Skip to main content
PMC home page
Clinical Cardiology logoLink to Clinical Cardiology
. 2008 Mar 26;31(Suppl 1):I21–I27. doi: 10.1002/clc.20360

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

Eugene Braunwald 1,✉, Dominick Angiolillo 2, Eric Bates 3, Peter B Berger 4, Deepak Bhatt 5, Christopher P Cannon 1, Mark I Furman 6, Paul Gurbel 7, Alan D Michelson 8, Eric Peterson 9, Stephen Wiviott 1
PMCID: PMC6653508  PMID: 18481819

Abstract

Hyporesponsiveness, or resistance, to antiplatelet therapy may be a major contributor to poorer outcomes among cardiac patients and may be attributed to an array of mechanisms—both modifiable and unmodifiable. Recent evidence has uncovered clinical, cellular, and genetic factors associated with hyporesponsiveness. Patients with severe acute coronary syndromes (ACS), type 2 diabetes, and increased body mass index appear to be the most at risk for hyporesponsiveness. Addressing modifiable mechanisms may offset hyporesponsiveness, while recognizing unmodifiable mechanisms, such as genetic polymorphisms and diseases that affect response to antiplatelet therapy, may help identify patients who are more likely to be hyporesponsive. Hyporesponsive patients might benefit from different dosing strategies or additional antiplatelet therapies. Trials correlating platelet function test results to clinical outcomes are required. Results from these studies could cause a paradigm shift toward individualized antiplatelet therapy, improving predictability of platelet inhibition, and diminishing the likelihood for hyporesponsiveness. Copyright © 2008 Wiley Periodicals, Inc.

Keywords: catheterization/diagnostic interventional<cardiac, platelets, acute coronary syndromes<ischemic heart disease, myocardial infarction<ischemic heart disease, thrombosis/hypercoagulable states

Full Text

The Full Text of this article is available as a PDF (128.0 KB).

References

  • 1. Antithrombotic Trialists Collaboration : Collaborative meta‐analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. The 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‐elevation. N Engl J Med 2001; 345: 494–502. [DOI] [PubMed] [Google Scholar]
  • 3. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, for the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group : Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo controlled trial. Lancet 2005; 366: 1607–1621. [DOI] [PubMed] [Google Scholar]
  • 4. Steinhubl SR, Berger PB, Mann JT III, Fry ETA, DeLago A, et al.: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411–2420. [DOI] [PubMed] [Google Scholar]
  • 5. Sabatine MS, Cannon CP, Gibson CM, López‐Sendón JL, Montalescot G, et al.: Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST‐segment elevation. N Engl J Med 2005; 352: 1179–1189. [DOI] [PubMed] [Google Scholar]
  • 6. Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, et al.: Aspirin‐resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, of cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650–1655. [DOI] [PubMed] [Google Scholar]
  • 7. Chen WH, Lee PY, Ng W, Tse HF, Lau CP: Aspirin resistance is associated with a high incidence of myonecrosis after non‐urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004; 43: 1122–1126. [DOI] [PubMed] [Google Scholar]
  • 8. Bhatt DL: Aspirin resistance: more than just a laboratory curiosity. J Am Coll Cardiol 2004; 43: 1127–1129. [DOI] [PubMed] [Google Scholar]
  • 9. Frelinger AL 3rd, Furman MI, Linden MD, Li Y, Fox ML, et al.: Residual arachidonic acid‐induced platelet activation via an adenosine diphosphate‐dependent but cyclooxygenase‐1‐ and cyclooxygenase‐2‐independent pathway: a 700‐patient study of aspirin resistance. Circulation 2006; 113: 2888–2896. [DOI] [PubMed] [Google Scholar]
  • 10. Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, et al.: Evaluation of dose‐related effects of aspirin on platelet function: results from the Aspirin‐Induced Platelet Effect study. Circulation 2007; 115: 3156–3164. [DOI] [PubMed] [Google Scholar]
  • 11. Catella‐Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, et al.: Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809–1817. [DOI] [PubMed] [Google Scholar]
  • 12. Peters RJG, Mehta SR, Fox KAA, Zhao F, Lewis BS, For the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial: 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 2003; 108: 1682–1687. [DOI] [PubMed] [Google Scholar]
  • 13. Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, et al.: Randomized, double‐blind, placebo‐controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation 2003; 108: 399–406. [DOI] [PubMed] [Google Scholar]
  • 14. Macchi L, Christiaens L, Brabant S, Sorel N, Allal J, et al.: Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res 2002; 107: 45–49. [DOI] [PubMed] [Google Scholar]
  • 15. Järemo P, Lindahl TL, Fransson SG, Richter A: Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233–238. [DOI] [PubMed] [Google Scholar]
  • 16. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM: Clopidogrel for coronary stenting: response variability, drug resistances, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908–2913. [DOI] [PubMed] [Google Scholar]
  • 17. Gurbel PA: The relationship of platelet reactivity to the occurrence of post‐stenting ischemic events: emergence of a new cardiovascular risk factor. Rev Cardiovasc Med 2006; 7: S20–S28. [PubMed] [Google Scholar]
  • 18. Matetzky S, Shenkman B, Guetta V, Shecter M, Bienart R, et al.: Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171–3175. [DOI] [PubMed] [Google Scholar]
  • 19. Müller I, Besta F, Schulz C, Massberg S, Schönig A, et al.: Prevalence of clopidogrel non‐responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783–787. [PubMed] [Google Scholar]
  • 20. Gurbel PA, Bliden KP: The stratification of platelet reactivity and activation in patients with stable coronary artery disease on aspirin therapy. Thromb Res 2003; 112: 9–12. [DOI] [PubMed] [Google Scholar]
  • 21. Samara WM, Bliden KP, Tantry US, Gurbel PA: The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res 2005; 115: 89–94. [DOI] [PubMed] [Google Scholar]
  • 22. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, et al.: Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: Is the current antiplatelet therapy adequate? J Am Coll Cardiol 2007; 49: 657–666. [DOI] [PubMed] [Google Scholar]
  • 23. Wang TH, Bhatt DL, Topol EJ: Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J 2006; 27: 647–654. [DOI] [PubMed] [Google Scholar]
  • 24. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, et al.: Impact of the degree of peri‐interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742–1750. [DOI] [PubMed] [Google Scholar]
  • 25. Cuisset T, Frere C, Quilici J, Morange P‐E, Nait‐Saidi L, et al.: Benefit of a 600‐mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non‐ST‐segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48: 1339–1345. [DOI] [PubMed] [Google Scholar]
  • 26. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, et al.: Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug‐drug interaction. Circulation 2003; 107: 32–37. [DOI] [PubMed] [Google Scholar]
  • 27. Clarke TA, Waskell LA: The metabolism of clopidogrel is catalyzed by human cytochrome P45 3A and is inhibited by atorvastatin. Drug Metab Dispos 2003; 31: 53–59. [DOI] [PubMed] [Google Scholar]
  • 28. Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, et al.: Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109: 166–171. [DOI] [PubMed] [Google Scholar]
  • 29. Angiolillo DJ, Fernandez‐Ortiz A, Bernardo E, Ramírez C, Cavallari U, et al.: Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006; 26: 1895–1900. [DOI] [PubMed] [Google Scholar]
  • 30. Hulot JS, Bura A, Billard E, Azizi M, Remones V, et al.: Cytochrome P450 2C19 loss‐of‐function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244–2247. [DOI] [PubMed] [Google Scholar]
  • 31. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM: Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908–2913. [DOI] [PubMed] [Google Scholar]
  • 32. Soffer D, Moussa I, Harjai KJ, Boura JA, Dixon SR, et al.: Impact of angina class on inhibition of platelet aggregation following clopidogrel loading in patients undergoing coronary intervention: do we need more aggressive dosing regimens in unstable angina? Catheter Cardiovasc Interv 2003; 59: 21–25. [DOI] [PubMed] [Google Scholar]
  • 33. Ferreira IA, Mocking AIM, Feijge MAH, Gorter G, van Haeften TW, et al.: Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417–422. [DOI] [PubMed] [Google Scholar]
  • 34. Ferroni P, Basili S, Falco A, Davi G: Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2: 1282–1291. [DOI] [PubMed] [Google Scholar]
  • 35. Angiolillo DJ, Fernandez‐Ortiz A, Bernardo E, Ramírez C, Sabaté M, et al.: Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005; 54: 2430–2435. [DOI] [PubMed] [Google Scholar]
  • 36. Angiolillo DJ, Bernardo E, Ramírez C, Costa MA, Sabaté M, et al.: Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006; 48: 298–304. [DOI] [PubMed] [Google Scholar]
  • 37. Geisler T, Langer H, Wydymus M, Gohring K, Zurn C, et al.: Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420–2425. [DOI] [PubMed] [Google Scholar]
  • 38. Geisler T, Anders N, Paterok M, Langer H, Stellos K, et al.: Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care 2007; 30: 372–374. [DOI] [PubMed] [Google Scholar]
  • 39. Angiolillo DJ, Fernandez‐Ortiz A, Bernardo E, Ramírez C, Sabaté M, et al.: Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading‐dose be weight adjusted? J Invasive Cardiol 2004; 16: 169–174. [PubMed] [Google Scholar]
  • 40. Sibbing D, von Beckerath O, Schömig A, Kastrati A, von Beckerath N: Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. Am J Cardiol 2007; 100: 203–205. [DOI] [PubMed] [Google Scholar]
  • 41. Lepäntalo A, Virtanen KS, Heikkilä J, Wartiovaara U, Lassila R: Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004; 25: 467–483. [DOI] [PubMed] [Google Scholar]
  • 42. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, et al.: Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27–33. [DOI] [PubMed] [Google Scholar]

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES