Our study, for the first time, characterized the effects of clopidogrel and ticagrelor on platelet function, using LTA and VASP assay, in a Chinese population undergoing PCI. This study first provide evidence that MPV is independently associated with HPR at VASP assay and could also be used to evaluate the platelet reactivity of patients receiving clopidogrel or ticagrelor. The three major findings in this study are as follows. (1) The effect of ticagrelor on platelet reactivity was significantly greater than that of clopidogrel, with a more potent inhibition of platelet activity measured by LTA and VASP assay. (2) ACS patients undergoing PCI who were received standard-of-care treatment with ticagrelor, on a basis of aspirin, had a lower prevalence of HPR when compared with those given clopidogrel. (3) MPV can independently indicate HPR in patients at VASP assay and was much higher in patients using clopidogrel, which potentially reflects a higher prevalence of HPR.
Many studies have previously assessed the pharmacodynamic effects of clopidogrel and ticagrelor in patients with ST-segment elevation myocardial infarction (STEMI) undergoing early PCI using different PFTs, and have reported that ticagrelor provided more potent and prompt platelet inhibition than clopidogrel. In particular, several clinical trials demonstrated that the primary efficacy end point and clinical benefits favored ticagrelor compared with clopidogrel in ACS patients; the former markedly reduced the mortality due to stroke, vascular causes, and myocardial infarction[25, 26]. In this study, the effect on platelet function of ticagrelor and clopidogrel in Chinese patients agreed with the findings reported in Western populations. Although there have been several studies investigating the pharmacology and bleeding risk associated with two anti-platelet drugs among Asian populations[27, 28], few studies have concentrated on their effects on platelet function in such populations.
Various kinds of PFTs have been applied to monitor platelet activity in the setting of DAPT (aspirin and clopidogrel or ticagrelor) in large clinical trials. Verify Now, LTA, MEA and flow cytometry are most intensively used among those techniques. LTA as a traditional technique has always been acknowledged as the most classical method. VASP phosphorylation measures activation-dependent platelet signaling. This assay required small sample volumes and the whole blood, maintaining high stability and dependent on the P2Y12 receptor, the site of action for clopidogrel and ticagrelor. Therefore, VASP assay was used in many clinical trials on the background of the above characteristics. Meanwhile, it has shown a pretty good correlation with LTA results, which was also seen in our results in Fig. S2. In our study, we used LTA and VASP assay and has found evidence for a significant effect of ticagrelor on platelet inhibition. In addition, use of LTA and VASP testing may identify patients who are at high risk of thrombotic events like cardiac death and stent thrombosis during follow up. Furthermore, a higher HPR rate in patients receiving clopidogrel was observed in our study. This finding indicated that clopidogrel was more prone to induce drug resistance in Chinese individuals. This could guide a more efficient tailored therapy for those patients who were identified as very high risk.
Further, we provided evidence that MPV, which has been proposed as a cheap and easy-to-obtain marker of platelet size, could indicate platelet reactivity and the level of HPR in patients receiving DAPT. A close relationship has been demonstrated between MPV and cardiovascular risk factors including obesity, diabetes mellitus, hypertension, hypercholesterolemia and other factors[31, 32]. However, data relating MPV with acute coronary and cerebrovascular events are still contrasting. Lippi et al. demonstrated that there was a significantly increase of MPV levels in ACS patients than that in non-ACS patients. And platelet size could predict impaired angiographic reperfusion and the death rate in STEMI patients undergoing PCI. Contrastingly, Tavil et al. demonstrated that MPV was related to central obesity, hypertension and hypercholesterolemia, but not to coronary artery disease (CAD), in patients referred for coronary angiography. The role of MPV in indicating the response to antiplatelet drugs has also raised great debate. Asher et al. documented a higher rate of HPR with larger platelets after clopidogrel loading dose received by patients with acute myocardial infarction. Kubica et al. has also reported similar findings in patients undergoing PCI. In addition, larger-sized platelets could independently predict the risk of high residual platelet reactivity for the treatment of aspirin + clopidogrel, also in patients treated with PCI. However, Monica et al. found no impact of larger platelet volume on the majority of platelet function tests, and in particular on ADP-mediated aggregation or the response to clopidogrel or ticagrelor. Our present study evaluated the role and effect of MPV on platelet function in patients with DAPT and confirmed the well-established strict association of MPV with other platelet function parameters, including ADP-induced aggregation conducted by LTA and PRI in the VASP assay. Regarding the variation in the role of MPV in indicating platelet function, it has been considered that this may be related to the various PFTs used in different studies. We found that MPV was related to HPR only at the VASP test but not at the LTA assay. Similar results for the association between MPV and HPR could be found at MEA test, according to Kim et al.. Of note, it presented a very low correlation between the results in MEA test and platelet volume indices, although there was a strong correlation between VASP test parameters and MPV. It could be noted that there was a significant difference in the baseline value of MPV in the two treatment arms. To avoid drawing conclusion on MPV questionable, the dual antiplatelet therapy was added into multivariate regression analysis to assess the independence of MPV and MPV tertiles in predicting HPR. Therefore, results obtained could be rational and the conclusion we made could also be reasonable.
It has been demonstrated that ticagrelor had superiority over clopidogrel in suppressing platelet function in ACS patients, with a more pronounced antiplatelet effect during the initial treatment phase and during maintenance therapy. Our present study is consistent with previous research. Recently, the EROSION study reported that DAPT with aspirin and ticagrelor without stenting may be an option for patients with ACS caused by plaque erosion. Therefore, the potential clinical application of ticagrelor in anti-thrombotic therapy for ACS patients should not be ignored.
In this study, several limitations about its design should be stated. Firstly, the absence of long-term follow-up of our patients should be considered, and, therefore, we cannot evaluate the impact of the two different DAPT treatment on clinical outcome. Furthermore, we need to enlarge the dataset in order to improve the representativeness and reliability of results. In addition, genetic factors’ impact was not evaluated in this study, such as CYP2C19 polymorphism, on anti-platelet drug responsiveness; the response to clopidogrel is closely associated with the polymorphism of CYP2C19. The results of this study may therefore have been confounded by the prevalence of CYP2C19 polymorphism.