Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrelResults from PRINCIPLE-TIMI 44 Financial support: Daiichi Sankyo Company Limited (Tokyo, Japan) and Eli Lilly and Company (Indianapolis, IN) sponsored the PRINCIPLE-TIMI 44 trial. The present analysis had no funding.
Received: 18. März 2011
Accepted after major revision: 17. Juni 2011
25. November 2017 (online)
It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18–24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18–24 h and 15 day reactivity to ADP (correlations 0.24–0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.
- 1 Snoep JD, Hovens MM, Eikenboom JC. et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221-231.
- 2 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.
- 3 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.
- 4 Marcucci R, Gori AM, Paniccia R. et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009; 119: 237-242.
- 5 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.
- 6 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.
- 7 Kushner FG, Hand M, Smith SC. Jr. et al. 2009; Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/ SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120: 2271-2306.
- 8 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.
- 9 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel compared with high loadingand 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.
- 10 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533-1537.
- 11 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.
- 12 McEver R. P-selectin/PSGL-1 and other interactions between platelets, leukocytes and endothelium. Michelson AD. editor. Platelets.. 2nd ed. Elsevier/Academic Press; San Diego: 2007: 231-249.
- 13 Michelson AD. Methods for the measurement of platelet function. Am J Cardiol 2009; 103 (Suppl. 03) 20A-26A.
- 14 Bonello L, Tantry US, Marcucci R. et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
- 15 Combescure C, Fontana P, Mallouk N. et al. Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 923-933.
- 16 Campo G, Fileti L, de Cesare N. et al. Long-term clinical outcome based on aspirin and clopidogrel responsiveness status after elective percutaneous coronary intervention: a 3T/2R (tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel) trial substudy. J Am Coll Cardiol 2010; 56: 1447-1455.
- 17 Pena A, Collet JP, Hulot JS. et al. Can we override clopidogrel resistance?. Circulation 2009; 119: 2854-2857.
- 18 Hulot JS, Fuster V. Antiplatelet therapy: Personalized medicine for clopidogrel resistance?. Nat Rev Cardiol 2009; 6: 334-336.
- 19 Jeong YH, Lee SW, Choi BR. et al. Randomized comparison of adjunctive cilostazol versus high maintenance dose clopidogrel in patients with high post-treatment platelet reactivity: results of the ACCEL-RESISTANCE (Adjunctive cilostazol Versus High Maintenance Dose Clopidogrel in Patients With Clopidogrel Resistance) randomized study. J Am Coll Cardiol 2009; 53: 1101-1109.
- 20 Sofi F, Marcucci R, Gori AM. et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost 2010; 103: 841-848.
- 21 Elsenberg EH, van Werkum JW, van de Wal RM. et al. The influence of clinical characteristics, laboratory and inflammatory markers on ‘high on-treatment platelet reactivity’ as measured with different platelet function tests. Thromb Haemost 2009; 102: 719-727.
- 22 Jaitner J, Stegherr J, Morath T. et al. Stability of the high on-treatment platelet reactivity phenotype over time in clopidogrel-treated patients. Thromb Haemost 2011; 105: 107-112.
- 23 Hetherington SL, Singh RK, Lodwick D. et al. Dimorphism in the P2Y1 ADP receptor gene is associated with increased platelet activation response to ADP. Arterioscler Thromb Vasc Biol 2005; 25: 252-257.
- 24 Fontana P, Dupont A, Gandrille S. et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y^ gene sequence variations in healthy subjects. Circulation 2003; 108: 989-995.
- 25 Hechler B, Zhang Y, Eckly A. et al. Lineage-specific overexpression of the P2Y1 receptor induces platelet hyper-reactivity in transgenic mice. J Thromb Haemost 2003; 1: 155-163.
- 26 Jones CI, Bray S, Garner SF. et al. A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways. Blood 2009; 114: 1405-1416.
- 27 Johnson AD, Yanek LR, Chen MH. et al. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet 2010; 42: 608-613.
- 28 Shuldiner AR, O’Connell JR, Bliden KP. et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. J Am Med Assoc 2009; 302: 849-857.