Efficacy, Safety, and Economics of Intravenous Levetiracetam for Status Epilepticus: A Systematic Review and Meta-Analysis

Zhan-Miao Yi,Suo-Di Zhai,Ming-Lu Wang,Yuan Zhang,Xu-Li Zhong

doi:10.3389/fphar.2020.00751

Abstract

ObjectiveTo evaluate efficacy, safety, and economics profiles of intravenous levetiracetam (LEV) for status epilepticus (SE).MethodsWe searched PubMed, Embase, the Cochrane Library, Clinicaltrials.gov, and OpenGrey.eu for eligible studies published from inception to June 12th 2019. Meta-analyses were conducted using random-effect model to calculate odds ratio (OR) of included randomized controlled trials (RCTs) with RevMan 5.3 software.ResultsA total of 478 studies were obtained. Five systematic reviews (SRs)/meta-analyses, 9 RCTs, 1 non-randomized trial, and 27 case series/reports and 1 economic study met the inclusion criteria. Five SRs indicated no statistically significant difference in rates of seizure cessation when LEV was compared with lorazepam (LOR), phenytoin (PHT), or valproate (VPA). Pooled results of included RCTs indicated no statistically significant difference in seizure cessation when LEV was compared with LOR [OR = 1.04, 95% confidence interval (CI) 0.37 to 2.92], PHT (OR = 0.90, 95% CI 0.64 to 1.27), and VPA (OR = 1.47, 95% CI 0.81 to 2.67); and no statistically significant difference in seizure freedom within 24 h compared with LOR [OR = 1.83, 95% CI 0.57 to 5.90] and PHT (OR = 1.08, 95% CI 0.63 to 1.87). Meanwhile, LEV did not increase the risk of mortality during hospitalization compared with LOR (OR = 1.03, 95% CI 0.31 to 3.39), PHT (OR = 0.89, 95% CI 0.37 to 2.10), VPA (OR = 1.28, 95% CI 0.32 to 5.07), and placebo (plus clonazepam, OR = 0.73, 95% CI 0.16 to 3.38). LEV had lower need for artificial ventilation (OR = 0.23, 95% CI 0.06 to 0.92) and a lower risk of hypotension (OR = 0.15, 95% CI 0.03 to 0.84) compared to LOR. A trend of lower risk of hypotension and higher risk of agitation was found when LEV was compared with PHT. Case series and case report studies indicated psychiatric and behavioral adverse events of LEV. Cost-effectiveness evaluations indicated LEV as the most cost-effective non-benzodiazepines anti-epileptic drug (AED).ConclusionsLEV has a similar efficacy as LOR, PHT, and VPA for SE, but a lower need for ventilator assistance and risk of hypotension, thus can be used as a second-line treatment for SE. However, more well-conducted studies to confirm the role of intravenous LEV for SE are still needed.

Highlights

Status epilepticus (SE) is a relatively common and life-threatening neurological emergency with an estimated incidence of up to 61 episodes per 100,000 population per year (Betjemann and Lowenstein, 2015; Trinka and Kalviainen, 2017)
288 studies were excluded after title/abstract screening, and 104 studies were selected for full-text review
Two systematic review (SR) compared LEV with VPA (Liu et al, 2012; Brigo et al, 2016), 1 SR compared LEV with PHT (Brigo et al, 2016), 1 SR compared LEV with LOR (Prasad et al, 2014) and 2 SRs evaluated the efficacy of LEV as first or second-line therapy in SE (Zelano and Kumlien, 2012; Yasiry and Shorvon, 2014) Among the two SRs, one SR evaluated the efficacy of five anti-epileptic drugs (AEDs) as a second-line therapy in benzodiazepine-resistant SE (Yasiry and Shorvon, 2014), another one evaluated LEV as a first-line AED, as single treatment or combined with benzodiazepines (Zelano and Kumlien, 2012)

Summary

Introduction

Status epilepticus (SE) is a relatively common and life-threatening neurological emergency with an estimated incidence of up to 61 episodes per 100,000 population per year (Betjemann and Lowenstein, 2015; Trinka and Kalviainen, 2017). Its substantial morbidity and mortality could incur high health care costs. The total direct and indirect costs for epilepsy in Europe would add up to €13.8 billion per year, of which SE was an important source of direct costs (Olesen et al, 2012). The total cost of direct hospitalization in the United States (US) caused by SE each year was even as high as $4 billion (Penberthy et al, 2005). The International League against Epilepsy (ILAE)'s updated definition of SE in 2015 highlights the long-term effects of prolonged seizure activity on the nervous system, including neuronal death and neuronal injury (Trinka et al, 2015a). The key of SE treatment strategy is to identify and terminate seizure activities as early as possible before irreversible neuronal damage occurs (Trinka and Kalviainen, 2017)

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