The impact of renal function on platelet reactivity and clinical outcome in patients undergoing percutaneous coronary intervention with stenting

Summary

Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease. Previous studies have suggested that patients with CKD have less therapeutic benefit of antiplatelet therapy. However, the relation between renal function and platelet reactivity is still under debate. On-treatment platelet reactivity was determined in parallel by ADP- and AA-induced light transmittance aggregometry (LTA) and the VerifyNow^® System (P2Y12 and Aspirin) in 988 patients on dual antiplatelet therapy, undergoing elective coronary stenting. Patients were divided into two groups according to the presence or absence of moderate/severe CKD (GFR<60 ml/min/1.73 m²). Furthermore, the incidence of all-cause death, non-fatal acute myocardial infarction, stent thrombosis and stroke at one-year was evaluated. Patients with CKD (n=180) had significantly higher platelet reactivity, regardless of the platelet function test used. Patients with CKD more frequently had high on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) regardless of the platelet function test used. After adjustment for potential confounders, this was no longer significant. The event-rate was the highest in patients with both high on-treatment platelet reactivity (HPR) and CKD compared to those with neither high on-treatment platelet reactivity nor CKD. In conclusion, the magnitude of platelet reactivity as well as the incidence of HPR was higher in patients with CKD. However, since the incidence of HPR was similar after adjustment, a higher rate of co-morbidities in patients with CKD might be the major cause for this observation rather than CKD itself. CKD-patients with HCPR were at the highest risk of long-term cardiovascular events.

Clinical Trial Registration: www.clinicaltrials.gov: NCT00352014.

Keywords

Light transmittance aggregometry - VerifyNow - clopidogrel - chronic kidney disease - clinical outcome

• References

• 1 Go AS, Chertow GM, Fan D. et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296-1305.
• 2 Shaw JA, Andrianopoulos N, Duffy S. et al. Renal impairment is an independent predictor of adverse events post coronary intervention in patients with and without drug-eluting stents. Cardiovasc Revasc Med 2008; 09: 218-223.
• 3 Best PJ, Lennon R, Ting HH. et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39: 1113-1119.
• 4 Steinhubl SR, Berger PB, Mann III JT. et al. Early and sustained dual oral anti-platelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
• 5 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.
• 6 Best PJ, Steinhubl SR, Berger PB. et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 2008; 155: 687-693.
• 7 Dasgupta A, Steinhubl SR, Bhatt DL. et al. Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin versus aspirin alone (a post hoc analysis of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance [CHARISMA] trial). Am J Cardiol 2009; 103: 1359-1363.
• 8 Angiolillo DJ, Bernardo E, Capodanno D. et al. Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy. J Am Coll Cardiol 2010; 55: 1139-1146.
• 9 Park SH, Kim W, Park CS. et al. A comparison of clopidogrel responsiveness in patients with versus without chronic renal failure. Am J Cardiol 2009; 104: 1292-1295.
• 10 Htun P, Fateh-Moghadam S, Bischofs C. et al. Low responsiveness to clopidogrel increases risk among CKD patients undergoing coronary intervention. J Am Soc Nephrol 2011; 22: 627-633.
• 11 Morel O, El GS, Jesel L. et al. Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel. J Am Coll Cardiol 2011; 57: 399-408.
• 12 Morel O, Muller C, Jesel L. et al. Impaired platelet P2Y12 inhibition by thienopyridines in chronic kidney disease: mechanisms, clinical relevance and pharmacological options. Nephrol Dial Transplant 2013; 28: 1994-2002.
• 13 Mangiacapra F, Cavallari I, Barbato E. et al. Impact of chronic kidney disease on platelet reactivity and outcomes of patients receiving clopidogrel and undergoing percutaneous coronary intervention. Am J Cardiol 2014; 113: 1124-1129.
• 14 Breet NJ, van Werkum JW, Bouman HJ. et al. Comparison between platelet function tests in predicting clinical outcome in patients undergoing coronary stent placement. J Am Med Assoc 2010; 303: 754-762.
• 15 Levey AS, Coresh J, Balk E. et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139: 137-147.
• 16 Breet NJ, van Werkum JW, Bouman HJ. et al. Do not adjust the platelet count in light transmittance aggregometry when predicting thrombotic events after PCI. J Thromb Haemost 2010; 08: 2326-2328.
• 17 van der Stelt CA, van Werkum JW, Seesing TH. et al. To adjust or not to adjust the platelet count in light transmission aggregometry in patients receiving dual aspirin/clopidogrel treatment. Platelets 2007; 18: 550-553.
• 18 Breet NJ, van Werkum JW, Bouman HJ. et al. Both peak and late aggregation are capable of identifying patients at risk for atherothrombotic events. Thromb Haemost 2011; 105: 197-199.
• 19 van Werkum JW, Kleibeuker M, Mieremet N. et al. Evaluation of the platelet response to clopidogrel with light transmittance aggregometry: peak aggregation or late aggregation?. J Thromb Haemost 2007; 05: 884-886.
• 20 van Werkum JW, Harmsze AM, Elsenberg EH. et al. The use of the VerifyNow system to monitor antiplatelet therapy: a review of the current evidence. Platelets 2008; 19: 479-488.
• 21 van Werkum JW, van der Stelt CA, Seesing TH. et al. A head-to-head comparison between the VerifyNowP2Y12-assay and light transmittance aggregometry for monitoring the individual platelet response to clopidogrel in patients undergoing elective PCI. J Thromb Haemost 2006; 04: 2516-2518.
• 22 Breet NJ, van Werkum JW, Bouman HJ. et al. High on-aspirin platelet reactivity as measured with aggregation based, COX-1 inhibition sensitive platelet function tests is associated with the occurrence of atherothrombotic events. J Thromb Haemost 2010; 08: 2140-2148.
• 23 Breet NJ, van Werkum JW, Bouman HJ. et al. High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention. Heart 2011; 97: 983-990.
• 24 Cutlip DE, Windecker S, Mehran R. et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115: 2344-2351.
• 25 TIMI study group: definitions used in TIMI-trials. Available at: http://www.timi.org 2009
• 26 Deray G, Bagnis C, Brouard R. et al. Clopidogrel activities in patients with renal function impairment. Clin Drug Invest 1998; 16: 319-328.
• 27 Schisterman EF, Cole SR, Platt RW. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology 2009; 20: 488-495.
• 28 Lindner A, Charra B, Sherrard DJ. et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974; 290: 697-701.
• 29 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.
• 30 Ioannidis JP, Tzoulaki I. What makes a good predictor?: the evidence applied to coronary artery calcium score. J Am Med Assoc 2010; 303: 1646-1647.
• 31 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.
• 32 James S, Budaj A, Aylward P. et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010; 122: 1056-1067.
• 33 Michelson AD, Cattaneo M, Eikelboom JW. et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005; 03: 1309-1311.
• 34 Fox CS, Muntner P, Chen AY. et al. Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patients with chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network registry. Circulation 2010; 121: 357-365.
• 35 Price MJ, Endemann S, Gollapudi RR. et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.