{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:03:34Z","timestamp":1768014214870,"version":"3.49.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T00:00:00Z","timestamp":1623888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European J of Heart Fail"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up\u2010titration of angiotensin\u2010converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi\/ARBs than men to achieve similar treatment benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high\u2010 vs. low\u2010dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66\u2009years and 30% of patients were women. Men appeared to have benefited more from high\u2010dose than from low\u2010dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high\u2010 vs. low\u2010dose losartan for the composite outcome of all\u2010cause death or all\u2010cause hospitalization: 0.89 (0.81\u20130.98) in men and 1.10 (0.95\u20131.28) in women; interaction\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u20090.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III\/IV, and estimated glomerular filtration rate &lt;60\u2009mL\/min. Patients with these features had a poorer response to high\u2010dose losartan. Subgroup analyses supported no benefit from high\u2010dose losartan in patients with poorer kidney function and severe heart failure symptoms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g. kidney function, age, and symptoms) may influence the response to high\u2010dose losartan, suggesting that sex\u2010based subgroup findings may be biased by other confounders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.2255","type":"journal-article","created":{"date-parts":[[2021,5,29]],"date-time":"2021-05-29T09:26:39Z","timestamp":1622280399000},"page":"1477-1484","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Dosing of losartan in men versus women with heart failure with reduced ejection fraction: the\n                    <scp>HEAAL<\/scp>\n                    trial"],"prefix":"10.1093","volume":"23","author":[{"given":"Jo\u00e3o Pedro","family":"Ferreira","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Lorraine, INSERM Centre d'Investigations Cliniques Plurith\u00e9matique 1433, UMR 1116, CHRU de Nancy, F\u2010CRIN INI\u2010CRCT Cardiovascular and Renal Clinical Trialists  Nancy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marvin A.","family":"Konstam","sequence":"additional","affiliation":[{"name":"The CardioVascular Center of Tufts Medical Center  Boston MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences BHF Glasgow Cardiovascular Research Centre, University of Glasgow  Glasgow UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javed","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Mississippi Medical Center  Jackson MS USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Girerd","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, INSERM Centre d'Investigations Cliniques Plurith\u00e9matique 1433, UMR 1116, CHRU de Nancy, F\u2010CRIN INI\u2010CRCT Cardiovascular and Renal Clinical Trialists  Nancy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Rossignol","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, INSERM Centre d'Investigations Cliniques Plurith\u00e9matique 1433, UMR 1116, CHRU de Nancy, F\u2010CRIN INI\u2010CRCT Cardiovascular and Renal Clinical Trialists  Nancy France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhinav","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Cardiology McGill University Health Centre, McGill University  Montreal Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriaan A.","family":"Voors","sequence":"additional","affiliation":[{"name":"University of Groningen University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn S.P.","family":"Lam","sequence":"additional","affiliation":[{"name":"National Heart Center Singapore, and Duke National University of Singapore  Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milton","family":"Packer","sequence":"additional","affiliation":[{"name":"Baylor University Medical Center  Dallas TX USA"},{"name":"Imperial College  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faiez","family":"Zannad","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Lorraine, INSERM Centre d'Investigations Cliniques Plurith\u00e9matique 1433, UMR 1116, CHRU de Nancy, F\u2010CRIN INI\u2010CRCT Cardiovascular and Renal Clinical Trialists  Nancy 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