LAUSR

The pharmacodynamic effects of oral anticoagulants (OACs) on the coagulation pathway and the effect of antiplatelet therapy (APT) on platelet activation, used in isolation, have been extensively investigated. However, OAC and APT are now frequently used in combination, most commonly for the coexistence of atrial fibrillation and acute coronary syndrome (ACS) or percutaneous coronary intervention. Antiplatelet agents and OACs have therefore become unintended bedfellows. In combination with dual APT (DAPT), the use of a nonvitamin K OAC (NOAC) has been shown to be superior to a vitamin K antagonist, with reduced bleeding and similar efficacy.1,2 However, the combined effect of DAPT and NOAC on clot formation has hitherto been underinvestigated, and little isknownaboutwhat effects theaddition ofeither aNOAC or APT exert, over that which either would achieve alone. In this issue of Thrombosis and Haemostasis, Franchi et al3 set out to specifically address this issue, by investigating the effects of the combination of edoxaban, clopidogrel, and aspirin on markers of in vitro clot formation, including clot strength using the TEG6S system, and platelet reactivity. In the first phase of the study, 75 patients on DAPT, comprising aspirin and clopidogrel, were randomized to high dose (60 mg once daily) or low dose (30mg once daily) edoxaban or DAPTonly. In the second phase, aspirin was dropped from triple therapy. The primary endpoint was the assessment of clot strength, measured as maximal amplitude (MA) using thromboelastography (TEG), which represents the termination phase of clot formation and is an evaluation of the maximal thrombin-induced platelet–fibrin clot strength. Surprisingly, while edoxaban dose-dependently prolonged the speed of thrombin generation, measured as the reaction time (TEG R) when added to DAPT, it had no effect on clot strength. Furthermore, clot stability was not influenced by whether DAPT or single APT (SAPT) was used, or by the addition of edoxaban to DAPT. As expected, discontinuation of aspirin resulted in an increase in the markers sensitive to cyclooxygenase-1 blockade but had no significant effect on markers of P2Y12 reactivity or clot kinetics. The authors conclude that although edoxaban delays thrombin generation, once thrombin is generated, the resultant clot has normal strength and stability. Prior studies investigating the effect of NOACs, notably in the absence of APT, also showed that rivaroxaban, apixaban, and dabigatran caused significant elongation of R-time4–7 with large interindividual variability.5 Another consistent finding is that NOACs have little, if any effect on clot strength, although notably edoxaban had not been studied.4,6,8 In fact, the group of Franchi et al have previously reported lackof any significant effect on in vitro clot strength when high dose dabigatran was added to DAPT.9 Nevertheless, the lack of effect of edoxaban on clot strength is surprising. NOACs have been shown to slow or block the amplification phase of coagulation, which can both delay and prevent large-scale thrombin generation.10 Spiking of blood from patients already taking DAPTwith the equivalent of very low (“vascular”) dose (2.5mg twice daily) rivaroxaban in vitro, led to significant reduction in coagulation-dependent thrombus formation and platelet-dependent thrombin generation,11 an effect most pronounced in clopidogrel nonresponders. Thrombin is the predominant determinant of arterial thrombosis and of the resistance of the arterial thrombus to thrombolysis. Despite DAPT, increased thrombin generation is documented in ACS patients,12,13 and linked to recurrent myocardial infarction.13,14 Inhibition of thrombin generation would therefore be expected to reduce arterial thrombosis. Indeed, the addition of rivaroxaban to DAPT in the ATLAS ACS 2-TIMI 51 study15 and to SAPT in the COMPASS study16 significantly reduced ischemic endpoints, albeit at a cost of increased bleeding, indicating that dual pathway inhibition may be attractive as a way of reducing thrombotic events in high-risk patients.17 Thus, the lack of effect of edoxaban (and other NOACs in previous studies) on MA is unexpected. Two possible