Valvular heart diseases represent a substantial public health concern, with a considerable prevalence of aortic stenosis (AS) estimated at approximately 0.4% of the general population.1 Over the course of the past two decades, transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of severe aortic stenosis. In many countries, the indications have been extended to low surgical risk patients; however, the presence of bicuspid aortic valve (BAV) remains a factor that often favors surgical aortic valve replacement (SAVR) over TAVR.2,3 The rates of moderate to severe paravalvular leak (PVL), annular rupture, cerebral ischemic events are still significant in BAV patients compared with tricuspid aortic valve (TAV) patients undergoing TAVR.4, 5, 6 Additionally, as found in general TAVR population, rates of complete heart block and permanent pacemaker implantation are higher in BAV patients compared with SAVR.7

Optimal sizing of transcatheter heart valves (THV) is crucial in TAVR procedures. Due to the distinctive anatomical characteristics of patients with BAV, modifications to conventional annular sizing strategies might be necessary.8 Several sizing strategies based on multi slice computed tomography (MSCT) and supra-annular structures (raphe, calcium and fusion), such as the inter-commissural distance measurement, the LIRA method and the CASPER algorithm, have been described as supplementary considerations for TAVR sizing in patients with BAV.9, 10, 11 However, randomized controlled trials may still be needed to determine whether an annular or a supra-annular method should be adopted. Most current studies have been based on patients with Type 1 bicuspid aortic valves due to their higher prevalence. There is currently a lack of specific sizing strategies for patients with Sievers type 0 bicuspid AS. Based on our clinical experience, the “waist sign” is frequently observed during balloon pre-dilatation, indicating that supra-annular structures may play a crucial role in anchoring the prosthesis. To address this, we present a novel Down Sizing Strategy (DSS) for TAVR in patients with Sievers type 0 bicuspid AS that evaluates supra-annular structures during balloon pre-dilatation. In this prospective, multi-center, single-blinded, randomized controlled study, we aim to test the superiority of Down Sizing Strategy based on the assessment of supra-annular structures, in comparison to the Standard Sizing Strategy (SSS) centered on annular measurements, in patients with Sievers type 0 bicuspid AS undergoing TAVR with a self-expanding valve.

Our study aims to compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. The working hypothesis of this study is that the Down Sizing Strategy will demonstrate superiority at the 30-day composite endpoint which includes VARC-3 defined device success,12 absence of permanent pacemaker implantation, and absence of new-onset complete left bundle branch block.

This is a prospective, multi-center, superiority, single-blinded, randomized controlled study. The complete clinical trial sites are listed in the protocol Appendix. Patients with severe type 0 bicuspid AS will be randomly assigned to either the Down Sizing Strategy group or the Standard Sizing Strategy group at a 1:1 ratio. Repositionable and recapturable self-expanding valves (Evolut PRO) will be implanted in both groups. Safety and efficacy assessments will be conducted at discharge, at one month post procedures, and subsequently on an annual basis, extending up to a five-year follow up period. An overview of the study flow can be found in Figure 1. The steering committee will be responsible for study design and execution. An independent data and safety monitoring board will review interim analysis and safety results. All the committees included in this study are listed in the protocol Appendix.

This study will be conducted in compliance with the latest version of the Declaration of Helsinki, the Clinical Trial Agreement and Clinical Investigation Plan, as well as relevant laws and regulations of China, to ensure the protection of subjects' rights and welfare. Prior to initiation of any protocol beyond standard of care, informed consent will be obtained from each patient, and study participants will retain the right to withdraw from the study at any time, irrespective of the reason.

To be considered eligible, patients must satisfy the following criteria: symptomatic severe aortic stenosis necessitating TAVR; age over 65 years or between 60 and 65 years with a high surgical risk; CT-confirmed Sievers type 0 bicuspid aortic valve with a native aortic annulus diameter ranging from 20 mm to 26 mm (inclusive of both values). Severe bicuspid AS is defined as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. The primary exclusion criteria encompasses patients with active sepsis, acute myocardial infarction (AMI) within one month, stroke or transient ischemic attack within three months, contraindications to antithrombotic medications, as well as the presence of hypertrophic obstructive cardiomyopathy, severe mitral stenosis requiring surgical intervention, or significant aortic disease. The criteria listed in Table 1 will be used to screen potential candidates. Those who fulfill all inclusion criteria and meet none of the exclusion criteria will be enrolled upon providing their written informed consent.

The CT core laboratory (The Second Affiliated Hospital Zhejiang University School of Medicine) will analyze the CT imaging data of all patients awaiting screening from each center. The screening committee will then review the data to determine whether patients are eligible for inclusion in the study. All symptomatic severe aortic stenosis patients who did not meet the inclusion criteria or declined participation in the trial will be recommended alternative TAVR prostheses or surgical treatment based on maximizing clinical benefit.

Statistician and participants are blinded to the grouping assignment. The participants underwent anesthesia during the procedure, and are unaware of the treatment method they received. The statistician responsible for interim analysis and outcome assessing are also blinded to the allocation by not granting access to randomization code nor intraoperative records. Moreover, the cite investigators and personnel responsible for follow-up are committed to limiting their involvement in data measurement and analysis, for they are not blind to the treatment allocation.

Patients will be randomly assigned to either the DSS group or the SSS group in a 1:1 ratio. A stratified block randomization method with a block size of four is utilized, with stratification by site. And the actual therapeutic plan that patients receive is determined by an interactive voice response system/interactive web response system (IVRS/IWRS).

The Medtronic CoreValve™ Evolut™ PRO System has been approved for use in AS patients in China. And the system is comprised of the following three components:

CoreValve™ Evolut™ PRO Transcatheter Aortic Valve. The valve sizes used in this study were 23mm, 26mm, and 29mm.

EnVeo™ PRO Delivery Catheter System.

EnVeo™ PRO Loading System.

In this study, a standardized procedural workflow has been implemented across all participating centers, with comprehensive training provided to ensure mitigation of outcome variations attributable to center and operator disparities. Every subject will undergo a preoperative MDCT examination to measure the valve annulus size and to determine the size of the pre-dilation balloon, fluoroscopy angle, and valve release angle. Patients with a mean perimeter-derived annular diameter measuring ≥20mm and ≤23mm will receive a 20mm balloon for pre-dilation. In cases where the annulus size falls within >23mm and ≤26mm, a 23mm balloon will be selected for the pre-dilation.

In the SSS group, the selection of the valve size for implantation will be based on the annular size: a 26mm valve for mean perimeter-derived diameter between ≥20mm and ≤23mm, and a 29mm valve for annular size between >23mm and ≤26mm. Conversely, in the DSS group, the valve size for implantation will be determined by both the annular size and balloon pre-dilatation results. A valve one size smaller will be implanted if the “waist sign” manifests along with less than mild regurgitation during pre-dilatation.

The valve release angle will be determined based on the preoperative CT measurement, with a target implant depth of 3mm for both groups. In cases where the implant depth is not appropriate, the valve will be retrieved and repositioned. In situations where there is an incomplete valve expansion or more than mild paravalvular leak, balloon post-dilation will be performed.

The sizing strategies for both groups are depicted in Figure 2. It is essential to note that both groups will use the same prosthetic valve system, follow the same surgical procedure, adhere to the same visit schedule, and undergo identical clinical observations and auxiliary examinations, except for differences in prosthetic valve sizing.

The primary endpoint of this study is the composite rate at 1 month, which includes VARC-3 defined device success,12 absence of permanent pacemaker implantation attributable to high-degree atrioventricular block, and absence of new-onset complete left bundle branch block (defined as QRS duration ≥ 120ms).

The secondary endpoints are as follows: (1) Incidence of new-onset complete left bundle branch block within one month post procedure; (2) Incidence of permanent pacemaker implantation within one month post procedure; (3) Incidence of VARC-3 defined device success at one month post procedure; (4) Incidence of moderate and higher-grade paravalvular leak at one month post procedure.

We pre-specified additional endpoint measures at various time points including perioperative, postoperative at 1 month, 1 year, and annually thereafter: All-cause mortality, Stroke, Permanent pacemaker implantation, Incidence of moderate and above paravalvular leak, Re-admission, procedural details, and complications, Structural valve deterioration, Kansas City Cardiomyopathy Questionnaire (KCCQ), NYHA classification, 6-minute walk test (6MWT).

Electrocardiogram and Echocardiograms were interpreted by blinded independent core labs (Fangtian He from Sir Run Run Shaw Hospital and Fang Fang from Department of Echocardiography of Anzhen Hospital, respectively).

Clinical follow-ups will be performed at one month and annually, up to five years post-procedure. All efforts will be undertaken to ensure patient's adherence to the established protocol and all scheduled follow-up appointments. The follow-up data of the study participants will be utilized for further subgroup analysis. The timetable for data collection is presented in Table 3.

The primary efficacy endpoint of the study is the composite incidence of VARC-3 defined device success, absence of permanent pacemaker implantation, and absence of new-onset complete left bundle branch block at 30 days after treatment. The composite event rate is estimated to be 70% in the DSS arm based on the TORCH study (NCT02803294) and 50% in the SSS arm based on the BEAT study (40% increase in risk ratio).13 We estimated that a sample of 206 patients (103 patients on each arm) would provide the trial with 80% power to show the superiority with a superior margin (δ=0) at a one-sided significance level of 0.025, accounting for an expected 10% dropout rate.

Since actual event rates may differ from the assumed event rates, an adaptive sample size re-estimation will be conducted using the “promising zone” methodology14 by blinded study statistician when 50% subjects have been enrolled. In brief, the conditional power (CP) is calculated based on actual event rates. If the CP falls within a pre-defined "promising zone," indicating that the actual event rates are lower, the sample size will be increased to achieve a final conditional power of 0.8 without exceeding the predetermined maximum sample size of 370 cases. If the CP falls within the "unfavorable zone" or "favorable zone", the sample size will remain unchanged. The calculation of sample size is performed utilizing the PASS® software version 15.05.

Continuous variables will be presented as means with standard deviations, medians with inter-quartile ranges or minimum and maximum values. Categorical variables will be reported as frequencies and percentages. The efficacy analysis will be carried out on the basis of Modified Intention-to-Treat (mITT) and Per Protocol Set (PPS). The mITT set includes patients who are randomized with attempted implant using the Evolut PRO system. The analysis is carried out by the randomized groups, regardless of the actually accepted procedural. All baseline demographic data analysis will be performed on mITT set. The safety evaluation will be conducted on the Safety Set (SS), including procedural complications, adverse events, and severe adverse events. All summaries and statistical analyses will be generated using SAS® version 9.4 or later.