Weekly Journal Scan: transcatheter aortic valve implantation in patients with small aortic annulus

Comment on ‘Self-Expanding or Balloon-Expandable TAVR in Patients with a Small Aortic Annulus’ which was published in the New England Journal Medicine 2024, https://doi.org/10.1056/NEJMoa2312573. The SMall Annuli Randomized To Evolut or SAPIEN (SMART) Trial is a multi-centre, industry-funded, randomized controlled trial (RCT), aimed at evaluating the clinical outcomes and valve performance of a self-expanding supra-annular valve as compared with a balloon-expandable valve in patients with symptomatic severe aortic stenosis and small aortic annulus undergoing transcatheter aortic valve implantation (TAVI).1 Patients with symptomatic severe aortic stenosis with an aortic valve annulus area of 430 mm2 or less (as assessed by multi-detector computed tomography), and suitable anatomy for transfemoral TAVI, were randomized 1:1 to receive a self-expanding supra-annular valve (Evolut PRO/PRO+/FX; Medtronic) or a balloon-expandable valve (SAPIEN 3/3 Ultra; Edwards Lifesciences). The sponsor (Medtronic) contributed to the protocol development and was responsible for site selection, data monitoring, and statistical analyses. The two co-primary endpoints, both of which were assessed through 12 months, were (i) a composite of death, disabling stroke, or re-hospitalization for heart failure (tested for non-inferiority, with an 8% margin, under the assumption that an event would occur in 16% of the patients in each group), and (ii) bioprosthetic valve dysfunction (tested for superiority), a composite endpoint including haemodynamic structural valve dysfunction (defined as aortic valve mean gradient ≥ 20 mmHg); non-structural valve dysfunction [defined as a severe prosthesis–patient mismatch (i.e. indexed effective orifice area < 0.65 cm2/m2) or at least moderate aortic regurgitation]; clinical valve thrombosis [defined according to Valve Academic Research Consortium (VARC)-2 criteria]; endocarditis (defined according to modified Duke criteria); or aortic valve re-intervention. Secondary endpoints included haemodynamic mean gradient, effective orifice area, haemodynamic structural valve dysfunction, bioprosthetic valve dysfunction in women (all assessed through 12 months), and moderate or severe prosthesis–patient mismatch at 30 days. From April 2021 through September 2022, a total of 716 patients (mean age, 80 years; 87% women; self-expanding valve, n = 355; balloon-expandable valve, n = 361) were treated at 83 sites in Canada, Europe, Middle East, and the USA. The mean Society of Thoracic Surgeons Predicted Risk of Mortality was 3.3%. The mean (± standard deviation) aortic annulus area was 382 ± 34 mm2. The prevalence of bicuspid aortic valve was 4%. The first co-primary clinical endpoint occurred in 9.4% of patients in the self-expanding valve group and in 10.6% of those in the balloon-expandable valve group [difference −1.2%; 90% confidence interval (CI), −4.9 to 2.5, P < .001 for non-inferiority; hazard ratio, 0.90; 95% CI, 0.56–1.43]. The second co-primary endpoint (bioprosthetic valve dysfunction at 12 months) occurred in 9.4% of patients in the self-expanding valve group and in 41.6% of those in the balloon-expandable valve group (difference −32.2%; 95% CI, −38.7 to −25.6; P < .001 for superiority). The aortic valve mean gradient at 12 months was 8 mmHg in the self-expanding valve group vs. 16 mmHg in the balloon-expandable valve group, and the mean effective orifice area was 1.99 cm2 in the self-expanding valve group vs. 1.50 cm2 in the balloon-expandable valve group. As compared with the balloon-expandable valve group, the self-expanding valve group showed lower 12-month rates of haemodynamic structural valve dysfunction (3% vs. 32%), non-structural valve dysfunction (6% vs. 18%), bioprosthetic valve dysfunction in women (10% vs. 43%), and moderate or severe prosthesis–patient mismatch at 30 days (11% vs. 35%). Both groups showed low incidence of clinical valve thrombosis (0.3% vs. 0.3%), endocarditis (0.6% vs. 2.3%), and aortic valve re-intervention (0.9% vs. 0.6%). The rate of permanent pacemaker implantation at 30 days was 12% in the self-expanding valve group and 8% in the balloon-expandable valve group. Transcatheter aortic valve implantation has revolutionized the management of patients with severe aortic stenosis, becoming a standard treatment option for a wide range of patients, from inoperable ones to those with high to intermediate and even low surgical risk.2 Despite uprising substantial advances, including a newer generation of devices, advanced pre-procedural imaging, and increasing operator expertise, some anatomical and technical aspects may still influence the success of TAVI procedures.2 Aortic valve annular size is one of the most relevant anatomic features impacting haemodynamic and clinical outcomes after TAVI.3 In particular, patients with small aortic valve annulus, accounting for approximately one-third of all TAVI recipients, represent a unique and challenging population, with a remarkable preponderance of women, frequently under-represented in clinical trials.4 These patients have an increased risk of suboptimal valve haemodynamics, including prosthesis–patient mismatch (a condition occurring when the effective area of a prosthetic valve is inferior to that of a native normal valve), which in turn may result in worse clinical outcomes.5 Evidence from observational studies, including the recent TAVI-SMALL and OPERA-TAVI Registries,6,7 indicated better haemodynamic performance of transcatheter self-expanding valves with a supra-annular design in patients with small annulus, as compared with intra-annular self-expanding valves and balloon-expandable valves.8 The SMART trial is the first RCT to compare the two most currently used TAVI prostheses in patients with small aortic annulus.1 Major strengths of the trial are the enrolment of a predominantly female population (almost 90% of patients), a finding that is unique among device-based cardiology trials,4 and the inclusion of patients across the entire spectrum of surgical risk, including those with bicuspid aortic valves. Compared with the balloon-expandable valve, the self-expanding supra-annular valve was non-inferior with respect to the clinical co-primary composite endpoints. This result should, however, be interpreted in light of the lower-than-expected event rate (10% observed vs. 16% assumed for sample size calculation), and the generous non-inferiority margin (i.e. 8 percentage points). The self-expanding valve was superior to the balloon-expandable valve with respect to bioprosthetic valve dysfunction, which might be associated with adverse clinical outcomes in the mid- or long-term follow-up.9 The relatively small sample size, lower-than-expected event rates, and short follow-up severely limited the statistical power for detecting differences in clinical outcomes related to impaired haemodynamics, and the planned 5-year follow-up of the trial will be more informative on this issue. Of note, the definition of haemodynamic structural valve dysfunction used in the SMART trial included only an increased aortic valve mean gradient (≥20 mmHg) without considering any morphological valve change, as indicated by the VARC-3 consensus.10 The actual impact of an elevated residual gradient without valve deterioration on patients’ clinical outcomes is controversial. Echocardiographic gradients are influenced by a number of factors, including patient haemodynamic status, blood viscosity, Doppler alignment, left ventricular ejection fraction, and the pressure recovery phenomenon.11 Interestingly, recent evidence indicates that Doppler-derived gradients could be consistently overestimated after TAVI as compared with invasive-derived gradients, especially in patients treated with a balloon-expandable valve and with smaller prosthesis.11 It remains therefore unknown whether the second co-primary endpoint of the trial would have been different if invasive gradients, rather than Doppler gradients, had been measured. The rate of moderate or severe prosthesis–patient mismatch at 30 days was substantially lower (i.e. absolute difference, −25%) in the self-expanding valve than in the balloon-expandable valve. This somewhat expected finding is largely explained by the supra-annular position of the leaflets in the self-expanding Evolut valve, where the internal stent orifice area and valve effective orifice area are larger than at the annular level, which is the site of balloon-expandable valve functioning. Recent studies and meta-analyses suggest that severe, but not moderate, prosthesis–patient mismatch is associated with unfavourable clinical outcomes, including higher mortality.5 Of note, if considering only severe prosthesis–patient mismatch, the incidence was less than 10% with both self-expanding and balloon-expandable valves in the SMART trial (absolute difference, −5% at 30 days). In conclusion, the SMART trial showed that, in a population predominantly represented by female patients with symptomatic aortic stenosis and small aortic annulus, TAVI with a self-expanding, supra-annular valve provides better haemodynamic performance compared with a balloon-expandable valve, with non-inferior clinical outcomes up to 1 year. The planned 5-year follow-up will be key to verify whether this superior haemodynamic performance has any impact on long-term clinical outcomes. R.V. received consulting or lecturing fees from Abbott Vascular, Abiomed, Amgen, Daiichi Sankyo, Medtronic, and Terumo. D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work.

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