{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:33:44Z","timestamp":1790375624902,"version":"4.1.0"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:00:00Z","timestamp":1768694400000},"content-version":"vor","delay-in-days":2897,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007405","name":"Danish Heart Foundation","doi-asserted-by":"publisher","award":["16-R107-A6786-22960"],"award-info":[{"award-number":["16-R107-A6786-22960"]}],"id":[{"id":"10.13039\/100007405","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril\/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27\u2009months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril\/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67\u20130.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71\u20130.89], the LWYY method (RR 0.78, 95% CI 0.68\u20130.90), and the joint frailty model (HR 0.75, 95% CI 0.66\u20130.86) (all P &amp;lt;\u20090.001). The effect of sacubitril\/valsartan vs. enalapril on recurrent HF hospitalizations\/CV death was similar.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril\/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1139","type":"journal-article","created":{"date-parts":[[2018,2,12]],"date-time":"2018-02-12T05:13:41Z","timestamp":1518412421000},"page":"760-768","source":"Crossref","is-referenced-by-count":80,"title":["Effect of Sacubitril\/Valsartan on Recurrent Events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF)"],"prefix":"10.1093","volume":"20","author":[{"given":"Ulrik M.","family":"Mogensen","sequence":"first","affiliation":[{"name":"BHF Cardiovascular Research Centre, University of Glasgow , Glasgow ,","place":["UK"]},{"name":"Rigshospitalet Copenhagen University Hospital , Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjian","family":"Gong","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceutical Corporation , East Hanover, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pardeep S.","family":"Jhund","sequence":"additional","affiliation":[{"name":"BHF Cardiovascular Research Centre, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Shen","sequence":"additional","affiliation":[{"name":"BHF Cardiovascular Research Centre, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"K\u00f8ber","sequence":"additional","affiliation":[{"name":"Rigshospitalet Copenhagen University Hospital , Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay S.","family":"Desai","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin P.","family":"Lefkowitz","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceutical Corporation , East Hanover, NJ ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton","family":"Packer","sequence":"additional","affiliation":[{"name":"Baylor Heart and Vascular Institute, Baylor University Medical Center , Dallas, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean L.","family":"Rouleau","sequence":"additional","affiliation":[{"name":"Institut de Cardiologie de Montr\u00e9al, Universit\u00e9 de Montr\u00e9al , Montr\u00e9al ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott D.","family":"Solomon","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Claggett","sequence":"additional","affiliation":[{"name":"Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Swedberg","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden, and National Heart and Lung Institute, Imperial College , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Zile","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina and Ralph H. Johnson Veterans Administration Medical Center , Charleston, SC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guenther","family":"Mueller-Velten","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"BHF Cardiovascular Research Centre, University of Glasgow , Glasgow ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,2,12]]},"reference":[{"key":"2026011721225683700_ejhf1139-bib-0001","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.cardfail.2005.08.350","article-title":"Key issues in end point selection for heart failure trials: composite end points","volume":"11","author":"Neaton","year":"2005","journal-title":"J Card Fail"},{"key":"2026011721225683700_ejhf1139-bib-0002","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.1093\/eurheartj\/ehs277","article-title":"Time to move on from \u2018time-to-first\u2019: should all events be included in the analysis of clinical trials?","volume":"33","author":"Anker","year":"2012","journal-title":"Eur Heart J"},{"key":"2026011721225683700_ejhf1139-bib-0003","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1161\/CIRCULATIONAHA.112.110536","article-title":"Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations","volume":"126","author":"Rogers","year":"2012","journal-title":"Circulation"},{"key":"2026011721225683700_ejhf1139-bib-0004","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/ejhf.29","article-title":"Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to CHARM-Preserved","volume":"16","author":"Rogers","year":"2014","journal-title":"Eur J Heart Fail"},{"key":"2026011721225683700_ejhf1139-bib-0005","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.jchf.2013.12.007","article-title":"Effect of rosuvastatin on repeat heart failure hospitalizations: the CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure)","volume":"2","author":"Rogers","year":"2014","journal-title":"JACC Heart Fail"},{"key":"2026011721225683700_ejhf1139-bib-0006","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1093\/eurheartj\/ehs259","article-title":"Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study","volume":"33","author":"Borer","year":"2012","journal-title":"Eur Heart J"},{"key":"2026011721225683700_ejhf1139-bib-0007","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/ejhf.516","article-title":"Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency","volume":"18","author":"Anker","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"2026011721225683700_ejhf1139-bib-0008","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":"2026011721225683700_ejhf1139-bib-0009","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":"2026011721225683700_ejhf1139-bib-0010","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1161\/CIRCULATIONAHA.114.013748","article-title":"Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure","volume":"131","author":"Packer","year":"2015","journal-title":"Circulation"},{"key":"2026011721225683700_ejhf1139-bib-0011","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1080\/01621459.1989.10478873","article-title":"Regression analysis of multivariate incomplete failure time data by modeling marginal distributions","volume":"84","author":"Wei","year":"1989","journal-title":"J Am Stat Assoc"},{"key":"2026011721225683700_ejhf1139-bib-0012","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1111\/1467-9868.00259","article-title":"Semiparametric regression for the mean and rate functions of recurrent events","volume":"62","author":"Lin","year":"2000","journal-title":"J R Stat Soc Series B Stat Methodol"},{"key":"2026011721225683700_ejhf1139-bib-0013","author":"PARADIGM study protocol and statistical analysis plan","year":"2017"},{"key":"2026011721225683700_ejhf1139-bib-0014","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1111\/j.0006-341X.2000.00554.x","article-title":"Nonparametric analysis of recurrent events and death","volume":"56","author":"Ghosh","year":"2000","journal-title":"Biometrics"},{"key":"2026011721225683700_ejhf1139-bib-0015","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1177\/0962280206071926","article-title":"Wei, Lin and Weissfeld's marginal analysis of multivariate failure time data: should it be applied to a recurrent events outcome?","volume":"16","author":"Metcalfe","year":"2007","journal-title":"Stat Methods Med Res"},{"key":"2026011721225683700_ejhf1139-bib-0016","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1214\/aos\/1176345976","article-title":"Cox's regression model for counting processes: a large sample study","volume":"10","author":"Andersen","year":"1982","journal-title":"Annals of Statistics"},{"key":"2026011721225683700_ejhf1139-bib-0017","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1002\/sim.6853","article-title":"Analysis of recurrent events with an associated informative dropout time: application of the joint frailty model","volume":"35","author":"Rogers","year":"2016","journal-title":"Stat Med"},{"key":"2026011721225683700_ejhf1139-bib-0018","year":"2017"},{"key":"2026011721225683700_ejhf1139-bib-0019","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S0140-6736(15)00723-0","article-title":"Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial","volume":"387","author":"Abraham","year":"2016","journal-title":"Lancet"},{"key":"2026011721225683700_ejhf1139-bib-0020","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/S0140-6736(16)00082-9","article-title":"Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial","volume":"387","author":"Greenberg","year":"2016","journal-title":"Lancet"},{"key":"2026011721225683700_ejhf1139-bib-0021","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.jchf.2017.04.013","article-title":"Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF Trial","volume":"5","author":"Solomon","year":"2017","journal-title":"JACC Heart Fail"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fejhf.1139","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/20\/4\/760\/66269846\/eurjhf_20_4_760.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/20\/4\/760\/66269846\/eurjhf_20_4_760.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T02:25:31Z","timestamp":1768703131000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/20\/4\/760\/8414784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,12]]},"references-count":21,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,2,12]]},"published-print":{"date-parts":[[2018,4,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.1139","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,4]]},"published":{"date-parts":[[2018,2,12]]}}}