Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials

Summary Purpose:  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 wit...

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Veröffentlicht in:Epilepsia (Copenhagen) Jg. 54; H. 1; S. 135 - 140
Hauptverfasser: Tomson, Torbjörn, Hirsch, Lawrence J., Friedman, Daniel, Bester, Nicolette, Hammer, Anne, Irizarry, Michael, Ishihara, Lianna, Krishen, Alok, Spaulding, Theodore, Wamil, Art, Leadbetter, Robert
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Oxford, UK Blackwell Publishing Ltd 01.01.2013
Wiley Subscription Services, Inc
Schlagworte:
Adult
Anticonvulsants - therapeutic use
Anticonvulsants - toxicity
Antiepileptic agents
Clinical trials
Confidence Intervals
Death
Death, Sudden - epidemiology
Death, Sudden - etiology
Drug therapy
Epilepsy
Epilepsy - drug therapy
Epilepsy - mortality
Female
Humans
Lamotrigine
Logistic Models
Male
Odds Ratio
Randomized Controlled Trials as Topic - statistics & numerical data
Reviews
Risk Factors
Seizures
Statistical analysis
Statistical methods
Statistics
Triazines - therapeutic use
Triazines - toxicity
ISSN:0013-9580, 1528-1167, 1528-1167
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Zusammenfassung:Summary Purpose:  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. Key Findings:  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). Significance:  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.
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ISSN:0013-9580
1528-1167
1528-1167
DOI:10.1111/j.1528-1167.2012.03689.x