Current Atherosclerosis Reports

, Volume 11, Issue 5, pp 364–370 | Cite as

Thienopyridine therapy and risk for cardiovascular events in secondary prevention



Platelets are critical modulators of atherothrombotic events. In the acute setting, platelets are activated and aggregate on the surface of atherosclerotic plaque that has ruptured, fissured, or developed erosions. The overlying thrombus leads to sudden development of arterial luminal obstruction, inducing ischemia and cellular necrosis. Inhibiting platelet reactivity is an important therapeutic goal in patients at risk for acute cardiovascular events. The thienopyridines are potent inhibitors of platelet aggregation and block the binding of adenosine 5′-diphosphate to purinergic receptors on the surface of the platelet membrane. The thienopyridine class includes ticlopidine, clopidogrel, and prasugrel. Clopidogrel is the most intensively studied. In recent years it has become apparent that approximately 20% to 25% of patients who would be expected to benefit from clopidogrel therapy are resistant to this drug, largely due to a polymorphism in the gene for cytochrome P450 2C19. The efficacy of clopidogrel can also be reduced if patients are receiving concomitant therapy with a proton pump inhibitor such as omeprazole. Prasugrel is a third-generation thienopyridine with faster time to onset and greater consistency in inhibiting platelet activity, and it has shown superiority to clopidogrel for reducing cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary interventions.


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References and Recommended Reading

  1. 1.
    Anderson JL, Adams CD, Antman EM, et al.: ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007, 116:e148–e304.PubMedCrossRefGoogle Scholar
  2. 2.
    Foster CJ, Prosser DM, Agans JM, et al.: Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 2001, 107:1591–1598.PubMedCrossRefGoogle Scholar
  3. 3.
    Balsano F, Rizzon P, Violi F, et al.: Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell’Angina Instabile Group. Circulation 1990, 82:17–26.PubMedGoogle Scholar
  4. 4.
    Scrutinio D, Cimminiello C, Marubini E, et al.: Ticlopidine versus aspirin after myocardial infarction (STAMI) trial. J Am Coll Cardiol 2001, 37:1259–1265.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    Yusuf S, Mehta SR, Zhao F, et al.: Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 2003, 107:966–972.PubMedCrossRefGoogle Scholar
  7. 7.
    Mehta SR, Yusuf S, Peters RJ, et al.: Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001, 358:527–533.PubMedCrossRefGoogle Scholar
  8. 8.
    Steinhubl SR, Berger PB, Mann JT 3rd, et al.: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002, 288:2411–2420.PubMedCrossRefGoogle Scholar
  9. 9.
    Steinhubl SR, Berger PB, Brennan DM, Topol EJ: Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006, 47:939–943.PubMedCrossRefGoogle Scholar
  10. 10.
    A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996, 348:1329–1339.Google Scholar
  11. 11.
    Sabatine MS, Cannon CP, Gibson CM, et al.: Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005, 294:1224–1232.PubMedCrossRefGoogle Scholar
  12. 12.
    Antman EM, Anbe DT, Armstrong PW, et al.: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Available at Accessed January 15, 2009.
  13. 13.
    Fox KA, Mehta SR, Peters R, et al.: Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004, 110:1202–1208.PubMedCrossRefGoogle Scholar
  14. 14.
    Chu MW, Wilson SR, Novick RJ, et al.: Does clopidogrel increase blood loss following coronary artery bypass surgery? Ann Thorac Surg 2004, 78:1536–1541.PubMedCrossRefGoogle Scholar
  15. 15.
    Hongo RH, Ley J, Dick SE, Yee RR: The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002, 40:231–237.PubMedCrossRefGoogle Scholar
  16. 16.
    Mehta RH, Roe MT, Mulgund J, et al.: Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. J Am Coll Cardiol 2006, 48:281–286.PubMedCrossRefGoogle Scholar
  17. 17.
    Eagle KA, Guyton RA, Davidoff R, et al.: ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation 2004, 110:e340–e437.PubMedCrossRefGoogle Scholar
  18. 18.
    Ang L, Palakodeti V, Khalid A, et al.: Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol 2008, 52:1052–1059.PubMedCrossRefGoogle Scholar
  19. 19.
    Serebruany VL, Steinhubl SR, Berger PB, et al.: Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005, 45:246–251.PubMedCrossRefGoogle Scholar
  20. 20.
    Lev EI, Patel RT, Maresh KJ, 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.PubMedCrossRefGoogle Scholar
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    Campo G, Valgimigli M, Gemmati D, et al.: Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol 2007, 50:1132–1137.PubMedCrossRefGoogle Scholar
  23. 23.
    Michelson AD, Linden MD, Furman MI, et al.: Evidence that pre-existent variability in platelet response to ADP accounts for ‘clopidogrel resistance’. J Thromb Haemost 2007, 5:75–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Nguyen TA, Diodati JG, Pharand C: Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005, 45:1157–1164.PubMedCrossRefGoogle Scholar
  25. 25.
    Hochholzer W, Trenk D, Bestehorn HP, 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.PubMedCrossRefGoogle Scholar
  26. 26.
    Trenk D, Hochholzer W, Fromm MF, et al.: Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008, 51:1925–1934.PubMedCrossRefGoogle Scholar
  27. 27.
    Simon T, Verstuyft C, Mary-Krause M, et al.: Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009, 360:363–375.PubMedCrossRefGoogle Scholar
  28. 28.
    Mega JL, Close SL, Wiviott SD, et al.: Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009, 360:354–362.PubMedCrossRefGoogle Scholar
  29. 29.
    Gurbel PA, Lau WC, Tantry US: Omeprazole: a possible new candidate influencing the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008, 51:261–263.PubMedCrossRefGoogle Scholar
  30. 30.
    Ho PM, Maddox TM, 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Braun OO, Johnell M, Varenhorst C, et al.: Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thromb Haemost 2008, 100:626–633.PubMedGoogle Scholar
  32. 32.
    Ernest CS 2nd, Small DS, Rohatagi S, et al.: Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease. J Pharmacokinet Pharmacodynam 2008 (in press).Google Scholar
  33. 33.
    Mega JL, Close SL, Wiviott SD, et al.: Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009, 119:2553–2560.PubMedCrossRefGoogle Scholar
  34. 34.
    Wiviott SD, Antman EM, Winters KJ, et al.: Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005, 111:3366–3373.PubMedCrossRefGoogle Scholar
  35. 35.
    Wiviott SD, Braunwald E, McCabe CH, et al.: Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007, 357:2001–2015.PubMedCrossRefGoogle Scholar
  36. 36.
    Wiviott SD, Trenk D, Frelinger AL, et al.: Prasugrel compared with high loading-and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007, 116:2923–2932.PubMedCrossRefGoogle Scholar
  37. 37.
    Wiviott SD, Braunwald E, McCabe CH, et al.: Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008, 371:1353–1363.PubMedCrossRefGoogle Scholar
  38. 38.
    Wiviott SD, Braunwald E, Angiolillo DJ, et al.: Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008, 118:1626–1636.PubMedCrossRefGoogle Scholar
  39. 39.
    Antman EM, Wiviott SD, Murphy SA, et al.: Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008, 51:2028–2033.PubMedCrossRefGoogle Scholar
  40. 40.
    Montalescot G, Wiviott SD, Braunwald E, et al.: Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009, 373:723–731.PubMedCrossRefGoogle Scholar
  41. 41.
    Nishiya Y, Hagihara K, Ito T, et al.: Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel. Drug Metab Disposition 2008 (in press).Google Scholar
  42. 42.
    Farid NA, Payne CD, Ernest CS 2nd, et al.: Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol 2008, 48:53–59.PubMedCrossRefGoogle Scholar
  43. 43.
    Small DS, Farid NA, Payne CD, et al.: Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008, 48:475–484.PubMedCrossRefGoogle Scholar
  44. 44.
    Erlinge D, Varenhorst C, Braun OO, et al.: Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 2008, 52:1968–1977.PubMedCrossRefGoogle Scholar
  45. 45.
    Brandt JT, Close SL, Iturria SJ, et al.: Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007, 5:2429–2436.PubMedCrossRefGoogle Scholar
  46. 46.
    Norgard NB, Abu-Fadel M: Future prospects in antiplatelet therapy: a review of potential P2Y12 and thrombin receptor antagonists. Recent Patents Cardiovasc Drug Discovery 2008, 3:194–200.CrossRefGoogle Scholar
  47. 47.
    Cannon CP, Husted S, Harrington RA, et al.: Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007, 50:1844–1851.PubMedCrossRefGoogle Scholar
  48. 48.
    James S, Akerblom A, Cannon CP, et al.: Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 2009, 157:599–605.PubMedCrossRefGoogle Scholar

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© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Sterling Rock Falls ClinicSterlingUSA

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