Efficacy and safety of new anti-epileptic drugs in the treatment of epilepsy: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

MAO Di ^1,2 , ZHANG Ling ³ , LU Yu ^1,2 , DONG Jianing ⁴ ,  ZHAO Hongyang ⁴ ,  XING Weiwei ⁵

1. Medical Integration and Practice Center, Shandong University, Jinan 250013, P .R. China;
2. Department of Pediatrics, Jinan Central Hospital, Jinan 250013, P. R. China;
3. Department of Pediatrics, Affiliated Hospital of Weifang Medical University, Weifang 261000, P. R. China;
4. Department of Pediatrics, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, P. R. China;
5. Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, P. R. China;

Corresponding author：

ZHAO Hongyang, Email: drzhaohongyang@163.com; XING Weiwei, Email: 1078124753@qq.com

Keywords：

New anti-epileptic drug; Epilepsy; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.202203161

Video：

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Objective To systematically review the efficacy and safety of new anti-epileptic drugs in the treatment of epilepsy. Methods PubMed, EMbase, The Cochrane Library, CNKI and WanFang Data databases were electronically searched to collect randomized controlled trials (RCTs) of new anti-epileptic drugs rufinamide, zonisamide, and perampanel in the treatment of epilepsy from January 2006 to May 2021. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies; then, meta-analysis was performed by using RevMan 5.3 and Stata 16.0 software. Results A total of 16 RCTs involving 4 382 patients were included. The results of meta-analysis showed that the effective rate (RR=1.66, 95%CI 1.45 to 1.89, P<0.000 01) and seizure-free rate (RR=2.82, 95%CI 2.01 to 3.96, P<0.000 01) in new anti-epileptic drugs group were higher than those in the control group, while it did not increase the serious adverse events (RR=0.95, 95%CI 0.72 to 1.27, P=0.75). Conclusion Current evidence shows that new anti-epileptic drugs have trends of better effectiveness, and their safety is satisfactory. Due to limited quality and quantity of the included studies, more high-quality studies are needed to verify above conclusion.

Citation： MAO Di, ZHANG Ling, LU Yu, DONG Jianing, ZHAO Hongyang, XING Weiwei. Efficacy and safety of new anti-epileptic drugs in the treatment of epilepsy: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2022, 22(11): 1272-1278. doi: 10.7507/1672-2531.202203161 Copy

1.	Quintas R, Raggi A, Giovannetti AM, et al. Psychosocial difficulties in people with epilepsy: a systematic review of literature from 2005 until 2010. Epilepsy Behav, 2012, 25(1): 60-67.
2.	Milligan TA. Epilepsy: a clinical overview. Am J Med, 2021, 134(7): 840-847.
3.	Engel J. The current place of epilepsy surgery. Curr Opin Neurol, 2018, 31(2): 192-197.
4.	Stefan H, Feuerstein TJ. Novel anticonvulsant drugs. Pharmacol Ther, 2007, 113(1): 165-183.
5.	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
6.	Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia, 2010, 51(4): 676-685.
7.	Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
8.	Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia, 2009, 50(3): 443-453.
9.	Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase Ⅲ study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology, 2012, 78(18): 1408-1415.
10.	Nishida T, Lee SK, Inoue Y, et al. Adjunctive perampanel in partial-onset seizures: Asia-Pacific, randomized phase Ⅲ study. Acta Neurol Scand, 2018, 137(4): 392-399.
11.	Meador KJ, Yang H, Piña-Garza JE, et al. Cognitive effects of adjunctive perampanel for partial-onset seizures: a randomized trial. Epilepsia, 2016, 57(2): 243-251.
12.	Lagae L, Villanueva V, Meador KJ, et al. Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: a randomized study evaluating behavior, efficacy, and safety. Epilepsia, 2016, 57(7): 1120-1129.
13.	Lu Y, Xiao Z, Yu W, et al. Efficacy and safety of adjunctive zonisamide in adult patients with refractory partial-onset epilepsy: a randomized, double-blind, placebo-controlled trial. Clin Drug Investig, 2011, 31(4): 221-229.
14.	Guerrini R, Rosati A, Segieth J, et al. A randomized phase Ⅲ trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia, 2013, 54(8): 1473-1480.
15.	Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology, 2008, 70(21): 1950-1958.
16.	French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase Ⅲ study 305. Epilepsia, 2013, 54(1): 117-125.
17.	French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology, 2015, 85(11): 950-957.
18.	French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase Ⅲ study 304. Neurology, 2012, 79(6): 589-596.
19.	Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia, 2009, 50(8): 1899-1909.
20.	Biton V, Krauss G, Vasquez-Santana B, et al. A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures. Epilepsia, 2011, 52(2): 234-242.
21.	张丽娜, 刘雅婧, 丁成赟, 等. 唑尼沙胺添加治疗部分性癫痫的临床疗效及安全性: 多中心随机双盲安慰剂对照研究. 中国现代神经疾病杂志, 2011, 11(4): 408-412.
22.	Brodie MJ, Duncan R, Vespignani H, et al. Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures. Epilepsia, 2005, 46(1): 31-41.
23.	Arzimanoglou A, Ferreira J, Satlin A, et al. Evaluation of long-term safety, tolerability, and behavioral outcomes with adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with Lennox-Gastaut syndrome: final results from randomized study 303. Eur J Paediatr Neurol, 2019, 23(1): 126-135.
24.	Ohtsuka Y, Yoshinaga H, Shirasaka Y, et al. Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan. Epilepsy Res, 2014, 108(9): 1627-1636.
25.	Gaitatzis A, Sisodiya SM, Sander JW. The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia, 2012, 53(8): 1282-1293.
26.	Rai D, Kerr MP, McManus S, et al. Epilepsy and psychiatric comorbidity: a nationally representative population-based study. Epilepsia, 2012, 53(6): 1095-1103.
27.	Fazel S, Wolf A, Långström N, et al. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet, 2013, 382(9905): 1646-1654.
28.	Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit, 2018, 40(5): 526-548.
29.	Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol, 2007, 30(4): 230-240.
30.	Potschka H, Trinka E. Perampanel: does it have broad-spectrum potential? Epilepsia, 2019, 60(Suppl 1): 22-36.
31.	Faulkner MA. Perampanel: a new agent for adjunctive treatment of partial seizures. Am J Health Syst Pharm, 2014, 71(3): 191-198.
32.	Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern nonenzyme-inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis. Epilepsia, 2012, 53(3): 512-520.
33.	Chapell R, Reston J, Snyder D, et al. Management of treatment-resistant epilepsy. Evid Rep Technol Assess (Summ), 2003, (77): 1-8.
34.	Gazzola DM, Balcer LJ, French JA. Seizure-free outcome in randomized add-on trials of the new antiepileptic drugs. Epilepsia, 2007, 48(7): 1303-1307.
35.	Lossius IMB, Svendsen T, Sødal HF, et al. Effect and tolerability of perampanel in patients with drug-resistant epilepsy. Epilepsy Behav, 2021, 119: 107965.
36.	Sharawat IK, Panda PK, Panda P, et al. Efficacy and safety of rufinamide as adjunctive therapy in patients with Lennox Gastaut syndrome: a systematic review and Meta-analysis. Seizure, 2021, 91: 296-307.
37.	Brigo F, Lattanzi S, Igwe SC, et al. Zonisamide add-on therapy for focal epilepsy. Cochrane Database Syst Rev, 2018, (10): CD001416.
38.	Birbeck GL, Hays RD, Cui X, et al. Seizure reduction and quality of life improvements in people with epilepsy. Epilepsia, 2002, 43(5): 535-538.
39.	Tsai JJ, Wu T, Leung H, et al. Perampanel, an AMPA receptor antagonist: from clinical research to practice in clinical settings. Acta Neurol Scand, 2018, 137(4): 378-391.
40.	Panebianco M, Prabhakar H, Marson AG. Rufinamide add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev, 2020, (11): CD011772.
41.	Janković SM. Evaluation of zonisamide for the treatment of focal epilepsy: a review of pharmacokinetics, clinical efficacy and adverse effects. Expert Opin Drug Metab Toxicol, 2020, 16(3): 169-177.

1. Quintas R, Raggi A, Giovannetti AM, et al. Psychosocial difficulties in people with epilepsy: a systematic review of literature from 2005 until 2010. Epilepsy Behav, 2012, 25(1): 60-67.
2. Milligan TA. Epilepsy: a clinical overview. Am J Med, 2021, 134(7): 840-847.
3. Engel J. The current place of epilepsy surgery. Curr Opin Neurol, 2018, 31(2): 192-197.
4. Stefan H, Feuerstein TJ. Novel anticonvulsant drugs. Pharmacol Ther, 2007, 113(1): 165-183.
5. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
6. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia, 2010, 51(4): 676-685.
7. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
8. Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia, 2009, 50(3): 443-453.
9. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase Ⅲ study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology, 2012, 78(18): 1408-1415.
10. Nishida T, Lee SK, Inoue Y, et al. Adjunctive perampanel in partial-onset seizures: Asia-Pacific, randomized phase Ⅲ study. Acta Neurol Scand, 2018, 137(4): 392-399.
11. Meador KJ, Yang H, Piña-Garza JE, et al. Cognitive effects of adjunctive perampanel for partial-onset seizures: a randomized trial. Epilepsia, 2016, 57(2): 243-251.
12. Lagae L, Villanueva V, Meador KJ, et al. Adjunctive perampanel in adolescents with inadequately controlled partial-onset seizures: a randomized study evaluating behavior, efficacy, and safety. Epilepsia, 2016, 57(7): 1120-1129.
13. Lu Y, Xiao Z, Yu W, et al. Efficacy and safety of adjunctive zonisamide in adult patients with refractory partial-onset epilepsy: a randomized, double-blind, placebo-controlled trial. Clin Drug Investig, 2011, 31(4): 221-229.
14. Guerrini R, Rosati A, Segieth J, et al. A randomized phase Ⅲ trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia, 2013, 54(8): 1473-1480.
15. Glauser T, Kluger G, Sachdeo R, et al. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology, 2008, 70(21): 1950-1958.
16. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase Ⅲ study 305. Epilepsia, 2013, 54(1): 117-125.
17. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology, 2015, 85(11): 950-957.
18. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase Ⅲ study 304. Neurology, 2012, 79(6): 589-596.
19. Brodie MJ, Rosenfeld WE, Vazquez B, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia, 2009, 50(8): 1899-1909.
20. Biton V, Krauss G, Vasquez-Santana B, et al. A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures. Epilepsia, 2011, 52(2): 234-242.
21. 张丽娜, 刘雅婧, 丁成赟, 等. 唑尼沙胺添加治疗部分性癫痫的临床疗效及安全性: 多中心随机双盲安慰剂对照研究. 中国现代神经疾病杂志, 2011, 11(4): 408-412.
22. Brodie MJ, Duncan R, Vespignani H, et al. Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures. Epilepsia, 2005, 46(1): 31-41.
23. Arzimanoglou A, Ferreira J, Satlin A, et al. Evaluation of long-term safety, tolerability, and behavioral outcomes with adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with Lennox-Gastaut syndrome: final results from randomized study 303. Eur J Paediatr Neurol, 2019, 23(1): 126-135.
24. Ohtsuka Y, Yoshinaga H, Shirasaka Y, et al. Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan. Epilepsy Res, 2014, 108(9): 1627-1636.
25. Gaitatzis A, Sisodiya SM, Sander JW. The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia, 2012, 53(8): 1282-1293.
26. Rai D, Kerr MP, McManus S, et al. Epilepsy and psychiatric comorbidity: a nationally representative population-based study. Epilepsia, 2012, 53(6): 1095-1103.
27. Fazel S, Wolf A, Långström N, et al. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet, 2013, 382(9905): 1646-1654.
28. Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther Drug Monit, 2018, 40(5): 526-548.
29. Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol, 2007, 30(4): 230-240.
30. Potschka H, Trinka E. Perampanel: does it have broad-spectrum potential? Epilepsia, 2019, 60(Suppl 1): 22-36.
31. Faulkner MA. Perampanel: a new agent for adjunctive treatment of partial seizures. Am J Health Syst Pharm, 2014, 71(3): 191-198.
32. Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern nonenzyme-inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis. Epilepsia, 2012, 53(3): 512-520.
33. Chapell R, Reston J, Snyder D, et al. Management of treatment-resistant epilepsy. Evid Rep Technol Assess (Summ), 2003, (77): 1-8.
34. Gazzola DM, Balcer LJ, French JA. Seizure-free outcome in randomized add-on trials of the new antiepileptic drugs. Epilepsia, 2007, 48(7): 1303-1307.
35. Lossius IMB, Svendsen T, Sødal HF, et al. Effect and tolerability of perampanel in patients with drug-resistant epilepsy. Epilepsy Behav, 2021, 119: 107965.
36. Sharawat IK, Panda PK, Panda P, et al. Efficacy and safety of rufinamide as adjunctive therapy in patients with Lennox Gastaut syndrome: a systematic review and Meta-analysis. Seizure, 2021, 91: 296-307.
37. Brigo F, Lattanzi S, Igwe SC, et al. Zonisamide add-on therapy for focal epilepsy. Cochrane Database Syst Rev, 2018, (10): CD001416.
38. Birbeck GL, Hays RD, Cui X, et al. Seizure reduction and quality of life improvements in people with epilepsy. Epilepsia, 2002, 43(5): 535-538.
39. Tsai JJ, Wu T, Leung H, et al. Perampanel, an AMPA receptor antagonist: from clinical research to practice in clinical settings. Acta Neurol Scand, 2018, 137(4): 378-391.
40. Panebianco M, Prabhakar H, Marson AG. Rufinamide add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev, 2020, (11): CD011772.
41. Janković SM. Evaluation of zonisamide for the treatment of focal epilepsy: a review of pharmacokinetics, clinical efficacy and adverse effects. Expert Opin Drug Metab Toxicol, 2020, 16(3): 169-177.

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Efficacy and safety of new anti-epileptic drugs in the treatment of epilepsy: a meta-analysis

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