow-up, and grossly inadequate statistical power. To underscore the unsatisfactory state of research in this area, initial monotherapy RCTs have never been performed in the vast majority of epilepsy syndromes, not even common syndromes such as juvenile myoclonic epilepsy.
These problems are compounded by the fact that the design of many studies are biased in favour of the sponsor’s product (ref. 9, ref. 10). Paradoxically, in a few cases, a questionable design was a key factor in endowing a drug with a high evidence rating: for example, attribution of Class I evidence of effectiveness to oxcarbazepine in pediatric partial seizures was only justified by its better trial retention in a long-term comparison with phenytoin, a clearly suboptimal comparator in this age group!
Because there are no fully objective criteria to rate adverse effect profiles, these were not addressed in the guidelines. Yet, they are a major consideration in chosing AEDs in everyday’s practice. As acknowledged in the guidelines, "it must ultimately remain for the individual physician to use his judgement and expertise when deciding on the most appropriate AEDs for a specific patient … This document is only the first attempt to create a working framework rather than a rulebook about the treatment of new onset epilepsy."
References
1. National Institute for Clinical Excellence (NICE). The clinical effectiveness and cost effectiveness of newer drugs for epilepsy in adults. Technology Appraisal 76; 2004
2. National Institute for Clinical Excellence (NICE). The clinical effectiveness and cost effectiveness of newer drugs for epilepsy in children. Technology Appraisal 79; 2004
3. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsy in adults. Guideline no. 70; 2003
4. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of epilepsies in children and young people. Guideline no. 81; 2005
5. Stokes T, Shaw EJ, Juarez-Garcia A, Camosso-Stefinovic J, Baker R. Clinical Guidelines and Evidence Review for the Epilepsies: diagnosis and management in adults and children in primary and secondary care. London: Royal College of General Practitioners
6. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2004; 45 (5); 401-409
7. Shorvon S. We live in the age of the clinical guideline. Epilepsia 2006; 47 (7); 1091-1093
8. Taylor R, Giles J. Cash interests taint drug advice. Nature 2005; 437 (7062); 1070-1071
9. Perucca E. What can we learn from clinical trials of anticonvulsant drugs in epilepsy? European Journal of Pain 2002; 6 Suppl A: 35-44
10. Perucca E, Tomson T. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Research 1999; 33 (2-3); 247-262