Elsevier

Respiratory Investigation

Volume 53, Issue 6, November 2015, Pages 271-278
Respiratory Investigation

Original article
Risk factors for acute exacerbation of idiopathic pulmonary fibrosis – Extended analysis of pirfenidone trial in Japan

https://doi.org/10.1016/j.resinv.2015.04.005Get rights and content

Abstract

Background

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a lifethreatening event and one of the important endpoints in clinical trials involving IPF. Despite this, there has been little evaluation of the potential risk factors for AE-IPF in clinical trials. We evaluated the risk factors for AE-IPF in a phase III clinical trial of pirfenidone in Japanese IPF patients.

Methods

The study population comprised 267 patients. The effects of various baseline characteristics as possible risk factors for AE-IPF during the study, as well as those of a ≥10% decline in percent vital capacity (%VC) within 6 months, were evaluated using Cox׳s proportional hazard model. The ≥10% decline in %VC was calculated in two ways: (1) an absolute decline (e.g. from 60% predicted to 50%); and (2) a relative decline (e.g. from 60% predicted to 54%).

Results

Over 52 weeks, 14 patients experienced AE-IPF. Univariate analysis using Cox׳s proportional hazards model showed that both relative and absolute ≥10% decline in %VC within 6 months were significant risk factors for AE-IPF. Stepwise multivariate analysis demonstrated that absolute or relative decline in both %VC and alveolar to arterial oxygen pressure difference (AaDO2) were significant risk factors for AE. The model using absolute decline [Hazard Ration (HR)=7.405, p=0.0007] and baseline AaDO2 (HR=1.063, p=0.0266) had a better fit than the model using relative decline and baseline AaDO2.

Conclusions

Rapid %VC decline (≥10% within 6 months), and high baseline AaDO2, may be risk factors for AE-IPF.

Introduction

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are episodes of acute respiratory worsening without an identifiable cause, which may occur at any time during the course of the disease [1], [2], [3]. The condition is associated with a very poor prognosis, accounting for about one third to one half of the deaths from IPF [4], [5], [6]. For this reason, prediction and prevention of AE-IPF is crucial, and almost all recent randomized controlled studies have included AE-IPF as a secondary endpoint. Although there have been several previous clinical trials involving IPF that also evaluated the degree to which clinical interventions can prevent AE, little has been elucidated with regard to the risk factors for AE-IPF [7], [8], [9], [10], [11], [12], [13].

The etiology of AE-IPF is unknown. However, two retrospective single center studies have reported that possible risk factors include a ≥10% decline of forced vital capacity (FVC) in 6 months, as well as several baseline factors such as never having smoked, low FVC, high body mass index (BMI), and high grade on the modified Medical Research Council (MRC) breathlessness scale [4], [5]. Furthermore, because a ≥10% decline of FVC in 6 months is thought to be an indicator of disease progression, a relationship between disease progression and AE-IPF has been speculated [5].

In this study, we sought to evaluate the risk factors for AE-IPF within the context of a phase III clinical trial of pirfenidone in Japanese IPF patients. We hypothesized that disease progression, defined as ≥10% decline in %VC, enhances the risk of early AE.

Section snippets

Study population

The possible risk factors for AE-IPF were evaluated in 267 patients. This comprised the full analysis set of our pirfenidone phase III clinical trial [9]. Because there was no significant difference between the pirfenidone and placebo groups with regard to the prevalence of AE-IPF in this trial (Fig. 1) [9], the risks were evaluated without regard to treatment assignment. In the clinical trial, 14 patients experienced AE-IPF during the 52-week course of the study (Fig. 2).

The trial design is

Results

Fourteen patients were diagnosed with AE-IPF without known causes, based on a review of the diagnoses that was carried out by the adjudication committee. Twelve of these 14 patients underwent HRCT upon diagnosis, and new bilateral ground-glass opacities that were superimposed on a background reticular or honeycomb pattern were confirmed in all 12 patients. The 30-day mortality rate was 50% (7/14). The clinical features and timeline of AE-IPF in the 14 patients are shown in Table 1. Fig. 1 shows

Discussion

This study suggests that high baseline AaDO2 and a ≥10% decline (absolute or relative) in %VC within 6 months were both candidate risk factors for AE-IPF over the 52 weeks of the study. That is to say, initial impairment of gas exchange and rapid decline in VC enhance the risk of AE-IPF.

This is the first study to explore the potential risk factors for AE-IPF using data from a multicenter study. The monthly evaluation of VC that was carried out as part of the phase III clinical trial enabled

Conclusions

In conclusion, high baseline AaDO2, and ≥10% decline in %VC within 6 months may be candidate risk factors for AE-IPF. Because AE-IPF affects prognosis, knowing the risk factors may be important in the development of future therapeutic strategies.

Conflicts of interest

The authors H. Taniguchi, M. Ebina, A. Azuma, Y. Taguchi, M. Suga, H. Takahashi, K. Nakata , Y. Sugiyama, S. Kudoh, and T. Nukiwa received consultancy fees for their roles within the advisory board, and H. Taniguchi, Y. Kondoh, M. Ebina, T. Ogura, A. Azuma, Y. Sugiyama, and T. Nukiwa received fees for giving a presentation from Shionogi & Co., Ltd. Y. Taguchi, A. Azuma, T. Ogura, Y. Sugiyama and T. Nukiwa received fees for advisory board consulting from Boehringer Ingelheim Co.

Each author׳s role in the study

Drs. Y. Kondoh and H. Taniguchi were involved in the conception, hypothesis, and design of the study. They had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs. M. Ebina, A. Azuma, T. Ogura, Y. Taguchi, M. Suga, H. Takahashi, K. Nakata, Y. Sugiyama, S. Kudoh, and T. Nukiwa contributed to interpretation of the data, and writing of the manuscript.

Acknowledgments

The authors would like to thank M. Ando (Omotesando Yoshida Hospital, Kumamoto, Japan), S. Kitamura (Minami-Tochigi Hospital, Oyama, Tochigi, Japan), Y. Nakai (Tanpopo Clinic, Sendai, Miyagi, Japan), and A. Kondo (Niigata Tetsudo Kenshin Center, Niigata, Japan) of the independent Data and Safety Monitoring Board; K. Murata (Shiga University of Medical Science Hospital, Ohtsu, Shiga, Japan), M. Takahashi (Shiga University of Medical Science Hospital, Ohtsu, Shiga, Japan), H. Hayashi (Japanese

References (28)

  • H Taniguchi et al.

    Pirfenidone in idiopathic pulmonary fibrosis

    Eur Respir J

    (2010)
  • TE King et al.

    BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2011)
  • L Richeldi et al.

    Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis

    N Engl J Med

    (2011)
  • I Noth et al.

    Idiopathic Pulmonary Fibrosis Clinical Research Network (IPF net). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2012)
  • Cited by (51)

    • Acute Exacerbation of Idiopathic Pulmonary Fibrosis

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    View all citing articles on Scopus
    View full text