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《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2024年06期

页码:

861-868

栏目:

论著

出版日期:

2024-12-25

文章信息/Info

Title:

Therapeutic effects of Nintedanib and Pirfenidone on idiopathic and non-idiopathic pulmonary fibrosis: A meta-analysis

作者:

陈天恩¹; 刘树安²; 薛欢家³; 王 慧¹; 邱会格¹; 高姗姗¹; 陈兰新¹; 经 慧¹; 武焱旻¹; 王 凯³

221009 徐州,徐州医科大学徐州临床学院呼吸与危重症医学科¹
221000 徐州,徐州市肿瘤医院呼吸与危重症医学科²
221009 徐州,徐州医科大学徐州临床学院麻醉科³

Author(s):

Chen Tianen¹;  Liu Shuan²;  Xue Huanjia³;  Wang Hui¹;  Qiu Huige¹;  Gao Shanshan¹;  Chen Lanxing¹;  Jing Hui¹;  Wu Yanmin¹;  Wang Kai³.

¹Pulmonary and Critical Care Medicine, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou 221009, China; ²Pulmonary and Critical Care Medicine, Xuzhou Cancer Hospital, Xuzhou 221009, China; ³Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou 221009, China

关键词:

特发性肺纤维化;  非特发性肺纤维化;  尼达尼布;  吡非尼酮;  用力肺活量

Keywords:

Idiopathic pulmonary fibrosis;  Non-idiopathic pulmonary fibrosis;  Nintedanib;  Pirfenidone;  Forced vital capacity

分类号:

R563

DOI:

10.3877/cma.j.issn.1674-6902.2024.06.003

摘要:

目的 分析尼达尼布与吡非尼酮对特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)及非特发性肺纤维化(non-idiopathic pulmonary fibrosis, Non-IPF)的抗纤维化疗效,对预后指标用力肺活量(forced vital capacity, FVC)及全因死亡的影响。方法 检索PubMed、Embase、MEDLINE数据库中尼达尼布或吡非尼酮治疗IPF及Non-IPF后FVC减损程度及病死率的RCT研究,检索截止2024年3月。纳入文献中结局指标格式采用SPSS 25.0软件标准化处理。采用Review Manager 5.4软件进行数据统计分析,应用随机效应模型合并效应值I²判断异质性,Egger's检验及漏斗图判断发表偏倚,敏感性分析判断结果稳健性。结果 纳入17篇文献,共5 099例患者,观察组2 684例,对照组2 415例,荟萃分析显示,采用吡非尼酮或尼达尼布治疗肺纤维化,观察组FVC减损小于对照组(SMD: 1.48, 95%CI: 0.82～2.15); 观察组与对照组比较全因病死率降低(OR:0.59, 95%CI:0.45～0.77),两组差异有统计学意义,敏感性分析显示结果稳定。亚组分析显示,尼达尼布治疗IPF(SMD:3.39, 95%CI:2.77～4.01)、Non-IPF(SMD:2.25, 95%CI:0.91～3.59)抑制FVC减损,敏感性分析显示结果稳定。吡非尼酮治疗IPF(SMD:0.37, 95%CI:0.06～0.67)、Non-IPF(SMD:1.13, 95%CI:0.14～2.12)可抑制FVC减损,敏感性分析显示部分小样本量结果不稳定。尼达尼布治疗IPF对全因病死率有改善(OR:0.60, 95%CI:0.38～0.94),尼达尼布治疗Non-IPF对全因病死率无改善(OR:0.81, 95%CI:0.43～1.54); 吡非尼酮治疗IPF对全因病死率有改善(OR:0.55, 95%CI:0.37～0.82),吡非尼酮治疗Non-IPF对全因病死率无改善(OR:0.40, 95%CI:0.13～1.23)。结论 尼达尼布与吡非尼酮可缓解多类肺纤维化FVC减损,降低病死率。尼达尼布治疗效果稳定,吡非尼酮对Non-IPF疗效缺乏大样本支持,需明确结论稳健性。

Abstract:

Objective To analyze the anti-fibrotic efficacy of Nintedanib and Pirfenidone in idiopathic pulmonary fibrosis(IPF)and non-idiopathic pulmonary fibrosis(Non-IPF). To clarify the impact of the two drugs on the important prognostic indicators of forced vital capacity(FVC)decrease and all-cause mortality. Method A comprehensive search was conducted in PubMed, Embase, and MEDLINE databases updated to March 2024. It was included the randomized controlled trials which evaluated the degree of FVC reduction and mortality in IPF and Non-IPF patients treated with nintedanib or pirfenidone. SPSS 25.0 software was used for data standardization when the data format of the outcomes was inconsistent. Review Manager 5.4 software was used for statistical analysis. The random effects model was used to assess standardized mean difference(SMD)and confidence intervals(CI). I² was used to assess the heterogeneity. Egger's test and funnel plot were used to evaluate publication bias. Egger's test showed(P<0.05)or the funnel plot showed asymmetry, indicating the presence of publication bias. Sensitivity analysis was conducted by conducting individual deletion studies and comparing the changes in the average effect size before and after deletion to determine the robustness of the summary results. Result A total of 17 articles with 5099 patients were included in this study, 2 684 cases in obseruation greup, 2 415 cases in control group. The Meta-analysis showed that when the treatment of various types of pulmonary fibrosis with Pirfenidone or Nintedanib, the grade of FVC decrease in the observation group was significantly smaller than that in the control group(SMD: 1.48, 95%CI: 0.82-2.15). The all-cause mortality rate was also significantly decreased in the observation group than in the control group(OR: 0.59, 95%CI: 0.45-0.77). There was no heterogeneity among the studies, I²=0%, P=0.62, and sensitivity analysis showed stable results. The Subgroup analysis results showed that Nintedanib treatment for IPF(SMD: 3.39, 95%CI: 2.77-4.01)and Non-IPF(SMD: 2.25, 95%CI: 0.91-3.59)both attenuated the FVC decrease, and sensitivity analysis showed stable results. Pirfenidone treatment for IPF(SMD: 0.37, 95%CI: 0.06-0.67)and Non-IPF(SMD: 1.13, 95%CI: 0.14-2.12)can also inhibited FVC decrease, but sensitivity analysis found that there were some small sample size studies, indicating unstable results. Nintedanib had a prior effect on the all-cause mortality when treated for IPF(OR: 0.60, 95%CI: 0.38-0.94), while had no significant effect on Non-IPF(OR: 0.81, 95%CI: 0.43-1.54). Pirfenidone had a prior effect on the all-cause mortality when treated for IPF(OR: 0.55, 95%CI: 0.37-0.82), while had no significant effect on Non-IPF(OR: 0.40, 95%CI: 0.13-1.23). Conclusion In the summary analysis of a large sample, the overall therapeutic effect of the two drugs is effective. Nintedanib and Pirfenidone can attenuate the FVC decrease in various types of pulmonary fibrosis patients and reduce the mortality. The therapeutic effect of nintedanib is stable. the effect of pirfenidone on Non-IPF is not so stable because of lack of big sample trials support and further research is needed to clarify the conclusion.

参考文献/References:

1 Raghu G, Anstrom KJ, King TE, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis[J]. N Engl J Med, 2012, 366: 1968-1977.
2 Lee JH, Park HJ, Kim S, et al. Epidemiology and comorbidities in idiopathic pulmonary fibrosis: a nationwide cohort study[J]. BMC Pulm Med, 2023, 23: 54.
3 Wells AU. Patterns of progression in non-IPF fibrotic interstitial lung disease[J]. Curr Opin Pulm Med, 2023, 29: 459-464.
4 Wakwaya Y, Brown KK. Idiopathic pulmonary fibrosis: Epidemiology, diagnosis and outcomes[J]. Am J Med Sci, 2019, 357: 359-369.
5 Laurenson S, Sidhu R, Goodall M, et al. NICE guidance on nintedanib for treating idiopathic pulmonary fibrosis[J]. Lancet Respir Med, 2016, 4: 176-177.
6 Raman L, Stewart I, Barratt SL, et al. Nintedanib for non-IPF progressive pulmonary fibrosis: 12-month outcome data from a real-world multicentre observational study[J]. ERJ Open Res, 2023, 9(2): 00423-2022.
7 Davis S, Rafia R, Carroll C, et al. Pirfenidone for treating idiopathic pulmonary fibrosis: An evidence review group perspective of a NICE single technology appraisal[J]. Pharmacoeconomics, 2019, 37: 763-775.
8 Wells AU. Pirfenidone in patients with non-IPF progressive fibrotic interstitial lung diseases: expert guidance is urgently needed[J]. Lancet Respir Med, 2021, 9: 437-438.
9 King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis[J]. N Engl J Med, 2014, 370: 2083-2092.
10 Fernández Pérez ER, Crooks JL, Lynch DA, et al. Pirfenidone in fibrotic hypersensitivity pneumonitis: a double-blind, randomised clinical trial of efficacy and safety[J]. Thorax, 2023, 78: 1097-1104.
11 Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis[J]. N Engl J Med, 2014, 370: 2071-2082.
12 Kreuter M, Maher TM, Corte TJ, et al. Pirfenidone in unclassifiable interstitial lung disease: A subgroup analysis by concomitant mycophenolate mofetil and/or previous corticosteroid use[J]. Adv Ther, 2022, 39: 1081-1095.
13 Ghazipura M, Mammen MJ, Bissell BD, et al. Pirfenidone in progressive pulmonary fibrosis: A systematic review and Meta-analysis[J]. Ann Am Thorac Soc, 2022, 19: 1030-1039.
14 Ghazipura M, Mammen MJ, Herman DD, et al. Nintedanib in progressive pulmonary fibrosis: A systematic review and Meta-analysis[J]. Ann Am Thorac Soc, 2022, 19: 1040-1049.
15 Higgins JP, Altman DG, Gøtzsche PC, et al. The cochrane collaboration's tool for assessing risk of bias in randomised trials[J]. Bmj, 2011, 343: d5928.
16 Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses[J]. BMJ, 2003, 327: 557-560.
17 Mathew JL. Systematic reviews and Meta-analysis: A guide for beginners [J]. Indian Pediatr, 2022, 59: 320-330.
18 Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis[J]. Am J Respir Crit Care Med, 2005, 171: 1040-1047.
19 Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis[J]. Eur Respir J, 2010, 35: 821-829.
20 Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis(CAPACITY): two randomised trials[J]. Lancet, 2011, 377: 1760-1769.
21 Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis[J]. N Engl J Med, 2011, 365: 1079-1087.
22 Huang H, Dai HP, Kang J, et al. Double-blind randomized trial of pirfenidone in Chinese idiopathic pulmonary fibrosis patients[J]. Medicine(Baltimore), 2015, 94: e1600.
23 Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease[J]. N Engl J Med, 2019, 380: 2518-2528.
24 Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases[J]. N Engl J Med, 2019, 381: 1718-1727.
25 Acharya N, Sharma SK, Mishra D, et al. Efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease-a randomised controlled trial[J]. Rheumatol Int, 2020, 40: 703-710.
26 Maher TM, Corte TJ, Fischer A, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial[J]. Lancet Respir Med, 2020, 8: 147-157.
27 Behr J, Prasse A, Kreuter M, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis(RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial[J]. Lancet Respir Med, 2021, 9: 476-486.
28 Cottin V, Richeldi L, Rosas I, et al. Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases[J]. Respir Res, 2021, 22: 84.
29 Kuwana M, Ogura T, Makino S, et al. Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial[J]. Mod Rheumatol, 2021, 31: 141-150.
30 Solomon JJ, Danoff SK, Woodhead FA, et al. Safety, tolerability, and efficacy of pirfenidone in patients with rhumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study[J]. Lancet Respir Med, 2023, 11: 87-96.
31 Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis(an Update)and progressive pulmonary fibrosis in adults: An official ATS/ERS/JRS/ALAT clinical practice guideline[J]. Am J Respir Crit Care Med, 2022, 205: e18-e47.
32 Wu X, Li W, Luo Z, et al. A comprehensive comparison of the safety and efficacy of drugs in the treatment of idiopathic pulmonary fibrosis: a network meta-analysis based on randomized controlled trials[J]. BMC Pulm Med, 2024, 24: 58.
33 Yang W, Pan L, Cheng Y, et al. Nintedanib alleviates pulmonary fibrosis in vitro and in vivo by inhibiting the FAK/ERK/S100A4 signalling pathway[J]. Int Immunopharmacol, 2022, 113: 109409.
34 Wollin L, Distler JHW, Redente EF, et al. Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases[J]. Eur Respir J, 2019, 54.
35 Lv Q, Wang J, Xu C, et al. Pirfenidone alleviates pulmonary fibrosis in vitro and in vivo through regulating Wnt/GSK-3β/β-catenin and TGF-β1/Smad2/3 signaling pathways[J]. Mol Med, 2020, 26: 49.
36 Tang Q, Xing C, Li M, et al. Pirfenidone ameliorates pulmonary inflammation and fibrosis in a rat silicosis model by inhibiting macrophage polarization and JAK2/STAT3 signaling pathways[J]. Ecotoxicol Environ Saf, 2022, 244: 114066.
37 Finnerty JP, Ponnuswamy A, Dutta P, et al. Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis(IPF)and non-IPF: a systematic review and meta-analysis[J]. BMC Pulm Med, 2021, 21: 411.
38 Zhang XL, Cao Y, Zheng B. Efficacy of N-acetylcysteine plus pirfenidone in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis[J]. BMC Pulm Med, 2023, 23: 479.
39 Naccache JM, Jouneau S, Didier M, et al. Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis(EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Respir Med, 2022, 10: 26-34.
40 周 璇, 谢 莉, 邹 娟. 尼达尼布对特发性肺纤维化肺功能、肺纤维化程度及PDGF、PGE2、TGF-β1的影响[J/CD]. 中华肺部疾病杂志(电子版), 2024, 17(3): 368-372.

备注/Memo

备注/Memo:

基金项目: 国家自然科学基金资助项目(81700078); 江苏省自然科学基金资助项目(BK20171172)
徐州市科技计划(KC21055); 徐州医科大学附属医院科技发展基金(XYFM2020005)
徐州市医学重点人才(XWRCHT20220051)
通信作者: 王 凯, Email: wangkaistream99@sina.com
武焱旻, Email: wym666@126.com

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更新日期/Last Update: 2024-12-25