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Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial

2019; American Thoracic Society; Volume: 201; Issue: 6 Linguagem: Inglês

10.1164/rccm.201908-1640oc

1535-4970

R. James White, Carlos Jerjes‐Sánchez, G. Meyer, Tomás Pulido, Pablo Sepúlveda, Kuo Yang Wang, Ekkehard Grünig, Shirish Hiremath, Zaixin Yu, Gangcheng Zhang, Wei Luen James Yip, Shuyang Zhang, Akram Khan, C. Q. Deng, R. Grover, Victor F. Tapson, Graciela Svetliza, Adrián Lescano, Guillermo Bortman, Fabián Diez, Christian Edgardo Botta, John E. Fitzgerald, Eelke Feenstra, F. Kermeen, Anne Keogh, Trevor J. Williams, Peter Paul Yousseff, Benjamin Ng, David M. Smallwood, Nathan Dwyer, M. Brown, Iréne Lang, Regina Steringer‐Mascherbauer, Jaquelina Sonoe Ota Arakaki, Frederico Thadeu Assis Figueiredo Campos, Ricardo de Amorim Corrêa, Rogério Souza, G. Meyer, Maria Auxiliadora Carmo Moreira, Hugo Hyung Bok Yoo, Mônica Silveira Lapa, John R. Swiston, Naushad Hirani, Sanjay Mehta, Evangelos D. Michelakis, Pablo Sepúlveda, Monica Maria Zagolin Blancaire, Jimming Liu, Shuyang Zhang, Lei Pan, Chunde Bao, Qun Yi, Xiaoshu Cheng, Yu Zaixin, Xinli Li, Hua Yao, Gangcheng Zhang, Xianyang Zhu, Yundai Chen, Zhaozhong Cheng, Yuanhua Yang, Zhou Daxin, Jie-yan Shen, Jens Erik Nielsen‐Kudsk, Jørn Carlsen, Arnaud Bourdin, É. Hachulla, Claire Dromer, Ari Chaouat, Martine Reynaud-Gauber, Marie‐France Seronde, Hans Klose, Michael Halank, G. Höffken, Ralf Ewert, Stephan Rosenkranz, Ekkehard Grünig, Ulrich Krüger, Juliane Kronsbein, B. Hauptmeier, Andrea Koch, Matthias Held, Tobias Lange, C Neurohr, Heinrike Wilkens, Hubert Wirtz, Stavros Konstantinides, Paraskevi Argyropoulou-Pataka, Stylianos E. Orfanos, Shirish Hiremath, Prafulla Kerkar, Pujar Venkateshacharya Suresh, Hemang Baxi, Abraham Oomman, Rajpal K. Abhaichand, Padma Kumar Edla Arjun, Vijay Chopra, Rahul Mehrotra, Rajeev Kumar Rajput, J.P.S. Sawhney, Subir Bimalendu, Kamal Sharma, B.K.S. Sastry, Mordechai R. Kramer, Michael J. Segel, Issahar Ben-Dov, Neville Berkman, Mordechai Yigla, Yochai Adir, Michael D’Alto, Carmine Dario Vizza, Laura Scelsi, Patrizio Vitulo, Tomas Rene Pulido, Carlos Jerjes‐Sánchez, Anko Boonstra, Madelon C Vonk, Bożena Sobkowicz, Tatiana Mularek‐Kubzdela, Adam Torbicki, Piotr Podolec, Lim Soo Teik, Wei Luen James Yip, Hyuk‐Jae Chang, Hyung‐Kwan Kim, Jun‐Bean Park, Sung‐A Chang, Duk‐Kyung Kim, Sung‐A Chang, Wook‐Jin Chung, Jong‐Min Song, Magnus Nissell, Clara Hjalmarsson, Bengt Rundqvist, Wei‐Chun Huang, Chin-Chang Cheng, Chih‐Hsin Hsu, Hsao‐Hsun Hsu, Kuo‐Yang Wang, John Gerard Coghlan, David G. Kiely, Joanna Wanda Pepke-Zaba, James Lawrence Lordan, Paul A. Corris, Linda Cadaret, Sif Hansdóttir, Ronald J. Oudiz, David B. Badesch, Michael A. Mathier, Robert Schilz, Nicholas S. Hill, Aaron B. Waxman, Catherine J. Markin, Diane Lynn Zwicke, Micah R. Fisher, Verónica Franco, Namita Sood, Myung H. Park, Roblee P. Allen, J.P. Feldman, Vijay Balasubramanian, Vandana Seeram, Abubakr Bajwa, Austin B. Thompson, Christina Migliore, Jean Elwing, John W. McConnell, J.P. Mehta, Franck Rahaghi, J. Eduardo Rame, Akram Khan, Bela Patel, Ron M. Oren, James R. Klinger, Hassan Alnuaimat, Samuel H. Allen, William T. Harvey, Michael Eggert, A. Hage, Chad E. Miller, Rana Awdish, Héctor Cajigas, Daniel Grinnan, Benjamin H. Trichon, Clark McDonough, R. James White, Franz Rischard,

Cardiovascular Issues in Pregnancy

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.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).