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To perform a structured, systematic, and transparent review of the evidence supporting ambulatory care prescribing cascades. Ninety\u2010four potential prescribing cascades identified through a previously published systematic review. Systematic search of the literature to further characterize prescribing cascades. (1) Grading of evidence based on observational studies investigating associations between index and marker drugs, including: Level I\u2014strong evidence [i.e. multiple high\u2010quality studies]; Level II\u2014moderate evidence [i.e. single high\u2010quality study]; Level III\u2014fair evidence [no high\u2010quality studies but one or more moderate\u2010quality studies]; and Level IV\u2014poor evidence [other]. (2) Listing of the adverse event associated with the index drug in the product's United States Food and Drug Administration (FDA) label. (3) Synthesis of the evidence supporting mechanisms linking index drugs and associated adverse events. Of 99 potential cascades, 94 were supported by one or more confirmatory observational studies and were therefore included in this review. The 94 cascades related to 30 types of adverse drug reactions affecting 10 different anatomic\/physiologic systems and were investigated by a total of 88 confirmatory studies, including prescription sequential symmetry analysis (<jats:italic>n<\/jats:italic>\u2009=\u200951), cohort (<jats:italic>n<\/jats:italic>\u2009=\u200930), and case\u2013control (<jats:italic>n<\/jats:italic>\u2009=\u20097) studies. Overall, the evidence from observational studies was strong for 18 (19.1%) prescribing cascades, moderate for 61 (64.9%), fair for 13 (13.8%), and poor for 2 (2.1%). Although the evidence supporting mechanisms that link index drugs and associated adverse events was variable, FDA labels included information about the adverse event associated with the index drug for most (<jats:italic>n<\/jats:italic>\u2009=\u200986) but not all of the 94 prescribing cascades. Although we identified 18 of 94 prescribing cascades supported by strong clinical evidence and most adverse events associated with index drugs are included in FDA label, the evidentiary basis for prescribing cascades varies, with many requiring further evidence of clinical relevance.<\/jats:p>","DOI":"10.1002\/phar.2880","type":"journal-article","created":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T04:05:14Z","timestamp":1695614714000},"page":"87-96","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Prescribing cascades in ambulatory care: A structured synthesis of evidence"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3132-0800","authenticated-orcid":false,"given":"Faiza","family":"Shahid","sequence":"first","affiliation":[{"name":"Institute of General Practice and Family Medicine, University Hospital, LMU Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4149-1574","authenticated-orcid":false,"given":"Ann","family":"Doherty","sequence":"additional","affiliation":[{"name":"Department of General Practice University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of General Practice University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Schmiedl","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Medicine, Faculty of Health Witten\/Herdecke University  Witten Germany"},{"name":"Philipp Klee\u2010Institute for Clinical Pharmacology Helios University Hospital Wuppertal  Wuppertal Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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