Results of a phase II trial showed twice daily dosing of low-dose aspirin was optimal in the setting of essential thrombocythemia (ET). These finding were reported in Blood.
ET, a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), is characterized by an increased production of platelets and an elevated risk of thrombosis. Based on mostly retrospective and observational studies, once daily low-dose aspirin is considered a standard-of-care for the treatment of patients with ET, given its inhibition of cyclooxygenase (COX)-1, an enzyme involved in the synthesis of thromboxane A2,a substance involved in platelet aggregation and blood clotting which is then converted into more stable thromboxane B2.
Nevertheless, inhibition of COX-1 has the potential to increase platelet production. Furthermore, more frequent dosing of low-dose aspirin may also inhibit the COX-2 enzyme involved in the production of prostacyclin I2 that facilitates preservation of the endothelium which itself has inhibitory effects on platelet production.
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The co-primary endpoints of the dose-finding components of this multicenter, randomized, double-blind clinical trial (Aspirin Regimens in Essential Thrombocythemia [ARES]; EudraCT 2016-002885-30) were to evaluate COX-1 inhibition (using serum thromboxane B2 as a surrogate measure) and COX-2 activity (based on the prostaglandin I2 metabolite in urine) associated with different low-dose aspirin regimens in patients with ET.1,2
Following a run-in of 7 to 10 days of once daily low-dose aspirin therapy taken at breakfast, 245 patients with ET on chronic aspirin therapy were randomly assigned in a 1:1:1 ratio to receive low-dose aspirin (100 mg) administered once-daily (at breakfast), twice-daily (at breakfast and dinner), or 3 times daily (at breakfast, lunch, and dinner). When necessary, matching placebo tablets were administered so that each patient received 3 tablets daily.
A key finding from this study was that, following 2 weeks of aspirin therapy, the median levels of serum thromboxane B2 were lower for those receiving low-dose aspirin 2 (4 ng/mL) or 3 times (2.5 ng/mL) daily compared with patients treated with once daily dosing (19.3 ng/mL). Furthermore, interpatient variability in serum thromboxane B2 levels was reduced for those receiving low-dose aspirin more than once daily.
In addition, a comparison across treatment groups did not show significant differences in the level of urinary prostacyclin I2 following 2 weeks of treatment, although patients receiving thrice daily doses of 100 mg aspirin reported a higher frequency of abdominal discomfort compared with patients in the other 2 study arms.
The study authors noted that “[w]e could demonstrate with high statistical confidence that a [twice daily] regimen of aspirin administration reduced interindividual variability in serum [thromboxane B2] and lowered by approximately 90% the residual serum [thromboxane B2] level. However, no further improvement in antiplatelet pharmacodynamics was achieved by a [3 times daily] regimen, suggesting that a ceiling effect was reached in matching accelerated renewal of the drug target with a shortened dosing interval.”
References
- Rocca B, Tosetto A, Betti S, et al. A randomized, double-blind trial of three aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia [published online April 7, 2020]. Blood. doi: 10.1182/blood.2019004596
- De Stefano V, Rocca B, Tosetto A, et al. 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.Blood Cancer J. 2018;8(6):49.
This article originally appeared on Oncology Nurse Advisor
