Aspirin Dosing Considerations In Essential Thrombocythemia: The ARES Trial
Overview
In patients diagnosed with essential thrombocythemia (ET), the standard treatment involves once-daily low-dose aspirin to mitigate the risk of thrombosis. However, due to accelerated platelet turnover in these patients, the antiplatelet effect of aspirin diminishes over time. A study called the Short-term Aspirin Regimens in Essential Thrombocythemia (SARITE) demonstrated that twice-daily dosing of aspirin restores persistent inhibition of platelet thromboxane (TX). Despite this finding, the long-term effectiveness, safety, and tolerability of the twice-daily regimen remained unexplored.
To address these gaps, we conducted a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial involving 242 ET patients. Participants were randomly assigned to receive either 100 mg of aspirin twice daily or once daily and were monitored over a period of 20 months. The primary endpoint was the maintenance of low serum TXB2 levels, a biomarker indicating the efficacy of the antithrombotic effect. Secondary endpoints included major and clinically relevant non-major bleeding, serious vascular events, symptom severity assessed through validated questionnaires, and in vivo platelet activation.
Throughout the study, serum TXB2 levels were consistently lower in the twice-daily group compared to the once-daily group across 10 visits spanning the 20-month period (median 3.9 ng/mL vs. 19.2 ng/mL, respectively; p < .001). This represented an 80% median reduction with a 95% confidence interval ranging from 74% to 85%. Importantly, there were no occurrences of major bleeding in either group. Clinically relevant non-major bleedings were slightly higher in the twice-daily group (6.6% vs. 1.7%). However, this difference was not seen to be statistically significant. Conversely, major thrombotic events were less frequent in the twice-daily group compared to the once-daily group (0.8% vs. 2.5%).
Patients on the twice-daily regimen reported significantly lower frequencies of disease-specific symptoms and less severe microvascular pain in the hands and feet compared to those on the once-daily regimen. Upper gastrointestinal pain was similar between both groups. Additionally, the twice-daily regimen resulted in a notable reduction in in vivo platelet activation.
In conclusion, among patients with ET, the twice-daily administration of low-dose aspirin demonstrated persistent superiority over the once-daily regimen in suppressing thromboxane biosynthesis and reducing symptom burden. Importantly, this regimen did not show any increased risk of bleeding or gastrointestinal discomfort. These findings suggest that twice-daily dosing of aspirin could be a more effective therapeutic approach in managing ET, warranting further consideration in clinical practice.
Introduction
Essential thrombocythemia (ET) is characterized by abnormal platelet production, posing an increased risk of thrombosis and other hematological complications. Current management typically includes low-dose aspirin (75-100 mg daily) to mitigate thrombotic events, despite varying responses among patients due to accelerated platelet generation and cyclooxygenase (COX)-1 activity recovery.
The Aspirin Regimens in Essential Thrombocythemia (ARES) study explored different dosing intervals of aspirin in 252 ET patients. It revealed that twice-daily administration of 100 mg aspirin optimally suppresses platelet thromboxane A2 production, crucial for inhibiting thrombosis without compromising vascular prostacyclin biosynthesis, essential for endothelial health.
This phase-2 trial aims to further investigate the long-term effectiveness of twice-daily 100 mg aspirin compared to the standard once-daily regimen in ET patients. The primary endpoint focuses on sustained pharmacodynamic superiority, assessing platelet thromboxane suppression. Additionally, the study will evaluate disease-related symptoms, treatment tolerability, adherence rates, and safety profiles associated with the intensified dosing regimen.
Understanding the optimal aspirin regimen is critical in managing ET to reduce thrombotic risk effectively while ensuring patient safety and treatment compliance. Results from this trial promise to refine therapeutic strategies and enhance outcomes for individuals with ET, addressing a significant clinical need in myeloproliferative neoplasm management.
Method
We conducted a randomized, open-label, blinded-endpoint trial over 20 months to evaluate the pharmacodynamic and clinical impacts of administering 100 mg aspirin either twice daily or once daily. This study, involving patients with essential thrombocythemia (ET), was carried out at ten hematological centers in Italy. It was registered under the EU clinical trial register (EudraCT 2016–2.002885-30) and approved by the Ethics Committee of Fondazione Policlinico Universitario A. Gemelli IRCCS (Protocol #28371/16, ID 1285). Written informed consent was obtained from all participants, and the protocol is detailed in the Supplemental Material.
Eligible participants were adults diagnosed with ET per the 2016 WHO criteria, on low-dose aspirin prophylaxis for at least one month. Exclusion criteria included platelet counts >1000 x 10^9/L, history of major bleeding, and chronic NSAID use. Detailed inclusion and exclusion criteria are in the Supplemental Material.
Baseline data recorded included cardiovascular risk factors, JAK2, CALR, and MPL gene mutational status, and history of thrombotic events. At each visit, blood counts, liver and kidney function tests, new comorbidities, medication changes, and thrombotic or hemorrhagic events were documented. Data were managed using REDCap.
Participants were randomized to receive 100 mg aspirin twice daily or once daily at breakfast, with stratification by center and sex. Investigators analyzing prostanoid measurements and data were blinded to treatment assignments.
Participants attended three initial visits within the first 5 ± 1 weeks, followed by quarterly visits for 20 months. Blood and urine samples were collected in the morning, fasting, before aspirin dosing.
The primary endpoint was the long-term pharmacodynamic efficacy of the twice-daily regimen, assessed by serum TXB2 measurements. Urinary 11-dehydro-TXB2 was used to evaluate in vivo platelet activation. Data on disease-specific symptoms were collected using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and other validated scales for gastrointestinal symptoms.
The primary endpoint was the persistent superior pharmacodynamic efficacy of twice-daily aspirin, reflected in serum TXB2 levels. Secondary endpoints included thrombotic complications, symptom burden, treatment tolerability, and in vivo platelet activation. Safety was monitored by recording major and clinically relevant non-major bleeding events and other adverse effects.
Statistical Analyses
The study required 112 patients per arm to detect a significant reduction in serum TXB2 with 80% power and a 5% significance level. Data analysis was intention-to-treat, with primary endpoint assessment using the Wilcoxon test and secondary endpoint frequencies evaluated by chi-square statistics. Subgroup analyses and post-hoc evaluations were also conducted.
The study was funded by the Italian Medicines Agency (AIFA), with trial medication provided by Bayer AG. The funding bodies had no influence on study design, data analysis, or manuscript preparation. All authors reviewed and approved the final manuscript and ensured adherence to the protocol.
Result
The study began with the first patient enrollment on November 14, 2018, and concluded with the last patient on March 30, 2019, ending on February 23, 2021. A total of 242 patients were randomized to receive either 100 mg of aspirin once daily (n=120) or twice daily (n=122). The completion rate was high, with 92% of participants finishing all planned evaluations. Due to the COVID-19 pandemic, 24 visits were conducted online.
The median age was 61 years, with 46% being male. Patients had a median platelet count of 528 x 10^9/L and a median disease duration of 6 years. Most participants were on low-dose aspirin for at least a month, and over half were also on hydroxyurea.
Adherence to the treatment was reported at 99% in both groups. During a 20-month follow-up, the primary endpoint showed that serum TXB2 levels were significantly lower in the twice-daily aspirin group compared to the once-daily group, with no time-related attenuation observed.
Secondary endpoints included symptom burden, thrombotic outcomes, and in vivo platelet activation. Patients in the twice-daily group reported significantly lower symptom scores and fewer severe symptoms compared to the once-daily group. Major thrombotic events were rare, with fewer occurrences in the twice-daily group. Additionally, in vivo platelet activation was significantly reduced in the twice-daily group, as indicated by lower urinary 11-dehydro-TXB2 excretion.
Safety profiles showed no major bleeding events, although clinically relevant non-major bleedings were slightly higher in the twice-daily group. The frequency of gastrointestinal discomfort was comparable between both groups. Other adverse events were deemed unrelated to the experimental treatment.
Overall, the study concluded that a twice-daily aspirin regimen resulted in better pharmacodynamic outcomes and symptom management compared to a once-daily regimen, with an acceptable safety profile.
Conclusion
Essential thrombocythemia (ET) is characterized by a heightened incidence of thrombotic and microvascular complications. A significant cohort study of 9429 myeloproliferative neoplasm (MPN) patients, including 3462 with ET, found that thrombosis rates were 1.7 to 3.5 times higher in ET patients compared to matched controls. Low-dose aspirin (81 to 100 mg daily) is widely regarded as the cornerstone of antithrombotic therapy for ET, though this is largely based on consensus rather than randomized trials. The benefits of aspirin for ET are extrapolated from studies on polycythemia vera and retrospective analyses.
The efficacy and safety of antiplatelet therapy in ET remain unproven due to the rarity of the disease and the low rate of vascular events, making large-scale trials impractical. Nonetheless, aspirin’s role as an antiplatelet agent was developed through the measurement of serum thromboxane B2 (TXB2), which is a surrogate for platelet aggregation and cardiovascular event prevention.
Human platelets have a high capacity to produce and release thromboxane A2 (TXA2), necessitating nearly complete suppression of platelet COX-1 activity to effectively reduce platelet activation. This level of suppression can be achieved with a daily aspirin regimen of 75-100 mg but not with other NSAIDs. Incomplete suppression by NSAIDs like ibuprofen or diclofenac has shown no cardioprotective effects and failed to prevent complications related to COX-2 inhibition.
Previous findings by the ARES Investigators indicated that standard low-dose aspirin often inadequately suppresses serum TXB2 in ET patients, likely due to accelerated renewal of platelet COX-1. This contrasts with results in polycythemia vera patients, questioning the validity of applying polycythemia vera study outcomes to ET patients.
In a study comparing once-daily and twice-daily low-dose aspirin regimens in ET patients, twice-daily dosing was found to be more effective in suppressing platelet COX-1 activity and reducing TXA2/TXB2 biosynthesis. This regimen showed a significant decrease in urinary 11-dehydro-TXB2 excretion, which is associated with lower all-cause and cardiovascular mortality and serious vascular events.
ET patients often experience microvascular disturbances such as erythromelalgia, headache, and visual disturbances, which impair quality of life. Approximately 29% of ET patients experience these symptoms, which can predict recurrent thrombotic events. Current guidelines suggest improving disease-specific symptoms as a treatment goal, but cytoreductive treatment is generally not recommended for low-risk patients.
The study demonstrated that twice-daily low-dose aspirin significantly reduces overall symptom burden compared to once-daily dosing, particularly in patients with severe symptoms. Improved platelet inhibition correlated with reduced severe peripheral microvascular pain, supporting the role of TXA2-mediated platelet activation and vasoconstriction in these symptoms.
Although the study had limitations, including its sample size and open-label design, the findings suggest that a twice-daily low-dose aspirin regimen could be a more effective strategy for managing ET. This regimen showed better suppression of platelet TXA2 production and reduced microvascular symptoms without increased bleeding or gastrointestinal issues. The results advocate for revising current clinical guidelines to incorporate this optimized aspirin regimen for ET patients.
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