{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T19:27:25Z","timestamp":1787686045338,"version":"build-2784847793"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":1205,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anaemia; however, no study has evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF). This study was designed to evaluate the safety and efficacy of daprodustat, a HIF-PH inhibitor, in patients with HF and renal anaemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We designed a pilot, multi-centre, open-label, randomized controlled study, in which 50 patients with HF complicated with chronic kidney disease and anaemia will be randomized 1:1 to either the daprodustat or control group at seven sites in Japan. Study entry requires New York Heart Association Class II HF symptoms or a history of hospitalization due to HF, an estimated glomerular filtration rate of &amp;lt;60 mL\/min\/1.73 m2, and a haemoglobin level of 7.5 to &amp;lt;11.0 g\/dl. Patients randomized to the daprodustat group will be treated with oral daprodustat, and the dose will be uptitrated according to the changes in the haemoglobin level from previous visits. In this study, we will evaluate the impact of HIF-PH inhibitors on cardiac function using advanced cardiovascular imaging modalities, including cardiac magnetic resonance imaging. The primary outcome is the haemoglobin level at 16 weeks of randomization, and all adverse events will be recorded and evaluated for any association with daprodustat treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Considering the hypothetical upside and downside of using HIF-PH inhibitors in anaemic patients with HF and chronic kidney disease, and because there are virtually no safe and effective treatments for patients with anaemia not caused by iron deficiency, our study results will contribute significantly to this field.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.14109","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T02:29:41Z","timestamp":1660876181000},"page":"4291-4297","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Daprodustat for Anaemia in Patients with Heart Failure and Chronic Kidney Disease: A Randomized Controlled Study"],"prefix":"10.1093","volume":"9","author":[{"given":"Takashi","family":"Iso","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2456-8525","authenticated-orcid":false,"given":"Yuya","family":"Matsue","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Mizukami","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Kameda Medical Center , Kamogawa ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Tokano","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Juntendo University Urayasu Hospital , Urayasu ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kikuo","family":"Isoda","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Juntendo University Nerima Hospital , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Suwa","sequence":"additional","affiliation":[{"name":"Department of Acute Critical Care Medicine, Shizuoka Hospital, Juntendo University , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsumi","family":"Miyauchi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Juntendo Tokyo Koto Geriatric Medical Center , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naotake","family":"Yanagisawa","sequence":"additional","affiliation":[{"name":"Medical Technology Innovation Center, Juntendo University , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Okumura","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Nihon University School of Medicine , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Minamino","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine , Tokyo ,","place":["Japan"]},{"name":"Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,18]]},"reference":[{"key":"2026012114135413400_ehf214109-bib-0001","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jchf.2017.08.023","article-title":"Anemia in heart failure: Still relevant?","volume":"6","author":"Grote Beverborg","year":"2018","journal-title":"JACC Heart Fail"},{"key":"2026012114135413400_ehf214109-bib-0002","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1253\/circj.CJ-15-0174","article-title":"Prognostic impact of anemia in patients with chronic heart failure- with special reference to clinical background: Report from the CHART-2 study","volume":"79","author":"Yamauchi","year":"2015","journal-title":"Circ J"},{"key":"2026012114135413400_ehf214109-bib-0003","first-page":"568","article-title":"Association between anemia, clinical features and outcome in patients hospitalized for acute heart failure syndromes","volume":"4","author":"Kajimoto","year":"2015","journal-title":"Eur Heart J Acute Cardiovasc Care"},{"key":"2026012114135413400_ehf214109-bib-0004","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S0735-1097(01)01470-X","article-title":"Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction","volume":"38","author":"al-Ahmad","year":"2001","journal-title":"J Am Coll Cardiol"},{"key":"2026012114135413400_ehf214109-bib-0005","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1161\/CIRCULATIONAHA.107.698514","article-title":"Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia","volume":"117","author":"Ghali","year":"2008","journal-title":"Circulation"},{"key":"2026012114135413400_ehf214109-bib-0006","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1056\/NEJMoa1214865","article-title":"Treatment of anemia with darbepoetin alfa in systolic heart failure","volume":"368","author":"Swedberg","year":"2013","journal-title":"N Engl J Med"},{"key":"2026012114135413400_ehf214109-bib-0007","first-page":"5447","article-title":"A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation","volume":"12","author":"Semenza","year":"1992","journal-title":"Mol Cell Biol"},{"key":"2026012114135413400_ehf214109-bib-0008","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.kisu.2017.09.002","article-title":"New options for the anemia of chronic kidney disease","volume":"7","author":"Coyne","year":"2017","journal-title":"Kidney Int Suppl"},{"key":"2026012114135413400_ehf214109-bib-0009","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1681\/ASN.2015030241","article-title":"Roxadustat (FG-4592): Correction of anemia in incident dialysis patients","volume":"27","author":"Besarab","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"2026012114135413400_ehf214109-bib-0010","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.freeradbiomed.2018.06.025","article-title":"Misdistribution of iron and oxidative stress in chronic kidney disease","volume":"133","author":"Nakanishi","year":"2019","journal-title":"Free Radic Biol Med"},{"key":"2026012114135413400_ehf214109-bib-0011","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.cardfail.2014.01.008","article-title":"Inappropriate expression of hepcidin by liver congestion contributes to anemia and relative iron deficiency","volume":"20","author":"Suzuki","year":"2014","journal-title":"J Card Fail"},{"key":"2026012114135413400_ehf214109-bib-0012","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nature05602","article-title":"p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload","volume":"446","author":"Sano","year":"2007","journal-title":"Nature"},{"key":"2026012114135413400_ehf214109-bib-0013","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3389\/fmed.2019.00093","article-title":"Thin air, thick vessels: Historical and current perspectives on hypoxic pulmonary hypertension","volume":"6","author":"Young","year":"2019","journal-title":"Front Med (Lausanne)"},{"key":"2026012114135413400_ehf214109-bib-0014","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/s00109-017-1543-3","article-title":"Prolyl-hydroxylase inhibition induces SDF-1 associated with increased CXCR4+\/CD11b+ subpopulations and cardiac repair","volume":"95","author":"Ghadge","year":"2017","journal-title":"J Mol Med (Berl)"},{"key":"2026012114135413400_ehf214109-bib-0015","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1681\/ASN.2014111139","article-title":"Four-week studies of Oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia","volume":"27","author":"Holdstock","year":"2016","journal-title":"J Am Soc Nephrol"},{"key":"2026012114135413400_ehf214109-bib-0016","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ijcard.2021.06.041","article-title":"Clinical and prognostic values of urinary alpha1-microglobulin as a tubular marker in acute heart failure","volume":"338","author":"Ishiwata","year":"2021","journal-title":"Int J Cardiol"},{"key":"2026012114135413400_ehf214109-bib-0017","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.jacc.2008.04.044","article-title":"Anemia and chronic heart failure implications and treatment options","volume":"52","author":"Anand","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2026012114135413400_ehf214109-bib-0018","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s10741-008-9089-7","article-title":"The prevalence of anemia in chronic heart failure and its impact on the clinical outcomes","volume":"13","author":"Tang","year":"2008","journal-title":"Heart Fail Rev"},{"key":"2026012114135413400_ehf214109-bib-0019","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.cardfail.2004.03.003","article-title":"Impact of congestive heart failure, chronic kidney disease, and anemia on survival in the Medicare population","volume":"10","author":"Herzog","year":"2004","journal-title":"J Card Fail"},{"key":"2026012114135413400_ehf214109-bib-0020","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1253\/circj.CJ-19-0342","article-title":"JCS 2017\/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure- digest version","volume":"83","author":"Tsutsui","year":"2019","journal-title":"Circ J"},{"key":"2026012114135413400_ehf214109-bib-0021","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nrneph.2015.193","article-title":"HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond","volume":"12","author":"Maxwell","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"2026012114135413400_ehf214109-bib-0022","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/j.1744-9987.2012.01089.x","article-title":"Shortened red blood cell lifespan is related to the dose of erythropoiesis-stimulating agents requirement in patients on hemodialysis","volume":"16","author":"Sato","year":"2012","journal-title":"Ther Apher Dial"},{"key":"2026012114135413400_ehf214109-bib-0023","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.xkme.2020.05.001","article-title":"Inflammation and erythropoiesis-stimulating agent Hyporesponsiveness: A critical connection","volume":"2","author":"Shah","year":"2020","journal-title":"Kidney Med"},{"key":"2026012114135413400_ehf214109-bib-0024","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1056\/NEJMoa1005109","article-title":"Erythropoietic response and outcomes in kidney disease and type 2 diabetes","volume":"363","author":"Solomon","year":"2010","journal-title":"N Engl J Med"},{"key":"2026012114135413400_ehf214109-bib-0025","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1053\/j.ajkd.2007.09.015","article-title":"Exploring relative mortality and epoetin alfa dose among hemodialysis patients","volume":"51","author":"Bradbury","year":"2008","journal-title":"Am J Kidney Dis"},{"key":"2026012114135413400_ehf214109-bib-0026","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.2215\/CJN.02380607","article-title":"Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets","volume":"2","author":"Fishbane","year":"2007","journal-title":"Clin J Am Soc Nephrol"},{"key":"2026012114135413400_ehf214109-bib-0027","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/ki.2008.295","article-title":"Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes","volume":"74","author":"Szczech","year":"2008","journal-title":"Kidney Int"},{"key":"2026012114135413400_ehf214109-bib-0028","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jacc.2004.03.052","article-title":"Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure","volume":"44","author":"van der Meer","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"2026012114135413400_ehf214109-bib-0029","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1056\/NEJMoa1813599","article-title":"Roxadustat for anemia in patients with kidney disease not receiving dialysis","volume":"381","author":"Chen","year":"2019","journal-title":"N Engl J Med"},{"key":"2026012114135413400_ehf214109-bib-0030","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1053\/j.ajkd.2015.06.030","article-title":"New treatment approaches for the anemia of CKD","volume":"67","author":"Bonomini","year":"2016","journal-title":"Am J Kidney Dis"},{"key":"2026012114135413400_ehf214109-bib-0031","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMoa1901713","article-title":"Roxadustat treatment for anemia in patients undergoing long-term dialysis","volume":"381","author":"Chen","year":"2019","journal-title":"N Engl J Med"},{"key":"2026012114135413400_ehf214109-bib-0032","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1001\/jama.2017.5427","article-title":"Effect of Oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: The IRONOUT HF randomized clinical trial","volume":"317","author":"Lewis","year":"2017","journal-title":"JAMA"},{"key":"2026012114135413400_ehf214109-bib-0033","first-page":"197","article-title":"Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: A historical overview and future perspectives","volume":"2","author":"Bishop","year":"2014","journal-title":"Hypoxia (Auckl)"},{"key":"2026012114135413400_ehf214109-bib-0034","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1038\/aps.2010.132","article-title":"Hypoxia inducible factor 1 (HIF-1) and cardioprotection","volume":"31","author":"Tekin","year":"2010","journal-title":"Acta Pharmacol Sin"},{"key":"2026012114135413400_ehf214109-bib-0035","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1161\/CIRCULATIONAHA.118.030099","article-title":"Anemia and iron deficiency in heart failure: Current concepts and emerging therapies","volume":"138","author":"Anand","year":"2018","journal-title":"Circulation"},{"key":"2026012114135413400_ehf214109-bib-0036","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1016\/j.jacc.2005.08.045","article-title":"Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse","volume":"46","author":"Kido","year":"2005","journal-title":"J Am Coll Cardiol"},{"key":"2026012114135413400_ehf214109-bib-0037","doi-asserted-by":"crossref","first-page":"S128","DOI":"10.1111\/1523-1747.ep12875018","article-title":"Abnormal cutaneous topobiology: The molecular basis for dermatopathologic mononuclear cell patterns in inflammatory skin disease","volume":"95","author":"Nickoloff","year":"1990","journal-title":"J Invest Dermatol"},{"key":"2026012114135413400_ehf214109-bib-0038","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1161\/CIRCULATIONAHA.109.922427","article-title":"Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy","volume":"122","author":"Moslehi","year":"2010","journal-title":"Circulation"}],"container-title":["ESC Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ehf2.14109","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ehf2.14109","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/9\/6\/4291\/65347738\/eschf_9_6_4291.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/9\/6\/4291\/65347738\/eschf_9_6_4291.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T19:16:05Z","timestamp":1769022965000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eschf\/article\/9\/6\/4291\/8322825"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,18]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,8,18]]},"published-print":{"date-parts":[[2022,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ehf2.14109","relation":{},"ISSN":["2055-5822"],"issn-type":[{"value":"2055-5822","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12]]},"published":{"date-parts":[[2022,8,18]]},"assertion":[{"value":"2022-05-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}