Weekly Journal Scan: Pushing the boundaries of transcatheter aortic valve implantation in asymptomatic patients with severe aortic stenosis

This comment refers to ‘Transcatheter Aortic-Valve Replacement for Asymptomatic Severe Aortic Stenosis’, published in N Engl J Med. https://doi.org/10.1056/NEJMoa2405880. The Evaluation of TAVR Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis (EARLY TAVR) trial was an industry-sponsored, prospective, multicentre, open-label, randomized controlled trial (RCT) aiming to test the superiority of transcatheter aortic valve implantation (TAVI) using a balloon-expandable valve (SAPIEN 3 or SAPIEN 3 Ultra, Edwards Lifesciences) over clinical surveillance among elderly patients with asymptomatic severe aortic stenosis.1 Patients 65 years of age or older with asymptomatic severe aortic stenosis, defined according to current guidelines,2,3 with a suitable anatomy for transfemoral TAVI were eligible. Asymptomatic status was confirmed by a negative treadmill stress test in the vast majority of patients (91%). Exclusion criteria included a Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score > 10% (range from 0% to 100%, with higher scores indicating a greater risk of death within 30 days after surgery), a left ventricular ejection fraction (LVEF) < 50%, or any other class I indication for aortic-valve replacement based on current guidelines.2,3 Patients randomized to the clinical surveillance group received standard care based on current guidelines, and those who developed symptoms or other indications for aortic-valve replacement during follow-up were evaluated by a case review board and treated with TAVI. The primary endpoint was a composite of death from any cause, stroke, or unplanned hospitalization for cardiovascular (CV) causes that included any aortic-valve intervention in the clinical surveillance group within 6 months after randomization or aortic-valve re-intervention in the TAVI group within 6 months after the trial procedure. Secondary endpoints were: (i) a favourable outcome at 2 years, defined as being alive with a Kansas City Cardiomyopathy Questionnaire (KCCQ) score of at least 75 (scores range from 0 to 100, with higher scores indicating fewer physical limitations and a greater feeling of wellness) without a decrease >10 points from baseline; (ii) a composite of integrated measures of left ventricular and left atrial health at 2 years; (iii) LVEF change from baseline to 2 years; (iv) new-onset atrial fibrillation; and (v) a composite of death or disabling stroke. Echocardiographic images (both at baseline and follow-up) were analysed by an independent core lab. From a total of 1578 patients screened between March 2017 and December 2021 at 75 sites in USA and Canada, 901 patients (mean age, 76 years; 31% female; mean STS-PROM score, 1.8%) were eligible and randomized in a 1:1 ratio to TAVI (n = 455) or clinical surveillance (n = 446). A bicuspid aortic valve was present in 8% of cases. Patients randomized to TAVI underwent the transfemoral procedure after a median time of 14 days [interquartile range (IQR), 9–24]. After a median follow-up of 3.8 years (IQR, 2.8–5.0), the incidence of the primary endpoint was significantly lower in the TAVI than in the clinical surveillance group [27% vs. 45%, respectively; hazard ratio (HR), .50; 95% confidence interval (CI), .40–.63; P < .001]. Death from any cause occurred in 38 patients (8%) in the TAVI group and in 41 patients (9%) in the clinical surveillance group (HR, .93; 95% CI, .60–1.44). In the latter group, 11 deaths occurred before conversion to aortic-valve replacement. Stroke occurred in 4% of patients in the TAVI group and in 6% of those in the clinical surveillance group (HR, .62; 95% CI, .35–1.10). Unplanned hospitalizations for CV causes were significantly less frequent in the TAVI group than in the clinical surveillance group (21% vs. 42%, respectively; HR, .43; 95% CI, .33–.55). In the clinical surveillance group, 87% of patients underwent aortic-valve replacement during follow-up, after a median time from randomization of 11 months (IQR, 5.0–19.7). A favourable outcome at 2 years was more frequent in the TAVI group than in the clinical surveillance group (87% vs. 68%, respectively), as were the integrated measures of left ventricular and left atrial health (48% vs. 36%, respectively). No differences in LVEF change at 2 years and in the rate of new-onset atrial fibrillation were observed between the two groups. In the TAVI group, the rates of periprocedural CV death, stroke, life-threatening/disabling or major bleeding, and new permanent pacemaker implantation were 0%, .9%, 2.5%, and 5.7%, respectively. Aortic stenosis is the most common valvular heart disease in Western countries with a prevalence of 2%–5% among adults 65 years of age or older, and carries high mortality risk across all severity degrees if left untreated, approaching 50% at 4 years in patients with severe stenosis.4 Increased operator experience, technical advances, and excellent performance in RCTs have broadened the indications of TAVI, with a progressive implementation of this treatment strategy in patients at intermediate or even low surgical risk.5 While symptomatic severe aortic stenosis has an undisputed indication for intervention, asymptomatic patients generally enter a watchful waiting follow-up in which intervention is triggered by the development of symptoms or systolic LV dysfunction.2,3 Current guidelines indicate intervention in patients with symptomatic severe aortic stenosis with a class I recommendation, while they recommend considering intervention (class IIa) in selected asymptomatic patients with LVEF < 55% without any other cause, a positive stress test, or other echocardiographic and/or laboratory high-risk criteria (e.g. very severe aortic stenosis, severe valvular calcifications, and markedly elevated B-type natriuretic peptide levels).2,3 Potential benefits of early intervention include reduced mortality, reduced rehospitalization, quality of life improvement, and prevention of occurrence or progression of cardiac damage.6 Recently, early intervention in patients with asymptomatic severe aortic stenosis has gained new attention after the results of two small RCTs showed a benefit of early surgical aortic-valve replacement (SAVR), as compared with a conservative strategy, with respect to hard clinical outcomes.7,8 The EARLY TAVR trial is the first RCT comparing TAVI with clinical surveillance among asymptomatic patients with severe aortic stenosis.1 The observed 50% reduction in the primary endpoint after a median follow-up of 3.8 years was largely driven by a reduction in unplanned hospitalization for CV causes, that in turn included aortic-valve interventions in the clinical surveillance group (over half of unplanned hospitalizations) or re-interventions within 6 months. During the first semester of follow-up, about one-fourth of patients randomized to clinical surveillance underwent aortic-valve replacement, and ∼40% of these patients were admitted with advanced or acute signs and symptoms, a finding that is in line with data from previous observational studies,9 yet to be interpreted in light of the open-label design of the trial. Almost 90% of patients in the clinical surveillance group underwent aortic-valve replacement during follow-up. This strict surveillance may not be reproducible in the real world, particularly in healthcare systems in which aortic stenosis is undertreated.10 The mortality rate was not different between the two groups, which is not completely unexpected given the design of the study, and was lower than that observed in previous RCTs of early SAVR in asymptomatic patients with severe aortic stenosis.7,8 There might be several explanations for this finding, including the high intensity of clinical surveillance, the less invasive nature of TAVI as compared with SAVR, and a relatively lower surgical risk of the EARLY TAVR population. In this regard, it is important to note that asymptomatic patients were identified almost systematically by a negative treadmill stress test, which represents a major strength of the trial. Two secondary endpoints worth noting were a favourable outcome (which included quality of life measures) and a composite of integrated measures of left ventricular and left atrial health at 2 years, both of which were more frequently observed in the early TAVI group than in the clinical surveillance group. In fact, even during the asymptomatic phase of aortic stenosis, the left ventricle and atrium are constantly exposed to progressive increases in pressure overload, with silent cardiac damage (both structural and functional) aggravating over time. It is often challenging for patients and clinicians to interpret symptoms of aortic stenosis, and delayed treatment may result in irreversible cardiac damage, such as myocardial fibrosis, with suboptimal clinical outcome.6 A limitation of the EARLY TAVR trial was the relatively short follow-up compared to other RCTs of early intervention in asymptomatic aortic stenosis.7 Of note, in the Randomized Comparison of Early Surgery versus Conventional Treatment in Very Severe Aortic Stenosis (RECOVERY) trial, the survival curves diverged after 4 years, with a net separation after 6 years of follow-up.7 Other limitations were the enrolment of a predominantly White population (96% of patients) and the relatively scarce representation of the female sex, which limit the generalizability of the results. Finally, the results apply to a population of low-risk elderly patients, so that they should not be extrapolated to other risk or age categories. Performing TAVI at an earlier stage implies that intervention is performed in patients with longer life expectancy, and this should always be put in a lifetime management perspective, taking into account a number of additional issues, including valve durability and risk of conduction disorders,11 paravalvular leak, re-intervention, and treatment of concomitant coronary artery disease.12 Furthermore, the potential impact of extending TAVI indication to asymptomatic patients on procedural waiting lists and use of healthcare resources needs to be considered. In conclusion, the EARLY TAVR trial showed that, in a selected population of low-risk patients with asymptomatic severe aortic stenosis, TAVI reduces the risk of unplanned hospitalizations for CV causes, which are often related to advanced or progressive symptoms requiring valve intervention. While the absence of benefit of early TAVI on mortality (up to ∼4 years) is reassuring about the appropriateness of the current practice of clinical surveillance, this trial underscores the importance of a strict follow-up and procedural planning in order to guarantee a prompt treatment of this rapidly progressive disease. R.V. received consulting or lecturing fees from Abbott Vascular, ABIOMED, Amarin, Amgen, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Novartis, and Philips, outside the submitted work. D.P. received lecturing fees from Daiichi Sankyo, outside the submitted work.

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