학술논문
Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: Dual-1 and Dual-2 randomized clinical trials
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Electronic Resource
Author
Khanna, Dinesh; Denton, Christopher P.; Merkel, Peter A.; Krieg, Thomas M.; Le Brun, Franck Olivier; Marr, Angelina; Papadakis, Kelly; Pope, Janet; Matucci Cerinic, Marco; Furst, Daniel E.; Zochling, Jane; Stevens, Wendy; Proudman, Susanna; Feenstra, John; Youssef, Peter; Soroka, Nikolay; Tyabut, Tamara; Mikhailova, Elena Ivanovna; Rashkov, Rasho; Batalov, Anasta; Yablanski, Kiril; Keystone, Edward; Jones, Niall; Dunne, Jame; Masetto, Ariel; Calabresse, Renato Jiménez; Cabezas, Pedro Claudio Miranda; Silva, Marta Ofelia Aliste; Sariego, Imgadt Annelise Goecke; Escalente, William José Otero; Anić, Branimir; Kaliterna, Dušanka Martinović; Morović Vergles, Jadranka; Novak, Srdan; Prus, Višnja; Artuković, Marinko; Soukup, Tomaáš; Bečvař, Radim; Fojtík, Zdeněk; Mouthon, Luc; Kollert, Florian; Riemekasten, Gabriela; Lahner, Nina; Fierlbeck, Gerhard; Ahmadi Simab, Keihan; Diehm, Curt; Szücs, Gabriella; Kumánovics, Gábor; Nagy, György; Pal, Sarvajeet; Veeravalli, Sarath Chandra Mouli; Danda, Debashish; Ferri, Clodeveo; Cozzi, Franco; Ferraccioli, Gianfranco; Wiland, Piotr; Rudnicak, Lidia; Zwolak, Robert; Roszkiewicz, Jadwiga; Oleynikov, Valentin; Nikulenkova, Natalya; Lesnyak, Olga; Kaydashev, Igor; Kurytar, Oleksandr; Piura, Olena; Chopyak, Valentyna; Chatterjee, Soumya; Hsu, Vivien; Hummers, Laura; Martin, Richard; Domsic, Robyn; Schiopu, Elena; Shanahan, Joseph; Murphy, Frederik T.; Kaine, Jeffrey; Davis, William; Grau, Rafael; Eimon, Alicia; Catoggio, Luis Jose; Laborde, Hugo Armando; Caeiro, Francisco; Savio, Veronica Gabriela; Amitrano, Cristina Beatriz; Vanthuyne, Marie; Zeng, Xioafeng; Zhang, Xiao; Zhu, Ping; Velásquez Franco, Carlos Jaime; Choueka, Philippe Selim Chalem; Sanchez, Patricia Julieta Vélez; Hermann, Walter; Sticherling, Michael; Steinbrink, Kerstin; Hein, Rüdiger; Aschoff, Roland; Sfikakis, Petro; Settas, Luka; Fraser, Alexander; Veale, Dougla; Balbir Gurman, Alexandra; Lidar, Merav; Litinsky, Irena; Levy, Yair; Carrillo Vazquez, Sandra Miriam; Rodriguez Reyna, Tatiana; Medrano Ramirez, Gabriel; Morales Torres, Jorge; Pacheco Tena, Cesar Francisco; Sanchez Ortiz, Adriana; Vonk, Madelon C.; Stebbings, Simon; Solanki, Kamal; Steele, Richard; Ng, Kristine; Zubrzycka Sienkiewicz, Anna; Brzosko, Marek; Szepietowski, Jacek C.; Hrycaj, Pawel; Da Silva, Ivone Fernandes Santo; Dos Santos, Lelita Da Conceiçao; Coelho, Paulo Jorge Clemente; Rios, Grissel; Chernykh, Tatiana; Grunina, Elena; Stanislav, Marina; Ally, Mahmood; Kalla, Asgar; Birlik, Ahmet Merih; Kovalenko, Volodymyr; Petrov, Andriy; Shevchuk, Sergiy; Stanislavchuk, Mykola; Anderson, Marina; Herrick, Ariane; Belch, Jill; Chung, Lorinda; Csuka, Mary Ellen; Frech, Tracy; Goldberg, Avram; Kahaleh, Bashar; Mayes, Maureen D.; Rothfield, Naomi; Simms, Robert William; Spiera, Robert; Steen, Virgina; Varga, John; Sikes, David; Derk, Chris T.; Kohen, Michael D.; Ferraccioli, Gianfranco (ORCID:0000-0001-6246-2428)
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Abstract
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 macitenta