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On Defining Aspirin Resistance*
Journal of the American College of Cardiology © 2005 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
On Defining Aspirin Resistance* David J. Schneider, MD, FACC Burlington, Vermont Aspirin resistance is an increasingly common topic of research and clinical discussion. From a clinical perspective, patients who suffer a thrombotic event while taking aspirin are considered by some to exhibit aspirin resistance. In this issue of the Journal, Tantry et al. (1) employ rigorous criteria to identify a very low prevalence (⬍0.5%, only 1 of 223 patients) of aspirin resistance. This low prevalence is in contrast to a much greater prevalence reported by others who have used a variety of criteria and methods to define aspirin resistance. The disparity may reflect multiple factors, including patient compliance, the mechanisms by which aspirin exerts its beneficial effects, and methods used to implicate aspirin resistance. See page 1705 Tantry et al. (1) found that approximately 3% of patients were noncompliant. Thus, the majority of patients who were identified as being aspirin resistant in their study were “pseudoresistant” secondary to noncompliance. From a clinical perspective, compliance with aspirin therapy must be evaluated and shown to be present among all patients in whom aspirin resistance is ascribed. Both investigators and clinicians must evaluate and exclude noncompliance as a cause of aspirin resistance. Nearly 30 years ago, Roth and Majerus (2) demonstrated that the exposure of platelets to aspirin acetylates cylcooxygenase 1 and thereby inhibits production of thromboxane A2, a platelet agonist. Thromboxane A2 is released by activated platelets and mediates the activation of additional platelets. Thus, a primary pharmacological effect of aspirin on platelets is to decrease recruitment and activation of other platelets. Although Roth and Majerus (2) demonstrated acetylation of multiple other platelet proteins, functional implications (particularly antiplatelet effects) of such acetylation have not been defined. Thus, the recognized but not necessarily exclusive effect of aspirin on platelets is inhibition of production of thromboxane A2 resulting from acetylation of cylcooxygenase 1. Additional antithrombotic properties of aspirin may be mediated by its effect on coagulation factors such as fibrinogen (3) and factor XIII (4). Moreover, prevention of cardiac events may be mediated, at least in part, by effects *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiology Unit, Department of Medicine, Cardiovascular Research Institute, University of Vermont, Burlington, Vermont.
Vol. 46, No. 9, 2005 ISSN 0735-1097/05/$30.00 doi:10.1016/j.jacc.2005.08.014
independent of effects of aspirin on platelets or the coagulation cascade. For example, attenuation of inflammation by decreasing the release of inflammatory cytokines from leukocytes may reduce the subsequent incidence of cardiac events (5). Variability in the effect of aspirin on any of these phenomena or on those that have not yet been defined may attenuate the beneficial effects of aspirin and contribute to clinical evidence of aspirin resistance. Accordingly, the phenomenon of aspirin resistance cannot be completely delineated until all mechanisms by which aspirin exerts its beneficial effects have been fully elucidated. Tantry et al. (1) identified aspirin resistance by characterizing the lack of attenuation of platelet activation in response to an agonist, arichidonic acid that requires cyclooxygenase 1 for conversion to thromboxane A2. Thus, patients defined as being aspirin resistant exhibited continued cyclooxygenase activity despite treatment with aspirin. This narrow definition of aspirin resistance is defensible because of its reliance on a defined pharmacologic effect of aspirin. A potential weakness is that it may not reflect “resistance” attributable to additional antithrombotic effects of aspirin, such as the effect of aspirin on fibrinogen and factor XIII. Nevertheless, specific criteria that reflect pharmacologic resistance to aspirin are necessary to distinguish true aspirin resistance from increased platelet reactivity and other prothrombotic states despite treatment with aspirin. Multiple genetic and environmental influences can alter platelet reactivity and the propensity for thrombosis. Increased platelet reactivity has been associated with an increased risk of cardiac events (6,7). Accordingly, patients identified as being aspirin resistant when less narrow criteria are used to define aspirin resistance are likely to comprise a heterogeneous group with increased platelet reactivity secondary to diverse environmental and genetic influences. The greater risk of subsequent cardiac events in those deemed to be aspirin resistant with the use of less narrow criteria emphasizes the importance of uniform criteria for definition of aspirin resistance. Delineation of the molecular, genetic, and environmental mechanisms responsible for increased platelet reactivity will likely identify novel targets for therapy. Until this is possible, treatment of those with increased platelet reactivity should include not only aspirin but also more powerful antiplatelet agents, such as clopidogrel. Such treatment is likely to be associated with greater benefit with respect to the prevention of cardiac events than is treatment of an unselected group of patients with aspirin plus clopidogrel. The results of the important study by Tantry et al. (1) underscore the critical nature of the dependence of results on the techniques used in specific studies. For example, exposure of platelets to an agent that chelates calcium such as sodium citrate alters both platelet reactivity (8) and the antiplatelet effects of glycoprotein IIb/IIIa antagonists (9). In addition, inhibitory effects of antiplatelet agents are influenced greatly by the particular agonist and the concen-
Schneider Editorial Comment
JACC Vol. 46, No. 9, 2005 November 1, 2005:1710–1
trations chosen. These factors account for the unfortunate reality that the development and successful clinical use of glycoprotein IIb/IIIa antagonists was impeded initially by limitations associated with the techniques used to assess their pharmacodynamic effect (10). Tantry et al. (1) are to be commended for their performance of a study that tested for aspirin resistance defined specifically, albeit narrowly, with respect to residual platelet cyclooxygenase 1 activity in the presence of aspirin. Moreover, they identified an important contributor to pseudoaspirin resistance, patient noncompliance. Definition of specific mechanisms responsible for the greater incidence of persistently increased platelet reactivity despite treatment with aspirin that has been called aspirin resistance in other studies should identify potentially novel and effective therapeutic targets. Lessons learned during the development of glycoprotein IIb/IIIa antagonists and from the present study underscore the need for standardization of methods used to characterize platelet function. Reprint requests and correspondence: Dr. David J. Schneider, University of Vermont, 208 South Park Drive, Suite 2, Colchester, Vermont 05446. E-mail: [email protected].
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REFERENCES 10. 1. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thromboelastography platelet mapping and
1711
validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 2005;46:1705–9. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets: I: acetylation of a particulate fraction protein. J Clin Invest 1975;56:624 –9. He S, Blomback M, Yoo G, Sinha R, Henschen-Edman AH. Modified clotting properties of fibrinogen in the presence of acetylsalicylic acid in a purified system. Ann N Y Acad Sci 2001;936:531–5. Undas A, Sydor WJ, Brummel K, Musial J, Mann KG, Szczeklik A. Aspirin alters the cardioprotective effects of the factor XIII Val34Leu polymorphism. Circulation 2003;107:17–20. Tiran A, Gruber HJ, Graier WF, Wagner AH, Van Leeuwen EB, Tiran B. Aspirin inhibits Chlamydia pneumoniae-induced nuclear factor-kappa B activation, cytokine expression, and bacterial development in human endothelial cells. Arterioscler Thromb Vasc Biol 2002;22:1075– 80. Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survival of myocardial infarction. N Engl J Med 1990;322:1549 –54. Kabbani SS, Watkins MW, Ashikaga T, et al. Platelet reactivity characterized prospectively: a determinant of outcome 90 days after percutaneous coronary intervention. Circulation 2001;104:181– 6. Schneider DJ, Tracy PB, Mann KG, Sobel BE. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997;96:2877– 83. Phillips DR, Teng W, Arfsten A, et al. Effect of Ca2⫹ on GP IIb/IIIa interactions with integrelin: enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reductions in concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997;96: 1488 –94. Schneider DJ, Aggarwal A. Development of glycoprotein IIb/IIIa antagonists, translation of pharmacodynamic effects into clinical benefit. Expert Rev Cardiovasc Ther 2004;2:903–13.
EDITORIAL COMMENT
On Defining Aspirin Resistance* David J. Schneider, MD, FACC Burlington, Vermont Aspirin resistance is an increasingly common topic of research and clinical discussion. From a clinical perspective, patients who suffer a thrombotic event while taking aspirin are considered by some to exhibit aspirin resistance. In this issue of the Journal, Tantry et al. (1) employ rigorous criteria to identify a very low prevalence (⬍0.5%, only 1 of 223 patients) of aspirin resistance. This low prevalence is in contrast to a much greater prevalence reported by others who have used a variety of criteria and methods to define aspirin resistance. The disparity may reflect multiple factors, including patient compliance, the mechanisms by which aspirin exerts its beneficial effects, and methods used to implicate aspirin resistance. See page 1705 Tantry et al. (1) found that approximately 3% of patients were noncompliant. Thus, the majority of patients who were identified as being aspirin resistant in their study were “pseudoresistant” secondary to noncompliance. From a clinical perspective, compliance with aspirin therapy must be evaluated and shown to be present among all patients in whom aspirin resistance is ascribed. Both investigators and clinicians must evaluate and exclude noncompliance as a cause of aspirin resistance. Nearly 30 years ago, Roth and Majerus (2) demonstrated that the exposure of platelets to aspirin acetylates cylcooxygenase 1 and thereby inhibits production of thromboxane A2, a platelet agonist. Thromboxane A2 is released by activated platelets and mediates the activation of additional platelets. Thus, a primary pharmacological effect of aspirin on platelets is to decrease recruitment and activation of other platelets. Although Roth and Majerus (2) demonstrated acetylation of multiple other platelet proteins, functional implications (particularly antiplatelet effects) of such acetylation have not been defined. Thus, the recognized but not necessarily exclusive effect of aspirin on platelets is inhibition of production of thromboxane A2 resulting from acetylation of cylcooxygenase 1. Additional antithrombotic properties of aspirin may be mediated by its effect on coagulation factors such as fibrinogen (3) and factor XIII (4). Moreover, prevention of cardiac events may be mediated, at least in part, by effects *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Cardiology Unit, Department of Medicine, Cardiovascular Research Institute, University of Vermont, Burlington, Vermont.
Vol. 46, No. 9, 2005 ISSN 0735-1097/05/$30.00 doi:10.1016/j.jacc.2005.08.014
independent of effects of aspirin on platelets or the coagulation cascade. For example, attenuation of inflammation by decreasing the release of inflammatory cytokines from leukocytes may reduce the subsequent incidence of cardiac events (5). Variability in the effect of aspirin on any of these phenomena or on those that have not yet been defined may attenuate the beneficial effects of aspirin and contribute to clinical evidence of aspirin resistance. Accordingly, the phenomenon of aspirin resistance cannot be completely delineated until all mechanisms by which aspirin exerts its beneficial effects have been fully elucidated. Tantry et al. (1) identified aspirin resistance by characterizing the lack of attenuation of platelet activation in response to an agonist, arichidonic acid that requires cyclooxygenase 1 for conversion to thromboxane A2. Thus, patients defined as being aspirin resistant exhibited continued cyclooxygenase activity despite treatment with aspirin. This narrow definition of aspirin resistance is defensible because of its reliance on a defined pharmacologic effect of aspirin. A potential weakness is that it may not reflect “resistance” attributable to additional antithrombotic effects of aspirin, such as the effect of aspirin on fibrinogen and factor XIII. Nevertheless, specific criteria that reflect pharmacologic resistance to aspirin are necessary to distinguish true aspirin resistance from increased platelet reactivity and other prothrombotic states despite treatment with aspirin. Multiple genetic and environmental influences can alter platelet reactivity and the propensity for thrombosis. Increased platelet reactivity has been associated with an increased risk of cardiac events (6,7). Accordingly, patients identified as being aspirin resistant when less narrow criteria are used to define aspirin resistance are likely to comprise a heterogeneous group with increased platelet reactivity secondary to diverse environmental and genetic influences. The greater risk of subsequent cardiac events in those deemed to be aspirin resistant with the use of less narrow criteria emphasizes the importance of uniform criteria for definition of aspirin resistance. Delineation of the molecular, genetic, and environmental mechanisms responsible for increased platelet reactivity will likely identify novel targets for therapy. Until this is possible, treatment of those with increased platelet reactivity should include not only aspirin but also more powerful antiplatelet agents, such as clopidogrel. Such treatment is likely to be associated with greater benefit with respect to the prevention of cardiac events than is treatment of an unselected group of patients with aspirin plus clopidogrel. The results of the important study by Tantry et al. (1) underscore the critical nature of the dependence of results on the techniques used in specific studies. For example, exposure of platelets to an agent that chelates calcium such as sodium citrate alters both platelet reactivity (8) and the antiplatelet effects of glycoprotein IIb/IIIa antagonists (9). In addition, inhibitory effects of antiplatelet agents are influenced greatly by the particular agonist and the concen-
Schneider Editorial Comment
JACC Vol. 46, No. 9, 2005 November 1, 2005:1710–1
trations chosen. These factors account for the unfortunate reality that the development and successful clinical use of glycoprotein IIb/IIIa antagonists was impeded initially by limitations associated with the techniques used to assess their pharmacodynamic effect (10). Tantry et al. (1) are to be commended for their performance of a study that tested for aspirin resistance defined specifically, albeit narrowly, with respect to residual platelet cyclooxygenase 1 activity in the presence of aspirin. Moreover, they identified an important contributor to pseudoaspirin resistance, patient noncompliance. Definition of specific mechanisms responsible for the greater incidence of persistently increased platelet reactivity despite treatment with aspirin that has been called aspirin resistance in other studies should identify potentially novel and effective therapeutic targets. Lessons learned during the development of glycoprotein IIb/IIIa antagonists and from the present study underscore the need for standardization of methods used to characterize platelet function. Reprint requests and correspondence: Dr. David J. Schneider, University of Vermont, 208 South Park Drive, Suite 2, Colchester, Vermont 05446. E-mail: [email protected].
2.
3.
4.
5.
6.
7.
8.
9.
REFERENCES 10. 1. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance detection by thromboelastography platelet mapping and
1711
validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol 2005;46:1705–9. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets: I: acetylation of a particulate fraction protein. J Clin Invest 1975;56:624 –9. He S, Blomback M, Yoo G, Sinha R, Henschen-Edman AH. Modified clotting properties of fibrinogen in the presence of acetylsalicylic acid in a purified system. Ann N Y Acad Sci 2001;936:531–5. Undas A, Sydor WJ, Brummel K, Musial J, Mann KG, Szczeklik A. Aspirin alters the cardioprotective effects of the factor XIII Val34Leu polymorphism. Circulation 2003;107:17–20. Tiran A, Gruber HJ, Graier WF, Wagner AH, Van Leeuwen EB, Tiran B. Aspirin inhibits Chlamydia pneumoniae-induced nuclear factor-kappa B activation, cytokine expression, and bacterial development in human endothelial cells. Arterioscler Thromb Vasc Biol 2002;22:1075– 80. Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survival of myocardial infarction. N Engl J Med 1990;322:1549 –54. Kabbani SS, Watkins MW, Ashikaga T, et al. Platelet reactivity characterized prospectively: a determinant of outcome 90 days after percutaneous coronary intervention. Circulation 2001;104:181– 6. Schneider DJ, Tracy PB, Mann KG, Sobel BE. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997;96:2877– 83. Phillips DR, Teng W, Arfsten A, et al. Effect of Ca2⫹ on GP IIb/IIIa interactions with integrelin: enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reductions in concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997;96: 1488 –94. Schneider DJ, Aggarwal A. Development of glycoprotein IIb/IIIa antagonists, translation of pharmacodynamic effects into clinical benefit. Expert Rev Cardiovasc Ther 2004;2:903–13.