Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation

Summary

Given conflicting data on temporal variability in pharmacodynamic platelet responses to clopidogrel, we investigated platelet reactivity on clopidogrel and aspirin for up to six months after elective percutaneous coronary intervention (PCI) with drug-eluting stents. Platelet reactivity was determined in 102 patients before loading with clopidogrel and aspirin, and on maintenance therapy after PCI on day 1, at one month and six months by VerifyNow™ P2Y12 and Aspirin assays and by residual platelet aggregation (RPA) on light transmission aggregometry using adenosine diphosphate and arachidonic acid. By VerifyNow testing, median (interquartile range) P2Y12 reaction units (PRU) on clopidogrel were 166 (90–234), 195 (124–257), and 198 (141–252) on day 1, one month and six months after PCI, respectively (p=0.005 day 1 to 1 month, and p=0.86 1 month to 6 months). Using a cut-off of > 208 PRU, 35% of patients had high platelet reactivity (HPR) to clopidogrel on day 1, 43% at one month, and 46% at six months after PCI. Between day 1 and six months after PCI, 38.2% of patients changed clopidogrel responder status at least once. Other cut-offs and RPA yielded similar results. Platelet inhibition by aspirin was consistent over time with only five patients being characterised as having HPR. Considerable variation in individual on-clopidogrel platelet reactivity was present during both the subacute and the late phases of maintenance therapy after elective PCI. Hence, the utility of contemporary platelet function testing to guide antiplatelet therapy may be limited.

Keywords

Clopidogrel - platelet reactivity - VerifyNow™ - ADAPT-DES - drug-eluting stent

• References

• 1 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.
• 2 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.
• 3 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
• 4 Geisler T, Zurn C, Simonenko R. et al. Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions. Eur Heart J 2010; 31: 59-66.
• 5 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. J Am Med Assoc 2010; 303: 754-762.
• 6 Park DW, Lee SW, Yun SC. et al. A point-of-care platelet function assay and C-reactive protein for prediction of major cardiovascular events after drug-eluting stent implantation. J Am Coll Cardiol 2011; 58: 2630-2639.
• 7 Price MJ, Angiolillo DJ, Teirstein PS. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 2011; 124: 1132-1137.
• 8 Stone GW, Witzenbichler B, Weisz G. et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013; 382: 614-623.
• 9 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. J Am Med Assoc 2011; 305: 1097-1105.
• 10 Collet JP, Cuisset T, Range G. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367: 2100-2109.
• 11 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59: 2159-2164.
• 12 Campo G, Parrinello G, Ferraresi P. et al. Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 2011; 57: 2474-2483.
• 13 Hochholzer W, Ruff CT, Mesa RA. et al. Variability of Individual Platelet Reactivity Over Time in Patients Treated With Clopidogrel: Insights From the ELEV-ATE-TIMI 56 Trial. J Am Coll Cardiol 2014; 64: 361-368.
• 14 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.
• 15 Malinin A, Pokov A, Swaim L. et al. Validation of a VerifyNow-P2Y12 cartridge for monitoring platelet inhibition with clopidogrel. Meth Find Exp Clin Pharmacol 2006; 28: 315-322.
• 16 Parodi G, Marcucci R, Valenti R. et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. J Am Med Assoc 2011; 306: 1215-1223.
• 17 Chen WH, Lee PY, Ng W. et al. 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.
• 18 Gum PA, Kottke-Marchant K, Welsh PA. et al. 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.
• 19 Saw J, Madsen EH, Chan S. et al. The ELAPSE (Evaluation of Long-Term Clopidogrel Antiplatelet and Systemic Anti-Inflammatory Effects) study. J Am Coll Cardiol 2008; 52: 1826-1833.
• 20 Codner P, Vaduganathan M, Rechavia E. et al. Clopidogrel response up to six months after acute myocardial infarction. Am J Cardiol 2012; 110: 321-325.
• 21 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
• 22 Geisler T, Kapp M, Gohring-Frischholz K. et al. Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease. Heart 2008; 94: 743-747.
• 23 Nagashima Z, Tsukahara K, Morita S. et al. Platelet reactivity in the early and late phases of acute coronary syndromes according to cytochrome P450 2C19 phenotypes. J Cardiol 2013; 62: 158-164.
• 24 Mega JL, Hochholzer W, Frelinger AL. 3rd et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. J Am Med Assoc 2011; 306: 2221-2228.
• 25 Freynhofer MK, Bruno V, Brozovic I. et al. Variability of on-treatment platelet reactivity in patients on clopidogrel. Platelets 2014; 25: 328-336.
• 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 Trenk D, Neumann FJ. Aspirin resistance an underestimated risk in patients with drug-eluting stents?. J Am Coll Cardiol 2008; 52: 740-742.
• 28 Ferreiro JL, Ueno M, Tomasello SD. et al. Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study. Circ Cardiovasc Interv 2011; 4: 273-279.
• 29 Sibbing D, Morath T, Stegherr J. et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 714-719.
• 30 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312-1319.
• 31 Wallentin L, James S, Storey RF. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.