Introduction
The treatment of severe aortic stenosis (AS) has undergone a paradigm shift over the last decade. Transcatheter Aortic Valve Replacement (TAVR), once reserved for inoperable or high-risk patients, has expanded its indications to include intermediate and low-risk populations. However, the expansion into younger, low-risk cohorts brings new challenges, particularly regarding long-term valve durability and the management of bicuspid aortic valve (BAV) anatomy. The NOTION-2 (Nordic Aortic Valve Intervention) trial provides critical insights into these areas, reporting outcomes up to three years for patients aged 75 and younger.
Highlights
The NOTION-2 trial yields several high-impact findings for the clinical community:
1. At three years, the primary composite endpoint of death, stroke, or rehospitalization was statistically similar between TAVR and surgical aortic valve replacement (SAVR).
2. Subgroup analysis reveals a notable trend toward higher risk in patients with bicuspid aortic stenosis treated with TAVR compared to surgery.
3. Rates of structural valve deterioration (SVD) and bioprosthetic valve failure (BVF) remain low and comparable between both treatment modalities at the three-year mark.
4. TAVR remains associated with higher rates of permanent pacemaker implantation and paravalvular regurgitation, while surgery carries a higher burden of atrial fibrillation and major bleeding.
Background: The Shifting Landscape of TAVR
For decades, surgical aortic valve replacement (SAVR) was the gold standard for treating severe symptomatic AS. The advent of TAVR introduced a less invasive alternative that has demonstrated non-inferiority, and in some cases superiority, to surgery across various risk profiles. Nevertheless, most pivotal low-risk trials, such as PARTNER 3 and Evolut Low Risk, primarily enrolled older patients (mean age >70) and largely excluded those with bicuspid anatomy. Bicuspid aortic stenosis is the most common congenital heart abnormality and is frequently encountered in younger patients requiring intervention. The NOTION-2 trial was specifically designed to address these gaps by enrolling low-risk patients aged 75 or younger, including those with both tricuspid and bicuspid valves.
Study Design and Methodology
NOTION-2 was a randomized, clinical trial conducted across multiple centers in the Nordic countries. It enrolled 370 patients with severe symptomatic AS and a low surgical risk profile. The mean age of the cohort was 71.1 years, and the mean Society of Thoracic Surgeons (STS) Predicted Risk of Mortality was 1.2%, reflecting a truly low-risk population.
Patients were randomized 1:1 to receive either TAVR (using contemporary balloon-expandable or self-expanding platforms) or SAVR. A significant feature of this trial was the inclusion of 100 patients with bicuspid aortic stenosis (approximately 27% of the total cohort). The primary endpoint was a composite of all-cause mortality, stroke, or rehospitalization related to the procedure, the valve, or heart failure. Clinical and echocardiographic follow-ups were conducted at 1 year and 3 years.
Key Findings at Three Years
Primary Composite Endpoint
The three-year follow-up data showed that the primary composite endpoint occurred in 16.1% of the TAVR group compared to 12.6% in the SAVR group. While the absolute percentage was higher for TAVR, the difference did not reach statistical significance (hazard ratio [HR], 1.3; 95% CI, 0.8-2.2; P=0.4). This suggests that for the overall younger low-risk population, TAVR and surgery offer comparable clinical safety and efficacy in the mid-term.
Tricuspid vs. Bicuspid Subgroups
The most provocative data emerged from the subgroup analysis based on valve morphology. Among patients with tricuspid aortic stenosis, the event rates were nearly identical between TAVR and surgery (14.5% vs. 14.4%). However, in the bicuspid subgroup, TAVR was associated with a higher risk of the primary endpoint (20.4% vs. 7.8%; HR, 2.9; 95% CI, 0.9-9.0). Although the small sample size of the bicuspid group (n=100) limited the statistical power and the interaction p-value was 0.1, the numerical disparity raises important questions about the optimal approach for BAV patients.
Valve Durability and Hemodynamics
Structural valve deterioration (SVD) is a primary concern in younger patients who have a longer life expectancy. At three years, the risk of moderate or greater SVD was 4.5% for TAVR and 5.2% for SAVR (HR, 1.2; 95% CI, 0.4-3.1). Bioprosthetic valve failure (BVF) rates were also low and comparable: 1.6% for TAVR and 2.9% for surgery. These findings are encouraging for the mid-term durability of transcatheter bioprostheses in younger cohorts.
Safety and Procedural Complications
The trial highlighted the traditional trade-offs between TAVR and SAVR. TAVR patients experienced lower rates of major bleeding and new-onset atrial fibrillation. Conversely, TAVR was associated with a higher risk of non-disabling strokes, permanent pacemaker implantation (PPI), and moderate or greater paravalvular regurgitation (PVR). The higher PPI and PVR rates in the TAVR group are consistent with previous literature and remain a focal point for technological refinement, particularly in bicuspid anatomies where asymmetric calcification can impede optimal valve expansion.
Expert Commentary: Navigating Lifetime Management
The NOTION-2 results underscore the necessity of a “lifetime management” strategy for younger patients with AS. Since these patients may require multiple interventions over their lifespan, the choice of the first valve is crucial. While TAVR is a viable option for tricuspid valves in this age group, the bicuspid data suggests that surgery might still be the preferred initial approach for many BAV patients, especially those with challenging root anatomy or high-risk features for PVR and stroke.
Physician-scientists note that the higher event rate in the TAVR-bicuspid group in NOTION-2 may be due to the technical complexities of treating BAV with TAVR, such as elliptical annulus shapes and heavy calcification of the raphe. Future trials specifically powered for bicuspid populations and utilizing the latest generation of transcatheter valves are essential to determine if technological iterations can close the gap seen in this study.
Conclusion
For patients aged 60 to 75 years with severe aortic stenosis and low surgical risk, the three-year outcomes of the NOTION-2 trial demonstrate that TAVR and SAVR provide similar protection against the composite of death, stroke, and rehospitalization. Both procedures exhibit excellent mid-term durability with low rates of structural valve deterioration. However, the signals of increased risk in the bicuspid population warrant a cautious, individualized approach. Heart teams should carefully weigh the anatomical complexities of bicuspid valves against the benefits of a less invasive procedure when treating younger, low-risk individuals.
Funding and Registration
The NOTION-2 trial was supported by various Nordic research foundations and clinical grants. The trial is registered at ClinicalTrials.gov with the unique identifier NCT02825134.
References
1. Jørgensen TH, et al. Three-Year Follow-Up of the NOTION-2 Trial: TAVR Versus SAVR to Treat Younger Low-Risk Patients With Tricuspid or Bicuspid Aortic Stenosis. Circulation. 2025 Nov 11;152(19):1326-1337.
2. Jørgensen TH, et al. Transcatheter aortic valve implantation in low-risk tricuspid or bicuspid aortic stenosis: the NOTION-2 trial. Eur Heart J. 2024 Oct 5;45(37):3804-3814.