Polytherapy, improved medication adherence reduce risk for SUDEP in Swedish cohort

Polytherapy, especially the use of three or more antiepileptic drugs, correlated with a substantially decreased risk for sudden unexpected death in epilepsy, according to findings from a nationwide case-control study conducted in Sweden.

The findings, which were published in Neurology, also demonstrated a link between statin use and a decreased risk for sudden unexpected death in epilepsy.

“There is an urgent need to reduce the risk of sudden unexpected death in epilepsy (SUDEP),” the researchers wrote. “Risk factors related to drug treatment may represent opportunities for prevention.”

However, data regarding the use of antiepileptic drugs (AEDs) and risk for SUDEP are limited, the researchers noted.

Olafur Sveinsson MD, PhD, of the departments of neurology and clinical neuroscience at the Karolinska Institute in Sweden, and colleagues performed the population-based, case-control study to determine the relationship between AEDs, selective serotonin reuptake inhibitors (SSRIs) and “other potentially relevant drugs” and SUDEP risk. The researchers used data from individual medical records, with information on potential confounders, and national registries, including specific data on drug exposure. Specifically, they adjusted for the following risk factors: type of epilepsy, living conditions, co-morbidity and frequency of generalized tonic-clonic seizures (GTCS).

The analysis included 255 cases of SUDEP and 1,148 matched controls. Individuals who died from SUDEP (cases) had longer durations of epilepsy and an increased likelihood of GTCS in the previous year, intellectual disability and history of substance abuse. Researchers found that cases were also less likely to share a bedroom compared with controls. Use of no AED was more common among controls than cases (23.1% vs. 18.4%, respectively).

The most commonly used AED overall was carbamazepine among cases (33.3%) and lamotrigine (24.5%) among controls. Polytherapy, particularly the use of three or more AEDs, correlated with a substantially decreased risk for SUDEP (OR = 0.31; 95% CI, 0.14-0.67). Combinations, including lamotrigine (OR = 0.55; 95% CI, 0.31-0.97), valproic acid (OR = 0.53; 95% CI, 0.29-0.98) and levetiracetam (OR = 0.49; 95% CI, 0.27-0.90) were related to reduced risk.

While the numbers for patients receiving monotherapy were limited, Sveinsson and colleagues observed the lowest risk for SUDEP among patients taking levetiracetam (OR = 0.10; 95% CI, 0.02-0.61). No monotherapy increased the risk for SUDEP.

The researchers found that statin use reduced SUDEP risk (OR = 0.34; 95% CI, 0.11-0.99), though the same observation was not made for SSRI use. Conversely, a mention of non-adherence in the medical record correlated with an increased SUDEP risk (OR = 2.75; 95% CI, 1.58-4.78).

“These results provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled GTCS in the efforts to reduce SUDEP risks and suggest that comedication with statins may reduce risks,” Sveinsson and colleagues wrote.

In a related editorial, Lina Nashef, MBChB, MD, FRCP, of the department of neurology at King’s College London Hospital, and Fergus Rugg-Gunn, MBBS, FRCP, PhD, of the department of clinical and experimental epilepsy at the National Hospital for Neurology and Neurosurgery, the UCL Institute of Neurology and the Chalfont Center for Epilepsy, wrote that “it was not that long ago that some believed there was little point in discussing [SUDEP] with patients.” The rationale, according to Nashef and Rugg-Gunn, was that clinicians saw no reason to cause anxiety when “it was wrongly argued” that the risk for the condition could not be changed. The results of the “landmark study” from Sveinsson and colleagues suggests otherwise, they continued.

Nashef and Rugg-Gunn emphasized that the findings from Sveinsson and colleagues need to be translated into ongoing surveillance and that trends need to be monitored. In particular, they highlight the need for more research into the differences between AEDs.

“Management and prescribing in epilepsy constantly, if slowly, evolve,” Nashef and Rugg-Gunn wrote. “The authors would continue to lead the way in this important field if the methodology of this study, which covered prescribing until 2011, could be extended in Sweden to ongoing prospective surveillance, linking prescribing and mortality.”