The European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) 2021 guidelines do not recommend routine oral anticoagulation use unless transcatheter aortic valve replacements (TAVR) patients have other indications that require oral anticoagulation (Level of evidence: B), which was echoed in expert consensus from the 2019 Canadian Cardiovascular Society Position Statement, where direct oral anticoagulants (DOACs) may be used for other indications as per standard guidelines or in combination with aspirin in TAVR patients with atrial fibrillation. The American College of Cardiology/American Heart Association Joint Committee (AHA/ACC) also clearly stated in their 2020 guidelines that in the absence of other indications that require oral anticoagulation, use of rivaroxaban is contraindicated (Level of evidence: B). The American College of Chest Physicians 2012 guidelines recommended the use of aspirin plus clopidogrel in the first 3 months over vitamin K antagonists (VKAs) and over no platelet therapy, but do not mention the use of DOACs in patients with bioprosthetic valves. In the absence of a compelling indication for chronic oral anticoagulation, single antiplatelet therapy is preferred over a DOAC, although authors of a 2022 review proposed there is a need for future randomized trials to bridge the knowledge gap for whether DOACs should be preferred over VKAs. The authors also do not specify whether a particular DOAC is preferred following TAVR. [1], [2], [3], [4], [5]
A 2022 narrative review discussed the use of DOACs in mechanical and bioprosthetic heart valves. DOACs are considered an option for patients with bioprosthetic heart valve/ transcatheter aortic valve implantation (TAVI) with concurrent indication for anticoagulation. Regarding the choice of anticoagulant, safety data exists for apixaban in patients undergoing TAVI and with a baseline indication for anticoagulation. Rivaroxaban may be used in younger patients who are at least 3 months out from the surgically placed bioprosthetic value. Edoxaban has demonstrated a possible increased risk of bleeding (especially gastrointestinal) for patients undergoing TAVI. Dabigatran has shown to have similar results to warfarin in preventing short-term intracardiac thrombus in surgically placed bioprosthetic mitral and/or aortic valves in younger patients in one trial. However, this trial was terminated early and statistical power was not attained. DOAC as a group may reduce mortality and bleeding compared to VKAs, although limitations of registry studies should be noted. [6]
For patients with bioprosthetic heart valves/TAVI without a baseline indication for anticoagulation, the goal is to utilize single antiplatelet therapy lifelong, without any additional antithrombotics. Harm has been shown with rivaroxaban and apixaban in this group of patients undergoing TAVI with possible increase in the risk of death, thromboembolism, and bleeding as well as non-cardiovascular mortality. Additionally, inclusive evidence exists for edoxaban and dabigatran. It was suggested that in the face of insufficient high-quality clinical trial evidence, there is significant heterogeneity in the antithrombotic regimen after a bioprosthetic valve. Further large, randomized-controlled trials should assess the long-term safety and efficacy of each DOAC in comparison to VKAs in older patients, as reflective of the typical bioprosthetic valve-receiving patient. Until robust randomized clinical trials are available, providers must remain cautious about DOAC use in bioprosthetic valves and consider individual patient characteristics when selecting an antithrombotic strategy. [6]
A 2022 literature review examined available evidence on the use of antithrombotic treatments in patients with mechanical and bioprosthetic heart valves (bPHV). Despite their lower structural durability, bPHVs are often preferred over mechanical prosthetic heart valves due to not requiring lifelong anticoagulation therapy. However, determining the optimal antithrombotic treatment and duration remains a matter of debate. Guidelines for bPHV are also predominantly based on limited nonrandomized studies and expert consensus. The use of DOACs after bPHV replacement can be considered in both the early post-operative phase as a replacement for traditional antithrombotic agents, and in the chronic post-surgical phase, particularly for patients requiring long-term oral anticoagulation therapy for reasons other than the bPHV implantation. Notably, many bPHV patients have a long-term anticoagulation need often due to atrial fibrillation. The evidence supporting DOAC use in bPHV patients without a pre-existing indication for long-term oral anticoagulation therapy is limited. This lack of supporting evidence is partly influenced by the outcomes observed in the RE-ALIGN trial, which investigated the use of dabigatran in patients with mechanical prosthetic heart valves and showed unfavorable outcomes, including excess thromboembolic and bleeding events, which lead to its premature termination. Encouraging findings have emerged from recent trials such as the ENAVLE trial, where patients receiving edoxaban (30 mg or 60 mg once daily) for the initial three months post-surgery demonstrated non-inferior efficacy and safety compared to warfarin. Additionally, similar positive outcomes were observed in other studies involving patients with bPHV who had a long-term indication for oral anticoagulation therapy. Despite these promising results, the need for further research and the development of formal guidelines regarding the definitive role of DOACs in this context is emphasized. It was noted that the introduction of TAVR has revitalized research in this field. However, due to its unique structural and procedural aspects, evidence for bPHV may not directly apply to TAVR. Applicable literature on DOACs in TAVR reveals that for patients without a prior indication for long-term anticoagulation, aspirin alone appears to be as effective as dual antiplatelet therapy in preventing cardiovascular events, with a lower bleeding risk. However, the use of DOACs in TAVR patients requiring long-term anticoagulation remains debated, as trials like GALILEO, which evaluated the use of rivaroxaban 10 mg daily in TAVR patients without a prior indication for long-term anticoagulation, were prematurely terminated due to safety concerns. Evaluation of the clinical benefits of DOACs over traditional anticoagulants in this context also requires further investigation. [7], [8], [9], [10]
A recent systematic review and meta-analysis (N= 10 articles; 4,088 patients) looked at the use of DOACs versus the use of warfarin in patients who underwent bioprosthetic valve replacement to assess safety and efficacy. Between DOACs and warfarin, pooled analyses revealed no significant differences in incidence of bleeds (16% vs. 17%; odds ratio [OR] 0.94; 95% confidence interval [CI] 0.56 to 1.57; p= 0.81; I2= 81%), stroke (2.5% vs. 3.3%; OR 0.75; 95% CI 0.41 to 1.38; p= 0.36; I2= 35%), nor all-cause mortality (9.2% vs. 13.7%; OR 0.85; 95% CI 0.68 to 1.07; p= 0.16; I2= 56%). A subgroup analysis of randomized controlled trials and prospective studies, however, revealed a lower risk of bleeding (9.8% vs. 13.4%; OR 0.70; 95% CI 0.52 to 0.95; p= 0.02; I2= 0%) and stroke (1.97% vs. 4.43%; OR 0.44; 95% CI 0.25 to 0.79; p= 0.006; I2= 0%) with DOACs. Conversely, there were no statistically significant differences in all-cause mortality between groups. Additionally, looking at retrospective and registry studies also did not reveal significant differences in the risk of stroke between both groups. The investigators concluded that DOAC use seemed to be as safe and effective as VKAs when used in patients with bioprosthetic valves for anticoagulation. Notably, heterogeneity was moderate to high among the studies, and variability in reporting may impact how compelling these findings are. [11]
Additionally, a recent 2022 observational study identified atrial fibrillation patients with valve repairs or replacements to compare the safety and effectiveness of DOACs versus warfarin. Between 2015 and 2019, patients with mitral valve repair and patients with TAVRs were divided into subgroups that received either warfarin or a DOAC (apixaban, rivaroxaban, and dabigatran). Of 8,089 bioprosthetic patients, DOACs were associated with a similar risk of mortality (adjusted hazard ratio [HR] 0.93; 95% CI 0.86 to 1.01; p= 0.08), a lower risk of bleeds (adjusted HR 0.86; 95% CI 0.80 to 0.93; p<0.001), and a higher risk of ischemic stroke (adjusted HR 1.27; 95% CI 1.13 to 1.43; p<0.001) versus warfarin after a median follow-up of 413 days. Notably, DOACs were associated with a higher risk of ischemic stroke regardless of valve location. Despite the increased risk in stroke, DOAC use provided a large reduction in major bleeding with similar all-cause mortality, and given warfarin's narrow therapeutic range and need for frequent monitoring, may benefit this patient population. It should be noted that as with other observational studies, results may be confounded by misclassification, inaccuracies in Medicare claims, and missing database information. [12]
PROACT Xa (ClinicalTrials.gov no. NCT04142658) was a phase 3 study evaluating the safety and efficacy of apixaban versus warfarin in patients with an aortic valve replacement, specifically an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. Patients were randomized 1:1 to receive apixaban 5 mg or 2.5 mg by mouth twice daily, or warfarin with an INR goal of 2 to 3. The primary endpoint was the composite of valve thrombosis and valve-related thromboembolism with a safety outcome of major bleeding. The trial was terminated after 863 participants were enrolled due to a great number of thromboembolic events occurring in the apixaban arm. [13], [14]