Advances in anticoagulation: patients with bioprosthetic heart valves

Valve replacement is the only definitive treatment for patients with severe valvular heart disease. Mechanical valves are usually preferred over biological valves in younger patients because they are more durable but require lifelong anticoagulation with a vitamin K antagonist (VKA) to prevent thromboembolism. Bioprosthetic valves are associated with low rates of clinical thromboembolism, thereby obviating the need for longterm anticoagulation. However, newer imaging technologies (4D echocardiography, 4D computed tomography) have demonstrated subclinical valve thrombosis in 10–20% of patients within the first year of implantation, which may be a cause of structural valve deterioration. Accordingly, there is increasing interest in the optimal choice of antithrombotic therapy in these patients, particularly during the first 3 months after valve implantation when the risk of subclinical thromboembolism appears to be greatest. In the absence of high-quality evidence from randomized trials, guidelines have given weak recommendations for the use of anticoagulants in patients with bioprosthetic valves. For patients with a surgical bioprosthetic valve, they suggest anticoagulation with VKA for 3–6 months, whereas for transcatheter valve replacement (TAVR), they suggest antiplatelet therapy. Guidelines recommend against the use of direct oral anticoagulants (DOACs) in patients with mechanical heart valves because in the REALIGN trial, dabigatran was associated with higher rates of both thromboembolism and bleeding than warfarin. However, factor Xa inhibitors have not been tested in patients with mechanical valves and it is unclear whether the results with dabigatran in mechanical valves can be extrapolated to bioprosthetic valves. Recent randomized trials (Table 1) have shed further light on the efficacy and safety of DOACs in patients with bioprosthetic heart valves. The first of these was GALILEO, published in 2020, which demonstrated in 1644 patients undergoing TAVR that the factor Xa inhibitor rivaroxaban 10 mg once daily (plus aspirin for the first 3 months) was less effective than aspirin (plus clopidogrel for the first 3 months) for prevention of death or thromboembolism. Patients in the rivaroxaban group, however, had markedly lower rates of valve leaflet-motion abnormalities at 3 months (2.1% vs. 10.9%, P = 0.01), suggesting the potential for DOACs to prevent subclinical valve thrombosis. The RIVER trial, also published in 2020, demonstrated in 1005 patients with a bioprosthetic mitral valve and atrial fibrillation (AF) ( 13.8% were taking antiplatelet therapy at baseline) that rivaroxaban 20 mg once daily was non-inferior to warfarin for prevention of death, major cardiovascular events or bleeding. However, only 189 patients in RIVER were enrolled within 3 months of surgery, and while clinical valve thrombosis was uncommon (1.04 vs. 0.62 per 100 patient-years), routine valve imaging was not performed. ENAVLE was a much smaller trial (n = 220) evaluating anticoagulation in patients during the first 3 months after surgical bioprosthetic aortic valve replacement (AVR) or valve repair. Presented in 2020 and published in 2021, the results were consistent with those of RIVER in demonstrating that the factor Xa inhibitor edoxaban was non-inferior to warfarin for the prevention of death, clinical thromboembolic events, or asymptomatic intracardiac thrombosis. ENVISAGE-TAVI AF is the latest trial in this field. In 1426 patients with AF and TAVR (60% received antiplatelet therapy), edoxaban was noninferior to warfarin for the prevention of the primary outcome of death from any cause, myocardial infarction, ischaemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding, although it did increase major bleeding. All patients were randomized within 7 days of TAVR, thereby confirming the results of RIVER that DOACs are similarly effective to warfarin for the prevention of clinical thromboembolism early after bioprosthetic valve replacement. However, like RIVER and ENAVLE, the ENVISAGE-TAVI AF trial did not include routine valve imaging. In parallel with efforts to evaluate the role of DOACs in patients with bioprosthetic heart valves, emerging evidence suggests that a new class of anticoagulant that targets coagulation factor XI (FXI) has the potential to replace VKAs for both mechanical and bioprosthetic heart valves. The promise of this new drug class was first suggested by the observation that patients with mild congenital FXI deficiency (FXI levels 10–20%) have low rates of both thromboembolism and bleeding. Because FXI inhibitors directly target the contact pathway, they selectively inhibit coagulation activation induced by exposure of blood to artificial surfaces, including the sewing rings and mechanical leaflets of prosthetic heart valves. Table 2 summarizes classes of FXI inhibitors that are in the most advanced stages of clinical evaluation. The phase 2 ANT-005 TKA trial, published earlier this year, demonstrated in 412 patients undergoing total knee arthroplasty that a single post-operative intravenous dose of abelacimab, a FXI monoclonal antibody inhibitor, was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. These results