SHORT DESCRIPTION OF THE ARTICLE:
Non-Vitamin K Antagonist Oral Anticoagulants (NOACs), currently apixaban, dabigatran, edoxaban and rivaroxaban, are recommended for stroke prevention, in preference to Vitamin K Antagonists (VKA), in patients with atrial fibrillation (AF), with class I level A indication, according to 2020 ESC Guidelines for Management of Atrial Fibrillation. (1)
However, there are several groups of patients who still benefit from VKA – patients with mechanical prosthetic heart valves or moderate-to-severe mitral stenosis, for example, in which NOACs are contraindicated (1) – and other groups of patients who, due to lack of representation in phase III randomized clinical trials (RCTs), we still do not know which therapeutic strategy is the best option.
Patients with AF and a Transcatheter Aortic Valve Implant (TAVI) are one of those groups where evidence is scarce and „EdoxabaN vs. standard of care and their effects on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation–Atrial Fibrillation“ (ENVISAGE-TAVI AF trial) was designed to investigate whether edoxaban or VKA was best in this population. It is a multinational, multicenter, prospective, randomized, open-label, blinded end point evaluation study comparing edoxaban to VKA-based therapy in approximately 1,400 patients with an indication for chronic oral anticoagulation after successful transfemoral TAVI. (2) The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. (3)
Edoxaban was noninferior to VKA for the composite primary outcome of adverse clinical events (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.85 to 1.31; noninferiority margin, 1.38; P=0.01 for inferiority). The incidence of major bleeding was higher with edoxaban than with VKA (HR, 1.40; 95% CI, 1.03 to 1.91; noninferiority margin, 1.38; P=0.93 for noninferiority), mainly due to more gastrointestinal bleeding.(3)
COMMENT BY THE DISCUSSANT #1 (RAG):
The ENVISAGE-TAVI AF trial is an important work by Nicolas M. Van Mieghem and colleagues regarding anticoagulation after TAVI in patients with AF. This subgroup of patients was under- or non-represented in the pivotal NOACs’ RCTs and there was a knowledge gap regarding the best anticoagulation strategy.
A small RCT (4) and some observational studies(5, 6) in this population found a lower rate of early thromboembolic and bleeding events with NOACs vs. VKA, but a dedicated large RCT was missing.
History has already showed us that findings from observational studies can be biased by confounders and that the best evidence arises from RCTs. ENVISAGE-TAVI AF might be one of those cases where results from a RCT do not confirm the preliminary results from observational studies.
In ENVISAGE-TAVI AF, edoxaban was non-inferior to VKA regarding the composite primary outcome of adverse clinical events. The primary efficacy outcome occurred in 170 patients (17.3 per 100 person-years) in the edoxaban group and in 157 patients (16.5 per 100 person-years) in the VKA group (HR, 1.05; 95% confidence interval [CI], 0.85–1.31) and that similarity was present in every efficacy component of the primary outcome: death from any cause (HR, 0.86; 95% CI, 0.64–1.15), myocardial infarction (HR, 1.65; 95% CI, 0.65–4.14), ischemic stroke (HR, 0.75; 95% CI 0.43–1.3), systemic thromboembolic event (0.2 vs. 0.3; HR not calculated) and valve thrombosis (0 vs. 0; HR not calculated).(3)
However, regarding primary safety outcome, the incidence of ISTH-defined major bleeding (clinically overt bleeding associated with reduced haemoglobin, blood transfusion, symptomatic bleeding at a critical site, or a fatal outcome) was higher with edoxaban than with VKA (HR, 1.40; 95% CI, 1.03–1.91), mainly due to more gastrointestinal bleeding (HR, 2.03; 95% CI, 1.28–3.22).(3)
In a meta-analysis of the four pivotal RCTs, NOACs were associated with a 19% significant stroke/systemic embolism risk reduction, a significant 52% reduction in intracranial haemorrhage but a 25% increase in gastrointestinal bleeding with NOACs vs. VKA.(7)
This increased gastrointestinal bleeding risk of NOACs compared to VKA is largely compensated by NOACs reduction in intracranial haemorrhage in the general population with AF, but that might not me the case in the population enrolled in ENVISAGE-TAVI AF: elderly and frail with multiple comorbidities.
Patients with severe aortic stenosis may have acquired von Willebrand’s disease and intestinal angiodysplasia (first described by Edward C. Heyde in 1958)(8) and that may play a crucial role in the increased gastrointestinal bleeding observed in ENVISAGE-TAVI AF.
This RCT highlights the need for continued research into pharmacodynamics, dosing efficacy and safety of each of the NOACs in elderly patients, that were not the focus of earlier trials, to try to find the antithrombotic sweet spot: to reduce the thrombotic risk at a minimal cost of bleeding.
COMMENT BY THE DISCUSSANT #2 (AR):
In the ENVISAGE-TAVI AF trial, where 1426 patients with atrial fibrillation (AF) undergoing transcatheter aortic valve implantation (TAVI) were enrolled (2), the occurrence of the primary efficacy endpoint, a net clinical composite of all-cause death, myocardial infarction, stroke, systemic thromboembolism, clinical valve thrombosis and major bleeding defined according to the International Society on Thrombosis and Haemostasis (ISTH), was non-inferior with edoxaban vs. vitamin K-antagonist (VKA) (annual incidence 17.3% vs. 16.5%; HR [hazard ratio] 1.05; 95% CI [confidence interval] from 0.85 to 1.31; p for non-inferiority = 0.01) (1). Conversely, non-inferiority in the occurrence of the primary safety endpoint of ISTH major bleeding, with edoxaban compared to VKA was not met, being edoxaban associated with a higher incidence per year of ISTH major bleeding (9.7% vs. 7.0% for VKA [HR 1.40 ; 95% CI 1.03 to 1.91; p for non-inferiority = 0.93] (2). The difference in bleeding between the two groups was driven by gastrointestinal bleeding. Despite this increase, life-threatening bleeds were numerically lower with edoxaban than with VKA (1.6% vs. 1.9%, respectively). Fatal bleeding occurred with a low incidence of 1% in both groups. In fact, almost all gastrointestinal bleeding (98.2%) was clinically manageable and successfully treated. Finally, the incidence of intracranial hemorrhages was numerically lower in the edoxaban group than in VKA (1.5% vs. 2.1%, respectively).
Now, how can the above results be interpreted and used in clinical practice? As regards the increase in major bleeding, which appears in contrast with the long established superior safety of non-vitamin K-antagonist oral anticoagulants (NOAC) vs. VKA, it needs to be noted that the population included in the ENVISAGE-TAVI AF trial (2) was old and with frequent co-morbidities, including gastrointestinal diseases and coagulation disorders, and therefore at higher risk of bleeding compared to historical populations enrolled in trials comparing NOAC to VKA in AF (2, 7). Also, in this already vulnerable population, the concomitant use of antiplatelet drugs, further increasing the risk of bleeding, was high (63%) (2). In a post-hoc analysis of the ENVISAGE-TAVI AF trial (2), concomitant antiplatelet therapy was associated with an increased risk of bleeding without additional benefits on ischemic endpoints. Major bleeds were similar with edoxaban vs. VKA in patients who did not receive antiplatelet therapy while they were increased with edoxaban in the group of patients in which antiplatelet therapy was added (2). This in accordance with the results of the POPular TAVI trial (9) where in patients on oral anticoagulation undergoing TAVI the incidence of bleeding was higher in the group randomized to the combination of clopidogrel plus anticoagulant vs. anticoagulant therapy alone (9). An additional factor that might have influenced the occurrence of bleeding in the ENVISAGE-TAVI AF trial (2) was the adjustment of the edoxaban dose: only in the subgroup not adjusting the dose the bleeding rate was significantly higher with edoxaban vs. VKA, while the net clinical benefit and major bleeding were similar between the two treatment groups in patients with criteria which induced dose reduction (2). Of note, all cause mortality was significantly reduced with edoxaban compared to VKA in patients receiving dose adjustment (8.1% vs. 12.7% per year, respectively; HR 0.64; 95% CI, 0.43 to 0.96). On the other hand, the increased bleeding with edoxaban, in the subgroup that did not receive the dose reduction, did not affect mortality that was similar with edoxaban vs. VKA. Furthermore, edoxaban at the adjusted lower dose maintained efficacy with similar incidences of stroke vs. VKA (2.3% and 3.0%, respectively, HR 0.80; 95% CI 0.36 to 1.78) .
As regards the primary efficacy endpoint, the ENVISAGE-TAVI AF trial (2) is the first randomized study strongly supporting previous observations and pathophysiological considerations which have suggested that NOAC may be a therapeutic option in AF patients undergoing TAVI. Edoxaban was indeed non-inferior vs. VKA regarding the net clinical endpoint including ischemic events and major bleeding, although the latter were more frequent in the edoxaban group (2). Non-inferiority was achieved despite edoxaban being compared to a high-quality VKA therapy, as demonstrated by the high time in therapeutic range (63%) (2).
In conclusion, the ENVISAGE-TAVI AF trial (2) demonstrated that in AF patients undergoing TAVI edoxaban is not inferior vs. VKA on the occurrence of the net clinical endpoint including haemorrhagic and ischemic events, thus being able to represent a valuable therapeutic option in this patient subset. Concomitant antiplatelet therapy should be avoided, and prescription of the lower edoxaban dose of 30 mg, when clinically indicated, should be considered as the therapy of choice.
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