PARIS — Despite some potential advantages, transcatheter aortic valve implantation (TAVI) failed to meet the primary prespecified threshold for noninferiority to surgical aortic valve replacement in younger low-risk patients with severe disease in a multicenter randomized trial.
Although the two approaches performed similarly in the tricuspid cohort at 1 year, there were fewer primary adverse outcomes in the bicuspid cohort after surgical aortic valve replacement than after TAVI, preventing noninferiority overall, reported Ole De Backer, MD, PhD, an interventional cardiologist at the Heart Center, Rigshospitalet, Copenhagen, Denmark.
"There are many studies comparing TAVI to surgical aortic valve replacement, but these have largely enrolled older patients — typically 75 years or at least 70 years or older — and they have generally excluded those with bicuspid valve stenosis," De Backer said.
This new trial, called NOTION-2, "is the first-ever randomized trial in younger low-risk patients," explained De Backer, who presented the findings during the major late-breaker session here at the Congress of the European Association of Percutaneous Coronary Interventions (EuroPCR) 2024.
Patients as Young as 60 Years
In this study, 370 people were assessed in the intention-to-treat analysis. Patients as young as 60 years were enrolled; the mean age was 71 years. Although about 70% had arterial hypertension, 15% had atrial fibrillation, 20% had diabetes, and 12% had concomitant coronary artery disease, the Society of Thoracic Surgeons Predicted Risk of Mortality score was low (< 1.2%).
There were 100 patients (27%) in the bicuspid cohort.
For the primary composite endpoint of death, stroke, and hospitalization related to the procedure, valve, or disease, rates at 1 year were nonsignificantly lower in the surgery group than in the TAVI group (7.1% vs 10.2%; P = .3). The same was true for death or disabling stroke alone (1.6% vs 3.2%; P = .3).
Although the 3.1% absolute difference in risk for the primary endpoint was below the 5% threshold prespecified as noninferior, the CIs were wide, surpassing the prespecified upper limit, according to De Backer.
The difference between TAVI and surgery was largely restricted to the bicuspid subgroup. In the tricuspid cohort, events were, in fact, more common in the surgery group during the first 6 months of the study. The difference then diminished over the course of the subsequent follow-up period so that events were slightly but nonsignificantly greater in the TAVI group than in the surgery replacement group at 12 months (8.7% vs 8.3%; P = .9).
In the bicuspid cohort, events climbed at a substantially steeper rate in the TAVI group from the beginning. By 1 month, the difference was substantial (10.2% vs 2.0%). Although rates plateaued in the TAVI group at 2 months, the margin of difference persisted to the end of the study, when nearly four times more patients in the TAVI group than in the surgery group reached the primary endpoint at 12 months (14.3% vs 3.9%; P = .07).
Stroke More Common in TAVI Patients
Overall, when the components of the primary endpoint were compared for the whole study, only stroke (5.4% vs 1.6%; P = .05) approached significance. And for this endpoint, nondisabling stroke (3.7% vs 0.5%; P = .03) did reach statistical significance.
For the secondary endpoints, "there were a couple of wins for TAVI and a couple of wins for surgery," De Backer said.
Specifically, the TAVI vs surgery cohort experienced less major or life-threatening bleeding (4.8% vs 17.5%; P < .001), less new-onset atrial fibrillation (3.2% vs 41.7%; P < .001), less severe patient-prosthesis mismatch (10.1% vs 19.4%; P = .02), and fewer median days in the hospital (3 vs 7 days; P < .001).
Conversely, the surgery vs TAVI group experienced fewer new permanent pacemaker placements (8.0% vs 15.1%; P = .03) and less moderate or greater perivalvular regurgitation (0% vs 4.7%; P = .005).
At 1 month, the mean improvement in quality-of-life scores favored TAVI over surgery, and a greater proportion of TAVI patients had no symptoms or physical limitations (New York Heart Association [NYHA] class I). At 1 year, the mean improvement in quality-of-life scores was exactly the same in the two groups, and the proportion in NYHA class I was only slightly greater in the TAVI group than in the surgery group (78% vs 72%).
Even though the NOTION-2 investigators expected that transcatheter aortic valve replacement (TAVR) would be noninferior to surgery in younger patients overall, the major message is that "TAVI outcomes in young bicuspid aortic stenosis patients are less favorable," according to De Backer.
He did not rule out the possibility of comparable results for TAVR and surgery in yet-to-be identified bicuspid phenotypes, and he suggested that more use of cerebral embolic protection, which was only offered to a small proportion of patients in this study, might have produced a different result, given the difference in stroke risk.
Pointing out the interpretation difficulties posed by noninferiority trials that narrowly miss prespecified margins, Davide Capodanno, MD, PhD, professor of cardiology, University of Catania, Catania, Italy, said that only minimal adjustments in the assumptions that drove the trial would have led to a different result.
Trial's Assumptions Questioned
Noting that the investigators had predicted that TAVI would yield a 5% lower risk for the primary endpoint than surgery, he suggested that different assumptions might have led to different upper and lower confidence margins to define equivalence. Even though the 3.1% greater rate of primary events fell within the prespecified noninferiority assumption, the upper allowed margin was surpassed.
However, the lower margin was also surpassed, Capodanno pointed out.
"Since the confidence interval touches both lines, the study is inconclusive," he explained.
This does not change the result or the conclusion, he cautioned, but, unlike superiority trials that "are much easier to interpret," the question of the noninferiority of TAVI relative to surgery in younger low-risk patients has not been conclusively answered, particularly in those with tricuspid valve repair.