Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs Elinor Ben-Menachem, MD, PhD Elinor Ben-Menachem, MD, PhD Institution for Clinical Neuroscience Institution for Clinical Neuroscience Sahlgrenska Academy Sahlgrenska Academy Sahlgrenska University Hospital Sahlgrenska University Hospital Göteborg, Sweden Göteborg, Sweden
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Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs Elinor Ben-Menachem, MD, PhD Institution for Clinical Neuroscience Sahlgrenska.
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Evidence-Based Guidelines for the Treatment of Epileptic Seizures with
AEDs
Evidence-Based Guidelines for the Treatment of Epileptic Seizures with
• electronic databases (MEDLINE, Current Contents)
• Cochrane library• published literature/references• unpublished data• English/non-English studies
Perform multiple searches
Guideline Development
• Translate evidence and develop recommendations
Usually 4 or 5 levels of recommendations
Levels defined using output of grading/rating scale
At least one recommendation per question
• Develop algorithm (if possible)
• Validate guideline
Internal/External Peer review
• Implement and disseminate guideline
Guidelines for newly diagnosed epilepsy
• International ILAE Treatment Guidelines: Evidence-based Analysis of
Anitepileptic Drug Efficacy and Effectiveness as Initial Monotherapy for Epileptic Seizures and Syndromes by Glauser, Ben-Menachem, Bourgeois, Cnaan, Chadwick, Guerreiro, Kälviäinen, Mattson,Perucca and Tomson. Epilepsia 47(7):1-27,2006
• National AAN (Efficacy and tolerability of the new AEDs I and II)
NICE (Diagnosis and management of the epilepsies in adults and children in primary and secondary care)
SIGN (Diagnosis and management of epilepsy in adults)
• Topic
Optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy
• Q1-Q3: Patients (adults/elderly/children) with partial-onset seizures
• Q4-Q5: Patients (adults/children) with generalized-onset tonic-clonic seizures
• Q6: Children with idiopathic localization-related epilepsies and syndromes (BECTS)
• Q7-Q8: Children with idiopathic-generalized epilepsies (CAE, JME)
• Evidence - Key rating variables
• Randomized
• Masked outcome assessment (Minimal potential for bias)
• Clearly defined efficacy/effectiveness outcome variable
• Appropriate statistical analysis
• Use of adequate comparator
• Appropriate minimal duration of treatment
• Acceptable minimally detectable difference
GuidelineMethodology
• Adequate comparator
Assay sensitivity
Criteria: AED superior to another drug, another dose of the same drug, another treatment modality or placebo
• Appropriate minimal duration of treatment
Set at 48 weeks
GuidelineMethodology
• Acceptable minimally detectable difference
Set at 20% by 1998 ILAE guideline
Set as relative difference for this project
• Assume comparator’s seizure freedom rate 50%
• AED with seizure freedom rate < 40% or > 60% (50% + 0.2 x 50%) would be clinically significant.
Protects against ineffective AEDs labeled as effective
Minimal detectable difference calculated for all RCTs based on 80% power, p set at < 0.05 and a non-inferiority analysis.
GuidelineMethodology-Statistics
Criteria for Class I Study-ILAE• A prospective, randomised, controlled clinical trial (RCT) or meta-
analysis of RCTs, in a representative population that meets all six criteria:
1. Primary outcome variable: efficacy or effectiveness
2. Treatment duration: ≥ 48 weeks (>24 wk seizure freedom data for efficacy or >48 wk retention data for effectiveness)
3. Study design: double blind
4. Superiority demonstrated or, if no superiority demonstrated, the study’s actual sample size was sufficient to show non-inferiority of no worse than a 20% relative difference in effectiveness/efficacy
5. Study exit: not forced by a predetermined number of treatment emergent seizures
6. Appropriate statistical analysis
Criteria for Class II Study-ILAE
• Class II: An RCT or meta-analysis meeting all the class I criteria except that:
1. No superiority was demonstrated and the study’s actual sample was sufficient only to show noninferiority at a 21-30% relative difference in effectiveness/efficay
OR
2. Treatment duration: ≥24 wks but ≤ 48 wks
Criteria for Class III-IV Studies-ILAE
• Class III: An RCT or meta-analysis not meeting the criteria for any class I or class II category
• Class IV: Evidence from nonrandomized, prospective, controlled or uncontrolled studies, case series or expert reports
• Recommendations – 6 Levels
Level A: 1 Class I RCTs OR 2 Class II RCTs
Level B: 1 Class II RCTs OR 3 Class III RCTs
Level C: 2 Class III RCTs
Level D: Class III, or IV RCTs OR expert opinions
Level E: Absence of clinical evidence
Level F: Positive evidence of lack of efficacy OR Significant risk of seizure aggravation
Guideline Methodology: Grading the evidence for each AED
Recommendation (Based on efficacy and effectiveness data only)
Evidence Level A-B
AED should be considered for initial monotherapy – First line monotherapy candidate
Evidence Level C
AED may be considered for initial monotherapy – Alternative first line monotherapy candidates
Recommendation (Based on efficacy and effectiveness data only)
Evidence Level D
Weak efficacy or effectiveness data available to support the use of the AED for initial monotherapy
Evidence Level E
Either no data or inadequate efficacy or effectiveness data available to decide if AED could be considered for initial monotherapy.
Evidence Level F
AED should not be used for initial monotherapy
ILAE GUIDELINES
Based on the best evidence available, what is the optimal
initial monotherapy for patients with newly diagnosed or untreated
epilepsy?
ILAE GUIDELINES
Based on the best evidence available, what is the optimal
initial monotherapy for patients with newly diagnosed or untreated
epilepsy?
Partial Seizures: AdultsAvailable Evidence
• A total of 33 randomized clinical trials (RCTs) and 5 meta-analyses examined initial monotherapy of adults with partial-onset seizures
• Division of trials
Class I (n=2)
Class II (n=1)
Class III (n=30)
Class IMattson (1985) CBZ, PB, PHT, PRM
Chadwick (99) CBZ, VGB
Class II
Mattson (92) CBZ, VPA
Class III ( Because of low power (DNIB) or forced exit)
Brodie (95) CBZ, LTG Chadwick (98) GBP
Brodie (02) GBP, LTG Sachdeo (00) TPM
Christe (97) OXC, VPA Gilliam (03) TPM
Bill (97) OXC, PHT Privitera (03) CBZ,TPM,VPA
Dam (89) CBZ,OXC Arroyo (05) TPM
Brodie (02) CBZ, REM Steiner (99) PHT, LTG
Ramsay (83) CBZ, PHT Gibberd (82) PHT, PNT
Mikkelsen (81) CBZ, CLP
Partial Seizures in AdultsListing of Class I-III Double-Blind RCTs
Level A: CBZ, PHT
Level B: VPA
Level C: GBP, LTG, OXC, PB, TPM, VGB
Level D: CZP, PRM
Level E: Others
Level F: None
Partial Seizures: AdultsRecommendations
Partial Seizures: ChildrenAvailable Evidence
• A total of 25 RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures