UPDATED May 16, 2021 // Use of transcatheter aortic valve replacement/implantation (TAVR or TAVI) swiftly expanded from the high surgical risk to the low surgical risk settings, the necessary clinical trials following one after the other. But a good understanding of optimal post-TAVR antithrombotic therapy has been slower coming.
Now, a 1500-patient trial has offered greater insight but also a few puzzles, including a concerning, unexplained signal of risk relating to the choice of post-TAVR antithrombotic agent.
Management with the factor Xa inhibitor apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) after TAVR was not superior to standard management at 1 year for the study's composite clinical endpoint, which included mortality, myocardial infarction (MI), bleeding, and a variety of thrombotic events. Standard care consisted of antiplatelet therapy or oral anticoagulation (OAC) with warfarin, the choice hinging on whether there was a separate OAC indication.
The overall parity also applied to two subanalyses: one of patients without a standard OAC indication and the other of those with an OAC indication other than TAVR.
But among those lacking an established OAC indication, patients assigned to apixaban showed an 86% jump in mortality driven by a tripling of risk for noncardiovascular death compared with those given standard care in the trial, ATLANTIS. Principal investigator Jean-Philippe Collet, MD, Groupe Hospitalier Pitié-Salpêtrière in Paris, France, presented the trial results at the American College of Cardiology (ACC) 2021 Scientific Session.
The excess noncardiovascular deaths weren't associated with bleeding events. Indeed, "most of these noncardiovascular deaths were related to sepsis or end-stage renal failure," Collet told theheart.org | Medscape Cardiology after his presentation.
The risk for bleeding, whether major or minor, was unaffected by treatment assignment overall and in both subanalyses.
The trial can't recommend apixaban as a default post-TAVR antithrombotic agent in all comers, Collet said. "But given its ease of use, the good safety profile of the drug, and the lack of difference versus vitamin K antagonists, it could be a first-choice therapy in those patients who have an indication for oral anticoagulation other than TAVI itself."
However, the approved indications for apixaban and the other direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) preclude their use in those with prosthetic valves, observed David J. Cohen, MD, MSc, University of Missouri-Kansas City and Saint Luke’s Mid America Heart Institute, at a panel discussion on ATLANTIS.
"And as a result of that," he said, "there are some clinicians in the United States who — when a patient with an indication for oral anticoagulants has a TAVI performed — switches the patient from the DOAC they were on to warfarin."
Do the trial's results, he asked, "suggest that it's reasonable to continue a DOAC in those patients rather than switching to warfarin?"
"I think it does," replied ATLANTIS trialist Gilles Montalescot, MD, PhD, Sorbonne Université and Hôpital Pitié-Salpêtrière, Paris, France. "In this study, at least, that group of patients performed very well on apixaban. I would say that is probably the most positive lesson that we have in ATLANTIS."
As for the noncardiovascular mortality signal with apixaban in the group without a standard OAC indication, Montelescot said only 9 such deaths separated the apixaban and standard-therapy groups, which questions the finding's clinical importance.
Vinod H. Thourani, MD, not associated with ATLANTIS, agreed. Many of the trial's patients were in their 80s and would normally have a substantial background mortality risk. The trial's noncardiovascular mortality finding "is a signal that we have to be careful about. But I also think noncardiovascular mortality in octogenarians with severe aortic stenosis is common, and it doesn't alarm me."
ATLANTIS doesn't provide a reason to change current post-TAVR antithrombotic management practices — except, he agreed, in patients already receiving a DOAC for an indication such as AF, Thourani, from the Piedmont Heart Institute, Atlanta, Georgia, told theheart.org | Medscape Cardiology.
"A lot of people come in like that," he said. "At the end of the day, I think we probably would consider going with apixaban instead of warfarin."
But for post-TAVR patients without an OAC indication, Thourani said, "this study does not unfortunately highlight that we should be treating them with anything more than just antiplatelet therapy."
Still, the question "remains open" for such patients, Collet said during a panel discussion. Apixaban "may be an option. But we need more data, especially with respect to noncardiovascular deaths. We had that same signal in the GALILEO trial."
In the 2019 GALILEO trial, the risk for death, thromboembolic events, and bleeding went up for post-TAVR patients who received rivaroxaban (Xarelto, Bayer/Janssen), another direct factor Xa inhibitor, compared with dual antiplatelet therapy.
Favorable but Inconclusive
There was a tantalizing but inconclusive signal favoring apixaban in the separately presented ATLANTIS 4-dimensional (4D) CT substudy, comprising 379 patients receiving apixaban and 392 assigned to standard care with evaluable scans.
The risk for subclinical valve thrombosis was cut significantly by 49% among patients assigned to apixaban vs standard care among the 558 patients with no OAC indication. There was no significant effect, either way, among those with an OAC indication.
Subclinical valve thrombosis has been a concern especially since the 2015 publication of a worrisome observational analysis of registry and single-center data pointing to the risk after TAVR. Although no effect from such leaflet thrombosis on outcomes was reported, the findings sharpened the field's focus on adjuvant antithrombotic therapy in patients who have undergone TAVR.
The trial defined subclinical valve thrombosis, a component of the primary endpoint, according to abnormal flow gradients or impaired leaflet mobility by transthoracic echocardiography (TTE), 4D CT, or both, performed after about 3 months.
"I think we can summarize the field right now by saying that valve thrombosis is common" after TAVR, Michael J. Mack, MD, Baylor Scott & White Health, Dallas, Texas, said as a panelist after the presentation.
"It's a dynamic process that some patients develop by 30 days, and resolve by a year," he added. "Other patients develop it after 30 days. It does not seem to be associated with clinical events, and there's no evidence," given the ATLANTIS findings, "that anything other than aspirin is beneficial to these patients."
The risk for subclinical valve thrombosis "was clearly reduced between apixaban versus standard of care, although we cannot draw any statistical conclusion because we failed to show any superiority with respect to the primary outcome," Collet told theheart.org | Medscape Cardiology.
Still, Collet said, "There are anatomical considerations which may drive the decision as to whether patients should be on oral anticoagulation or antiplatelet therapy. I think we have now evidence that valve-in-valve procedures are associated with more subclinical valve thrombosis, leaving the patient at risk, and it is the same for patients with small aortic-valve annulus."
And that, he said, could potentially "drive the decision to choose one over the other, irrespective of the underlying bleeding risk."
A reduced subclinical valve thrombosis risk during apixaban therapy in the group with no OAC indication, however, did not translate into a clinical benefit at 1 year with respect to the overall primary endpoint of death; MI; stroke or transient ischemic attack (TIA); pulmonary embolism; deep vein thrombosis (DVT); intracardiac or bioprosthesis thrombus; or life-threatening, disabling, or major bleeding.
With ATLANTIS and other studies suggesting "that the relationship between valve thrombosis and clinical outcomes is not so clear, perhaps weak at best," Cohen said to Montalescot during the panel discussion, "do you think it's time we should stop chasing valve thrombosis as an endpoint in transcatheter valve replacement — are we really just chasing an imaging finding? Or is it something still worth trying to prevent?"
The study was too small and its follow-up too short to say, Montalescot replied. "We had only 1-year follow-up. Clearly you could imagine that these patients may accumulate strokes along the way if they have valve thrombosis that is not diagnosed."
In addition, "Valve thrombosis may have an impact on the durability of these valves," he said. "We know that, at least for surgical valves, there is a link between valve thrombosis and their durability. I think we need to accumulate data on valve thrombosis after TAVI with long-term follow-ups, more than 1 year, to see what's going on."
More Than a Fourth Had AF
ATLANTIS researchers randomly assigned 1510 patients (mean age, about 82 years), who had successfully undergone TAVR in France, Spain, Germany, and Italy from 2016 to 2019, using any approved TAVR valve, to receive the factor Xa inhibitor or standard care.
About a third of the population had an OAC indication unrelated to their aortic valve disease, including AF in 28.3% of patients in the apixaban group and 26.5% of those assigned to standard care.
Those with and without an OAC indication were randomly assigned separately; the first group received either apixaban or standard care with warfarin, the latter group apixaban or standard care with antiplatelet therapy. Those getting warfarin made up about 21% of the total standard-care group.
Apixaban was primarily given at 5 mg twice daily; the dosage was 2.5 mg twice daily for about 34% of the group based on poor renal function, advanced age, or low body weight.
The two groups overall fared similarly for the primary endpoint at 1 year: 18.4% of those receiving apixaban and 20.1% of those assigned to standard care (hazard ratio [HR], 0.92; 95% CI, 0.73 - 1.16). Nor were there significant differences in the two stratification groups: those with and without an OAC indication.
Life-threatening, disabling, or major bleeding — the primary safety endpoint — developed in 8.5% of patients regardless of whether they received apixaban or standard care.
Patients receiving apixaban showed a significant benefit on two secondary outcomes; their risk for prosthetic thrombosis dropped 77% and risk for DVT by 91%; no such benefit was seen among those receiving warfarin in the standard-care group.
In post hoc analyses by stratification group, there were no significant differences between apixaban and standard care for any of the primary and secondary endpoints among patients with an OAC indication. But among those without an OAC indication (that is, in the apixaban vs antiplatelet comparison), the factor Xa inhibitor was associated with elevated risks for the following:
Death or any stroke, TIA, or systemic embolism: HR, 1.56 (95% CI, 1.01 - 2.43)
Death: HR, 1.86 (95% CI, 1.04 - 3.34)
Noncardiovascular death: HR, 2.99 (95% CI, 1.07 - 8.35)
But there were fewer instances of valve thrombosis in the apixaban group: 1.1% vs 6.1% (HR, 0.19; 95% CI, 0.08 - 0.47).
Insights From ATLANTIS 4D-CT
In the prospectively defined 4D CT substudy, which included 370 patients assigned to apixaban and 392 in the standard-care group, the odds ratio (OR) was 0.65 (95% CI, 0.41 - 1.04), favoring the factor Xa inhibitor for the primary endpoint: at least one prosthetic valve leaflet with grade 3 or 4 reduced leaflet mobility or grade 3 or 4 hypoattenuated leaflet thickening.
The OR was 0.51 (95% CI, 0.30 - 0.86; P for interaction = .011) among the substudy's 558 patients with no OAC indication, reported Montalescot in his presentation of the substudy during the virtual ACC session.
If such imaging were to be performed periodically in post-TAVR patients, Collet told theheart.org | Medscape Cardiology, it would likely detect even a higher prevalence of subclinical thrombosis, which "probably" would increase the risk for events such as stroke. "This is especially relevant for low-risk patients in whom subclinical valve thrombosis may be a key player in valve degeneration and valve durability."
It may be that such serial imaging, he said, could identify patients for whom OAC may be the best post-TAVR choice even in the absence of other indications.
ATLANTIS was partially funded by the Pfizer/Bristol-Myers Squibb alliance. Collet discloses receiving consulting fees or honoraria from AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, and Medtronic. Montalescot discloses consultant fees or honoraria from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly, Medtronic, Pfizer, and Sanofi-Aventis and conducting research for or receiving research grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis.
American College of Cardiology (ACC) 2021 Scientific Session. Presented May 15, 2021.
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Cite this: ATLANTIS Hints at How to Choose Post-TAVR Antithrombotics - Medscape - May 15, 2021.