Comparative efficacy of intravenous levetiracetam and phenytoin in status epilepticus: a systematic review and meta-analysis of randomized controlled trials
DOI:
https://doi.org/10.13181/mji.oa.236685Keywords:
levetiracetam, phenytoin, status epilepticusAbstract
BACKGROUND Status epilepticus (SE) is a neurological emergency, with the current guidelines for second-line anticonvulsants may include phenytoin, levetiracetam, valproic acid, and phenobarbital. However, some studies suggest that levetiracetam may be better at stopping seizures in SE. This study aimed to compare the efficacy of intravenous (IV) levetiracetam and phenytoin in SE.
METHODS We searched PubMed, ScienceDirect, Cochrane, and Google Scholar for randomized controlled trials (RCTs) on administering IV levetiracetam or phenytoin in patients with SE. RCTs were screened using eligibility criteria, and their quality was assessed using the Cochrane risk of bias tool. Heterogeneity was assessed using the I² test, and publication bias was evaluated using Egger’s test. All analyses were performed using Review Manager version 5.4 (The Cochrane Collaboration, UK) and Stata 17 (StataCorp LLC, USA).
RESULTS 12 RCTs involving 2,137 patients (1,099 receiving levetiracetam) met the inclusion criteria. Pooled analysis showed that levetiracetam therapy had a significantly higher rate of seizure cessation than phenytoin (RR: 1.10, 95% CI = 1.05−1.14, p = 0.02, I² = 51%). Less adverse events were observed in the levetiracetam group (9.34%) than in the phenytoin group (11.62%; RR: 0.82, 95% CI = 0.66–1.02, p = 0.07). However, there was no significant difference regarding IV levetiracetam or phenytoin administration with the incidence of admission to critical care (RR: 1.01; 95% CI = 0.93–1.10, p = 0.80) and mortality (RR: 1.08; 95% CI = 0.54–2.15; p = 0.82).
CONCLUSIONS IV levetiracetam was significantly better in the cessation of seizures in SE patients than phenytoin.
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References
Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol. 2015;14(6):615-24. https://doi.org/10.1016/S1474-4422(15)00042-3
Pichler M, Hocker S. Management of status epilepticus. Handb Clin Neurol. 2017;140:131-51. https://doi.org/10.1016/B978-0-444-63600-3.00009-X
Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23. https://doi.org/10.1007/s12028-012-9695-z
Dell'Aquila J, Soti V. Treating status epilepticus: phenytoin versus levetiracetam. Cureus. 2021;13(10):e18515. https://doi.org/10.7759/cureus.18515
Parums DV. Editorial: review articles, systematic reviews, meta-analysis, and the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Guidelines. Med Sci Monit. 2021;27:e934475. https://doi.org/10.12659/MSM.934475
Appleton RE, Rainford NE, Gamble C, Messahel S, Humphreys A, Hickey H, et al. Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT. Health Technol Assess. 2020;24(58):1-96. https://doi.org/10.3310/hta24580
Chakravarthi S, Goyal MK, Modi M, Bhalla A, Singh P. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci. 2015;22(6):959-63. https://doi.org/10.1016/j.jocn.2014.12.013
Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020;395(10231):1217-24. Erratum in: Lancet. 2023;401(10387):1498.
Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019;393(10186):2135-45. https://doi.org/10.1016/S0140-6736(19)30722-6
Gujjar AR, Nandhagopal R, Jacob PC, Al-Hashim A, Al-Amrani K, Ganguly SS, et al. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study. Seizure. 2017;49:8-12. https://doi.org/10.1016/j.seizure.2017.05.001
Mundlamuri RC, Sinha S, Subbakrishna DK, Prathyusha PV, Nagappa M, Bindu PS, et al. Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam--pilot study. Epilepsy Res. 2015;114:52-8. https://doi.org/10.1016/j.eplepsyres.2015.04.013
Nakamura K, Marushima A, Takahashi Y, Mochizuki M, Kimura A, Fukuda Y, et al. Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial. J Neurol Neurosurg Psychiatry. 2023;94(1):42-8. https://doi.org/10.1136/jnnp-2022-329485
Nalisetty S, Kandasamy S, Sridharan B, Vijayakumar V, Sangaralingam T, Krishnamoorthi N. Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus. Indian J Pediatr. 2020;87(7):512-9. https://doi.org/10.1007/s12098-020-03221-2
Nazir M, Tarray RA, Asimi R, Syed WA. Comparative efficacy of IV phenytoin, IV valproate, and IV levetiracetam in childhood status epilepticus. J Epilepsy Res. 2020;10(2):69-73. https://doi.org/10.14581/jer.20011
Noureen N, Khan S, Khursheed A, Iqbal I, Maryam M, Sharib SM, et al. Clinical efficacy and safety of injectable levetiracetam versus phenytoin as second-line therapy in the management of generalized convulsive status epilepticus in children: an open-label randomized controlled trial. J Clin Neurol. 2019;15(4):468-72. https://doi.org/10.3988/jcn.2019.15.4.468
Vignesh V, Rameshkumar R, Mahadevan S. Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial. Indian Pediatr. 2020;57(3):222-7. https://doi.org/10.1007/s13312-020-1755-4
Wani G, Imran A, Dhawan N, Gupta A, Giri JI. Levetiracetam versus phenytoin in children with status epilepticus. J Family Med Prim Care. 2019;8(10):3367-71. https://doi.org/10.4103/jfmpc.jfmpc_750_19
Shi R, Yin HQ, Wang ZZ. [Efficacy and safety of levetiracetam versus phenytoin as second-line drugs for the treatment of children with convulsive status epilepticus: a meta analysis]. Zhongguo Dang Dai Er Ke Za Zhi. 2021;23(4):356-62. Chinese.
Xue T, Wei L, Shen X, Wang Z, Chen Z, Wang Z. Levetiracetam versus phenytoin for the pharmacotherapy of benzodiazepine-refractory status epilepticus: a systematic review and meta-analysis of randomized controlled trials. CNS Drugs. 2020;34(12):1205-15. https://doi.org/10.1007/s40263-020-00770-0
Li L, Zhang Y, Jia L, Jia D, Faramand A, Chong W, et al. Levetiracetam versus phenytoin for the treatment of established status epilepticus: a systematic review and meta-analysis of randomized controlled trials. Seizure. 2020;78:43-8. https://doi.org/10.1016/j.seizure.2020.03.002
Feng Y, Chen Y, Jia Y, Wang Z, Wang X, Jiang L, et al. Efficacy and safety of levetiracetam versus (fos)phenytoin for second-line treatment of epilepticus: a meta-analysis of latest randomized controlled trials. Seizure. 2021;91:339-45. https://doi.org/10.1016/j.seizure.2021.07.012
Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, et al. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-23. https://doi.org/10.1111/epi.13121
Chu SS, Wang HJ, Zhu LN, Xu D, Wang XP, Liu L. Therapeutic effect of intravenous levetiracetam in status epilepticus: a meta-analysis and systematic review. Seizure. 2020;74:49-55. https://doi.org/10.1016/j.seizure.2019.11.007
Contreras-García IJ, Cárdenas-Rodríguez N, Romo-Mancillas A, Bandala C, Zamudio SR, Gómez-Manzo S, et al. Levetiracetam mechanisms of action: from molecules to systems. Pharmaceuticals (Basel). 2022;15(4):475. https://doi.org/10.3390/ph15040475
Weinstock A, Ruiz M, Gerard D, Toublanc N, Stockis A, Farooq O, et al. Prospective open-label, single-arm, multicenter, safety, tolerability, and pharmacokinetic studies of intravenous levetiracetam in children with epilepsy. J Child Neurol. 2013;28(11):1423-9. https://doi.org/10.1177/0883073813480241
Morrell MJ, Leppik I, French J, Ferrendelli J, Han J, Magnus L. The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study. Epilepsy Res. 2003;54(2-3):153-61. Erratum in: Epilepsy Res. 2003;56(2-3):209-10. https://doi.org/10.1016/j.eplepsyres.2003.09.001
Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004;43(11):707-24. https://doi.org/10.2165/00003088-200443110-00002
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