{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:43:30Z","timestamp":1790790210622,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"26","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Statistics in Medicine"],"published-print":{"date-parts":[[2021,11,20]]},"abstract":"<jats:p>In heart failure (HF) trials efficacy is usually assessed by a composite endpoint including cardiovascular death (CVD) and heart failure hospitalizations (HFHs), which has traditionally been evaluated with a time\u2010to\u2010first\u2010event analysis based on a Cox model. As a considerable fraction of events is ignored that way, methods for recurrent events were suggested, among others the semiparametric proportional rates models by Lin, Wei, Yang, and Ying (LWYY model) and Mao and Lin (Mao\u2010Lin model). In our work we apply least false parameter theory to explain the behavior of the composite treatment effect estimates resulting from the Cox model, the LWYY model, and the Mao\u2010Lin model in clinically relevant scenarios parameterized through joint frailty models. These account for both different treatment effects on the two outcomes (CVD, HFHs) and the positive correlation between their risk rates. For the important setting of beneficial outcome\u2010specific treatment effects we show that the correlation results in composite treatment effect estimates, which are decreasing with trial duration. The estimate from the Cox model is affected more by the attenuation than the estimates from the recurrent event models, which both demonstrate very similar behavior. Since the Mao\u2010Lin model turns out to be less sensitive to harmful effects on mortality, we conclude that, among the three investigated approaches, the LWYY model is the most appropriate one for the composite endpoint in HF trials. Our investigations are motivated and compared with empirical results from the PARADIGM\u2010HF trial (ClinicalTrials.gov identifier: NCT01035255), a large multicenter trial including 8399 chronic HF patients.<\/jats:p>","DOI":"10.1002\/sim.9149","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T07:41:36Z","timestamp":1627630896000},"page":"5702-5724","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A comparison of semiparametric approaches to evaluate composite endpoints in heart failure trials"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9745-9437","authenticated-orcid":false,"given":"Gerrit","family":"Toenges","sequence":"first","affiliation":[{"name":"Institute of Medical Biostatistics, Epidemiology and Informatics University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4111-1941","authenticated-orcid":false,"given":"Tobias","family":"M\u00fctze","sequence":"additional","affiliation":[{"name":"Statistical Methodology Novartis Pharma AG Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Jahn\u2010Eimermacher","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Natural Sciences Darmstadt University of Applied Sciences Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.12.048"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hft095"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.023538"},{"key":"e_1_2_11_5_1","unstructured":"EMA's Committee for Medicinal Products for Human Use (CHMP) Guideline on multiplicity issues in clinical trials;2017.https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/draft\u2010guide%line\u2010multiplicity\u2010issues\u2010clinical\u2010trials_en.pdf. 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