Durability of bioprosthetic aortic valves in patients under the age of 60 years – rationale and design of the international INDURE registry

Patients under the age of 60 years undergoing SAVR and receiving the INSPIRIS RESILIA aortic valve prosthesis will be enrolled on a consecutive basis. In addition to the applicable criteria of the device Instructions for Use (IFU), the registry inclusion criteria stipulate that patients require a planned replacement of their native valve as indicated in a preoperative evaluation, are scheduled to undergo planned AVR with or without concomitant root replacement and/or coronary bypass surgery. The latter is understood as isolated AVR with or without CABG and ascending aortic replacement. Also allowed is pulmonary vein isolation if it is not a full cox-maze procedure. Patients with a Bentall procedure or any surgery on other valves are not allowed in this registry. Patients need to be available to attend yearly follow-up visits at the registry centre for up to 5 years and all patients are required to provide written informed consent.

Patients will be excluded from the study if 1) they have active endocarditis/myocarditis at the time of surgery or have had it within the last 3 months of the scheduled SAVR, 2) have had previous AVR, 3) valve implantation is not possible in accordance with the device IFU, or 4) they have an estimated life expectancy of less than 12 months for any reason. The intraoperative exclusion criterion is that valve implantation is not possible in accordance with the device IFU.

The primary objectives (Table 1) are to 1) determine the time-related valve safety at 1-year (composite endpoint according to the VARC-2 criteria) depicted as freedom from events [23] and 2) determine freedom from stage 3 SVD following the Salaun definition at 5 years [23, 24]. Events include SVD (either valve-related dysfunction, defined by haemodynamic parameters or the need for repeat procedure), prosthetic valve endocarditis, prosthetic valve thrombosis, thromboembolic events (e.g., stroke) and valve-related bleeding.

The secondary objectives are designed to assess haemodynamic performance and further durability parameters, clinical outcomes and quality-of-life (QoL). The first group of objectives is further defined as the haemodynamic performance of the INSPIRIS RESILIA aortic valve including patient prosthesis mismatch (PPM); SVD following the Salaun definition; and the description of potential valve-in-valve procedures and clinical outcomes. Clinical outcomes of interest are NYHA functional class compared to baseline and freedom from valve-related hospitalisation. Quality-of-life will be assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Short Form-12 Health Survey (SF-12) [24]. Various additional exploratory analyses regarding rehospitalisation, costs and safety will also be performed.

The clinical outcome data collected will be based on the site’s standard-of-care for surgical AVR. Data will be collected prospectively, according to the timetable set out in Table 2, and include medical history, physical assessments, electrocardiogram (ECG), laboratory results, computerised tomography (CT) scans (if performed as a standard-of-care), transthoracic/transoesophageal echocardiography and QoL measures. Anti-thrombotic therapy and medications are at the discretion of each investigator. Data will be captured on an electronic case report form (eCRF) by either a study nurse or physician, and data will be checked automatically for plausibility and completeness.

Digital imaging and communication in medicine (DICOM) files of echocardiograms generated at years 1 and 5 will be collected for analysis by the Echo Core Laboratory to ensure unbiased and consistent analysis of the diagnostic data and, with the use of serial echocardiographic studies conducted on the same patient, for evaluating patient status over the course of 5 years.

Mechanical valves are generally preferred over bioprosthetic valves for younger patients undergoing AVR because of their perceived greater durability with the 15-year rates of redo-surgery being 6.9% for mechanical and 12.1% for biological heart valves [10]. It is suggested that mechanical valves will last throughout the remainder of the patient’s lifetime [25]. Mechanical valves do, however, require daily treatment with anticoagulants, which will increase the risk of bleeding. Lifelong anticoagulation can be difficult for patients with a history of bleeding issues or an increased risk of injury related to an active lifestyle. There may also be dietary restrictions, including reducing the intake of foods rich in vitamin K when taking vitamin K antagonists [26]. Newer (or non-vitamin K) oral anticoagulants (NOACs) are strictly contraindicated in patients with any mechanical prostheses [15, 27, 28]. Next to all the anticoagulation-related problems, reoperations can be needed even in mechanical valves in case of pannus overgrowth. Bioprosthetic valves do not require long-term daily anticoagulants but are at risk of SVD requiring reoperation [26]. The risk/benefit profile of mechanical versus bioprosthetic valves has led to both American and European guidelines on valvular heart disease recommending the use of mechanical valves in patients younger than 50 years [14, 15] with the European version extending this recommendation to patients up to 60 years (class IIa, level C) and the American guidelines considering both mechanical and bioprosthetic valves in patients between 50 and 70 years of age (class IIa, level B, no RCT data). Despite these recommendations, the use of bioprosthetic valves has significantly increased over the last few decades across all age groups [26]. Currently bioprosthetic valves are being developed that avoid the risk of valve required anticoagulation while reducing the reoperation rates seen with earlier generation bioprosthetic valves.

The ultimate goal when developing durable bioprosthetic valves, which are particularly required for younger patients, is to ascertain an uncompromised haemodynamic function over the very long term with no structural degeneration that would otherwise lead to a requirement for valve replacement or valve-in-valve (ViV) interventions or death [29, 30]. The data required, however, would take 10, 15 or even 20 years to be collected and assessed and, as such, shorter-term surrogates of valve degeneration have been developed which facilitate shorter valve development cycles. The criteria are plenty, but have been recently reviewed by different author groups including Capodanno et al. [31], Dvir et al. [32] and Salaun et al. [24], partly in an attempt to provide standardised definitions of SVD for bioprosthetic aortic valves. The definition of SVD by Salaun [24] (Table 3) has been adopted in the current project as it incorporates terminology proposed by both Dvir [32] and Capodanno [31] and was compatible with the definition used by Pibarot et al. [34] (see below). We will, however, capture the components of the other definitions as well aiming to explore and compare these as well.

The RESILIA tissue has been studied in two trials to date [17, 18] with a total of 812 patients showing that its use results in excellent haemodynamic performance and safety up to 2 years. Both the RESILIENCE trial [34] and the INDURE registry were set up in order to assess the long-term performance and structural integrity of bioprosthetic valves using the RESILIA tissue in younger patients. RESILIA tissue incorporates an anti-calcification process, by permanently blocking the residual aldehyde groups that are known to bind calcium. Calcification is known to occur more commonly on bioprosthetic valves than mechanical valves [35]. It, therefore, has the potential to increase valve longevity and consequently reduce re-intervention rates.

Both INDURE and RESILIENCE (Table 4) are prospective studies, including patients with either the INSPIRIS RESILIA valve (INDURE) or any RESILIA tissue bearing valve (RESILIENCE). While INDURE will follow patients from the time of surgery for 5 years, RESILIENCE pursues retrospective inclusion of patients with the first visit being 5-years after surgical intervention and a prospective follow-up (up to year 11 after the implant). On the one hand, INDURE puts emphasis on a combination of time-related valve safety at 1-year, SVD defined according to Salaun [24] using a CoreLab and clinical outcomes, while on the other hand RESILIENCE focuses on the multi-slice computed tomography (MSCT) and echo-based (both CoreLab) prediction of re-intervention or valve-related death. Projected completion dates are 2025 (INDURE) and 2027 (RESILIENCE), respectively.

Up and beyond INDURE and RESILIENCE there is a third long-term data collection ongoing (IMPACT; NCT04053088) using the INSPIRIS RESILIA valve. It is being conducted in Germany, Austria, Switzerland and The Netherlands and will follow up to 500 patients for 5 years. The principal objective of IMPACT is the assessment of the impact of comorbidities such as chronic kidney disease (CKD), diabetes, hypertension, metabolic syndrome and inflammation on all-cause mortality. Among the secondary objectives there is, again, assessment of SVD, which will complement the data derived from INDURE and RESILIENCE.

The INDURE registry is a prospective, open-label, multicentre, international registry. The multinational nature of this registry increases the applicability of findings to clinical practice all over Europe and Canada. However, it has no control group making a comparison of different bioprosthetic valves or valve generations impossible. Furthermore, there is no comparison of the bioprosthetic valve data with the outcomes of mechanical valve implantation, which would be desirable, but goes beyond the possibilities of such a project. Because of the multicentre design, an Echo CoreLab has been established to have a uniform assessment of SVD over the time course of the 5-year follow-up. We considered establishing an MSCT CoreLab, as has been incorporated in the RESILIENCE trial, but it would have violated the non-interventional nature of the INDURE registry as most sites reported that an MSCT is not standard-of-care at their institution, which may be considered as a limitation. Nonetheless these data can be documented in case they are available from routine practice. Finally, the same INSPIRIS RESILIA valve will be used in all patients in the INDURE registry which will abolish any bias introduced by the use of different bioprosthetic valves.