{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:57:56Z","timestamp":1790834276308,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":2194,"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":[[2020,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56\u20130.97; P\u2009=\u20090.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro\u2013brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil\u2013assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12\u201360. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT01560624).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201908-1640oc","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T17:19:48Z","timestamp":1574702388000},"page":"707-717","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":148,"title":["Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial"],"prefix":"10.1093","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1399-5206","authenticated-orcid":false,"given":"R. James","family":"White","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine and the Mary M. Parkes Center, University of Rochester Medical Center, Rochester, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Jerjes-Sanchez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Cl\u00ednica en Medicina, Monterrey, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela Martina","family":"Bohns Meyer","sequence":"additional","affiliation":[{"name":"Complexo Hospitalar Santa Casa de Porto Alegre, Porto Alegre, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Pulido","sequence":"additional","affiliation":[{"name":"Departamento de Cardioneumolog\u00eda, Instituto Nacional de Cardiolog\u00eda Ignacio Ch\u00e1vez, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Sepulveda","sequence":"additional","affiliation":[{"name":"Pontifica Universidad Cat\u00f3lica de Chile, Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Taichung Veterans General Hospital, Taichung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekkehard","family":"Gr\u00fcnig","sequence":"additional","affiliation":[{"name":"Thoraxclinic at University Hospital Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirish","family":"Hiremath","sequence":"additional","affiliation":[{"name":"Ruby Hall Clinic, Grant Medical Foundation, Pune, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaixin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xiangya Hospital of Central South University, Changsha, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Gangcheng","sequence":"additional","affiliation":[{"name":"Wuhan Asia Heart Hospital, Wuhan Shi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei Luen James","family":"Yip","sequence":"additional","affiliation":[{"name":"Department of Cardiology, National University Heart Centre, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Peking Union Medical College Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akram","family":"Khan","sequence":"additional","affiliation":[{"name":"Oregon Health and Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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