Patients with Essential Thrombocythemia may be Poor Responders to Enteric-Coated Aspirin, but not to Plain Aspirin

Essential thrombocythemia (ET) patients are treated with aspirin (acetylsalicylic acid [ASA]) to prevent thrombosis. Previous studies showed that serum thromboxane (Tx) B2 was high 24 hours after enteric-coated (EC)-ASA in ET patients, due to increased number of noninhibited reticulated platelets (RPs), consequent to high platelet turnover, and that ASA should be given twice a day to ET patients. We studied ET patients (n = 17) and healthy subjects (n = 10) on 100 mg EC-ASA once daily; experiments were repeated after 14-day treatment with 100 mg plain-ASA once daily. Serum TxB2, plasma ASA, and salicylic acid (SA) were measured before the morning dose and up to 8 hours thereafter. Blood activity of ASA-deacethylating esterases, in vitro inhibition of collagen-induced TxB2 production by ASA (10–1,000 µM), and number of RP were measured. TxB2 inhibition by ASA in vitro and esterases activities were normal in all subjects. EC-ASA elicited highly variable responses; 6 ET patients were poor responders, as their serum TxB2 was high after EC-ASA; their plasma levels of ASA and SA were low/undetectable. In contrast to EC-ASA, plain ASA decreased serum TxB2 and increased plasma ASA and SA in all subjects. Serum TxB2 was high in ET patients at 24 hours and significantly correlated with RP count (but not RP percentage) and platelet count. Plain ASA should be used in ET patients to inhibit platelets efficiently. The identification of ET patients who might benefit from twice a day ASA could simply be based on their platelet count: since their platelet turnover is not increased, ET patients with normalized platelet count should not need twice a day ASA treatment.

P1935Pharmacokinetic and pharmacodynamic assessment of a lipid-based aspirin formulation: results of a prospective, randomised, crossover study

Objectives Aspirin, or acetylsalicylic acid (ASA), can lead to gastrointestinal mucosal injury through disruption of its protective phospholipid bilayer, underscoring the need for ASA formulations with a more favorable safety profile while maintaining an effective pharmacologic profile. A liquid formulation using a novel pharmaceutical lipid aspirin complex (PL-ASA) has been designed to prevent the disruption of the protective mucosal bilayer. We sought to determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of PL-ASA compared with traditional, immediate release aspirin (IR-ASA). Methods In this active-control crossover study, 16 healthy volunteers were randomized to receive a single dose of either IR-ASA 325 mg or PL-ASA 325 mg in a sequential fashion with a 2-week washout period between treatment assignments. The primary objectives of the study were to assess PK (i.e., plasma salicylic acid levels) and PD (i.e., serum thromboxane B2 levels) bioequivalence over a 24–hour period after drug administration, of PL-ASA and IR-ASA using established criteria. Results The PK parameter values were similar for PL-ASA and IR-ASA, with median AUC 0-t and Cmax values nominally higher for PL-ASA. Log-transformed PK parameters meeting FDA-criteria for bioequivalence (80% to 125%) are provided in the Table. Serum thromboxane B2 levels were similar for PL-ASA and IR-ASA, with Cmin values below 3.1 ng/mL (cut-off associated with decreased cardiovascular events) for both drugs. Both drugs also showed >99% inhibition of serum thromboxane B2 levels (≥95% inhibition represents the cut-off to define aspirin responders). Several secondary PK/PD parameters showed similarities between the two drugs (data not shown). Overall, these findings support functional and clinical equivalence between PL-ASA and IR-ASA. PK Results Parameter Ratio (PL-ASA/IR-ASA) 90% Confidence Interval AUC0-t 96.51 89.24, 104.37 Cmax 103.73 92.06, 116.89 Conclusions PL-ASA's novel liquid formulation has similar PK and PD performance compared with IR-ASA. The improved endoscopic safety profile of PL-ASA coupled with its pharmacologic efficacy equivalent to IR-ASA may result in an improved benefit-risk performance, warranting evaluation in future trials. Acknowledgement/Funding PLx Pharma, Inc.

Aspirin Resistance and Stroke

Stroke is a leading cause of death and disability worldwide. Aspirin is the most commonly used antiplatelet drug in both primary and secondary prevention of cerebrovascular and cardiovascular diseases. A proportion of patients may have stroke recurrence while they are on treatment with aspirin, giving rise to term aspirin resistance or aspirin failure. Studies have suggested that such recurrence could partly be attributed to biochemical aspirin resistance, with an estimated prevalence ranging between 5% and 65% among patients with ischemic stroke in the published studies. Common methods to evaluate laboratory aspirin resistance include light transmission aggregometry, PFA-100, VerifyNow-Aspirin assay, serum thromboxane B2, and urinary 11-dehydrothromboxane B2. Aspirin resistance is multifactorial in origin and involves diverse environmental and genetic factors, including single-nucleotide polymorphisms, miRNAs, drug interactions, and co-morbid risk factors. The current review overviews the concept of aspirin resistance, its evaluation and relationship with stroke recurrence, its outcome, and its implications on stroke management in the future.