American Journal of Cardiology
Volume 103, Issue 3, Supplement , Pages 27A-34A , 2 February 2009

Variability in Responsiveness to Oral Antiplatelet Therapy

  • Dominick J. Angiolillo, MD, PhD

      Affiliations

    • Corresponding Author InformationAddress for reprints: Dominick J. Angiolillo, MD, PhD, Division of Cardiology, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209

References 

  1. Smith JC, Feldman TE, Hirshfeld JW, Jacobs AK, Kern MJ, King SB, et al ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol. 2006;47:e1–e121
  2. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, et al ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: executive summary. Circulation. 2007;116:803–877
  3. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996;348:1329–1339
  4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK 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. N Engl J Med. 2001;345:494–502
  5. Michelson AD. Platelet function testing in cardiovascular disease. Circulation. 2004;110:e489–e493
  6. Wallentin LC Research Group on Instability in Coronary Artery Disease in Southeast Sweden. 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. J Am Coll Cardiol. 1991;18:1587–1593
  7. Quick AJ. Salicylates and bleeding: the aspirin tolerance test. Am J Med Sci. 1966;252:265–269
  8. Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990;322:1549–1554
  9. Grotemeyer KH, Scharafinski HW, Husstedt IW. Two-year follow-up of aspirin responder and aspirin non responder: a pilot-study including 189 post-stroke patients. Thromb Res. 1993;71:397–403
  10. Mueller MR, Salat A, Stangle P, Murabito M, Pulaki S, Boehm D, et al. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost. 1997;78:1003–1007
  11. Grundmann K, Jaschonek K, Kleine B, Dichgans J, Topka H. Aspirin non-responder status in patients with recurrent cerebral ischemic attacks. J Neurol. 2003;250:63–66
  12. Eikelboom JW, Hirsch J, Weitz JI, Johnston M, Yi Q, Yusuf S. 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
  13. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. 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. Gengo FM, Rainka M, Robson M, Gengo MF, Forrest A, Hourihane M, et al. Prevalence of platelet nonresponsiveness to aspirin in patients treated for secondary stroke prophylaxis and in patients with recurrent ischemic events. J Clin Pharmacol. 2008;48:335–343
  15. Tantry US, Bliden KP, Gurbel PA. Overestimation of platelet aspirin resistance: detection by thromboelastograph platelet mapping and validation by conventional aggregometry using arachidonic acid stimulation. J Am Coll Cardiol. 2005;46:1705–1709
  16. Michelson AD, Cattaneo M, Elkelboom JW. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost. 2005;3:1309–1311
  17. Gengo FM, Rubin L, Robson M, Rainka M, Gengo MF, Mager DE, et al. Effects of ibuprofen on the magnitude and duration of aspirin's inhibition of platelet aggregation: clinical consequences in stroke prophylaxis. J Clin Pharmacol. 2008;48:117–122
  18. Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, et al. Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect (ASPECT) study. Circulation. 2007;115:3156–3164
  19. DiChiara J, Bliden KP, Tantry US, Hamed MS, Antonino MJ, Suarez TA, et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes. 2007;56:3014–3019
  20. Snoep JD, Hovens MMC, Eikenboom JCJ, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review and meta-analysis. Arch Intern Med. 2007;167:1593–1599
  21. Buchanan MR, Schwartz L, Bourassa M, Brister SJ, Peniston CM. Results of the BRAT study: a pilot study investigating the possible significance of ASA nonresponsiveness on the benefits and risks of ASA on thrombosis in patients undergoing coronary artery bypass surgery. Can J Cardiol. 2000;16:1385–1390
  22. Andersen K, Hurlen M, Arnesen H, Seljeflot I. Aspirin non-responsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res. 2002;108:37–42
  23. Cotter G, Shemesh E, Zehavi M, Dinur I, Rudnick A, Milo O, et al. Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?. Am Heart J. 2004;147:293–300
  24. Pamukcu B, Oflaz H, Oncul A, Umman B, Mercanoglu F, Ozcan M, et al. The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events. J Thromb Thrombolysis. 2006;22:103–110
  25. Stejskal D, Václavík J, Lacnák B, Prosková J. Aspirin resistance measured by cationic propyl gallate platelet aggregometry and recurrent cardiovascular events during 4 years of follow-up. Eur J Intern Med. 2006;17:349–354
  26. Ziegler S, Maca T, Alt E, Speiser W, Schneider B, Minar E. Monitoring of antiplatelet therapy with the PFA-100 in peripheral angioplasty patients. Platelets. 2002;13:493–497
  27. Poston RS, Gu J, Brown JM, Gammie JS, White C, Nie L, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2006;131:122–130
  28. 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
  29. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T, 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
  30. Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost. 2005;31:174–183
  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
  32. Müller I, Best F, Schulz C, Massberg S, Schönig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost. 2003;89:783–787
  33. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 2007;49:1505–1515
  34. Samara WM, Bliden KP, Tantry US, Gurbel PA. The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res. 2005;115:89–94
  35. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109:3171–3175
  36. Gurbel PA, Bliden KP, Guyer KE, Cho PW, Zaman KA, Kreutz RP, 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
  37. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation. 2005;111:1153–1159
  38. Cuisset T, Frere C, Quilici J, Barbou F, Morange PE, Hovasse T, et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost. 2006;4:542–549
  39. Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Carvajal J, 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
  40. Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective stent placement. J Am Coll Cardiol. 2006;48:1742–1750
  41. Geisler T, Langer H, Wydymus M, Göhring K, Zürn C, Bigalke B, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J. 2006;27:2420–2425
  42. Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with thigh platelet aggregation on chronic clopidogrel therapy undergoing PCI: is the current antiplatelet therapy adequate?. J Am Coll Cardiol. 2007;49:657–666
  43. Cuisset T, Frere C, Quilici J, Morange PE, Nait-Saidi L, Mielot C, et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost. 2007;97:282–287
  44. Bonello L, Paganelli F, Arpin-Bornet M, Auguier P, Sampol J, Dignat-George F, et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007;5:1630–1636
  45. Angiolillo DJ, Bernardo E, Sabaté M, Jimenez-Quevedo P, Costa MA, Palazuelos J, et al Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol. 2007;50:1541–1547
  46. Frere C, Cuisset T, Quilici J, Camoin L, Carvajal J, Morange PE, et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome. Thromb Haemost. 2007;98:838–843
  47. Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv. 2003;59:295–302
  48. Ajzenberg N, Aubry P, Huisse MG, Cachier A, El Amara W, Feldman LJ, et al. Enhanced shear-induced platelet aggregation in patients who experience subacute stent thrombosis: a case-control study. J Am Coll Cardiol. 2005;45:1753–1756
  49. Buonamici P, Marcucci R, Migliorini A, Gensini GF, Santini A, Paniccia R, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol. 2007;49:2312–2317
  50. Angiolillo DJ, Alfonso F. Clopidogrel-statin interaction: myth or reality?. J Am Coll Cardiol. 2007;50:296–298
  51. Patrono C, Coller B, Dalen J, FitzGerald GA, Fuster V, Gent M, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001;119(suppl):39S–63S
  52. Hirsh J, Dalen JE, Fuster V, Harker LB, Salzman EW. Aspirin and other platelet-active drugs: the relationship between dose, effectiveness, and side effects. Chest. 1992;102(suppl):327S–336S
  53. Pettersen AA, Seljeflot I, Abdelnoor M, Arnesen H. Unstable angina, stroke, myocardial infarction and death in aspirin non-responders: a prospective, randomized trial: the ASCET (Aspirin non-responsiveness and Clopidogrel Endpoint Trial) design. Scand Cardiovasc J. 2004;38:353–356
  54. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005;111:2099–2106
  55. von Beckerath N, Taubert D, Pogasta-Murray G, Schömig E, Kastrati A, Schömig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation. 2005;112:2946–2950
  56. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche N, Steg PG, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol. 2006;48:931–938
  57. Kastrati A, von Beckerath N, Joost A, Pogatsa-Murray G, Gorchakova O, Schömig A. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation. 2004;110:1916–1919
  58. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation. 2007;115:708–716
  59. von Beckerath, Kastrati A, Wieczorek A, Pogatsa-Murray G, Sibbing D, Graf I, et al. A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J. 2007;28:1814–1819
  60. Fontana P, Senouf D, Mach F. Biological effect of increased maintenance dose of clopidogrel in cardiovascular outpatients and influence of the cytochrome P450 2C19*2 allele on clopidogrel responsiveness. Thromb Res. 2008;121:463–468
  61. Angiolillo DJ, Bernardo E, Palazuelos J, Desai B, Weisberg I, Alfonso F, et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous interventions: results of a randomized study. Thromb Haemost. 2008;99:161–168
  62. Angiolillo DJ, Costa MA, Shoemaker SB, Desai B, Bernardo E, Suzuki Y, et al. Functional effects of high clopidogrel maintenance dosing in patients with inadequate platelet inhibition on standard dose treatment. Am J Cardiol. 2008;101:440–445
  63. Angiolillo DJ, Capranzano P, Goto S, Aslam M, Desai B, Charlton RK, et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J. 2008;29:2202–2211
  64. Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol. 2005;46:1833–1837
  65. Lee SW, Park SW, Kim YH, Yun SC, Park DW, Lee CW, et al Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial). Am J Cardiol. 2007;100:1103–1108

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(08)02030-4

doi: 10.1016/j.amjcard.2008.11.020

American Journal of Cardiology
Volume 103, Issue 3, Supplement , Pages 27A-34A , 2 February 2009

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