Dual oral antiplatelet therapy, aspirin plus thienopyridine, has permitted a rapid increase in the use of coronary intervention procedures. Clopidogrel is the thienopyridine of choice for dual antiplatelet therapy in patients treated with percutaneous coronary intervention. However, there are two issues with clopidogrel: (1) clopidogrel's antiplatelet activity is delayed because the drug needs to be metabolized into its active form and (2) variability in patient response to clopidogrel has been demonstrated. To overcome these shortcomings of clopidogrel, new more potent inhibitors of P2Y12 receptors, which have a more rapid onset of action have been introduced for clinical evaluation. This article is a nonexhaustive review of the literature and concentrates on prasugrel, a third-generation, oral thienopyridine. The purpose is to summarize the current knowledge about the benefits and risks of prasugrel and to outline the most prudent strategies for the drug's clinical use.

3rd Medical Faculty of Charles University and University Hospital Kralovske Vinohrady Prague Czech Republic

Zobrazit více v PubMed

Neumann FJ, Gawaz M, Ott I, May A, Mössmer G, Schömig A. Prospective evaluation of hemostatic predictors of subacute stent thrombosis after coronary Palmaz-Schatz stenting. J Am Coll Cardiol. 1996;27:15–21. PubMed

Makkar RR, Eigler S, Kaul S, et al. Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis. Eur Heart J. 1998;19:1538–1546. PubMed

Lenzen MJ, Boersma E, Bertrand ME, et al. European Society of Cardiology Management and outcome of patients with established coronary artery disease: the Euro Heart Survey on coronary revascularization. Eur Heart J. 2005;26(12):1169–1179. PubMed

Thom T, Haase N, Rosamond W, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics – 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85–e101. PubMed

Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000;84:891–896. PubMed

Ibanez B, Vilahur G, Badimon JJ. Pharmacology of thienopyridines: rationale for dual pathway inhibition. Eur Heart J Suppl. 2006;8:G3–G9.

Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) Circulation. 2000;102:624–629. PubMed

Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine and clopidogrel after stenting. J Am Coll Cardiol. 2002;39:9–14. PubMed

Silber S, Albertsson P, Aviles FF, et al. for Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J. 2005;26(8):804–847. PubMed

Eshaghian S, Kaul S, Amin S, Shah PK, Diamond GA. Role of clopido-grel in managing atherothrombotic cardiovascular disease. Ann Intern Med. 2007;146(6):434–441. PubMed

Quinn MJ, Bhatt DL, Zidar F, et al. Effect of clopidogrel pretreatment on inflammatory marker expression in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2004;93:679–684. PubMed

Vivekananthan DP, Bhatt DL, Chew DP, et al. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol. 2004;94:358–360. PubMed

Pereillo JM, Maftouh M, Andrieu A, et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos. 2002;30:1288–1295. PubMed

Clarke TA, Waskell LA. The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos. 2003;31:53–59. PubMed

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. PubMed

Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:246–251. PubMed

Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21–30. PubMed

Taubert D, von Beckerath N, Grimberg G, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006;80:486–501. PubMed

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. PubMed

Motovska Z, Widimsky P, Petr R, et al. on behalf of the PRAGUE-8 Study Investigators Factors influencing clopidogrel efficacy in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention: statin’s advantage and the smoking “paradox” J Cardiovasc Pharmacol 2009February25[Epub ahead of print] PubMed

Motovska Z, Widimsky P, Petr R, et al. Optimal pretreatment timing for high load dosing (600 mg) of clopidogrel before planned percutaneous coronary intervention for maximal antiplatelet effectiveness Int J Cardiol 2009February14[Epub ahead of print] PubMed

Davì G, Gresele P, Violi F, et al. Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation. 1997;96(1):69–75. PubMed

Soffer D, Moussa I, Harjai K, 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. PubMed

Montalescot G, Sideris G, Meuleman C, et al. for the ALBION Trial Investigators 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. PubMed

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(20):2420–2425. PubMed

Angiolillo DJ, Bernardo E, Sabate M, 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. PubMed

von Beckerath N, Taubert D, Pogatsa-Murray G, Schomig E, Kastrati A, Schomig 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(19):2946–2950. PubMed

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(24):2312–2317. PubMed

Farid NA, Smith RL, Gillespie TA, et al. The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos. 2007;35:1096–1104. PubMed

Jakubowski JA, Winters KJ, Naganuma H, Wallentin L. Prasugrel: A novel thienopyridine antiplatelet agent. Cardiovasc Drug Rev. 2007;25(4):357–374. PubMed

Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: Magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153:e9–e16. PubMed

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. PubMed

Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo anti-platelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost. 2007;5:1545–1551. PubMed

Muller I, Besta F, Schulz C, Massberg S, Schomig 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. PubMed

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(1):27–33. PubMed

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. PubMed

Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006;27:1166–1173. PubMed

Motovska Z, Kala P. Benefits and risks of clopidogrel use in patients with coronary artery disease: Evidence from randomized studies and registries. Clin Ther. 2008;30P2:2191–2202. PubMed

Wiviott SD, Braunwald E, McCabe CH, et al. TRITON-TIMI 38 Investigators Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Eng J Med. 2007;357:2001–2015. PubMed

Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM, TRITON-TIMI 38 investigators 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(9665):723–731. PubMed

US National Institutes of Health. A comparison of prasugrel and clopi-dogrel in acute coronary syndrome subjects (TRILOGY ACS). April 20, 2009. Accessed on May 6, 2009. Available from: http://clinicaltrials.gov/ct2/show/NCT00699998

Wenaweser P, Rey C, Eberli F, et al. Stent thrombosis following bare-metal stent implantation success of emergency percutaneous coronary intervention and predictors of adverse outcome. Eur Heart J. 2005;26(12):1180–1187. PubMed

Cook S, Windecker S. Early stent thrombosis: Past, present, and future. Circulation. 2009;119:657–659. PubMed

Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126–2130. PubMed

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 sub-analysis of a randomised trial. Lancet. 2008;371(9621):1353–1363. PubMed

Wiviott SD, Braunwald E, Angiolillo DJ, et al. TRITON-TIMI 38 Investigators 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(16):1626–1636. PubMed

Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298:765–775. PubMed

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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. PubMed

Angiolillo DJ, Showmaker 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 anti-platelet therapy in diabetes mellitus (OPTIMUS) study. Circulation. 2007;115(6):708–716. PubMed

Angiolillo DJ, Bernardo E, Sabate M, 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. PubMed

Erlinge D, Varenhorst C, Braun OÖ, 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. PubMed

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 TRITON-TIMI 38. Circulation. 2008;118:1626–1636. PubMed

Motovska Z, Widimsky P, Kvasnicka J, et al. on behalf of the PRAGUE-8 study investigators High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism – a genetic substudy of PRAGUE-8 trial Blood Coagul Fibrin 2009March16doi:10.1097/MBC.0b013e328325455b. PubMed

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. PubMed

Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–362. PubMed

Brandt JT, Close SL, Iturria SJ, et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacody-namic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007;5:2429–2436. PubMed

Eli Lilly and Company European Commission approves EFIENT (prasugrel) for patients with acute coronary syndrome undergoing PCI [press release]. February 23, 2009. Accessed on May 6, 2009. Available from: http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=366955

Eli Lilly and Company Prasugrel receives unanimous approval recommendation from FDA Advisory Committee. February 3, 3009. Accessed on May 6, 2009. Available from: http://www.drugs.com/nda/effient_090204.html