Clinical trial NCT05438862: Early Aortic vaLve surgEry Versus wAtchful waitiNg Strategy in Severe Asymptomatic aOrtic reguRgitation
Official title: Early Aortic Valve Surgery Versus Watchful Waiting Strategy in Severe Asymptomatic Aortic Regurgitation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Aortic Valve Regurgitation
Keywords: aortic regurgitation
cardiac magnetic resonance
echocardiography
early surgical intervention
Lead sponsor: Na Homolce Hospital
Sponsor class: OTHER
Collaborators: name: University Hospital Hradec Kralove
name: Centre of Cardiovascular and Transplantation Surgery, Czech Republic
name: St. Anne's University Hospital Brno, Czech Republic
name: VZW Cardiovascular Research Center Aalst
name: General University Hospital, Prague
name: University Clinical Centre of Republic of Srpska
First posted: 2022-06-30
Enrollment: 217
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization between early surgical and conventional watchful waiting strategy.
Primary purpose: TREATMENT

Brief summary: The optimal timing of surgical intervention in asymptomatic patients with severe aortic regurgitation remains controversial. As per cardiac magnetic resonance assessment, early surgical treatment will be compared with conventional guideline-based strategy in asymptomatic patients with severe aortic regurgitation.

Detailed description: Introduction:

Aortic regurgitation (AR) is the third most frequent valvular heart disease in Western countries affecting rather young patients, mostly men. The degenerative process on the trileaflet aortic valve is the main cause of AR, followed by a congenital valve disease, typically bicuspid aortic valve. The high prevalence of bicuspid aortic valve in the general population which is frequently associated with aortic dilatation, another important cause of AR, can explain the unusual distribution of significant AR mainly among the population of males in their average 5th decade. Infective or rheumatic endocarditis and aortic dissection are less frequent reasons for AR.

Hemodynamically significant AR leads to volume and pressure overload of the left ventricle (LV). Severe LV dilatation and moderate LV hypertrophy are the main compensatory mechanisms that help to maintain cardiac output and relieve the increased LV wall stress. Doubling the cardiomyocyte size is accompanied by an increase in extracellular volume, including multiplying collagen fibres and increasing the volume of the non-collagen extracellular matrix. Untreated severe AR leads to advanced LV remodeling and LV dysfunction causing the development of heart failure.

The only appropriate treatment for chronic haemodynamically significant AR is aortic valve surgery. The indications for AR surgical treatment are summarized in the 2021 ESC/EATS Guidelines for the management of the valvular disease. Class I indications of aortic valve surgery are based on the presence of symptoms of heart failure (exertional dyspnoea, chest tightness) and/or presence of severe LV remodelling (LV ejection fraction ≤50% or LV end-systolic diameter (ESD) \>50 mm or LV ESD Index \>25 mm/m2 in patients with small body size). There is increasing evidence that patients undergoing surgery at such an advanced stage of the disease have already irreversible myocardial damage. There is also evidence that surgical risk in a relatively younger and low-risk population has decreased with novel surgical techniques and perioperative care, including aortic valve-sparing surgery with documented excellent long-term effects. Concerning these facts, it might be reasonable to shift the surgical treatment towards an earlier stage of the disease.

Available evidence including our study suggests higher clinical accuracy of cardiac magnetic resonance (CMR)-derived AR quantification than that of the guidelines-based echocardiographic (ECHO) Integrative approach (12-14). Severe AR defined as regurgitation fraction (RF) \>33% and/or regurgitant volume (RV) \>44 ml with LV dilatation defined as LV end-diastolic volume index (LVEDVI) \>123 ml/m2 present the most accurate marker of early disease progression requiring surgery in a median of 399 (IQR 209) days (unpublished data).

Project Hypothesis:

1. The investigators hypothesize that early surgical treatment in patients with low surgical risk and severe AR as per CMR assessment will be a non-inferior, safe procedure with a low incidence of early and late periprocedural complications.
2. The investigators hypothesize that early surgical treatment will lead to early LV reverse remodelling leading to complete normalization of LV structure and function.
3. The investigators hypothesize that early surgical treatment will lead to early improvement in quality of life and exercise performance in most patients.
4. The investigators hypothesize that early surgical treatment will lead to the improvement in long-term mortality and morbidity of patients

Project Plan:

1. All consecutive patients referred to the participating centre for a hemodynamically significant chronic AR will be screened. Patients with AR grade 3 and grade 4 without an indication for aortic valve surgery as per current Guidelines and who comply with the inclusion and exclusion criteria will be offered to participate in the study.
2. All patients will undergo CMR at baseline and after 12 months, including T1 mapping, contrast-enhanced imaging and flow sequence measurement at sinotubular junction according to study protocol in a particular centre. All CMR studies will be anonymized and digitally transferred to CoreLab based in University Hospital Hradec Králové. The off-line analysis will consist of the left and right ventricular volumes, mass and ejection fraction calculation. AR will be quantified utilising flow sequence measurement at the sinotubular junction. A correction for Eddy's current will be applied. Native T1 relaxation time will be measured in the midventricular septum.
3. All patients will undergo a comprehensive 2-dimensional (2D) and 3-dimensional (3D) ECHO at baseline and every six months of follow-up in each participating centre. Echocardiography will be performed using Vivid 7, Vivid E9, and Vivid E95 (GE Healthcare, Horten, Norway) to allow for advanced analysis. The off-line analysis will include the left ventricular volume, mass, ejection fraction and global longitudinal strain calculation. Aortic regurgitation will be quantified utilizing a widely accepted Integrative approach. Vena contracta area will be measured whenever possible. Moreover, baseline and 12-month images will be analysed centrally by one operator (Cardiovascular Center, Aalst, Belgium).
4. All patients will undergo 12-lead electrocardiography (ECG) and blood sample analysis at baseline and every six months of follow-up in each participating centre. One blood sample (serum and plasma) will be stored frozen at -80 C° for further analysis.
5. All patients will undergo an exercise stress test - spiroergometry (CPET) - at baseline and a 12-month follow-up in each participating centre. CPET will be used to validate asymptomatic status and to assess changes in exercise performance during follow-up.
6. All patients will fill out the questionnaire (RAND 36-Item Health Survey 1.0 Questionnaire Items) at baseline and 12 months after randomization.

6. Randomization will be computer-based, utilizing the covariate adaptive randomization method to achieve a balanced distribution of both patients' groups in between participating centres, age and gender.

7. Aortic valve surgery will be performed in each participating centre by an experienced surgeon who is a member of the study team. The type of surgery will be based on a "state of art" approach and local expertise with the preference for valve-sparing surgery or Ross procedure in carefully selected patients. Transesophageal ECHO will be performed in all patients to evaluate valve morphology and suitability for valve-sparing surgery. The surgery will be scheduled within 3 months after randomization for early surgery. Patients in the watchful waiting group study arm will undergo surgical treatment in agreement with current Guidelines for the disease progression during the study follow-up.

Methods:

Design The study will be prospective, randomized and multicenter, including international collaboration. Imaging data will be analyzed in a CoreLab based in the Czech Republic for CMR data (Faculty Hospital Hradec Králové) and Belgium for ECHO data (Cardiovascular Center Aalst).

Patients Patients with chronic grade 3 and grade 4 AR without an indication for surgical treatment as per current Guidelines will be enrolled in the study after signing the informed consent. The baseline examination consists of a clinical examination, ECG, blood test analysis (including N-terminal pro-brain natriuretic peptide), a comprehensive 2D and 3D ECHO, exercise stress test (CPET preferably) and CMR.

Patients with CMR-derived RF \>35% or RV \>45 ml and LV EDVI \>125 mL/m2 will be randomised in a 1:1 ratio between early surgery (Group A) or watchful waiting (Group B). Patients, not fulfilling these CMR criteria, will enter the registry (Group C).

Patients in Group A will undergo aortic valve surgery within 3 months after randomisation. Their follow-up will consist of a repeat CMR and spiroergometry 12 months after enrolment. The regular follow-up will be every 6 months including a clinical examination, 2D and 3D ECHO and blood tests. Patients who will decline early surgical treatment might be reassigned to Group B but the total number must not exceed 6% of the total number of enrolled patients in a particular centre. The results will be statistically tested for both, intention to treat and as treated.

Patients in Group B and C will be reviewed every 6 months including a clinical examination, 2D and 3D ECHO and blood tests. A repeat CMR study and spiroergometry will be performed 12 months after enrolment. Patients who develop an indication for aortic valve surgery as per current Guidelines during the watchful waiting period of the study will undergo aortic valve surgery within 3 months after the onset of the indication.

Eligibility criteria: Inclusion Criteria:

* Chronic asymptomatic aortic regurgitation grade 3 (moderate to severe) and grade 4 (severe)
* No indication for the surgical treatment at the time of enrolment
* LV ejection fraction \>50%
* Absence of more than mild-to-moderate concomitant valve disease or complex congenital heart disease

Exclusion Criteria:

* Age \<18 years
* Clearance Creatinine \<30 mL/min
* Contraindication for magnetic resonance (implanted active device, ferromagnetic implant incompatible with magnetic resonance scanner, cerebral aneurysm clip, metallic fragment in the eye or near sensitive tissue)
* Pregnancy
* Permanent atrial fibrillation.

Primary outcomes:
measure: Composite safety and efficacy endpoint at 12 months post-randomization (all 3 criteria must be fulfilled):
timeFrame: 12 months
Secondary outcomes:
measure: Change in comparison to baseline:
timeFrame: 12 months
measure: Change in comparison to baseline:
timeFrame: 12 months
measure: Normalization of N-terminal pro B-natriuretic peptide serum level
timeFrame: 12 months
measure: In hospital and 30 days mortality
timeFrame: 30 day postoperatively
measure: Time to cardiovascular death
timeFrame: 12 months
measure: Time to first heart failure hospitalization
timeFrame: 12 months
measure: Number of Participants with Major bleeding
timeFrame: 12 months
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: Cardiovascular Center OLV Clinic Aalst
city: Brno
country: Czechia
facility: International Clinical Research Center, St. Anne´s University Hospital Brno
city: Brno
country: Czechia
facility: Center of Cardiovascular and Transplant Surgery
city: Hradec Králové
country: Czechia
facility: University Hospital Hradec Králové
city: Prague
country: Czechia
facility: 2nd Department of Internal Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague
city: Prague
country: Czechia
facility: Na Homolce Hospital
city: Belgrade
country: Serbia
facility: University Clinical Center of Serbia
Study officials:
affiliation: Na Homolce Hospital
name: Radka Kočková, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Faculty Hospital Hradec Králové
name: Jan Vojáček, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiovascular Center OLV Clinic
name: Martin Pěnička, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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