title: Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials.
abstract: OBJECTIVE
  Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic-clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009.
  
  
  METHODS
  Among 7,774 subjects in 42 randomized clinical trials, there were 39 all-cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo-controlled, active-comparator, crossover), using exact statistical methods.
  
  
  RESULTS
  Of 29 on-treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non-SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000-patient years (95% confidence interval [95% CI] 0.70-5.4). The odds ratios (OR) for on-treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo-controlled, OR 0.22 (95% CI 0.00-3.14; p = 0.26); active-comparator, OR 2.18 (95% CI 0.17-117; p = 0.89); and placebo-controlled cross-over, OR 1.08 (95% CI 0.00-42.2; p = 1.0).
  
  
  CONCLUSIONS
  There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Tomson
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hirsch
authors.forename: Daniel
authors.initials: D
authors.lastname: Friedman
authors.forename: Nicolette
authors.initials: N
authors.lastname: Bester
authors.forename: Anne
authors.initials: A
authors.lastname: Hammer
authors.forename: Michael
authors.initials: M
authors.lastname: Irizarry
authors.forename: Lianna
authors.initials: L
authors.lastname: Ishihara
authors.forename: Alok
authors.initials: A
authors.lastname: Krishen
authors.forename: Theodore
authors.initials: T
authors.lastname: Spaulding
authors.forename: Art
authors.initials: A
authors.lastname: Wamil
authors.forename: Robert
authors.initials: R
authors.lastname: Leadbetter
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use / Q000633:toxicity*; D016001:Confidence Intervals; D003645:Death, Sudden / Q000453:epidemiology / Q000209:etiology; D004827:Epilepsy / Q000188:drug therapy / Q000401:mortality*; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012307:Risk Factors; D014227:Triazines / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine