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

Deepak L. Bhatt, Tilo Grosser, Jing fei Dong, Douglas Logan, Walter Jeske, Dominick J. Angiolillo, Andrew L. Frelinger, Lanyu Lei, Juan Liang, Jason E. Moore, Byron Cryer, Upendra Marathi

Research output: Contribution to journalArticle

49 Citations (Scopus)

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)

Original languageEnglish (US)
Pages (from-to)603-612
Number of pages10
JournalJournal of the American College of Cardiology
Volume69
Issue number6
DOIs
StatePublished - Feb 14 2017

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Aspirin
Thromboxane B2
Biological Availability
Serum
Thromboxanes
Cross-Over Studies
Area Under Curve

Keywords

  • acetylsalicylic acid
  • enteric coating
  • pharmacodynamics
  • pharmacokinetics
  • platelet function
  • thromboxane

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Bhatt, D. L., Grosser, T., Dong, J. F., Logan, D., Jeske, W., Angiolillo, D. J., ... Marathi, U. (2017). Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. Journal of the American College of Cardiology, 69(6), 603-612. https://doi.org/10.1016/j.jacc.2016.11.050

Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. / Bhatt, Deepak L.; Grosser, Tilo; Dong, Jing fei; Logan, Douglas; Jeske, Walter; Angiolillo, Dominick J.; Frelinger, Andrew L.; Lei, Lanyu; Liang, Juan; Moore, Jason E.; Cryer, Byron; Marathi, Upendra.

In: Journal of the American College of Cardiology, Vol. 69, No. 6, 14.02.2017, p. 603-612.

Research output: Contribution to journalArticle

Bhatt, DL, Grosser, T, Dong, JF, Logan, D, Jeske, W, Angiolillo, DJ, Frelinger, AL, Lei, L, Liang, J, Moore, JE, Cryer, B & Marathi, U 2017, 'Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus', Journal of the American College of Cardiology, vol. 69, no. 6, pp. 603-612. https://doi.org/10.1016/j.jacc.2016.11.050
Bhatt, Deepak L. ; Grosser, Tilo ; Dong, Jing fei ; Logan, Douglas ; Jeske, Walter ; Angiolillo, Dominick J. ; Frelinger, Andrew L. ; Lei, Lanyu ; Liang, Juan ; Moore, Jason E. ; Cryer, Byron ; Marathi, Upendra. / Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus. In: Journal of the American College of Cardiology. 2017 ; Vol. 69, No. 6. pp. 603-612.
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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)",
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T1 - Enteric Coating and Aspirin Nonresponsiveness in Patients With Type 2 Diabetes Mellitus

AU - Bhatt, Deepak L.

AU - Grosser, Tilo

AU - Dong, Jing fei

AU - Logan, Douglas

AU - Jeske, Walter

AU - Angiolillo, Dominick J.

AU - Frelinger, Andrew L.

AU - Lei, Lanyu

AU - Liang, Juan

AU - Moore, Jason E.

AU - Cryer, Byron

AU - Marathi, Upendra

PY - 2017/2/14

Y1 - 2017/2/14

N2 - 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)

AB - 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)

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KW - pharmacodynamics

KW - pharmacokinetics

KW - platelet function

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