Clinical trial NCT03143361: Prospective European Multicenter Study on Aortic Valve Replacement: (E-AVR Registry)
Official title: Outcome Comparison of Different Surgical Strategies for the Management of Severe Aortic Valve Stenosis: Study Protocol of a Prospective Multicentre European Registry (E-AVR Registry)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Aortic Valve Stenosis
Valve Heart Stenosis
Keywords: aortic valve stenosis
heart valves
heart surgery
Lead sponsor: University of Parma
Sponsor class: OTHER
Collaborators: name: University of Genova
name: University Hospitals, Leicester
name: University of Hamburg-Eppendorf
name: San Camillo Hospital, Rome
name: University of Turin, Italy
name: Centre Hospitalier Universitaire de Besancon
name: University Hospital, Udine, Italy
name: Hospital Clinic of Barcelona
name: University of Lausanne Hospitals
name: Hopital Universitaire Robert-Debre
name: Paracelsus Medical University
name: University of Campania Luigi Vanvitelli
name: University of Texas, Southwestern Medical Center at Dallas
name: Clinique Pasteur
name: Cardiocentro Ticino
name: Universita di Verona
First posted: 2017-05-08
Enrollment: 8000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients referred for a surgical treatment of severe aortic valve stenosis (either traditional - through full-sternotomy - or minimally-invasive, or transcatheter - with both "sutured" and "sutureless" valves), isolated or associated with coronary artery bypass grafting

Brief summary: Traditional and transcatheter surgical treatments of severe aortic valve stenosis (SAVS) are increasing in parallel with the improved life-expectancy. Recent randomized trials (RCTs) reported comparable or non-inferior mortality with transcatheter treatments compared to traditional surgery. However, RCTs have the limitation of being a mirror of the predefined inclusion/exclusion criteria, without reflecting the "real clinical world".

Technological improvements have recently allowed the development of minimally invasive surgical accesses and the use of sutureless valves, but their impact on the clinical scenario is difficult to assess because of the monocentric design of published studies and limited sample-size. A prospective multicentre registry including all patients referred for a surgical treatment of SAVS (traditional, through full-sternotomy; minimally-invasive; or transcatheter; with both "sutured" and "sutureless" valves) will provide a "real-world" picture of available results of current surgical options, and will help to clarify the "grey zones" of current guidelines.

E-AVR is a prospective observational open registry designed to collect all data from patients admitted for SAVS, with or without coronary artery disease, in 16 cardiac surgery Centres located in six countries (France, Germany, Italy, Spain, Switzerland, and United Kingdom). Patients will be enrolled over a 2-year period and followed-up for a minimum of 5 years to a maximum of 10 years after enrolment. Outcome definitions are concordant with VARC-2 criteria and established guidelines. Primary outcome is 5-year all-cause mortality. Secondary outcomes aim at establishing "early" 30-day all-cause and cardiovascular mortality, as well as major morbidity, and "late" cardio-vascular mortality, major morbidity, structural and non-structural valve complications, quality of life and echocardiographic results.

The study protocol is approved by Local Ethics Committees. Any formal presentation or publication of data will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship.

Detailed description: Robust early and follow-up data on the safety and efficacy of surgical TAVR, last-generation sutureless surgical valves, and minimally-invasive approaches compared with standard SAVR, with or without a contemporary (surgical or interventional) treatment of concurrent CAD, are still lacking for a real-world large population of patients at variable surgical risk. Such data is urgently required for the correct allocation of therapy in daily surgical practice. Furthermore, data on quality of life and functional echocardiographic results with different surgical alternatives might similarly help physicians in decision-making in local "Heart Teams". Data from a multicentre, real-world, open registry enrolling all patients with SAVS±CAD consecutively referred to several Centres at different European latitudes should help to answer some of these open questions.

The main strength of a prospective clinical open registry is the high external validity, given that data are collected in the settings of standard clinical practice. Moreover, large sample size enables a better estimation of event rates, and allows the investigation of hard endpoints and outcomes, by means of a wide population of patients from different institutions and with extremely limited exclusion criteria.

Importantly, clinical registries may provide data on long-term outcomes occurring after the study period of a trial. They are more practical than randomized controlled trials, require fewer resources, and have less stringent inclusion and exclusion criteria for patient enrolment. Finally, clinical findings from registries have even more significance when patient-populations derive from different geographic areas, with heterogeneous referral pathways, baseline clinical characteristics, and perioperative treatment strategies. All these features substantiate the concept of "a real world practice" underlying any "registry-study".

Therefore, the rationale of this European multicenter observational open registry is to prospectively collect data on baseline characteristics, treatment options, perioperative management and postoperative outcome of all patients consecutively undergoing surgical treatment of SAVS (regardless of gradients, AVA or AVAi)±CAD or aortic prosthetic dysfunction±CAD at 16 European university or non-university tertiary hospitals located in six European countries (France, Germany, Italy, Spain, Switzerland, and United Kingdom).

The primary aim of the study is a 5-year comparison between SAVR and surgical TAVR: we hypothesize to report a 10% superiority in terms of all-cause mortality in favor of SAVR vs TAVR. For the purpose of this study, patients will be consecutively enrolled for a 2-year period, and will be followed-up for a minimum of 5 years after the index surgical treatment. Maximum follow-up length will be 10 years after surgery.

The following surgical options will be considered:

1. SAVR with mechanical valves
2. SAVR with biological valves (either sutured or sutureless, stented or stentless)
3. Surgical TAVR (either transapical, trans-axillary, or transaortic)

Similarly, the following surgical approaches will be considered:

1. Full sternotomy
2. Mini-thoracotomy (either left-sided for TAVR or right-sided for SAVR)
3. Partial-sternotomy Patient allocation to a specific surgical procedure will be based on the local Heart Team decision at each Institution, according to standard clinical practice and current guidelines.

Patients will be recruited in a consecutive series from each institution, and their data collected in a dedicated on-line datasheet. The recruitment period will be 24 months, from 1st October 2017 to 30th September 2019. Every patient will be followed up at 30 days, 6 months, 1 year, and yearly thereafter, up to a minimum of 5 years after the index surgical procedure. Afterwards yearly follow-up will be closed at the completion of the 10th year from surgery for each patient.

On the basis of historical cohort data of local institutions, we expect to enrol a minimum of 4000 patients at the end of the first year, and a minimum of 8000 patients at the end of the second year of enrolment.

Written informed consent will be obtained from the patient or patient's authorized representative prior to enrolment in the Registry. In case of emergent surgery, informed consent will be collected from the patient's family (or legal representative) before surgery, as well as from the patient after surgery (if unable to give it before intervention). This consent will be waived in case of death or severe neurological damage precluding adequate postoperative patient informed consent. The study will be conducted in accordance with the provisions of the Declaration of Helsinki.

Data management and monitoring Data will be collected into a dedicated datasheet with predefined variables. Each patient enrolled in the Registry will be anonymized by the generation of a code consisting of the initials of the enrolling Centre (2 letters), the initial of name (1 letter) and surname (1 letter), and the date of birth (dd.mm.yyyy) (e.g. Mr. John Smith, born on February 18th, 1953; enrolled in London = LOJS18021953). It is responsibility of the E-AVR Steering Committee local member to generate the sequence to maintain anonymized the entire set of data. It is also responsibility of the E-AVR Steering Committee local member to protect confidentiality about patient identity before, during and after the trial. Accordingly, external Central Statistical Core Lab (as well as all the other E-AVR investigators) will be blinded towards patient identity.

All data will be retained in a secure location at each study-site during the conduct of the study and for the 5-years after the end of the study, when all patient identifiable paper records will be destroyed by confidential means.

Baseline characteristics, operative details and outcome data pertaining hospitalization will be prospectively collected from hospital registries. Variables and events occurring after the index hospital discharge will be collected from outpatient clinics at the individual Institutions, and linking with regional Social Security Death and Events Master files where available. In case of absent/missing data, variables and events will be collected by direct phone contact with general practitioners, and only if persistently missed by phone contact with patients and families.

Events and outcome variables will be adjudicated after agreement of two local E-AVR Investigators, and collected at local Institutions. In the event of controversy on outcome adjudication between the two local E-AVR Investigators, the outcome will be discussed and adjudicated after a final consult inside the E-AVR Steering Committee.

Storage, analysis and auditing of data will be accomplished by an independent Central Core Laboratory. Auditing of the dataset will be performed every six months by checking the data of a minimum of 40% of the patients. Data without any patient identification code will be submitted to the Principal Investigator and E-AVR Steering Committee for further data checking and merging. Incomplete or contradictory data with patient identification code will be sent from Central Core Statistical Lab to the E-AVR Steering Committee local member for further data checking, review, correction and merging. The entire set of statistical analyses will be available to all E-AVR researchers for the interpretation of data.

Ethics and Dissemination The study is approved by the local Institutional Review Boards/Ethical Committees, according to local or national guidelines for approval of registry studies. Patient's informed consent will be always obtained.

This multicenter, prospective open registry is designed with the aim of investigating a number of controversial issues regarding current treatment-options and risk factors for the surgical therapy of SAVS with or without CAD. Several studies and information are expected to derive from the data collected in the registry. These data will provide further knowledge on the mechanisms leading to adverse events during or after surgery for SAVS and help their prevention, thus allowing a "tailored" surgical approach for the treatment of this disease.

Research findings from the E-AVR registry will be disseminated among the scientific community. They will be presented at international congresses and published in peer reviewed international journals in the fields of cardiac surgery and cardiology. Any formal presentation or publication of data will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship. Data collection, analysis and writing process will be monitored by the Steering Committee of the E-AVR, which is made up of the Principal Investigator and a local Representing Member from each of the participating centres. It is expected that periodical E-AVR Steering Committee meetings will occur, every 6 months for the first 2 years, yearly thereafter up to the end of follow-up. The Members of the Steering Committee will take responsibility for the quality of data through local audit.

Investigators will be eligible for authorship if they contribute substantially to study planning, data collection, data analysis and interpretation, writing and critical review of the manuscripts. Two authors per centre will be included as main authors of each study. As a member of the Steering Committee, the local Representing Member will take any decisions on co-authorship related to his/her centre on the basis of the above criteria. Those researchers who plan a sub-study, interpret the analysis and write the article will be the first and last authors of the study. Analyses will be performed and/or monitored by an independent Central Core Statistic Laboratory. When an article is submitted to a journal with a maximum number of co-authors, the Steering Committee will decide on the authors on the basis of their contribution to the design of the study, data collection, interpretation of data, writing, and critical review of the paper.

In the event of future merging with other contemporary registries (e.g. collecting data on concurrent interventional - i.e. percutaneous transfemoral, transcarotid or trans-axillary - TAVR procedures), the co-authorship of comparative studies (e.g. between surgical and interventional treatments) will be defined by the Steering Committees of the different registries involved. However, data will not be made available for sharing until after publication of the principal results of the study. Thereafter, anonymized individual patient data will be made available for secondary research, conditional on assurance from the secondary researcher that the proposed used of the data is compliant with the MRC Policy on Data Preservation and Sharing regarding scientific quality, ethical requirements, and value for money. Anonymized data will be shared as long as the patient has agreed and consented to this. A minimum requirement with respect to scientific quality will be a publicly available pre-specified protocol describing the purpose, methods and analysis of the secondary research.

Eligibility criteria: Inclusion criteria

* Age \>18 yy
* Isolated SAVS with or without concomitant aortic valve regurgitation
* Isolated prosthetic aortic dysfunction
* SAVS + coronary artery disease (CAD)
* Prosthetic aortic dysfunction + CAD
* Elective, urgent and emergent procedures
* Endocarditic aetiology

Exclusion criteria

* Patients undergoing concomitant mitral valve surgery, or tricuspid valve surgery, or aortic surgery (i.e. composite aortic valve and ascending aorta replacement with or without circulatory arrest), or atrial fibrillation surgery, or any other associated cardiac surgical procedure (with the exception of CABG)
* Concomitant aortic root procedure (i.e. Bentall operation, David operation, homografts, autografts)
* SAVR with techniques of aortic annular enlargement
* Porcelain aorta
* Pure aortic valve regurgitation
* Percutaneous TAVR requiring surgical cut-down (i.e. failure to comply with a full percutaneous approach, thus configuring a "hybrid procedure")
* Patient refusal

Primary outcomes:
measure: 5-year all-cause mortality
timeFrame: The outcome measure will be assessed at 5 years after surgery
Secondary outcomes:
measure: Follow-up all-cause mortality
timeFrame: The outcome measure will be assessed at time point (30 days, and yearly from 1 to 4 years after surgery, then from 6 to 10 years)
measure: Cardiovascular mortality
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly up to 10 years after surgery
measure: Stroke
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
measure: Acute myocardial infarction
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
measure: Prolonged use of inotropes
timeFrame: Participants will be followed up to 72 hours after surgery
measure: Intra-aortic balloon pump
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Extra-corporeal membrane oxygenator (ECMO)
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Surgical site infection
timeFrame: Participants will be followed up to 3 months after surgery
measure: Blood losses
timeFrame: Participants will be followed 12 hours after surgery
measure: Use of blood products
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Nadir hematocrit
timeFrame: Participants will be followed up to 24 hours after the operation
measure: Nadir hemoglobin
timeFrame: Participants will be followed up to 24 hours after the operation
measure: Resternotomy for bleeding
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Atrial fibrillation
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Cardiac conduction disturbances
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Permanent pace-maker
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
measure: Acute kidney injury
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Pericardial effusion
timeFrame: Participants will be followed up to 3 months after surgery
measure: Length of stay in the intensive care unit
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Length of in-hospital stay
timeFrame: Participants will be followed for the duration of hospital stay (expected: 10 days)
measure: Early repeat surgery
timeFrame: Participants will be followed up to discharge to home or to rehabilitation clinic (expected: 10 days)
measure: Post procedural aortic prostheses performance
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year and yearly thereafter up to 10 years after surgery
measure: Re-intervention on the aortic valve
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year and yearly thereafter up to 10 years after surgery
measure: Repeat revascularization
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
measure: Aortic valve -related adverse events
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
measure: Cardioverter-defibrillator implantation
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
measure: Major Adverse Cardiovascular and Cerebrovascular Event (MACCE)
timeFrame: The outcome measure will be assessed at time point (30 days, 1 year, and yearly thereafter up to 10 years after surgery
Other outcomes:
measure: Quality of Life
timeFrame: The outcome measure will be assessed at time point (before surgery, at discharge, at 30 days, 6 months, 1 year, and yearly thereafter up to 10 years after surgery
Locations:
city: Verona
country: Italy
facility: University of Verona
Study officials:
affiliation: Universita di Verona
name: Francesco Onorati, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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