Abstract 20955: Synergistic Effects of Rivaroxaban With Direct-Acting Anti-Platelet Agents on Platelet Reactivity and Thrombin Generation

Abstract

Introduction: Direct-acting oral anticoagulants (DOACs) are increasingly evaluated for the secondary prevention of thrombosis-related events; however, DOAC dose-related effects on platelet function, particularly with anti-platelet agents, are unknown. Hypothesis: Factor Xa inhibitors do not have direct anti-platelet activity; however, by their capacity to inhibit thrombin generation (TG), they indirectly regulate thrombin-dependent platelet activation. This indirect mode of action may have additive effects with anti-platelet agents such as aspirin or P2Y12 antagonists. Methods: Platelet-rich plasma (PRP) from healthy individuals (n=6) was incubated with increasing amounts, and combinations of rivaroxaban (Riva), aspirin (ASA) and/or ticagrelor(T). The impact on platelet function was studied using light transmission aggregometry (LTA) and fluorogenic TG assays (TGA). For LTA, maximal aggregation (MA) was measured after initiation of tissue factor (TF)-induced TG. Similarly, for TG assays in platelet-poor plasma (PPP) and PRP low TF concentrations were used to initiate TG. Results and Conclusions: Riva treatment alone decreased % MA by TF-generated thrombin by 24% (15 ng/ml; akin to 2.5 mg bid dosing) and 71% (120 ng/ml; akin to 10 - 20 mg bid dosing). Riva, in combination with both anti-platelet agents, decreased MA substantially by 69% at 15 ng/ml and significantly by 89% at 120 ng/ml (p<0.05). However, when PRP is treated only with ASA or T (sans Riva), thrombin-mediated MA decreased by 12% and 25%, respectively. In TGA, Riva alone in PPP caused significant inhibition of TG (p <0.05). At 15 ng/ml, ~40% inhibition of peak TG was noted in PPP, though in PRP, inhibition was only 22% with donor variability observed. At 120 ng/ml Riva, peak TG inhibition was 90% and 64% for PPP or PRP, respectively. Though evident at higher Riva doses, the 15 ng/ml dose showed no synergy with ASA or T or the ASA/T combination in inhibiting TG in PRP. These results demonstrate that Riva provides an additive effect in reducing platelet reactivity, and its impact is highly dose-dependent and influenced by anti-platelet therapies. Such findings should be taken into consideration for anti-FXa dosing, either when anti-platelet therapies are or are not part of a treatment regimen.