Combination therapy with oral treprostinil for pulmonary arterial hypertension: A double-blind placebo-controlled clinical trial
- Authors
- White R.J.; Jerjes-Sanchez C.; Meyer G.M.B.; Pulido T.; Sepulveda P.; Wang K.Y.; Grünig E.; Hiremath S.; Yu Z.; Zhang G.; Yip W.L.J.; Zhang S.; Khan A.; Deng C.Q.; Grover R.; Tapson V.F.; Svetliza G.N.; Lescano A.J.; Bortman G.R.; Diez F.A.; Botta C.E.; Fitzgerald J.; Feenstra E.; Kermeen F.D.; Keogh A.M.; Williams T.J.; Yousseff P.P.; Ng B.J.-H.; Smallwood D.M.; Dwyer N.B.; Brown M.R.; Lang I.M.; Steringer-Mascherbauer R.; Arakaki J.O.; Campos F.; De Amorim Correa R.; De Souza R.; Meyer G.M.B.; Moreira M.C.; Yoo H.; Lapa M.S.; Swiston J.; Hirani N.; Mehta S.; Michelakis E.; Sepulveda P.; Zagolin M.; Liu J.; Zhang S.; Pan L.; Chunde B.; Qun Y.; Cheng X.; Yu Z.; Li X.; Hua Y.; Zhang G.; Zhu X.; Chen Y.; Cheng Z.; Yang Y.; Zhou D.; Shen J.; Nielsen-Kudsk J.E.; Carlsen J.; Bourdin A.; Hachulla E.; Dromer C.; Chaouat A.; Reynaud-Gauber M.; Seronde M.-F.; Klose H.; Halank M.; Hoffken G.; Ewert R.; Rosenkranz S.; Grunig E.; Kruger U.; Kronsbein J.; Hauptmeier B.M.; Koch A.; Held M.; Lange T.J.; Neurohr C.; Wilkens H.; Wirtz H.; Konstantinides S.; Argyropoulou-Pataka P.; Orfanos S.; Hiremath S.; Kerkar P.G.; Suresh P.V.; Baxi H.A.; Oomman A.; Abhaichand R.K.; Edla Kumar P.K.; Chopra V.; Mehrotra R.; Rajput R.K.; Sawhney J.S.; Bimalendu S.; Sharma K.H.; Srinivasa Sastry B.K.; Kramer M.R.; Segel M.J.; Ben-Dov I.; Berkman N.; Yigla M.; Adir Y.; D'Alto M.; Vizza C.D.; Scelsi L.; Vitulo P.; Pulido T.R.; Jerjes-Sanchez C.; Boonstra A.; Vonk M.C.; Sobkowicz B.; Mularek-Kubzdela T.; Torbicki A.; Podolec P.; Teik L.S.; Yip W.L.J.; Chang H.-J.; Kim H.-K.; Park J.-B.; Chang S.-A.; Kim D.-K.; Chung W.-J.; Song J.-M.; Nissell M.; Hjalmarsson C.; Rundqvist B.; Huang W.-C.; Cheng C.-C.; Hsu C.-H.; Hsu H.-H.; Wang K.-Y.; Coghlan J.G.; Kiely D.G.; Pepke-Zaba J.W.; Lordan J.L.; Corris P.A.; Cadaret L.; Hansdottir S.; Oudiz R.J.; Badesch D.B.; Mathier M.; Schilz R.; Hill N.; Waxman A.; Markin C.J.; Zwicke D.L.; Fisher M.; Franco V.; Sood N.; Park M.H.; Allen R.; Feldman J.P.; Balasubramanian V.; Seeram V.K.; Bajwa A.; Thompson A.B. III; Migliore C.; Elwing J.; McConnell J.W.; Mehta J.P.; Rahaghi F.F.; Rame J.E.; Khan A.; Patel B.; Oren R.M.; Klinger J.R.; Alnuaimat H.; Allen S.; Harvey W.; Eggert M.S.; Hage A.; Miller C.E.; Awdish R.; Cajigas H.; Grinnan D.; Trichon B.H.; McDonough C.; White R.J.; Rischard F.
- Issue Date
- Mar-2020
- Publisher
- American Thoracic Society
- Keywords
- Clinical study; Combination therapy; Oral treprostinil; Pulmonary arterial hypertension; Sequential therapy
- Citation
- American Journal of Respiratory and Critical Care Medicine, v.201, no.6, pp.707 - 717
- Journal Title
- American Journal of Respiratory and Critical Care Medicine
- Volume
- 201
- Number
- 6
- Start Page
- 707
- End Page
- 717
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/78877
- DOI
- 10.1164/rccm.201908-1640OC
- ISSN
- 1073-449X
- 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. Copyright © 2020 by the American Thoracic Society
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