Abstract
Once-daily (od), low-dose aspirin (75–100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB2, a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB2 as a reliable end point for dose-finding studies of novel aspirin regimens.
Highlights
Introduction and rationaleEssential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by clonal thrombocytosis and enhanced risk of arterial and venous thrombosis[1,2,3]
Part B The experimental aspirin regimen associated with a significantly lower serum TXB2 level and non-inferior urinary PGIM excretion rate (i.e., ≤30% reduction) as compared to aspirin 100 mg od, will be selected for part B, and patients will be randomized in an open-label fashion to the standard vs. the optimized multiple dosing regimen
112 patients/arm will be needed to assess with an α-error of 0.05 and 80% power, a reduction of at least 50% in serum TXB2 with the optimized regimen (100 mg bid or tid) vs. the standard aspirin regimen (100 mg od), in at least 6 out of 10 determinations performed over 20 months
Summary
Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by clonal thrombocytosis and enhanced risk of arterial and venous thrombosis[1,2,3]. Guidelines[4] indicating a lower platelet count threshold for diagnosing ET, led to an apparent increase in ET incidence[5]. ET incidence approximates 1.0–1.7 per 100 000 individuals per year, with a likely increase in the near future due to the continuous rise of occasional, asymptomatic diagnoses, and an estimated prevalence of approximately 20 per 100 000 individuals[6,7,8]. 50% of ET patients experience a thrombotic event, including myocardial infarction, ischemic stroke, transient ischemic attack, or venous thromboembolism[1], with an estimated incidence of 1.3–6.6% per year in spite of cytoreductive agents and/or antiplatelet drugs[9]. An optimal use of antiplatelet agents seems of outmost clinical relevance
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