학술논문
Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial
Document Type
article
Author
White, R James; Jerjes-Sanchez, Carlos; Bohns Meyer, Gisela Martina; Pulido, Tomas; Sepulveda, Pablo; Wang, Kuo Yang; Grünig, Ekkehard; Hiremath, Shirish; Yu, Zaixin; Gangcheng, Zhang; Yip, Wei Luen James; Zhang, Shuyang; Khan, Akram; Deng, CQ; Grover, Rob; Tapson, Victor F; Svetliza, Graciela Noemi; Lescano, Adrian Jose; Bortman, Guillermo Roberto; Diez, Fabian Antonio; Botta, Christian Edgardo; Fitzgerald, John; Feenstra, Eelke; Kermeen, Fiona Dawn; Keogh, Anne Margaret; Williams, Trevor John; Yousseff, Peter Paul; Ng, Benjamin Joh-Han; Smallwood, David McNaughton; Dwyer, Nathan Brent; Brown, Martin Russell; Lang, Irene M; Steringer-Mascherbauer, Regina; Arakaki, Jaquelina Sonoe Ota; Campos, Frederico Thadeu Assis Figueiredo; de Amorim Correa, Ricardo; de Souza, Rogerio; Bohns Meyer, Gisela M; Moreira, Maria Auxiliadora Carmo; Yoo, Hugo Hyung Bok; Lapa, Monica Silveira; Swiston, John; Hirani, Naushad; Mehta, Sanjay; Michelakis, Evangelos; Sepulveda, Pablo Andres; Blancaire, Monica Maria Zagolin; Liu, Jimming; Shuyang, Zhang; Pan, Lei; Chunde, Bao; Qun, Yi; Xiaoshu, Cheng; Zaixin, Yu; Li, Xinli; Hua, Yao; Zhu, Xianyang; Chen, Yundai; Zhaozhong, Cheng; Yang, Yuanhua; Daxin, Zhou; Jieyan, Shen; Nielsen-Kudsk, Jens Erik; Carlsen, Jorn; Bourdin, Arnaud; Hachulla, Eric; Dromer, Claire; Chaouat, Ari; Reynaud-Gauber, Martine; Seronde, Marie-France; Klose, Hans; Halank, Michael; Hoffken, Gert; Ewert, Ralf; Rosenkranz, Stephan; Grunig, Ekkehard; Kruger, Ulrich; Kronsbein, Juliane; Hauptmeier, Barbara Monika; Koch, Andrea; Held, Matthias; Lange, Tobias Johannes; Neurohr, Claus; Wilkens, Heinrike; Wilhelm Wirtz, Hubert Rolf; Konstantinides, Stavros; Argyropoulou-Pataka, Paraskevi; Orfanos, Stylianos; Kerkar, Prafulla Gopinath; Suresh, Pujar Venkateshacharya; Baxi, Hemang Ashwinkumar; Oomman, Abraham; Abhaichand, Rajpal Kanaklal; Arjun, Padma Kumar Edla; Chopra, Vijay; Mehrotra, Rahul; Rajput, Rajeev Kumar; Sawhney, Jitendra Pal Singh
Source
American Journal of Respiratory and Critical Care Medicine. 201(6)
Subject
Language
Abstract
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).