In patients with severe valvular heart disease, guideline-based surgical valve replacement or transcatheter implantation of a prosthetic heart valve is associated with improved survival and relief of symptoms. Prosthetic heart valves are designed to replicate the function of native valves by maintaining unidirectional blood flow and can be separated into two broad categories, mechanical and bioprosthetic (also called tissue) valves, each with different advantages and disadvantages.
This mini-series is divided into 4 parts:
Part 1 – Prosthetic valves: selection
Part 2 – Prosthetic valves: antithrombotic therapy
Part 3 – Prosthetic valves: imaging
Part 4 – Prosthetic valves: complications and dysfunction, pregnancy
Antithrombotic therapy in mechanical valves
The term antithrombotic therapy refers to anticoagulant, antiplatelet therapy or both. All mechanical valves require lifelong oral anticoagulation using a vitamin K antagonist (VKA) (Class I) [1,2]. It is preferable to specify a single international normalised ratio (INR) target median value for each patient and to concede that the acceptable range includes 0.5 INR units either side of this target. A specific target is preferable over a range to reduce the likelihood of patients having INR values consistently near the upper or lower limit of the range. The target INR depends on the type and location of the mechanical heart valve (MHV) as well as coexistent risk factors for thromboembolism (e.g., atrial fibrillation, hypercoagulable state, previous thromboembolic event or LV dysfunction).
Briefly, for mechanical bileaflet or newer-generation single tilting-disc valves in the aortic position without risk factors, an INR target of 2.5 and with risk factors of 3.0 is recommended. A somewhat higher INR target is advised in older-generation MHV or other than aortic positions [1,2]. The bileaflet On-X valve (On-X Life Technologies, Austin, TX, USA) is a new MHV designed with a lower prosthesis thrombogenicity and approved for a lower INR range (1.5-2.0) in conjunction with low-dose aspirin (75 to 100 mg daily) starting not earlier than 3 months after aortic valve replacement and where there are no additional thromboembolic risk factors . However, this recommendation is based only on a single randomised controlled trial (RCT) .
There are no data to support the use of non-vitamin K oral anticoagulants (NOACs) in patients with MHVs. In fact, dabigatran, an oral direct thrombin inhibitor, was associated with a higher rate of valve thrombosis and bleeding complications in patients shortly after placement of an MHV compared with warfarin in the RE-ALIGN study . No trial has been conducted to assess the safety and efficacy of anti-Xa direct oral anticoagulants. Therefore, anti-IIa and anti-Xa direct oral anticoagulants are strictly contraindicated (Class III) in patients with any MHV with and without atrial fibrillation [1,2].
There is no longer a general recommendation for concomitant antiplatelet therapy in combination with anticoagulation in patients with MHVs because the lower risk of thromboembolic events is offset by a higher bleeding rate [1,2]. However, such a dual antithrombotic therapy may be considered in patients with coexistent atherosclerotic (e.g., peripheral artery, coronary artery or cerebrovascular) disease (Class IIb).
Bridging therapy during interruption of oral anticoagulation for planned invasive procedures is a complex issue associated with multiple factors including the type and location of the prosthetic valve, type of the diagnostic or therapeutic procedure, thromboembolic risk and duration of interruption of oral anticoagulation . Many procedures at low risk of bleeding or in which bleeding can be controlled easily (including dental procedures) do not require interruption of anticoagulation at all.
While the European guidelines  recommend bridging anticoagulation therapy for major surgery in all patients with MHVs and interruption of VKA (Class I), the U.S. guidelines  do not see the need for bridging for short interruptions in patients with aortic MHV in the absence of risk factors for thromboembolism (Class I). In all other scenarios, the risks of bleeding should be weighed against the benefits of thromboembolism prevention (Class IIa). Unfractionated heparin (UFH) remains the only approved heparin treatment in patients with MHV with intravenous administration favoured over the subcutaneous route because of more predictable pharmacokinetics, the option for rapid dose changes and neutralisation by protamine in case of bleeding. The use of subcutaneous low molecular weight heparin (LMWH) adapted to body weight and renal function, although off-label, is an alternative to UFH for bridging and should preferably be monitored by its anti-Xa activity (target of 0.5-1.0 U/mL). Practical modalities of anticoagulation bridging displayed as a timeline are described elsewhere . Fondaparinux, a synthetic pentasaccharide indirect factor Xa inhibitor, should not be used for bridging therapy in patients with an MHV .
Adjunctive antithrombotic pharmacotherapy in bioprosthetic valves
Compared to MHVs, the long-term risk of thromboembolism in patients with bioprosthetic valves (BPV) and sinus rhythm is low, with a slightly higher incidence in mitral as compared to aortic BPV. The first 90 to 180 postoperative days constitute a higher-risk period. The current guidelines recommend considering short-term (3 to 6 months) anticoagulation using a VKA (INR target of 2.5) after surgical valve implantation and in the absence of another indication for chronic anticoagulation (Class IIb) based on a small protective effect on the risk of thromboembolism until the BPV is fully endothelialised [1,2]. Alternatively, low-dose aspirin (75 to 100 mg daily) could be given for the first 3 months (Class IIb) following aortic BPV implantation  or even lifelong . In the absence of supporting evidence this may also apply to mitral BPV by inference . However, the optimal antithrombotic strategy following BPV implantation remains a matter of debate until randomised controlled trials (RCTs) fill this gap in knowledge.
While the European guidelines from 2017 favour dual antiplatelet therapy for the first 3 to 6 months after TAVI followed by lifelong single antiplatelet therapy (Class IIa) over single antiplatelet therapy (Class IIb), the recently updated U.S. guidelines make just the opposite recommendation [1,2] based on a meta-analysis ahead of ongoing RCTs. Alternatively, anticoagulation with a VKA (INR target 2.5) may be reasonable in patients with a low bleeding risk for at least 3 months (Class IIb). The GALILEO RCT comparing low-dose rivaroxaban (10 mg daily) plus low-dose aspirin (75-100 mg) to a dual antiplatelet-based strategy for the prevention of early transcatheter aortic valve implantation (TAVI) thrombosis in patients without an established indication for long-term anticoagulation (e.g., atrial fibrillation) was halted prematurely due to an increase in all-cause mortality, thromboembolic events and bleeding in the rivaroxaban arm . Other RCTs exploring the role of NOACs in TAVI patients without a coexisting indication for long-term anticoagulation are ongoing.
Valvular heart disease is independently associated with atrial fibrillation and – in the absence of absolute contraindications – anticoagulation carries a Class I indication for stroke prevention [1,7]. Although NOACs are generally recommended in preference to VKAs, they are contraindicated in MHVs (Class III). The European guidelines  favour VKA in patients who have atrial fibrillation associated with a surgical or transcatheter aortic BPV (Class I), although NOACs are listed as an alternative (Class IIa) on both sides of the Atlantic Ocean not earlier than 3 months after implantation, due to gaps in evidence and conflicting data. Observational studies and registries indicate that NOACs are safe for long-term treatment of atrial fibrillation in TAVI pending evidence-based recommendations from ongoing RCTs.
Other comorbidities with established indications for oral anticoagulation include venous thromboembolism/pulmonary embolism, LV thrombus, pulmonary hypertension and hypercoagulable states. The optimal antithrombotic treatment for TAVI patients with an established indication for anticoagulation remains an area of uncertainty with respect to adjunctive antiplatelet agents. Initial results indicate that anticoagulation alone compared to a dual-agent strategy is associated with a lower incidence of serious bleeding in conjunction with an otherwise similar (non-inferior) outcome .