{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:52:34Z","timestamp":1788058354501,"version":"build-2784847793"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":935,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"The SHIFT trial was sponsored by Servier, France"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) \u226570\u2009bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR \u226570\u2009bpm) and at HR \u226575\u2009bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102\u2009days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR \u226570\u2009bpm. In the population with a baseline HR \u226575\u2009bpm, a reduction of the primary outcome occurred after 67\u2009days, HF hospitalization after 78\u2009days, cardiovascular death after 169\u2009days, death from HF after 157\u2009days and all-cause death after 169\u2009days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of \u226570\u2009bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR \u226575\u2009bpm. At HR \u226575\u2009bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.2870","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T04:54:32Z","timestamp":1682312072000},"page":"1429-1435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Time to Benefit of Heart Rate Reduction with Ivabradine in Patients with Heart Failure and Reduced Ejection Fraction"],"prefix":"10.1093","volume":"25","author":[{"given":"Michael","family":"B\u00f6hm","sequence":"first","affiliation":[{"name":"Klinik f\u00fcr Innere Medizin III, Universit\u00e4tsklinikum des Saarlandes, Saarland University , Homburg\/Saar ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Abdin","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Innere Medizin III, Universit\u00e4tsklinikum des Saarlandes, Saarland University , Homburg\/Saar ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Slawik","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Innere Medizin III, Universit\u00e4tsklinikum des Saarlandes, Saarland University , Homburg\/Saar ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Mahfoud","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Innere Medizin III, Universit\u00e4tsklinikum des Saarlandes, Saarland University , Homburg\/Saar ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Borer","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine and the Howard Gilman Institute for Heart Valve Disease, State, University of New York Downstate Medical Center , Brooklyn, NY ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Ford","sequence":"additional","affiliation":[{"name":"Robertson Centre for Biostatistics, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Swedberg","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg , G\u00f6teborg ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Tavazzi","sequence":"additional","affiliation":[{"name":"Ettore Sansavini Health Science Foundation, Maria Cecilia Hospital, GVM Care and Research , Cotignola (RA) ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Batailler","sequence":"additional","affiliation":[{"name":"Institut de Recherches Internationales Servier , Suresnes ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Komajda","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Groupe Hospitalier Paris Saint Joseph Paris, Paris Sorbonne University , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,15]]},"reference":[{"key":"2026010913103612900_ejhf2870-bib-0001","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1002\/ejhf.813","article-title":"Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry","volume":"19","author":"Chioncel","year":"2017","journal-title":"Eur J Heart Fail"},{"key":"2026010913103612900_ejhf2870-bib-0002","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrcardio.2015.14","article-title":"The vulnerable phase after hospitalization for heart failure","volume":"12","author":"Greene","year":"2015","journal-title":"Nat Rev Cardiol"},{"key":"2026010913103612900_ejhf2870-bib-0003","doi-asserted-by":"crossref","first-page":"4444","DOI":"10.1002\/ehf2.13646","article-title":"'Time is prognosis' in heart failure: time-to-treatment initiation as a modifiable risk factor","volume":"8","author":"Abdin","year":"2021","journal-title":"ESC Heart Fail"},{"key":"2026010913103612900_ejhf2870-bib-0004","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/ejhf.2333","article-title":"2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 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