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

doi:10.3877/cma.j.issn.1674-6902.2024.06.003

Abstract

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.

Key words: Idiopathic pulmonary fibrosis, Non-idiopathic pulmonary fibrosis, Nintedanib, Pirfenidone, Forced vital capacity

Tianen Chen, Shuan Liu, Huanjia Xue, Hui Wang, Huige Qiu, Shanshan Gao, Lanxing Chen, Hui Jing, Yanmin Wu, Kai Wang. Therapeutic effects of Nintedanib and Pirfenidone on idiopathic and non-idiopathic pulmonary fibrosis：A meta-analysis[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2024, 17(06): 861-868.

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第一作者	发表年份	收录杂志	试验类型	时长（月）	疾病名称	研究药物	观察组（n）	对照组（n）	药物用法	FVC	全因死亡
Azuma^［18］	2005	美国呼吸重症	常规RCT	9	IPF	P	73	36	200 mg tid 两天，400 mg tid两天，600 mg tid维持	ml/9月	N/A
Taniguc-hi^［19］	2010	欧洲呼吸	Ⅲ期临床	12	IPF	P	104	103	1 800 mg qd	ml/年	N/A
Noble（004）^［20］	2011	柳叶刀	CAPACITY/Ⅱ期临床	18	IPF	P	174	174	801 mg tid	%预测值	Y
Noble（006）^［20］	2011	柳叶刀	CAPACITY/Ⅱ期临床	18	IPF	P	171	173	801 mg tid	%预测值	Y
Richeldi^［21］	2011	新英格兰医学	Ⅱ期临床	12	IPF	N	84	83	150 mg bid	ml/年	Y
Richeldi^［11］	2014	新英格兰医学	INPULSIS trial 1	12	IPF	N	309	204	150 mg bid	ml/年	Y
Richeldi^［11］	2014	新英格兰医学	INPULSIS trial 2	12	IPF	N	329	219	150 mg bid	ml/年	Y
King^［9］	2014	新英格兰医学	ASCEND/Ⅲ期临床	12	IPF	P	278	277	2 403 mg qd	ml/年	Y
Huang^［22］	2015	医学	Ⅱ期临床	11	IPF	P	38	38	1 800 mg qd	ml/11月	Y
Flaherty^［24］	2019	新英格兰医学	INBUILD trial	12	Non-IPF/NSIP，uIIP，HP，RA-ILD，SSc-ILD	N	332	331	150 mg bid	ml/年	Y
Distler^［23］	2019	新英格兰医学	SENSCIS/Ⅲ期临床	12	Non-IPF/SSc-ILD	N	288	288	150 mg bid	ml/年	Y
Maher^［26］	2020	柳叶刀呼吸医学	Ⅱ期临床	6	Non-IPF/uILD	P	118	119	2 403 mg qd	ml/6月	Y
Acharya^［25］	2020	风湿病学	常规RCT	6	Non-IPF	P	17	17	600 mg qd；每周增加 600 mg qd；直至 2 400 mg qd	ml/年	N/A
Behr^［27］	2021	柳叶刀呼吸医学	Ⅱ期临床	11	Non-IPF/NSIP，HP，RA-ILD，SSc-ILD，ALF	P	35	32	第一周267 mg bid；第二周534 mg bid；之后801 mg bid	ml/11月	Y
Cottin^［28］	2021	呼吸研究	INBUILD trial	12	Non-IPF	N	155	147	150 mg bid	ml/年	Y
Kuwana^［29］	2021	现代风湿病学	SENSCIS/Ⅲ期临床	12	Non-IPF/SSc-ILD	N	34	36	150 mg bid	ml/年	Y
Kreuter^［12］	2022	治疗进展	Ⅱ期临床	6	Non-IPF/μILD	P	60	69	2 403 mg qd	ml/年	Y
Fernández^［10］	2023	胸腔	常规RCT	12	Non-IPF/FHP	P	27	13	2 403 mg qd	%预测值	N/A
Solomon^［30］	2023	柳叶刀呼吸医学	常规RCT	12	Non-IPF/RA-ILD	P	63	60	2 403 mg qd	ml/年	Y

第一作者	发表年份	收录杂志	试验类型	时长（月）	疾病名称	研究药物	观察组（n）	对照组（n）	药物用法	FVC	全因死亡
Azuma^［18］	2005	美国呼吸重症	常规RCT	9	IPF	P	73	36	200 mg tid 两天，400 mg tid两天，600 mg tid维持	ml/9月	N/A
Taniguc-hi^［19］	2010	欧洲呼吸	Ⅲ期临床	12	IPF	P	104	103	1 800 mg qd	ml/年	N/A
Noble（004）^［20］	2011	柳叶刀	CAPACITY/Ⅱ期临床	18	IPF	P	174	174	801 mg tid	%预测值	Y
Noble（006）^［20］	2011	柳叶刀	CAPACITY/Ⅱ期临床	18	IPF	P	171	173	801 mg tid	%预测值	Y
Richeldi^［21］	2011	新英格兰医学	Ⅱ期临床	12	IPF	N	84	83	150 mg bid	ml/年	Y
Richeldi^［11］	2014	新英格兰医学	INPULSIS trial 1	12	IPF	N	309	204	150 mg bid	ml/年	Y
Richeldi^［11］	2014	新英格兰医学	INPULSIS trial 2	12	IPF	N	329	219	150 mg bid	ml/年	Y
King^［9］	2014	新英格兰医学	ASCEND/Ⅲ期临床	12	IPF	P	278	277	2 403 mg qd	ml/年	Y
Huang^［22］	2015	医学	Ⅱ期临床	11	IPF	P	38	38	1 800 mg qd	ml/11月	Y
Flaherty^［24］	2019	新英格兰医学	INBUILD trial	12	Non-IPF/NSIP，uIIP，HP，RA-ILD，SSc-ILD	N	332	331	150 mg bid	ml/年	Y
Distler^［23］	2019	新英格兰医学	SENSCIS/Ⅲ期临床	12	Non-IPF/SSc-ILD	N	288	288	150 mg bid	ml/年	Y
Maher^［26］	2020	柳叶刀呼吸医学	Ⅱ期临床	6	Non-IPF/uILD	P	118	119	2 403 mg qd	ml/6月	Y
Acharya^［25］	2020	风湿病学	常规RCT	6	Non-IPF	P	17	17	600 mg qd；每周增加 600 mg qd；直至 2 400 mg qd	ml/年	N/A
Behr^［27］	2021	柳叶刀呼吸医学	Ⅱ期临床	11	Non-IPF/NSIP，HP，RA-ILD，SSc-ILD，ALF	P	35	32	第一周267 mg bid；第二周534 mg bid；之后801 mg bid	ml/11月	Y
Cottin^［28］	2021	呼吸研究	INBUILD trial	12	Non-IPF	N	155	147	150 mg bid	ml/年	Y
Kuwana^［29］	2021	现代风湿病学	SENSCIS/Ⅲ期临床	12	Non-IPF/SSc-ILD	N	34	36	150 mg bid	ml/年	Y
Kreuter^［12］	2022	治疗进展	Ⅱ期临床	6	Non-IPF/μILD	P	60	69	2 403 mg qd	ml/年	Y
Fernández^［10］	2023	胸腔	常规RCT	12	Non-IPF/FHP	P	27	13	2 403 mg qd	%预测值	N/A
Solomon^［30］	2023	柳叶刀呼吸医学	常规RCT	12	Non-IPF/RA-ILD	P	63	60	2 403 mg qd	ml/年	Y

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