{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T10:06:11Z","timestamp":1787997971150,"version":"build-2784847793"},"reference-count":53,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"unspecified","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006093","name":"Patient Centered Outcomes Research Institute","doi-asserted-by":"crossref","award":["NCT02810704"],"award-info":[{"award-number":["NCT02810704"]}],"id":[{"id":"10.13039\/100006093","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006093","name":"Patient Centered Outcomes Research Institute","doi-asserted-by":"crossref","award":["PCS-1402-09328-IC"],"award-info":[{"award-number":["PCS-1402-09328-IC"]}],"id":[{"id":"10.13039\/100006093","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>More than 1 million elective total hip and knee replacements are performed annually in the USA with 2% risk of clinical pulmonary embolism (PE), 0.1%\u20130.5%\u2009fatal PE, and over 1000 deaths. Antithrombotic prophylaxis is standard of care but evidence is limited and conflicting. We will compare effectiveness of three commonly used chemoprophylaxis agents to prevent all-cause mortality (ACM) and clinical venous thromboembolism (VTE) while avoiding bleeding complications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and analysis<\/jats:title><jats:p>Pulmonary Embolism Prevention after HiP and KneE Replacement is a large randomised pragmatic comparative effectiveness trial with non-inferiority design and target enrolment of 20\u2009000 patients comparing aspirin (81\u2009mg two times a day), low-intensity warfarin (INR (International Normalized Ratio) target 1.7\u20132.2) and rivaroxaban (10\u2009mg\/day). The primary effectiveness outcome is aggregate of VTE and ACM, primary safety outcome is clinical bleeding complications, and patient-reported outcomes are determined at 1, 3 and 6 months. Primary data analysis is<jats:italic>per protocol<\/jats:italic>, as preferred for non-inferiority trials, with secondary analyses adherent to<jats:italic>intention-to-treat<\/jats:italic>principles. All non-fatal outcomes are captured from patient and clinical reports with independent blinded adjudication. Study design and oversight are by a multidisciplinary stakeholder team including a 10-patient advisory board.<\/jats:p><\/jats:sec><jats:sec><jats:title>Ethics and dissemination<\/jats:title><jats:p>The Institutional Review Board of the Medical University of South Carolina provides central regulatory oversight. Patients aged 21 or older undergoing primary or revision hip or knee replacement are block randomised by site and procedure; those on chronic anticoagulation are excluded. Recruitment commenced at 30 North American centres in December 2016. Enrolment currently exceeds 13\u2009500 patients, representing 33% of those eligible at participating sites, and is projected to conclude in July 2024; COVID-19 may force an extension. Results will inform antithrombotic choice by patients and other stakeholders for various risk cohorts, and will be disseminated through academic publications, meeting presentations and communications to advocacy groups and patient participants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02810704\">NCT02810704<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjopen-2021-060000","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T16:51:18Z","timestamp":1646758278000},"page":"e060000","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct02810704","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02810704","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7492-0684","authenticated-orcid":false,"given":"Vincent D","family":"Pellegrini, Jr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4126-1285","authenticated-orcid":false,"given":"John William","family":"Eikelboom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C McCollister","family":"Evarts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4441-0533","authenticated-orcid":false,"given":"Patricia D","family":"Franklin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9288-8104","authenticated-orcid":false,"given":"Kevin L","family":"Garvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel Z","family":"Goldhaber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Iorio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4939-1746","authenticated-orcid":false,"given":"Carol Ann","family":"Lambourne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Magaziner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Magder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,3,8]]},"reference":[{"key":"2023030803132186000_12.3.e060000.1","doi-asserted-by":"crossref","unstructured":"Charnley J . 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