Impact of Aspirin Dosing on the Effects of P2Y12 Inhibition in Patients with Acute Coronary Syndromes

Article

Abstract

The discovery of the antiplatelet effect of low-dose aspirin led to the hugely successful strategy of dual antiplatelet therapy in patients with acute coronary syndromes (ACS). Increasing the dose of aspirin beyond 75–100 mg has never been shown to offer additional efficacy in ACS patients but could possibly increase the risk of bleeding. In the Platelet Inhibition and Patients Outcome (PLATO) study, higher doses of aspirin appeared to neutralise the additional benefit of the potent P2Y12 inhibitor ticagrelor compared to clopidogrel (Circulation 124: 544–554, 2011). However, higher doses of aspirin have not been shown to have an adverse interaction with the potent P2Y12 inhibition provided by prasugrel and double-dose clopidogrel (Journal of the American College of Cardiology, 2013, in press; N Engl J Med 363: 930–942, 2010). This potentially suggests that the mechanism for this interaction is not related to the inhibition of platelet P2Y12 receptors or could simply be a chance finding.

Keywords

Aspirin dose P2Y12 inhibitor Acute coronary syndromes Ticagrelor Prasugrel Clopidogrel 

References

  1. 1.
    Mahaffey, K. W., Wojdyla, D. M. D., Carroll, K. K., Becker, R. C., Storey, R. F., Angiolillo, D. J., et al. (2011). Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation, 124, 544–554.PubMedCrossRefGoogle Scholar
  2. 2.
    Kohli, P., Udell, J.A. Murphy, S.A., Cannon, C.P., Antman, E.M., Braunwald, E., Wiviott. S.D. (2013). Discharge Aspirin Dose and Clinical Outcomes in Patients with Acute Coronary Syndromes treated with Prasugrel vs. Clopidogrel: An Analysis from the TRITON-TIMI 38 Study. Journal of the American College of Cardiology ; in press.Google Scholar
  3. 3.
    CURRENT-OASIS 7 Investigators, Mehta, S. R., Bassand, J.-P., Chrolavicius, S., Diaz, R., Eikelboom, J. W., et al. (2010). Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. New England Journal of Medicine, 363, 930–942.PubMedCrossRefGoogle Scholar
  4. 4.
    ISIS-2 (Second International Study of Infarct Survival) Collaborative Group 1. (1988). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. The Lancet, 2, 349–360.Google Scholar
  5. 5.
    Warner, T. D., Armstrong, P. C. J., Curzen, N. P., & Mitchell, J. A. (2010). Dual antiplatelet therapy in cardiovascular disease: does aspirin increase clinical risk in the presence of potent P2Y12 receptor antagonists? Heart, 96, 1693–1694.PubMedCrossRefGoogle Scholar
  6. 6.
    Maclagan, T. ( 1876). The treatment of rheumatism by salicin and salicylic acid. BMJ BMJ Group;1: 627.Google Scholar
  7. 7.
    Vane, J. R., & Botting, R. M. (2003). The mechanism of action of aspirin. Thrombosis Research, 110, 255–258.PubMedCrossRefGoogle Scholar
  8. 8.
    Patrono, C., García-Rodríguez, L. A., Landolfi, R., & Baigent, C. (2005). Low-dose aspirin for the prevention of atherothrombosis. New England Journal of Medicine, 353, 2373–2383.PubMedCrossRefGoogle Scholar
  9. 9.
    Roth, G. J., Stanford, N., & Majerus, P. W. (1975). Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA National Acad Sciences, 72, 3073–3076.CrossRefGoogle Scholar
  10. 10.
    Hamberg, M., Svensson, J., & Samuelsson, B. (1974). Letter: mechanism of the anti-aggregating effect of aspirin on human platelets. The Lancet, 2, 223–224.CrossRefGoogle Scholar
  11. 11.
    Pinckard, R. N., Hawkins, D., & Farr, R. S. (1968). In vitro acetylation of plasma proteins, enzymes and DNA by aspirin. Nature, 219, 68–69.PubMedCrossRefGoogle Scholar
  12. 12.
    Rocca, B., Secchiero, P., Ciabattoni, G., Ranelletti, F. O., Catani, L., Guidotti, L., et al. (2002). Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci USA National Acad Sciences, 99, 7634–7639.CrossRefGoogle Scholar
  13. 13.
    FitzGerald, G. A., Oates, J. A., Hawiger, J., Maas, R. L., Roberts, L. J., Lawson, J. A., et al. (1983). Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. Journal of Clinical Investigation, 71, 676–688.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Pedersen, A. K., & FitzGerald, G. A. (1984). Dose-related kinetics of aspirin. New England Journal of Medicine, 311, 1206–1211.PubMedCrossRefGoogle Scholar
  15. 15.
    Bochner, F., Williams, D. B., Morris, P. M., Siebert, D. M., & Lloyd, J. V. (1988). Pharmacokinetics of low-dose oral modified release, soluble and intravenous aspirin in man, and effects on platelet function. European Journal of Clinical Pharmacology, 35, 287–294.PubMedCrossRefGoogle Scholar
  16. 16.
    Thiessen, J. J. J. (1983). Aspirin: plasma concentration and effects. Thrombosis Research, 4, 105–111.CrossRefGoogle Scholar
  17. 17.
    Jaffe, E. A., & Weksler, B. B. (1979). Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. Journal of Clinical Investigation, 63, 532–535.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Mehta, J. L., Mehta, P., Lopez, L., Ostrowski, N., & Aguila, E. (1984). Platelet function and biosynthesis of prostacyclin and thromboxane A2 in whole blood after aspirin administration in human subjects. Journal of the American College of Cardiology, 4, 806–811.PubMedCrossRefGoogle Scholar
  19. 19.
    Weksler, B. B., Pett, S. B., Alonso, D., Richter, R. C., Stelzer, P., Subramanian, V., et al. (1983). Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med Massachusetts Medical Society, 308, 800–805.CrossRefGoogle Scholar
  20. 20.
    De Caterina, R., Giannessi, D., Bernini, W., Gazzetti, P., Michelassi, C., L'abbate, A., et al. (1985). Selective inhibition of thromboxane-related platelet function by low-dose aspirin in patients after myocardial infarction. The American Journal of Cardiology, 55, 589–590.PubMedCrossRefGoogle Scholar
  21. 21.
    Hanley, S. P., Bevan, J., Cockbill, S. R., & Heptinstall, S. (1981). Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis. The Lancet, 1, 969–971.CrossRefGoogle Scholar
  22. 22.
    Patrignani, P., Filabozzi, P., & Patrono, C. (1982). Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. Journal of Clinical Investigation, 69, 1366–1372.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Patrono, C., Ciabattoni, G., Patrignani, P., Pugliese, F., Filabozzi, P., Catella, F., et al. (1985). Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation, 72, 1177–1184.PubMedCrossRefGoogle Scholar
  24. 24.
    Belton, O., Byrne, D., Kearney, D., Leahy, A., & Fitzgerald, D. J. (2000). Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation, 102, 840–845.PubMedCrossRefGoogle Scholar
  25. 25.
    Schrör, K. (1990). Thromboxane A2 and platelets as mediators of coronary arterial vasoconstriction in myocardial ischaemia. European Heart Journal, 11(Suppl B), 27–34.PubMedCrossRefGoogle Scholar
  26. 26.
    FitzGerald, G. A. (1991). Mechanisms of platelet activation: thromboxane A 2 as an amplifying signal for other agonists. The American Journal of Cardiology Elsevier, 68, B11–B15.CrossRefGoogle Scholar
  27. 27.
    Weiss, H. J., Aledort, L. M., & Kochwa, S. (1968). The effect of salicylates on the hemostatic properties of platelets in man. Journal of Clinical Investigation, 47, 2169–2180.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Evans, G., Packham, M. A., Nishizawa, E. E., Mustard, J. F., & Murphy, E. A. (1968). The effect of acetylsalicylic acid on platelet function. J Exp Med Rockefeller Univ Press, 128, 877–894.Google Scholar
  29. 29.
    Masotti, G., Poggesi, L., Galanti, G., Abbate, R., & Serneri, G. G. N. (1979). Differential inhibition of prostacyclin production and platelet aggregation by aspirin. The Lancet Elsevier, 314, 1213–1216.CrossRefGoogle Scholar
  30. 30.
    Taylor, M. L., Misso, N. L., Stewart, G. A., & Thompson, P. J. (1992). The effects of varying doses of aspirin on human platelet activation induced by PAF, collagen and arachidonic acid. British Journal of Clinical Pharmacology, 33, 25–31.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Moshfegh, K. K., Redondo, M. M., Julmy, F. F., Wuillemin, W. A. W., Gebauer, M. U. M., Haeberli, A. A., et al. (2000). Antiplatelet effects of clopidogrel compared with aspirin after myocardial infarction: enhanced inhibitory effects of combination therapy. Journal of the American College of Cardiology, 36, 7–7.CrossRefGoogle Scholar
  32. 32.
    Dabaghi, S. F., Kamat, S. G., Payne, J., Marks, G. F., Roberts, R., Schafer, A. I., et al. (1994). Effects of low-dose aspirin on in vitro platelet aggregation in the early minutes after ingestion in normal subjects. The American Journal of Cardiology, 74, 720–723.PubMedCrossRefGoogle Scholar
  33. 33.
    Capodanno, D., Patel, A., Dharmashankar, K., Ferreiro, J. L., Ueno, M., Kodali, M., et al. (2011). Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circulation. Cardiovascular Interventions, 4, 180–187.PubMedCrossRefGoogle Scholar
  34. 34.
    Pope, J. E., Anderson, J. J., & Felson, D. T. (1993). A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Archives of Internal Medicine, 153, 477–484.PubMedCrossRefGoogle Scholar
  35. 35.
    Grosser, T., Fries, S., & FitzGerald, G. A. (2006). Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest Am Soc Clin Investig, 116, 4–15.CrossRefGoogle Scholar
  36. 36.
    Guazzi, M.D., Campodonico, J., Celeste, F., Guazzi, M., Santambrogio G, Rossi M, Trabattoni D, Alimento M. Antihypertensive efficacy of angiotensin converting enzyme inhibition and aspirin counteraction. Clinical Pharmacology & Therapeutics 63: 79–86.Google Scholar
  37. 37.
    Schwartz, K. A., Schwartz, D. E., Ghosheh, K., Reeves, M. J., Barber, K., & DeFranco, A. (2005). Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. The American Journal of Cardiology, 95, 973–975.PubMedCrossRefGoogle Scholar
  38. 38.
    Rocca, B., Santilli, F., Pitocco, D., Mucci, L., Petrucci, G., Vitacolonna, E., et al. (2012). The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. Journal of Thrombosis and Haemostasis, 10, 1220–1230.PubMedCrossRefGoogle Scholar
  39. 39.
    Reilly, I. A., & FitzGerald, G. A. (1987). Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood, 69, 180–186.PubMedGoogle Scholar
  40. 40.
    Armstrong, P. C. J., Truss, N. J., Ali, F. Y., Dhanji, A.-R. A., Vojnovic, I., Zain, Z. N. M., et al. (2008). Aspirin and the in vitro linear relationship between thromboxane A2-mediated platelet aggregation and platelet production of thromboxane A2. Journal of Thrombosis and Haemostasis, 6, 1933–1943.PubMedCrossRefGoogle Scholar
  41. 41.
    Aradi, D., Storey, R.F., Komócsi, A., Trenk, D., Gulba, D., Kiss R.G., Husted, S., Bonello L., Sibbing, D., Collet. J.-P., Huber, K. (2013). on behalf of the Working Group on Thrombosis of the European Society of Cardiology. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. European Heart Journal . doi: 10.1093/eurheartj/eht375.
  42. 42.
    Kong, D. F. D., Hasselblad, V. V., Kandzari, D. E. D., Newby, L. K. L., & Califf, R. M. R. (2002). Seeking the optimal aspirin dose in acute coronary syndromes. The American Journal of Cardiology, 90, 622–625.PubMedCrossRefGoogle Scholar
  43. 43.
    Antithrombotic Trialists' Collaboration. (2002). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ, 324, 71–86.CrossRefGoogle Scholar
  44. 44.
    McQuaid, K. R., & Laine, L. (2006). Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. The American Journal of Medicine Elsevier, 119, 624–638.CrossRefGoogle Scholar
  45. 45.
    Storey, R. F., Sanderson, H. M., White, A. E., May, J. A., Cameron, K. E., & Heptinstall, S. (2000). The central role of the P(2 T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. British Journal of Haematology, 110, 925–934.PubMedCrossRefGoogle Scholar
  46. 46.
    Storey, R. F., Angiolillo, D. J., Patil, S. B., Desai, B., Ecob, R., Husted, S., et al. (2010). Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes. Journal of the American College of Cardiology, 56, 1456–1462.PubMedCrossRefGoogle Scholar
  47. 47.
    Michelson, A. D., Frelinger, A. L., Braunwald, E., Downey, W. E., Angiolillo, D. J., Xenopoulos, N. P., et al. (2009). For the TRITON-TIMI 38 Investigators. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. European Heart Journal, 30, 1753–1763.PubMedCrossRefGoogle Scholar
  48. 48.
    Hamm, C. W., Bassand, J.-P., Agewall, S., Bax, J., Boersma, E., Bueno, H., et al. (2011). ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal, 32, 2999–3054.PubMedCrossRefGoogle Scholar
  49. 49.
    Jneid, H., Anderson, J. L., Wright, R. S., Adams, C. D., Bridges, C. R., Casey, D. E., et al. (2012). 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation, 126, 875–910.PubMedCrossRefGoogle Scholar
  50. 50.
    Yusuf, S., Zhao, F., Mehta, S. R., Chrolavicius, S., Tognoni, G., & Fox, K. K. (2001). Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New England Journal of Medicine, 345, 494–502.PubMedCrossRefGoogle Scholar
  51. 51.
    Peters, R.J.G., Mehta, S.R., Fox, K.A.A., Zhao, F., Lewis, B.S., Kopecky, S.L., Diaz, R., Commerford, P.J., Valentin, V., Yusuf, S. (2003). Investigators CIUATPRECT. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation, 108, 1682–1687.Google Scholar
  52. 52.
    van Giezen, J. J. J., Sidaway, J., Glaves, P., Kirk, I., & Bjorkman, J. A. (2012). Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. Journal of Cardiovascular Pharmacology and Therapeutics, 17, 164–172.PubMedCrossRefGoogle Scholar
  53. 53.
    Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C., et al. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 361, 1045–1057.PubMedCrossRefGoogle Scholar
  54. 54.
    Cattaneo, M. M., & Lecchi, A. A. (2007). Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. Journal of Thrombosis and Haemostasis, 5, 577–582.PubMedCrossRefGoogle Scholar
  55. 55.
    Teng, R., Maya, J., & Butler, K. (2013). Evaluation of the pharmacokinetics and pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers. Platelets, 24(8), 615–624.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Varenhorst, C., Alstrom, U., Scirica, B. M., Hogue, C. W., Åsenblad, N., Storey, R. F., et al. (2012). Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. Journal of the American College of Cardiology, 60, 1623–1630.PubMedCrossRefGoogle Scholar
  57. 57.
    Storey RF, James SK, Siegbahn A, Varenhorst C, Held C, Ycas J, Husted SE, Cannon CP, Becker RC, Steg PG, Åsenblad N, Wallentin L. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2013; doi:10.3109/09537104.2013.842965.
  58. 58.
    Grzesk, G. G., Kozinski, M. M., Navarese, E. P. E., Krzyzanowski, M. M., Grzesk, E. E., Kubica, A. A., et al. (2012). Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats. Thrombosis Research, 130, 65–69.PubMedCrossRefGoogle Scholar
  59. 59.
    Högberg, C., Svensson, H., Gustafsson, R., Eyjolfsson, A., & Erlinge, D. (2010). The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. International Journal of Cardiology, 142, 187–192.PubMedCrossRefGoogle Scholar
  60. 60.
    Grzesk, G., Kozinski, M., Tantry, U. S., Wicinski, M., Fabiszak, T., Navarese, E. P., et al. (2013). High-dose, but not low-dose, aspirin impairs anticontractile effect of ticagrelor following ADP stimulation in rat tail artery smooth muscle cells. Biomed Res Int, 2013, 928271.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Wiviott, S. D., Braunwald, E., McCabe, C. H., Montalescot, G., Ruzyllo, W., Gottlieb, S., et al. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 357, 2001–2015.PubMedCrossRefGoogle Scholar
  62. 62.
    Warner, T. D., Nylander, S., & Whatling, C. (2011). Anti‐platelet therapy: cyclo‐oxygenase inhibition and the use of aspirin with particular regard to dual anti‐platelet therapy. Br J Clin Pharmacol Wiley Online Library; 72, 619–633.CrossRefGoogle Scholar
  63. 63.
    Iyú, D. D., Glenn, J. R. J., White, A. E. A., Fox, S. C. S., van Giezen, H. H., Nylander, S. S., et al. (2011). Mode of action of P2Y(12) antagonists as inhibitors of platelet function. Thrombosis and Haemostasis, 105, 96–106.PubMedCrossRefGoogle Scholar
  64. 64.
    Armstrong, P. C. J. P., Leadbeater, P. D. P., Chan, M. V. M., Kirkby, N. S. N., Jakubowski, J. A. J., Mitchell, J. A. J., et al. (2011). In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. Journal of Thrombosis and Haemostasis, 9, 552–561.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Kirkby, N. S. N., Leadbeater, P. D. M. P., Chan, M. V. M., Nylander, S. S., Mitchell, J. A. J., & Warner, T. D. T. (2011). Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. Journal of Thrombosis and Haemostasis, 9, 2103–2105.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Dewilde, W. J., Oirbans, T., Verheugt, F. W., Kelder, J. C., De Smet, B. J., Herrman, J.-P., et al. (2013). Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. The Lancet, 381, 1107–1115.CrossRefGoogle Scholar
  67. 67.
    Eikelboom, J. W., Mehta, S. R., Anand, S. S., Xie, C., Fox, K. A. A., & Yusuf, S. (2006). Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation, 114, 774–782.PubMedCrossRefGoogle Scholar
  68. 68.
    Hurlen, M., Abdelnoor, M., Smith, P., Erikssen, J., & Arnesen, H. (2002). Warfarin, aspirin, or both after myocardial infarction. N Engl J Med Mass Medical Soc, 347, 969–974.CrossRefGoogle Scholar
  69. 69.
    Wallentin, L. C. (1991). Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden. Journal of the American College of Cardiology, 18, 1587–1593.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cardiovascular ScienceUniversity of SheffieldSheffieldUK

Personalised recommendations