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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

2006; Elsevier BV; Volume: 4; Issue: 11 Linguagem: Inglês

10.1111/j.1538-7836.2006.02187.x

1538-7933

Jochem W. van Werkum, C.A.K. VAN DER STELT, Toine H. Seesing, C. M. Hackeng, Jurriën M. ten Berg,

Acute Myocardial Infarction Research

Clopidogrel on top of aspirin lowers the rate of thrombotic events in patients undergoing percutaneous coronary intervention (PCI) with coronary stenting. However, a number of ex vivo studies have demonstrated that the response to aspirin and clopidogrel is not uniform, and 'poor response' has been associated with an increased risk for cardiovascular events [1Serebruany V.L. Steinhubl S.R. Berger P.B. Malinin A.I. Bhatt D.L. Topol E.J. Variability in platelet responsiveness to clopidogrel among 544 individuals.J Am Coll Cardiol. 2005; 45: 246-51Crossref PubMed Scopus (734) Google Scholar, 2Matetzky S. Shenkman B. Guetta V. et al.Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction.Circulation. 2004; 109: 3171-5Crossref PubMed Google Scholar]. Light transmittance aggregometry (LTA) is considered to be the gold standard for determining the effects of antiplatelet therapy on platelet function, but the logistical demands make it impossible to use in daily practice. Therefore, the VerifyNow® P2Y12 assay was recently introduced as a rapid point‐of‐care test; however, there is a lack of experimental evidence for the usefulness of this assay in monitoring clopidogrel's efficacy. In the present study, we prospectively studied the platelet response to clopidogrel (and aspirin) in 211 consecutive patients undergoing elective PCI with stenting. Owing to different protocols in referring hospitals, all patients received different but adequate clopidogrel pretreatment. Regimens were defined as maintenance therapy of 75 mg for > 5 days (n = 116) or a loading dose of 300 mg at least 24 h before PCI (n = 75) or 600 mg at least 4 h before PCI (n = 20). All patients were on ≥ 80 mg of aspirin for at least 7 days. The local institutional review board approved the protocol, and written informed consent was obtained before elective PCI. 'Classic' LTA induced by 20 μmol L−1 adenosine‐diphosphate (ADP) was quantified in non‐adjusted platelet rich plasma (PRP) at maximal (peak) aggregation and after 600 s (late aggregation). The VerifyNow® P2Y12 test cartridge system (Accumetrics, San Diego, CA, USA) was used as described previously [3Von Beckerath N. Pogatsa‐Murray G. Wieczorek A. Sibbing D. Schomig A. Kastrati A. Correlation of a new point‐of‐care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness.Thromb Haemost. 2006; 95: 910-1Crossref PubMed Scopus (100) Google Scholar]. Given the fact that the majority of the studies linking low clopidogrel response to atherothrombotic events have used absolute post‐treatment aggregation as the measure of clopidogrel response, we preferred using absolute P2Y12 Reaction Units (PRUs) over the reported BASE values of the VerifyNow® P2Y12 assay in the present study. A P‐value of < 0.05 of the Pearson correlation coefficient was considered statistically significant in comparing the results obtained from both tests. The three regimen groups were not significantly different with respect to both demographic and clinical characteristics (data not shown). Peak aggregation and late aggregation were significantly more strongly inhibited by the 600 mg loading dose of clopidogrel than by the 300 mg loading dose or a 'chronic' daily 75 mg maintenance dose (Fig. 1). Furthermore, the absolute number of PRUs was also significantly lower in patients who had received a 600 mg loading dose than in the two other groups. No significant differences in peak aggregation, late aggregation or the absolute number of PRUs were observed between the 300 mg loading dose group and the 75 mg maintenance group. As shown in Fig. 2, absolute PRUs were strongly correlated with peak and late aggregation (r = 0.73, P < 0.01, and r = 0.75, P < 0.01, respectively). Bland–Altman analysis of both correlations did not show any proportional or systematic bias, with minimal clustering of values (not shown).Figure 2The correlations between (A) peak aggregation and P2Y12 Reaction Units (PRUs) and (B) late aggregation and PRUs. The three different regimen groups are represented by different colors. The 'chronic' (75 mg) clopidogrel users are depicted as white dots, patients who received a 300 mg loading dose are depicted as gray dots, and patients who received a 600 mg loading dose are depicted as black dots.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The purpose of this study was to evaluate the results obtained with the point‐of‐care VerifyNow® P2Y12 assay as compared to LTA in assessing the inhibitory effects of clopidogrel therapy on platelet function in a large cohort of patients. It is important to note that the VerifyNow® P2Y12 differs from LTA because it uses prostaglandin E1 in the cartridge to suppress the additional but unwanted contribution of the ADP‐induced activation of the P2Y1 pathway resulting in a relatively higher magnitude of platelet inhibition. The relatively high y‐intercept (∼37%) of the regression line in Fig. 2 confirms this observation. A similar observation of approximately 40% was recently reported by von Beckerath et al. [3Von Beckerath N. Pogatsa‐Murray G. Wieczorek A. Sibbing D. Schomig A. Kastrati A. Correlation of a new point‐of‐care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness.Thromb Haemost. 2006; 95: 910-1Crossref PubMed Scopus (100) Google Scholar]. However, despite this major difference, both tests are based on the same principle (agonist‐induced, fibrinogen‐mediated aggregation that is measured and expressed as a change in light transmittance) and should therefore theoretically produce similar results. The results of our study in a large cohort of patients confirm that a strong correlation exists between the two methods of measurement, without any systemic bias. Recently, Labarthe et al. [4Labarthe B. Theroux P. Angioi M. Ghitescu M. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug.J Am Coll Cardiol. 2005; 46: 638-45Crossref PubMed Scopus (0) Google Scholar] demonstrated that much lower interpatient variability in the response to clopidogrel is found when the stabilization of aggregation (measured by disaggregation and late aggregation) is looked at, because this is driven mainly by blockade of the P2Y12 receptor. For this reason, we assessed the correlation between late aggregation and PRU. Interestingly, the Pearson correlation coefficients of late aggregation vs. PRU and peak aggregation vs. PRU in our study are almost similar. Moreover, the degrees of scatter in both Bland–Altman plots are also quite similar, with an approximately equal amount of outliers. As a result, we conclude that peak and late aggregation are almost interchangeable with the VerifyNow® P2Y12 measurement. Recently, von Beckerath et al. [3Von Beckerath N. Pogatsa‐Murray G. Wieczorek A. Sibbing D. Schomig A. Kastrati A. Correlation of a new point‐of‐care test with conventional optical aggregometry for the assessment of clopidogrel responsiveness.Thromb Haemost. 2006; 95: 910-1Crossref PubMed Scopus (100) Google Scholar] and Malinin et al. [5Malinin A. Pokov A. Spergling M. Defranco A. Schwartz K. Schwartz D. Mahmad E. Atar D. Serebruany V. Monitoring platelet inhibition after clopidogrel with the VerifyNow‐P2Y12(R) rapid analyzer: the VERIfy Thrombosis risk ASsessment (VERITAS) study.Thromb Res. 2006; Google Scholar] demonstrated a much lower post‐treatment PRU after 600 and 450 mg loading doses within 4 and 24 h, respectively. However, it has to be taken into account that this difference from our results might be explained by a more heterogeneous clopidogrel treatment regimen. Specifically, the study by von Beckerath et al. suggests that the correlation between peak aggregation and PRU is higher when platelets are least inhibited by clopidogrel. The results of our study are in agreement with this observation. Although all our patients were adequately pretreated, most of the patients were on 75 mg of clopidogrel for at least 5 days, and relatively few patients had received a 600 mg loading dose. Several studies have demonstrated a faster onset, higher responsiveness and greater platelet inhibition after the administration of a 600 mg loading dose of clopidogrel [6Gurbel P.A. Bliden K.P. Hiatt B.L. O'Connor C.M. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity.Circulation. 2003; 107: 2908-13Crossref PubMed Scopus (1443) Google Scholar]. However, it remains questionable whether a higher loading dose regimen (and perhaps a higher maintenance dose) should be applied in patients with stable angina pectoris. The authors state that they have no conflict of interest.