{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T10:52:33Z","timestamp":1794135153406,"version":"4.8.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction \u226540%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan\/placebo], 1.02 [90% CI, 0.88\u20131.19];\n                      <jats:italic>P<\/jats:italic>\n                      =0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, \u22123.5 [90% CI, \u22128.2 to +1.2];\n                      <jats:italic>P<\/jats:italic>\n                      =0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83\u20132.67];\n                      <jats:italic>P<\/jats:italic>\n                      =0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved\/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>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 identifiers: NCT03153111 and NCT03714815.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.123.011381","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T05:01:49Z","timestamp":1741669309000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Macitentan for Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Pulmonary Vascular Disease: Results of the SERENADE Randomized Clinical Trial and Open-Label Extension Study"],"prefix":"10.1161","volume":"18","clinical-trial-number":[{"clinical-trial-number":"nct03153111","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03714815","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5655-8201","authenticated-orcid":true,"given":"Sanjiv J.","family":"Shah","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6885-5924","authenticated-orcid":true,"given":"Diana","family":"Bonderman","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Favoriten Clinic, Wiener Gesundheitsverbund, Vienna, Austria (D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-0596","authenticated-orcid":true,"given":"Barry A.","family":"Borlaug","sequence":"additional","affiliation":[{"name":"Division of Circulatory Failure, Department of Cardiovascular Disease, Mayo Clinic and Foundation, Rochester, MN (B.A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1471-7016","authenticated-orcid":true,"given":"John G.F.","family":"Cleland","sequence":"additional","affiliation":[{"name":"British Hearth Foundation Centre of Research Excellence, School of Cardiovascular &amp; Metabolic Health, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (J.G.F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Lack","sequence":"additional","affiliation":[{"name":"R&amp;D Cardiopulmonary Clinical Sciences, Johnson &amp; Johnson, Allschwil, Switzerland (G.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Lu","sequence":"additional","affiliation":[{"name":"Statistics &amp; Decision Sciences, Johnson &amp; Johnson, Raritan, NJ (W.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5417-4415","authenticated-orcid":true,"given":"Adriaan A.","family":"Voors","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Center Groningen, the Netherlands (A.A.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1570","authenticated-orcid":true,"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, Inserm Centre d\u2019Investigations Cliniques Plurith\u00e9matique 1433 and CHRU, Nancy, France (F.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7267-9006","authenticated-orcid":true,"given":"Mark T.","family":"Gladwin","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Maryland School of Medicine, Baltimore (M.T.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-015-9523-6"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2014.12.028"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.11.051"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz626"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2018.0128"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001079"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.319967"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac184"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy331"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccm.2020.11.002"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2004.05.006"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2017.02.021"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2013.12.002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01886-2017"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.113.000359"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2017.3983"},{"key":"e_1_3_3_18_2","first-page":"1259","article-title":"Defining accelerometer thresholds for activity intensities in adolescent girls.","volume":"36","author":"Treuth MS","year":"2004","unstructured":"Treuth MS, Schmitz K, Catellier DJ, McMurray RG, Murray DM, Almeida MJ, Going S, Norman JE, Pate R. 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