{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T02:28:28Z","timestamp":1780367308087,"version":"3.54.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T00:00:00Z","timestamp":1593043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Biomedical Research Council Asian neTwork for Translational Research and Cardiovascular Trials","award":["SPF2014\/005"],"award-info":[{"award-number":["SPF2014\/005"]}]},{"name":"Biomedical Research Council Asian neTwork for Translational Research and Cardiovascular Trials","award":["SPF2014\/004"],"award-info":[{"award-number":["SPF2014\/004"]}]},{"name":"Biomedical Research Council Asian neTwork for Translational Research and Cardiovascular Trials","award":["SPF2014\/003"],"award-info":[{"award-number":["SPF2014\/003"]}]},{"name":"Boston Scientific Investigator Sponsored Research Program, National Medical Research Council of Singapore","award":["R-172-003-219-511"],"award-info":[{"award-number":["R-172-003-219-511"]}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["EudraCT 2010-020808-29"],"award-info":[{"award-number":["EudraCT 2010-020808-29"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FP7-242209-BIOSTAT-CHF"],"award-info":[{"award-number":["FP7-242209-BIOSTAT-CHF"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["EudraCT 2010\u2010020808\u201029"],"award-info":[{"award-number":["EudraCT 2010\u2010020808\u201029"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FP7\u2010242209\u2010BIOSTAT\u2010CHF"],"award-info":[{"award-number":["FP7\u2010242209\u2010BIOSTAT\u2010CHF"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Angiotensin-converting enzyme inhibitors (ACEi)\/angiotensin receptor blockers (ARB) and \u03b2-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi\/ARBs and \u03b2-blockers with all-cause mortality and its combination with hospitalization for HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>A total of 6787 HFrEF patients (mean age 62.6\u2009\u00b1\u200913.2\u2009years, 77.7% men, mean left ventricular ejection fraction 27.7\u2009\u00b1\u20097.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi\/ARB and \u03b2-blocker therapy, adjusted for<\/jats:p>\n                    <jats:p>indication bias. Only 14% (n = 981) patients achieved \u226550% GRTD for both ACEi\/ARB and \u03b2-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi\/ARB and \u03b2-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26\u20130.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating \u03b2-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25\u20130.63) than corresponding ACEi\/ARB up-titration (HR 0.75, 95% CI 0.53\u20131.07).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study shows that best outcomes were observed in patients attaining GRTD for both ACEi\/ARB and \u03b2-blockers, unfortunately this was rarely achieved. Achieving &amp;gt;50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating \u03b2-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi\/ARB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1869","type":"journal-article","created":{"date-parts":[[2020,6,25]],"date-time":"2020-06-25T08:24:10Z","timestamp":1593073450000},"page":"1472-1482","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Effects of Combined Renin\u2013Angiotensin\u2013Aldosterone System Inhibitor and Beta-Blocker Treatment on Outcomes in Heart Failure with Reduced Ejection Fraction: Insights from BIOSTAT-CHF and ASIAN-HF Registries"],"prefix":"10.1093","volume":"22","author":[{"given":"Wouter","family":"Ouwerkerk","sequence":"first","affiliation":[{"name":"National Heart Centre Singapore , Singapore ,","place":["Singapore"]},{"name":"Department of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiew-Hwa K.","family":"Teng","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore , Singapore ,","place":["Singapore"]},{"name":"School of Population and Global Health, University of Western Australia , Nedlands ,","place":["Australia"]},{"name":"Duke\u2013National University of Singapore Medical School , Singapore ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Tromp","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore , Singapore ,","place":["Singapore"]},{"name":"Duke\u2013National University of Singapore Medical School , Singapore ,","place":["Singapore"]},{"name":"Department of Cardiology, University of Groningen, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Ting","family":"Tay","sequence":"additional","affiliation":[{"name":"National Heart Centre Singapore , Singapore ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Cleland","sequence":"additional","affiliation":[{"name":"National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk J.","family":"van Veldhuisen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University of Groningen, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Dickstein","sequence":"additional","affiliation":[{"name":"University of Bergen , Bergen ,","place":["Norway"]},{"name":"Stavanger University Hospital , Stavanger ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leong L.","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital , Leicester ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chim C.","family":"Lang","sequence":"additional","affiliation":[{"name":"School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School , Dundee ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan D.","family":"Anker","sequence":"additional","affiliation":[{"name":"Division of Cardiology and Metabolism-Heart Failure, Cachexia & Sarcopenia; Department of Cardiology (CVK), Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charit\u00e9 University Medicine , Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Inserm CIC-P 1433, Universit\u00e9 de Lorraine, CHRU de Nancy, FCRIN INI-CRCT , Nancy ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Lieh","family":"Hung","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Brigham and Women\u2019s Hospital , Boston, MA ,","place":["USA"]},{"name":"Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital , Taipei ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitendra P.S.","family":"Sawhney","sequence":"additional","affiliation":[{"name":"Sir Gangaram Hospital , New Delhi ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Naik","sequence":"additional","affiliation":[{"name":"CIMS Hospital , Ahmedabad ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Tokyo Women\u2019s Medical University , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhisa","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School , Tokyo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurpreet Singh","family":"Wander","sequence":"additional","affiliation":[{"name":"Dayanand Medical College and Hospital , Ludhiana ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inder","family":"Anand","sequence":"additional","affiliation":[{"name":"Veterans Affairs Medical Center , Minneapolis, MN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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