Epilepsy patients with previously uncontrolled seizures have a much lower rate of sudden death if they are given adjunctive anti-epilepsy drugs, a meta-analysis has found.
In an examination of 112 trials, the odds ratio for sudden unexpected death (SUDEP) in patients randomly assigned to anti-epileptic drugs (AEDs) at efficacious doses versus those assigned to placebo was 0.17 (95% CI 0.05 to 0.57, P=0·0046), Philippe Ryvlin, MD, of Hospices Civils de Lyon in France, and colleagues reported online in The Lancet Neurology.
“To the best of our knowledge, this post-hoc analysis offers the first controlled evidence that an intervention may modify the risk of SUDEP,” the authors wrote. “The more than seven-fold difference in SUDEP incidence noted between patients randomly assigned to placebo and those receiving AEDs at efficacious doses points to a significant finding with magnitude that cannot be ignored.”
SUDEP is the main reason behind an increased death rate in uncontrolled epilepsy, occurring at a rate between 3.5 and 9.3 per 1,000 person-years, the authors noted. Most SUDEP victims are young adults, with an average age of 35.
Although the process is typically unwitnessed, those deaths that have been observed are usually triggered by a seizure “through mechanisms that remain uncertain,” they explained. And although some potential risk factors for SUDEP have been identified, suggesting that the outcome might be avoided if optimal care is given, no interventions have been studied.
To help clarify the issue, the researchers searched the Medline and Cochrane databases for double-blind, placebo-controlled, randomized trials of add-on AEDs used in adult patients with uncontrolled partial or primary generalized tonic-clonic seizures. They also searched for additional studies in several other places including the metaRegister of Controlled Trials and ClinicalTrials.gov.
In their search, they defined SUDEP as “a sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning death of patients with epilepsy with or without evidence of a seizure, excluding documented status epilepticus, in whom post-mortem examination did not reveal a structural or toxicological cause of death.”
The researchers then classified every death studied as possible, probable, or definite SUDEP.
The study’s primary endpoint was to compare the incidence of definite and probable SUDEP between patients receiving AEDs at efficacious doses and those receiving placebo. Secondary endpoints included the comparison of all SUDEP (possible, probable, or definite) deaths, cause of deaths other than SUDEP, and all causes of death between the same two groups.
The investigators initially identified 6,718 reports, and whittled those down to 112 eligible trials, including 106 involving refractory partial epilepsy and six involving refractory primary generalized tonic-clonic seizures. The chosen trials involved 21,224 patients and 5,589 patient-years. A total of 27 AEDs were used in the trials at 86 doses, eight of which were not found to be efficacious.
In all, 33 deaths occurred in the selected trials, of which a specific cause of death other than SUDEP was established in 13 patients. SUDEP was diagnosed in 20 patients spread among 14 trials, with detailed reports of death for 19 of the patients. Of those, 11 fulfilled the criteria of definite SUDEP, including unremarkable post-mortem data, except for hypothermia in one patient and mild-to-moderate coronary atheroma in another.
Another seven patients met the criteria for probable SUDEP, including one patient for whom a cardiac sudden death was also suspected in the original report, the authors noted. SUDEP was categorized as “possible” in two patients, whose data were not used in primary analysis.
In all, 10 of the 33 deaths, including three (15%) of the 20 SUDEP cases, occurred in the efficacious AED group; four deaths, including three (15%) SUDEP occurred in the nonefficacious AED group; and 19 deaths, including 14 (70%) SUDEP, occurred in the placebo group. Because all of the definite or probable SUDEP deaths occurred in the partial epilepsy trials, no odds ratio could be calculated for definite and probable SUDEP in trials of primary generalized tonic-clonic seizures, they noted.
When comparing overall deaths between patients randomized to efficacious AEDs and those randomized to placebo, the odds ratio was 0.37 (95% CI 0.17 to 0.81, P=0.0131). However, if the comparison between the groups included only non-SUDEP deaths, the odds ratio was a nonsignificant 0.89 (95% CI 0.28 to 2.79, P=0.84).
Limitations of the study include the fact that the majority of trials (87%) were non-event trials, and that a few patients were randomly assigned to AED doses that were judged to be nonefficacious based on “conservative, yet disputable, criteria,” the authors noted. However, pooling the data with those of patients in either the efficacious AED or placebo groups did not change the results, they added.
The study “provides strong evidence for an effective intervention to reduce SUDEP risk: adjunctive therapy in patients with refractory seizures,” Dale C. Hesdorffer, PhD, of Columbia University in New York, and Torbjörn Tomson, MD, of Karolinska Institute in Stockholm, wrote in an accompanying commentary.
In addition, the study results also suggest that “polytherapy does not increase risk of SUDEP during the time period of a randomised trial,” they wrote. “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 AED when appropriate to enhance seizure control.”
Source: MedPageToday.com
