Original Investigation
Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus

https://doi.org/10.1016/j.jacc.2016.11.050Get rights and content
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Abstract

Background

A limitation of aspirin is that some patients, particularly those with diabetes, may not have an optimal antiplatelet effect.

Objectives

The goal of this study was to determine if oral bioavailability mediates nonresponsiveness.

Methods

The rate and extent of serum thromboxane generation and aspirin pharmacokinetics were measured in 40 patients with diabetes in a randomized, single-blind, triple-crossover study. 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 h after 3 daily aspirin doses.

Results

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 (63% and 70% lower geometric mean maximum plasma concentration [Cmax] and 77% and 82% lower AUC0–t [area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximum decrease of TXB2, with marked interindividual variability.

Conclusions

A high proportion of patients treated with EC aspirin failed to achieve complete inhibition of TXB2 generation due to incomplete absorption. Reduced bioavailability may contribute to “aspirin resistance” in patients with diabetes. (Pharmacodynamic Evaluation of PL2200 Versus Enteric-Coated and Immediate Release Aspirin in Diabetic Patients; NCT01515657)

Key Words

acetylsalicylic acid
enteric coating
pharmacodynamics
pharmacokinetics
platelet function
thromboxane

Abbreviations and Acronyms

AA
arachidonic acid
ASA
acetylsalicylic acid
AUC0–t
area under the curve from time 0 to the last time measured
Cmax
maximum plasma concentration
Cmin
minimum concentration
COX
cyclooxygenase
EC
enteric-coated
PD
pharmacodynamic
PK
pharmacokinetic
T99%inhibition
time to ≥99% inhibition of serum thromboxane B2
TX
thromboxane
TXB2
thromboxane B2

Cited by (0)

This study was funded by PLx Pharma Inc. Dr. Bhatt has served on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; chair for the American Heart Association Quality Oversight Committee; data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor and Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); served as Deputy Editor for Clinical Cardiology; served as chair for the NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has received research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as a site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical; has served as a trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma Inc., and Takeda. Dr. Grosser has received consulting fees from PLx Pharma Inc., Bayer Healthcare, and Aralez Pharmaceuticals; and is an Associate Editor for Circulation: Cardiovascular Genetics. Dr. Angiolillo has received payment as an individual for consulting fee or honorarium from Sanofi, Daiichi-Sankyo, Inc., Eli Lilly and Company, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, Amgen, Bayer, Pfizer, and PLx Pharma; participation in review activities from CeloNova, Johnson & Johnson, and St. Jude Medical; and institutional payments for grants from GlaxoSmithKline, Daiichi-Sankyo, Inc., Eli Lilly and Company, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc., Novartis, CSL Behring, and Gilead. Dr. Jeske is the principal investigator on a research grant to Loyola University Chicago from BioData Corporation; and is a consultant to PLx Pharma Inc., Machaon Diagnostics, and Repros Therapeutics. Dr. Frelinger is the principal investigator or co-investigator on research grants to Boston Children’s Hospital from Baxalta, Bristol-Myers Squibb, Eisai, Eli Lilly, Daiichi-Sankyo, GE Healthcare, GLSynthesis, Pfizer, and Sysmex; and is a consultant to PLx Pharma. Mr. Moore is an officer and employee of PLx Pharma Inc. Dr. Marathi is an investor, officer, and employee of PLx Pharma Inc.; is the co-inventor of the PL2200 technology; and holds equity and options to buy equity in 7 Hills Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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© 2017 by the American College of Cardiology Foundation. Published by Elsevier.