Efficacy and safety of second-line medications for status epilepticus: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Haikun , WU Na , LI Cunming ,  LIN Ziwei

Bozhou Hospital Affiliated to Anhui University of Science and Technology, Bozhou 236800, P.R.China;

Corresponding author：

LIN Ziwei, Email: 18712225783@139.com

Keywords：

Status epilepticus; Second-line medication; Network meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202107099

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To systematically review the efficacy and safety of second-line medications for status epilepticus (SE). Methods The Cochrane Library, PubMed, EMbase, CNKI, CBM, and WanFang Data databases were electronically searched to collect randomized controlled trials (RCTs) of second-line medications for SE from inception to May, 2021. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Network meta-analysis was then performed using Stata 15.1 software and R 4.1.0 software. Results A total of 23 RCTs were included and 4 regimens were involved: levetiracetam (LEV), phenytoin/fosphenytoin (PHT), valproate (VPA), and phenobarbital (PHB). The results of network meta-analysis showed SE control rate validity sorting to be PHB>LEV>VPA>PHT, the epilepsy recurrence rate in 24 hour validity sorting to be VPA>PHB>LEV>PHT, those requiring further antiepileptic drug treatment rate validity sorting to be LEV>PHT>VPA, and drug safety security sorting to be VPA>LEV>PHT>PHB. Subgroup analysis showed PHB was optimal for SE control in children and adults, VPA had the optimal effect on other efficacy indicators in children, LEV was the safest in children and elderly patients, and VPA was the safest in adults. Conclusions Current evidence suggests that PHB is the optimal for SE control, however, the safety is unsatisfactory; VPA and LEV have their own advantages in the treatment of SE, and their safety is satisfactory. VPA is recommended for adult patients, and LEV is recommended for children and elderly patients.

Citation： WANG Haikun, WU Na, LI Cunming, LIN Ziwei. Efficacy and safety of second-line medications for status epilepticus: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2021, 21(11): 1278-1285. doi: 10.7507/1672-2531.202107099 Copy

1.	Li L, Zhang Y, Jia L, 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: 43-48.
2.	晋琅, 刘永红. 成簇癫痫发作. 中华神经科杂志, 2021, 54(1): 55-59.
3.	Pichler M, Hocker S. Management of status epilepticus. Handb Clin Neurol, 2017, 140: 131-151.
4.	Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American epilepsy society. Epilepsy Curr, 2016, 16(1): 48-61.
5.	Brigo F, Bragazzi NL, Lattanzi S, et al. A critical appraisal of randomized controlled trials on intravenous phenytoin in convulsive status epilepticus. Eur J Neurol, 2018, 25(3): 451-463.
6.	Silbergleit R, Elm JJ. Levetiracetam no better than phenytoin in children with convulsive status epilepticus. Lancet, 2019, 393(10186): 2101-2102.
7.	杨俊超, 陈君颖, 许春艳, 等. 运动疗法治疗慢性腰痛效果的网状Meta分析. 中国循证医学杂志, 2021, 21(1): 28-39.
8.	易跃雄, 张蔚, 刘小媛, 等. 网状Meta分析图形结果解读. 中国循证医学杂志, 2015, 15(1): 103-109.
9.	Chamberlain JM, Kapur J, Shinnar S, 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): 1217-1224.
10.	Nalisetty S, Kandasamy S, Sridharan B, et al. Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus. Indian J Pediatr, 2020, 87(7): 512-519.
11.	Handral A, Veerappa BG, Gowda VK, et al. Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial. J Pediatr Neurosci, 2020, 15(3): 252-256.
12.	Nazir M, Tarray RA, Asimi R, et al. Comparative efficacy of IV phenytoin, IV valproate, and IV levetiracetam in childhood status epilepticus. J Epilepsy Res, 2020, 10(2): 69-73.
13.	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): 222-227.
14.	Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med, 2019, 381(22): 2103-2113.
15.	Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet, 2019, 393(10186): 2125-2134.
16.	Dalziel SR, Borland ML, Furyk J, 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): 2135-2145.
17.	Wani G, Imran A, Dhawan N, et al. Levetiracetam versus phenytoin in children with status epilepticus. J Family Med Prim Care, 2019, 8(10): 3367-3371.
18.	Burman RJ, Ackermann S, Shapson-Coe A, et al. A comparison of parenteral phenobarbital vs. parenteral phenytoin as second-line management for pediatric convulsive status epilepticus in a resource-limited setting. Front Neurol, 2019, 10: 506.
19.	Noureen N, Khan S, Khursheed A, 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): 468-472.
20.	Nene D, Mundlamuri RC, Satishchandra P, et al. Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): a prospective randomized controlled pilot study. Seizure, 2019, 65: 111-117.
21.	Senthilkumar C, Selvakumar P, Kowsik M. Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children. Int J Pediatr Res, 2018, 5(4): 237-242.
22.	Khajeh A, Yaghoubinia F, Yaghoubi S, et al. Comparison of the effect of phenobarbital versus sodium valproate in management of children with status epilepticus. Iran J Child Neurol, 2018, 12(4): 85-93.
23.	Singh K, Aggarwal A, Faridi MMA, et al. IV levetiracetam versus IV phenytoin in childhood seizures: a randomized controlled trial. J Pediatr Neurosci, 2018, 13(2): 158-164.
24.	Amiri-Nikpour MR, Nazarbaghi S, Eftekhari P, et al. Sodium valproate compared to phenytoin in treatment of status epilepticus. Brain Behav, 2018, 8(5): e00951.
25.	Gujjar AR, Nandhagopal R, Jacob PC, et al. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: a prospective, randomized study. Seizure, 2017, 49: 8-12.
26.	Su Y, Liu G, Tian F, et al. Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China. CNS Drugs, 2016, 30(12): 1201-1207.
27.	Mundlamuri RC, Sinha S, Subbakrishna DK, 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: 52-58.
28.	Chakravarthi S, Goyal MK, Modi M, et al. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci, 2015, 22(6): 959-963.
29.	Malamiri RA, Ghaempanah M, Khosroshahi N, et al. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol, 2012, 16(5): 536-541.
30.	Agarwal P, Kumar N, Chandra R, et al. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure, 2007, 16(6): 527-532.
31.	Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology, 2006, 67(2): 340-342.
32.	Nakamura K, Ohbe H, Matsui H, et al. Phenytoin versus fosphenytoin for second-line treatment of status epilepticus: propensity score matching analysis using a nationwide inpatient database. Seizure, 2020, 80: 124-130.
33.	Brigo F, Del Giovane C, Nardone R, et al. Intravenous antiepileptic drugs in adults with benzodiazepine-resistant convulsive status epilepticus: A systematic review and network meta-analysis. Epilepsy Behav, 2019, 101(PtB): 106466.
34.	王绚, 张永, 张媛媛. 基于AERS的丙戊酸不良反应信号挖掘与数据分析. 中国医院药学杂志, 2020, 40(1): 71-77.
35.	张天照. 左乙拉西坦和卡马西平治疗癫痫的临床研究. 中国临床药理学杂志, 2021, 37(8): 962-965.
36.	Thibault C, Naim MY, Abend NS, et al. A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates. Epilepsia, 2020, 61(4): 627-635.
37.	周静. 癫痫患者172例丙戊酸钠血药浓度分析. 临床合理用药杂志, 2021, 14(10): 147,149.
38.	Arroyo S, Crawford P. Safety profile of levetiracetam. Epileptic Disord, 2003, 5(Suppl1): S57-S63.

1. Li L, Zhang Y, Jia L, 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: 43-48.
2. 晋琅, 刘永红. 成簇癫痫发作. 中华神经科杂志, 2021, 54(1): 55-59.
3. Pichler M, Hocker S. Management of status epilepticus. Handb Clin Neurol, 2017, 140: 131-151.
4. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American epilepsy society. Epilepsy Curr, 2016, 16(1): 48-61.
5. Brigo F, Bragazzi NL, Lattanzi S, et al. A critical appraisal of randomized controlled trials on intravenous phenytoin in convulsive status epilepticus. Eur J Neurol, 2018, 25(3): 451-463.
6. Silbergleit R, Elm JJ. Levetiracetam no better than phenytoin in children with convulsive status epilepticus. Lancet, 2019, 393(10186): 2101-2102.
7. 杨俊超, 陈君颖, 许春艳, 等. 运动疗法治疗慢性腰痛效果的网状Meta分析. 中国循证医学杂志, 2021, 21(1): 28-39.
8. 易跃雄, 张蔚, 刘小媛, 等. 网状Meta分析图形结果解读. 中国循证医学杂志, 2015, 15(1): 103-109.
9. Chamberlain JM, Kapur J, Shinnar S, 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): 1217-1224.
10. Nalisetty S, Kandasamy S, Sridharan B, et al. Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus. Indian J Pediatr, 2020, 87(7): 512-519.
11. Handral A, Veerappa BG, Gowda VK, et al. Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial. J Pediatr Neurosci, 2020, 15(3): 252-256.
12. Nazir M, Tarray RA, Asimi R, et al. Comparative efficacy of IV phenytoin, IV valproate, and IV levetiracetam in childhood status epilepticus. J Epilepsy Res, 2020, 10(2): 69-73.
13. 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): 222-227.
14. Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med, 2019, 381(22): 2103-2113.
15. Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet, 2019, 393(10186): 2125-2134.
16. Dalziel SR, Borland ML, Furyk J, 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): 2135-2145.
17. Wani G, Imran A, Dhawan N, et al. Levetiracetam versus phenytoin in children with status epilepticus. J Family Med Prim Care, 2019, 8(10): 3367-3371.
18. Burman RJ, Ackermann S, Shapson-Coe A, et al. A comparison of parenteral phenobarbital vs. parenteral phenytoin as second-line management for pediatric convulsive status epilepticus in a resource-limited setting. Front Neurol, 2019, 10: 506.
19. Noureen N, Khan S, Khursheed A, 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): 468-472.
20. Nene D, Mundlamuri RC, Satishchandra P, et al. Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): a prospective randomized controlled pilot study. Seizure, 2019, 65: 111-117.
21. Senthilkumar C, Selvakumar P, Kowsik M. Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children. Int J Pediatr Res, 2018, 5(4): 237-242.
22. Khajeh A, Yaghoubinia F, Yaghoubi S, et al. Comparison of the effect of phenobarbital versus sodium valproate in management of children with status epilepticus. Iran J Child Neurol, 2018, 12(4): 85-93.
23. Singh K, Aggarwal A, Faridi MMA, et al. IV levetiracetam versus IV phenytoin in childhood seizures: a randomized controlled trial. J Pediatr Neurosci, 2018, 13(2): 158-164.
24. Amiri-Nikpour MR, Nazarbaghi S, Eftekhari P, et al. Sodium valproate compared to phenytoin in treatment of status epilepticus. Brain Behav, 2018, 8(5): e00951.
25. Gujjar AR, Nandhagopal R, Jacob PC, et al. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: a prospective, randomized study. Seizure, 2017, 49: 8-12.
26. Su Y, Liu G, Tian F, et al. Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China. CNS Drugs, 2016, 30(12): 1201-1207.
27. Mundlamuri RC, Sinha S, Subbakrishna DK, 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: 52-58.
28. Chakravarthi S, Goyal MK, Modi M, et al. Levetiracetam versus phenytoin in management of status epilepticus. J Clin Neurosci, 2015, 22(6): 959-963.
29. Malamiri RA, Ghaempanah M, Khosroshahi N, et al. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol, 2012, 16(5): 536-541.
30. Agarwal P, Kumar N, Chandra R, et al. Randomized study of intravenous valproate and phenytoin in status epilepticus. Seizure, 2007, 16(6): 527-532.
31. Misra UK, Kalita J, Patel R. Sodium valproate vs phenytoin in status epilepticus: a pilot study. Neurology, 2006, 67(2): 340-342.
32. Nakamura K, Ohbe H, Matsui H, et al. Phenytoin versus fosphenytoin for second-line treatment of status epilepticus: propensity score matching analysis using a nationwide inpatient database. Seizure, 2020, 80: 124-130.
33. Brigo F, Del Giovane C, Nardone R, et al. Intravenous antiepileptic drugs in adults with benzodiazepine-resistant convulsive status epilepticus: A systematic review and network meta-analysis. Epilepsy Behav, 2019, 101(PtB): 106466.
34. 王绚, 张永, 张媛媛. 基于AERS的丙戊酸不良反应信号挖掘与数据分析. 中国医院药学杂志, 2020, 40(1): 71-77.
35. 张天照. 左乙拉西坦和卡马西平治疗癫痫的临床研究. 中国临床药理学杂志, 2021, 37(8): 962-965.
36. Thibault C, Naim MY, Abend NS, et al. A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates. Epilepsia, 2020, 61(4): 627-635.
37. 周静. 癫痫患者172例丙戊酸钠血药浓度分析. 临床合理用药杂志, 2021, 14(10): 147,149.
38. Arroyo S, Crawford P. Safety profile of levetiracetam. Epileptic Disord, 2003, 5(Suppl1): S57-S63.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of second-line medications for status epilepticus: a network meta-analysis

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