{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:46:06Z","timestamp":1790858766449,"version":"4.1.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,1,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Patients with Eisenmenger syndrome aged \u226512 years and in World Health Organization functional class II\u2013III were randomized 1:1 to placebo or macitentan 10 mg once daily for 16 weeks. Patients with complex cardiac defects, Down syndrome and background PAH therapy were eligible. The primary end point was change from baseline to week 16 in 6-minute walk distance. Secondary end points included change from baseline to week 16 in World Health Organization functional class. Exploratory end points included NT-proBNP (N-terminal pro-B-type natriuretic peptide) at end of treatment expressed as a percentage of baseline. In a hemodynamic substudy, exploratory end points included pulmonary vascular resistance index (PVRi) at week 16 as a percentage of baseline.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Two hundred twenty six patients (macitentan n=114; placebo n=112) were randomized. At baseline, 60% of patients were in World Health Organization functional class II and 27% were receiving phosphodiesterase type-5 inhibitors. At week 16, the mean change from baseline in 6-minute walk distance was 18.3 m and 19.7 m in the macitentan and placebo groups (least-squares mean difference, -4.7 m; 95% confidence limit (CL), -22.8, 13.5;\n                      <jats:italic>P<\/jats:italic>\n                      =0.612). World Health Organization functional class improved from baseline to week 16 in 8.8% and 14.3% of patients in the macitentan and placebo groups (odds ratio, 0.53; 95% CL, 0.23, 1.24). NT-proBNP levels decreased with macitentan versus placebo (ratio of geometric means, 0.80; 95% CL, 0.68, 0.94). In the hemodynamic substudy (n=39 patients), macitentan decreased PVRi compared with placebo (ratio of geometric means, 0.87; 95% CL, 0.73, 1.03). The most common adverse events with macitentan versus placebo were headache (11.4 versus 4.5%) and upper respiratory tract infection (9.6 versus 6.3%); a hemoglobin decrease from baseline of \u22652 g\/dL occurred in 36.0% versus 8.9% of patients. Five patients (3 macitentan; 2 placebo) prematurely discontinued treatment and 1 patient died (macitentan group).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Macitentan did not show superiority over placebo on the primary end point of change from baseline to week 16 in exercise capacity in patients with Eisenmenger syndrome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n                      . Unique identifier: NCT01743001.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.118.033575","type":"journal-article","created":{"date-parts":[[2018,12,28]],"date-time":"2018-12-28T14:00:47Z","timestamp":1546005647000},"page":"51-63","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":112,"title":["Evaluation of Macitentan in Patients With Eisenmenger Syndrome"],"prefix":"10.1161","volume":"139","author":[{"given":"Michael A.","family":"Gatzoulis","sequence":"first","affiliation":[{"name":"The Royal Brompton Hospital and National Heart &amp; Lung Institute, Imperial College, London, United Kingdom (M.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Landzberg","sequence":"additional","affiliation":[{"name":"The Royal Brompton Hospital and National Heart &amp; Lung Institute, Imperial College, London, United Kingdom (M.A.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Beghetti","sequence":"additional","affiliation":[{"name":"Centre Universitaire de Cardiologie et Chirurgie Cardiaque P\u00e9diatrique, Congenital Heart Center (CHUV et HUG) H\u00f4pital des Enfants, University of Geneva and Lausanne, Geneva, Switzerland (M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf M.","family":"Berger","sequence":"additional","affiliation":[{"name":"Center for Congenital Heart Diseases, Department of Paediatric and Congenital Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands (R.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Efficace","sequence":"additional","affiliation":[{"name":"Actelion Pharmaceuticals Italia, Imperia, Italy (M.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Gesang","sequence":"additional","affiliation":[{"name":"Actelion Pharmaceuticals, Allschwil, Switzerland (S.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2019guo","family":"He","sequence":"additional","affiliation":[{"name":"Pulmonary Vascular Diseases Department, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Papadakis","sequence":"additional","affiliation":[{"name":"Actelion Clinical Research Inc, Cherry Hill, NJ (K.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Pulido","sequence":"additional","affiliation":[{"name":"Cardiopulmonary Department, Ignacio Ch\u00e1vez National Heart Institute, Mexico City, Mexico (T.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazzareno","family":"Gali\u00e8","sequence":"additional","affiliation":[{"name":"Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Italy (N.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"On behalf of the MAESTRO Study 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