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The short\u2010term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice\u2010daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long\u2010term pharmacodynamic efficacy, safety and tolerability of twice\u2010daily aspirin remain untested. We performed a multicenter, randomized, open\u2010label, blinded\u2010endpoint, phase\u20102 trial in which 242 patients with ET were randomized to 100\u2009mg aspirin twice\u2010 or once\u2010daily and followed for 20\u2009months. The primary endpoint was the persistence of low serum TXB<jats:sub>2<\/jats:sub>, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non\u2010major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB<jats:sub>2<\/jats:sub> was consistently lower in the twice\u2010daily versus once\u2010daily regimen on 10 study visits over 20\u2009months: median 3.9\u2009ng\/mL versus 19.2\u2009ng\/mL, respectively; <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001; 80% median reduction; 95% CI, 74%\u201385%. No major bleeding occurred. Clinically relevant non\u2010major bleedings were non\u2010significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice\u2010daily versus once\u2010daily group. Patients on the twice\u2010daily regimen had significantly lower frequencies of disease\u2010specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice\u2010daily regimen. In patients with ET, twice\u2010daily was persistently superior to once\u2010daily low\u2010dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.<\/jats:p>","DOI":"10.1002\/ajh.27418","type":"journal-article","created":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T04:59:40Z","timestamp":1718427580000},"page":"1462-1474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Long\u2010term pharmacodynamic and clinical effects of twice\u2010 versus once\u2010daily low\u2010dose aspirin in essential thrombocythemia: The <scp>ARES<\/scp> trial"],"prefix":"10.1002","volume":"99","author":[{"given":"Bianca","family":"Rocca","sequence":"first","affiliation":[{"name":"Department of Safety and Bioethics, Section of Pharmacology Catholic University School of Medicine  Rome Italy"},{"name":"Department NeuroFarBa University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0119-5204","authenticated-orcid":false,"given":"Alberto","family":"Tosetto","sequence":"additional","affiliation":[{"name":"Hematology Department San Bortolo Hospital  Vicenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Petrucci","sequence":"additional","affiliation":[{"name":"Department of Safety and Bioethics, Section of Pharmacology Catholic University School of Medicine  Rome Italy"},{"name":"Department of Radiological and Hematological Sciences, Section of Hematology Catholic University School of Medicine  Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Radiological and Hematological Sciences, Section of Hematology Catholic University School of Medicine  Roma Italy"},{"name":"Fondazione Policlinico Universitario A. 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