DOAC vs. standard of care after TAVR: risk of valve thrombosis and clinical outcomes
Apixaban and Valve Thrombosis After Transcatheter Aortic Valve Replacement: The ATLANTIS-4D-CT Randomized Clinical Trial Substudy
Introduction and methods
Transcatheter aortic valve replacement (TAVR) is possibly associated with subclinical leaflet thrombosis of the implanted bioprosthetic aortic valves, with or without valve dysfunction [1-3]. Furthermore, this early valve thrombosis could be linked to the occurrence of thromboembolic events, such as ischemic stroke, after TAVR [2-5]. Previous analyses have indicated that oral anticoagulation (OAC ) therapy perhaps prevents subclinical leaflet thrombosis [2,6,7].
Aim of the study
The study aims were to examine: (1) the incidence of subclinical obstructive valve thrombosis 90 days after successful TAVR; (2) the relationship between valve thrombosis and clinical outcomes at 1 year; and (3) the effect of anticoagulation with apixaban versus current standard of care on the occurrence of valve thrombosis (and to determine whether there was an interaction according to OAC indication status).
This was a prespecified substudy of the international, randomized, open-label, superiority, phase 3 ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis) trial. Previously, this trial showed that apixaban 5 mg twice daily was not superior to standard of care (i.e., VKA or antiplatelet therapy, depending on OAC indication) after successful TAVR . In addition, apixaban treatment was associated with similar safety but also with more non–CV deaths compared with standard of care .
To detect subclinical valve thrombosis, all randomized patients in the main ATLANTIS trial (i.e., intention-to-treat population) were offered dynamic cardiac 4-dimensional (4D) CT, 3–6 months after randomization. The 4D-CT images were assessed for the presence of valvular thrombosis and leaflet motion. In total, 762 patients were included in the ATLANTIS-4D-CT substudy, of whom 370 received apixaban and 392 received standard of care. There was no specific power calculation for the substudy.
The primary endpoint was the presence of subclinical valve thrombosis, which was defined as ≥1 prosthetic valve leaflet with reduced leaflet motion (RLM) of grade 3 or 4 (on a 5-point scale) or hypoattenuated leaflet thickening (HALT) of grade 3 or 4 (on a 5-point scale), 90 days after TAVR. Secondary endpoints included the percentage of patients with thrombi.
The authors defined 2 composite ischemic event endpoints: (1) death, MI, stroke, or peripheral embolism and (2) death, MI, or any stroke/TIA, both assessed at 1 year. The number of bleeding events (including any bleeding and life-threatening bleeding) was also determined.
Incidence of subclinical valve thrombosis
- The primary endpoint (≥1 prosthetic valve leaflet with grade 3–4 RLM or grade 3–4 HALT) occurred in 33 patients in the apixaban group (8.9%) and in 51 patients in the standard-of-care group (13.0%).
- Apixaban reduced the percentage of patients who met the primary endpoint compared with antiplatelet therapy (8.7% vs. 15.9%; odds ratio (OR): 0.51; 95%CI: 0.30–0.86) but not compared with VKA therapy (9.5% vs. 5.5%; OR: 1.80; 95%CI: 0.62–5.25) (P value for interaction by OAC indication status=0.0375).
- When looking at patients with marked valve dysfunction (i.e., ≥1 prosthetic valve leaflet with grade 3–4 RLM), apixaban also decreased this percentage compared with standard of care (1.4% vs. 7.1%; OR: 0.18; 95%CI: 0.07–0.42 ). Again, this difference was mostly driven by the comparison of apixaban with antiplatelet therapy.
- Similar results were found in the group of patients with ≥1 prosthetic valve leaflet with grade 3–4 HALT: 8.1% in the apixaban group versus 11.0% in the standard-of-care group (P value for interaction by OAC indication status=0.0307).
- Additionally, there was no difference in the incidence of visible thrombi on CT scans between the 2 groups (19.2% in apixaban group vs. 25.0% in standard-of-care group; P=non-significant).
- The composite endpoint of death, MI, stroke, or peripheral embolism at 1 year occurred in 10.7% of the patients who had subclinical valve thrombosis at 90 days and in 7.1% of those without this type of thrombosis (hazard ratio: 1.68; 95%CI: 0.82–3.44).
- After 1 year, any bleeding event were seen in 14.3% of the patients with subclinical valve thrombosis at 90 days and in 25.2% of those without this type of thrombosis. There was no significant interaction by OAC indication status.
- Apixaban did not significantly influence the clinical outcomes compared with standard of care, although both the thromboembolic and bleeding event rates were numerically higher in apixaban-treated patients.
In this substudy of the ATLANTIS trial, apixaban reduced the risk of subclinical valve thrombosis 90 days after successful TAVR compared with antiplatelet therapy in patients who did not have an OAC indication. However, this coincided with a nonsignificant higher rate of thromboembolic and bleeding events 1 year after the procedure. There was no benefit of apixaban over VKA therapy. As apixaban was overall not superior to standard of care in the main ATLANTIS trial, the authors warn that the results of this substudy should be interpreted with caution.