Enteric Coating and Aspirin Nonresponsiveness in Diabetes

Study Questions:

What is the influence of aspirin formulation on its drug response?


For this study, the rate and extent of serum thromboxane generation and aspirin pharmacokinetics were measured in 40 patients with diabetes mellitus in a randomized, single-blind, triple-crossover design. Patients were exposed to three 325 mg aspirin formulations: plain aspirin, PL2200 (a modified-release lipid-based aspirin), and a delayed-release enteric-coated (EC) aspirin. Onset of antiplatelet activity was determined by the rate and extent of inhibition of serum thromboxane B2 (TXB2) generation. Aspirin nonresponsiveness was defined as a level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/ml) within 72 hours after 3 daily aspirin doses. T99%inhibition was analyzed by using a mixed-effects model, with sequence, period, and treatment as fixed effects, and patient as a random effect.


The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin–treated subjects had serum TXB2 levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (ASA) (63% and 70% lower geometric mean maximum plasma concentration and 77% and 82% lower AUC0–t [area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximal decrease of TXB2, with marked interindividual variability.


The authors concluded that a high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB2 generation due to incomplete absorption.


This study reports a substantial variability in antiplatelet response to dosing with 325 mg of EC aspirin in patients with diabetes mellitus. A significant proportion of patients receiving EC aspirin meeting the criteria for nonresponders had no detectable plasma aspirin level at the times measured. It seems that among the various mechanisms of aspirin resistance invoked, the simplest explanation for reduced aspirin responsiveness may be due to reduced bioavailability or absorption of ASA. While additional studies are indicated to assess the clinical relevance of this observation, EC aspirin use should be discouraged for now, at least among diabetic individuals.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism

Keywords: Aspirin, Biological Availability, Diabetes Mellitus, Diabetes Mellitus, Type 2, Metabolic Syndrome X, Pharmacokinetics, Platelet Aggregation Inhibitors, Primary Prevention, Tablets, Enteric-Coated, Thromboxane B2, Thromboxanes

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