The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting

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.

Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

“…The protocol was approved by the Institutional Ethics Committee (approval P/852/CE/2012). Nonobese (BMI of <30 kg/m 2 ) healthy controls were chosen from a large database of previously published cohorts of healthy volunteers, receiving or not receiving aspirin for 3‐5 weeks to match 1:1 with obese subjects for sex and age.…”

Measurement of Thromboxane Biosynthesis in Health and Disease

“…Petrucci et al (2016) investigated whether a variable delay in 37°C incubation and/or analytical discrepancies may affect the assessment of aspirin pharmacodynamics based on serum TXB 2 determinations. They found that a longer than 5-min delay in the 37°C incubation of whole-blood samples may variably influence the assessment of platelet COX-1 inhibition by low-dose aspirin and confound the analysis of aspirin responsiveness in the clinical setting (Petrucci et al, 2016; De Stefano et al, 2018). In contrast, a GC/MS-validated immunoassay and liquid chromatography-tandem mass-spectrometry yielded quite comparable TXB 2 concentrations in the same serum samples (Petrucci et al, 2016).…”

Addressing and proposing solutions for unmet clinical needs in the management of myeloproliferative neoplasm-associated thrombosis: A consensus-based position paper

“…Serum TXB 2 and urinary 2,3-dinor-6-keto-PGF 1a 60 are the most attainable biomarkers to test the adequacy of platelet COX-1 inactivation and sparing of endothelial COX-2, respectively, throughout a variable dosing interval of aspirin in the low-dose range. Recently, the design of a prospective study to find the most appropriate schedule of LDA based on biological biomarker modifications has been published and results are awaited soon 61 .…”