Combination therapy with oral treprostinil for pulmonary arterial hypertension: A double-blind placebo-controlled clinical trial
Journal
American Journal of Respiratory and Critical Care Medicine
Journal Volume
201
Journal Issue
6
Pages
707-717
Date Issued
2020
Author(s)
White R.J.
Jerjes-Sanchez C.
Meyer G.M.B.
Pulido T.
Sepulveda P.
Wang K.Y.
Gr?nig 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.
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.
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
Subjects
Clinical study; Combination therapy; Oral treprostinil; Pulmonary arterial hypertension; Sequential therapy
SDGs
Other Subjects
amino terminal pro brain natriuretic peptide; prostacyclin; treprostinil; antihypertensive agent; placebo; prostacyclin; treprostinil; adult; Article; combination drug therapy; controlled study; death; diarrhea; disease exacerbation; double blind procedure; drug efficacy; drug withdrawal; dyspnea; female; headache; hospitalization; human; influenza; lung artery pressure; lung wedge pressure; major clinical study; male; middle aged; monotherapy; mortality risk; multicenter study; nausea and vomiting; outcome assessment; priority journal; pulmonary hypertension; randomized controlled trial; tablet; treatment response; walking distance; adolescent; aged; clinical trial; oral drug administration; pulmonary hypertension; young adult; Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Epoprostenol; Female; Humans; Male; Middle Aged; Placebos; Pulmonary Arterial Hypertension; Young Adult
Publisher
American Thoracic Society
Type
journal article