Differential Inhibition of Platelet Reactivity by Dual Therapy With Aspirin and Low-Dose Rivaroxaban in Peripheral Arterial Disease: A Pilot Study

Abstract

Patients with peripheral arterial disease (PAD) benefit from combination therapy with acetylsalicylic acid (ASA, 100 mg, one time per day) plus low-dose rivaroxaban (2.5 mg, two times per day) compared to ASA monotherapy. In particular, major adverse cardiac and limb events were significantly reduced after peripheral endovascular revascularization (EVR). In this pilot study, the platelet activation status in vivo and platelet reactivity in vitro were longitudinally analyzed by flow cytometric assays and calibrated automated thrombography in platelet-rich plasma (PRP) from 10 patients with PAD receiving ASA (100 mg, one time per day) before EVR, ASA plus clopidogrel (75 mg, one time per day) after EVR, and ASA plus rivaroxaban (2.5 mg, two times per day) during a long-term follow-up. Platelet responsiveness to clopidogrel was compared to additional 10 patients with stable PAD and clopidogrel (75 mg, one time per day) monotherapy. ASA plus rivaroxaban treatment resulted in a significantly decreased thrombin peak in PRP for two triggers, namely, low concentration of tissue factor (TF) and thrombin, compared to ASA monotherapy. TF-controlled thrombin generation was additionally characterized by a significantly prolonged lag time in PRP and platelet-free plasma during ASA plus rivaroxaban combination therapy. In comparison, ASA plus clopidogrel treatment presented a significant reduction of the thrombin peak in PRP, which was less pronounced than during subsequent ASA plus rivaroxaban therapy. Platelet responsiveness to clopidogrel was observed for 60% of patients receiving ASA plus clopidogrel and clopidogrel monotherapy, respectively. Blocking of CD36 on the platelet surface further reduced the thrombin peak in PRP induced by TF for all three therapy regimes. Platelet activation in vivo and in response to the GPVI-agonist convulxin or thrombin in vitro was similar, whereas integrin αIIbβ3 activation and α-granule release induced by the PAR-1 activating peptide TRAP-6 were significantly diminished during ASA plus rivaroxaban treatment compared to ASA monotherapy. In conclusion, the data of this pilot study indicate an inhibitory effect of rivaroxaban on the thrombin propagation phase of CD36-sensitive platelet thrombin formation in patients with PAD treated with ASA plus rivaroxaban combination therapy, which is associated with decreased PAR-1 but not thrombin-mediated platelet activation.

Synergistic inhibitory effects of clopidogrel and rivaroxaban on platelet function and platelet‐dependent thrombin generation in cats

“…The underlying mechanisms of DAT‐mediated attenuation in platelet reactivity to thrombin, however, remain unclear. A previous study found that in vitro treatment of human platelets with rivaroxaban and aspirin resulted in similar modulation in reactivity to the PAR‐1 activating peptide, TRAP‐6, but no effects were observed in the presence of thrombin 34 . This discrepancy may be because of species differences because PAR receptor subtypes (1‐4) have not been characterized in feline platelets.…”

“…A previous study found that in vitro treatment of human platelets with rivaroxaban and aspirin resulted in similar modulation in reactivity to the PAR‐1 activating peptide, TRAP‐6, but no effects were observed in the presence of thrombin. 34 This discrepancy may be because of species differences because PAR receptor subtypes (1‐4) have not been characterized in feline platelets. In addition, it is plausible that the PAR‐1 receptor may play a more prominent role in mediating platelet activation in cats because FXa has been shown to directly activate platelets via PAR‐1 in human platelets.…”

Low-dose aspirin and rivaroxaban combination therapy to overcome aspirin non-sensitivity in patients with vascular disease

“…The authors concluded that aggregation may be inversely related to dosage, with higher doses associated with reduced platelet aggregation ( 25 ). A recent publication by Jurk et al ( 26 ) has also demonstrated that rivaroxaban reduces platelet activation through the PAR-1 receptor, a receptor for thrombin induced platelet activation ( 26 ). In our study, we demonstrated that there may be an additional mechanism of platelet inhibition by rivaroxaban through the arachidonic acid pathway, affecting the formation of pro-aggregatory TxA2.…”

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial

“…In addition to its role in the coagulation cascade, factor Xa has been identified as a direct agonist of PAR-1 leading to thrombin independent platelet activation and thrombus formation. By inhibiting factor Xa, rivaroxaban can attenuate platelet aggregation, in addition to its antithrombotic effect ( 7 , 8 , 38 , 39 ). In mice, administration of rivaroxaban for 20 weeks reduced thrombus formation and atherosclerotic plaque destabilization ( 38 , 40 ).…”