High on‐treatment platelet reactivity assessed by various platelet function tests: is the consensus‐defined cut‐off of VASP‐P platelet reactivity index too low?

Recent consensus of the Working Group has suggested that high on-treatment platelet reactivity (HPR) to ADP is a major cardiovascular risk factor [1]. This document also has provided the potential cut-offs of HPR to ADP for the most commonly used platelet function tests (PFTs), including light transmittance aggregometry (LTA), the VerifyNow P2Y12 assay (VerifyNow), Multiplate and the vasodilator-stimulated phosphoprotein-phosphorylation (VASP-P) assay. Although the concept of HPR is a major step forward for a personalized antiplatelet therapy strategy in high-risk patients undergoing percutaneous coronary intervention (PCI), several issues have been raised and delayed the clinical adoption of PFT [2,3]. The different correlations and degree of agreement between HPR determined by various PFTs are important concerns. Although the various PFTs identify different aspects of platelet biology, several studies have suggested matched cut-offs of HPR measured by LTA, VerifyNow and Multiplate [4,5], strengthening the reliability of the hypothesis of HPR being an important indicator of risk. The higher prevalence of HPR determined by the VASP-P assay in clopidogrelor prasugrel-treated patients (> 50% and 25%, respectively) compared with other assays during clopidogrel therapy (20 40%) [6–10], questions that the consensus-defined cut-off value of > 50% platelet reactivity index (PRI) may be so low that the true proportion of high-risk patients for ischemic events is overestimated [2,3]. If we keep in mind the relatively low rate of post-PCI ischemic events, an estimation of HPR exceeding 50% during clopidogrel therapy may cause unnecessary application of potent P2Y12 receptor inhibitors with an attendant increased risk of bleeding. We therefore performed the current pharmacodynamic analysis to determine the agreement for the definition and the prevalence of HPR among various PFTs in patients with stable coronary artery disease treated with dual antiplatelet therapy [6]. Platelet function measurements from two prospective randomized studies [6] were used in this analysis; 37 and 39 patients were enrolled from our institution and treated with ticagrelor (180-mg loading-dose [LD] and 90-mg twice a day maintenance-dose [MD]) and clopidogrel (600-mg LD and 75mg d MD), respectively. Serial LTA, VerifyNow and VASPP assays were performed, and a total of 1002 matched pairs (ticagrelor = 498 pairs; clopidogrel = 504 pairs) were available for this analysis. The overall inter-assay correlation and receiver-operating characteristics (ROC) curve analysis determined by the level of platelet inhibition were consistent irrespective of clopidogrel or ticagrelor administration. The LTA values correlated most with VerifyNow (Fig. 1A, r = 0.821) and less well with the VASP-P assay (Fig. 1B, r = 0.688). PRI values in low/ medium responsive patients were more scattered compared with LTAmeasurements, a finding that is in line with previous observations [11,12]. The frequency ofHPR (based on consensus-defined cut-offs) was the greatest by VASP-P PRI (47.5%) compared with 5 lM ADP-induced aggregation > 46% (37.3%) and P2Y12 reaction units (PRU) > 235 (40.0%). A PRU cut-off > 235 showed substantial agreement with > 46% LTA cut-off (j = 0.737; concordance, 87.5%; balanced distribution of discordance) (Fig. 1A). The VASP-P PRI cut-off showed moderate agreement with the LTA cut-off (j = 0.585; concordance, 79.6%; relatively unbalanced distribution of discordance) (Fig. 1B). ROC curve analysis was used to assess the corresponding points to 5 lM ADP-induced aggregation > 46%, PRU > 234 and VASP-P PRI > 60% (Fig. 1C, D). When the new HPR criteria of a VASP PRI > 60% were applied, the agreement with the LTA cut-off improved (j = 0.634; concordance, 82.6%; narrowed discordance) (Fig. 1B: green arrow and numbers). We also performed ROC curve analysis to assess the corresponding cut-offs to VASP-P PRI > 50%. The matched point with 5 lM ADPinduced aggregation was > 37% (AUC [area under curve], 0.887; 95% confidence interval [CI], 0.843–0.890; P < 0.001; sensitivity, 79.5%; specificity, 82.7%). PRU > 167 was identified as the matched point to > 50% VASP-P PRI (AUC, 0.897; 95% CI, 0.875–0.918; P < 0.001; sensitivity, 87.1%; and specificity, 80.3%). To the best of our knowledge, this is the first comparative analysis describing the agreement between the definitions of the Correspondence: Paul A. Gurbel, Sinai Center for Thrombosis Research, Cardiac Catheterization Laboratory, 2401 W. Belvedere Ave., Baltimore, MD 21215, USA. Tel. : +1 410 601 9600; fax: +1 410 601 9601. E-mail: pgurbel@lifebridgehealth.org