Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel

Summary

Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. The role and usefulness of PR with regard to levels of cardiovascular risk are unclear. We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischaemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20 μM ADP. Thirteen prospective studies totaled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5 %) during a median follow-up of 12 months. The strength of the association between the risk of MACE and PR increased significantly (p=0.04) with the number of risk factors present (age> 75 years, ACS at inclusion, diabetes, and hypertension). No association was detected in patients with no risk factor (p=0.48). In patients presenting one risk factor, only high-PR was associated with an increased risk of MACE (HR 3.2, p=0.001). In patients presenting ≥ 2 risk factors, the increase of risk started from medium-PR (medium-PR: HR=2.9, p=0.0004; high-PR: HR=3.7, p=0.0003). PR allowed the reclassification of 44 % of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high risk patients. In conclusion, the magnitude of the association between PR and MACE risk is strongly dependent on the level of cardiovascular risk faced by patients on clopidogrel.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Clopidogrel - drug response - platelets - cardiovascular diseases - ischaemic events

• References

• 1 Eikelboom JW, Hirsh J, Spencer FA. et al. Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) Suppl e89S-119S.
• 2 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.
• 3 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.
• 4 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.
• 5 Snoep JD, Hovens MM, Eikenboom JC. et al. 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.
• 6 Aradi D, Komocsi A, Vorobcsuk A. et al. Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis. Am Heart J 2010; 160: 543-551.
• 7 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; 08: 923-933.
• 8 Reny JL, Berdague P, Poncet A. et al. Antiplatelet Drug Response Status Does Not Predict Recurrent Ischaemic Events in Stable Cardiovascular Patients: Results of the Antiplatelet Drug Resistances and Ischaemic Events Study. Circulation 2012; 125: 3201-3210.
• 9 Pettersen AA, Seljeflot I, Abdelnoor M. et al. High On-Aspirin Platelet Reactivity and Clinical Outcome in Patients With Stable Coronary Artery Disease: Results From ASCET (Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial). Journal of the American Heart Association 2012; 1: e000703.
• 10 Gurbel PA, Erlinge D, Ohman EM. et al. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascu-larisation: the TRILOGY ACS platelet function substudy. J Am Med Assoc 2012; 308: 1785-1794.
• 11 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 randomised prospective study. J Am Coll Cardiol 2008; 51: 1404-1411.
• 12 Bonello L, Camoin-Jau L, Armero S. et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009; 103: 5-10.
• 13 Price MJ, Berger PB, Teirstein PS. et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomised trial. J Am Med Assoc 2011; 305: 1097-1105.
• 14 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.
• 15 Aradi D, Komocsi A, Price MJ. et al. Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis. Int J Cardiol 2013; 167: 2140-2148.
• 16 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.
• 17 Brar SS, ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011; 58: 1945-1954.
• 18 Yamaguchi Y, Abe T, Sato Y. et al. Effects of VerifyNow P2Y12 test and CYP2C19*2 testing on clinical outcomes of patients with cardiovascular disease: a systematic review and meta-analysis. Platelets 2013; 24: 352-361.
• 19 Moher D, Pham B, Klassen TP. et al. What contributions do languages other than English make on the results of meta-analyses?. J Clin Epidemiol 2000; 53: 964-972.
• 20 Berlin JA. Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group. Lancet 1997; 350: 185-186.
• 21 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.
• 22 Tantry US, Bonello L, Aradi D. et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischaemia and bleeding. J Am Coll Cardiol 2013; 62: 2261-2273.
• 23 Stewart GB, Altman DG, Askie LM. et al. Statistical analysis of individual participant data meta-analyses: a comparison of methods and recommendations for practice. PLoS One 2012; 07: e46042.
• 24 Akritas MG. Nearest neighbor estimation of a bivariate distribution under random censoring. Ann Stat 1994; 22: 1299-1327.
• 25 Pencina MJ, DAgostino Sr. RB, Steyerberg EW. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 2011; 30: 11-21.
• 26 Stroup DF, Berlin JA, Morton SC. et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. J Am Med Assoc 2000; 283: 2008-2012.
• 27 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.
• 28 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-inter-ventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
• 29 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.
• 30 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.
• 31 Geisler T, Grass D, Bigalke B. et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost 2008; 06: 54-61.
• 32 Gurbel PA, Antonino MJ, Bliden KP. et al. Platelet reactivity to adenosine diphosphate and long-term ischaemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets 2008; 19: 595-604.
• 33 Cuisset T, Frere C, Quilici J. et al. Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogrel-treated patients. Am J Cardiol 2009; 104: 1078-1082.
• 34 Yong G, Rankin J, Ferguson L. et al. Randomised trial comparing 600- with 300-mg loading dose of clopidogrel in patients with non-ST elevation acute coronary syndrome undergoing percutaneous coronary intervention: results of the Platelet Responsiveness to Aspirin and Clopidogrel and Troponin Increment after Coronary intervention in Acute coronary Lesions (PRACTICAL) Trial. Am Heart J 2009; 157 (60) e1-9..
• 35 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.
• 36 Marcucci R, Gori AM, Paniccia R. et al. High on-treatment platelet reactivity by more than one agonist predicts 12-month follow-up cardiovascular death and non-fatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting. Thromb Haemost 2010; 104: 279-286.
• 37 Beigel R, Hod H, Fefer P. et al. Relation of aspirin failure to clinical outcome and to platelet response to aspirin in patients with acute myocardial infarction. Am J Cardiol 2011; 107: 339-342.
• 38 Aradi D, Rideg O, Vorobcsuk A. et al. Justification of 150 mg clopidogrel in patients with high on-clopidogrel platelet reactivity. Eur J Clin Invest 2012; 42: 384-392.
• 39 Gagne JJ, Bykov K, Choudhry NK. et al. Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. Br Med J 2013; 347: f5307.
• 40 Lafitte M, Pucheu Y, Latry K. et al. Predictors of cardiovascular prognosis in patients receiving optimized secondary prevention measures after acute coronary syndrome. Eur J Prevent Cardiol 2013; 20: 283-290.
• 41 Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue of drug resistance. Arterioscler Thromb Vasc Biol 2004; 24: 1980-1987.
• 42 Jeong YH, Bliden KP, Antonino MJ. et al. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J 2012; 164: 35-42.
• 43 Van Werkum J, Van Der Stelt CA, Seesing TH. et al. A head-to-head comparison between the VerifyNow P2Y12 assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective percutaneous coronary intervention. J Thromb Haemost 2006; 04: 2516-2518.
• 44 Coleman CI, Limone BL. Universal versus platelet reactivity assay-driven use of P2Y12 inhibitors in acute coronary syndrome patients: cost-effectiveness analyses for six European perspectives. Thromb Haemost 2014; 111: 103-110.
• 45 Cayla G, Cuisset T, Silvain J. et al. Platelet function monitoring in elderly patients on prasugrel after stenting for an acute coronary syndrome: Design of the randomised antarctic study. Am Heart J 2014; 168: 674-681.