Direct and indirect comparison meta-analysis of levetiracetam versus phenytoin or valproate for convulsive status epilepticus

Aim: The aim of this study was to conduct a meta-analysis of published studies to directly compare intravenous (IV) levetiracetam (LEV) with IV phenytoin (PHT) or IV valproate (VPA) as second-line treatment of status epilepticus (SE), to indirectly compare intravenous IV LEV with IV VPA using common reference-based indirect comparison meta-analysis, and to verify whether results of indirect comparisons are consistent with results of head-to-head randomized controlled trials (RCTs) directly comparing IV LEV with IV VPA.

Methods: Random-effects Mantel-Haenszel meta-analyses to obtain odds ratios (ORs) for efficacy and safety of LEV versus VPA and LEV or VPA versus PHT were used. Adjusted indirect comparisons between LEV and VPA were used.

Results: Two RCTs comparing LEV with PHT (144 episodes of SE) and 3 RCTs comparing VPA with PHT (227 episodes of SE) were included. Direct comparisons showed no difference in clinical seizure cessation, neither between VPA and PHT (OR: 1.07; 95% CI: 0.57 to 2.03) nor between LEV and PHT (OR: 1.18; 95% CI: 0.50 to 2.79). Indirect comparisons showed no difference between LEV and VPA for clinical seizure cessation (OR: 1.16; 95% CI: 0.45 to 2.97). Results of indirect comparisons are consistent with results of a recent RCT directly comparing LEV with VPA.

Conclusion: The absence of a statistically significant difference in direct and indirect comparisons is due to the lack of sufficient statistical power to detect a difference. Conducting a RCT that has not enough people to detect a clinically important difference or to estimate an effect with sufficient precision can be regarded a waste of time and resources and may raise several ethical concerns, especially in RCT on SE.