ReviewDirect and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus
Introduction
Status epilepticus (SE) is defined as a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [1]. If seizure activity persists over time, long-term consequences, including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures, may occur [1]. It is therefore crucial to promptly recognize and adequately treat this condition, as SE is associated with high risk of morbidity and mortality [2].
Benzodiazepines represent the first-line treatments for SE. However, in approximately 30–40% of cases, SE in patients fails to respond to benzodiazepines, requiring an intravenous (IV) administration of antiepileptic drugs (AEDs). The most common second-line treatments for SE include phenytoin (PHT), phenobarbital, valproate (VPA), levetiracetam (LEV), and lacosamide [3].
To date, the evidence supporting the use of LEV in SE is mostly limited to retrospective case series [4], [5]. Only two recent randomized controlled trials (RCTs) have directly compared IV LEV with either IV VPA [6] or IV PHT [6], [7] showing no differences with the comparator(s) in terms of clinical seizure cessation.
The data supporting the use of VPA as second-line treatment for SE are more robust, as this drug has been studied in six randomized controlled trials [8], [9], [10], [11], [12], [13] showing good efficacy and tolerability [14], [15].
The relative efficacy of VPA, LEV, and the other second-line treatments for SE (lacosamide, phenytoin, and phenobarbital) has been assessed in a systematic review with meta-analysis [5]. Efficacy of LEV (68.5%; 95% CI: 56.2–78.7%) and VPA (75.7%; 95% CI: 63.7–84.8%) were found to be comparable with that of phenobarbital (73.6%; 95% CI: 58.3–84.8%) and somewhat higher than that of PHT (50.2%; 95% CI: 34.2–66.1%), suggesting that LEV and VPA may represent valid alternatives to phenobarbital and PHT as second-line treatments of SE.
In this study, we aimed 1. to perform a meta-analysis of IV LEV compared with IV VPA or IV PHT as second-line treatment of convulsive SE (generalized or focal) in patients of any age, 2. to indirectly estimate the efficacy of IV LEV and IV VPA through indirect comparison meta-analyses using IV PHT as common comparator, and 3. to assess whether results of indirect comparisons are consistent with results of a recent head-to-head RCT directly comparing IV LEV with IV VPA [6].
Section snippets
Criteria for considering studies for this review
Randomized controlled trials comparing IV LEV or IV VPA against IV PHT and RCTs comparing IV LEV versus IV VPA used as second-line treatment for convulsive SE (generalized or focal) were included in the meta-analysis.
Patients from any age group diagnosed with convulsive SE persisting despite first-line AEDs (benzodiazepines) were included. Status epilepticus was defined as convulsive seizures lasting > 5 min [1], [16]. We included all RCTs, blinded or not blinded, and excluded uncontrolled and
Statistical analysis
For each outcome, an intention-to-treat primary analysis was made to include all patients in the treatment group to which they were allocated, irrespective of the treatment they actually received.
Analyses were conducted using RevMan 5 (conventional meta-analysis for each AED), Excel and R 2.15.1 (common reference-based indirect comparison meta-analysis).
Results
The search strategy described above yielded 2671 results (1958 MEDLINE, 201 CENTRAL, 500 EMBASE, and 12 ClinicalTrials.gov) (Fig. 2). One study initially included was eventually excluded, as it assessed the efficacy of IV VPA used as first-line (and not as second-line) treatment for SE [8]. Hence, four studies were included (with a total of 321 episodes of SE), three comparing IV VPA with IV PHT [6], [9], [11] and two comparing IV LEV with IV PHT [7] or with IV VPA and IV PHT [6]. The study by
Discussion
Direct comparisons meta-analyses showed no difference in clinical seizure cessation, neither between IV VPA and IV PHT nor between IV LEV and IV PHT. The indirect-comparison meta-analysis using data generated from individual comparisons versus IV PHT showed no difference in efficacy between IV LEV and IV VPA used as second-line AEDs for convulsive SE.
Results of indirect comparisons are consistent with the results of the only RCT directly comparing IV LEV with IV VPA published so far [6] and,
Conflict of interest
There was no funding related to the preparation of this article.
Dr. Francesco Brigo received speakers΄ honoraria from Eisai, PeerVoice, and Sigma-Tau; has acted as a paid consultant to Eisai; has received travel support from UCB, Eisai, and ITALFARMACO.
Prof. Eugen Trinka has acted as a paid consultant to Bial, Biogen Idec, Eisai, Ever Neuropharma, Medtronics, Takeda, Upsher-Smith, and UCB; has received speakers' honoraria from Bial, Boehringer, Eisai, GL Lannacher, and UCB Pharma; and has
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