{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T12:11:01Z","timestamp":1768997461708,"version":"3.49.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2013,8,1]],"date-time":"2013-08-01T00:00:00Z","timestamp":1375315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>A total of 495 chronic HF patients, aged \u226560, with an LVEF \u226445%, NYHA class \u2265II, randomized to NT-proBNP-guided or symptom-guided therapy and \u22651 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs\/patient-year 4.7 (2.8\u20139.4) vs. 5.4 (2.7\u201311.4), P = 0.69; number of severe AEs\/patient-year 0.7 (0\u20132.7) vs. 1.3 (0\u20133.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects\u2014although small and related to non-severe AEs only\u2014were only seen in the older and more co-morbid patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ISRCTN43596477<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurjhf\/hft079","type":"journal-article","created":{"date-parts":[[2013,5,10]],"date-time":"2013-05-10T21:29:37Z","timestamp":1368221377000},"page":"910-918","source":"Crossref","is-referenced-by-count":16,"title":["Safety and Tolerability of Intensified, N-Terminal Pro Brain Natriuretic Peptide-Guided Compared with Standard Medical Therapy in Elderly Patients with Congestive Heart Failure: Results from TIME-CHF"],"prefix":"10.1093","volume":"15","author":[{"given":"Sandra","family":"Sanders-van Wijk","sequence":"first","affiliation":[{"name":"Maastricht University Medical Center, CARIM , Maastricht ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Muzzarelli","sequence":"additional","affiliation":[{"name":"Universit\u00e4tsspital Basel , Basel ,","place":["Switzerland"]},{"name":"Cardiocentro Ticino , Lugano ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Neuhaus","sequence":"additional","affiliation":[{"name":"Kantonsspital Baden , Baden ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Kiencke","sequence":"additional","affiliation":[{"name":"Kantonsspital Bruderhol , Bruderholz ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha","family":"Maeder","sequence":"additional","affiliation":[{"name":"Kantonsspital St. Gallen , St. Gallen ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Werner","family":"Estlinbaum","sequence":"additional","affiliation":[{"name":"Kantonsspital Liestal , Liestal ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Tobler","sequence":"additional","affiliation":[{"name":"Universit\u00e4tsspital Basel , Basel ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt","family":"Mayer","sequence":"additional","affiliation":[{"name":"Kantonsspital Graub\u00fcnden , Chur ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Erne","sequence":"additional","affiliation":[{"name":"Luzerner Kantonsspital , Lucerne ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias E.","family":"Pfisterer","sequence":"additional","affiliation":[{"name":"Universit\u00e4tsspital Basel , Basel ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Peter","family":"Brunner-La Rocca","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Center, CARIM , Maastricht ,","place":["The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the TIME-CHF investigators","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,1,27]]},"reference":[{"key":"2026011921153847000_ejhfhft079-bib-0001","first-page":"803","article-title":"Task Force for the D, Treatment of A, Chronic Heart Failure of the European Society of CDeveloped in collaboration with the Heart Failure Association (HFA) of the ESC","volume":"14","author":"McMurray","year":"2012","journal-title":"Eur J Heart Fail"},{"key":"2026011921153847000_ejhfhft079-bib-0002","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1001\/jama.297.1.61","article-title":"Association between performance measures and clinical outcomes for patients hospitalized with heart failure","volume":"297","author":"Fonarow","year":"2007","journal-title":"JAMA"},{"key":"2026011921153847000_ejhfhft079-bib-0003","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/S0195-668X(02)00700-5","article-title":"The EuroHeart Failure Survey programme\u2014a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment","volume":"24","author":"Komajda","year":"2003","journal-title":"Eur Heart J"},{"key":"2026011921153847000_ejhfhft079-bib-0004","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1067\/mhj.2002.119608","article-title":"Clinical features and outcomes of elderly outpatients with heart failure followed up in hospital cardiology units: data from a large nationwide cardiology database (IN-CHF Registry)","volume":"143","author":"Pulignano","year":"2002","journal-title":"Am Heart J"},{"issue":"754\u2013762","key":"2026011921153847000_ejhfhft079-bib-0005","article-title":"Influence of patient age and sex on delivery of guideline-recommended heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF","volume":"157","author":"Yancy","year":"2009","journal-title":"Am Heart J"},{"key":"2026011921153847000_ejhfhft079-bib-0006","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.acvd.2012.04.003","article-title":"Optimization of heart FailUre medical Treatment after hospital discharge according to left ventricUlaR Ejection fraction: the FUTURE survey","volume":"105","author":"Cohen Solal","year":"2012","journal-title":"Arch Cardiovasc Dis"},{"key":"2026011921153847000_ejhfhft079-bib-0007","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.jacc.2003.09.044","article-title":"Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure","volume":"43","author":"Logeart","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0008","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.jacc.2008.04.069","article-title":"Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial)","volume":"52","author":"Masson","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0009","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1161\/01.CIR.0000143059.68996.A7","article-title":"Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial","volume":"110","author":"Hartmann","year":"2004","journal-title":"Circulation"},{"key":"2026011921153847000_ejhfhft079-bib-0010","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1161\/CIRCULATIONAHA.108.809194","article-title":"Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study","volume":"119","author":"Iraqi","year":"2009","journal-title":"Circulation"},{"key":"2026011921153847000_ejhfhft079-bib-0011","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1177\/1753944708103658","article-title":"Effects of enalapril, candesartan or both on neurohumoral activation and LV volumes and function in patients with heart failure not treated with a beta-blocker","volume":"3","author":"White","year":"2009","journal-title":"Ther Adv Cardiovasc Dis"},{"key":"2026011921153847000_ejhfhft079-bib-0012","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1016\/S0140-6736(00)02060-2","article-title":"Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations","volume":"355","author":"Troughton","year":"2000","journal-title":"Lancet"},{"key":"2026011921153847000_ejhfhft079-bib-0013","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1016\/j.jacc.2010.07.030","article-title":"Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study","volume":"56","author":"Eurlings","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0014","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/j.jacc.2011.03.072","article-title":"Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction","volume":"58","author":"Januzzi","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0015","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/j.jacc.2006.10.081","article-title":"Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study","volume":"49","author":"Jourdain","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0016","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jacc.2009.02.095","article-title":"N-terminal pro-B-type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial","volume":"55","author":"Lainchbury","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0017","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ahj.2009.06.018","article-title":"Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials","volume":"158","author":"Felker","year":"2009","journal-title":"Am Heart J"},{"key":"2026011921153847000_ejhfhft079-bib-0018","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1001\/archinternmed.2010.35","article-title":"B-type natriuretic peptide-guided heart failure therapy: a meta-analysis","volume":"170","author":"Porapakkham","year":"2010","journal-title":"Arch Intern Med"},{"key":"2026011921153847000_ejhfhft079-bib-0019","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ijcard.2007.10.018","article-title":"Use of B-type natriuretic peptide outside of the emergency department","volume":"127","author":"Maeder","year":"2008","journal-title":"Int J Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0020","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.amjopharm.2009.10.001","article-title":"A review of heart failure management in the elderly population","volume":"7","author":"Cheng","year":"2009","journal-title":"Am J Geriatr Pharmacother"},{"key":"2026011921153847000_ejhfhft079-bib-0021","doi-asserted-by":"crossref","first-page":"991","DOI":"10.2165\/00002512-200724120-00003","article-title":"Drug treatment of chronic heart failure in the elderly","volume":"24","author":"Leibundgut","year":"2007","journal-title":"Drugs Aging"},{"key":"2026011921153847000_ejhfhft079-bib-0022","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.ahj.2005.10.022","article-title":"Management of elderly patients with congestive heart failure\u2014design of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)","volume":"151","author":"Brunner-La Rocca","year":"2006","journal-title":"Am Heart J"},{"key":"2026011921153847000_ejhfhft079-bib-0023","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1001\/jama.2009.2","article-title":"BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial","volume":"301","author":"Pfisterer","year":"2009","journal-title":"JAMA"},{"key":"2026011921153847000_ejhfhft079-bib-0024","author":"ICH Good Clinical Practice","year":"2002"},{"key":"2026011921153847000_ejhfhft079-bib-0025"},{"key":"2026011921153847000_ejhfhft079-bib-0026","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ahj.2009.06.018","article-title":"Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials","volume":"158","author":"Felker","year":"2009","journal-title":"Am Heart J"},{"key":"2026011921153847000_ejhfhft079-bib-0027","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1001\/archinternmed.2010.35","article-title":"B-type natriuretic peptide-guided heart failure therapy: a meta-analysis","volume":"170","author":"Porapakkham","year":"2010","journal-title":"Arch Intern Med"},{"key":"2026011921153847000_ejhfhft079-bib-0028","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.jacc.2009.08.078","article-title":"N-terminal pro-B-type natriuretic peptide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure a 3-arm, prospective, randomized pilot study","volume":"55","author":"Berger","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0029","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1016\/j.jacc.2006.10.081","article-title":"Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study","volume":"49","author":"Jourdain","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0030","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1093\/eurjhf\/hfr078","article-title":"Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome","volume":"13","author":"Karlstr\u00f6m","year":"2011","journal-title":"Eur J Heart Fail"},{"key":"2026011921153847000_ejhfhft079-bib-0031","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1093\/eurjhf\/hfq169","article-title":"Improved pharmacological therapy of chronic heart failure in primary care: a randomized Study of NT-proBNP Guided Management of Heart Failure\u2013SIGNAL-HF (Swedish Intervention study\u2013Guidelines and NT-proBNP AnaLysis in Heart Failure)","volume":"12","author":"Persson","year":"2010","journal-title":"Eur J Heart Fail"},{"key":"2026011921153847000_ejhfhft079-bib-0032","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1056\/NEJMoa040135","article-title":"Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study","volume":"351","author":"Juurlink","year":"2004","journal-title":"N Engl J Med"},{"key":"2026011921153847000_ejhfhft079-bib-0033","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.amjcard.2011.10.027","article-title":"TIME-CHF InvestigatorsFrequency and predictors of hyperkalemia in patients \u226560 years of age with heart failure undergoing intense medical therapy","volume":"109","author":"Muzzarelli","year":"2012","journal-title":"Am J Cardiol"},{"key":"2026011921153847000_ejhfhft079-bib-0034","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ahj.2011.12.003","article-title":"TIME-CHF InvestigatorsIncidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy","volume":"163","author":"Maeder","year":"2012","journal-title":"Am Heart J"},{"key":"2026011921153847000_ejhfhft079-bib-0035","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.ejheart.2003.12.019","article-title":"Tolerability of carvedilol and ACE-inhibition in mild heart failure. Results of CARMEN (Carvedilol ACE-Inhibitor Remodelling Mild CHF EvaluatioN)","volume":"6","author":"Komajda","year":"2004","journal-title":"Eur J Heart Fail"},{"key":"2026011921153847000_ejhfhft079-bib-0036","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ahj.2009.04.011","article-title":"Clinical characteristics, management, and prognosis of octogenarians with acute heart failure admitted to cardiology wards: results from the Italian Survey on Acute Heart Failure","volume":"158","author":"Miani","year":"2009","journal-title":"Am Heart J"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1093%2Feurjhf%2Fhft079","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1093%2Feurjhf%2Fhft079","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1093\/eurjhf\/hft079","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1093\/eurjhf\/hft079","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/15\/8\/910\/66441602\/eurjhf_15_8_910.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/15\/8\/910\/66441602\/eurjhf_15_8_910.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T02:19:06Z","timestamp":1768875546000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/15\/8\/910\/8428763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,8,1]]},"references-count":36,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,1,27]]},"published-print":{"date-parts":[[2013,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/eurjhf\/hft079","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,8]]},"published":{"date-parts":[[2013,8,1]]}}}