Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

Abstract

Background:The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. Objectives:To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin.Patients/Methods: Otherwise healthy, obese (BMI > 30 kg/m 2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B 2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; agematched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB 2 data from obese subjects. At baseline, the major urinary TXA 2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. Results:In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m 2 ), residual serum TXB 2 values between 4 and 48 hours after aspirin intake were increased 3-to 5-fold as compared with controls. At 24 hours, the residual serum TXB 2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA 2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. Conclusions:Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional lowdose aspirin may affect antithrombotic efficacy.

Measurement of Thromboxane Biosynthesis in Health and Disease

“…Thus, under conditions of normal thrombopoiesis, the efficacy of a short-lived drug given once daily reflects irreversible inactivation of a slowly renewable drug target (platelet COX-1) combined with an effect on bone-marrow platelet progenitors, leading to a new platelet progeny with largely non-functioning COX-1 for the vast majority of the 24-h dosing interval (Giaretta et al, 2017). However, reduced systemic bioavailability of aspirin, as may occur with some enteric-coated formulations (Maree et al, 2005) and in association with obesity (Petrucci et al, 2019), or faster renewal of platelet COX-1, as reported under conditions of altered megakaryopoiesis (Pascale et al, 2012), may shorten the duration of the antiplatelet effect of aspirin and dictate a more frequent dosing regimen (Patrono et al, 2013).…”

“…Obesity is associated with biochemical evidence of persistently enhanced platelet activation (Davì et al, 2002; Petrucci et al, 2019) and high risk of atherothrombotic complications (reviewed by Rocca et al, 2018). Recently, Rothwell et al (2018) analyzed individual data of 117,279 subjects recruited into 10 primary prevention trials and reported that low doses of aspirin (75–100 mg) were only effective in preventing major vascular events in subjects with body weight lower than 70 kg, and had no benefit in the vast majority of men and nearly 50% of all women weighing 70 kg or more.…”

“…Increased body size, fat excess, and the associated changes in volume of distribution and liver function may all reduce the bioavailability of a lipophilic drug such as aspirin (Patrono and Rocca, 2017). Petrucci et al (2019) recently reported measurements of serum TXB 2 at the end of the 24-h dosing interval in 100 aspirin-treated subjects with a wide range of body mass index (BMI) and body weight values. A statistically significant exponential association was observed between body size, expressed as either BMI or body weight, and residual serum TXB 2 values ( Figure 5 ) (Petrucci et al, 2019).…”

“…Petrucci et al (2019) recently reported measurements of serum TXB 2 at the end of the 24-h dosing interval in 100 aspirin-treated subjects with a wide range of body mass index (BMI) and body weight values. A statistically significant exponential association was observed between body size, expressed as either BMI or body weight, and residual serum TXB 2 values ( Figure 5 ) (Petrucci et al, 2019). Thus, a standard, once‐daily 100-mg aspirin regimen appears to be inadequate to fully inhibit platelet COX‐1 activity throughout the 24-h dosing interval in moderately to severely obese subjects.…”

Highlights from the 2019 International Aspirin Foundation Scientific Conference, Rome, 28 June 2019: benefits and risks of antithrombotic therapy for cardiovascular disease prevention

“…Currently, we rely on consensus expert advice to guide these clinical scenarios, for example, the ESC Working Group on Thrombosis consensus statement on aspirin and obesity, which advices that while limited data is available on aspirin dosing in people with a body mass index (BMI) above 40 kg/m 2 , it is reasonable to double the daily low dose of aspirin or give a twice-daily low dose. Recent work has shown a higher residual TXB 2 in moderate-to-severe obese people in contrast to non-obese subjects in their response to once-daily low dose aspirin, and in fact, increasing residual serum TXB 2 was found to be exponentially correlated with BMI and body weight in 100 subjects taking standard low-dose aspirin (100 mg once daily) [50].…”