Dabigatran had little effect on mechanical heart valve-induced thrombin generation at concentrations <400 ng/mL, whereas warfarin suppressed it at INR >1.5.
Does dabigatran attenuate mechanical heart valve-induced thrombin generation as effectively as warfarin in plasma?
Mechanical heart valves induce thrombin generation via the intrinsic pathway, which overwhelms clinically relevant dabigatran concentrations but is effectively suppressed by warfarin, explaining the clinical failure of dabigatran in these patients.
BACKGROUND: Patients with mechanical heart valves (MHV) require warfarin to prevent thromboembolism. Although dabigatran was as effective as warfarin for stroke prevention in atrial fibrillation when compared with warfarin in patients with MHV, the study was stopped early because of more strokes and bleeding with dabigatran. To determine why dabigatran was less effective than warfarin, we compared their effects on thrombin generation induced by MHV. METHODS AND RESULTS: Thrombin generation in the absence or presence of valve leaflets or sewing ring segments (SRS) was quantified. Studies were done in control plasma, plasma depleted of factors (F) XII, XI, or VII, plasma containing varying concentrations of dabigatran, or plasma from patients on dabigatran or warfarin with varying dabigatran concentrations or international normalized ratio (INR) values. Mean endogenous thrombin potential (ETP) increased 1.2-, 1.5-, and 1.8-fold in the presence of leaflets, Teflon SRS, and Dacron SRS, respectively. Whereas ETP in FVII-depleted and control plasma was similar, ETP was reduced to background levels in FXII-depleted plasma and abrogated in FXI-depleted plasma. Dabigatran had little effect on ETP at concentrations below 400 ng/mL, whereas in plasma from warfarin-treated patients, ETP was suppressed with INR values over 1.5. CONCLUSIONS: MHV induce thrombin generation via the intrinsic pathway and generate sufficient thrombin to overwhelm clinically relevant dabigatran concentrations. In contrast, warfarin is more effective than dabigatran at suppressing MHV-induced thrombin generation. These data explain why dabigatran failed in MHV patients and suggest that strategies targeting FXII or FXI may suppress the root cause of thrombosis in such patients.
Jaffer et al. (Tue,) conducted a other in Mechanical heart valves. Dabigatran vs. Warfarin was evaluated on Endogenous thrombin potential (ETP). Dabigatran had little effect on mechanical heart valve-induced thrombin generation at concentrations <400 ng/mL, whereas warfarin suppressed it at INR >1.5.