Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials

Abstract

SUMMARYPurpose: 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.

A prospective open‐label trial of a CBD/THC cannabis oil in dravet syndrome

“…SUDEP is reported in clinical trials in those with DRE . Dravet syndrome is associated with higher rates of SUDEP, reportedly 9.3/1000 patient years in a recent study, almost double the rate quoted for adults with DRE .…”

Safety, tolerability, and seizure control during long‐term treatment with adjunctive brivaracetam for partial‐onset seizures

“…For BRV doses 5–200 mg/day, the mortality rate in adults reported across these studies of <6 deaths/1,000 patient‐years is comparable with other AED drug development programs and community‐based epidemiologic studies, as is the SUDEP rate of <2 deaths/1,000 patient‐years for definite or probable SUDEP. Mortality rates (95% CI) recently published are 5.9 (4.1–8.2) from a large systematic review, 9.1 (7.6–10.8) from pooled study data taken from drug applications, and 12.3 (8.9–16.6) from the lamotrigine clinical development program . SUDEP rates published by others have varied from 0.9 (95% CI 0.2–2.7) to 3.8 (95% CI 2.9–5.0) .…”

Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention

“…However, these findings are difficult to interpret since polytherapy can be a surrogate for more severe epilepsy. Additionally, across epidemiological studies, these findings are inconsistent 12 16 17. Increasing evidence from meta-analyses and randomised controlled studies suggests that monotherapy and polytherapy at efficacious doses reduce SUDEP 18.…”