Jul 15, 2014 - Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-2082. 14. Nathan SD, Meyer KC.
EDITORIALS References 1. Guo Y, Xiao L, Sun L, Liu F. Wnt/b-catenin signaling: a promising new target for fibrosis diseases. Physiol Res 2012;61:337–346. 2. Konigshoff ¨ M, Kramer M, Balsara N, Wilhelm J, Amarie OV, Jahn A, Rose F, Fink L, Seeger W, Schaefer L, et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 2009;119: 772–787. 3. Flozak AS, Lam AP, Russell S, Jain M, Peled ON, Sheppard KA, Beri R, Mutlu GM, Budinger GR, Gottardi CJ. b-Catenin/T-cell factor signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells. J Biol Chem 2010;285:3157–3167. 4. Henderson WR Jr, Chi EY, Ye X, Nguyen C, Tien YT, Zhou B, Borok Z, Knight DA, Kahn M. Inhibition of Wnt/b-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci USA 2010;107:14309–14314. 5. Chilosi M, Poletti V, Zamo` A, Lestani M, Montagna L, Piccoli P, Pedron S, Bertaso M, Scarpa A, Murer B, et al. Aberrant Wnt/b-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol 2003; 162:1495–1502. 6. Konigshoff ¨ M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, Eickelberg O. Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One 2008;3:e2142. 7. Lam AP, Herazo-Maya J, Sennello J, Flozak A, Russell S, Mutlu G, Budinger G, DasGupta R, Varga J, Kaminski N, et al. Wnt co-receptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014;190:185–195.
8. Akhmetshina A, Palumbo K, Dees C, Bergmann C, Venalis P, Zerr P, Horn A, Kireva T, Beyer C, Zwerina J, et al. Activation of canonical Wnt signalling is required for TGF-b–mediated fibrosis. Nat Commun 2012; 3:735. 9. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011;145:926–940. 10. Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 2009;15:1077–1081. 11. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ. Reversal of persistent fibrosis in aging by targeting Nox4–Nrf2 redox imbalance. Sci Transl Med 2014;6:231ra47. 12. Thannickal VJ. Aging, antagonistic pleiotropy and fibrotic disease. Int J Biochem Cell Biol 2010;42:1398–1400. 13. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 2007;317:807–810. 14. Herazo-Maya JD, Noth I, Duncan SR, Kim S, Ma SF, Tseng GC, Feingold E, Juan-Guardela BM, Richards TJ, Lussier Y, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 2013;5:205ra136.
Copyright © 2014 by the American Thoracic Society
Pulmonary Hypertension due to Fibrotic Lung Disease: Hidden Value in a Neutral Trial Pulmonary hypertension (PH) complicating lung disease as a target of therapy makes intuitive sense. Numerous studies have demonstrated that PH complicating idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic interstitial pneumonias, is associated with worse functional status, increased oxygen requirements, and greater mortality (1). In this issue of the Journal, Corte and associates (pp. 207–216) report the results of a randomized, placebo-controlled study of the endothelin receptor antagonist (ERA) bosentan in a group of patients with fibrotic idiopathic interstitial pneumonia (2). Three previous studies demonstrated no effect of the ERA class of agents on the fibrotic component of IPF (3–5). This study also attests to a lack of benefit and lays to rest the notion of treating PH in the context of idiopathic fibrosing lung disorders with ERAs. However, is it the end of the story for treating PH associated with fibrotic lung diseases, or is it the beginning of the next chapter? In fact, there are data to suggest that treating the PH of IPF with other classes of agents might be a worthy endeavor with efficacy demonstrated in multiple domains from the STEP-IPF study of sildenafil (6, 7). If this is the end of just another chapter, what can be learned from this study that might provide a foundation for forthcoming efforts? Indeed, there are numerous lessons in terms of future clinical trial design. Key among these is what not to choose as the primary endpoint. After all, the fate of any trial and the therapeutic agent at stake are inextricably bound to the designated primary endpoint. In this study, the authors used the pulmonary vascular
Editorials
resistance index (PVRi) as the primary outcome measure. This was based on their prior demonstration of a strong link between the pulmonary vascular resistance and early mortality (8). This association is pathophysiologically sound, since the impact of PH on patient outcomes is determined by whether the right ventricle (RV) compensates or decompensates. The PVRi represents a composite of three parameters: the mean pulmonary artery pressure, the pulmonary arterial wedge pressure, and the cardiac index, the latter being a surrogate for RV function (9). What was unknown heading into this study is the utility of a change in the PVRi as a meaningful outcome measure. A surprising finding was that almost 30% of patients in both groups had a 20% or more improvement in their PVRi. As noted by the authors, this undoubtedly does not denote an actual improvement, but rather is reflective of the precision and reproducibility of the measurements. The downside of a composite such as this is that the variability of each component is compounded when all three are computed in one formula. It is of interest that baseline PVRi is a useful prognosticator, whereas change in this parameter is not, a scenario akin to what has emerged with the 6-minute-walk test (9–11). Another lesson from this study pertains to the trial duration. Was 16 weeks sufficient time to see a difference? Whereas 12- or 16-week studies were previously commonplace in the pulmonary arterial hypertension arena, this might not be a sufficient period of time when addressing PH associated with lung disease. What if the PH medication being studied prevents progression of PH, rather than affecting an improvement? Maintaining relative stability of
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EDITORIALS the PH may be analogous to preventing a decline in the FVC in a patient with IPF, this being commonly regarded as a salutary effect (12, 13). In this regard, the natural history of PH in the context of lung disease may require a longer trial duration for the placebo arm to manifest sufficient deterioration in the outcome measure. Although it is possible that PH therapy might prevent deterioration in some patients, it is also likely that improvement will be seen in others. Capturing the full spectrum of treatment effects might therefore be best accomplished through a competing risk analysis with three possible outcomes of interest: improvement, stability, or worsening in the chosen endpoint. If prevention of progression is one of the decided goals, then this would provide a rationale for inclusion of patients with PH beyond just those with severe disease. A broader range of patients with PH would also facilitate enrollment in the necessary trial(s) to demonstrate efficacy. Recruitment was clearly an issue for this current trial, with 43 months needed for eight centers to enroll 60 patients. Can recruitment be further enabled by not only allowing a lower limit of acceptable pulmonary artery pressures, but also broadening the scope of fibrotic disorders? The authors raise the notion that the idiopathic interstitial pneumonias follow a final common path that is determined by their pulmonary vasculopathy. Is this concept applicable to all fibrotic lung disease? If so, should patients with other fibrotic disorders, such as those with chronic hypersensitivity pneumonitis and occupational lung disease, also be included in future clinical trials? It is beyond the scope of this editorial to pontificate on the best endpoint(s) for such studies. Suffice it to state that there are many candidate parameters that may be used as primary or secondary endpoints, either alone or together in the form of composites. These include categorical changes in the 6-minute-walk test, patient-reported outcomes, changes in functional class, indices of RV function, biomarkers, hospitalizations, and all-cause mortality (14). The latter is the most definitive and broadly accepted, and although not feasible in patients with early fibrotic disease, might be attainable in sicker cohorts such as those recruited into this study (15). Indeed, over a relatively short period of time, a mortality rate of 10% was noted (2). The authors of this article are to be congratulated for undertaking and completing this study, which we are loath to label as “negative” because there are many “positive” lessons that may be gleaned, a few of which we have attempted to highlight. The editors of the Journal are also to be commended for recognizing the value of this “negative” trial. n Author disclosures are available with the text of this article at www.atsjournals.org. Steven D. Nathan, M.D. Department of Medicine Inova Fairfax Hospital Falls Church, VA Roberto G. Carbone, M.D. Respiratory Unit Regional Hospital Aosta, Italy
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References 1. Nathan SD, Noble PW, Tuder RM. Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med 2007;175:875–880. 2. Corte TJ, Keir GJ, Dimopoulos K, Howard L, Corris PA, Parfitt L, Foley C, Yanez-Lopez M, Babalis D, Marino P, et al. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2014;190:207–216. 3. Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, Martinez FJ, Nathan SD, Wells AU, Collard HR, et al.; ARTEMIS-IPF Investigators. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med 2013;158: 641–649. 4. King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de Andrade JA, Stahler ¨ G, Leconte I, Roux S, Raghu G. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008;177:75–81. 5. Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J; MUSIC Study Group. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013;42: 1622–1632. 6. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW; Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363:620–628. 7. Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ; IPFnet Investigators. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013;143: 1699–1708. 8. Corte TJ, Wort SJ, Gatzoulis MA, Macdonald P, Hansell DM, Wells AU. Pulmonary vascular resistance predicts early mortality in patients with diffuse fibrotic lung disease and suspected pulmonary hypertension. Thorax 2009;64:883–888. 9. Carbone RG, Monselise A, Bottino G. Pulmonary hypertension in interstitial lung disease. In: Baughman RP, Carbone RG, Bottino G, editors. Pulmonary arterial hypertension and interstitial lung diseases: a clinical guide. New York: Springer; 2009. pp. 13–50. 10. Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, Halpern SD. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012; 126:349–356. 11. Fritz JS, Blair C, Oudiz RJ, Dufton C, Olschewski H, Despain D, Gillies H, Kawut SM. Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest 2013;143:315–323. 12. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, et al.; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370: 2083–2092. 13. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, et al.; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071–2082. 14. Nathan SD, Meyer KC. IPF clinical trial design and endpoints. Curr Opin Pulm Med (In press) 15. King TE Jr, Albera C, Bradford WZ, Costabel U, du Bois RM, Leff JA, Nathan SD, Sahn SA, Valeyre D, Noble PW. All-cause mortality rate in patients with idiopathic pulmonary fibrosis: implications for the design and execution of clinical trials. Am J Respir Crit Care Med 2014;189:825–831.
Copyright © 2014 by the American Thoracic Society
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 2 | July 15 2014
