Antifibrotic therapy for idiopathic pulmonary fibrosis: time to treat

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a dismal prognosis. The average life expectancy of untreated patients with IPF is only 3 to 4 years. Decline in forced vital capacity (FVC) in patients with IPF appears to be almost linear, with patients with well-preserved FVC at baseline experiencing the same rate of decline in FVC as patients with more advanced disease. Two antifibrotic therapies have been approved for the treatment of IPF: nintedanib and pirfenidone. These drugs slow decline in lung function and reduce the risk of acute respiratory deteriorations, which are associated with very high morbidity and mortality. Individual clinical trials have not been powered to show reductions in mortality, but analyses of pooled data from clinical trials, as well as observational studies, suggest that antifibrotic therapies improve life expectancy. Despite this, many individuals with IPF remain untreated. In many cases, this is because the physician perceives that the disease is stable and so does not warrant therapy, or has concerns over the potential side-effects of antifibrotic drugs. There remains a need to educate pulmonologists that IPF is a progressive, irreversible and fatal disease and that prompt treatment is critical to preserving patients' lung function and improving outcomes. Most individuals can tolerate antifibrotic therapy, and dose adjustment has been shown to be effective at reducing side effects without compromising efficacy. In addition to anti-fibrotic therapies, individuals with IPF benefit from a holistic approach to their care that includes symptom management and supportive care tailored to the needs of the individual. An animation illustrating the themes covered in this article will be available at: http://www.usscicomms.com/respiratory/maher/treatment-of-IPF .

Keywords: Interstitial lung disease; Mortality; Nintedanib; Pirfenidone; Therapeutics; Treatment.

Fig. 1

Kaplan-Meier analysis of survival in patients with incident IPF [3]. Population-based study of all incident cases of IPF in the United Kingdom identified using a broad case definition based on diagnostic codes. Republished with permission of Adv Ther, from Incidence, prevalence, and survival of patients with idiopathic pulmonary fibrosis in the UK, Strongman et al., 35, 2018; permission conveyed through Copyright Clearance Center, Inc.

Fig. 2

Decline in FVC in patients with IPF based on daily home spirometry [10]. Linear regression lines for every subject were based on all readings obtained between baseline and day 365 without imputation. FVC, forced vital capacity. Reprinted with permission of the American Thoracic Society. Copyright© 2018 American Thoracic Society. Russell AM, et al. 2016. Daily home spirometry: an effective tool for detecting progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 194:989–97. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society

Fig. 3

Decline in FVC in subjects with baseline FVC > 90% and ≤ 90% predicted in the INPULSIS trials of nintedanib [13]. Error bars show the standard error. FVC, forced vital capacity. Republished with permission of Thorax, from Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume, Kolb et al., 72, 2017; permission conveyed through Copyright Clearance Center, Inc.

Fig. 4

Standardized treatment effect of pirfenidone versus placebo on change in FVC % predicted from baseline to 1 year based on pooled data from the CAPACITY and ASCEND trials (N = 1247) [24]. 6MWD, 6-min walk distance; DLco, diffusing capacity of the lungs for carbon monoxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity. Error bars show the 95% confidence interval. Reproduced with permission of the © ERS 2018. European Respiratory Journal Jan 2016, 47 (1) 243–253; DOI: 10.1183/13993003.00026-2015. This material has not been reviewed prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content

Fig. 5

Annual rate of decline in FVC in the INPULSIS trials and their open-label extension INPULSIS-ON [26]. Annual rate of decline in FVC over 52 weeks in INPULSIS and over 192 weeks in INPULSIS-ON. Patients who took nintedanib in an INPULSIS trial continued nintedanib in INPULSIS-ON. Patients who took placebo in an INPULSIS trial initiated nintedanib in INPULSIS-ON. Error bars show the standard error. FVC, forced vital capacity. Republished with permission of Lancet Respir Med, from Long-term treatment with nintedanib in patients with idiopathic pulmonary fibrosis: results from INPULSIS-ON, Crestani et al., doi: 10.1016/S2213-2600(18)30339-4, 2018; permission conveyed through Copyright Clearance Center, Inc.

Fig. 6

Changes from baseline in SGRQ total and domain scores (A) and UCSD-SOBQ score (B) at week 52 in subgroups by changes in FVC % predicted at week 52 in the INPULSIS trials [40]. SGRQ, St George’s Respiratory Questionnaire; UCSD-SOBQ, University of California San Diego Shortness of Breath Questionnaire; FVC, forced vital capacity

Fig. 7

Reasons given by pulmonologists for not treating with “mild” IPF in an international survey [48]. *p < 0.05. a. IPF was defined as “mild” by the physician. b. Physicians who monitored the majority of patients with IPF for > 4 months after diagnosis before initiating treatment. c. Physicians who initiated antifibrotic treatment within 4 months of diagnosis in the majority of patients with IPF. NICE, National Institute for Health and Care Excellence (in the UK). Data from survey of pulmonologist in Canada, France, Germany, Italy, Spain and the UK. Republished with permission of Respiration, from Identifying barriers to idiopathic pulmonary fibrosis treatment: a survey of patient and physician views, Maher et al., doi: 10.1159/000490667, 2018; permission conveyed through Copyright Clearance Center, Inc.