{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T05:59:10Z","timestamp":1774159150503,"version":"3.50.1"},"reference-count":19,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AstraZeneca"},{"DOI":"10.13039\/501100022572","name":"NIHR Sheffield Biomedical Research Centre","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022572","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>The ONSET\u2013OFFSET study was a multicentre study assessing the pharmacodynamic responses to ticagrelor and clopidogrel in aspirin-treated patients with chronic coronary syndromes. Recent concerns have been raised about the study methodology, including at the single United Kingdom (UK) site in Sheffield. Here, we report data generated at this site along with additional analyses. The UK site recruited 40 out of 123 of the study participants. Platelet P2Y12 receptor inhibition was assessed using light transmission aggregometry and whole-blood methodologies. Samples were obtained during the onset and offset dosing periods. Percentage inhibition of platelet aggregation (%IPA) was calculated with (pre-specified) and without (post hoc) truncation of values [0, 100]. Study conduct was monitored by an external contract research organisation. The results from the UK site were concordant with the main study findings. %IPA at 2 h after ticagrelor loading: main study 88%, UK site 91% (truncated), UK site 91% (untruncated). %IPA correlated with other measures of P2Y12 inhibition (VerifyNow: p &lt; 0.0001; VASP phosphorylation assay: p &lt; 0.0001). One patient treated with ticagrelor had &gt;2 h delay in the onset of platelet inhibition associated with co-administration of metformin. The primary endpoint for the offset period was also similar to the main study findings. The UK site data confirm the more rapid onset and offset of inhibitory effects and greater mean levels of platelet inhibition with ticagrelor compared with clopidogrel, regardless of the mode of %IPA data analysis. Study conduct was rigorously monitored in order to demonstrate the integrity and validity of the results. Metformin may delay the onset of action of a ticagrelor loading dose.<\/jats:p>","DOI":"10.3390\/jcdd13030144","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:44:41Z","timestamp":1773999881000},"page":"144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Site Experience in the ONSET\u2013OFFSET Study Demonstrates Pharmacodynamic and Pharmacokinetic Advantages of Ticagrelor over Clopidogrel in Patients with Chronic Coronary Syndromes"],"prefix":"10.3390","volume":"13","author":[{"given":"Heather M.","family":"Judge","sequence":"first","affiliation":[{"name":"Cardiovascular Research Unit, Division of Clinical Medicine, University of Sheffield, Sheffield S10 2TN, UK"},{"name":"NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William A. E.","family":"Parker","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Unit, Division of Clinical Medicine, University of Sheffield, Sheffield S10 2TN, UK"},{"name":"NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6677-6229","authenticated-orcid":false,"given":"Robert F.","family":"Storey","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Unit, Division of Clinical Medicine, University of Sheffield, Sheffield S10 2TN, UK"},{"name":"NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1161\/CIRCULATIONAHA.109.912550","article-title":"Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET\/OFFSET study","volume":"120","author":"Gurbel","year":"2009","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.31083\/j.rcm2202044","article-title":"Ticagrelor: Clinical development and future potential","volume":"22","author":"Sanderson","year":"2021","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1016\/j.jcin.2024.08.027","article-title":"International Consensus Statement on Platelet Function and Genetic Testing in Percutaneous Coronary Intervention: 2024 Update","volume":"17","author":"Angiolillo","year":"2024","journal-title":"JACC Cardiovasc. Interv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"r1201","DOI":"10.1136\/bmj.r1201","article-title":"Ticagrelor doubts: Inaccuracies uncovered in key studies for AstraZeneca\u2019s billion dollar drug","volume":"389","author":"Doshi","year":"2025","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1016\/j.jacc.2013.07.101","article-title":"Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding","volume":"62","author":"Tantry","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1161\/CIRCULATIONAHA.118.034790","article-title":"Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease","volume":"138","author":"Orme","year":"2018","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1056\/NEJMoa0904327","article-title":"Ticagrelor versus clopidogrel in patients with acute coronary syndromes","volume":"361","author":"Wallentin","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1161\/CIRCULATIONAHA.109.919456","article-title":"Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: The RESPOND study","volume":"121","author":"Gurbel","year":"2010","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1111\/jth.12231","article-title":"Recommendations for the Standardization of Light Transmission Aggregometry: A Consensus of the Working Party from the Platelet Physiology Subcommittee of SSC\/ISTH","volume":"11","author":"Cattaneo","year":"2013","journal-title":"J. Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1016\/j.jacc.2010.03.100","article-title":"Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy","volume":"56","author":"Storey","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1080\/09537104.2019.1709631","article-title":"Offset of ticagrelor prior to coronary artery bypass graft surgery for acute coronary syndromes: Effects on platelet function and cellular adenosine uptake","volume":"31","author":"Ow","year":"2020","journal-title":"Platelets"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/bcp.13436","article-title":"Pharmacodynamics and pharmacokinetics of ticagrelor vs. clopidogrel in patients with acute coronary syndromes and chronic kidney disease","volume":"84","author":"Wang","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ahj.2009.01.003","article-title":"Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial","volume":"157","author":"James","year":"2009","journal-title":"Am. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/S0140-6736(10)61274-3","article-title":"Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: A genetic substudy of the PLATO trial","volume":"376","author":"Wallentin","year":"2010","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1136\/heartjnl-2014-305619","article-title":"Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes","volume":"100","author":"Varenhorst","year":"2014","journal-title":"Heart"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/j.jacc.2012.07.021","article-title":"Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery","volume":"60","author":"Varenhorst","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1093\/eurheartj\/ehr422","article-title":"Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial","volume":"32","author":"Becker","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e948812","DOI":"10.12659\/AJCR.948812","article-title":"Gastric Emptying Delay with Pre-Meal Administration of Metformin and Anagliptin in Type 2 Diabetes: Effects on Postprandial Glucose and Triglyceride Levels in a Two-Case Report","volume":"26","author":"Murata","year":"2025","journal-title":"Am. J. Case Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"611","DOI":"10.2337\/db24-0830","article-title":"Effects of Metformin on Postprandial Blood Pressure, Heart Rate, Gastric Emptying, GLP-1, and Prevalence of Postprandial Hypotension in Type 2 Diabetes: A Double-Blind Placebo-Controlled Crossover Study","volume":"32","author":"Quast","year":"2025","journal-title":"Diabetes"}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/13\/3\/144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T05:13:48Z","timestamp":1774156428000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/13\/3\/144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":19,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jcdd13030144"],"URL":"https:\/\/doi.org\/10.3390\/jcdd13030144","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,20]]}}}