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

Obesity is raising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects drug's pharmacokinetics and/or pharmacodynamics. OBJECTIVES: To investigate pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects and to assess whether body weight (BW) or body mass index (BMI) would affect aspirin pharmacology. PATIENTS/METHODS: Otherwise healthy, obese (BMI>30kg/m2 ) subjects were studied before and after 3-4 weeks of 100mg once-daily aspirin. Aspirin pharmacodynamics was assessed by serum thromboxane (TX)B2 measured at 4, 24 (i.e. posological interval) and 48 hours after the last witnessed intake; age- 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 sixteen obese subjects (47±11 years, BMI 39.4±5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours post-aspirin were 3 to 5 folds increased compared to controls. At 24 hours, residual serum TXB2 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 reduced aspirin bioavailability inversely related to body size and rescued by 200 mg 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 due to body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.