Hamostaseologie 2009; 29(03): 285-290
DOI: 10.1055/s-0037-1617036
Review
Schattauer GmbH

The present state of aspirin and clopidogrel resistance

K. E. Guyer
1   Department of Chemistry, Indiana University South Bend, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
05. Februar 2018 (online)

Summary

Antiplatelet therapy has demonstrated significant clinical benefit in the treatment of acute coronary syndrome. However, as with any treatment strategy it has been unable to prevent all cardiovascular events. This is far from surprising when considering the complexity of arterial thrombosis and more specifically platelet physiology. This lack of treatment success has provoked the introduction of various diagnostic tests and testing platforms with the intent of guiding and optimizing clinical treatment. Such tests have resulted in the generation of clinical data that suggest suboptimal response to antiplatelet agents such as aspirin and clopidogrel.

In the case of both aspirin and clopidogrel, this suboptimal response has been termed resistance. Drug resistance would imply a lack of pharmacological response that has not been specifically investigated in many of the clinical studies performed to date. Rather, the term resistance has been used to describe various facets of platelet activation and aggregation relative to the testing method. Many of these measured parameters are not addressed in the therapeutic intent of the antiplatelet drug in question.

 
  • References

  • 1 Antithrombotic Trialists Collaboration Collaborative meta-analysis of randomized trials of anti-platelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
  • 2 Awtry E, Loscalzo J. Aspirin. Circulation 2000; 101: 1206-1218.
  • 3 Becker R, Moliterno D, Jennings L. et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet 2009; 373: 919-928.
  • 4 Bedossa M, Letocart V, Gueret P. Incidence of true clopidogrel resistance in high-risk percutaneous coronary intervention patients using VASP test. J Car Rev 2008; 9: 111.
  • 5 Bhatt DL, Fox KA, Hacke W. et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706-1717.
  • 6 Bhatt DL, Topol EJ. CHARISMA Executive Committee.. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the CHARISMA trial. Am Heart J 2004; 148: 263-268.
  • 7 Born GV. Aggregation of blood platelets by adeno-sine diphosphate and its reversal. Nature 1962; 194: 927-929.
  • 8 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
  • 9 Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P4503A and is inhibited by atorvastatin. Drug Metab Dispos 2003; 31: 53-59.
  • 10 Eikelboom JW, Hankey GJ, Thom J. et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk. Circulation 2008; 118: 1705-1712.
  • 11 Eikelboom JW, Hirsh J, Weitz JI. et al. Aspirin-resistant Thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650-1655.
  • 12 Grines C, Bonow R, Casey D. et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents. Circulation 2007; 115: 813-818.
  • 13 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
  • 14 Gurbel PA, Bliden KP, Guyer K. et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46: 1820-1826.
  • 15 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
  • 16 Ho P, Maddox T, Wang L. et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301: 937-944.
  • 17 Hulot J-S, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-247.
  • 18 Jaffe EA, Weksler BB. Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. J Clin Invest 1979; 63: 532-535.
  • 19 Krasopoulos G, Brister SJ, Beattie WS. et al. Aspirin “resistance” and risk of cardiovascular morbidity: systemic review and meta-analysis. Br Med J 2008; 336: 195-198.
  • 20 Lopez AD, Murray CCJL. The global burden of dis-ease. Nat Med 1998; 4: 1241-1243.
  • 21 Mancini JA, O’Neill GP, Bayly C, Vickers PJ. Mutation of serine-516 in human prostaglandin G/H synthase-2 to methionine or aspirin acetylation of this residue stimulates 15-R-HETE synthesis. FEBS Lett 1994; 342: 33-37.
  • 22 Maree AO, Curtin RJ, Chubb A. et al. Cyclooxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost 2005; 3: 2340-2345.
  • 23 Maree AO, Fitzgerald DJ. Aspirin and coronary artery disease. Thromb Haemost 2004; 92: 1175-1181.
  • 24 Mason PJ, Jacobs AK, Freedman JE. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol 2005; 46: 986-993.
  • 25 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
  • 26 McAdam BF, Catella-Lawson F, Mardini IA. et al. Systemic biosynthesis of prostacyclin by cyclooxygenase-2. The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-277.
  • 27 O’Neill G, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993; 330: 156-130.
  • 28 Patrono C, Bachman F, Baigent C. et al. Expert Consensus Document on the Use of Antiplatelet Agents. Eur Heart J 2004; 25: 166-181.
  • 29 Patrono C, García Rodriguez LA, Landolfi R, Bai-gent C.. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
  • 30 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-1672.
  • 31 Reilly IA, Doran JB, Smith B, Fitzgerald DJ. Increased thromboxane biosynthesis in a human preparation of platelet activation: biochemical and functional consequences of selective inhibition of thromboxane synthase. Circulation 1986; 73: 1300-1309.
  • 32 Reilly IA, Fitzgerald GA. Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs. Blood 1987; 69: 180-186.
  • 33 Rocca B, Secchiero P, Ciabattoni G. et al. Cycloxygenase-2 expression is induced during human megakaryopoieses and characterizes newly formed platelets. Proc Natl Acad Sci USA 2002; 99: 7634-7639.
  • 34 Sanderson S, Emery J, Baglin T. et al. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med 2005; 142: 370-380.
  • 35 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: 624-632.
  • 36 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
  • 37 Samuelsson B, Granström E, Green K. et al. Prosta -glandins. Ann Rev Biochem 1975; 44: 669-695.
  • 38 Sanderson S, Emery J, Baglin T. et al. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med 2005; 142: 370-380.
  • 39 Santilli F, Rocca B, De Cristofaro R. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function as-says. JACC 2009; 53: 667-677.
  • 40 Savi P, Labouret C, Guette F. et al. P2Y12, a new platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Comm 2001; 283: 379-383.
  • 41 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
  • 42 Schonbeck U, Sukhova GK, Graber P. et al. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155: 1281-1291.
  • 43 Schwartz K, Schwartz D, Ghosheh K. et al. Compliance as critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Am J Cardiol 2005; 95: 973-975.
  • 44 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
  • 45 Snoep JD, Hovens MM, Eikenboom JC. et al. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: as systemic review and meta-analysis. Arch Intern Med 2007; 167: 1593-1599.
  • 46 Spear BB, Heath-Chiozzi M, Huff J. et al. Clinical application of pharmacogenetics. Trends Mol Med 2002; 7: 201-204.
  • 47 Spertus J, Kettelkamp R, Vance C. et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation 2006; 113: 2803-2809.
  • 48 Tantry U, Bliden K, Gurbel P. Overestimation of platelet aspirin resistance detection by thrombo -elastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. JACC 2005; 49: 1705-1709.
  • 49 Tran H, Anand S, Hankey G, Eikelboom J. Aspirin resistance. Thromb Res 2007; 120: 337-346.
  • 50 Weber AA, Zimmerman KC, Meyer-Kirchrath J, Schrör K. Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance. Lancet 1999; 353: 900.
  • 51 Weiss HJ. Discovery of the antiplatelet effect of aspirin: a personal reminiscence. J Thromb Haemost 2003; 1: 1869-1875.
  • 52 Wiviott S, Braunwald E, McCabe C. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2008; 357: 2001-2015.
  • 53 Yusuf S, Zhao F, Mehta SR. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.