ENVISAGE-TAVI AF: edoxaban vs. vitamin K antagonists after TAVI in patients with atrial fibrillation
Reported from the European Society of Cardiology ESC Congress 2021
Context
At the European Society of Cardiology 2021 Digital Congress, George Dangas presented the primary results of the ENVISAGE-TAVI AF trial, comparing edoxaban versus warfarin after transcatheter aortic valve implantation (TAVI) in patients with indications for oral anticoagulation due to prevalent or incident atrial fibrillation.
The results of this trial were awaited due to the significant inconsistency in available evidence and paucity of high-quality data on direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) in patients undergoing TAVI with indications for oral anticoagulation.
More in detail, observational data have provided contradictory findings:
- some studies supporting a benefit form DOAC over VKA in terms of both mortality and major bleeding,
- others showing non-significant differences between treatments with respect to the same outcomes,
- and others even revealing higher rates of ischemic outcomes associated with DOAC as compared with VKA.
However, recent data from the cohort of patients requiring OAC randomized to apixaban or VKA in the ATLANTIS trial showed no significant difference in terms of efficacy and safety between anticoagulant agents.
Principle of the study and its methodology
The ENVISAGE-TAVI AF is an international, randomized clinical trial of 1,426 patients with prevalent or incident atrial fibrillation and conventional indications for oral anticoagulationn comparing in a 1:1 ratio edoxaban with VKA after successful TAVI.
The mean age of patients was 82.1 years, 47.5 % were women, mean STS score for 30-day mortality was 4.9 %, and mean CHA2DS2-VASC score was 4.5.
Before randomization, 46.0 % of patients in the edoxaban group and 50.4 % patients in the VKA group were on concomitant antiplatelet therapy.
A total of 677 patients (47.5 %) received a balloon-expandable bioprosthesis, 653 patients (45.9 %) a supra-annular self-expandable bioprosthesis, and 95 patients (6.7 %) an intra-annular self-expandable bioprosthesis.
After enrollment, 46.4 % of patients met any criteria for dose reduction and received low-dose edoxaban.
The median follow-up duration was 554 days in the edoxaban group and 530 days in the VKA group.
In patients assigned to VKA, the median time in therapeutic range 68.2 %.
After randomization, 409 patients (57.4 %) assigned to edoxaban and 415 patients (58.2 %) assigned to VKA received single antiplatelet therapy; 72 patients (10.1%) assigned to edoxaban and 78 patients (10.9%) assigned to VKA received dual antiplatelet therapy.
During the entire trial period, 215 patients (30.2 %) in the edoxaban group and 289 patients (40.5 %) in the VKA group discontinued oral anticoagulation.
Main results
Main trial results were assessed by four-step hierarchical testing sequentially comparing edoxaban with VKA for the following primary hypotheses:
- noninferiority for the primary net composite endpoint,
- noninferiority for major bleeding,
- superiority for major bleeding,
- and superiority for the primary net composite endpoint.
At follow-up, the primary hypothesis of noninferiority of edoxaban compared to VKA with respect to the efficacy composite endpoint of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolic event, valve thrombosis, or major bleeding, according to the International Society on Thrombosis and Haemostasis (ISTH) definition, was met (170 events, 17.3 events per 100 person-year versus 157 events, 16.5 events per 100 person-year; pnoninferiority = 0.01; HR 1.05, 95 % CI 0.85–1.31).
However, the co-primary hypothesis of noninferiority of edoxaban compared to VKA with respect to ISTH major bleeding was not met (98 events, 9.7 events per 100 person-year versus 68 events, 7.0 events per 100 person-year; pnoninferiority= 0.93; HR 1.40, 95 % CI 1.03-1.91).
The excess of events in the edoxaban group compared with the VKA group was not formally assessed for superiority since hierarchical testing failed at this step.
- Results were consistent in terms of Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding (87 events, 8.5 events per 100 person-year versus 53 events, 5.5 events per 100 person-year; HR 1.58, 95 % CI 1.12-2.22)
- Results were also consistent in terms of Global Utilization of Streptokinase and Tissue Plasminogen Activator of the Occluded Coronary Arteries (GUSTO) moderate, severe, or life-threatening bleeding (80 events, 7.8 events per 100 person-year versus 48 events, 4.9 events per 100 person-year; HR 1.59, 95 % CI 1.11-2.28)
- While differences between groups in terms of Thrombolysis in Myocardial infarction (TIMI) major bleeding were less pronounced (39 events, 3.7 events per 100 person-year versus 26 events, 2.6 events per 100 person-year; HR 1.41, 95 % CI 0.86-2.32).
- Death occurred in 85 patients assigned to edoxaban, for a rate of 7.8 events per 100 person-year, and in 93 patients assigned to VKA, for a rate of 9.1 events per 100 person-year (HR 0.86, 95 % CI 0.64-1.15).
- Ischemic stroke occurred in 22 patients assigned to edoxaban, for a rate of 2.1 events per 100 person-year, and in 28 patients assigned to VKA, for a rate of 28 events per 100 person-year (HR 0.75, 95 % CI 0.43-1.30).
Conclusion
The results of the ENVISAGE-TAVI AF trial do not support the use of apixaban in place of VKA in patients with indications for oral anticoagulation undergoing TAVI due to an excess in major bleeding at long-term follow-up.
The disappointing results of the ENVISAGE-TAVI AF trial are challenging to interpret when considering that DOAC have not been associated with increased rates of major bleeding compared with VKA in large-scale regulatory randomized clinical trials of patients with atrial fibrillation, and more recently the ATLANTIS study comparing apixaban with VKA in patients undergoing TAVI has not shown signals of harm associated with DOAC therapy.
Interestingly, the results of the ENVISAGE-TAVI AF trial confirm that, in patients undergoing TAVI with indications for oral anticoagulation, the risk of major bleeding is superior to the risk of thromboembolic complications. Indeed, in the ENVISAGE-TAVI AF trial, the incidence of major bleeding was approximately 4 folds higher than that of ischemic stroke.
These conclusions are in line with the recent results of the POPular TAVI trial, revealing lower rates of major bleeding with oral anticoagulation alone compared with oral anticoagulation plus clopidogrel-based single antiplatelet therapy in patients undergoing TAVI requiring oral anticoagulation. Of note, in the POPular TAVI trial, no significant differences in ischemic endpoints were observed between anticoagulation alone and anticoagulation plus antiplatelet monotherapy.
The predictable anticoagulant effects of DOAC should theoretically confer advantages in terms of major bleeding and it is known that VKA not infrequently result in unstable and supra- or subtherapeutic values of international normalized ratio. In light of the unfavorable results of the ENVISAGE-TAVI AF trial and the absence of a clearer explanation, it might be possible that DOAC pharmacokinetics and pharmacodynamics need to be revisited in elderly and frail patients with multiple significant comorbid conditions undergoing TAVI.
Finally, consistently with previous evidence from observational studies and randomized clinical trials, the results of the ENVISAGE-TAVI AF trial support the noninferior antithrombotic efficacy of DOAC compared to VKA in patients undergoing TAVI. These favorable results, along with the absence of other high-quality studies indicating an increased risk of major bleeding with DOAC in patients with indications for oral anticoagulation undergoing TAVI, warrant further analysis before drawing definitive conclusions on the topic.
Author
No comments yet!