Enoxaparin Produces Sustained Antithrombotic Effects in Comparison to Fondaparinux and Rivaroxaban: Clinical Implications.

Abstract 3128

Poster Board III-65

Enoxaparin (Lovenox®), fondaparinux (Arixtra®) and rivaroxaban (Xarelto®) have been shown to be effective in mediating antithrombotic effects in post-surgical indications. Because of marked differences in the pharmacokinetic and pharmacodynamic behavior of these drugs we hypothesized that after the last dosage, the duration of the residual antithrombotic activity of the various drugs also differs. In order to compare the duration of effect of these three drugs, a rabbit stasis-thrombosis model (RSTM) utilizing FEIBA as the thrombogenic challenge and a rabbit ear bleeding model (REBM) were employed. Individual groups of rabbits (n=5) were treated with doses to mimic prophylactic, therapeutic and supratherapeutic (5x therapeutic) drug levels. Enoxaparin and fondaparinux were administered subcutaneously and rivaroxaban was administered by oral gavage. Blood samples were collected at baseline and at 16-18 hours post-administration of the last dose on day 1 or after 4 days of repeated dosing in the RSTM or at 3 hours post-administration in the REBM. At the 16-18 hour time point, circulating anti-Xa levels were not observed in any of the treatment groups. Despite this, enoxaparin treated animals exhibited a strong antithrombotic response following administration of the therapeutic dose (clot score = 1.3 ± 0.6 vs. 2.7 ± 0.6 for saline controls). Dosing once daily for four days did not enhance the antithrombotic activity of enoxaparin. In the plasmatic thrombin generation assays, a reduction in thrombin generation was noted in samples from enoxaparin-treated animals. For enoxaparin, no increase in bleeding was observed at prophylactic or therapeutic doses when compared to saline. An increase in bleeding (∼5 fold vs. saline) was observed at 3 and 6 hours post-administration of the ‘overdose’. A dose-dependent increase in anti-Xa activity was observed in blood samples collected 3 hours post-administration. For fondaparinux, no increase in bleeding was observed with any of the doses tested. There was a moderate increase in anti-Xa activity in the samples from rabbits treated with the ‘overdose’ of fondaparinux. This level was comparable to that observed with the therapeutic dose of enoxaparin. These studies suggest that enoxaparin produces a sustained antithrombotic effect in contrast to rivaroxaban and fondaparinux. These observations underscore that residual/sustained antithrombotic effects of enoxaparin may be partly responsible for the prolonged antithrombotic actions associated with the clinical use of enoxaparin.