Is there a ‘therapeutic window’ for antiplatelet therapy?

This editorial refers to ‘Determinants of agreement between proposed therapeutic windows of platelet function tests in vulnerable patients’, by M.J. Vries et al., on page 11. Complicated mechanism of platelet activation induced by various receptor stimulation and through various activation pathways. There are many pathways for platelet activation. Even when aspirin inhibited cyclo-oxygenase (COX)-1 as its pharmacological target, circulating platelets may be activated through other pathways. The extent of platelet aggregation is influenced by many factors such as platelet activation through glycoprotein Ibα mediated by von Willebrand factor, and so on. One potential reason for heated discussion regarding ‘aspirin resistance’ was the lack of an appropriate clinically available bedside assay system for determination of platelet function in response to the effects of aspirin. The pharmacological effects of aspirin can be precisely assessed by measuring arachidonic acid-induced production of thromboxane (Tx)-A2 by platelets. However, this assay is not easy to perform. First, we have to separate platelets to avoid contributing effects of other cells. Secondly, the complicating measurement of the lipid metabolite of Tx-B2 is necessary.13 Aspirin is known to inhibit collagen and arachidonic acid-induced platelet aggregation. Light transmission aggregometry has been the established procedure to measure platelet aggregation since the 1960s.14 Thus, many investigators attempted to evaluate the antiplatelet effects of aspirin with the use of platelet aggregation induced by collagen. However, unlike production of Tx-A2 from activated platelets, platelet aggregation is more complicated. Finally, the variability of platelet aggregation, even though different doses of aspirin inhibit production of Tx-A2, similarly was proven to be substantially large. Thus, platelet aggregation should not be an appropriate assay target for the antiplatelet effects of aspirin.13 As shown in Figure 1, the variability of the extent of platelet aggregation even when the COX-1 pathway was fully blocked may be dependent on the variability of platelet activation status through other receptor stimulation such as platelet cell activation though their interaction with von Willebrand factor expressed on endothelial cells in the whole body.15,16 Unlike aspirin, there still is discussion regarding the best daily dose of P2Y12 ADP receptor antagonists. Indeed, P2Y12 ADP receptor-deficienct patients were reported to have spontaneous bleeding disorders.17 Nobody wants 100% inhibition of P2Y12 even for prevention of serious thrombotic events. However, the best balance between antithrombotic effects and bleeding complication with the extent of P2Y12 ADP receptor antagonism is still unclear, despite a huge number of publications suggesting the positive relationship between the dose of thienopyridine antiplatelet agents [the active metabolite(s) of which is known to block the P2Y12 ADP receptor] and the extent of ADP-induced platelet aggregation inhibition.18 However, there are only a few data demonstrating the relationship between actual P2Y12 ADP receptor occupation by the active metabolite(s) of clopidogrel and the extent of inhibition of platelet aggregation.19 Moreover, there are almost no clear data demonstrating the relationship between the extent of ADP-induced platelet aggregation and the future cardiovascular and/or bleeding events in patients treated by P2Y12 ADP receptor antagonists. Interestingly, almost all the clinical trials attempting to show the superior effects in patients treated with so-called tailored ‘dose-adjusted P2Y12 ADP receptor inhibition’ as compared with non-dose-adjusted treatment failed.20,21 So far, a ‘dose-adjusted strategy for P2Y12 ADP receptors’ looks not to be necessary for individualization of antiplatelet therapy as long as the approved dose in each country is used. Still, an existing difficulty is the difference in dose approved in each country, e.g. 20 mg loading dosing followed by 3.75 mg prasugrel is approved in Japanese patients with acute coronary syndrome, while a three-fold larger dose is approved in other countries.18 A dose-adjustment strategy is useful in some cases, but is not precise enough with currently available technology for personalization of antiplatelet therapy. Vitamin K antagonists prolong the prothrombin time–international normalized ratio (PT–INR). Vitamin K antagonists decrease thrombotic events, but increase bleeding events. However, vitamin K antagonists do not decrease thrombotic events or increase bleeding events by prolongation of the PT–INR. The positive relationships between them are shown by accumulation of clinical data. PT–INR is not a magic number as recently demonstrated by experience with direct thrombin or Xa antagonists. The same might be true for the platelet function test with the use of P2Y12 ADP receptor antagonists. P2Y12 ADP receptor antagonists inhibit ADP-induced platelet aggregation measured by light transmission aggregometry, VerifyNow P2Y12, and PFA-100. P2Y12 ADP receptor antagonists prevent thrombotic events and increase bleeding events. However, P2Y12 ADP receptor antagonists do not prevent thrombotic events or increase bleeding by inhibiting ADP-induced platelet aggregation. The huge variation in numerical data obtained with three distinct assay systems shown in the study published this issue of the journal may suggest that all three of them show only noise.22 However, there still is a potential that one of the modalities the authors discussed might show a strong enough relationship for future thrombotic and/or bleeding events in the future. Selecting ‘vulnerable patients’ as the authors applied in this study probably is a nice initial strategy to collect clinical data. In conclusion, there might be a ‘therapeutic window’ for P2Y12 ADP receptor antagonists. However, our understanding of the function of the P2Y12 ADP receptor for thrombotic/bleeding events is still not mature enough to develop an appropriate and simple bedside assay system. Continuous accumulation of platelet function assay results in addition to clinical outcome results may lead us further towards understanding the relationship between platelet function and clinical events. Profound understanding of the quantitative relationship between the extent of P2Y12 ADP receptor antagonism and the results of bedside assay and clinical events is awaited. Conflict of interest: S.