COMPARISON OF THE EFFECT OF NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS AND WARFARIN ON MECHANICAL HEART VALVE-INDUCED THROMBIN GENERATION

Abstract

Although the non-vitamin k antagonist oral anticoagulants (NOACs) are at least as effective as warfarin in atrial fibrillation and venous thromboembolism, dabigatran was less effective than warfarin in patients with mechanical heart valves (MHVs) in the RE-ALIGN trial. However, the utility of rivaroxaban in this setting is unknown. To compare the capacities of dabigatran and/or rivaroxaban to suppress thrombin generation (TG) induced by components of MHVs with that of warfarin. TG was quantified in the absence or presence of valve leaflets or sewing ring segments (SRS). Studies were done in recalcified plasma from healthy volunteers containing varying concentrations of dabigatran or rivaroxaban, or from patients on warfarin with varying international normalized ratio (INR) values. Mean endogenous thrombin potential (ETP) increased by 17, 80, and 52% (from a background of 4401 ± 192 nM·min to 5170 ± 90, 7951 ± 204, and 6675 ± 463 nM·min) in the presence of leaflets, Dacron SRS, and Teflon SRS, respectively. With INR values greater than 1.5, warfarin significantly reduced ETP and at INR values over 2, ETP was reduced below background levels. By contrast the concentrations of dabigatran and rivaroxaban required to reduce the ETP to a similar extent as warfarin at an INR of 2 were 260 and 91ng/ml, respectively; concentrations considerably higher than those measured at trough in patients taking these drugs. Similar results were obtained with other measures of TG, including the lag time, time to peak and peak thrombin concentration. Using the target dabigatran trough concentration of 50ng/ml used in RE-ALIGN, dabigatran was combined with rivaroxaban at concentrations up to 800ng/ml and their effect on TG examined. Although dabigatran alone had no effect, with rivaroxaban addition, ETP was reduced by 55, 84, and 100% at rivaroxaban concentrations of 100, 200, and 400ng/ml, respectively. MHVs induce TG in concentrations that overwhelm clinically acceptable concentrations of the NOACs. Our data suggest that like the findings with dabigatran, with the currently licensed regimen, rivaroxaban is unlikely to be as effective as warfarin in patients with MHVs. Although a combination of rivaroxaban and dabigatran may be better than either agent alone, the optimal dose of each needs to be determined.