Study protocol for an international prospective non-randomized trial evaluating the long term outcomes of Sutureless Aortic Valve Replacement Versus Stented Aortic Valve Replacement for Aortic-Valve Stenosis in Patients at Risk to Severe Valve Obstruction: The SAVI-AVR trial

Study protocol for an international prospective non-randomized trial evaluating the long term outcomes of Sutureless Aortic Valve Replacement Versus Stented Aortic Valve Replacement for Aortic-Valve Stenosis in Patients at Risk to Severe Valve Obstruction: The SAVI-AVR trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Study protocol for an international prospective non-randomized trial evaluating the long term outcomes of Sutureless Aortic Valve Replacement Versus Stented Aortic Valve Replacement for Aortic-Valve Stenosis in Patients at Risk to Severe Valve Obstruction: The SAVI-AVR trial Francesco Nappi, Antonio Salsano, Sanjeet Singh Avtaar Singh, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6251208/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Apr, 2026 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted 8 You are reading this latest preprint version Abstract Background Aortic valve (AV) stenosis (AVS) constitutes the most common major primary valvular pathology requiring surgical or transcatheter intervention in Europe and North America. This condition is increasing in prevalence at a rapid rate, consequent to the ageing population. There exists a range of mechanical interventions for the treatment of aortic valve stenosis (AVS), but there is currently a lack of robust evidence comparing the effectiveness of surgical aortic valve replacement (SAVR) with conventional stented xenograft aortic valve (St-AV) or sutureless aortic valves (Su-AV). The objective of the present study is to make a comparison between the effectiveness and clinical outcomes of SAVR using St-AV or Su-AV in patients with AVS. Methods The conception of the SAVI-AVR trial (NCT:05261204; IRB: 2022011057) is the result of a collaboration between three cardiac surgery centres across two European countries. The SAVI-AVR registry will enrol consecutive patients who have undergone surgical interventions for AVS using sutureless aortic valve implant (Su-AVI) and stented aortic valve replacement (St-AVR). The study period will span from January 2015 to December 2025, encompassing a total of patients who will be enrolled. The primary objective of the research is to assess the differences between the standard surgical approaches Su-AVI and St-AVR. The primary clinical outcome under consideration will be operative mortality and survival. That is to say, the mortality rates recorded within a given time period after the procedure has been completed at 10 years. The present study will also encompass a number of secondary endpoints, including time to explant for structural valve degeneration, occurrence of stroke, necessity for reoperation, readmission due to any cause, and emergence of new-onset atrial fibrillation within 30 days, 1 year, 5 years and 10 years. Additionally, the study will examine the length of primary hospitalization and the presence of poor treatment outcomes. Discussion The hypothesis that the nature of the trials will serve to minimise bias related to institutional volume and surgical experience is postulated. Participating centres are obliged to possess an aortic valve programme, with the capability to ensure adequate postoperative follow-up and management of late complications arising from aortic valve replacement surgeries for AVS. The data that will be collected will provide valuable insight into the comparative effectiveness of various surgical approaches, both standard and advanced, in aortic valve replacement surgery. This will be achieved using Su-AVI and St-AVR. It is further expected that this comprehensive analysis will contribute significantly to the development of robust international guidelines. Trial Registration: Clinical Trial Gov. Com. ID: NCT05261204 IRB. ID: 2022011057 Aortic valve stenosis Surgical aortic valve replacement Sutureless aortic valve implantation Transcatheter aortic valve implantation Figures Figure 1 1. Introduction Aortic valve (AV) stenosis (AVS) is identified as the most prevalent cardiac valve disease necessitating surgical correction [ 1 – 3 ]. The amelioration of aortic valve dysfunction has been demonstrated to significantly enhance patient quality of life and prolong life expectancy [ 4 , 5 ]. Advancements in the design and manufacturing of the novel platform technologies for the treatment of structural heart disease, coupled with the emergence of studies substantiating the safety of the procedures in low-risk populations, have led to a progressive broadening of indications for catheter-based valve implantation. This has encompassed lower-risk patients, in addition to those deemed high-risk candidates for surgical intervention [ 2 , 3 , 6 ]. However, surgical aortic valve replacement (SAVR) remains the procedure of choice for AVS in several clinical settings [ 1 – 3 ]. The impact of age on the risk of reoperation has received only limited attention in research conducted in the context of novel prosthetic valve technology based on rapid deployment techniques and the elimination of anchoring sutures. In the case of sutureless aortic valves (Su-AV), research is yet to be sufficiently extensive in this regard, and there is a paucity of long-term follow-up studies [ 7 – 10 ]. On the contrary, it has been reported by several institutions that the Carpentier-Edwards (CE) pericardial valve has been shown to yield excellent clinical outcomes [ 11 – 14 ]. The valve-related event rate is low at 20 years, and the rate of structural valve deterioration (SVD) is particularly low. In the aortic position, the CE Perimount pericardial bioprosthesis (BP) remains a reliable choice for tissue valves, especially for patients over 60 years of age [ 15 , 16 ]. A recent study demonstrated that the CE Perimount Magna Ease pericardial BP remains a reliable choice for tissue valves in the aortic position. The study revealed that, despite an infrequent rate of explantation due to SVD events at 10 years, and a particularly low rate of moderate or severe SVD based on echocardiographic Valve Academic Research (VARC) Consortium 3 criteria, the bioprosthesis continues to demonstrate reliability [ 17 ]. With regard to the matter of surgical intervention, Su-AVI innovations represent a significant development in surgical technology, marrying the accuracy of surgical implantation with the technological sophistication of transcatheter interventions. These advancements aim to minimise the physiological impact of surgical procedures on patients. In addition, the duration of cardiopulmonary bypass (CPB) and operative time are reduced, simplifying the process of valve implantation. Sutureless devices are similar to transcatheter heart valve (THV) devices in terms of design and conceptualization. These ballon-expandable valves have a stent that exerts a radial force, and cuffs that enhance sealing and mitigate the risk of paravalvular leak. Sutureless aortic valve implant (Su-AVI) has been shown to have certain advantages over transcatheter aortic valve replacement (TAVR). These include the option of removing the diseased native valve, decalcifying the aortic annulus, or removing infected material. In patients with aortic stenosis who are deemed to be at high risk and for whom TAVR is contraindicated due to anatomical reasons or who require concomitant cardiac procedures (e.g. multivalve or combined coronary procedures), Su-AVI has the potential to mitigate the surgical burden by decreasing cross-clamp time and operative duration. In light of the aforementioned factors, it is conceivable that SuAVI could be a suitable option in redo operations involving calcified aortic root [ 18 ]. Furthermore, the simplicity of valve deployment without the necessity for sutures renders the technology a complementary adjunct to minimally invasive approaches, such as hemisternotomy or minithoracotomy, where annulus access may be restricted. (online supplemental material S1) The question of whether these characteristics offer a competitive edge over conventional SAVR remains a subject of debate, with the extant evidence primarily comprising observational studies. Moreover, the surgical community is polarised with regard to the optimal utilisation of these devices. The purported clinical benefit of reducing CPB time is not a consensus amongst healthcare professionals, particularly in light of the financial implications of the devices, which are not supported by long-term follow-up data [ 19 ] In view of the rising use of rapid-deployment techniques, the cardiovascular community has recognised the need for clinical trials to assess the long-term safety and clinical effectiveness of Su-AVI in comparison to sutured bioprostheses. In this context, the prospective non-randomised trial Sutureless Aortic Valve Implant versus Stented Aortic Valve Replacement (SAVI-AVR) was conducted to evaluate the long-term outcomes of treating AVS, with or without concomitant coronary artery disease, compared with conventional stented xenograft prostheses. 2. Methods and analysis SAVI-AVR is a prospective, nonrandomized, controlled, multi-centre trial. Patients are enrolled 1:1 to receive either stented aortic valve replacement (St-AVR) with a commercial bioprosthesis (BP) or Su-AVI. At designated centers, patients will be enrolled in a computed tomography (CT) substudy (online supplementary material S3). During the planned study duration, a total of 1,020 qualified patients will enter the study at up to three trial sites in European countries (two in France and one in Italy) which are actively recruiting patients (Table 1). A CT sub-study (online supplementary material S3) will enrol a total of 100 eligible patients in each arm (St-AVR and Su-AVI). This trial will include an extensive review of patient data. The aim of this initiative is to provide a substantial body of data to inform future clinical research efforts in this area. Data on consecutive patients with AVS will be accurately recorded in a Microsoft Access datasheet (Redmond, Washington, USA). Prespecified baseline, operative and outcome variables will be included in this datasheet. The study will begin in 2014 and patient enrolment is expected to continue through 2025 (with an initial completion date of 30/05/2025). This timeline is subject to the results of the interim analyses that will follow. Institutional review board or local ethics committee approval (IRB 2022011057) will be sought for this trial in accordance with local legislation. The trial is registered at ClinicalTrials.gov (NCT05261204) (online supplementary material S2). 2.1. SAVI-AVR study patient entry criteria 2.1.1. Characterization of patient populations Inclusion criteria for the trial were as follows: patients must have severe, calcific, symptomatic aortic valve disease with or without concomitant coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) and be at low surgical risk for SAVR. In addition, patients must have undergone one of the following surgical approaches: an open surgical approach using either a conventional stented xenograft bioprosthesis (Carpentier-Edwards Perimount Magna Ease [CEPME] bioprosthesis [Edwards Lifesciences]) or Perceval sutureless prosthesis ( LivaNova plc, UK). The database houses information pertaining to the participation of women and minority groups in clinical studies, a matter of significance due to its implications for scientific, ethical and social reasons, in addition to the generalisability of study results. SAVI-AVR is committed to the attainment of scientific results whilst ensuring equitable recruitment of patients irrespective of gender or ethnicity. The SAVI-AVR registry has recruited a minimum of 30% women and 25% minorities. To ensure adequate representation of these demographic groups, the recruitment centres implemented two measures: Firstly, they have to ensure that they document the number of women and minorities selected and then enrolled, in relation to their respective screening and subsequent exclusion protocols. Secondly, they have to ensure that they monitor these records on an annual basis, on behalf of the respective Clinical Centre involved, in relation to the follow-up procedures that are carried out at that particular centre each year. ¨ Aortic valve stenosis severity assessment criteria The pathological basis of AVS is characterised by increased afterload. This is accompanied by progressive left ventricular hypertrophy, valve obstruction and subsequent reduction in systemic and coronary blood flow. Patients usually remain asymptomatic (eg, angina, syncope and/or heart failure) until late in their disease course. However, without intervention, the prognosis remains poor once clinical manifestations become apparent. Survival curves have shown that the time from symptom onset to death is approximately two years in patients with heart failure, three years in those with syncope, and five years in those with angina [20].It has also been documented that in medically treated patients with moderate to severe AVS, the mortality rate after symptom onset is approximately 25% within one year and 50% within two years. In addition, it is noteworthy that more than 50% of deaths in the literature have been of a sudden nature [21]. Assessing the severity of AVS is guided by a range of haemodynamic and natural history data as outlined in the ACC/AHA Guidelines. It is possible to conceptualise AVS as a continuous spectrum [2,3] . Symptom relief and improvement in haemodynamic parameters, global left ventricular (LV) systolic function and reversal of left ventricular (LV) hypertrophy are often seen with improvement in AV obstruction [22,23]. The subsequent table (Table 2) provides a comprehensive overview of the echocardiographic indicators that are utilised for the purpose of evaluating the severity of AVS, as delineated in the 2021 practice guidelines published by the joint ACC/AHA Task Force [3]. ¨ Inclusion criteria · Individuals who have reached the age of 65 years or older at the time of consent. · NYHA Functional Class ≥ II (Supplementary table 1) · The patient exhibits symptoms consistent with severe calcific aortic stenosis, as indicated by the following tissue Doppler transthoracic echocardiography (TTE) criteria: - Jet velocity ≥ 4.0 m/s or mean gradient ≥ 40 mmHg - Aortic valve area (AVA) ≤ 1.0 cm² or AVA index ≤ 0.6 cm² /m² According to the established criteria, qualifying echocardiograms must be conducted within the specified 90-day period prior to the enrollement process. · The aortic valve annulus ranges from 273 millimeters squared to 683 millimeters squared, as measured through three-dimensional imaging techniques, including computed tomography (CT), transesophageal echocardiography (TEE), and magnetic resonance imaging (MRI). Table 3 lists the other inclusion criteria ¨ Exclusion Criteria Candidates exhibiting any of the following conditions will be excluded from the study: · Estimated life expectancy < 24 months. · The AV is characterized by its congenital state, with the presence of either a unicuspid or a bicuspid configuration. Additionally, it may be non-calcified, further contributing to its distinct characteristics. · Severe aortic valve regurgitation (>3+) · Severe mitral valve regurgitation (>3+) · Aortic coarctation · The presence of a pre-existing mechanical or bioprosthetic valve, irrespective of position, is to be noted. It is noteworthy that the inclusion of the mitral ring does not constitute an exclusion. · The presence of one or more of the following criteria serves to diagnose an acute myocardial infarction (MI) ≤ 1 month (30 days) prior to enrollment, with evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. (Supplementary table 2) § Identification of an intracoronary thrombus by angiography · Lventricular dysfunction with left ventricular ejection fraction (LVEF) < 45% · Hypertrophic cardiomyopathy with or without obstruction (HOCM) · The patient demonstrated an inability to maintain tolerance for anti-thrombotic and anticoagulation therapy during and following the valve implant procedure. · The occurrence of a stroke or transient ischemic attack (TIA) within 180 days following the valve implant procedure is a potential complication that should be noted. · The patient exhibited hemodynamic or respiratory instability, necessitating inotropic support, mechanical ventilation, or mechanical heart assistance within 30 days of the initial screening visit. Table 3 lists the other exclusion criteria 2.2. Trial Design and Endpoints The schematic of the trial design is presented in Figure 1. ¨ Primary The primary endpoints encompass operative mortality and survival; that is to say, the mortality rates which are recorded within a given time period after the procedure has been completed. The occurrence of late deaths at a linear rate will be defined as valve-related and non-valve-related deaths within the time period of one, five and ten years following the completion of the procedure. Another of interest is the composite treatment failure endpoint. This comprises cardiac death, reoperation for SVD and time to explant due to SVD. ¨ Secondary A number of key secondary outcomes have been predetermined with a view to managing Type I error and implementing a hierarchical approach to testing. Secondary endpoints of particular pertinence are to be established, incorporating such metrics as the time to explant for structural valve degeneration, the occurrence of stroke, the necessity for reoperation, readmission due to any cause, and the emergence of new-onset atrial fibrillation within 30 days, 1, 5 and 10 years, in addition to the duration of primary admissions and the presence of poor treatment outcomes. Neurological examinations of all patients will be conducted at baseline, and subsequently at 30 days, as well as during scheduled follow-up periods. The neurological examinations, incorporating assessments using the National Institutes of Health Stroke Scale and the modified Rankin Scale, will be performed at 90 days for any patient demonstrating signs of stroke following the procedure. The definition of readmission to hospital encompasses any occurrence related to this study, the valve, or heart failure. The endpoint will be evaluated through a non-inferiority analysis, with a relative non-inferiority margin set at 35%. Secondary endpoints encompassed longitudinal echocardiographic measurement of postoperative aortic valve hemodynamic stability, incorporating AV mean and peak gradients (mm Hg), AV regurgitation grade, AV stenosis (AV orifice area), left ventricular dimensions and function. These parameters were assessed in the context of explant for indications other than SVD and mortality prior to valve explantation. The secondary endpoint also constituted a composite of major adverse cardiac or cerebrovascular events, which were defined as the following: mortality rate, incidence of stroke, subsequent aortic valve surgery, hospitalisation due to heart failure, or increase in New York Heart Association classification by ≥1. These events were observed over the following time periods: 30 days, 1 year, 5 years and 10 years. The Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, a metric ranging from 0 to 100 with higher scores denoting a reduced physical limitation burden and enhanced well-being, was also analysed. This analysis spanned the 30-day period, as well as the 1-year, 5-year and 10-year periods. At the 30-day, 1-year, and scheduled follow-up points, the study team assessed changes in New York Heart Association (NYHA) functional class, six-minute walk distance, and KCCQ summary score. The study also examined secondary safety and efficacy endpoints, with these terms defined in Table 4 . 3. Medical Histories and Physical Assessments Comprehensive medical histories and physical assessments, incorporating parameters such as height, weight, blood pressure, and heart rate. The system will also encompass all medications administered for cardiovascular indications, along with all antithrombotic and anticoagulant medications. ¨ Assessment of Cardiopulmonary Status. The assessment of the cardiovascular and respiratory apparatuses is facilitated by the following methodologies: • The Canadian Cardiovascular Society (CCS) status of angina should be documented, along with a 12-lead ECG. (Supplementary table 2) • The New York Heart Association (NYHA) classification should also be included. (Supplementary table 1) • A comprehensive TTE is conducted, encompassing an evaluation of aortic valve gradients (mean and peak), areas, indices, and the extent of regurgitation. This extensive assessment should also comprise a measurement of left ventricle systolic function (global and segmental).It is imperative that this initial echocardiogram is conducted within 90 days prior to the enrolment process. • Cardiac imaging is an essential part of the pre-enrolment evaluation process. This imaging should include TEE, CT or MRI with 3D reconstruction to determine the area of the aortic valve annulus. This qualifying cardiac imaging must be performed within one year before enrolment, unless contraindicated. • Aortic stenosis and coronary artery disease will be assessed using left and right heart catheterisation. Cardiac catheterisation must be undertaken within one year of enrolment, unless contraindicated. • The SYNTAX score constitutes a mandatory element in the assessment of significant native coronary artery disease (CAD). • A full lung check is vital for patients with a history of respiratory diseases. ¨ Functional Assessment and Evaluation • The Six Minute Walk Test (6MWT) is a clinical evaluation used to assess functional mobility and frailty in patients. The test involves a five-metre walk, grip strength assessment, and a series of activities of daily living (ADL) to evaluate the patient's autonomy and independence. Additionally, laboratory parameters such as albumin levels are monitored to provide a comprehensive health picture. • Quality of life assessments play a pivotal role in evaluating the impact of health conditions on patients' well-being. The Kansas City Cardiovascular Questionnaire (KCCQ) is a patient-reported outcome measure that focuses on symptoms, functionality, and quality of life. • The EuroQol-5D-5L (EQ-5D-5L) is a well-established tool that quantifies health-related quality of life, providing a standardized metric for comparing health states across different populations. The Short Form 36 (SF-36) is a health survey that assesses physical and mental health, providing a comprehensive assessment of health status. ¨ Clinical Laboratory Tests A complete compendium of clinical laboratory tests is provided below. These include white blood cells (WBC), haemoglobin (Hgb), and platelet count. Other tests comprise prothrombin time (PT) or international normalized ratio (INR) and Creatine kinase (CK)/CK-MB and/or troponin. The maximum time frame for these tests is 72 hours prior to the valve implant procedure. ¨ Neurological Assessment and Evaluation The Mini Mental State Examination (MMSE), the National Institutes of Health Stroke Scale (NIHSS), and the Modified Rankin Scale (mRS) are three well-established tools used to assess cognitive function and the severity of neurological impairment in patients with stroke. ¨ Safety · Incidence of serious adverse events · Reoperation for SVD/NSVD and freedom from re-operation in general. ¨ Peri-operative Measures. · Operative time for each procedure. For the standard surgical mitral valve operation, cardiopulmonary bypass (CPB) and cross clamp time are required. · Blood loss and transfusion. 4. Therapeutic Interventions It is recommended that valve implantation should be scheduled to take priority before 14 and 21 days after enrolment for prospective allocation and no later than 30 days after informed consent has been obtained. The date of valve implantation will be considered as day 0. The preliminary encounter (Day 0) is designated for the scheduling of all subsequent encounters and the calculation of visit windows. Patients who undergo either Su-AVI or St-AVR will remain enrolled in the study and will complete it through Year 10, in line with the visits and events delineated in the study procedure and schedule of procedures. On the preliminary day (Day 0) of the valve implant procedure, a thorough review of the patient's cardiovascular system is to be conducted. This review involves the administration of medications designed to regulate cardiovascular function and anti-thrombotic/anti-coagulant therapies. Additionally, an evaluation of potential adverse events will be conducted. The evaluation process will be complemented by a comprehensive transthoracic echocardiogram (TTE) or transesophageal echocardiogram (TEE), as well as a supra-aortic angiogram or TEE, as deemed necessary by the attending medical team. It is recommended that patients participating in the study receive prophylactic therapy against endocarditis in accordance with the recommendations promulgated by the American Heart Association [24,25] As displayed in Table 5 , the recommended anticoagulation/antithrombotic regimen is outlined. 4.1. Standard aortic valve replacement procedure In cases of aortic valve malfunction, two distinct treatment options exist, namely the implementation of synthetic graft prostheses. These options encompass the utilisation of a conventional stented xenograft bioprosthesis and a rapid-deployment, sutureless prosthesis. The concomitant surgical interventions deemed permissible in such cases include coronary artery bypass grafting (CABG), treatment for atrial fibrillation, septal myotomy and aortic root enlargement (see online supplemental material S1 for further details on the procedure). The guidelines do not provide any specifications regarding the utilisation of St-AVR or Su-AVI in the treatment of AVS. This is due to an absence of conclusive evidence that indicates the superiority of one of these interventions in the long term (i.e. following surgery) with regard to survival and the prevention of structural valve deterioration necessitating reoperation. According to ACC/AHA guidelines, transcatheter aortic valve replacement (TAVR) and SAVR are both reasonable options for symptomatic patients aged 65-80 with severe aortic AVS and no anatomical contraindications. The decision must be made on an individual patient basis, balancing survival duration and valve durability. In such cases, TAVR or SAVR is recommended (Class I recommendation, Level of Evidence [LOE]: A). For patients with severe aortic valve stenosis (AVS) over 80 or younger with a life expectancy of less than 10 years and no anatomical contraindication to transfemoral TAVR, transfemoral TAVR is recommended over SAVR (Class I recommendation, Level of Evidence [LOE]: A) (Table 6) [3] . The latest ESC/EACTS Guide to the Management of Valvular Heart Disease recommends TAVI for patients over 75 or at high risk of mortality. STS-PROM/EuroSCORE II >8% or deemed unsuitable for surgery (Class I recommendation, Level of Evidence [LOE]: A). In contrast, SAVR is recommended for low-risk patients under 75 (STS-PROM/EuroSCORE II <4% or unsuitable for TAVI) (Table 6) [2]. As illustrated in Table 6 , the timing and advice for patients deemed suitable for SAVR or TAVR, categorised as COR 1 and LOE A or B, is outlined. ¨ AV replacement using conventional stented xenograft bioprosthesis (St-AVR) For patients undergoing SAVR, the standard of care as outlined by the institution dictates the usage of a bioprosthetic surgical valve and associated components that are commercially available. The CEPME is constituted of three leaflets, which are made of bovine pericardial tissue. These leaflets are mounted beneath a flexible cobalt-chromium stent. In comparison with the preceding Perimount and Magna valves, this model is distinguished by its reduced profile, its narrower sewing ring, and the incorporation of the Thermafix anti-calcification process (Edwards Lifesciences; Irvine, CA, USA) ( see online supplementary material S1 ). ¨ AV replacement using rapid deployment sutureless aortic valve implant (Su-AVI) The Perceval sutureless prosthesis (manufactured by LivaNova plc, a United Kingdom-based enterprise) is intended for use in patients diagnosed with severe AVS, with the aim of improving their quality of life. To minimise the impact of selection bias, patients were required to undergo a CT scan during the enrolment phase prior to the implantation of the Su-AVI. The purpose of the scan was threefold: firstly, to confirm the eligibility for the current sutureless valve implantation; secondly, to ascertain the suitability for the proposed surgical access (full sternotomy or ministernotomy); and thirdly, to reach a decision regarding an isolated or concomitant procedure. The use of a right anterior minithoracotomy was precluded due to the variable experience of the centres with this procedure, as well as its unsuitability for the purpose of serving as a comparator to the standard valve. Further elucidation on the sutureless valve and implantation procedure may be consulted in the supplementary material ( see online supplementary material S1 ). 5. Endpoint Measurement 5.1. Perioperative Measures The ensuing parameters are to be measured: operative time, cardiopulmonary bypass time, cross-clamp time, blood loss and transfusions. ¨ Cardiopulmonary bypass parameters The prospective collection of patient data will encompass the duration of myocardial ischaemia, cardiopulmonary bypass and retrograde or antegrade cardiac cardioplegia perfusion. ¨ Blood loss and transfusions The documentation of transfused red blood cell unit numbers is mandatory. A streamlined modification of the E-CABG perioperative bleeding classification will be adopted [26] ,which has been demonstrated to be commensurate with the Universal Definition of Perioperative Bleeding [27] in terms of predicting early mortality [28]. Significant bleeding is outlined as the transfusion of a minimum of four units of red blood cells during and after the procedure and/or reoperation due to excessive intra-thoracic bleeding. (Online supplementary table 3) ¨ Reoperation for bleeding The designation "reoperation for bleeding" is employed to denote any instance in which the sternum has been left open and subsequent surgery is required in order to address severe bleeding. It is of paramount importance to emphasise that instances of reopening the chest for haemodynamic instability without excessive bleeding, and pericardial or pleural puncture or chest tube placement for the retention of blood, do not fall under the classification of reoperations for bleeding . 5.2. Post Procedure Follow Up Visit and Measures The post-implantation period is defined as the 48 hours following the patient's departure from the catheterisation laboratory/operation theatre. Study patients will be subjected to continuous monitoring on a clinical, haemodynamic and electrocardiographic basis during catheterisation for all local, systemic adverse events and complications. Following completion of the implantation procedure, all study patients will be monitored in accordance with the institution's standard of care and will be subject to follow-up in accordance with the institution's standard of care. The following information (Table 7) will be collected during the postoperative period, which includes discharge, and at subsequent follow-up visits at 30 days, 6 months, 12 months, and 2 to 10 years post-surgery. Discharge is the date and time a patient is released from care. For patients discharged within 48 hours of leaving the catheterisation laboratory or surgical suite, repeat tests collected during the post-procedure period do not need to be done again for discharge. If discharged on a weekend or public holiday, assessments may be conducted on the previous weekday. The period following valve implantation, which is defined as the 30-day postoperative visit window, commences on the day of the procedure and extends for a period of +14 days. The six-month follow-up visit is scheduled to take place from the initial visit date, while the 12-month postoperative follow-up evaluation visit window is set at +30 days. This is calculated from the valve implant date on the initial visit. ¨ SVD definition SVD is defined by the deterioration of the leaflets or supporting structures of a bioprosthetic valve, which can result in thickening, calcification, tearing and disruption of the prosthetic valve materials. This leads to valve dysfunction. The underlying mechanisms of SVD remain to be fully elucidated, although several hypotheses have been postulated to date. These include tissue disruption or thickening due to mechanical stress and abnormal shear stresses; collagen fibre disruption; and tissue calcification. SVD excludes other forms of clinical valve abnormality not attributable to valve tissue deterioration. These include patient-prosthesis mismatch, device malposition, paravalvular regurgitation and abnormal frame expansion, although these may be associated with early SVD. As illustrated in Table 8 , the stages of bioprosthetic valve deterioration is demonstrated according to the stipulated recommendations of VARC-3, with a focus on the categorisation of stent and stentless xenograft cases. [29] Readers are directed to supplemental material S1 , in which the potential risks associated with SVD is documented. ¨ Functional Status · MACE (Major Adverse Cardiac Events) MACE is specified as an unweighted composite score. It consists of the following components • Death • Stroke • Aortic valve re-intervention • Worsening heart failure (+1 NYHA Class) • CHF hospitalization · New York Heart Association (NYHA) Classification The determination of functional status is achieved through the utilisation of the NYHA classification scale. (Supplementary table 1) · Angina Class The classification of angina is determined in accordance with the Canadian Cardiovascular Society Classification (CCSC) [30]. (Supplementary table 2) · Re-operation A rigorous and comprehensive documentation of all re-operations will be performed, with particular attention allocated to aortic valve SVD/NSVD procedures. A time-to-event analysis will be utilised to evaluate the freedom from re-operation. · Peak VO2 The patients' functional status will be evaluated by measuring the maximal oxygen uptake (VO2 peak) through cardiopulmonary exercise testing. This will be conducted at pre-specified intervals in patients without contraindications. The exercise test will be administered uniformly to all patients, with a consistent verbal prompting protocol used to encourage them to exercise. If patients can't reach an RER ≥ 1.0, Borg's CR10 RPE scale will be used to assess exertion level every 2 minutes during the study. The RPE scale will be used with instructions for all exercise tests and cards showing the scale will be given to each patient. Cardiopulmonary exercise testing will follow a standard protocol and will be interpreted by the cardiologist in charge at each centre. · Neurocognition The study's primary objective is to compare treatment groups using a range of neurocognitive assessments. These include the Hopkins Verbal Learning Test, Trailmaking Tests A and B, MCG Complex Figures, the Boston Naming Test, Digit Span, and Digit Symbol Substitution Test. Clinical site staff will conduct the tests. Experienced neuropsychologists will train them. Neurology specialists will score the tests. ¨ Hospitalization · Index Hospitalization The length of stay for the index admission will be measured and subsequently disaggregated according to the number of days spent in the intensive care unit. Furthermore, the discharge location will be documented. · Readmission Readmission ratios will be calculated for the initial 30 days following the procedure, as well as for the duration of the subsequent follow-up period. Hospitalisation data will be categorised for all conditions, including heart failure readmissions. To ascertain whether a readmission is heart failure related, at least two of the following signs and conditions of acute decompensated heart failure must be observed: • Dyspnea felt related to HF • Administration of vasodilators, intravenous diuretics or inotropes • PCWP or LVEDP > 18 mmHg • On physical examination, rales may indicate the presence of pulmonary edema or pulmonary vascular congestion as seen on X-ray. The investigator will classify all readmissions, which are then reviewed by the cardiologist overseeing the patient's hospitalisation. · Days Spent Alive and Outside of Hospital The objective of the study is twofold: firstly, to compare the total number of days alive and out of the hospital between the treatment groups; and secondly, to determine the percentage of days out of the hospital in relation to the total days alive post-procedure. · Appropriateness of revascularisation Before surgery, coronary arteries are checked to see if they are suitable for bypass. Afterwards, it is very important to closely monitor these arteries. To identify regions receiving coronary flow, the following should be used: LAD proximal, LAD distal, proximal diagonal, distal diagonal, proximal circumflex, distal circumflex, distal dominant circumflex, right posterolateral, and right posterior descending. ¨ Quality of Life As previously outlined in Section 2.3 on the assessment of cardiopulmonary status, quality of life assessments have been thoroughly documented. ¨ Adverse Events Su-AVI is not without its potential risks. The inherent risks associated with the overall procedures themselves are due to SAVR and general anaesthesia. In addition to these, there are risks unique to the use of the study valve and its delivery systems. The reader is referred to supplementary table 9 , where the potential risks associated with anaesthesia and Su-AVI procedures are reported. Adverse events (AEs) are delineated as any medically undesirable incident, unintended disease or injury, or aberrant clinical symptom (including atypical laboratory findings) in patients, users, or other subjects, irrespective of their association with the investigational medical device. AEs may be reported by patients, either on their own initiative or at the prompting of the Investigator or their designee. They may also be identified through observation by the Investigator, the CEC, the Safety Team, or the Monitoring Team. The AEs to ascertain their relationship to the device and/or implant procedure, subsequently categorising them as related or unrelated to serious criteria based on their gravity. Should an AE be adjudged to have occurred, the Investigator is obligated to obtain all information necessary to complete the AE form. Additionally, patients are strongly advised to contact both the Investigator and/or the Study Coordinator should they experience significant adverse events occurring between scheduled study visits (see Table 10). · Reporting of Serious Adverse Events Investigators conducting NHLBI-supported clinical studies must report all serious adverse events (protocol-defined and unexpected) directly to the IRB and Case Examination Committee (CEC) within 10 working days of knowledge, or as dictated by the specific IRB policy. The same applies to all deaths and unexpected serious adverse events, which must also be reported to the Case Examination Committee (CEC) and the clinical centre's IRB within 24 hours. · Specific Adverse Event Definitions MI, a term denoting the death of heart muscle resulting from a lack of blood supply to the heart, is diagnosed when there is clinical evidence of myocardial necrosis consistent with myocardial ischaemia. [31] The following diagnosis may be made if any one of the following criteria are met: • Myocardial Infarction Evidence of an increase and/or decrease in cardiac biomarkers (ideally troponin) with at least one value above the 99th percentile of the upper limit of reference (URL), together with evidence of myocardial ischaemia with at least one of the following: o ECG changes indicating new ischemia, such as new ST-T changes or new left bundle branch block (LBBB). o Ischemia signs o Pathological Q waves have developed in the ECG. o Imaging findings of new loss of viable myocardium or new regional wall motion abnormalities. • Peri-CABG Myocardial Infarction In patients undergoing coronary artery bypass graft (CABG) with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. Conventionally, biomarker elevations greater than 5 times the 99th percentile URL, in addition to new Q waves or new LBBB, new graft or native coronary artery occlusion documented by angiography, or imaging findings of new loss of viable myocardium, have been considered to diagnose CABG-related MI. • Peri-Percutaneous Intervention (PCI) Myocardial Infarction For patients undergoing PCI with normal baseline troponin values, cardiac biomarker elevations above the 99th percentile URL indicate peri-procedural myocardial necrosis. Those over 3 times the 99th percentile are conventionally interpreted as PCI-related MI. There is a recognised subset associated with documented stent thrombosis. Sudden unexplained cardiac mortality linked to cardiac arrest, often with symptoms consistent with heart attack, and associated with suspected new ST elevation or new LBBB, and/or evidence of fresh blood clots by coronary angiography and/or autopsy, where death occurs before the collection of blood samples or the expected appearance of heart biomarkers in the blood, is classified as death due to heart attack. • Cardiac Arrhythmias Record any arrhythmia that causes impairment, e.g. heart failure, lack of urine, loss of consciousness or fainting, and this must be reported to hospital or doctor. Cardiac arrhythmias are classified into two categories: o Persistent ventricular arrhythmia necessitating defibrillation or cardioversion o Persistent supraventricular arrhythmia necessitating drug treatment or cardioversion • Right-sided heart insufficiency The diagnosis of persistent right ventricular dysfunction (RVD) is made when the central venous pressure (CVP) exceeds 18 mmHg and the cardiac index falls below 2.0 L/min/m2. This is in the absence of elevated left atrial/pulmonary capillary wedge pressure (> 18 mmHg), tamponade, ventricular arrhythmias or pneumothorax. Treatment may necessitate the implantation of a right ventricular assist device (RVAD), inhalation of nitric oxide or inotropic therapy for a duration exceeding seven days. • Major Infection A novel episode of clinical infection, accompanied by manifestations of pain, fever, drainage and/or leukocytosis, occurs within the context of antimicrobial treatment, specifically non-prophylactic regimens. A positive culture from the infected site or organ is required for a diagnosis, unless there is strong clinical evidence that treatment is required despite a negative culture. The following categories of infection are recognised: [24,25] o Localized Infection The infection is confined to a specific organ or region, such as mediastinitis, and there is an absence of evidence of systemic involvement (as defined by sepsis). This determination is made through the utilisation of standard clinical methodologies and may be accompanied by indications of bacterial, viral, fungal, or protozoal infection, or necessitate empirical therapeutic intervention. [24,25] o Endocarditis The ensuing clinical signs, symptoms and laboratory tests have been identified as manifestations of endocarditis: fever of 38. 0°C or higher, positive blood cultures, new regurgitant murmurs or heart failure, the presence of embolic phenomena (e.g. focal neurologic impairment, glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and peripheral cutaneous or mucocutaneous lesions (e.g. petechiae, conjunctival or splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth spots). If echocardiography reveals a new intra-cardiac vegetation, along with or without other signs and symptoms, this should be considered sufficient evidence to support the diagnosis of endocarditis. TEE is the recommended diagnostic tool for prosthetic valve endocarditis. [24,25] o Sepsis There is sign of systemic involvement by infection as evidenced by positive blood cultures and/or hypotension. [24,25] • Neurologic Dysfunction The presence of any new neurological deficit, whether transient or permanent, focal or global, must be identified by means of a standard neurological examination (performed by a neurologist or other qualified physician and documented by appropriate diagnostic tests and consultation notes). The physician conducting the investigation is tasked with distinguishing between transient ischaemic attack (TIA) and stroke. The term "transient ischemic attack (TIA)" refers to a fully reversible condition that occurs within 24 hours and does not demonstrate evidence of infarction. Conversely, the term "stroke" denotes a condition that persists for more than 24 hours or lasts less than 24 hours but does demonstrate evidence of infarction. The presence and severity of neurological deficits must be documented by means of the administration of the Modified Rankin Scale and the NIH Stroke Scale at two points in time: firstly, at the time of the event (within 72 hours following the event); and secondly, 90 days following the event. Subcategories must be assigned to each neurological event as: o Ischemic or Hemorrhagic Stroke, also known as Cerebrovascular Accident, is considered to be an event lasting more than 24 hours or less than 24 hours and accompanied by infarction on imaging. If an ischemic stroke undergoes hemorrhagic conversion, it should still be classified as ischemic. o Toxic metabolic encephalopathy is characterised by a disturbance in brain function resulting from abnormal systemic metabolism or exogenous agents. This disturbance in function can alter an individual's level of awareness and/or consciousness. The neurological examination and brain scan are both non-focal. o Other • Renal Events The classification of renal function will be based on the estimated glomerular filtration rate (eGFR), which will be calculated using both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [32] and the European Kidney Function Consortium (EKFC) equation [33]. The severity of renal failure will be classified into different stages, as listed in Supplementary Table 4. Two types of kidney related events will be recognised: o Renal Dysfunction Abnormal kidney function is defined as a rise in serum creatinine (Cr) of more than 100% from baseline, and a Cr level greater than 2.0. o Renal Failure New requirement for hemodialysis related to renal dysfunction. This definition excludes aquapheresis for volume removal alone. • Hepatic Dysfunction If any two of the following liver test results (total bilirubin, aspartate aminotransferase/AST and alanine aminotranferease/ALT) are three times higher than the upper limit of normal for the hospital, or if liver dysfunction is the main cause of death. • Respiratory insufficiency Respiratory function impairment that requires re-intubation, tracheostomy, or the inability to discontinue ventilatory support within 48 hours after surgery. This does not include intubation for re-operation or temporary intubation for diagnostic or treatment purposes. • Bleeding A bleeding incident is characterised by any of the following · Death due to hemorrhage can occur when more than 10 units of red blood cells are transfused within the first 24 hours following surgery. · Re-operation may be necessary in cases of hemorrhage or tamponade. NOTE: A hemorrhagic stroke is classified as a neurological event rather than a distinct bleeding event • Pericardial Fluid Trapping Pericardial effusion is the collection of fluid or thrombus in the pericardial space requiring surgical intervention or percutaneous catheter drainage. This event can be further classified into two categories: those with clinical signs of tamponade (such as increased central venous pressure and decreased cardiac output) and those without signs of tamponade. • Arterial Non-CNS Thromboembolism Confirmation of an acute systemic arterial perfusion deficit in any non-cerebrovascular organ system due to thromboembolism can be made by one or more of the following: o Standard clinical and laboratory testing o Operative findings o Autopsy findings This definition excludes neurological events. • Wound Dehiscence Surgical incision disruption, not caused by infection, that needs to be surgically repaired. • Venous Thromboembolic Event Clinical and laboratory evidence of a venous thromboembolic event, such as deep vein thrombosis or pulmonary embolism, can be detected using standard tests. • Other An occurrence that results in a clinically significant alteration in the patient's state of health, or any event that is life-threatening, results in death, leads to permanent disability, necessitates hospitalisation or prolongs an existing hospital course. 6. Assesment for statistical analysis 6.1. Sample Size Calculations The trial sample size was derived based on achieving at least 85% power to detect the 1-, 5-, and 10-year safety and effectiveness endpoint. Data from previous studies were used to derive event rate estimates for the primary safety and efficacy endpoint. As the current study population is a lower risk cohort, rates have been adjusted to account for procedural refinements over time in both groups and changes in definitions of endpoint components. Sample sizes are driven by the composite primary outcome assuming an event rate of 16.6% in the St-AVR arm and 14.6% in the Su-AVI arm. The study would have 85% power to detect the endpoint with a sample size of 867 patients and 10-year data. This sample size is calculated using a one-tailed Score test (Farrington & Manning) with a significance level of alpha = 0.025 and incorporating the required non-inferiority margin of relative 35%. The estimate of the primary sample size has been derived using a pure frequency analysis; however, the Kaplan-Meier estimates will be used for the endpoint analysis. The sample size is expected to be adequate given the equivalence of the two methods in the absence of censoring and the expected sufficiency of uncensored patients. However, an actual sample size of 1,020 has been set, representing a 15% increase over the minimum size considered statistically justified, given the highly uncertain feasibility assumptions associated with this previously unstudied population. This increased sample size is designed not only to meet the trial's needs, but also to allow additional flexibility for unforeseen events, such as dropouts or loss to follow-up, that are inherent in clinical trials. For several unpowered secondary endpoints, this size is also expected to improve the power of the analysis. 6.2. Analysis Populations The Intention to Treat (ITT) population consists of all patients enrolling in the study, while the As Treated (AT) population consists of all patients initiating the index intervention, regardless of whether they complete the index intervention. In cases where multiple procedures are performed, the last procedure that involves implanting the investigational valve is considered to be the index procedure. This procedure will then be used to determine the as-treated study allocation, and the date of the index procedure will be used to determine all subsequent follow-up visits and associated assessments. The valve implantation (VI) population is the subset of the as-treated (AT) population, which comprises all patients who will receive and will retain the designated valve at the index procedure. In addition, patients who are converted from SuAVR to StVR during the procedure will also be part of the VI population. For endpoint analysis, the AT population will be used as the primary population. The VI population is used to analyse echocardiographic data and related outcomes, while selected sensitivity analyses are conducted using the ITT population. 6.3. Endpoint analysis Primary endpoints include operative mortality and survival. Late deaths at a linearised rate will be defined as valve and non-valve related deaths at one, five and ten years after procedure completion. As outlined in the study protocol, a non-inferiority analysis will be conducted on these endpoints, with a relative non-inferiority margin set at 35%. The components of the composite endpoint will undergo systematic analysis by the CEC. Patients will be classified as having experienced the endpoint once any component of that endpoint is documented. Conversely, if no such record is found, the subject will be deemed to be free of the endpoint, resulting in their exclusion from subsequent analyses. The analysis will instead be based on a maximum of one record of the individual's survival and absence of events. The event rate difference endpoint test will be conducted with a non-inferiority margin of a relative 35%.The one-sided non-inferiority test will be performed at an alpha level of 0.025, and the two-sided 95% confidence limit for the event rate ratio (SuAVR/StAVR) will be computed. It is imperative to highlight that the stipulated acceptance criterion is contingent upon the upper confidence limit not exceeding 1.35.In the event that the non-inferiority analysis yields a satisfactory outcome, the subsequent superiority analysis will be conducted. The type I error rate for this analysis is safeguarded by the non-inferiority analysis, thereby obviating the necessity for an alpha adjustment. Secondary endpoints have been divided into two categories. For the key secondary endpoints, a prespecified hierarchical order will be used to conduct testing for superiority, with the implementation of a gatekeeping method to control for multiple comparisons. P values will be presented alongside claims of significance. Conversely, for other secondary endpoints, analyses will be conducted without the application of a correction for multiple comparisons. As a consequence of this decision, the presentation of hazard ratios and 95% confidence intervals will not include P values or any statements as to significance. It is important to note that inferences derived from these 95% confidence intervals may lack reproducibility. In order to facilitate the accurate comparison of continuous variables, it is recommended that Student's t-test or Wilcoxon rank-sum test be utilised. Similarly, for categorical and ordinal data presented as proportions, Fisher's exact test or Wilcoxon rank-sum test will be appropriate. Following the implementation of a baseline, the continuous variables will be analysed through the utilisation of an analysis of variance with adjustment for baseline measurement. Time-To-Event analyses will employ Kaplan-Meier estimates, which will subsequently undergo comparison with the utilisation of a log-rank test. Echocardiographic analyses will be conducted on the valve-implant population, which comprises patients in whom the intended valve is inserted. All statistical analyses will be conducted using R software (R Foundation for Statistical Computing, Vienna, Austria). 7. Discussion 4.1 The context in which SAVI-AVR operates Sutureless valve technology is believed to offer a number of key benefits, including a reduction in ischemic surgical time in comparison to conventional sutured valves [ 34 ]. However, there is currently an absence of compelling data to suggest that the decrease in aortic cross-clamp time, which is facilitated by the use of the aforementioned sutureless valve technology, may result in improvements in morbidity or mortality [ 35 , 36 , 37 – 41 ]. A study was conducted to investigate the effects of cross-clamp times in patients undergoing Su-AVI and full sternotomy SAVR. The results showed a significant reduction in cross-clamp times in the SuAVI group when compared with the full sternotomy SAVR group. However, no significant differences were observed in terms of cumulative CPB time or clinical outcomes [ 10 ]. The findings under consideration were obtained from the CADENCE-MIS trial [ 10 ], a randomised study that compared minimally invasive Su-AVI with rapid deployment valves with full sternotomy SAVR. Nevertheless, several retrospective observational studies have posited an association between prolonged cross-clamp or CPB times and an increased risk of postoperative complications, including renal failure, respiratory failure, postoperative low-output syndrome, postoperative atrial fibrillation, increased transfusion demands, and prolonged postoperative hospital stays, as well as trends in mortality [ 42 – 44 ]. We conducted a pooled cumulative analysis of the utilisation of the Su-AVI as a wireless option for patients with AVR, incorporating both observational and randomised evidence. This analysis drew parallels between Su-AVI and St-AVR, and revealed no statistically significant difference in mortality at one year (OR: 1.01; 95% CI: 0.87–1.16; P = 0.97). A further finding of interest was that when the results of RCTs were compared with those of retrospective or propensity-matched cohorts, no statistically significant difference in 1-year mortality was found [ 7 ]. It has been posited that analysis of data collated during the course of the SAVI-AVR prospective trial may have the capacity to produce contemporary results for a substantial number of patients suffering from severe aortic valve stenosis. This analysis would benefit from an extended follow-up period, thus providing valuable insights into the natural history of the condition. The SAVI-AVR trial's primary objective lies in the compilation of data intended to offer insight into the consequences of varied surgical interventions on standard aortic valve surgery involving St-AVR or Su-AVI. Subsequent to the PERSIST-AVR trial [ 8 ], which encompasses a minimum of five years of observation (less than the ten years of SAVI-AVR), the present study has been initiated at opportune juncture. The overarching objective of the SAVI-AVR investigation is to systematically collate substantial clinical data, with a focus on elucidating the implications of diverse surgical interventions on conventional aortic valve surgery, employing either the St-AVR or Su-AVI approach. The present undertaking constitutes an ambitious endeavour, encompassing a comprehensive evaluation of long-term outcomes in addition to an in-depth assessment of mortality rates. The investigation will focus on the incidence of valve-related mortalities and the necessity for re-interventions due to structural valve degeneration. Likewise, the PERSIST-AVR trial has considered freedom from major cerebral and cardiovascular events (MACCE) as the primary outcome [ 8 ]. MACCE is a composite of death from any cause, myocardial infarction, stroke, or valve reintervention at 1 year. This RCT has demonstrated that Su-AVI prove noninferior to St-AVR with regard to MACCEs at one-year follow-up in patients undergoing aortic valve replacement (either as a standalone procedure or in conjunction with coronary artery bypass grafting). It is important to note that the RCT conducted by Fischlein et al. [ 8 ] demonstrated the superiority of the sutureless valve in terms of reduced procedural times, both in isolated and combined procedures. These results, however, failed to manifest as discernible clinical benefits at either 30-day or 1-year follow-up, as observed in the comprehensive study findings. 4.2. The lack of reliable evidence in guidelines is the driving force behind the present study. In the preceding two decades, the cardiology and cardiac surgery community has achieved considerable progress in the domain of biological prosthetic valve design and implantation techniques [ 1 , 7 – 9 , 45 , 46 ].These advancements have proven instrumental in the management of AVS through the utilisation of novel platform technologies for the treatment of structural heart disease. The recent progress witnessed in this field have precipitated the emergence of both transcatheter and minimally invasive approaches, thereby signifying a substantial evolution in the realm of cardiovascular medicine. [ 1 , 8 – 9 , 45 , 46 ]. Consequently, there is a pressing need for an increased number of prospective randomised and non-randomised trials in order to assess the safety and clinical efficacy of Su-AVI in comparison to St-AVR. This necessity has arisen as a consequence of an increased utilisation of rapid-deployment techniques. Following the first transcatheter aortic valve replacement (TAVR) procedure carried out by Cribier in 2002, [ 47 ] over 1.500.000 patients have undergone TAVR worldwide [ 48 ]. The development of international guidelines recommending TAVR over conventional methods has been demonstrated [ 6 , 49 – 59 ]. The utilisation of TAVR in lieu of traditional surgical intervention for the treatment of AVS is endorsed by substantial research findings, as evidenced by numerous randomised, multicentre trials. These findings substantiate the efficacy and safety of the procedure, thus classifying it as a Class of Recommendation (COR) I, Level of Evidence (LOE) A, representing the highest level of recommendation available [ 2 , 3 ]. Conversely, the estimated number of SuAVR implants is projected to reach 75,000 by the year 2022. However, the number of patients who have undergone Su-AVI since the pioneering Percevalve sutureless valve implantation in 2007 remains significantly lower [ 60 ].As a consequence, the robustness of the results is substantially different between the two procedures, as evidenced by a limited number of multicentre RCTs supporting the use of Su-AVI [ 47 ].(43–45) The aforementioned findings bear significant implications for the safety and efficacy recommendations outlined in international guidelines and supported by COR 1, LOE A[ 2 , 3 , 60 ]. Limitation In the preceding decade, there have been notable developments in surgical technique and experience with regard to the treatment of AVS. The utilisation of age-adjusted statistics serves to mitigate this effect to a certain extent. The present paper sets out the findings on how the protocol's definitions for the Su-AVI and St-AVR, as well as long-term outcomes, have not been standardised. The dearth of multicentre RCTs encompassing a substantial number of patients has impeded the acquisition of recommendations categorised as COR 1 LOE A for the utilisation of Su-AVI. Nevertheless, this prospective study design is inherently constrained by the non-randomised nature of the study, and this variability introduces potential inaccuracies into the study data. Moreover, the crossover rate may be relatively high, with the potential for divergent outcomes between the per-protocol and modified intention-to-treat populations. The decision regarding valve size is delegated to the attending surgeon's discretion. However, the relatively high incidence of sizes 19 and 21 mm may be possible in the stented valve group, aligning with the findings of numerous other clinical studies [ 11 – 17 , 61 – 65 ] that reported outcomes in BP at the aortic valve position. The management of intraoperative, intensive care, and anticoagulation protocols will be determined by the treating physician and the specific centre. The study involved centres with expertise in the techniques, but recruitment rates were heterogeneous across sites. The present study will involve the completion of one of the largest multicentre prospective non-randomised trials currently available, comparing Su-AVI and St-AVR. The protocol under development has the potential to address a significant knowledge gap, particularly in the context of the paucity of large, randomised studies that have yielded substantial results. Conclusion Participation in the SAVI-AVR prospective non-randomised trial by healthcare facilities is dependent on the demonstration of a minimum annual number of aortic valve stenosis procedures, set at 200. In addition, the centres must implement a programme that enables effective follow-up and management of any late aortic events following surgical replacement. It is imperative that the surgical procedure in question utilises conventional St-AVR or a rapid deployment Su-AVI. A comprehensive synthesis of the outcomes from the analytical investigation, which drew parallels across two distinct surgical procedures of SAVR for AVS– Su-AVI and St-AVR – is presented below. This is facilitated through the prospective study's multicentre approach, which enabled a comprehensive evaluation. The study sets out to ascertain whether there are any differences in the occurrence of late deaths at a linear rate both as valve-related and non-valve-related between cohorts at 10 years following St-AVR or Su-AVI. Specifically, it seeks to identify which procedure leads to the optimal outcome for composite treatment failure endpoint. This comprises cardiac death, reoperation for SVD and time to explant due to SVD. Which of the two procedures (Su-AVI and St-AVR) achieves the low risk of SVD and what percentage of patients can benefit from this in the long term follow up in term of freedom from reoperation. LV remodelling and improved LV dimensions over a 10-year period. Whether patients with improved LVEF also exhibit a lower rate of readmission due to improved HF symptoms and a lower rate of NYHA class worsening. Which of the two procedures achieves low rates of MACEEs and what percentage of patients can benefit from this in the long term. Which of the two cohorts, defined by the percentage of patients who experienced residual aortic AV regurgitation progression during follow-up, will demonstrate more severe HF symptoms. Abbreviations AV ; Aortic valve AVS; Aortic valve stenosis BP; bioprosthesis CABG; coronary artery bypass graft CAD; coronary artery disease CPB; cardiopulmonary bypass CE; Carpentier-Edwards CEPME; Carpentier Edwards Perimount Magna Ease CT; computed tomography LVEF ; left ventricular ejection fraction MRI; magnetic resonance imaging NYHA; New York Heart Association Class PCI; percutaneous coronary intervention SAVI-AVR; Sutureless Aortic Valve Replacement Versus Stented Aortic Valve Replacement for Aortic-Valve Stenosis SAVR; surgical aortic valve replacement St-AV; stented aortic valve St-AVR; stented aortic valve replacement Su-AV; sutureless aortic valves Su-AVI; sutureless aortic valve implant SVD; structural valve deterioration TAVR; transcatheter aortic valve replacement TEE; transesophageal echocardiography THV; transcatheter heart valve TTE; transthoracic echocardiography VARC; Valve Academic Research Consortium Declarations Acknowledgements Not applicable Author contributions FN, AS, SSAS, ZED, AF, CS contributed to planning this prospective non randomized trial and its related studies as well as to develop the datasheet for data collection. All authors read and approved the final manuscript. Funding This study will be performed without external financial support. Data availability No datasets were generated or analysed during the current study Ethics approval and consent to participate This study does not contain individual patient data and ethics approval is not applicable. Consent for publication This manuscript does not contain individual person’s data in any form. Competing interests The authors declare no competing interests . References Otto CM, Prendergast B. Aortic-valve stenosis–from patients at risk to severe valve obstruction. N Engl J Med. 2014;371:744-56. Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, et al . 2021 ESC/EACTS Guidelines for the management of valvular heart disease. ESC/EACTS Scientific Document Group; ESC National Cardiac Societies. European Heart Journal. 2022; 43: 561–632. 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Bartoszko J, Wijeysundera DN, Karkouti K, et al. Comparison of Two Major Perioperative Bleeding Scores for Cardiac Surgery Trials: Universal Definition of Perioperative Bleeding in Cardiac Surgery and European Coronary Artery Bypass Grafting Bleeding Severity Grade. Anesthesiology 2018;129:1092–100. VARC-3 Writing Committee, Genereux P, Piazza N, Alu MC, Nazif T,Hahn RT, Pibarot P, et al. Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research. J Am Coll Cardiol. 2021 Jun 1;77(21):2717-2746 Campeau L. Grading of angina pectoris. Circulation. 1976; 54: 522-523 Borger MA, A.A., Murphy PM et al. , Chronic lschemic Mitral Regurgitation: Repair, Replace or Rethink? Ann Thor Surg, 2006. 81 : p. 1 153-1 161. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. Coresh J; CKD-EPI (chronic kidney disease epidemiology collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12. https://doi.org/10.7326/0003-4819-150-9-200905050- 00006. Pottel H, Björk J, Courbebaisse M, Couzi L, Ebert N, Eriksen BO, et al. Development and validation of a modified full age spectrum creatinine- based equation to estimate glomerular filtration rate : a cross-sectional analysis of pooled data. Ann Intern Med. 2021;174(2):183–91. Mazine A, Bonneau C, Karangelis D, Yanagawa B, Verma S, Bonneau D. Sutureless aortic valves: who is the right patient? Curr OpinCardiol. 2017;32(2):130–136. Schaff HV. Sutureless prostheses for aortic valve replacement: quicker may not be better. J Am Coll Cardiol. 2018;71(13):1429–1431 Michelena HI, Michler RE, Enriquez-Sarano M, Schaff HV, Suri RM. Alternative for surgical management of calcific aortic valve stenosis: sutureless valve implants. J Card Surg. 2014;29(4):490–493. White A, Bozso SJ, Lakey O, et al. Rapid deployment valves versus conventional tissue valves for aortic valve replacement. J Thorac Cardiovasc Surg. 2022;163(6):2036–2042 Phan K, Tsai YC, Niranjan N, et al. Sutureless aortic valve replacement: a systematic review and meta-analysis. Ann Cardiothorac Surg. 2015;4(2):100–111. Shrestha M, Fischlein T, Meuris B, et al. European multicentre experience with the sutureless Perceval valve: clinical and haemodynamic outcomes up to 5 years in over 700 patients. Eur J Cardiothorac Surg. 2016;49(1):234–241. Rahmanian PB, Kaya S, Eghbalzadeh K, Menghesha H, Madershahian N, Wahlers T. Rapid deployment aortic valve replacement: excellent results and increased effective orifice areas. Ann Thorac Surg. 2018;105(1):24–30. Barnhart GR, Accola KD, Grossi EA, et al. TRANSFORM (Multicenter Experience With Rapid Deployment Edwards INTUITY Valve System for Aortic Valve Replacement) US clinical trial: performance of a rapid deployment aortic valve. J Thorac Cardiovasc Surg. 2017;153(2):241–251.e242. Salis S, Mazzanti VV, Merli G, et al. Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth. 2008;22(6): 814–822. Al-Sarraf N, Thalib L, Hughes A, et al. Crossclamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. Int J Surg. 2011;9(1):104–109. Mikus E, Fiorentino M, Sangiorgi D, et al. Less is more? Combined approaches to improve mortality and morbidity after aortic valve replacement. Biomedicines. 2023;11(11):2989 Wahlers TC, Haverich A, Borger MA, Shrestha M, Kocher AA, Walther T, et al. Early outcomes after isolated aortic valve replacement with rapid deployment aortic valve. J Thorac Cardiovasc Surg. 2016;151:1639-47 Berretta P, Andreas M, Carrel TP, Solinas M, Teoh K, Fischlein T, et al. Minimally invasive aortic valve replacement with sutureless and rapid deployment valves: a report from an international registry (sutureless and rapid deployment international registry). Eur J Cardiothorac Surg. 2019;56:793-9. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006-8. Nhan VT, Khoa NQ, Thuy T, Van Duong N, Van Tan N, Ngoc The TH, Vuong NL, Cong ND, Su LQ, Finkelstein A, Lafont A. Early safety and mid-term clinical outcomes of technology transfer of transcatheter aortic valve implantation in patients with severe aortic valve stenosis in Vietnam: a single-center experience of 90 patients. Lancet Reg Health West Pac. 2023 Nov 4;42:100956. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-607 Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-98. Reardon MJ, Van Mieghem NM, Popma JJ, Kleiman NS, Søndergaard L,Mumtaz M, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med 2017;376:1321-31. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016; 374: 1609-20. Kapadia SR, Leon MB, Makkar RR, et al. 5-Year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015; 385: 2485-91. Mack MJ, Leon MB, Smith CR, et al. 5-Year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet 2015; 385:2477-84. Webb JG, Doshi D, Mack MJ, et al. A randomized evaluation of the SAPIEN XT transcatheter heart valve system in patients with aortic stenosis who are not candidates for surgery. JACC Cardiovasc Interv 2015;8:1797-806. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet 2016; 387: 2218-25. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790-8. Gleason TG, Reardon MJ, Popma JJ, et al. 5-Year outcomes of self-expanding transcatheter versus surgical aortic valve replacement in high-risk patients. J Am Coll Cardiol 2018;72:2687-96. SAVR TAVR volumes. Presented at a meeting of the Society of Thoracic Surgeons–American College of Cardiology TVT Registry Stakeholder Advisory Group, Washington, DC, March 4, 2019. Meuris B, Lamberigts M, Szecel D. The importance of sizing in sutureless valves. Interact Cardiovasc Thorac Surg. 2022 Aug 3;35(3):ivac206 Goldstone AB, Chiu P, Baiocchi M, Lingala B, Patrick WL, Fischbein MP, Woo YJ. Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement. N Engl J Med. 2017 Nov 9;377(19):1847-18 Blackstone EH, Cosgrove DM, Jamieson WR, Birkmeyer NJ, Lemmer JH Jr, Miller DC, et al. Prosthesis size and long-term survival after aortic valve replacement. J Thorac Cardiovasc Surg. 2003;126:783-96. ISTHMUS Investigators. The Italian study on the Mitroflow postoperative results (ISTHMUS): a 20-year, multicentre evaluation of Mitroflow pericardial bioprosthesis. Eur J Cardiothorac Surg. 2011;39:18-26. Goldman S, Cheung A, Bavaria JE, Petracek MR, Groh MA, Schaff HV. Midterm, multicenter clinical and hemodynamic results for the Trifecta aortic pericardial valve. J Thorac Cardiovasc Surg. 2017;153:561-9. e2. Yoshikawa Y, Okada Y, Okita Y, Yaku H, Kobayashi J, Uesugi H, et al. Long-term outcomes of the mosaic aortic porcine bioprosthesis in Japan–results from the Japan mosaic valve long-term multicenter study. Circ J. 2020;84:1261-70. Tables Tables 1 to 10 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Table4.docx Table5.docx Table6.docx Table7.docx Table8.docx Table9.docx Table10.docx SupplementalMaterial.docx SupplementaryFigure1.png SupplementaryFigure2.png Supplementarytable1.docx SupplementaryTable2.docx SupplementaryTable3.docx SupplementaryTable4.docx Cite Share Download PDF Status: Published Journal Publication published 21 Apr, 2026 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted Editorial decision: Revision requested 18 Aug, 2025 Reviewers agreed at journal 30 Jun, 2025 Reviews received at journal 13 May, 2025 Reviewers agreed at journal 01 May, 2025 Reviewers invited by journal 29 Apr, 2025 Editor assigned by journal 20 Mar, 2025 Submission checks completed at journal 20 Mar, 2025 First submitted to journal 18 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6251208","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":450722128,"identity":"902c4ce8-dcc7-4e70-bd9a-ac2a523d18e3","order_by":0,"name":"Francesco 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1","display":"","copyAsset":false,"role":"figure","size":412005,"visible":true,"origin":"","legend":"\u003cp\u003eStudy Design Schematic\u003c/p\u003e\n\u003cp\u003eAbbreviations; AVS, aortic valve stenosis; BP, bioprosthetics; CABG, coronary artery bypass grafting; LV, left ventricle; SAVI, sutureless aortic valve implantation; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation; TAVISAR, transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement\u003c/p\u003e","description":"","filename":"Figure11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6251208/v1/7f58c025d8f45df8ed249ff9.jpg"},{"id":107928453,"identity":"9caddad0-97e5-40cf-9aa1-d4808b795a84","added_by":"auto","created_at":"2026-04-27 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14:58:23","extension":"docx","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":14674,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6251208/v1/5952b4f5abfa175bd3097626.docx"},{"id":82279080,"identity":"16023ba3-4739-47d3-bc93-9385ca3786d2","added_by":"auto","created_at":"2025-05-08 14:58:23","extension":"docx","order_by":16,"title":"","display":"","copyAsset":false,"role":"supplement","size":14813,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable4.docx","url":"https://assets-eu.researchsquare.com/files/rs-6251208/v1/37b75e54ca1687516fd42e3f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Study protocol for an international prospective non-randomized trial evaluating the long term outcomes of Sutureless Aortic Valve Replacement Versus Stented Aortic Valve Replacement for Aortic-Valve Stenosis in Patients at Risk to Severe Valve Obstruction: The SAVI-AVR trial","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAortic valve (AV) stenosis (AVS) is identified as the most prevalent cardiac valve disease necessitating surgical correction [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The amelioration of aortic valve dysfunction has been demonstrated to significantly enhance patient quality of life and prolong life expectancy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Advancements in the design and manufacturing of the novel platform technologies for the treatment of structural heart disease, coupled with the emergence of studies substantiating the safety of the procedures in low-risk populations, have led to a progressive broadening of indications for catheter-based valve implantation. This has encompassed lower-risk patients, in addition to those deemed high-risk candidates for surgical intervention [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, surgical aortic valve replacement (SAVR) remains the procedure of choice for AVS in several clinical settings [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe impact of age on the risk of reoperation has received only limited attention in research conducted in the context of novel prosthetic valve technology based on rapid deployment techniques and the elimination of anchoring sutures. In the case of sutureless aortic valves (Su-AV), research is yet to be sufficiently extensive in this regard, and there is a paucity of long-term follow-up studies [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. On the contrary, it has been reported by several institutions that the Carpentier-Edwards (CE) pericardial valve has been shown to yield excellent clinical outcomes [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The valve-related event rate is low at 20 years, and the rate of structural valve deterioration (SVD) is particularly low. In the aortic position, the CE Perimount pericardial bioprosthesis (BP) remains a reliable choice for tissue valves, especially for patients over 60 years of age [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A recent study demonstrated that the CE Perimount Magna Ease pericardial BP remains a reliable choice for tissue valves in the aortic position. The study revealed that, despite an infrequent rate of explantation due to SVD events at 10 years, and a particularly low rate of moderate or severe SVD based on echocardiographic Valve Academic Research (VARC) Consortium 3 criteria, the bioprosthesis continues to demonstrate reliability [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith regard to the matter of surgical intervention, Su-AVI innovations represent a significant development in surgical technology, marrying the accuracy of surgical implantation with the technological sophistication of transcatheter interventions. These advancements aim to minimise the physiological impact of surgical procedures on patients. In addition, the duration of cardiopulmonary bypass (CPB) and operative time are reduced, simplifying the process of valve implantation. Sutureless devices are similar to transcatheter heart valve (THV) devices in terms of design and conceptualization. These ballon-expandable valves have a stent that exerts a radial force, and cuffs that enhance sealing and mitigate the risk of paravalvular leak. Sutureless aortic valve implant (Su-AVI) has been shown to have certain advantages over transcatheter aortic valve replacement (TAVR). These include the option of removing the diseased native valve, decalcifying the aortic annulus, or removing infected material. In patients with aortic stenosis who are deemed to be at high risk and for whom TAVR is contraindicated due to anatomical reasons or who require concomitant cardiac procedures (e.g. multivalve or combined coronary procedures), Su-AVI has the potential to mitigate the surgical burden by decreasing cross-clamp time and operative duration. In light of the aforementioned factors, it is conceivable that SuAVI could be a suitable option in redo operations involving calcified aortic root [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Furthermore, the simplicity of valve deployment without the necessity for sutures renders the technology a complementary adjunct to minimally invasive approaches, such as hemisternotomy or minithoracotomy, where annulus access may be restricted. \u003cb\u003e(online supplemental material S1)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe question of whether these characteristics offer a competitive edge over conventional SAVR remains a subject of debate, with the extant evidence primarily comprising observational studies. Moreover, the surgical community is polarised with regard to the optimal utilisation of these devices. The purported clinical benefit of reducing CPB time is not a consensus amongst healthcare professionals, particularly in light of the financial implications of the devices, which are not supported by long-term follow-up data [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] In view of the rising use of rapid-deployment techniques, the cardiovascular community has recognised the need for clinical trials to assess the long-term safety and clinical effectiveness of Su-AVI in comparison to sutured bioprostheses. In this context, the prospective non-randomised trial Sutureless Aortic Valve Implant versus Stented Aortic Valve Replacement (SAVI-AVR) was conducted to evaluate the long-term outcomes of treating AVS, with or without concomitant coronary artery disease, compared with conventional stented xenograft prostheses.\u003c/p\u003e"},{"header":"2. Methods and analysis","content":"\u003cp\u003eSAVI-AVR is a prospective, nonrandomized, controlled, multi-centre trial. Patients are enrolled 1:1 to receive either stented aortic valve replacement (St-AVR) with a commercial bioprosthesis (BP) or Su-AVI. At designated centers, patients will be enrolled in a computed tomography (CT) substudy \u003cstrong\u003e(online supplementary material S3).\u003c/strong\u003e\u0026nbsp; During the planned study duration, a total of 1,020 qualified patients will enter the study at up to three trial sites in European countries (two in France and one in Italy) which are actively recruiting patients \u003cstrong\u003e(Table 1).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA CT sub-study \u003cstrong\u003e(online supplementary material S3)\u003c/strong\u003e will enrol a total of 100 eligible patients in each arm (St-AVR and Su-AVI). This trial will include an extensive review of patient data. The aim of this initiative is to provide a substantial body of data to inform future clinical research efforts in this area.\u003c/p\u003e\n\u003cp\u003eData on consecutive patients with AVS will be accurately recorded in a Microsoft Access datasheet (Redmond, Washington, USA). Prespecified baseline, operative and outcome variables will be included in this datasheet. The study will begin in 2014 and patient enrolment is expected to continue through 2025 (with an initial completion date of 30/05/2025). This timeline is subject to the results of the interim analyses that will follow. Institutional review board or local ethics committee approval (IRB 2022011057) will be sought for this trial in accordance with local legislation. The trial is registered at ClinicalTrials.gov (NCT05261204) \u003cstrong\u003e(online supplementary material S2).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1. \u0026nbsp; SAVI-AVR study patient entry criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1.1. \u0026nbsp; Characterization of patient populations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria for the trial were as follows: patients must have severe, calcific, symptomatic aortic valve disease with or without concomitant coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) and be at low surgical risk for SAVR. In addition, patients must have undergone one of the following surgical approaches: an open surgical approach using either \u0026nbsp;a conventional stented xenograft bioprosthesis (Carpentier-Edwards Perimount Magna Ease [CEPME] bioprosthesis [Edwards Lifesciences]) or Perceval sutureless prosthesis ( LivaNova plc, UK). The database houses information pertaining to the participation of women and minority groups in clinical studies, a matter of significance due to its implications for scientific, ethical and social reasons, in addition to the generalisability of study results. SAVI-AVR is committed to the attainment of scientific results whilst ensuring equitable recruitment of patients irrespective of gender or ethnicity. The SAVI-AVR registry has recruited a minimum of 30% women and 25% minorities. To ensure adequate representation of these demographic groups, the recruitment centres implemented two measures: Firstly, they have to ensure that they document the number of women and minorities selected and then enrolled, in relation to their respective screening and subsequent exclusion protocols. Secondly, they have to ensure that they monitor these records on an annual basis, on behalf of the respective Clinical Centre involved, in relation to the follow-up procedures that are carried out at that particular centre each year.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eAortic valve stenosis severity assessment criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pathological basis of AVS is characterised by increased afterload. This is accompanied by progressive left ventricular hypertrophy, valve obstruction and subsequent reduction in systemic and coronary blood flow. Patients usually remain asymptomatic (eg, angina, syncope and/or heart failure) until late in their disease course. However, without intervention, the prognosis remains poor once clinical manifestations become apparent. Survival curves have shown that the time from symptom onset to death is approximately two years in patients with heart failure, three years in those with syncope, and five years in those with angina [20].It has also been documented that in medically treated patients with moderate to severe AVS, the mortality rate after symptom onset is approximately 25% within one year and 50% within two years. In addition, it is noteworthy that more than 50% of deaths in the literature have been of a sudden nature [21].\u003c/p\u003e\n\u003cp\u003eAssessing the severity of AVS is guided by a range of haemodynamic and natural history data as outlined in the ACC/AHA Guidelines. It is possible to conceptualise AVS as a continuous spectrum [2,3] . Symptom relief and improvement in haemodynamic parameters, global left ventricular (LV) systolic function and reversal of left ventricular (LV) hypertrophy are often seen with improvement in AV obstruction [22,23]. The subsequent table \u003cstrong\u003e(Table 2)\u003c/strong\u003e provides a comprehensive overview of the echocardiographic indicators that are utilised for the purpose of evaluating the severity of AVS, as delineated in the 2021 practice guidelines published by the joint ACC/AHA Task Force [3].\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eInclusion criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Individuals who have reached the age of 65 years or older at the time of consent.\u003c/p\u003e\n\u003cp\u003e\u0026middot; NYHA Functional Class \u0026ge; II \u003cstrong\u003e(Supplementary table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; The patient exhibits symptoms consistent with severe calcific aortic stenosis, as indicated by the following tissue Doppler transthoracic echocardiography (TTE) criteria:\u003c/p\u003e\n\u003cp\u003e- \u0026nbsp; \u0026nbsp; Jet velocity \u0026ge; 4.0 m/s or mean gradient \u0026ge; 40 mmHg\u003c/p\u003e\n\u003cp\u003e- \u0026nbsp; \u0026nbsp; Aortic valve area (AVA) \u0026le; 1.0 cm\u0026sup2; or AVA index \u0026le; 0.6 cm\u0026sup2; /m\u0026sup2;\u003c/p\u003e\n\u003cp\u003eAccording to the established criteria, qualifying echocardiograms must be conducted within the specified 90-day period prior to the enrollement process.\u003c/p\u003e\n\u003cp\u003e\u0026middot; The aortic valve annulus ranges from 273 millimeters squared to 683 millimeters squared, as measured through three-dimensional imaging techniques, including computed tomography (CT), transesophageal echocardiography (TEE), and magnetic resonance imaging (MRI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e lists the other inclusion criteria\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eExclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCandidates exhibiting any of the following conditions will be excluded from the study:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Estimated life expectancy \u0026lt; 24 months.\u003c/p\u003e\n\u003cp\u003e\u0026middot; The AV is characterized by its congenital state, with the presence of either a unicuspid or a bicuspid configuration. Additionally, it may be non-calcified, further contributing to its distinct characteristics.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Severe aortic valve regurgitation (\u0026gt;3+)\u003c/p\u003e\n\u003cp\u003e\u0026middot; Severe mitral valve regurgitation (\u0026gt;3+)\u003c/p\u003e\n\u003cp\u003e\u0026middot; Aortic coarctation\u003c/p\u003e\n\u003cp\u003e\u0026middot; The presence of a pre-existing mechanical or bioprosthetic valve, irrespective of position, is to be noted. It is noteworthy that the inclusion of the mitral ring does not constitute an exclusion.\u003c/p\u003e\n\u003cp\u003e\u0026middot; The presence of one or more of the following criteria serves to diagnose an acute myocardial infarction (MI) \u0026le; 1 month (30 days) prior to enrollment, with evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. \u003cstrong\u003e(Supplementary table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026sect; Identification of an intracoronary thrombus by angiography\u003c/p\u003e\n\u003cp\u003e\u0026middot; Lventricular dysfunction with left ventricular ejection fraction (LVEF) \u0026lt; 45%\u003c/p\u003e\n\u003cp\u003e\u0026middot; Hypertrophic cardiomyopathy with or without obstruction (HOCM)\u003c/p\u003e\n\u003cp\u003e\u0026middot; The patient demonstrated an inability to maintain tolerance for anti-thrombotic and anticoagulation therapy during and following the valve implant procedure.\u003c/p\u003e\n\u003cp\u003e\u0026middot; The occurrence of a stroke or transient ischemic attack (TIA) within 180 days following the valve implant procedure is a potential complication that should be noted.\u003c/p\u003e\n\u003cp\u003e\u0026middot; The patient exhibited hemodynamic or respiratory instability, necessitating inotropic support, mechanical ventilation, or mechanical heart assistance within 30 days of the initial screening visit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e lists the other exclusion criteria\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2. \u0026nbsp; Trial Design and \u0026nbsp;Endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe schematic of the trial design is presented in \u003cstrong\u003eFigure 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003ePrimary\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoints encompass operative mortality and survival; that is to say, the mortality rates which are recorded within a given time period after the procedure has been completed. The occurrence of late deaths at a linear rate will be defined as valve-related and non-valve-related deaths within the time period of one, five and ten years following the completion of the procedure. Another of interest is the composite treatment failure endpoint. This comprises cardiac death, reoperation for SVD and time to explant due to SVD.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eSecondary\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA number of key secondary outcomes have been predetermined with a view to managing Type I error and implementing a hierarchical approach to testing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecondary endpoints of particular pertinence are to be established, incorporating such metrics as the time to explant for structural valve degeneration, the occurrence of stroke, the necessity for reoperation, readmission due to any cause, and the emergence of new-onset atrial fibrillation within 30 days, 1, 5 and 10 years, in addition to the duration of primary admissions and the presence of poor treatment outcomes. Neurological examinations of all patients will be conducted at baseline, and subsequently at 30 days, as well as during scheduled follow-up periods. The neurological examinations, incorporating assessments using the National Institutes of Health Stroke Scale and the modified Rankin Scale, will be performed at 90 days for any patient demonstrating signs of stroke following the procedure. The definition of readmission to hospital encompasses any occurrence related to this study, the valve, or heart failure. The endpoint will be evaluated through a non-inferiority analysis, with a relative non-inferiority margin set at 35%.\u003c/p\u003e\n\u003cp\u003eSecondary endpoints encompassed longitudinal echocardiographic measurement of postoperative aortic valve hemodynamic stability, incorporating AV mean and peak gradients (mm Hg), AV regurgitation grade, AV stenosis (AV orifice area), left ventricular dimensions and \u0026nbsp;function. These parameters were assessed in the context of explant for indications other than SVD and mortality prior to valve explantation.\u003c/p\u003e\n\u003cp\u003eThe secondary endpoint also constituted a composite of major adverse cardiac or cerebrovascular events, which were defined as the following: mortality rate, incidence of stroke, subsequent aortic valve surgery, hospitalisation due to heart failure, or increase in New York Heart Association classification by \u0026ge;1. These events were observed over the following time periods: 30 days, 1 year, 5 years and 10 years.\u003c/p\u003e\n\u003cp\u003eThe Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, a metric ranging from 0 to 100 with higher scores denoting a reduced physical limitation burden and enhanced well-being, was also analysed. This analysis spanned the 30-day period, as well as the 1-year, 5-year and 10-year periods. At the 30-day, 1-year, and scheduled follow-up points, the study team assessed changes in New York Heart Association (NYHA) functional class, six-minute walk distance, and KCCQ summary score. The study also examined secondary safety and efficacy endpoints, with these terms defined in \u003cstrong\u003eTable 4\u003c/strong\u003e.\u003c/p\u003e"},{"header":"3. Medical Histories and Physical Assessments","content":"\u003cp\u003eComprehensive medical histories and physical assessments, incorporating parameters such as height, weight, blood pressure, and heart rate. The system will also encompass all medications administered for cardiovascular indications, along with all antithrombotic and anticoagulant medications.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eAssessment of Cardiopulmonary Status.\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe assessment of the cardiovascular and respiratory apparatuses is facilitated by the following methodologies:\u003c/p\u003e\n\u003cp\u003e\u0026bull; The Canadian Cardiovascular Society (CCS) status of angina should be documented, along with a 12-lead ECG.\u003cstrong\u003e\u0026nbsp;(Supplementary table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; The New York Heart Association (NYHA) classification should also be included. \u003cstrong\u003e(Supplementary table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; A comprehensive TTE is conducted, encompassing an evaluation of aortic valve gradients (mean and peak), areas, indices, and the extent of regurgitation. This extensive assessment should also comprise a measurement of left ventricle systolic function (global and segmental).It is imperative that this initial echocardiogram is conducted within 90 days prior to the enrolment process.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Cardiac imaging is an essential part of the pre-enrolment evaluation process. This imaging should include TEE, CT or MRI with 3D reconstruction to determine the area of the aortic valve annulus. This qualifying cardiac imaging must be performed within one year before enrolment, unless contraindicated.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Aortic stenosis and coronary artery disease will be assessed using left and right heart catheterisation. Cardiac catheterisation must be undertaken within one year of enrolment, unless contraindicated.\u003c/p\u003e\n\u003cp\u003e\u0026bull; The SYNTAX score constitutes a mandatory element in the assessment of significant native coronary artery disease (CAD).\u003c/p\u003e\n\u003cp\u003e\u0026bull; A full lung check is vital for patients with a history of respiratory diseases.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eFunctional Assessment and Evaluation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; The Six Minute Walk Test (6MWT) is a clinical evaluation used to assess functional mobility and frailty in patients. The test involves a five-metre walk, grip strength assessment, and a series of activities of daily living (ADL) to evaluate the patient\u0026apos;s autonomy and independence. Additionally, laboratory parameters such as albumin levels are monitored to provide a comprehensive health picture.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Quality of life assessments play a pivotal role in evaluating the impact of health conditions on patients\u0026apos; well-being. The Kansas City Cardiovascular Questionnaire (KCCQ) is a patient-reported outcome measure that focuses on symptoms, functionality, and quality of life.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; The EuroQol-5D-5L (EQ-5D-5L) is a well-established tool that quantifies health-related quality of life, providing a standardized metric for comparing health states across different populations. The Short Form 36 (SF-36) is a health survey that assesses physical and mental health, providing a comprehensive assessment of health status.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eClinical Laboratory Tests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA complete compendium of clinical laboratory tests is provided below. These include white blood cells (WBC), haemoglobin (Hgb), and platelet count. Other tests comprise prothrombin time (PT) or international normalized ratio (INR) and Creatine kinase (CK)/CK-MB and/or troponin. The maximum time frame for these tests is 72 hours prior to the valve implant procedure.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eNeurological Assessment and Evaluation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Mini Mental State Examination (MMSE), the National Institutes of Health Stroke Scale (NIHSS), and the Modified Rankin Scale (mRS) are three well-established tools used to assess cognitive function and the severity of neurological impairment in patients with stroke.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eSafety\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Incidence of serious adverse events\u003c/p\u003e\n\u003cp\u003e\u0026middot; Reoperation for SVD/NSVD and freedom from re-operation in general.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003ePeri-operative Measures.\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Operative time for each procedure. For the standard surgical mitral valve operation, cardiopulmonary bypass (CPB) and cross clamp time are required.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Blood loss and transfusion.\u0026nbsp;\u003c/p\u003e"},{"header":"4. Therapeutic Interventions","content":"\u003cp\u003eIt is recommended that valve implantation should be scheduled to take priority before 14 and 21 days after enrolment for prospective allocation and no later than 30 days after informed consent has been obtained. The date of valve implantation will be considered as day 0. The preliminary encounter (Day 0) is designated for the scheduling of all subsequent encounters and the calculation of visit windows. Patients who undergo either Su-AVI or St-AVR will remain enrolled in the study and will complete it through Year 10, in line with the visits and events delineated in the study procedure and schedule of procedures.\u003c/p\u003e\n\u003cp\u003eOn the preliminary day (Day 0) of the valve implant procedure, a thorough review of the patient\u0026apos;s cardiovascular system is to be conducted. This review involves the administration of medications designed to regulate cardiovascular function and anti-thrombotic/anti-coagulant therapies. Additionally, an evaluation of potential adverse events will be conducted. The evaluation process will be complemented by a comprehensive transthoracic echocardiogram (TTE) or transesophageal echocardiogram (TEE), as well as a supra-aortic angiogram or TEE, as deemed necessary by the attending medical team. It is recommended that patients participating in the study receive prophylactic therapy against endocarditis in accordance with the recommendations promulgated by the American Heart Association [24,25]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs displayed in \u003cstrong\u003eTable 5\u003c/strong\u003e, the recommended anticoagulation/antithrombotic regimen is outlined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.1.\u0026nbsp; \u0026nbsp;Standard aortic valve replacement procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn cases of aortic valve malfunction, two distinct treatment options exist, namely the implementation of synthetic graft prostheses. These options encompass the utilisation of a conventional stented xenograft bioprosthesis and a rapid-deployment, sutureless prosthesis. The concomitant surgical interventions deemed permissible in such cases include coronary artery bypass grafting (CABG), treatment for atrial fibrillation, septal myotomy and aortic root enlargement (see online \u003cstrong\u003esupplemental material S1\u003c/strong\u003e for further details on the procedure).\u003c/p\u003e\n\u003cp\u003eThe guidelines do not provide any specifications regarding the utilisation of St-AVR or Su-AVI in the treatment of AVS. This is due to an absence of conclusive evidence that indicates the superiority of one of these interventions in the long term (i.e. following surgery) with regard to survival and the prevention of structural valve deterioration necessitating reoperation. According to ACC/AHA guidelines, transcatheter aortic valve replacement (TAVR) and SAVR are both reasonable options for symptomatic patients aged 65-80 with severe aortic AVS and no anatomical contraindications. The decision must be made on an individual patient basis, balancing survival duration and valve durability. In such cases, TAVR or SAVR is recommended (Class I recommendation, Level of Evidence [LOE]: A). For patients with severe aortic valve stenosis (AVS) over 80 or younger with a life expectancy of less than 10 years and no anatomical contraindication to transfemoral TAVR, transfemoral TAVR is recommended over SAVR (Class I recommendation, Level of Evidence [LOE]: A) \u003cstrong\u003e(Table 6)\u0026nbsp;\u003c/strong\u003e[3]\u003cstrong\u003e.\u003c/strong\u003e The latest ESC/EACTS Guide to the Management of Valvular Heart Disease recommends TAVI for patients over 75 or at high risk of mortality. STS-PROM/EuroSCORE II \u0026gt;8% or deemed unsuitable for surgery (Class I recommendation, Level of Evidence [LOE]: A). In contrast, SAVR is recommended for low-risk patients under 75 (STS-PROM/EuroSCORE II \u0026lt;4% or unsuitable for TAVI) \u003cstrong\u003e(Table 6)\u0026nbsp;\u003c/strong\u003e[2]. As illustrated in \u003cstrong\u003eTable 6\u003c/strong\u003e, the timing and advice for patients deemed suitable for SAVR or TAVR, categorised as COR 1 and LOE A or B, is outlined.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eAV replacement using conventional stented xenograft bioprosthesis (St-AVR)\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor patients undergoing SAVR, the standard of care as outlined by the institution dictates the usage of a bioprosthetic surgical valve and associated components that are commercially available. The CEPME is constituted of three leaflets, which are made of bovine pericardial tissue. These leaflets are mounted beneath a flexible cobalt-chromium stent. In comparison with the preceding Perimount and Magna valves, this model is distinguished by its reduced profile, its narrower sewing ring, and the incorporation of the Thermafix anti-calcification process (Edwards Lifesciences; Irvine, CA, USA) (\u003cstrong\u003esee online supplementary material S1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eAV replacement using rapid deployment sutureless aortic valve implant (Su-AVI)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Perceval sutureless prosthesis (manufactured by LivaNova plc, a United Kingdom-based enterprise) is intended for use in patients diagnosed with severe AVS, with the aim of improving their quality of life. To minimise the impact of selection bias, patients were required to undergo a CT scan during the enrolment phase prior to the implantation of the Su-AVI. The purpose of the scan was threefold: firstly, to confirm the eligibility for the current sutureless valve implantation; secondly, to ascertain the suitability for the proposed surgical access (full sternotomy or ministernotomy); and thirdly, to reach a decision regarding an isolated or concomitant procedure. The use of a right anterior minithoracotomy was precluded due to the variable experience of the centres with this procedure, as well as its unsuitability for the purpose of serving as a comparator to the standard valve. Further elucidation on the sutureless valve and implantation procedure may be consulted in the supplementary material (\u003cstrong\u003esee online supplementary material S1\u003c/strong\u003e).\u003c/p\u003e"},{"header":"5. Endpoint Measurement","content":"\u003cp\u003e\u003cstrong\u003e5.1. \u0026nbsp; Perioperative Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ensuing parameters are to be measured: operative time, cardiopulmonary bypass time, cross-clamp time, blood loss and transfusions.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eCardiopulmonary bypass parameters\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prospective collection of patient data will encompass the duration of myocardial ischaemia, cardiopulmonary bypass and retrograde or antegrade cardiac cardioplegia perfusion.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eBlood loss and transfusions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe documentation of transfused red blood cell unit numbers is mandatory. A streamlined modification of the E-CABG perioperative bleeding classification will be adopted [26] ,which has been demonstrated to be commensurate with the Universal Definition of Perioperative Bleeding [27] in terms of predicting early mortality [28]. \u0026nbsp;Significant bleeding is outlined as the transfusion of a minimum of four units of red blood cells during and after the procedure and/or reoperation due to excessive intra-thoracic bleeding. \u003cstrong\u003e(Online supplementary table 3)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003e\u003cem\u003eReoperation for bleeding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe designation \u0026quot;reoperation for bleeding\u0026quot; is employed to denote any instance in which the sternum has been left open and subsequent surgery is required in order to address severe bleeding. It is of paramount importance to emphasise that instances of reopening the chest for haemodynamic instability without excessive bleeding, and pericardial or pleural puncture or chest tube placement for the retention of blood, do not fall under the classification of reoperations for bleeding\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.2. \u0026nbsp; Post Procedure Follow Up Visit \u0026nbsp;and Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe post-implantation period is defined as the 48 hours following the patient\u0026apos;s departure from the catheterisation laboratory/operation theatre. Study patients will be subjected to continuous monitoring on a clinical, haemodynamic and electrocardiographic basis during catheterisation for all local, systemic adverse events and complications. Following completion of the implantation procedure, all study patients will be monitored in accordance with the institution\u0026apos;s standard of care and will be subject to follow-up in accordance with the institution\u0026apos;s standard of care. The following information \u003cstrong\u003e(Table 7)\u003c/strong\u003e will be collected during the postoperative period, which includes discharge, and at subsequent follow-up visits at 30 days, 6 months, 12 months, and 2 to 10 years post-surgery. Discharge is the date and time a patient is released from care. For patients discharged within 48 hours of leaving the catheterisation laboratory or surgical suite, repeat tests collected during the post-procedure period do not need to be done again for discharge. If discharged on a weekend or public holiday, assessments may be conducted on the previous weekday. The period following valve implantation, which is defined as the 30-day postoperative visit window, commences on the day of the procedure and extends for a period of +14 days. The six-month follow-up visit is scheduled to take place from the initial visit date, while the 12-month postoperative follow-up evaluation visit window is set at +30 days. This is calculated from the valve implant date on the initial visit.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eSVD definition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSVD is defined by the deterioration of the leaflets or supporting structures of a bioprosthetic valve, which can result in thickening, calcification, tearing and disruption of the prosthetic valve materials. This leads to valve dysfunction. The underlying mechanisms of SVD remain to be fully elucidated, although several hypotheses have been postulated to date. These include tissue disruption or thickening due to mechanical stress and abnormal shear stresses; collagen fibre disruption; and tissue calcification. SVD excludes other forms of clinical valve abnormality not attributable to valve tissue deterioration. These include patient-prosthesis mismatch, device malposition, paravalvular regurgitation and abnormal frame expansion, although these may be associated with early SVD. As illustrated in \u003cstrong\u003eTable 8\u003c/strong\u003e, the stages of bioprosthetic valve deterioration is demonstrated according to the stipulated recommendations of VARC-3, with a focus on the categorisation of stent and stentless xenograft cases. [29] Readers are directed to \u003cstrong\u003esupplemental material S1\u003c/strong\u003e, in which the potential risks associated with SVD is documented.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eFunctional Status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eMACE (Major Adverse Cardiac Events)\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMACE is specified as an unweighted composite score. It consists of the following components\u003c/p\u003e\n\u003cp\u003e\u0026bull; Death\u003c/p\u003e\n\u003cp\u003e\u0026bull; Stroke\u003c/p\u003e\n\u003cp\u003e\u0026bull; Aortic valve re-intervention\u003c/p\u003e\n\u003cp\u003e\u0026bull; Worsening heart failure (+1 NYHA Class)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026bull; CHF hospitalization\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eNew York Heart Association (NYHA) Classification\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe determination of functional status is achieved through the utilisation of the NYHA classification scale. \u003cstrong\u003e(Supplementary table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eAngina Class\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe classification of angina is determined in accordance with the Canadian Cardiovascular Society Classification (CCSC) [30]. \u003cstrong\u003e(Supplementary table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eRe-operation\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA rigorous and comprehensive documentation of all re-operations will be performed, with particular attention allocated to aortic valve SVD/NSVD procedures. A time-to-event analysis will be utilised to evaluate the freedom from re-operation.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003ePeak VO2\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patients\u0026apos; functional status will be evaluated by measuring the maximal oxygen uptake (VO2 peak) through cardiopulmonary exercise testing. This will be conducted at pre-specified intervals in patients without contraindications. The exercise test will be administered uniformly to all patients, with a consistent verbal prompting protocol used to encourage them to exercise. If patients can\u0026apos;t reach an RER \u0026ge; 1.0, Borg\u0026apos;s CR10 RPE scale will be used to assess exertion level every 2 minutes during the study. The RPE scale will be used with instructions for all exercise tests and cards showing the scale will be given to each patient. Cardiopulmonary exercise testing will follow a standard protocol and will be interpreted by the cardiologist in charge at each centre.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eNeurocognition\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study\u0026apos;s primary objective is to compare treatment groups using a range of neurocognitive assessments. These include the Hopkins Verbal Learning Test, Trailmaking Tests A and B, MCG Complex Figures, the Boston Naming Test, Digit Span, and Digit Symbol Substitution Test. Clinical site staff will conduct the tests. Experienced neuropsychologists will train them. Neurology specialists will score the tests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eHospitalization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eIndex Hospitalization\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe length of stay for the index admission will be measured and subsequently disaggregated according to the number of days spent in the intensive care unit. Furthermore, the discharge location will be documented.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eReadmission\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReadmission ratios will be calculated for the initial 30 days following the procedure, as well as for the duration of the subsequent follow-up period. Hospitalisation data will be categorised for all conditions, including heart failure readmissions. To ascertain whether a readmission is heart failure related, at least two of the following signs and conditions of acute decompensated heart failure must be observed:\u003c/p\u003e\n\u003cp\u003e\u0026bull; Dyspnea felt related to HF\u003c/p\u003e\n\u003cp\u003e\u0026bull; Administration of vasodilators, intravenous diuretics or inotropes\u003c/p\u003e\n\u003cp\u003e\u0026bull; PCWP or LVEDP \u0026gt; 18 mmHg\u003c/p\u003e\n\u003cp\u003e\u0026bull; On physical examination, rales may indicate the presence of pulmonary edema or pulmonary vascular congestion as seen on X-ray.\u003c/p\u003e\n\u003cp\u003eThe investigator will classify all readmissions, which are then reviewed by the cardiologist overseeing the patient\u0026apos;s hospitalisation.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eDays Spent Alive and Outside of Hospital\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe objective of the study is twofold: firstly, to compare the total number of days alive and out of the hospital between the treatment groups; and secondly, to determine the percentage of days out of the hospital in relation to the total days alive post-procedure.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cem\u003eAppropriateness of revascularisation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore surgery, coronary arteries are checked to see if they are suitable for bypass. Afterwards, it is very important to closely monitor these arteries. To identify regions receiving coronary flow, the following should be used: LAD proximal, LAD distal, proximal diagonal, distal diagonal, proximal circumflex, distal circumflex, distal dominant circumflex, right posterolateral, and right posterior descending.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eQuality of Life\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs previously outlined in Section 2.3 on the assessment of cardiopulmonary status, quality of life assessments have been thoroughly documented.\u003c/p\u003e\n\u003cp\u003e\u0026uml; \u003cstrong\u003eAdverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSu-AVI is not without its potential risks. The inherent risks associated with the overall procedures themselves are due to SAVR and general anaesthesia. In addition to these, there are risks unique to the use of the study valve and its delivery systems. The reader is referred to supplementary \u003cstrong\u003etable 9\u003c/strong\u003e, where the potential risks associated with anaesthesia and Su-AVI procedures are reported.\u003c/p\u003e\n\u003cp\u003eAdverse events (AEs) are delineated as any medically undesirable incident, unintended disease or injury, or aberrant clinical symptom (including atypical laboratory findings) in patients, users, or other subjects, irrespective of their association with the investigational medical device. AEs may be reported by patients, either on their own initiative or at the prompting of the Investigator or their designee. They may also be identified through observation by the Investigator, the CEC, the Safety Team, or the Monitoring Team. The AEs to ascertain their relationship to the device and/or implant procedure, subsequently categorising them as related or unrelated to serious criteria based on their gravity. Should an AE be adjudged to have occurred, the Investigator is obligated to obtain all information necessary to complete the AE form. Additionally, patients are strongly advised to contact both the Investigator and/or the Study Coordinator should they experience significant adverse events occurring between scheduled study visits \u003cstrong\u003e(see Table 10).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eReporting of Serious Adverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInvestigators conducting NHLBI-supported clinical studies must report all serious adverse events (protocol-defined and unexpected) directly to the IRB and Case Examination Committee (CEC) \u0026nbsp;within 10 working days of knowledge, or as dictated by the specific IRB policy. The same applies to all deaths and unexpected serious adverse events, which must also be reported to the Case Examination Committee (CEC) \u0026nbsp;and the clinical centre\u0026apos;s IRB within 24 hours.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eSpecific Adverse Event Definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMI, a term denoting the death of heart muscle resulting from a lack of blood supply to the heart, is diagnosed when there is clinical evidence of myocardial necrosis consistent with myocardial ischaemia. [31] The following diagnosis may be made if any one of the following criteria are met:\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eMyocardial Infarction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvidence of an increase and/or decrease in cardiac biomarkers (ideally troponin) with at least one value above the 99th percentile of the upper limit of reference (URL), together with evidence of myocardial ischaemia with at least one of the following:\u003c/p\u003e\n\u003cp\u003eo ECG changes indicating new ischemia, such as new ST-T changes or new left bundle branch block (LBBB).\u003c/p\u003e\n\u003cp\u003eo Ischemia signs\u003c/p\u003e\n\u003cp\u003eo Pathological Q waves have developed in the ECG.\u003c/p\u003e\n\u003cp\u003eo Imaging findings of new loss of viable myocardium or new regional wall motion abnormalities.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003ePeri-CABG Myocardial Infarction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patients undergoing coronary artery bypass graft (CABG) with normal baseline troponin values, elevations of cardiac biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. Conventionally, biomarker elevations greater than 5 times the 99th percentile URL, in addition to new Q waves or new LBBB, new graft or native coronary artery occlusion documented by angiography, or imaging findings of new loss of viable myocardium, have been considered to diagnose CABG-related MI.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003ePeri-Percutaneous Intervention (PCI) Myocardial Infarction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor patients undergoing PCI with normal baseline troponin values, cardiac biomarker elevations above the 99th percentile URL indicate peri-procedural myocardial necrosis. Those over 3 times the 99th percentile are conventionally interpreted as PCI-related MI. There is a recognised subset associated with documented stent thrombosis.\u003c/p\u003e\n\u003cp\u003eSudden unexplained cardiac mortality linked to cardiac arrest, often with symptoms consistent with heart attack, and associated with suspected new ST elevation or new LBBB, and/or evidence of fresh blood clots by coronary angiography and/or autopsy, where death occurs before the collection of blood samples or the expected appearance of heart biomarkers in the blood, is classified as death due to heart attack.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eCardiac Arrhythmias\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecord any arrhythmia that causes impairment, e.g. heart failure, lack of urine, loss of consciousness or fainting, and this must be reported to hospital or doctor. Cardiac arrhythmias are classified into two categories:\u003c/p\u003e\n\u003cp\u003eo Persistent ventricular arrhythmia necessitating defibrillation or cardioversion\u003c/p\u003e\n\u003cp\u003eo Persistent supraventricular arrhythmia necessitating drug treatment or cardioversion\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eRight-sided heart insufficiency\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe diagnosis of persistent right ventricular dysfunction (RVD) is made when the central venous pressure (CVP) exceeds 18 mmHg and the cardiac index falls below 2.0 L/min/m2. This is in the absence of elevated left atrial/pulmonary capillary wedge pressure (\u0026gt; 18 mmHg), tamponade, ventricular arrhythmias or pneumothorax. Treatment may necessitate the implantation of a right ventricular assist device (RVAD), inhalation of nitric oxide or inotropic therapy for a duration exceeding seven days.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eMajor Infection\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA novel episode of clinical infection, accompanied by manifestations of pain, fever, drainage and/or leukocytosis, occurs within the context of antimicrobial treatment, specifically non-prophylactic regimens. A positive culture from the infected site or organ is required for a diagnosis, unless there is strong clinical evidence that treatment is required despite a negative culture. The following categories of infection are recognised:\u0026nbsp;[24,25]\u003c/p\u003e\n\u003cp\u003eo Localized Infection\u003c/p\u003e\n\u003cp\u003eThe infection is confined to a specific organ or region, such as mediastinitis, and there is an absence of evidence of systemic involvement (as defined by sepsis). This determination is made through the utilisation of standard clinical methodologies and may be accompanied by indications of bacterial, viral, fungal, or protozoal infection, or necessitate empirical therapeutic intervention.\u0026nbsp;[24,25]\u003c/p\u003e\n\u003cp\u003eo Endocarditis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe ensuing clinical signs, symptoms and laboratory tests have been identified as manifestations of endocarditis: fever of 38. 0\u0026deg;C or higher, positive blood cultures, new regurgitant murmurs or heart failure, the presence of embolic phenomena (e.g. focal neurologic impairment, glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and peripheral cutaneous or mucocutaneous lesions (e.g. petechiae, conjunctival or splinter hemorrhages, Janeway lesions, Osler\u0026apos;s nodes, and Roth spots). If echocardiography reveals a new intra-cardiac vegetation, along with or without other signs and symptoms, this should be considered sufficient evidence to support the diagnosis of endocarditis. TEE is the \u0026nbsp;recommended diagnostic tool for prosthetic valve endocarditis. [24,25]\u003c/p\u003e\n\u003cp\u003eo Sepsis\u003c/p\u003e\n\u003cp\u003eThere is sign of systemic involvement by infection as evidenced by positive blood cultures and/or hypotension.\u0026nbsp;[24,25]\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eNeurologic Dysfunction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe presence of any new neurological deficit, whether transient or permanent, focal or global, must be identified by means of a standard neurological examination (performed by a neurologist or other qualified physician and documented by appropriate diagnostic tests and consultation notes). The physician conducting the investigation is tasked with distinguishing between transient ischaemic attack (TIA) and stroke. The term \u0026quot;transient ischemic attack (TIA)\u0026quot; refers to a fully reversible condition that occurs within 24 hours and does not demonstrate evidence of infarction. Conversely, the term \u0026quot;stroke\u0026quot; denotes a condition that persists for more than 24 hours or lasts less than 24 hours but does demonstrate evidence of infarction. The presence and severity of neurological deficits must be documented by means of the administration of the Modified Rankin Scale and the NIH Stroke Scale at two points in time: firstly, at the time of the event (within 72 hours following the event); and secondly, 90 days following the event.\u003c/p\u003e\n\u003cp\u003eSubcategories must be assigned to each neurological event as:\u003c/p\u003e\n\u003cp\u003eo Ischemic or Hemorrhagic Stroke, also known as Cerebrovascular Accident, is considered to be an event lasting more than 24 hours or less than 24 hours and accompanied by infarction on imaging. If an ischemic stroke undergoes hemorrhagic conversion, it should still be classified as ischemic.\u003c/p\u003e\n\u003cp\u003eo Toxic metabolic encephalopathy is characterised by a disturbance in brain function resulting from abnormal systemic metabolism or exogenous agents. This disturbance in function can alter an individual\u0026apos;s level of awareness and/or consciousness. The neurological examination and brain scan are both non-focal.\u003c/p\u003e\n\u003cp\u003eo Other\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eRenal Events\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe classification of renal function will be based on the estimated glomerular filtration rate (eGFR), which will be calculated using both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [32] and the European Kidney Function Consortium (EKFC) equation [33]. The severity of renal failure will be classified into different stages, as listed in \u003cstrong\u003eSupplementary Table 4.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo types of kidney related events will be recognised:\u003c/p\u003e\n\u003cp\u003eo Renal Dysfunction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbnormal kidney function is defined as a rise in serum creatinine (Cr) of more than 100% from baseline, and a Cr level greater than 2.0.\u003c/p\u003e\n\u003cp\u003eo Renal Failure\u003c/p\u003e\n\u003cp\u003eNew requirement for hemodialysis related to renal dysfunction. This definition excludes aquapheresis for volume removal alone.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eHepatic Dysfunction\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf any two of the following liver test results (total bilirubin, aspartate aminotransferase/AST and alanine aminotranferease/ALT) are three times higher than the upper limit of normal for the hospital, or if liver dysfunction is the main cause of death.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eRespiratory insufficiency\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRespiratory function impairment that requires re-intubation, tracheostomy, or the inability to discontinue ventilatory support within 48 hours after surgery. This does not include intubation for re-operation or temporary intubation for diagnostic or treatment purposes.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eBleeding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA bleeding incident is characterised by any of the following\u003c/p\u003e\n\u003cp\u003e\u0026middot; Death due to hemorrhage can occur when more than 10 units of red blood cells are transfused within the first 24 hours following surgery.\u003c/p\u003e\n\u003cp\u003e\u0026middot; Re-operation may be necessary in cases of hemorrhage or tamponade.\u003c/p\u003e\n\u003cp\u003eNOTE: A hemorrhagic stroke is classified as a neurological event rather than a distinct bleeding event\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003ePericardial Fluid Trapping\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePericardial effusion is the collection of fluid or thrombus in the pericardial space requiring surgical intervention or percutaneous catheter drainage. This event can be further classified into two categories: those with clinical signs of tamponade (such as increased central venous pressure and decreased cardiac output) and those without signs of tamponade.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eArterial Non-CNS Thromboembolism\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConfirmation of an acute systemic arterial perfusion deficit in any non-cerebrovascular organ system due to thromboembolism can be made by one or more of the following:\u003c/p\u003e\n\u003cp\u003eo Standard clinical and laboratory testing o Operative findings\u003c/p\u003e\n\u003cp\u003eo Autopsy findings\u003c/p\u003e\n\u003cp\u003eThis definition excludes neurological events.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eWound Dehiscence\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurgical incision disruption, not caused by infection, that needs to be surgically repaired.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eVenous Thromboembolic Event\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical and laboratory evidence of a venous thromboembolic event, such as deep vein thrombosis or pulmonary embolism, can be detected using standard tests.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u003cstrong\u003e\u003cem\u003eOther\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn occurrence that results in a clinically significant alteration in the patient\u0026apos;s state of health, or any event that is life-threatening, results in death, leads to permanent disability, necessitates hospitalisation or prolongs an existing hospital course.\u003c/p\u003e"},{"header":"6. Assesment for statistical analysis","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e6.1. Sample Size Calculations\u003c/h2\u003e \u003cp\u003eThe trial sample size was derived based on achieving at least 85% power to detect the 1-, 5-, and 10-year safety and effectiveness endpoint. Data from previous studies were used to derive event rate estimates for the primary safety and efficacy endpoint. As the current study population is a lower risk cohort, rates have been adjusted to account for procedural refinements over time in both groups and changes in definitions of endpoint components.\u003c/p\u003e \u003cp\u003eSample sizes are driven by the composite primary outcome assuming an event rate of 16.6% in the St-AVR arm and 14.6% in the Su-AVI arm. The study would have 85% power to detect the endpoint with a sample size of 867 patients and 10-year data. This sample size is calculated using a one-tailed Score test (Farrington \u0026amp; Manning) with a significance level of alpha\u0026thinsp;=\u0026thinsp;0.025 and incorporating the required non-inferiority margin of relative 35%.\u003c/p\u003e \u003cp\u003eThe estimate of the primary sample size has been derived using a pure frequency analysis; however, the Kaplan-Meier estimates will be used for the endpoint analysis. The sample size is expected to be adequate given the equivalence of the two methods in the absence of censoring and the expected sufficiency of uncensored patients. However, an actual sample size of 1,020 has been set, representing a 15% increase over the minimum size considered statistically justified, given the highly uncertain feasibility assumptions associated with this previously unstudied population. This increased sample size is designed not only to meet the trial's needs, but also to allow additional flexibility for unforeseen events, such as dropouts or loss to follow-up, that are inherent in clinical trials. For several unpowered secondary endpoints, this size is also expected to improve the power of the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e6.2. Analysis Populations\u003c/h2\u003e \u003cp\u003eThe Intention to Treat (ITT) population consists of all patients enrolling in the study, while the As Treated (AT) population consists of all patients initiating the index intervention, regardless of whether they complete the index intervention. In cases where multiple procedures are performed, the last procedure that involves implanting the investigational valve is considered to be the index procedure. This procedure will then be used to determine the as-treated study allocation, and the date of the index procedure will be used to determine all subsequent follow-up visits and associated assessments.\u003c/p\u003e \u003cp\u003eThe valve implantation (VI) population is the subset of the as-treated (AT) population, which comprises all patients who will receive and will retain the designated valve at the index procedure.\u003c/p\u003e \u003cp\u003eIn addition, patients who are converted from SuAVR to StVR during the procedure will also be part of the VI population. For endpoint analysis, the AT population will be used as the primary population. The VI population is used to analyse echocardiographic data and related outcomes, while selected sensitivity analyses are conducted using the ITT population.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e6.3. Endpoint analysis\u003c/h2\u003e \u003cp\u003ePrimary endpoints include operative mortality and survival. Late deaths at a linearised rate will be defined as valve and non-valve related deaths at one, five and ten years after procedure completion. As outlined in the study protocol, a non-inferiority analysis will be conducted on these endpoints, with a relative non-inferiority margin set at 35%. The components of the composite endpoint will undergo systematic analysis by the CEC. Patients will be classified as having experienced the endpoint once any component of that endpoint is documented. Conversely, if no such record is found, the subject will be deemed to be free of the endpoint, resulting in their exclusion from subsequent analyses. The analysis will instead be based on a maximum of one record of the individual's survival and absence of events.\u003c/p\u003e \u003cp\u003eThe event rate difference endpoint test will be conducted with a non-inferiority margin of a relative 35%.The one-sided non-inferiority test will be performed at an alpha level of 0.025, and the two-sided 95% confidence limit for the event rate ratio (SuAVR/StAVR) will be computed. It is imperative to highlight that the stipulated acceptance criterion is contingent upon the upper confidence limit not exceeding 1.35.In the event that the non-inferiority analysis yields a satisfactory outcome, the subsequent superiority analysis will be conducted. The type I error rate for this analysis is safeguarded by the non-inferiority analysis, thereby obviating the necessity for an alpha adjustment.\u003c/p\u003e \u003cp\u003eSecondary endpoints have been divided into two categories. For the key secondary endpoints, a prespecified hierarchical order will be used to conduct testing for superiority, with the implementation of a gatekeeping method to control for multiple comparisons. P values will be presented alongside claims of significance. Conversely, for other secondary endpoints, analyses will be conducted without the application of a correction for multiple comparisons. As a consequence of this decision, the presentation of hazard ratios and 95% confidence intervals will not include P values or any statements as to significance. It is important to note that inferences derived from these 95% confidence intervals may lack reproducibility.\u003c/p\u003e \u003cp\u003eIn order to facilitate the accurate comparison of continuous variables, it is recommended that Student's t-test or Wilcoxon rank-sum test be utilised. Similarly, for categorical and ordinal data presented as proportions, Fisher's exact test or Wilcoxon rank-sum test will be appropriate. Following the implementation of a baseline, the continuous variables will be analysed through the utilisation of an analysis of variance with adjustment for baseline measurement. Time-To-Event analyses will employ Kaplan-Meier estimates, which will subsequently undergo comparison with the utilisation of a log-rank test. Echocardiographic analyses will be conducted on the valve-implant population, which comprises patients in whom the intended valve is inserted. All statistical analyses will be conducted using R software (R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e \u003c/div\u003e"},{"header":"7. Discussion","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.1 The context in which SAVI-AVR operates\u003c/h2\u003e \u003cp\u003eSutureless valve technology is believed to offer a number of key benefits, including a reduction in ischemic surgical time in comparison to conventional sutured valves [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, there is currently an absence of compelling data to suggest that the decrease in aortic cross-clamp time, which is facilitated by the use of the aforementioned sutureless valve technology, may result in improvements in morbidity or mortality [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38 CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA study was conducted to investigate the effects of cross-clamp times in patients undergoing Su-AVI and full sternotomy SAVR. The results showed a significant reduction in cross-clamp times in the SuAVI group when compared with the full sternotomy SAVR group. However, no significant differences were observed in terms of cumulative CPB time or clinical outcomes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The findings under consideration were obtained from the CADENCE-MIS trial [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], a randomised study that compared minimally invasive Su-AVI with rapid deployment valves with full sternotomy SAVR. Nevertheless, several retrospective observational studies have posited an association between prolonged cross-clamp or CPB times and an increased risk of postoperative complications, including renal failure, respiratory failure, postoperative low-output syndrome, postoperative atrial fibrillation, increased transfusion demands, and prolonged postoperative hospital stays, as well as trends in mortality [\u003cspan additionalcitationids=\"CR43\" citationid=\"CR43\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe conducted a pooled cumulative analysis of the utilisation of the Su-AVI as a wireless option for patients with AVR, incorporating both observational and randomised evidence. This analysis drew parallels between Su-AVI and St-AVR, and revealed no statistically significant difference in mortality at one year (OR: 1.01; 95% CI: 0.87\u0026ndash;1.16; P\u0026thinsp;=\u0026thinsp;0.97). A further finding of interest was that when the results of RCTs were compared with those of retrospective or propensity-matched cohorts, no statistically significant difference in 1-year mortality was found [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt has been posited that analysis of data collated during the course of the SAVI-AVR prospective trial may have the capacity to produce contemporary results for a substantial number of patients suffering from severe aortic valve stenosis. This analysis would benefit from an extended follow-up period, thus providing valuable insights into the natural history of the condition.\u003c/p\u003e \u003cp\u003eThe SAVI-AVR trial's primary objective lies in the compilation of data intended to offer insight into the consequences of varied surgical interventions on standard aortic valve surgery involving St-AVR or Su-AVI. Subsequent to the PERSIST-AVR trial [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], which encompasses a minimum of five years of observation (less than the ten years of SAVI-AVR), the present study has been initiated at opportune juncture.\u003c/p\u003e \u003cp\u003eThe overarching objective of the SAVI-AVR investigation is to systematically collate substantial clinical data, with a focus on elucidating the implications of diverse surgical interventions on conventional aortic valve surgery, employing either the St-AVR or Su-AVI approach. The present undertaking constitutes an ambitious endeavour, encompassing a comprehensive evaluation of long-term outcomes in addition to an in-depth assessment of mortality rates. The investigation will focus on the incidence of valve-related mortalities and the necessity for re-interventions due to structural valve degeneration.\u003c/p\u003e \u003cp\u003eLikewise, the PERSIST-AVR trial has considered freedom from major cerebral and cardiovascular events (MACCE) as the primary outcome [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. MACCE is a composite of death from any cause, myocardial infarction, stroke, or valve reintervention at 1 year. This RCT has demonstrated that Su-AVI prove noninferior to St-AVR with regard to MACCEs at one-year follow-up in patients undergoing aortic valve replacement (either as a standalone procedure or in conjunction with coronary artery bypass grafting). It is important to note that the RCT conducted by Fischlein et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] demonstrated the superiority of the sutureless valve in terms of reduced procedural times, both in isolated and combined procedures. These results, however, failed to manifest as discernible clinical benefits at either 30-day or 1-year follow-up, as observed in the comprehensive study findings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.2. The lack of reliable evidence in guidelines is the driving force behind the present study.\u003c/h2\u003e \u003cp\u003eIn the preceding two decades, the cardiology and cardiac surgery community has achieved considerable progress in the domain of biological prosthetic valve design and implantation techniques [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e46\u003c/span\u003e].These advancements have proven instrumental in the management of AVS through the utilisation of novel platform technologies for the treatment of structural heart disease. The recent progress witnessed in this field have precipitated the emergence of both transcatheter and minimally invasive approaches, thereby signifying a substantial evolution in the realm of cardiovascular medicine. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Consequently, there is a pressing need for an increased number of prospective randomised and non-randomised trials in order to assess the safety and clinical efficacy of Su-AVI in comparison to St-AVR. This necessity has arisen as a consequence of an increased utilisation of rapid-deployment techniques.\u003c/p\u003e \u003cp\u003eFollowing the first transcatheter aortic valve replacement (TAVR) procedure carried out by Cribier in 2002, [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e47\u003c/span\u003e] over 1.500.000 patients have undergone TAVR worldwide [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The development of international guidelines recommending TAVR over conventional methods has been demonstrated [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR50 CR51 CR52 CR53 CR54 CR55 CR56 CR57 CR58\" citationid=\"CR50\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. The utilisation of TAVR in lieu of traditional surgical intervention for the treatment of AVS is endorsed by substantial research findings, as evidenced by numerous randomised, multicentre trials. These findings substantiate the efficacy and safety of the procedure, thus classifying it as a Class of Recommendation (COR) I, Level of Evidence (LOE) A, representing the highest level of recommendation available [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Conversely, the estimated number of SuAVR implants is projected to reach 75,000 by the year 2022. However, the number of patients who have undergone Su-AVI since the pioneering Percevalve sutureless valve implantation in 2007 remains significantly lower [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e60\u003c/span\u003e].As a consequence, the robustness of the results is substantially different between the two procedures, as evidenced by a limited number of multicentre RCTs supporting the use of Su-AVI [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e47\u003c/span\u003e].(43\u0026ndash;45) The aforementioned findings bear significant implications for the safety and efficacy recommendations outlined in international guidelines and supported by COR 1, LOE A[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e60\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn the preceding decade, there have been notable developments in surgical technique and experience with regard to the treatment of AVS. The utilisation of age-adjusted statistics serves to mitigate this effect to a certain extent. The present paper sets out the findings on how the protocol's definitions for the Su-AVI and St-AVR, as well as long-term outcomes, have not been standardised.\u003c/p\u003e \u003cp\u003eThe dearth of multicentre RCTs encompassing a substantial number of patients has impeded the acquisition of recommendations categorised as COR 1 LOE A for the utilisation of Su-AVI. Nevertheless, this prospective study design is inherently constrained by the non-randomised nature of the study, and this variability introduces potential inaccuracies into the study data. Moreover, the crossover rate may be relatively high, with the potential for divergent outcomes between the per-protocol and modified intention-to-treat populations. The decision regarding valve size is delegated to the attending surgeon's discretion. However, the relatively high incidence of sizes 19 and 21 mm may be possible in the stented valve group, aligning with the findings of numerous other clinical studies [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR62 CR63 CR64\" citationid=\"CR62\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e65\u003c/span\u003e] that reported outcomes in BP at the aortic valve position. The management of intraoperative, intensive care, and anticoagulation protocols will be determined by the treating physician and the specific centre. The study involved centres with expertise in the techniques, but recruitment rates were heterogeneous across sites.\u003c/p\u003e \u003cp\u003eThe present study will involve the completion of one of the largest multicentre prospective non-randomised trials currently available, comparing Su-AVI and St-AVR. The protocol under development has the potential to address a significant knowledge gap, particularly in the context of the paucity of large, randomised studies that have yielded substantial results.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eParticipation in the SAVI-AVR prospective non-randomised trial by healthcare facilities is dependent on the demonstration of a minimum annual number of aortic valve stenosis procedures, set at 200. In addition, the centres must implement a programme that enables effective follow-up and management of any late aortic events following surgical replacement. It is imperative that the surgical procedure in question utilises conventional St-AVR or a rapid deployment Su-AVI.\u003c/p\u003e \u003cp\u003eA comprehensive synthesis of the outcomes from the analytical investigation, which drew parallels across two distinct surgical procedures of SAVR for AVS\u0026ndash; Su-AVI and St-AVR \u0026ndash; is presented below. This is facilitated through the prospective study's multicentre approach, which enabled a comprehensive evaluation.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe study sets out to ascertain whether there are any differences in the occurrence of late deaths at a linear rate both as valve-related and non-valve-related between cohorts at 10 years following St-AVR or Su-AVI.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSpecifically, it seeks to identify which procedure leads to the optimal outcome for composite treatment failure endpoint. This comprises cardiac death, reoperation for SVD and time to explant due to SVD.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhich of the two procedures (Su-AVI and St-AVR) achieves the low risk of SVD and what percentage of patients can benefit from this in the long term follow up in term of freedom from reoperation.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLV remodelling and improved LV dimensions over a 10-year period.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhether patients with improved LVEF also exhibit a lower rate of readmission due to improved HF symptoms and a lower rate of NYHA class worsening.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhich of the two procedures achieves low rates of MACEEs and what percentage of patients can benefit from this in the long term.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhich of the two cohorts, defined by the percentage of patients who experienced residual aortic AV regurgitation progression during follow-up, will demonstrate more severe HF symptoms.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAV ; Aortic valve\u003c/p\u003e \u003cp\u003eAVS; Aortic valve stenosis\u003c/p\u003e \u003cp\u003eBP; bioprosthesis\u003c/p\u003e \u003cp\u003eCABG; coronary artery bypass graft\u003c/p\u003e \u003cp\u003eCAD; coronary artery disease\u003c/p\u003e \u003cp\u003eCPB; cardiopulmonary bypass\u003c/p\u003e \u003cp\u003eCE; Carpentier-Edwards\u003c/p\u003e \u003cp\u003eCEPME; Carpentier Edwards Perimount Magna Ease\u003c/p\u003e \u003cp\u003eCT; computed tomography\u003c/p\u003e \u003cp\u003eLVEF ; left ventricular ejection fraction\u003c/p\u003e \u003cp\u003eMRI; magnetic resonance imaging\u003c/p\u003e \u003cp\u003eNYHA; New York Heart Association Class\u003c/p\u003e \u003cp\u003ePCI; percutaneous coronary intervention\u003c/p\u003e \u003cp\u003eSAVI-AVR; Sutureless Aortic Valve Replacement Versus Stented Aortic Valve Replacement for Aortic-Valve Stenosis\u003c/p\u003e \u003cp\u003eSAVR; surgical aortic valve replacement\u003c/p\u003e \u003cp\u003eSt-AV; stented aortic valve\u003c/p\u003e \u003cp\u003eSt-AVR; stented aortic valve replacement\u003c/p\u003e \u003cp\u003eSu-AV; sutureless aortic valves\u003c/p\u003e \u003cp\u003eSu-AVI; sutureless aortic valve implant\u003c/p\u003e \u003cp\u003eSVD; structural valve deterioration\u003c/p\u003e \u003cp\u003eTAVR; transcatheter aortic valve replacement\u003c/p\u003e \u003cp\u003eTEE; transesophageal echocardiography\u003c/p\u003e \u003cp\u003eTHV; transcatheter heart valve\u003c/p\u003e \u003cp\u003eTTE; transthoracic echocardiography\u003c/p\u003e \u003cp\u003eVARC; Valve Academic Research Consortium\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFN, AS, SSAS, ZED, AF, CS contributed to planning this \u0026nbsp;prospective non randomized trial and its related studies as well as to develop the datasheet for data collection. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be performed without external financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study does not contain individual patient data and ethics approval is not \u0026nbsp;applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript does not contain individual person\u0026rsquo;s data in any form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eOtto CM, Prendergast B. 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N Engl J Med 2014;370:1790-8.\u003c/li\u003e\n \u003cli\u003eGleason TG, Reardon MJ, Popma JJ, et al. 5-Year outcomes of self-expanding transcatheter versus surgical aortic valve replacement in high-risk patients. J Am Coll Cardiol 2018;72:2687-96.\u003c/li\u003e\n \u003cli\u003eSAVR TAVR volumes. Presented at a meeting of the Society of Thoracic Surgeons\u0026ndash;American College of Cardiology TVT Registry Stakeholder Advisory Group, Washington, DC, March 4, 2019.\u003c/li\u003e\n \u003cli\u003eMeuris B, Lamberigts M, Szecel D. The importance of sizing in sutureless valves. Interact Cardiovasc Thorac Surg. 2022 Aug 3;35(3):ivac206\u003c/li\u003e\n \u003cli\u003eGoldstone AB, Chiu P, Baiocchi M, Lingala B, Patrick WL, Fischbein MP, Woo YJ. Mechanical or Biologic Prostheses for Aortic-Valve and Mitral-Valve Replacement. N Engl J Med. 2017 Nov 9;377(19):1847-18\u003c/li\u003e\n \u003cli\u003eBlackstone EH, Cosgrove DM, Jamieson WR, Birkmeyer NJ, Lemmer JH Jr, Miller DC, et al. Prosthesis size and long-term survival after aortic valve replacement. J Thorac Cardiovasc Surg. 2003;126:783-96.\u003c/li\u003e\n \u003cli\u003eISTHMUS Investigators. The Italian study on the Mitroflow postoperative results (ISTHMUS): a 20-year, multicentre evaluation of Mitroflow pericardial bioprosthesis. Eur J Cardiothorac Surg. 2011;39:18-26.\u003c/li\u003e\n \u003cli\u003eGoldman S, Cheung A, Bavaria JE, Petracek MR, Groh MA, Schaff HV. Midterm, multicenter clinical and hemodynamic results for the Trifecta aortic pericardial valve. J Thorac Cardiovasc Surg. 2017;153:561-9. e2.\u003c/li\u003e\n \u003cli\u003eYoshikawa Y, Okada Y, Okita Y, Yaku H, Kobayashi J, Uesugi H, et al. Long-term outcomes of the mosaic aortic porcine bioprosthesis in Japan\u0026ndash;results from the Japan mosaic valve long-term multicenter study. Circ J. 2020;84:1261-70.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 10 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Aortic valve stenosis, Surgical aortic valve replacement, Sutureless aortic valve implantation, Transcatheter aortic valve implantation","lastPublishedDoi":"10.21203/rs.3.rs-6251208/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6251208/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAortic valve (AV) stenosis (AVS) constitutes the most common major primary valvular pathology requiring surgical or transcatheter intervention in Europe and North America. This condition is increasing in prevalence at a rapid rate, consequent to the ageing population. There exists a range of mechanical interventions for the treatment of aortic valve stenosis (AVS), but there is currently a lack of robust evidence comparing the effectiveness of surgical aortic valve replacement (SAVR) with conventional stented xenograft aortic valve (St-AV) or sutureless aortic valves (Su-AV). The objective of the present study is to make a comparison between the effectiveness and clinical outcomes of SAVR using St-AV or Su-AV in patients with AVS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe conception of the SAVI-AVR trial (NCT:05261204; IRB: 2022011057) is the result of a collaboration between three cardiac surgery centres across two European countries. The SAVI-AVR registry will enrol consecutive patients who have undergone surgical interventions for AVS using sutureless aortic valve implant (Su-AVI) and stented aortic valve replacement (St-AVR). The study period will span from January 2015 to December 2025, encompassing a total of patients who will be enrolled. The primary objective of the research is to assess the differences between the standard surgical approaches Su-AVI and St-AVR. The primary clinical outcome under consideration will be operative mortality and survival. That is to say, the mortality rates recorded within a given time period after the procedure has been completed at 10 years. The present study will also encompass a number of secondary endpoints, including time to explant for structural valve degeneration, occurrence of stroke, necessity for reoperation, readmission due to any cause, and emergence of new-onset atrial fibrillation within 30 days, 1 year, 5 years and 10 years. Additionally, the study will examine the length of primary hospitalization and the presence of poor treatment outcomes.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThe hypothesis that the nature of the trials will serve to minimise bias related to institutional volume and surgical experience is postulated. Participating centres are obliged to possess an aortic valve programme, with the capability to ensure adequate postoperative follow-up and management of late complications arising from aortic valve replacement surgeries for AVS. The data that will be collected will provide valuable insight into the comparative effectiveness of various surgical approaches, both standard and advanced, in aortic valve replacement surgery. This will be achieved using Su-AVI and St-AVR. It is further expected that this comprehensive analysis will contribute significantly to the development of robust international guidelines.\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e \u003cp\u003eClinical Trial Gov. Com. ID: NCT05261204 IRB. 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