Status Epilepticus: Efficacy of IV Drugs

Levetiracetam seems to be generally more effective at ending status epilepticus than valproate, phenytoin, and lacosamide, according to a study that tested four different efficacy criteria for comparing intravenous antiepileptic drugs (AEDs). Results were published online in Epilepsy & Behavior.¹

The aim of the study was to identify which criteria best evaluate AED efficacy in ending status epilepticus. The results have implications for future trials designed to investigate the efficacy of these drugs. 

“[C]ombining theoretical considerations and the results of this study, criterion 3 (i.e. “the last drug introduced into the antiepileptic therapy or increased in dose within 24 hours before termination of the status epilepticus without changes in the co-medication”) appears to be the most appropriate for the evaluation of efficacy of an antiepileptic drug in the treatment of status epilepticus. Further studies on the treatment of status epilepticus should use this criterion at least as one of their efficacy criteria,” wrote first author Juliane Redecker, of the University of Rostock, Germany, and colleagues.

Only a small number of randomized controlled trials (RCTs) have been done on the treatment of status epilepticus. As a result, guidelines from the American Epilepsy Society have had to rely mainly on class III (nonrandomized) trials, as well as observational studies and expert opinion.² Moreover, studies have used a wide variety of criteria for determining the relative effectiveness of AEDs in status epilepticus, creating confusion about which drugs are most effective. 

To evaluate the issue, researchers did a retrospective medical records study of 145 treatment episodes for status epilepticus that occurred in 124 patients (77 female, 47 male) at Rostock University hospital between January 2010 and June 2013. Using four different criteria, they compared the efficacy of intravenous phenytoin (PHT), valproate (VPA), levetiracetum (LEV), and lacosamide (LCM) in ending status epilepticus. The criteria included:

• Criteria 1: the last AED given before status epilepticus ended

• Criterion 2: the last drug introduced in the AED therapy 72 hours before the end of status epilepticus, without changes in dosage or number of co-medications

• Criterion 3: the last drug introduced into AED therapy or increased in dose within 24 hours before ending status epilepticus, without changes in co-medication

• Criterion 4: the last drug introduced into AED therapy within 72 hours before the end of status epilepticus, allowing for changes in co-medication.

Key Results for the overall treatment of status epilepticus:

• Large range of efficacy rates using the different criteria

• Only criteria 1 and 3 showed significant results, with comparisons of the four criteria showing 23 significant differences (P<0.001-0.05)

• Criteria 1: LEV had highest percentage of effective administrations:

♦ LEV (52%) > LCM (37.5%) > VPA (33.9%) > PHT (16.1%)

• Criteria 2: LCM had highest percentage of effective administrations:

♦ LCM (18.8%) > LEV (16.8%) > VPA (11.3%) > PHT (9.7%)

• Criteria 3: LEV had highest percentage of effective administrations:

♦ LEV (36.6%) > LCM (31.3%) > VPA (24.2%) > PHT (6.5%)

• Criteria 4: LEV had highest percentage of effective administrations:

♦ LEV (27.7%) > PHT (26.8%) > VPA (22.6%) >LCM (21.9%)

Subgroup analyses showed that efficacy may differ depending on status epilepticus subtype (convulsive, focal motor, nonconvulsive with coma, nonconvulsive without coma). Using criteria 1, for example, VPA (50%) was most effective in treating convulsive status epilepticus, followed by LEV (47.1%), LCM (25%), and PHT (20%).

The authors noted that criteria 3 seems “more reasonable” than criterion 1, which may be “questionable.” Criterion 1 identifies the termination drug as one that may have been used repeatedly over days or weeks, and may have had many ineffective administrations.  

The authors noted that the study could not control for the order in which AEDs were administered. LEV was mainly given in patients with established status epilepticus, while the other three AEDs were used in cases of refractory or super-refractory status epilepticus. This practice may have influenced results in favor of LEV.

Take-home Points

• A study that tested four different efficacy criteria for comparing intravenous AEDs suggested that levetiracetam is generally more effective at ending status epilepticus than valproate, phenytoin, and lacosamide.

• Subgroup analyses showed that efficacy may differ depending on status epilepticus subtype.

• The study showed that criteria 3 (the last drug introduced into AED therapy or increased in dose within 24 hours before ending status epilepticus, without changes in co-medication) may be most appropriate for evaluating efficacy of AEDs.  

One or more authors reports honoraria, advisory role, travel grants, and/or financial support from Eisai and/or UCB.

References:

1. Redecker J, et al. The efficacy of different kinds of intravenously applied antiepileptic drugs in the treatment of status epilepticus. How can it be determined? Epilepsy Behav. 2017 Apr 28;71(Pt A):35-38.

2. Glauser T, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guidelines Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16:48-61.