Nonadherence remains a significant problem in SUDEP

Polytherapy with antiepileptic drugs (AEDs) was associated with a reduced risk of sudden unexpected death in epilepsy (SUDEP) compared with not taking any AEDs, a population-based case-control study found.

“We found that polytherapy with three or more AEDs was associated with a reduction of SUDEP risk by two-thirds after taking GTCS into account [OR 0.31, 95% 0.14-0.67],” Olafur Sveinsson, MD, PhD, of Karolinska University in Stockholm, Sweden, and colleagues wrote in Neurology. “Given the conflicting results with some previous reports, our data on polytherapy should be interpreted cautiously, although adding an AED to existing baseline AED treatment of patients with refractory seizures has been associated with a reduced SUDEP risk in the context of randomized controlled trials.”

Sveinsson and colleagues also noted that the results “provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled generalized tonic clonic seizures in the efforts to reduce SUDEP risks and suggest that co-medication with statins may reduce risks.”

The analyses were adjusted for history and frequency of generalized tonic clonic seizure (GTCS) and nocturnal GTCS during the prior year. Statin use was associated with reduced SUDEP risk (OR 0.34, 95% CI 0.11-0.99), but selective serotonin reuptake inhibitor (SSRI) use was not.

In an accompanying editorial, Lina Nashef, MBChB, MD, of King’s College Hospital in London, England, and Fergus Rugg-Gunn, MBBS, PhD, of University College London, noted that this research, in parallel with newer biomarker-based approaches to studying and preventing SUDEP, supports “applying what we already know: preventing GTCS through optimal medical treatment, avoiding seizure-triggers, improving adherence to treatment and discussing the protection offered by living with others for patients with uncontrolled epilepsy.”

“A reasonable, if unproven, assumption is that polytherapy reduces risk through better seizure control, particularly of convulsive seizures, rather than through other mechanisms,” they wrote. “If so, polytherapy in itself is not the goal, rather control of seizures. These results, however, support the use of polytherapy where needed, in the prevention of SUDEP, if GTCS are uncontrolled.

SUDEP is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic, non-drowning death of patients with epilepsy, with or without evidence of a seizure, excluding documented status epilepticus, with no postmortem evidence for a structural or toxicologic cause for death.

A SUDEP risk factor study showed that GTCS during the last year (OR 26.81), nocturnal GTCS during the last year (OR 15.31), living alone (OR 5.01), and the combination of not sharing a bedroom and having GTCS (OR 67.10) raised SUDEP risk.

AED and non-AED drugs have been proposed to moderate risk of SUDEP. AED polytherapy is inconsistently associated with SUDEP, but was not seen in a meta-analysis that controlled for GTCS. Another meta-analysis found that adding an AED rather than placebo to the existing AED regimen reduced SUDEP incidence in refractory epilepsy. SSRIs and statins have been proposed to affect SUDEP risk.

In the present study, Sveinsson and colleagues used data from epilepsy patients registered between 1998 and 2005 in the Swedish National Patient Register who were alive on June 30, 2006 (n=60,952). The researchers linked these records to the National Cause of Death Registry and followed patients from July 2006 to December 2011. They also obtained clinical and prescription information through individual medical records and the National Prescribed Drug Register.

Of 9,605 deaths overall, researchers included 167 definite and 88 probable SUDEP cases for a case total of 255. Each SUDEP case was assigned 5 same-sex controls with epilepsy who were alive at the case time of death (n=1,148).

Men made up about 60% of both groups. Comparing cases with controls, respective proportions of findings were:

  • Median epilepsy duration: 19 years versus 15 years.
  • Shared bedroom: 12.5% versus 34%.
  • History of GTCS: 98% versus 82%.
  • History of GTCS in the last year: 85% versus 12%.
  • Nocturnal GTCS in the last year: 43% versus 9%.

No AED use was identified in 18.4% of cases and 23.1% of controls; this population was used as a reference group for comparisons.

SUDEP risk was not increased by any AED considered in the analysis (caribemazepine, lamotrigine, valproic acid, levitaracetam, phenytoin, topiramate, and oxcarbazepine). “No AED in monotherapy significantly increased the risk of SUDEP which, importantly, addresses previous concerns with carbamazepine and lamotrigine,” the editorialists noted.

The lowest risk of SUDEP with monotherapy was seen with levetiracetam (OR 0.10, 95% CI 0.02-0.61), while lamotrigine, valproic acid, and levetiracetam were associated with reduced risk when used as part of a polytherapy.

“SUDEP risk in relation to lamotrigine use was analyzed separately for females, and there was no indication of excess risk neither when used as mono- nor polytherapy,” the authors wrote.

An increased risk for SUDEP was seen in those with mention of nonadherence in medical records, with OR 2.75 (95% CI 1.58-4.78).

“Whether intentional or unintentional, [nonadherence] remains a significant problem,” the editorialists said. “Its routine identification in the clinic, aided by linked data sets, and how it can be minimized, need to become a focus for research and efforts directed at SUDEP prevention. This has been a relatively neglected area so far.”

Limitations of the study include those inherent to observational data, with possible confounding.

  1. Polytherapy with antiepileptic drugs (AEDs) was associated with a reduced risk of sudden unexpected death in epilepsy (SUDEP) compared with not taking any AEDs in a a population-based case-control study.

  2. Given conflicting results with some previous reports, findings should be interpreted cautiously, although adding an AED to baseline treatment in patients with refractory seizures has been linked to reduced SUDEP in randomized trials, the authors noted.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was supported by funding from Stockholm County Council, GlaxoSmithKline and Citizens United for Research in Epilepsy (CURE).

Sveinsson has received grants from GSK, personal fees Biogen, honoraria to his institution from Biogen and UCB for lectures and advisory board, outside the submitted work.

Nashef has received a speaker’s fee from UCB and served on an advisory board for GW Pharmaceuticals. Rugg-Gunn has received a speaker’s fee from LivaNova.

Cat ID: 130

Topic ID: 82,130,254,130,34,192,925