High on-treatment platelet reactivity - why should we be concerned?

Antiplatelet drugs are the cornerstone in prevention and treatment of atherothrombotic vessel occlusions, i.e. myocardial infarction and stroke. The introduction of clopidogrel and its use in dual antiplatelet treatment (DAPT) has substantially reduced both the incidence and mortality of acute coronary syndromes (ACS) and has improved the efficacy of percutaneous coronary interventions (PCI) (1). The development of further, more potent antiplatelet drugs, such as the newer generation ADPreceptor antagonists prasugrel and ticagrelor has further added to improved clinical outcome (2). The price to be paid was an increased risk of bleeding, because the targeted clotting factors in physiological haemostasis and pathological thrombosis are largely the same. Thus, the question came up, whether even more potent antiplatelet drugs, such as the direct thrombin inhibitors vorapaxar or atopaxar will further reduce the thrombotic risk or merely increase the risk of bleeding without enlarging the therapeutic window between prevention of thrombosis and inhibition of haemostasis. In this context, the concept of “High ontreatment platelet reactivity (HTPR)” – for definition and measurement see the overview of Cattaneo in this issue (3) has attracted much attention (4-9). Indeed, HTPR is a quite frequent event in clinical practice, i.e. DAPT in ACS and/or percutaneous (PCI), and a key variable for the patients’ outcome. Its’ possible reasons, determination, clinical significance and possible ways to deal with it are the topics to be discussed in more detail in various ‘state of the art’ articles in this theme issue of Thrombosis and Haemostasis (3, 10-14). Recently, the measurement of reticulated platelets has also attracted the interest of researchers, as outlined also by Cesari et al. in this issue who found an association between an increase of reticulated platelets and CV mortality in patients with acute coronary syndromes (15). For several reasons, HTPR has been mostly studied with clopidogrel (16), the best studied ADP-antagonist. Specifically, the variable, and in general moderate antiplatelet efficacy of the compound has raised concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients (17). As also discussed by Trenk et al. in this issue (14), the individual response variability could be linked to both genetic and clinical factors (18, 19). However, the impact on activity of cytochrome P450 enzymes, which are influenced by both genetic and environmental factors, the factors identified so far could only explain up to about 12% of clopidogrel variability in terms of inhibition of ADP -induced platelet aggregation ex vivo (20). Thus, additional and possibly diseaseor alternative treatment-related variables need also to be considered. This includes stimulation of platelets by agents, such as collagen, thrombin or thromboxane in ACS, which are not sensitive to ADP-antagonists. Alternatively, proton-pump inhibitors (PPIs) or statins can at least pharmacologically modify the antiplatelet effect of clopidogrel and ticagrelor, respectively (21, 22). Diabetes is another clinical condition with reduced antiplatelet effects of clopidogrel and there are certainly more (19, 23). Another possibility to deal with HTPR is the choice of drug alternatives (24, 25). Despite DAPT with the more effective P2Y12-inhibitors, the one-year event rate after ACS varies from 9-12%. Accordingly, the addition of an anticoagulant or a third antiplatelet agent to DAPT has been discussed and investigated. As pointed out by Brouwer and colleagues in this issue (10), among the new oral anticoagulants (NOACs), only rivaroxaban has been demonstrated to improve outcome in secondary prevention after ACS, including cardiovascular and all-cause mortality, albeit at the cost of bleeding, and this only as adjunctive therapy to DAPT (26). In addition, in patients on DAPT who require additional anticoagulation, e.g. patients with atrial fibrillation and increased atherothrombotic risk, adjunctive therapy (“triple therapy”) with dose adjusted vitamin-K antagonists (INR 2.0-2.5) has to be considered as well (27-29). Whether vitamin-K antagonists could be replaced by (lower-dose) NOACs is still matter of discussion. Alternatively, as shown in the WOEST trial, a combination of an oral anticoagulant with only one antiplatelet drug, such as clopidogrel, might cause less bleeding at no excess of thrombotic events and reduced all-cause mortality (30). In contrast, the use of the thrombin receptor antagonist voraxapar as a third antiplatelet agent in ACS and/or in secondary prevention after ACS did not fulfill its expectations because of higher bleeding complications despite a better efficacy as compared to DAPT alone (31, 32). There might be a potential of this strategy for specific subgroups with high thrombotic but low bleeding risk that have to be better defined before this strategy might become clinical routine (33). Importantly, the impact of prolonged anticoagulation (low-dose rivaroxaban, vitamin-K antagonists) as adjunctive to DAPT after ACS has not been addressed with the most potent antiplatelet agents (prasugrel, ticagrelor) and this merits further study. As demonstrated by Dahlen et al. in this issue (11), one of the most heavily discussed issues in this context is how to measure platelet function and what is the predictive value of standard laboratory measurements