Clinical implications of clopidogrel resistance

Summary

The benefits of clopidogrel in the treatment and prevention of coronary artery disease are well established, however, not all individuals respond in the same way to clopidogrel; there are patients who suffer adverse events despite clopidogrel treatment. This review focuses on the definition, potential mechanisms for and clinical implications of clopidogrel resistance, as well as the strategies to improve the response to this antiplatelet drug. There is an inter-individual variability in response to clopidogrel therapy, and a sub-optimal response (clopidogrel resistance) has been associated with adverse cardiovascular events. Nevertheless, there is no clear and consensual definition of clopidogrel resistance. Response to clopidogrel therapy follows a normal, bell-shaped distribution, so a more appropriate description would be variable response rather than clopidogrel resistance. Independent of the term used, lower response to clopidogrel therapy seems to be associated with a higher probability of suffering thrombotic events. Due to the misleading definition of resistance and non-standardized method for assessing platelet inhibition, current guidelines do not recommend the use of platelet function assays to monitor the inhibitory effect of antiplatelet drugs. Current guidelines also do not recommend clopidogrel loading doses higher than 300 mg and daily maintenance doses higher than 75 mg, even though a regimen of 600 mg clopidogrel loading dose seems to be preferred for patients undergoing percutaneous coronary interventions.

Keywords

Clopidogrel resistance - variable response - platelet function assay - percutaneous coronary intervention - late in-stent thrombosis

• References

• 1 Ibanez B, Vilahur G, Badimon J. Plaque progression and regression in atherothrombosis. J Thromb Haemost 2007; 05: 292-299.
• 2 Fuster V, Fayad ZA, Moreno PR. et al. Atherothrombosis and high-risk plaque: Part II: approaches by noninvasive computed tomographic/magnetic resonance imaging. J Am Coll Cardiol 2005; 46: 1209-1218.
• 3 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 05: 230-237.
• 4 Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99: 466-472.
• 5 Ibanez B, Vilahur G, Badimon J. Pharmacology of thienopyridines: rationale for dual pathway inhibition. Eur Heart J 2006; Suppl 08: G3-G9.
• 6 Steinhubl SR, Berger PB, Mann 3rd JT. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
• 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.
• 8 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 PCICLARITY study. J Am Med Assoc 2005; 294: 1224-1232.
• 9 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.
• 10 Sabatine MS, Cannon CP, Gibson CM. 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.
• 11 Chen ZM, Jiang LX, Chen YP. et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-1621.
• 12 Zeymer U, Gitt A, Junger C. et al. Clopidogrel in addition to aspirin reduces in-hospital major cardiac and cerebrovascular events in unselected patients with acute ST segment elevation myocardial. Thromb Haemost 2008; 99: 155-160.
• 13 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.
• 14 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.
• 15 Stone GW, Moses JW, Ellis SG. et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med 2007; 356: 998-1008.
• 16 Lagerqvist B, James SK, Stenestrand U. et al. Long-term outcomes with drugeluting stents versus baremetal stents in Sweden. N Engl J Med 2007; 356: 1009-1019.
• 17 Gurbel PA, Bliden KP, Hayes KM. et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
• 18 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.
• 19 Muller I, Besta F, Schulz C. 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.
• 20 Jaremo P, Lindahl TL, Fransson SG. et al. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233-238.
• 21 Mobley JE, Bresee SJ, Wortham DC. et al. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am J Cardiol 2004; 93: 456-458.
• 22 Lepantalo A, Virtanen KS, Heikkila J. et al. Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004; 25: 476-483.
• 23 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005; 115: 101-108.
• 24 Dziewierz A, Dudek D, Heba G. et al. Inter-individual variability in response to clopidogrel in patients with coronary artery disease. Kardiol Pol 2005; 62: 108-118.
• 25 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.
• 26 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.
• 27 Cuisset T, Frere C, Quilici 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.
• 28 Campo G, Valgimigli M, Gemmati D. et al. Value of platelet reactivity in predicting response to treatment and clinical outcome in patients undergoing primary coronary intervention: insights into the STRATEGY Study. J Am Coll Cardiol 2006; 48: 2178-2185.
• 29 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.
• 30 Samara WM, Bliden KP, Tantry US. et al. The difference between clopidogrel responsiveness and post-treatment platelet reactivity. Thromb Res 2005; 115: 89-94.
• 31 Bliden KP, DiChiara J, Tantry US. 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.
• 32 Hovens MM, Snoep JD, Eikenboom JC. et al. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J 2007; 153: 175-181.
• 33 King 3rd SB, Smith Jr. SC, Hirshfeld Jr. JW. et al. 2007 focused update of the 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. J Am Coll Cardiol 2008; 51: 172-209.
• 34 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. J Am Coll Cardiol 2007; 50: e1-e157.
• 35 Bassand JP, Hamm CW, Ardissino D. et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28: 1598-1660.
• 36 Simoons ML. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357: 1915-1924.
• 37 Topol EJ. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001; 357: 1905-1914.
• 38 Lau WC, Waskell LA, Watkins PB. et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 2003; 107: 32-37.
• 39 Neubauer H, Gunesdogan B, Hanefeld C. et al. Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function--a flow cytometry study. Eur Heart J 2003; 24: 1744-1749.
• 40 Mitsios JV, Papathanasiou AI, Rodis FI. et al. Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 2004; 109: 1335-1338.
• 41 Gorchakova O, von Beckerath N, Gawaz M. et al. Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting. Eur Heart J 2004; 25: 1898-1902.
• 42 Michelson AD, Frelinger 3rd AL, Furman MI. Current options in platelet function testing. Am J Cardiol 2006; 98: 4N-10N.
• 43 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
• 44 Cuisset T, Frere C, Quilici J. 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.
• 45 Marcucci R, Paniccia R, Antonucci E. et al. Residual platelet reactivity is an independent predictor of myocardial injury in acute myocardial infarction patients on antiaggregant therapy. Thromb Haemost 2007; 98: 844-851.
• 46 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.
• 47 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. J Am Med Assoc 2005; 293: 2126-2130.
• 48 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.
• 49 Grines CL, Bonow RO, Casey Jr. DE. et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007; 115: 813-818.
• 50 Muller I, Seyfarth M, Rudiger S. et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001; 85: 92-93.
• 51 Kandzari DE, Berger PB, Kastrati A. et al. Influence of treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization. J Am Coll Cardiol 2004; 44: 2133-2136.
• 52 Patti G, Colonna G, Pasceri V. et al. 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.
• 53 von Beckerath N, Taubert D, Pogatsa-Murray G. et al. 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.
• 54 Montalescot G, Sideris G, Meuleman C. 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.
• 55 Neubauer H, Lask S, Engelhardt A. et al. How to optimise clopidogrel therapy? Reducing the low-response incidence by aggregometry-guided therapy modification. Thromb Haemost 2008; 99: 357-362.
• 56 Bonello L, Camoin-Jau L, Arques S. et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
• 57 Angiolillo DJ, Shoemaker SB, Desai B. 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.
• 58 von Beckerath N, Kastrati A, Wieczorek A. 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.
• 59 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.
• 60 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirintreated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.
• 61 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.