{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:15:13Z","timestamp":1760238913279,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"the US National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG025152","R01AG060975","R01AG064589","R01DA048001","T32GM075766"],"award-info":[{"award-number":["R01AG025152","R01AG060975","R01AG064589","R01DA048001","T32GM075766"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Warfarin and a skeletal muscle relaxant are co-treatments in nearly a quarter-million annual United States (US) office visits. Despite international calls to minimize patient harm arising from anticoagulant drug interactions, scant data exist on clinical outcomes in real-world populations. We examined effects of concomitant use of warfarin and individual muscle relaxants on rates of hospitalization for thromboembolism among economically disadvantaged persons. Materials and Methods: Using 1999\u20132012 administrative data of four US state Medicaid programs, we conducted 16 retrospective self-controlled case series studies: half included concomitant users of warfarin + one of eight muscle relaxants; half included concomitant users of an inhaled corticosteroid (ICS) + one of eight muscle relaxants. The ICS analyses served as negative control comparisons. In each study, we calculated incidence rate ratios (IRRs) comparing thromboembolism rates in the co-exposed versus warfarin\/ICS-only exposed person-time, adjusting for time-varying confounders. Results: Among ~70 million persons, we identified 8693 warfarin-treated subjects who concomitantly used a muscle relaxant, were hospitalized for thromboembolism, and met all other inclusion criteria. Time-varying confounder-adjusted IRRs ranged from 0.31 (95% confidence interval: 0.13\u20130.77) for metaxalone to 3.44 (95% confidence interval: 1.53\u20137.78) for tizanidine. The tizanidine finding was robust after quantitatively adjusting for negative control ICS findings, and in numerous prespecified secondary analyses. Conclusions: We identified a potential &gt;3-fold increase in the rate of hospitalized thromboembolism in concomitant users of warfarin + tizanidine vs. warfarin alone. Alternative explanations for this finding include confounding by indication, a native effect of tizanidine, or chance.<\/jats:p>","DOI":"10.3390\/medicina58091171","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T22:53:42Z","timestamp":1661813622000},"page":"1171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thromboembolic Events in Users of Warfarin Treated with Different Skeletal Muscle Relaxants"],"prefix":"10.3390","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-9657","authenticated-orcid":false,"given":"Charles E.","family":"Leonard","sequence":"first","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colleen M.","family":"Brensinger","sequence":"additional","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Warren B.","family":"Bilker","sequence":"additional","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha E.","family":"Soprano","sequence":"additional","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Dhopeshwarkar","sequence":"additional","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd E. H.","family":"Hecht","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott E.","family":"Kasner","sequence":"additional","affiliation":[{"name":"Division of Vascular Neurology, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith A.","family":"Nutescu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice and Center for Pharmacoepidemiology and Pharmacoeconomic Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3371-4187","authenticated-orcid":false,"given":"Anne","family":"Holbrook","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology and Toxicology, Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Carr","sequence":"additional","affiliation":[{"name":"Center for Pharmacoepidemiology and Drug Safety, Division of Pharmacy & Optometry, School of Health Sciences, University of Manchester, Manchester M13, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2958-915X","authenticated-orcid":false,"given":"Darren M.","family":"Ashcroft","sequence":"additional","affiliation":[{"name":"Center for Pharmacoepidemiology and Drug Safety, Division of Pharmacy & Optometry, School of Health Sciences, University of Manchester, Manchester M13, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-8153","authenticated-orcid":false,"given":"Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Hennessy","sequence":"additional","affiliation":[{"name":"Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"ref_1","unstructured":"U.S. Department of Health and Human Services\u2019 Office of Disease Prevention and Health Promotion (2021, September 27). 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