ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes

Tracy Glauser, Elinor Ben-Menachem, Blaise Bourgeois, Avital Cnaan, David Chadwick, Carlos Guerreiro, Reetta Kalviainen, Richard Mattson, Emilio Perucca, Torbjorn Tomson

Research output: Contribution to journalArticle

545 Citations (Scopus)

Abstract

Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. Methods: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, ≥48-week treatment duration without forced exit criteria, information on ≥24-week seizure freedom data (efficacy) or ≥48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a ≤20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21-30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. Results: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic-clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. Conclusions: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

Original languageEnglish
Pages (from-to)1094-1120
Number of pages27
JournalEpilepsia
Volume47
Issue number7
DOIs
Publication statusPublished - Jul 2006

Fingerprint

Anticonvulsants
Epilepsy
Seizures
Guidelines
Therapeutics
Rolandic Epilepsy
Juvenile Myoclonic Epilepsy
Pediatrics
Absence Epilepsy
Generalized Epilepsy
antineoplaston A10
Carbamazepine
Expert Testimony
Valproic Acid
Phenytoin
MEDLINE
Libraries
Meta-Analysis
Randomized Controlled Trials
Pharmacokinetics

Keywords

  • Antiepileptic drugs
  • Effectiveness
  • Efficacy
  • Epilepsy treatment
  • Guidelines

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

ILAE treatment guidelines : Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. / Glauser, Tracy; Ben-Menachem, Elinor; Bourgeois, Blaise; Cnaan, Avital; Chadwick, David; Guerreiro, Carlos; Kalviainen, Reetta; Mattson, Richard; Perucca, Emilio; Tomson, Torbjorn.

In: Epilepsia, Vol. 47, No. 7, 07.2006, p. 1094-1120.

Research output: Contribution to journalArticle

Glauser, T, Ben-Menachem, E, Bourgeois, B, Cnaan, A, Chadwick, D, Guerreiro, C, Kalviainen, R, Mattson, R, Perucca, E & Tomson, T 2006, 'ILAE treatment guidelines: Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes', Epilepsia, vol. 47, no. 7, pp. 1094-1120. https://doi.org/10.1111/j.1528-1167.2006.00585.x
Glauser, Tracy ; Ben-Menachem, Elinor ; Bourgeois, Blaise ; Cnaan, Avital ; Chadwick, David ; Guerreiro, Carlos ; Kalviainen, Reetta ; Mattson, Richard ; Perucca, Emilio ; Tomson, Torbjorn. / ILAE treatment guidelines : Evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. In: Epilepsia. 2006 ; Vol. 47, No. 7. pp. 1094-1120.
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AU - Cnaan, Avital

AU - Chadwick, David

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N2 - Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long-term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. Methods: A 10-member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double-blind randomized controlled trial (RCT) design, ≥48-week treatment duration without forced exit criteria, information on ≥24-week seizure freedom data (efficacy) or ≥48-week retention data (effectiveness), demonstration of superiority or 80% power to detect a ≤20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21-30% relative difference. Class III studies included other randomized double-blind and open-label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation. Results: A total of 50 RCTs and seven meta-analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial-onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial-onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial-onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type [adults with generalized-onset tonic-clonic (GTC) seizures], two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy. Conclusions: This evidence-based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence-based guideline aimed at identifying the overall optimal recommended initial-monotherapy AED. There is an especially alarming lack of well-designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.

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