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/m² ) 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) B₂ levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB₂ data from obese subjects. At baseline, the major urinary TXA₂ 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/m² ), residual serum TXB₂ 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 TXB₂ 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 TXA₂ 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 low-dose aspirin may affect antithrombotic efficacy.

Keywords: aspirin; body mass index; obesity; platelets; thromboxane A2.