{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:10:38Z","timestamp":1788387038754,"version":"build-2803163510"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":2285,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>In the INSTAGE trial in patients with idiopathic pulmonary fibrosis (IPF) and severely impaired gas exchange, nintedanib plus sildenafil was associated with numerical benefits on St. George\u2019s Respiratory Questionnaire (SGRQ) total score, brain natriuretic peptide (BNP), and FVC decline versus nintedanib alone. Exploratory analyses of the STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial suggested that sildenafil may have a greater effect on SGRQ score in patients with IPF who have right heart dysfunction (RHD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Assess whether RHD influenced the effects of nintedanib plus sildenafil versus nintedanib alone in the INSTAGE trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Subgroup analyses of patients with (n\u2009=\u2009117) versus those without (n\u2009=\u2009156) echocardiographic signs of RHD at baseline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>There was no heterogeneity between subgroups by presence of RHD in the effect of nintedanib plus sildenafil versus nintedanib alone on change in SGRQ total score at Week 12 (P\u2009=\u20090.74) or Week 24 (P\u2009=\u20090.90), or change in FVC at Week 12 (P\u2009=\u20090.58) or Week 24 (P\u2009=\u20090.55). In both subgroups, nintedanib plus sildenafil had a numerically greater effect on reducing FVC decline versus nintedanib alone. Between-group differences in change in BNP at Week 24 were \u2212119.9 ng\/L (95% confidence interval\u2009=\u2009\u2212171.3 to \u221268.5) and \u22123.6 ng\/L (95% confidence interval\u2009=\u2009\u221247.2 to 40.0) in patients with and without signs of RHD at baseline, respectively (P\u2009&amp;lt;\u20090.01).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In the INSTAGE trial, there were no significant differences in the effects of nintedanib plus sildenafil versus nintedanib alone on changes in SGRQ and FVC between patients with or without echocardiographic signs of RHD at baseline. The benefit of combination therapy on stabilizing BNP was more pronounced in patients with RHD at baseline.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT02802345).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201903-0488oc","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T17:55:06Z","timestamp":1564595706000},"page":"1505-1512","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":61,"title":["Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction. A Prespecified Subgroup Analysis of a Double-Blind Randomized Clinical Trial (INSTAGE)"],"prefix":"10.1093","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9151-4829","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Behr","sequence":"first","affiliation":[{"name":"Department of Internal Medicine V, University of Munich, LMU, and Asklepios Chest Clinic Gauting, Memeber of the German Center for Lung Research, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Kolb","sequence":"additional","affiliation":[{"name":"McMaster University and St. Joseph\u2019s Healthcare, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5121-3522","authenticated-orcid":false,"given":"Jin Woo","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Luppi","sequence":"additional","affiliation":[{"name":"University of Milan Bicocca, San Gerardo Hospital, Azienda Socio Sanitaria Territoriale Monza, Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Schinzel","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Stowasser","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Quaresma","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando J.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Weill Cornell Medicine, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,12,15]]},"reference":[{"key":"2026030321303812900_bib1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s12931-017-0621-y","article-title":"Health related quality of life in patients with idiopathic pulmonary fibrosis in clinical practice: insights\u2014IPF registry","volume":"18","author":"Kreuter","year":"2017","journal-title":"Respir Res"},{"key":"2026030321303812900_bib2","doi-asserted-by":"crossref","first-page":"e44","DOI":"10.1164\/rccm.201807-1255ST","article-title":"Diagnosis of idiopathic pulmonary fibrosis: an official ATS\/ERS\/JRS\/ALAT clinical practice guideline","volume":"198","author":"Raghu","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030321303812900_bib3","first-page":"797","article-title":"Idiopathic pulmonary fibrosis","volume":"379","author":"Lederer","year":"2018","journal-title":"N Engl J Med"},{"key":"2026030321303812900_bib4","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s12916-015-0412-6","article-title":"Why do patients get idiopathic pulmonary fibrosis? 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