{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T16:55:16Z","timestamp":1793638516707,"version":"4.5.1"},"reference-count":12,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":3538,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation, USA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To assess the tolerability of initiating\/uptitrating sacubitril\/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction \u226435%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>A 5-day open-label run-in (sacubitril\/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily (\u2018condensed\u2019 regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily (\u2018conservative\u2019 regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor\/angiotensin-receptor blocker (ACEI\/ARB; low-dose stratum included ACEI\/ARB-na\u00efve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in (\u2018condensed\u2019 vs. \u2018conservative\u2019) 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure &amp;lt;95 mmHg, serum potassium &amp;gt;5.5 mmol\/L, and serum creatinine &amp;gt;3.0 mg\/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril\/valsartan 200 mg twice daily without dose interruption\/down-titration over 12 weeks (77.8% vs. 84.3% for \u2018condensed\u2019 vs. \u2018conservative\u2019; P = 0.078). Rates by ACEI\/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose\/\u2018condensed\u2019 vs. high-dose\/\u2018conservative\u2019 and 84.9% vs. 73.6% (P = 0.030) for low-dose\/\u2018conservative\u2019 vs. low-dose\/\u2018condensed\u2019.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Initiation\/uptitration of sacubitril\/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation\/uptitration maximized attainment of target dose in the low-dose ACEI\/ARB group.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.548","type":"journal-article","created":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T02:25:49Z","timestamp":1463019949000},"page":"1193-1202","source":"Crossref","is-referenced-by-count":203,"title":["Initiating Sacubitril\/Valsartan (LCZ696) in Heart Failure: Results of TITRATION, a Double-Blind, Randomized Comparison of Two Uptitration Regimens"],"prefix":"10.1093","volume":"18","author":[{"given":"Michele","family":"Senni","sequence":"first","affiliation":[{"name":"Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII , Bergamo, Piazza OMS, 24127, Bergamo ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"British Heart Foundation Cardiovascular Research Centre, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Wachter","sequence":"additional","affiliation":[{"name":"University Medicine Goettingen, Clinic for Cardiology and Pneumology , Goettingen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh F.","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Hon Reader in Medicine, Brighton and Sussex Medical School \u00a0","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Reyes","sequence":"additional","affiliation":[{"name":"University Hospital Virgen de Valme, Medicina Interna , Sevilla ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Majercak","sequence":"additional","affiliation":[{"name":"Outpatient Internal Medicine, Cardiology , Kosice ,","place":["Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Andreka","sequence":"additional","affiliation":[{"name":"Gottsegen Gyorgy, Orszagos Kardiologiai Intezet, Felnott Kardiologiai Osztaly , Budapest ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Shehova-Yankova","sequence":"additional","affiliation":[{"name":"MHAT Bratan Shukerov, Cardiology Department , Smolian ,","place":["Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inder","family":"Anand","sequence":"additional","affiliation":[{"name":"Veterans Medical Center -Minneapolis , Minneapolis, MN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet B.","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Cumhuriyet University Medical Faculty Cardiology , Sivas ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harinder","family":"Gogia","sequence":"additional","affiliation":[{"name":"Cardiology Consultants of Orange County , Anaheim, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Martinez-Selles","sequence":"additional","affiliation":[{"name":"Hospital Gregorio Maranon, Servicio de Cardiologia, and Universidad Europea y Universidad Complutense , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Fischer","sequence":"additional","affiliation":[{"name":"Praxis Dr Fischer , Leipzig ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Zilahi","sequence":"additional","affiliation":[{"name":"Kardiologiai Szakrendeles , Nyiregyh\u00e1za ,","place":["Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Cosmi","sequence":"additional","affiliation":[{"name":"P.O. Ospedale Valdichiana S. Margherita, U.O. di Cardiologia , Cortona ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeri","family":"Gelev","sequence":"additional","affiliation":[{"name":"MHAT Tokuda Hospital Sofia, Clinic of Cardiology and Angio , Sofia ,","place":["Bulgaria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Galve","sequence":"additional","affiliation":[{"name":"Hospital Vall D\u2019Hebron, Cardiology, Paseo Valle de Hebron , Barcelona ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjo J.","family":"G\u00f3mez-Doblas","sequence":"additional","affiliation":[{"name":"Hospital Virgen de la Victoria, Cardiologia, Campus Universitario Teatinos , Malaga ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Nociar","sequence":"additional","affiliation":[{"name":"Kardio 1 s.r.o. , Lucenec ,","place":["Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Radomska","sequence":"additional","affiliation":[{"name":"Letesia s.r.o. , Trebisov ,","place":["Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Sokolova","sequence":"additional","affiliation":[{"name":"Galenum s.r.o., Ambulancia v odbore Vutorne Lekarstvo , Bratislava ,","place":["Slovakia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Volterrani","sequence":"additional","affiliation":[{"name":"IRCCS San Raffaele Pisana , Rome ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnab","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Novartis HC Ltd , Hyderabad ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Reimund","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Chen","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation , East Hanover, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Charney","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation , East Hanover, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,5,12]]},"reference":[{"key":"2026011721160784800_ejhf548-bib-0001","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N Engl J Med"},{"key":"2026011721160784800_ejhf548-bib-0002","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1093\/eurjhf\/hft052","article-title":"Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)","volume":"15","author":"McMurray","year":"2013","journal-title":"Eur J Heart Fail"},{"key":"2026011721160784800_ejhf548-bib-0003","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1093\/fampra\/cmn105","article-title":"Evaluation of the management of heart failure in primary care","volume":"26","author":"Calvert","year":"2009","journal-title":"Fam Pract"},{"key":"2026011721160784800_ejhf548-bib-0004","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1093\/eurheartj\/ehs104","article-title":"ESC Committee for Practice Guidelines. 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