A Network Meta-analysis Of Third-generation Antiepileptic Drugs For Refractory Partial-onset Epilepsy

ObjectivesAnticonvulsants that already obtained marketing approval since 2008 are considered as third-generation antiepileptic drugs including lacosamide,rufinamide retigabine,perampanel,eslicarbazepine acetate,brivaracetam and stiripentol.The aim of this article is to evaluate the efficacy and tolerability of the third-generation antiepileptic drugs in the treatment of refractory partial-onset epilepsy.MethodsStudies were identified through PubMed,Embase and Cochrane Library from inception to February 2018.Randomized controlled trials focused on the efficacy and tolerability of the third-generation antiepileptic drugs including lacosamide,rufinamide retigabine,perampanel,eslicarbazepine acetate,brivaracetam and stiripentol in the treatment of refractory partial-onset epilepsy were enrolled for network meta-analysis.The primary efficacy outcome was percentage of 50% or greater reduction in seizure frequency.The primary tolerability outcome was withdrawal rate due to adverse events and the secondary outcomes was seizure freedom rate and serious adverse events rate.ResultsA total of six antiepileptic drugs including 25 studies were enrolled for network meta-analysis.There were 1307 subjects in lacosamide group,846 in rufinamide group,862 in retigabine group,1140 in perampanel group,1282 in eslicarbazepine acetate group,1358 in brivaracetam group and 3091 in placebo group.The percentage of 50% or greater reduction in seizure frequency for subjects in the lacosamide group(RR=1.85,95%CI=1.38-2.48),rufinamide group(R R=1.69,95%CI=1.15-2.47),retigabine group(RR=2.30,95%CI=1.62-3.27),pera mpanel group(RR=1.62,95%CI=1.19-2.22),eslicarbazepine acetate group(RR=1.80,95%CI=1.35-2.39)and brivaracetam group(RR=2.40,95%CI=1.78-3.23)was significantly higher than those in the placebo group(P<0.05).The withdrawal rate for subjects in the lacosamide group(RR=2.44,95%CI=1.62-3.68),rufinamide group(RR=2.23,95%CI=1.42-3.50),retigabine group(RR=2.38,95%C I=1.71-3.32),perampanel group(RR=1.93,95%CI=1.22-3.03),eslicarbazepine ac etate group(RR=2.21,95%CI=1.51-3.24)and brivaracetam group(RR=1.71,95%CI=1.02-2.87)was significantly higher than those in the placebo group(P<0.05).The seizure freedom rate for subjects in the retigabine group(RR=3.72,95%CI=1.11-12.44),perampanel group(RR=3.11,95%CI=1.16-8.32),eslicarbazep ine acetate group(RR=2.83,95%CI=1.48-5.42)and brivaracetam group(RR=4.55,95%CI=1.83-11.83)was significantly higher than those in the placebo group(P<0.05).But there was no significant difference in the lacosamide group and rufinamide group for seizure freedom rate when respectively compared with placebo group(P>0.05).Significant difference was not found in the lacosamide group,rufinamide group,retigabine group,perampanel group,eslicarbazepine acetate group and brivaracetam group when respectively compared with placebo group(P>0.05).There was no significant difference in the percentage of 50% or greater reduction in seizure frequency,withdrawal rate due to adverse events,seizure freedom rate and serious adverse events rate when the six kinds of third-generation antiepileptic drugs including lacosamide,rufinamide,retigabine,perampanel,eslicarbazepine acetate and brivaracetam compared with each other.The surface under the cumulative ranking curve(SUCRA)analysis showed that the effect of brivaracetam was best(SUCRA = 88.2%)in terms of the percentage of 50%or greater reduction in seizure frequency,followed by retigabine(SUCRA=81.6%);Placebo has the best tolerability in terms of withdrawal rate due to adverse events(SUCRA=99.5%),followed by brivaracetam(SUCRA=66.3%)and per ampanel(SUCRA=54.7%).Clustering analysis by comparing the efficacy and tolerability of six kinds of third-generation antiepileptic drugs showed that briva racetam was characterized by the highest percentage of 50% or greater reduction in seizure frequency and the lowest withdrawal rate due to adverse events.The funnel plot showed that there was no significant publication bias for the two major outcomes of percentage of 50% or greater reduction in seizure frequency and withdrawal rate due to adverse events.Conclusion1.Compared with placebo,the efficacy of lacosamide,rufinamide,retigabine,perampanel,eslicarbazepine acetate and brivaracetam was significantly better,but the tolerability was also significantly lower at the same time.2.Significant difference was not identified in the efficacy and tolerability when lacosamide,rufinamide,retigabine,perampanel,eslicarbazepine acetate and brivaracetam compared with each other.