Abstract: Background. The impact of platelet reactivity on periprocedural myonecrosis (PMN) in East Asian patients with stable ischemic heart disease or non-ST elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unclear. Methods. We enrolled 256 patients with normal high-sensitivity troponin I levels who underwent PCI for stable ischemic heart disease or non-ST elevation acute coronary syndrome. Residual platelet reactivity was assessed by VerifyNow point-of-care P2Y12 assay before PCI and at 18-24 hours following PCI. High platelet reactivity (HPR) was defined using three cut-off scores for platelet reactivity units (PRUs). PMN was defined as a high-sensitivity troponin I elevation of >5x the 99th percentile upper reference limit (URL) in patients with normal baseline values (<99th percentile URL). Results. The rate of PMN was 55.9% (n = 143) and was significantly higher for pre-PCI and post-PCI PRU values in the fourth quartile compared with those in the first quartile (15% vs 37% [P<.001] and 20% vs 36% [P<.001], respectively). The rate of PMN was higher in patients with HPR, regardless of the criteria used (PRU >208, PRU >235, and PRU >272) and time point. Multivariable analysis revealed that pre-PCI HPR (PRU >208) was an independent predictor of increased risk of PMN (odds ratio, 3.39; 95% confidence interval, 1.87-6.17; P<.001). Conclusion. Pre-PCI HPR (PRU >208) was associated with an increased risk of PMN in East Asian patients with stable ischemic heart disease or non-ST elevation acute coronary syndrome undergoing PCI. Achievement of optimal platelet reactivity may decrease the risk of PMN.
J INVASIVE CARDIOL 2019;31(12):E369-E375.
Key words: myocardial injury, percutaneous coronary intervention, platelets, VerifyNow
Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is required to adequately inhibit platelet activity in patients undergoing percutaneous coronary intervention (PCI) to reduce the risk of ischemic complications.1-3 Clopidogrel, a P2Y12 inhibitor used in elective PCI, has considerable interindividual variability and may result in inadequate platelet inhibition.4-6 East Asians have a high prevalence of high platelet reactivity (HPR) on clopidogrel therapy;7 HPR on antiplatelet therapy is not only associated with an increased risk of major adverse cardiovascular events, but may also contribute to periprocedural myonecrosis (PMN).8-10 PMN is relatively common after PCI and has been associated with higher risk of ischemic complications and death.10-16 The relationship between PCI and subsequent PMN is dependent on several aspects, including angiographic factors, procedural characteristics, and the cardiac biomarker used for its detection.17 This prospective study evaluated the relationship between HPR and PMN in East Asian patients with stable ischemic heart disease or non-ST elevation acute coronary syndrome undergoing PCI.
Between February 2015 and December 2016, a total of 256 patients with stable ischemic heart disease or non-ST elevation myocardial infarction (NSTEMI) who underwent PCI at Dong-A University Medical Center in Busan, Korea were recruited for this prospective, observational, cross-sectional study. All patients received the standard loading dose of clopidogrel 600 mg and aspirin 500 mg at least 12 hours prior to PCI. All patients underwent PCI with unfractionated heparin (70-100 IU/kg) and received maintenance DAPT (clopidogrel 75 mg/day, prasugrel 10 mg/day, or ticagrelor 180 mg/day, as well as aspirin 100 mg) after PCI. Exclusion criteria included platelet count <100,000/µL, hemoglobin levels <8.0 g/dL, malignancies, active bleeding or major surgery within 4 weeks, severe chronic renal failure, and treatment with other antiplatelet agent types (cilostazol or a glycoprotein IIb/IIIa receptor blocker).Written informed consent was obtained from all patients. The study protocol was approved by the ethical review board of Dong-A University Hospital.
Blood samples for high-sensitivity troponin I and residual platelet reactivity were drawn in all patients before PCI and at 1 and 8-24 hours after PCI. Blood samples were obtained by venipuncture after 2 mL were discarded. Residual platelet reactivity was assessed by VerifyNow point-of-care P2Y12 assay (Accumetrics). Blood samples for platelet function test were drawn into Greiner Bio-One 1.8 mL Vacuette blood collection tubes containing 3.2% sodium citrate (Greiner Bio-One), and platelet function was tested within 4 hours of collection. The VerifyNow P2Y12 assay is a whole-blood, cartridge-based, optical detection system designed to measure platelet aggregation.18 The P2Y12receptor response to adenosine diphosphate (ADP) is measured in a cartridge channel of the P2Y12 assay containing ADP as a platelet agonist and prostaglandin E1 as a suppressor of intracellular free calcium levels (which reduces the nonspecific contribution of ADP binding to P2Y12 receptors).
The P2Y12 assay results are expressed in P2Y12 reaction units (PRUs). An electronic quality-control test and positive and negative control tests were performed on each instrument every day prior to analyzing patient samples. The internal electronic quality-control device and kits with negative and positive control tests were provided by the assay manufacturer.
The primary endpoint of the study was the correlation between occurrence of PMN in patients undergoing PCI and the presence of HPR. PMN was defined as a high-sensitivity troponin I elevation >5x the 99th percentile upper reference limit (URL) in patients with normal baseline values (<99th percentile URL) or a rise of high-sensitivity troponin I values >20% if the baseline values were elevated and stable or falling.19 The secondary endpoint was the HPR rate in patients with and without PMN. The cut-off values for HPR were defined by three criteria: PRU >208,20 PRU >235,21 and PRU >272.22
Statistical analysis. Continuous variables are expressed as mean values with standard deviations, and categorical variables as frequencies (percentages). Comparisons between two mean values for continuous variables were analyzed using Student’s t-test. Categorical variables were compared with Pearson’s Chi-square or Fisher’s exact test. Univariable and multivariable logistic regression analyses were used to determine independent factors associated with the incidence of PMN. All data with a P-value <.20 in the univariable analysis were then entered into a multivariable model. The ability of the assay to discriminate between patients with and without PMN was assessed by deriving their C-statistics, using receiver operating characteristic (ROC) curve analysis with MedCalc, version 12.2.1 (MedCalc software). In general, a model with a C-statistic >0.70 is considered to have acceptable discriminatory capacity.23 P-values <.05 were considered to indicate significance. Statistical analyses were performed using SPSS, version 18.0 (SPSS).
PMN occurred in 143 patients (55.9%), while 113 patients (44.1%) did not experience PMN (Table 1). Compared with the no-PMN group, the PMN group was older, and was more frequently female and smokers. The PMN group also had more patients who were treated with clopidogrel, had left ventricular ejection fraction <50%, and had a higher mean creatinine. Both pre-PCI and post-PCI PRU values were significantly higher in the PMN group vs the no-PMN group (230.9 ± 84.8 vs 182.5 ± 76.4 [P<.001] and 155.4 ± 93.4 vs 109.1 ± 77.3 [P<.001], respectively) (Figure 1). The procedural characteristics were not significantly different between the PMN and no-PMN groups (Table 2).
The overall rate of pre-PCI HPR (PRU >208) was 49% (Table 3). The rates of both pre-PCI and post-PCI HPR (PRU >208, PRU >235, and PRU >272) were significantly higher in the PMN group. The rate of PMN was significantly more frequent in pre-PCI and post-PCI PRU values in the fourth quartile compared with those in the first quartile (15% vs 37% [P<.001] and 20% vs 36% [P<.001], respectively) (Figure 2). However, there were no significant differences in the rate of PMN according to the PRU change rate between pre-PCI and post-PCI (22% vs 29%; P=.10) (Figure 3). ROC curve analysis demonstrated that pre-PCI and post-PCI PRU values could significantly discriminate between patients with and without PMN (area under the curve [AUC], 0.68 and 0.65, respectively) (Figure 4). The point estimate of the AUC value for the prediction of PMN was similar between pre-PCI and post-PCI PRU values (P=.16). A pre-PCI PRU value of >205 was the optimal cut-off point to predict PMN, with a sensitivity of 68% and specificity of 68%. Post-PCI PRU >164 was the optimal cut-off point to predict PMN, with a sensitivity of 52% and specificity of 82%.
Univariable analysis demonstrated that older age, female sex, serum creatinine, left ventricular ejection fraction <50%, and pre-PCI and post-PCI HPR were significantly associated with PMN (Table 4). Multivariable analysis revealed that pre-PCI HPR (PRU >208) was the strongest independent predictor of increased risk of PMN (odds ratio, 3.39; 95% confidence interval, 1.87-6.17; P<.001) (Table 5).
The main finding of our study was that after loading with a P2Y12 inhibitor, pre-PCI HPR (PRU >208), was a better predictor of PMN compared with post-PCI HPR in East Asian patients with stable ischemic heart disease or non-ST elevation acute coronary syndrome undergoing PCI. Whereas previous studies used one-time platelet function assessment for the relationship with HPR and PMN, the strength of this study was that two sequential parameters suggested that pre-PCI HPR was more important than post-PCI HPR in predicting PMN.
Various criteria were used to define HPR (PRU >208, PRU >235, and PRU >272) after P2Y12 inhibitor therapy. In the ADAPT-DES study,20 a PRU value >208 was found to be the optimal cut-off to discriminate patients at higher risk of 1-year occurrence of stent thrombosis and myocardial infarction. Furthermore, Park et al21 demonstrated that HPR (PRU >235) was independently associated with the primary composite endpoint of death, myocardial infarction, stent thrombosis, or stroke in East Asian patients undergoing PCI with acute coronary syndrome. Similarly, in East Asian patients, HPR (PRU >272) was associated with ischemic events after PCI at 1-month follow-up.22 However, our study revealed that HPR, defined as a PRU >208, had a stronger correlation with PMN than PRU >235 and PRU >272 in East Asian patients undergoing PCI.
Several studies have reported a correlation between HPR and increased atherosclerotic burden. Keating et al24 demonstrated that on-clopidogrel HPR was associated with increased coronary atherosclerotic burden. In addition, Mangiacapra et al25 reported that multivessel coronary artery disease was associated with an increased rate of HPR in patients undergoing PCI and Yun et al26 demonstrated that HPR was associated with high plaque burden and increased culprit-lesion atherosclerotic burden.
Several other studies have reported the predictive role of on-clopidogrel HPR in PMN during PCI.8-10 Although the prognostic value of PMN is controversial,27,28 growing evidence supports the assertion that even small increases in cardiac biomarkers are significantly associated with long-term clinical events, including mortality.14-16 Selvanayagam et al29 provided insights into the association between PMN and long-term clinical outcomes. Irreversible myocardial injury detected by delayed-enhancement magnetic resonance imaging was observed in patients with postprocedural troponin elevation. In addition, the risk of adverse events increased proportionally with cardiac biomarker elevation, translating into an even higher risk for patients with PMN.19
Pre-PCI HPR, defined as PRU >208, was superior at predicting PMN compared with post-PCI HPR. Pre-PCI HPR was the strongest independent predictor of increased risk of PMN.
Based upon on our results, pre-PCI evaluation of platelet reactivity provides important prognostic information and may guide the therapeutic approach for those patients with suboptimal platelet inhibition. Assessment for on-clopidogrel HPR may help identify patients who are at higher risk for future events. However, a randomized trial is needed to demonstrate that this strategy, as well as escalation to more potent antiplatelet therapy for patients with HPR, improves clinical outcomes.
Patients with on-clopidogrel HPR may benefit from a fast-acting, potent antiplatelet agent at the time of PCI. In the CHAMPION PHOENIX trial, the direct-acting platelet ADP P2Y12 inhibitor cangrelor reduced the rate of ischemic events, including stent thrombosis, during PCI.30 However, cangrelor is currently not available in Asia.
Study limitations. This was a small, single-center study, with a short follow-up duration. Clinical outcomes including death, myocardial infarction, and stent thrombosis were not reported. This study included patients with non-ST elevation myocardial infarction, who have elevated baseline troponin I levels. Therefore, the definition of PMN in patients is often difficult. Patients with NSTEMI also exhibit higher levels of platelet activation. The incidence of PMN was relatively high compared with previous studies because high-sensitivity troponin I was measured in this analysis, rather than creatine kinase and creatinine kinase-MB. We used the third universal definition of myocardial infarction,19 in which the high-sensitivity troponin I value for myocardial infarction was almost one-tenth the previous cut-off value.
In East Asian patients with stable ischemic heart disease or non-ST elevation acute coronary syndrome undergoing PCI, pre-PCI HPR (PRU >208) was associated with an increased risk of PMN. Achievement of optimal platelet reactivity may decrease the risk of PMN. A randomized trial with a larger sample size and long-term follow-up is needed to confirm these results.
1. Patti G, Colonna G, Pasceri V, Pepe LL, Montinaro A, Di Sciascio G. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005;111:2099-2106.
2. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POSTSTENTING study. J Am Coll Cardiol. 2005;46:1820-1826.
3. Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2015;65:1298-1310.
4. 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.
5. 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.
6. Bonello L, Tantry US, Marcucci R, et al; Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010;56:919-933.
7. Hwang SJ, Jeong YH, Kim IS, et al. The cytochrome 2C19*2 and *3 alleles attenuate response to clopidogrel similarly in East Asian patients undergoing elective percutaneous coronary intervention. Thromb Res. 2011;127:23-28.
8. 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;47:27-33.
9. Buch AN, Singh S, Roy P, et al. Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2007;99:1518-1522.
10. Cuisset T, Hamilos M, Sarma J, et al. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris. Am J Cardiol. 2008;101:1700-1703.
11. Cavallini C, Savonitto S, Violini R, et al; Italian Atherosclerosis Thrombosis, Vascular Biology, Society for Invasive Cardiology. Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study. Eur Heart J. 2005;26:1494-1498.
12. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol. 1998;31:241-251.
13. Akkerhuis KM, Alexander JH, Tardiff BE, et al. Minor myocardial damage and prognosis: are spontaneous and percutaneous coronary intervention-related events different? Circulation. 2002;105:554-556.
14. Ioannidis JP, Karvouni E, Katritsis DG. Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention. J Am Coll Cardiol. 2003;42:1406-1411.
15. Tardiff BE, Califf RM, Tcheng JE, et al. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention: IMPACT-II Investigators Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II. J Am Coll Cardiol. 1999;33:88-96.
16. Prasad A, Rihal CS, Lennon RJ, et al. Significance of periprocedural myonecrosis on outcomes after percutaneous coronary intervention: an analysis of preintervention and postintervention troponin T levels in 5487 patients. Circ Cardiovasc Interv. 2008;1:10-19.
17. Herrmann J. Peri-procedural myocardial injury. Eur Heart J. 2005;26:2493-2519.
18. Malinin A, Pokov A, Spergling M, et al. Monitoring platelet inhibition after clopidogrel with the VerifyNow-P2Y12 rapid analyzer: the Verify Thrombosis Risk Assessment (VERITAS) study. Thromb Res. 2007;119:277-284.
19. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Writing Group on the Joint ESC/ACCF/AHA/WHF/Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Eur Heart J. 2012;33:2551-2567.
20. Stone GW, Witzenbichler B, Weisz G, et al; ADAPT-DES Investigators. 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.
21. Park DW, Ahn JM, Song HG, et al. Differential prognostic impact of high on-treatment platelet reactivity among patients with acute coronary syndromes versus stable coronary artery disease undergoing percutaneous coronary intervention. Am Heart J. 2013;165:34-42.
22. Zhang HZ, Kim MH, Jeong YH. Predictive values of post-clopidogrel platelet reactivity assessed by different platelet function tests on ischemic events in East Asian patients treated with PCI. Platelets. 2014;25:292-299.
23. Núñez E, Steyerberg EW, Núñez J. Regression modeling strategies. Rev Esp Cardiol. 2011;64:501-507.
24. Keating FK, Whitaker DA, Kabbani SS, Ricci MA, Sobel BE, Schneider DJ. Relation of augmented platelet reactivity to the magnitude of distribution of atherosclerosis. Am J Cardiol. 2004;94:725-728.
25. Mangiacapra F, De Bruyne B, Muller O, et al. High residual platelet reactivity after clopidogrel: extent of coronary atherosclerosis and periprocedural myocardial infarction in patients with stable angina undergoing percutaneous coronary intervention. JACC Cardiovasc Interv. 2010;3:35-40.
26. Yun KH, Mintz GS, Witzenbichler B, et al. Relationship between platelet reactivity and culprit lesion morphology: an assessment from the ADAPT-DES intravascular ultrasound substudy. JACC Cardiovasc Imaging. 2016;9:849-854.
27. Bhatt DL, Topol EJ. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes. Circulation. 2005;112:906-915.
28. Cutlip DE, Kuntz RE. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Cardiac enzyme elevation after successful percutaneous coronary intervention is not an independent predictor of adverse outcomes. Circulation. 2005;112:916-922.
29. Selvanayagam JB, Cheng AS, Jerosch-Herold M, et al. Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention: a quantitative magnetic resonance perfusion study. Circulation. 2007;116:1458-1464.
30. Bhatt DL, Stone GW, Mahaffey KW, et al; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303-1313.
From the 1Department of Cardiology, Dong-A University Hospital, Busan, South Korea; 2Department of Biomedical Laboratory Science, Daegu Health College, Daegu, South Korea; 3Department of Clinical Laboratory Science, Dong-Eui University, Busan, Korea; and 4Division of Cardiology, UCLA Medical Center, Los Angeles, California.
Funding. This research was supported by a grant from the Ministry of Education, Science and Technology (NRF-2015R1D1A1A09057025) to MHK, as well as support from the Ministry of Education (NRF-2017R1D1A3B03035713) to SYC.
Disclosure. The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 27, 2019, provisional acceptance given June 4, 2019, final version accepted June 6, 2019.
Address for correspondence: Moo Hyun Kim, MD, FACC, Department of Cardiology, Dong-A University Hospital, 26 Daesingongwon-ro, Seo-gu, Busan, South Korea 602-715. Email: email@example.com