Antiepileptic drugs associated with sevenfold drop in sudden, unexpected deaths

Treatment with adjunctive antiepileptic drugs at efficacious doses may reduce sudden unexpected death in epilepsy (SUDEP) by more than seven times compared with placebo in patients with previously uncontrolled seizures.

Researchers performed a meta-analysis of double-blind, placebo-controlled, randomized trials of add-on antiepileptic drugs done in adult patients with uncontrolled partial or primary generalized tonic-clonic seizures. The number and causes of death in patients allocated to antiepileptic drugs at efficacious doses were compared to outcomes in patients given antiepileptic drugs at non-efficacious doses or placebo. Results were published online Sept. 20 by The Lancet Neurology.

SUDEP was defined as a sudden, unexpected, non-traumatic and nondrowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, while in a reasonable state of health (apart from their epilepsy), without any obvious medical cause.

SUDEP was classified into three categories:

• definite, for cases that fulfilled the definition,
• probable, for cases in which post-mortem data were not available, but all other criteria were fulfilled, and
• possible, for cases in which there was missing information about the circumstances of death or because there was a plausible competing explanation for death.

Data on 33 deaths, including 20 cases of SUDEP, were extracted from 112 eligible randomized trials, including 106 (95%) in refractory partial epilepsy and six (5%) in refractory primary generalized tonic-clonic seizures. The trials included a total of 21,224 patients and 5,589 patient-years. Eighteen deaths were classified as definite or probable SUDEP and two as possible SUDEP.

Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious antiepileptic drug group than in the placebo group, with odds ratios of 0.17 (95% CI, 0.05 to 0.57; P=0.0046), 0.17 (95% CI, 0.05 to 0.57; P=0.0046), and 0.37 (95% CI, 0.17 to 0.81; P=0.0131), respectively. Rates of definite or probable SUDEP per 1,000 person-years were 0.9 (95% CI, 0.2 to 2.7) in patients who received efficacious doses and 6.9 (95% CI, 3.8 to 11.6) in patients who received placebo.

Despite the small scale and short duration of the trials and the low rate of SUDEP, the authors wrote, “[T]he more than seven-fold difference in SUDEP incidence noted between patients randomly assigned to placebo and those receiving antiepileptic drugs at efficacious doses points to a significant finding with magnitude that cannot be ignored.” An editorial commented that the study provides strong evidence for adjunctive therapy in patients with refractory seizures, that seizure control could be extremely important for SUDEP prevention, and that polytherapy does not increase risk of SUDEP during the short time period of a randomized trial.

“This alone is very useful clinical information, and the overall results highlight the importance of revision of treatment in patients with refractory epilepsy, such as addition of an extra antiepileptic drug when appropriate to enhance seizure control,” the editorial said.

Also, the editorial criticized practices in epilepsy research and noted that the significantly higher incidence of SUDEP should prompt serious discussions about minimizing clinical trial durations, especially for patients who do not respond to treatment, as well as about the practice of using suboptimal doses of antiepileptic drugs as placebos in trials.