Abstract
The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.
Highlights
Many patients who require long-term vitamin K antagonist (VKA; e.g., warfarin) therapy experience difficulties in maintaining a therapeutic international normalized ratio (INR) (Ageno et al, 2012)
The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy
The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin
Summary
Many patients who require long-term vitamin K antagonist (VKA; e.g., warfarin) therapy experience difficulties in maintaining a therapeutic international normalized ratio (INR) (Ageno et al, 2012). VKAs are indirect anticoagulants that target multiple enzymes in the coagulation cascade They inhibit vitamin K-dependent clotting factors including Factors II, VII, IX, and X, and they inhibit the carboxylation of the anticoagulant proteins C and S; VKAs have the potential to be procoagulants (Ansell et al, 2008). INR values measured in the therapeutic range of rivaroxaban are significantly lower than those required under warfarin therapy, indicating that INR measurements are not valid in this case (Kubitza et al, 2005a,b; Ansell et al, 2008; Douketis et al, 2008; Kearon et al, 2012)
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