Twice-Daily Low-Dose Aspirin Improves Antiplatelet Response in Essential Thrombocythemia

Once-daily aspirin 75 to 100 mg is the current recommended antithrombotic regimen for patients with essential thrombocythemia (ET), but once-daily aspirin may not be enough to consistently inhibit platelet cyclooxygenase (COX)-1. According to a study published in Blood, twice-daily aspirin 100 mg administered could improve the antiplatelet response compared with once-daily low-dose aspirin in these patients, the authors, led by Bianca Rocca, MD, of the Universitá Cattolica in Milan, Italy, wrote.

To define the optimal antiplatelet regimen in patients with ET, Dr. Rocca and colleagues conducted the multicenter, double-blind, phase II Aspirin Regimens in Essential Thrombocythemia (ARES) trial. The researchers examined the efficacy of three aspirin regimens, and compared the degree of platelet COX-1 inhibition and preservation of COX-2-dependent vascular thromboresistance between arms.

A total of 245 patients with ET who were receiving chronic once-daily low-dose aspirin for prevention of a cardiovascular-event and thromboembolism were randomized to receive one of the following three aspirin protocols:

  • once-daily aspirin 100 mg (n=86)
  • twice-daily aspirin 100 mg (n=79)
  • thrice-daily aspirin 100 mg (n=80)

Participants were instructed to take their usual once-daily aspirin for 7 to 10 consecutive days prior to randomization. Then, during the 2-week randomized treatment period, all patients in the first two groups took a matching placebo to equal or mimic a thrice-daily treatment regimen.

Researchers collected fasting blood and urine samples from patients prior to the next aspirin dosing at randomization and 2-week follow-up to evaluate the pharmacodynamic efficacy of each low-dose aspirin strategy, determined by residual serum thromboxane B2 (sTXB₂), a metabolite biomarker of platelet COX-1 activity. The other co-primary endpoint was vascular safety, assessed by urinary prostacyclin metabolite (PGIM) excretion, an index of endothelial COX-2 activity.

In addition to PGIM, the researchers also examined urinary thromboxane metabolite (TXM) excretion. Furthermore, gastrointestinal tolerance and microvascular symptoms were assessed by the following questionnaires:

  • Severity of Dyspepsia Assessment (SODA)
  • a validated questionnaire that assessed symptoms related to myeloproliferative neoplasms
  • self-scored Pain Numeric Rating Scale (PNRS) for erythromelalgia of hands and feet

The median age of enrolled patients was 60 years (interquartile range [IQR] = 51-67 years), and the median TXB₂ prior to randomization was 19 ng/ml (IQR=9.3-43.2 ng/mL). The serum TXB₂ levels at randomization were similar across all treatment groups.

One patient assigned to once-daily aspirin 100 mg exited the study due to abdominal pain and 1 patient had no serum sample available at the last follow-up visit, leaving 243 patients evaluable for the endpoints.

The authors reported that, after 2 weeks of treatment, patients who received aspirin 100 mg twice- or thrice-daily experienced substantial reductions in serum TXB₂ values. Between randomization and follow-up, the median values of serum TXB₂ reductions were as follows:

  • twice-daily aspirin 100 mg: from 20 ng/mL (IQR=11.6-6.4) to 4 ng/mL (IQR=2.1-6.7)
  • thrice-daily aspirin 100 mg: from 23.3 ng/mL (IQR=9.6-46.4) to 2.5 ng/mL (IQR=1.4-5.7)

In comparison, patients who were assigned to receive once-daily aspirin experienced “no appreciable short-term change in platelet COX-1 inhibition,” the authors reported.

When the investigators analyzed median PGIM values, they found that both the twice-daily and thrice-daily treatment arms demonstrated a 35% reduction in urinary TXM from baseline to 2-week follow-up. However, there was no significant difference between the three arms at randomization (p=0.96) or follow-up (p=0.70).

According to patient responses to questionnaires, treatment with aspirin 100 mg thrice daily was associated with a significantly higher gastrointestinal (GI) disturbances score than with once- or twice-daily dosing, but the researchers noted that these GI events did not require medical intervention during the 2-week study duration. There was no difference between the treatment arms regarding microvascular disturbance scores. In addition, the researchers reported no major bleeding events or adverse cardiovascular events during the 2-week treatment period or during the following 2-week observation period.

“We found high absolute values and marked interindividual variability in serum TXB₂, a validated biomarker of low-dose aspirin efficacy, with the vast majority of ET patients displaying biochemical evidence of inadequate platelet inhibition when treated with a standard low-dose aspirin regimen,” the authors concluded. While twice-daily aspirin reduced interindividual variability in serum TXB₂ and lowered the residual serum TXB₂ level, there was no further improvement in antiplatelet pharmacodynamics achieved with the thrice-daily regimen.

Limitations of this study include the small sample sizes in each randomized group, as well as the short 2-week duration of treatment. The study authors added that, based on the results from this dose-finding portion of ARES, they selected the twice-daily aspirin regimen for evaluation in an ongoing phase of the trial, which will re-randomize patients with ET to examine “long-term superiority, compliance, and tolerability of an optimized aspirin regimen.”

The study authors report no relevant conflicts of interest.


Rocca B, Tosetto A, Betti S, et al. A randomized, double-blind trial of three aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia. Blood. 2020 April 7. [Epub ahead of print]

Controlled studies have confirmed the anti-thrombotic value of low-dose aspirin in polycythemia vera (PV) across all risk categories.1 The rationale for aspirin use in ET, especially in JAK2 mutated cases, is inferred from the aforementioned controlled experience in PV.1 Aspirin therapy has also been reported, in a retrospective study, to be beneficial in JAK2-mutated low-risk ET.2

Despite our current cornerstone treatment approach of low-dose aspirin therapy with or without cytoreduction, the rate of thrombotic events in both ET and PV remain high enough to warrant either additional or alternative anti-thrombotic treatment or modification of drug dosing.3,4 The authors of this paper demonstrate the superiority of twice-daily versus once-daily dosing in suppressing platelet COX-1 activity while preserving COX-2-dependent vascular effect, with no additional value from thrice-daily dosing. The putative mechanism at work is believed to stem from the inadequacy of once-daily aspirin in securing 24-hour coverage in suppressing COX-1 activity as a result of accelerated platelet production that overcomes the otherwise normally observed irreversible acetylation of COX-1 in platelets and megakaryocytes.

In the absence of overt contraindications to aspirin use, I am currently using the twice-daily dosing schedule in my patients with JAK2-mutated ET and PV. Controlled clinical trials are needed to confirm the safety and value of this approach.

Ayalew Tefferi, MD
Mayo Clinic
Rochester, MN


  1. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350:114-24.
  2. Alvarez-Larran A, Cervantes F, Pereira A, et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood. 2010; 116:1205-10.
  3. Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J. 2015;5:e369.
  4. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-33.