Acute Exacerbation and Decline in Forced Vital Capacity Are Associated with Increased Mortality in Idiopathic Pulmonary Fibrosis
Acute Exacerbation and Decline in Forced Vital Capacity Are Associated with Increased Mortality in Idiopathic Pulmonary Fibrosis
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DOI：
10.1513/annalsats.201606-458oc
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发表时间：
2017-09-01
影响因子：
8.3
通讯作者：
Chowdhury, Badrul A.
中科院分区：
文献类型：
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作者：
Paterniti, Miya O.;Bi, Youwei;Chowdhury, Badrul A.
基本原理：探索FVC与特发性肺纤维化（IPF）（一种慢性、进行性和最终致死性肺实质疾病）死亡率的关系在临床上和当前药物开发模式中都很重要。我们评估了FVC下降与死亡率之间的关系，据我们所知，这是迄今为止最大的特征良好的安慰剂队列。此外，我们试图探索急性加重引起的死亡风险，并进一步验证之前确定的死亡率基线预测因素。目标：验证并进一步描述FVC下降、急性加重和之前确定的基线预测因素，因为它们与死亡风险相关。方法：本分析共纳入了6项用于尼达尼布和吡非尼酮治疗IPF临床开发的研究中的1，132例安慰剂受试者。死亡被记录为全因死亡。采用分层考克斯比例风险模型检验基线预测因子、FVC %预测值较基线下降、急性加重和死亡之间的相关性。FVC %预测值的下降和急性加重被视为随时间变化的协变量。结果：受试者平均随访60周。基线时，年龄、吸烟状态、FVC %预测值较低和肺一氧化碳弥散量%预测值较低与死亡风险增加相关。发生一次或多次急性加重的受试者的死亡风险也增加，风险比（HR）为10. 3（95%置信区间[CI]，5. 7 - 18. 7）。与研究期间任何时间FVC %预测相对于基线的绝对下降小于5%相比，下降大于或等于10%至小于15%与死亡风险增加相关，HR为2.2（95% CI，1.1-4.4），下降大于或等于15%，估计HR为6.1（95% CI，3.1-11.8）。从大于或等于5%到小于10%的下降与死亡率增加无关。我们的分析验证了基线FVC、肺一氧化碳弥散量、年龄和吸烟状态作为死亡率预测因子的重要性，并加强了FVC下降与急性加重死亡之间的相关性，证实FVC下降是IPF药物开发的适当终点。
Rationale: Exploration of FVC as it relates to mortality in idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and ultimately fatal parenchymal lung disease, is important both clinically and to the current drug development paradigm. We evaluated the association between FVC decline and mortality in what is to our knowledge the largest well-characterized placebo cohort to date. Additionally, we sought to explore the risk of death caused by acute exacerbations and to further validate previously identified baseline predictors of mortality.Objectives: To validate and further characterize FVC decline, acute exacerbations, and previously identified baseline predictors as they relate to risk of death.Methods: A total of 1,132 placebo subjects from six studies used for the clinical development of nintedanib and pirfenidone for the treatment of IPF were included in the present analysis. Deaths were captured as all-cause mortality. A stratified Cox proportional hazards model was used to test the association between baseline predictors, decline in FVC % predicted from baseline, acute exacerbations, and death. Decline in FVC % predicted and exacerbations were treated as time-varying covariates.Results: Subjects were followed for a mean of 60 weeks. At baseline, age, smoking status, lower FVC % predicted, and lower diffusing capacity of the lung for carbon monoxide % predicted were associated with an increased risk of death. The risk of death was also increased for subjects having one or more exacerbations with a hazard ratio (HR) of 10.3 (95% confidence interval [CI], 5.7-18.7). Compared with an FVC % predicted absolute decline from baseline at any time during the study of less than 5%, a decline greater than or equal to 10% to less than 15% was associated with an increased risk of death, with an HR of 2.2 (95% CI, 1.1-4.4), as was a decline greater than or equal to 15%, which was estimated with an HR of 6.1 (95% CI, 3.1-11.8). A decline ranging from greater than or equal to 5% to less than 10% was not associated with increased mortality.Conclusions: Our analyses validate the importance of baseline FVC, diffusing capacity of the lung for carbon monoxide, age, and smoking status as predictors of mortality and strengthen the association between decline in FVC and exacerbations with death, verifying a decline in FVC as an appropriate endpoint in IPF drug development.