TY - JOUR
T1 - Combination therapy with oral treprostinil for pulmonary arterial hypertension
T2 - a double-blind placebo-controlled clinical trial
AU - White, R. James
AU - Jerjes-Sanchez, Carlos
AU - Meyer, Gisela Martina Bohns
AU - Pulido, Tomas
AU - Sepulveda, Pablo
AU - Wang, Kuo Yang
AU - Grünig, Ekkehard
AU - Hiremath, Shirish
AU - Yu, Zaixin
AU - Gangcheng, Zhang
AU - Yip, Wei Luen James
AU - Zhang, Shuyang
AU - Khan, Akram
AU - Deng, C. Q.
AU - Grover, Rob
AU - Tapson, Victor F.
AU - FREEDOM-EV Investigators
AU - Svetliza, Graciela Noemi
AU - Lescano, Adrian Jose
AU - Bortman, Guillermo Roberto
AU - Diez, Fabian Antonio
AU - Botta, Christian Edgardo
AU - Fitzgerald, John
AU - Feenstra, Eelke
AU - Kermeen, Fiona Dawn
AU - Keogh, Anne Margaret
AU - Williams, Trevor John
AU - Yousseff, Peter Paul
AU - Ng, Benjamin Joh Han
AU - McNaughton Smallwood, David
AU - Dwyer, Nathan Brent
AU - Brown, Martin Russell
AU - Lang, Irene M.
AU - Steringer-Mascherbauer, Regina
AU - Arakaki, Jaquelina Ota
AU - Campos, Frederico
AU - De Amorim Correa, Ricardo
AU - De Souza, Rogerio
AU - Moreira, Maria Carmo
AU - Yoo, Hugo
AU - Lapa, Monica Silveira
AU - Swiston, John
AU - Hirani, Naushad
AU - Mehta, Sanjay
AU - Michelakis, Evangelos
AU - Zagolin, Monica
AU - Liu, Jimming
AU - Pan, Lei
AU - Chunde, Bao
AU - Qun, Yi
AU - Xiaoshu, Cheng
AU - Li, Xinli
AU - Hua, Yao
AU - Zhu, Xianyang
AU - Chen, Yundai
AU - Zhaozhong, Cheng
AU - Yang, Yuanhua
AU - Zhou, Daxin
AU - Jieyan, Shen
AU - Nielsen-Kudsk, Jens Erik
AU - Carlsen, Jorn
AU - Bourdin, Arnaud
AU - Hachulla, Eric
AU - Dromer, Claire
AU - Chaouat, Ari
AU - Reynaud-Gauber, Martine
AU - Seronde, Marie-France
AU - Klose, Hans
AU - Halank, Michael
AU - Hoffken, Gert
AU - Ewert, Ralf
AU - Rosenkranz, Stephan
AU - Kruger, Ulrich
AU - Kronsbein, Juliane
AU - Hauptmeier, Barbara Monika
AU - Koch, Andrea
AU - Held, Matthias
AU - Lange, Tobias Johannes
AU - Neurohr, Claus
AU - Wilkens, Heinrike
AU - Wirtz, Hubert
AU - Konstantinides, Stavros
AU - Argyropoulou-Pataka, Paraskevi
AU - Orfanos, Stylianos
AU - Kerkar, Prafulla Gopinath
AU - Suresh, Pujar Venkateshacharya
AU - Baxi, Hemang Ashwinkumar
AU - Oomman, Abraham
AU - Abhaichand, Rajpal Kanaklal
AU - Edla Kumar, P. K.
AU - Chopra, Vijay
AU - Mehrotra, Rahul
AU - Rajput, Rajeev Kumar
AU - Sawhney, Jitendra Singh
AU - Bimalendu, Subir
AU - Sharma, Kamal Harishchandra
AU - Srinivasa Sastry, B. K.
AU - Kramer, Mordechai Reuben
AU - Segel, Michael Jonathan
AU - Ben-Dov, Issahar
AU - Berkman, Neville
AU - Yigla, Mordechai
AU - Adir, Yochai
AU - D'Alto, Michael
AU - Vizza, Carmine Dario
AU - Scelsi, Laura
AU - Vitulo, Patrizio
AU - Boonstra, Anko
AU - Vonk, Madelon Clementina
AU - Sobkowicz, Bozena
AU - Mularek-Kubzdela, Tatiana
AU - Torbicki, Adam
AU - Podolec, Piotr
AU - Teik, Lim Soo
AU - Chang, Hyuk-Jae
AU - Kim, Hyung-Kwan
AU - Park, Jun-Bean
AU - Chang, Sung A.
AU - Kim, Duk Kyung
AU - Chung, Wook Jin
AU - Song, Jong Min
AU - Nissell, Magnus
AU - Hjalmarsson, Clara
AU - Rundqvist, Bengt
AU - Huang, Wei-Chun
AU - Cheng, Chin-Chang
AU - Hsu, Chih-Hsin
AU - Hsu, Hsao-Hsun
AU - Coghlan, John Gerard
AU - Kiely, David Gerard
AU - Pepke-Zaba, Joanna Wanda
AU - Lordan, James Lawrence
AU - Corris, Paul Anthony
AU - Cadaret, Linda
AU - Hansdottir, Sif
AU - Oudiz, Ronald Jack
AU - Badesch, David B.
AU - Mathier, Michael
AU - Schilz, Robert
AU - Hill, Nicholas
AU - Waxman, Aaron
AU - Markin, Catherine J.
AU - Zwicke, Diane Lynn
AU - Fisher, Micah
AU - Franco, Veronica
AU - Sood, Namita
AU - Park, Myung H.
AU - Allen, Roblee
AU - Feldman, Jeremy P.
AU - Balasubramanian, Vijay
AU - Seeram, Vandana Kavita
AU - Bajwa, Abubakr
AU - Thompson, Austin B.
AU - Migliore, Christina
AU - Elwing, Jean
AU - McConnell, John W.
AU - Mehta, Jinesh P.
AU - Rahaghi, Franck Farzad
AU - Rame, J. Eduardo
AU - Patel, Bela
AU - Oren, Ron M.
AU - Klinger, James R.
AU - Alnuaimat, Hassan
AU - Allen, Samuel
AU - Harvey, William
AU - Eggert, Michael S.
AU - Hage, Antoine
AU - Miller, Chad E.
AU - Awdish, Rana
AU - Cajigas, Hector
AU - Grinnan, Daniel
AU - Trichon, Benjamin Howard
AU - McDonough, Clark
AU - Rischard, Franz
N1 - Copyright the American Thoracic Society 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: 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. Methods: 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. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.
AB - Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: 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. Methods: 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. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.
KW - Clinical study
KW - Combination therapy
KW - Oral treprostinil
KW - Pulmonary arterial hypertension
KW - Sequential therapy
UR - http://www.scopus.com/inward/record.url?scp=85081891528&partnerID=8YFLogxK
U2 - 10.1164/rccm.201908-1640OC
DO - 10.1164/rccm.201908-1640OC
M3 - Article
C2 - 31765604
AN - SCOPUS:85081891528
SN - 1073-449X
VL - 201
SP - 707
EP - 717
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 6
ER -