1. R1 정수웅

2.  Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that occurs primarily in older adults with no currently approved therapy.  Diagnosis of IPF require a multidisciplinary clinical, radiologic, and pathologic review of a patient’s data.  The disease is associated with usual interstitial pneumonia (UIP), a distinctive pathologic pattern on surgical lung biopsy.  A specific pattern of features on high-resolution computed tomography (HRCT) has a strong positive predictive value for the presence of the pathologic UIP pattern.

3. Am J Respir Crit Care Med Vol 183, 2011

5. α-SMA = α-smooth muscle actin; CCN2 = connective tissue growth factor; ECM = extracellular matrix; EMT = epithelial–mesenchymal transition; ET-1 = endothelin-1; MMP-1 = matrix metalloproteinase-1; SMC = smooth muscle cell; TGF-β = transforming growth factor-β. Schematic of profibrotic pathways that may be modulated by endothelin receptor antagonists. Endothelin-1 is one of many profibrotic cytokines and growth factors believed to be involved in the pathogenesis of IPF. ET A receptor : contractile activity of activated lung fibroblasts endothelin-1–induced lung fibroblast proliferation Promotion of epithelial–mesenchymal transition through the activation of transforming growth factor. Endothelin receptor expression is increased in IPF lung tissue, and data from preclinical models suggest that antagonism of endothelin receptors may decrease the severity of pulmonary fibrosis

6.  Ambrisentan is a selective ET A receptor antagonist that is approved for treatment of patients with pulmonary arterial hypertension.  The potency, pharmacokinetics, pharmacodynamics, and nonendothelin receptor– based effects of ambrisentan are sufficiently distinct from those of bosentan that their expected clinical effects in IPF may differ.  A phase 3 study, ARTEMIS-IPF, that evaluated the effects of ambrisentan on disease progression among patients with IPF

7.  ARTEMIS-IPF was a randomized, double-blind, placebo-controlled, multicenter, event-driven phase 3 trial to evaluate whether ambrisentan is effective in reducing the rate of IPF progression.  Eligible patients were men and women aged 40 to 80 years who had a diagnosis of IPF  We excluded patients with greater than 5% honeycombing on HRCT scans.  Other key exclusion criteria congestive heart failure history of collagen vascular disease evidence of coexisting obstructive airflow defect prominent emphysema on HRCT scans hospitalization or respiratory infection within the past 60 days long-term treatment of pulmonary hypertension (PH) long-term treatment with immunosuppressive therapy

8.  Given the potential effect of pulmonary hypertension on IPF outcomes, stratified randomization on the basis of presence of PH were used. (a mean pulmonary artery pressure 25 mm Hg a pulmonary capillary wedge pressure 15 mm Hg)  randomly assigned in a 2:1 ratio to receive ambrisentan or placebo

9.  The composite primary end point : time to IPF disease progression death from any cause hospitalization due to adjudicated respiratory events (respiratory hospitalization) a categorical decrease in lung function a 10% or greater decrease in FVC plus a 5% or greater decrease in DLCO a 5% or greater decrease in FVC plus a 15% or greater decrease in DLCO

13. Mean change from baseline for FVC (top), Dlco(middle), and MWD (bottom), by treatment group.

14.  Results of analyses of disease progression that were stratified on the basis of baseline PH status were similar to those of the overall analysis Results of analyses of disease progression ambrisentan vs placebo hazard ratio for presence of PH 2.42 [CI, 0.79 to 7.38] P 0.121 ambrisentan vs. placebo hazard ratio for absence of PH 1.64 [CI, 1.04 to 2.60] P 0.03

15. The proportion of patients with at least 1 treatment-emergent AE was similar between groups : 278 (84%) in the ambrisentan group : 136 (83%) in the placebo group

16. 9(3%) in the ambrisentan group and 2 (1%) in the placebo group discontinued the study because of safety and tolerability. The most frequently reported treatment- emergent AE leading to study drug discontinuation was worsening IPF followed by dyspnea and pneumonia.

17.  The results of this study indicate that ambrisentan actually increases the likelihood of disease progression.  It was also associated with more respiratory hospitalizations  Possible explanations for worse clinical outcomes in patients with IPF treated with ambrisentan  The modulation of vascular remodeling by ambrisentan in patients with IPF, which could lead to impaired vascular response and hypoxemia during additional respiratory stress (for example, infections or exacerbations), ultimately predisposing patients to respiratory hospitalizations.  We conclude that ambrisentan should not be used to treat patients with IPF.