A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia

Abstract

<jats:title>Abstract</jats:title> <jats:p>Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).</jats:p>

Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature

“…60 The possible absence of impact of aspirin on thrombosis and bleeding risk may be due to an insufficient control of platelet COX-1 activity with a once-daily low dose of aspirin. 67 Studies on VKAs or DOACs are also lacking in this population. Such studies have been conducted in the general population, e.g., VKAs versus placebo, 50 DOACs versus VKAs, 51,52 and the combination of DOAC and aspirin versus DOAC and placebo.…”

Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk‐stratification and management

“…78 Finally, we believe it is reasonable to use twice-daily aspirin in patients with arterial thrombosis if they are older or harbor JAK2 mutations or in the presence of CV risk factors (Figures 5 and 6). 47 In patients with venous thrombosis, systemic anticoagulation is advised and the addition of once-daily low dose aspirin, in the presence of JAK2 mutation or CV risk factors, is reasonable. The therapeutic role of direct oral anticoagulants is currently being investigated and has been suggested in retrospective studies, 107 as well as in those with splanchnic vein thrombosis, where recurrence might 108 or might not 109 mutation and without history of thrombosis) and treatment approach in such cases should be individualized.…”

Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism – results from clinical observation studies

“…For patients requiring ASA after discontinuation of the standard anticoagulant treatment, it is important to reassess the response to ASA and in case of low responders to consider alternative prophylactic measures. It has been recently demonstrated that twice daily low dose ASA significantly improves the antiplatelet response in patients with Essential Thrombocythemia, recognized as low-responders to once daily low dose ASA [35] .…”