Abstract
The Nordic Aortic Valve Intervention-2 (NOTION-2) trial is the first randomized controlled trial to compare transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) in low-risk patients, specifically focusing on relatively younger patients and those with bicuspid valves. It randomized 370 patients (mean age 71 years) to assess outcomes at 1 year. Results indicated a higher composite primary endpoint rate for TAVI (10.2%) compared to SAVR (7.1%) in the overall cohort, with even more pronounced differences in patients with bicuspid valves (14.3% for TAVI vs. 3.9% for SAVR). The risk of death or disabling stroke at 1 year was also three times higher with TAVI.
Keywords: NOTION-2, TAVI, SAVR, Bicuspid valves, Young
A number of trials comparing transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) have now been carried out in low-risk patients. However, most of these studies included elderly patients with predominantly tricuspid valve morphology. Outcomes in bicuspid valves have mainly been limited to observational studies and the Nordic Aortic Valve Intervention (NOTION)-2 trial is the only randomized controlled trial comparing TAVI with SAVR that has included a significant number of patients with bicuspid valve, in a relatively younger patient cohort[1].
Trial design
The NOTION-2 trial was an investigator-initiated, multicentre, randomized, non-inferiority trial in patients ≤ 75 years of age who were deemed to have low surgical risk as defined by the Society of Thoracic Surgeons (STS) mortality risk score (< 4%). Nine centres across five countries (Denmark, Norway, Sweden, Finland, and Iceland) participated in the study. Patients with an ascending aorta ≥ 45 mm were excluded, so were patients with coronary artery disease who were not amenable to both percutaneous coronary intervention (PCI) as well as coronary artery bypass graft (CABG). The choice of type of transcatheter or surgical valve was left to the treating physician. A composite of death from any cause, stroke, or rehospitalization at 1 year constituted the primary endpoint.
Trial findings
Of the 376 patients initially recruited, 370 patients were randomized. Of these, 187 were randomized to TAVI and 183 to surgery. Cross-over was low (2.9%) with only two patients crossing over from TAVI to surgery and nine from surgery to TAVI. Both self-expanding (72.7%) and balloon-expandable (25.7%) transcatheter aortic valves were used for TAVI and CE Magna or Perimount bioprostheses valves were used in the surgical arm. In the TAVI group, 5.9% of patients underwent PCI and 9.8% underwent concomitant CABG in the SAVR group.
The mean age was 71.1 ± 3.1 years in the TAVI group and 71.0 ± 3.2 years in the SAVR group. Majority of patients in both groups were male (63.6% for TAVI vs. 61.7% for SAVR). Society of Thoracic Surgeons–predicted risk of mortality (STS-PROM) and European system for cardiac operative risk evaluation II (EuroSCORE II) were also comparable between the groups. A slightly higher prevalence of previous myocardial infarction (7.0% vs. 2.7%) and coronary artery disease was seen in the TAVI group (13.4% vs. 9.8%). Moderate or severe mitral regurgitation was also more common in the TAVI group (4.0% vs. 1.7%). Other baseline characteristics, such as arterial hypertension, diabetes mellitus, and atrial fibrillation, were similarly distributed between the two groups.
Findings in the overall cohort
At 1 year, the composite primary endpoint (death, stroke, or re-hospitalization) was 10.2% in the TAVI group and 7.1% in the SAVR group. Similar results were observed in the as-treated population, with a primary end-point risk of 9.8% in the TAVI group and 7.4% in the SAVR group. TAVI showed a higher incidence of stroke compared to surgery (5.4% vs. 1.6%, p = 0.05), as well as permanent pacemaker implantation (15.1% vs. 8.0%, p = 0.03) and paravalvular regurgitation (4.7% vs. 0%, p = 0.005). However, it was associated with a lower incidence of major or life-threatening bleeding (4.8% vs. 17.5%, p < 0.001), new-onset atrial fibrillation (3.2% vs. 41.7%, p < 0.001), and moderate to severe patient-prosthesis mismatch (10.1% vs. 19.4%, p = 0.02) compared to surgery. Other endpoints did not show statistically significant differences between the two treatment modalities.
TAVI versus SAVR in bicuspid valve
Among patients with a bicuspid aortic valve morphology, the risk of the primary end-point was higher in the TAVI group (14.3%) compared to the SAVR group (3.9%). The risk of death or disabling stroke at 1 year was also higher in the TAVI group (6.1% versus 2.0%). Additionally, there was a higher rate of moderate to severe paravalvular regurgitation in the bicuspid TAVI cohort (hazard ratio—9.1(0.6–17.6)).
Comparison of TAVI in bicuspid versus tricuspid valve morphology
Patients with bicuspid aortic valve undergoing TAVI experienced higher rates of non-disabling stroke (6.1% vs. 2.2%) and paravalvular regurgitation (9.1% vs. 3.1%) compared to tricuspid valve patients.
Strengths of the NOTION-2 trial
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I.
It is the first-ever randomized trial comparing TAVI with SAVR in a relatively young patient population (≤ 75 years) with severe aortic stenosis (AS).
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II.
This is also the first study to include a significant number of patients with bicuspid aortic valves.
Weaknesses of the NOTION-2 trial
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I.
The sample size was small and underpowered to detect a difference.
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II.
Follow-up limited to just 1 year.
Main take-home points
Compared to TAVI, SAVR showed a trend towards better outcomes for patients with bicuspid aortic valves. Even among patients who underwent TAVI, it is important to highlight that the risk of experiencing both non-disabling stroke and moderate or greater paravalvular leak was three times higher in patients with bicuspid aortic valves compared to those with tricuspid aortic valves. Thus, the study confirmed that TAVI is associated with greater procedural complexity and adverse outcome in patients with bicuspid valves.
The NOTION-2 trial recruited patients who were younger than previous low-risk studies [2–6]. However, the mean age in the study was still 71 years and the findings of this study cannot be extrapolated to patients significantly younger than this age group. In this context, it has to be highlighted here that despite clear-cut guidelines recommending usage of a mechanical valve below the age of 50 years, almost 3–4% of patients below the age of 50 are treated with TAVI in England, Germany, Spain, and France [7]. According to the Society of Thoracic Surgeons, > 50% of patients younger than 60 years undergo TAVI in the USA [8]. The mean age of 71 years is the lowest among randomized controlled trials to date, and the use of TAVI in patients in their 5th and 6th decade is not supported by high-level clinical evidence.
The authors of the NOTION-2 trial concluded that there was clinical equipoise between TAVI and SAVR regarding the primary composite end-point of death, stroke, or re-hospitalization at 1 year. However, this conclusion is contradicted by their admission that the study’s sample size was under-powered to detect a difference. Considering the definite trend towards improved outcomes with SAVR, especially in patients with bicuspid valves, the apparent clinical equipoise seems to be a direct result of an under-powered study. In addition, the study only has reported outcomes at 1 year and longer-term outcomes in these patients remain unknown.
The NOTION-2 trial is a step in the right direction, but it raises more questions than it actually answers. The take-home message provided by the study “For low-risk patients ≤ 75 years of age with severe AS, one-year outcomes are comparable between TAVI and surgery” may be factually correct, but does not emphasize that the study may not have been designed to detect a difference in the first place.
Funding
None.
Data sharing
Data used in the review is freely available.
Declarations
Ethical approval
Not applicable as a review article.
Informed consent
Not applicable as a review article.
Conflict of Interest
None.
Footnotes
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References
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Data Availability Statement
Data used in the review is freely available.