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

Background There is an ever-growing number of patients requiring aortic valve replacement (AVR). Limited data is available on the long-term outcomes and structural integrity of bioprosthetic valves in younger patients undergoing surgical AVR. Methods The INSPIRIS RESILIA Durability Registry (INDURE) is a prospective, open-label, multicentre, international registry with a follow-up of 5 years to assess clinical outcomes of patients younger than 60 years who undergo surgical AVR using the INSPIRIS RESILIA aortic valve. INDURE will be conducted across 20–22 sites in Europe and Canada and intends to enrol minimum of 400 patients. Patients will be included if they are scheduled to undergo AVR with or without concomitant root replacement and/or coronary bypass surgery. The primary objectives are to 1) determine VARC-2 defined time-related valve safety at one-year (depicted as freedom from events) and 2) determine freedom from stage 3 structural valve degeneration (SVD) presenting as morphological abnormalities and severe haemodynamic valve degeneration at 5 years. Secondary objectives include the assessment of the haemodynamic performance of the valve, all stages of SVD, potential valve-in-valve procedures, clinical outcomes (in terms of New York Heart Association [NYHA] function class and freedom from valve-related rehospitalisation) and change in patient quality-of-life. Discussion INDURE is a prospective, multicentre registry in Europe and Canada, which will provide much needed data on the long-term performance of bioprosthetic valves in general and the INSPIRIS RESILIA valve in particular. The data may help to gather a deeper understanding of the longevity of bioprosthetic valves and may expand the use of bioprosthetic valves in patients under the age of 60 years. Trial registration ClinicalTrials.gov identifier: NCT03666741 (registration received September, 12th, 2018).


Background
There is an ever-growing number of patients requiring aortic valve replacement (AVR) [1]. The two principal reasons for AVR are aortic regurgitation (AR) and aortic stenosis (AS), the latter being the most common indication. Although the majority of patients is older [2], younger patients are of particular concern as they have a longer lifespan with their replaced valve and are dependent on properly functioning, non-deteriorated valves over this much longer term.
In general, a wide spectrum of therapies can be offered to younger patients such as sparing valve techniques and mechanical valve replacement. Homografts are possible but less popular due to inferior longevity. The Ross procedure gains in popularity in selected expert centres. Mechanical valves have been preferred over bioprosthetic valves in younger patients, but this is not equivocal. While some studies have shown a survival benefit of mechanical valves in younger patients [3][4][5][6][7], large retrospective observational studies [8][9][10][11][12] and one randomized controlled trial [13] have shown similar long-term survival in patients 50 to 69 years of age undergoing mechanical versus bioprosthetic valve replacement.
Based on these data, the 2017 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines on valvular heart disease [14] recommend mechanical over bioprosthetic valves in patients below the age of 50 years (class IIa, lowered from 60 years in the 2014 version) and suggest an individualised choice (so called grey-zone) of either a mechanical or bioprosthetic valve in patients between 50 and 70 years. Conversely, the 2017 European guidelines recommend the use of mechanical valves in patients under the age of 60 years unless good quality anticoagulation is unlikely and a grey zone between 60 and 65 years [15]. Both guidelines emphasize the need to consider the desire of an informed patient when it comes to the choice of the valve treatment.
The INSPIRIS RESILIA aortic Valve™ (Edwards Lifesciences, Irvine, USA) is a stented bioprosthetic, trileaflet valve comprised of bovine pericardial tissue. Specific new tissue preservation techniques result in a stable capping process, which blocks residual aldehyde groups known to bind calcium, in addition to a phospholipid removal process. A final tissue glycerolisation step allows valve storage without further tissue exposure to glutaraldehyde. Finally, INSPIRIS RESILIA features an expansion feature, called VFit, intended for future potential valve in valve procedures.
RESILIA tissue demonstrated, in a large pre-clinical randomized control trial conducted in juvenile sheep in mitral position, to significantly reduce tissue calcification (− 72%) and even to improve haemodynamic performance compared with the Perimount valve [16]. The RESILIA tissue also has been studied in two clinical trials to date [17,18]. Bartus et al. found, in a single-arm observational study of 133 patients, that the RESILIA tissue provided excellent performance and safety without structural valve deterioration (SVD) [18][19][20]. In the COMMENCE trial [17,20], 679 patients underwent Carpentier-Edwards PERIMOUNT Magna Ease™ aortic valve replacement with RESILIA™ tissue (Model 11000A) and similar excellent safety and effectiveness were demonstrated for up to 4 years without SVD. Both of these trials have included relatively young patients, with a mean age between 65 and 67 years and up to 26% of patients aged less than 60 years.
These trials generated useful insights on the safety and effectiveness of the RESILIA tissue, but they were not specifically designed to assess durability in younger patients which received the INSPIRIS RESILIA aortic valve and data on this topic in general is scarce [21,22].
It is for this reason that we designed a prospective long-term registry around the INSPIRIS RESILIA aortic Valve™. With 400 patients under the age of 60 years included and a follow-up of 5 years, we will collect data on the short-term clinical effectiveness of the valve's implantation, as well as pivotal data on the long-term haemodynamic and structural performance of the valve.

Methods/design
The INDURE registry is a prospective, open-label, multicentre, international registry with a follow-up of 5 years to assess the clinical outcomes of patients younger than 60 years of age who undergo surgical AVR with the INSPIRIS RESILIA aortic valve (Edwards Lifesciences). The registry is conducted according to ISO 14155:2011. Approximately 400 patients will be enrolled across 20-22 European sites (including Austria, Belgium, France, Germany, Italy, the Netherlands, Spain, and UK) and Canada, resulting in about 20 patients per site. It was estimated, from the COMMENCE Trial dataset [17,20], that freedom from time-related valve safety events at 1year (composite endpoint according to VARC-2 criteria) is around 91.5%, suggesting that 400 patients will arrive at a 95% confidence interval (CI) of ±2.14%. Lower rates (80%) will broaden the 95% CI to ±3.92% and higher rates (99%) narrow it down to ±1%.

Patients
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.

Objectives
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.

Data collection
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.

Echocardiography core lab
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.

Statistical analysis
Continuous variables will be presented as mean ± standard deviation (SD) or as median with interquartile range (IQR), and categorical variables (e.g., gender) will be reported as frequencies and percentages. The Kolmogorov-Smirnov test will be used to test for normal distribution. Accordingly, the Student t-test or Mann-Whitney U test will be used to test for statistically significant differences. The Chi-Square or Fisher Exact test will be used for statistical distribution analysis of categorical variables. Kaplan-Meier analyses will be performed for survival and safety outcomes. Linearized rates and actuarial probability statistics will be used where appropriate for adverse event reporting. A P-value of < 0.05 will be considered statistically significant. Statistical analysis will be performed using SPSS Version 24.0 (Armonk, NY, IBM Corp.).

Discussion
The INDURE registry has been designed to provide prospectively collected data that can be used to elucidate the benefits and risks of the surgical implantation of INSPIRIS RESILIA in patients with AVR who are younger than 60 years of age, as well as the long-term haemodynamic and structural performance of the valve in patients in this age group. Analysis of the data may also provide additional support for the earlier use (e.g., at a younger age) of bioprosthetic valves in patients undergoing AVR.

Bioprosthetic vs. mechanical valves
Mechanical valves are generally preferred over bioprosthetic valves for younger patients undergoing AVR because of their perceived greater durability with the 15year 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.

Determinants and surrogates of valve failure
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.

INDURE in perspective
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 longterm performance and structural integrity of bioprosthetic valves using the RESILIA tissue in younger patients. RESI-LIA tissue incorporates an anti-calcification process, by permanently blocking the residual aldehyde groups that The classification and criteria presented in this table are based on recommendations and standardised definitions of medical societies or group of experts [31][32][33] Stage 0 refers to a normal valve. Stage 1 consists in the presence of morphological abnormalities of valve leaflets but with no evidence of HVD. At echocardiography, the leaflets are thickened (> 2 mm), often irregular and hyperechogenic. MDCT without contrast may be used to detect and quantitate macroscopic valve leaflet calcification by the modified Agatston method or the volumetric method. Stage 2 consists in SVD with moderate HVD defined as: (1) an increase in mean transprosthetic gradient ≥10 mmHg since early post-SAVR or TAVI echocardiography with concomitant decrease in valve EOA and DVI; and/or (2) a new onset or worsening of transprosthetic regurgitation by at least one grade with a final grade of moderate. An increase in transprosthetic velocity and gradients with concomitant increase in valve EOA and DVI is actually related to an increase in flow during follow-up and should not be mistaken for an HVD. Stage 3 consists in SVD with severe HVD characterised by: (1) an increase in mean transprosthetic gradient ≥20 mmHg since SAVR or TAVI with concomitant marked decrease in valve EOA and DVI and/or (2)  This criterium is corroborative but should not be used in isolation to define HVD 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 reintervention rates. Both INDURE and RESILIENCE (Table 4)  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.

Appreciation of the study design
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 RESILI-ENCE trial, but it would have violated the noninterventional 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.

Conclusions
INDURE is a prospective, multicentre registry in Europe and Canada that will provide much needed data on the long-term durability of bioprosthetic valves in general