Monitoring direct FXa-inhibitors and fondaparinux by Prothrombinase-induced Clotting Time (PiCT): relation to FXa-activity and influence of assay modifications.
ABSTRACT FXa-activity can be measured by the Prothrombinase induced Clotting time (PiCT). The manufactured assay uses bovine FXa as component and employs a incubation period before re-calcification. Its use with new direct FXa-inhibitors is challenged by reports on decreased sensitivity.
Blood was incubated with 3 investigational, structurally related (oxazolidinones) direct FXa-inhibitors including the recently approved agent rivaroxaban (0 - 2.0 microM), with the structurally distinct direct FXa-inhibitor DX 9065a (0 - 18 microM) and with the indirect inhibitor fondaparinux (0 - 0.6 microM). We tested modifications of PiCT regarding the source of FXa (bovine or human) and the incubation step (incubation before re-calcification=2-step, no incubation =1-step), and compared results with inhibition of human or bovine FXa-activity.
The bovine 2-step PiCT showed a paradoxical decrease with all direct FXa-inhibitors, this effect is surmounted only at high concentrations and is not seen with the bovine 1-step PiCT. The decrease in PiCT is not observed in antithrombin-depleted plasma. The humanized PiCT (1 or 2 step) showed a consistent prolongation under all direct inhibitors. Fondaparinux prolonged PiCT with either assay. The correlation between PiCT and corresponding FXa-activity was significant both for humanized 2-step PiCT or bovine 1 step PiCT (r2=0.80), but the 95% prediction interval was large and covered a span of 40% FXa-activity between one agent and another.
The customary bovine PiCT should only be used to monitor direct FXa-inhibitors when modified as 1-step procedure. PiCT is not suitable to assess similarity of FXa-inhibition when different agents are interchanged.
[Show abstract] [Hide abstract]
ABSTRACT: Background: Routine drug monitoring is not required for the two novel direct factor Xa inhibitors apixaban and rivaroxaban. Rapidly available test results might be beneficial in case of bleeding or prior to urgent surgery. Objectives: The aim of this study was to evaluate the applicability of the two rotational thrombelastometry (ROTEM (R)) -modifications Low-tissue factor activated ROTEM (R) (LowTF-ROTEM (R)) and Prothrombinase induced clotting time - activated ROTEM (R) (PiCT (R)-ROTEM (R)) for determination of apixaban and rivaroxaban in vitro and ex vivo. Methods: Blood samples from 20 volunteers were spiked with apixaban / rivaroxaban to yield samples with ascending drug concentrations ranging from 50 - 400 ng/mL. LowTF - and PiCT (R) modified ROTEM (R) tests and determination of the corresponding antifactor Xa activity were performed in duplicate in 280 samples. LowTF-ROTEM (R) tests were performed in samples from 20 patients on apixaban or rivaroxaban therapy and 20 controls. Results: There was a strong correlation between apixaban / rivaroxaban plasma concentrations and the LowTF-ROTEM (R) parameters Clotting time (CT; spearman correlation coefficient (SCC) 0.81 and 0.81, respectively) and Time to maximum velocity (t,MaxVel; SCC: 0.81 and 0.80, resp.) and a low to moderate correlation for the PiCT (R)-ROTEM (R) parameters CT (SCC: 0.38 and 0.59, resp.) and t, MaxVel. (0.51 and 0.69, resp.) in the in vitro experiments. LowTF-ROTEM CT was significantly prolonged in patients on apxiaban or rivaroxaban therapy compared to controls. Conclusions: LowTF-ROTEM (R) could be a valuable diagnostic tool for rapid determination of the effect of apixaban and rivaroxaban at the point of care.Thrombosis Research 08/2014; 134(4). DOI:10.1016/j.thromres.2014.08.006 · 2.43 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Rivaroxaban (Xarelto®), a direct factor Xa inhibitor, is approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in Canada or those with nonvalvular AF (NVAF) in the EU, US and Japan. It is administered at a fixed oral dose and generally does not require routine monitoring of coagulation parameters. In the ROCKET AF trial in patients with NVAF and a moderate to high risk of stroke, oral rivaroxaban 20 mg once daily (15 mg once daily in patients with moderate renal impairment) was noninferior to oral dose-adjusted warfarin once daily in preventing primary endpoint events (i.e. stroke and systemic embolism) in the per-protocol population (primary noninferiority analysis) and superior in the on-treatment safety population (primary superiority analysis). Several ROCKET AF subgroup analyses indicated that the treatment effect of rivaroxaban was consistent across patient subgroups stratified according to baseline factors, including the presence or absence of previous stroke or transient ischaemic attack. Patients with moderate renal impairment receiving the reduced rivaroxaban dosage (15 mg once daily) showed a treatment effect consistent with that seen with rivaroxaban 20 mg once daily in patients with normal renal function. The tolerability profile of rivaroxaban was generally acceptable in ROCKET AF, with no significant difference between rivaroxaban and warfarin in the incidence of major or nonmajor clinically-relevant bleeding events (primary safety endpoint). In the Japanese ROCKET AF trial, rivaroxaban 15 mg once daily (10 mg once daily in patients with moderate renal impairment) was noninferior to oral dose-adjusted warfarin once daily in the incidence of major or nonmajor clinically-relevant bleeding (primary study outcome). Thus, rivaroxaban is a reasonable alternative to warfarin for the prevention of stroke and systemic embolism in patients with NVAF.Drugs 05/2013; 73(7). DOI:10.1007/s40265-013-0056-9 · 4.13 Impact Factor
British Journal of Haematology 06/2014; 166(6). DOI:10.1111/bjh.12975 · 4.96 Impact Factor