TY - JOUR
T1 - Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis
T2 - Dual-1 and Dual-2 randomized clinical trials
AU - DUAL-1 and DUAL-2 Investigators
AU - Khanna, Dinesh
AU - Denton, Christopher P.
AU - Merkel, Peter A.
AU - Krieg, Thomas M.
AU - Le Brun, Franck Olivier
AU - Marr, Angelina
AU - Papadakis, Kelly
AU - Pope, Janet
AU - Matucci-Cerinic, Marco
AU - Furst, Daniel E.
AU - Zochling, Jane
AU - Stevens, Wendy
AU - Proudman, Susanna
AU - Feenstra, John
AU - Youssef, Peter
AU - Soroka, Nikolay
AU - Tyabut, Tamara
AU - Mikhailova, Elena Ivanovna
AU - Rashkov, Rasho
AU - Batalov, Anastas
AU - Yablanski, Kiril
AU - Keystone, Edward
AU - Jones, Niall
AU - Dunne, James
AU - Masetto, Ariel
AU - Calabresse, Renato Jiménez
AU - Cabezas, Pedro Claudio Miranda
AU - Silva, Marta Ofelia Aliste
AU - Sariego, Imgadt Annelise Goecke
AU - Escalente, William José Otero
AU - Anić, Branimir
AU - Kaliterna, Dušanka Martinović
AU - Morović-Vergles, Jadranka
AU - Novak, Srdan
AU - Prus, Višnja
AU - Artuković, Marinko
AU - Soukup, Tomaáš
AU - Bečvař, Radim
AU - Fojtík, Zdeněk
AU - Mouthon, Luc
AU - Kollert, Florian
AU - Riemekasten, Gabriela
AU - Lahner, Nina
AU - Fierlbeck, Gerhard
AU - Ahmadi-Simab, Keihan
AU - Diehm, Curt
AU - Szücs, Gabriella
AU - Kumánovics, Gábor
AU - Nagy, György
AU - Velásquez-Franco, Carlos Jaime
N1 - Publisher Copyright:
Copyright © 2016 American Medical Association. All rights reserved.
PY - 2016/5/10
Y1 - 2016/5/10
N2 - Importance: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. Objective: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. Design, Setting, And Participants: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. Interventions: Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or >3). Main Outcomes and Measures: The primary outcome for each trialwas the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. Results: In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. Conclusions and Relevance: Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.
AB - Importance: Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. Objective: To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. Design, Setting, And Participants: Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. Interventions: Patients were randomized (1:1:1) to receive oral doses of 3 mg of macitentan, 10 mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (≤3 or >3). Main Outcomes and Measures: The primary outcome for each trialwas the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. Results: In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10 mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3 mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. Conclusions and Relevance: Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population.
UR - http://www.scopus.com/inward/record.url?scp=84968808222&partnerID=8YFLogxK
U2 - 10.1001/jama.2016.5258
DO - 10.1001/jama.2016.5258
M3 - Artículo en revista científica indexada
C2 - 27163986
AN - SCOPUS:84968808222
SN - 0098-7484
VL - 315
SP - 1975
EP - 1988
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 18
ER -