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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 AEDs . Elinor Ben-Menachem, MD, PhD Institution for Clinical Neuroscience Sahlgrenska Academy Sahlgrenska University Hospital Göteborg, Sweden. Guideline Development . Find the evidence

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Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs

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  1. Evidence-Based Guidelines for the Treatment of Epileptic Seizures with AEDs Elinor Ben-Menachem, MD, PhD Institution for Clinical NeuroscienceSahlgrenska Academy Sahlgrenska University Hospital Göteborg, Sweden

  2. Guideline Development • Find the evidence • Define inclusion/exclusion criteria • Search clinical question + inclusion/exclusion criteria • Potential sources to search • electronic databases (MEDLINE, Current Contents) • Cochrane library • published literature/references • unpublished data • English/non-English studies • Perform multiple searches

  3. 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

  4. 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)

  5. GuidelineMethodology • Topic • Optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy • Team • 10 members • Epileptologists • Clinical pharmacologists • Statistician • Methodologist • 6 countries

  6. ILAE Initial Monotherapy GuidelinesClinical Questions (n=8) : • 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)

  7. GuidelineMethodology • 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

  8. 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

  9. GuidelineMethodology-Statistics • 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.

  10. 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: • Primary outcome variable: efficacy or effectiveness • Treatment duration: ≥ 48 weeks (>24 wk seizure freedom data for efficacy or >48 wk retention data for effectiveness) • Study design: double blind • 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 • Study exit: not forced by a predetermined number of treatment emergent seizures • Appropriate statistical analysis

  11. Criteria for Class II Study-ILAE • Class II: An RCT or meta-analysis meeting all the class I criteria except that: • 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

  12. 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

  13. Guideline Methodology: Grading the evidence for each AED • 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

  14. 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

  15. 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

  16. ILAE GUIDELINESBased on the best evidence available, what is the optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy?

  17. Partial Seizures: AdultsAvailable Evidence • A total of 33randomized 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)

  18. Partial Seizures in AdultsListing of Class I-III Double-Blind RCTs Class I Mattson (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

  19. Partial Seizures: AdultsRecommendations 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

  20. Partial Seizures: ChildrenAvailable Evidence • A total of 25RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures • Division of trials • Class I (n=1) • Class II (n=0) • Class III (n=17)

  21. Partial Seizures: ChildrenClass I-III RCTs Class I Guerreiro (97) OXC, PHT Class II 0 Class III TPM (n=2), CBZ/CZP (n=1), CBZ/ CLB (n=1), TPM/VPA/CBZ (n=1)

  22. Partial Seizures: ChildrenRecommendations Level A: OXC Level B: None Level C: CBZ, PB, PHT, TPM, VPA Level D: LTG,VGB Level E: Others Level F: None

  23. Partial Seizures: ElderlyAvailable Evidence • A total of 30 RCTS with elderly participants included which examined initial monotherapy for partial-onset seizures • Division of trials • Class I (n=1) • Class II (n=1) • Class III (n=2)

  24. Partial Seizures: ElderlyClass I RCTs Class I Rowan (05) CBZ, GBP, LTG Class II Brodie ( 99) CBZ,LTG Class III Privitera (03) CBZ, TPM, VPA Nieto-Barrera (01) CBZ, LTG (Open Label)

  25. Partial Seizures: ElderlyRecommendations Level A: GBP, LTG Level B: None Level C: CBZ Level D: TPM, VPA Level E: Others Level F: None

  26. Generalized Tonic Clonic Seizures: AdultsAvailable Evidence • A total of 23RCTs and 5 meta-analyses examined initial monotherapy of adults with generalized-onset tonic clonic seizures • Division of trials • Class I (n=0) • Class II (n=0) • Class III (n=10):CBZ, GBP, LTG, OXC, PB, PHT, TPM, VPA

  27. Generalized Tonic Clonic Seizures: AdultsRecommendations Level A: None Level B: None Level C: CBZ*,LTG,OXC*, PB, PHT*,TPM,VPA Level D: GBP,VGB Level E: Others Level F: None • *=may aggravate tonic clonic seizures and more commonly other generalized seizure types, should be used with caution

  28. Generalized Tonic Clonic Seizures: ChildrenAvailable Evidence • A total of 20 RCTs examined initial monotherapy of children with generalized onset tonic clonic seizures • Division of trials • Class I (n=0) • Class II (n=0) • Class III (n=14): CBZ, CLB, OXC, PB, PHT, TPM, VPA

  29. Generalized Tonic Clonic Seizures: ChildrenRecommendations Level A: None Level B: None Level C: CBZ*,PB, PHT*,TPM,VPA Level D: OXC* Level E: Others Level F: None *may aggravate tonic clonic seizures and more commonly other generalized seizure types, should be used with caution

  30. Childhood Absence Epilepsy:Available Evidence • A total of 6RCTs examined initial monotherapy of children with Childhood Absence Epilepsy • Division of trials • Class I (n=0) • Class II (n=0) • Class III (n=6) -3 Double Blinded ETX, LTG, VPA

  31. Childhood Absence Epilepsy:Recommendations Level A: None Level B: None Level C: ESM, LTG, VPA Level D: None Level E: Others Level F: CBZ, GBP, OXC, PB, PHT,TGB,VGB

  32. Initial MonotherapyIdiopathic Localization RelatedEpilepsy Syndromes:Benign Epilepsy with Centro-temporal Spikes (BECTS)

  33. BECTS:Available Evidence • A total of 3RCTs examined initial monotherapy of children with BECTS, 2 were DB • Division of trials • Class I (n=0) • Class II (n=0) • Class III (n=2)

  34. BECTS:Recommendations Level A: None Level B: None Level C:CBZ, VPA Level D: GBP,STM Level E: Others Level F: None

  35. Initial MonotherapyIdiopathic Generalized Epilepsy Syndromes:Juvenile Myoclonic Epilepsy

  36. Juvenile Myoclonic Epilepsy:Available Evidence • A total of 0RCTs examined initial monotherapy of children with Juvenile Myoclonic Epilepsy • Division of trials • Class I (n=0) • Class II (n=0) • Class IIII (n=0)

  37. Juvenile Myoclonic Epilepsy :Recommendations Level A: None Level B: None Level C: None Level D: CZP, LTG*, LEV, TPM, VPA, ZNS Level E: Others Level F: CBZ*, GBP, OXC*, PHT*, TGB, VGB *may aggravate myoclonic seizure types, should be used with caution

  38. Juvenile myoclonic epilepsy • Drugs to be avoided • Clinical evidence has been provided that PHT, CBZ, OXC, VGB, TGB, GBP (PRE?) may aggravate absence and myoclonic seizures • LTG has been shown to aggravate severe myoclonic epilepsies in infancy and in JME Level of Evidence III-IV, Recommendation C

  39. Summary of Evidence and RecommendationsPartial onset seizures

  40. Summary of Evidence and RecommendationsGeneralized onset seizures

  41. Summary of Evidence and RecommendationsEpilepsy syndromes

  42. Variables that affect initial AED selection

  43. Elinor Ben-Menachem, Chairman Tracy Glauser, USA Blaise Bourgeois, USA David Chadwick, UK Avital Cnaan, USA Carlos Guerreiro, Brazil Reetta Kalviainen, Finland Richard Mattson, USA Emilio Perruca, Italy Torbjörn Tomson, Sweden Participants in the ILAE Subcommission on Antiepileptic Drug Guidelines

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