Early Aortic vaLve surgEry Versus wAtchful waitiNg Strategy in Severe Asymptomatic aOrtic reguRgitation

Aortic Valve Regurgitation Clinical Trial

— ELEANOR  

Official title:

Early Aortic Valve Surgery Versus Watchful Waiting Strategy in Severe Asymptomatic Aortic Regurgitation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05438862
• Other study ID #: 6.4.2022/5
• Status: Recruiting
• Phase: N/A
• Start date: September 1, 2022
• Est. completion date: December 31, 2027

Study information

• Verified date: January 2024
• Source: Na Homolce Hospital
• Contact: Radka Kocková, MD,PhD
• Phone: +420606483586
• Email: radka.kockova[@]centrum.cz
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 217
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Aortic Valve Insufficiency
• Aortic Valve Regurgitation

Intervention

Procedure:
• State of art aortic valve surgery
Optimal surgical treatment (aortic valve-sparing surgery, aortic valve replacement, Ross procedure).

Locations

Country	Name	City	State
Belgium	Cardiovascular Center OLV Clinic Aalst	Aalst
Czechia	Center of Cardiovascular and Transplant Surgery	Brno
Czechia	International Clinical Research Center, St. Anne´s University Hospital Brno	Brno
Czechia	University Hospital Hradec Králové	Hradec Králové
Czechia	2nd Department of Internal Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague	Prague
Czechia	Na Homolce Hospital	Prague
Serbia	University Clinical Center of Serbia	Belgrade

Sponsors (7)

Lead Sponsor	Collaborator
Na Homolce Hospital	Centre of Cardiovascular and Transplantation Surgery, Czech Republic, General University Hospital, Prague, St. Anne's University Hospital Brno, Czech Republic, University Clinical Centre of Republic of Srpska, University Hospital Hradec Kralove, VZW Cardiovascular Research Center Aalst

Countries where clinical trial is conducted

Belgium,  Czechia,  Serbia, 

References & Publications (17)

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Kockova R, Linkova H, Hlubocka Z, Praveckova A, Polednova A, Sukupova L, Blaha M, Maly J, Honsova E, Sedmera D, Penicka M. New Imaging Markers of Clinical Outcome in Asymptomatic Patients with Severe Aortic Regurgitation. J Clin Med. 2019 Oct 11;8(10):165 — View Citation

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Mentias A, Feng K, Alashi A, Rodriguez LL, Gillinov AM, Johnston DR, Sabik JF, Svensson LG, Grimm RA, Griffin BP, Desai MY. Long-Term Outcomes in Patients With Aortic Regurgitation and Preserved Left Ventricular Ejection Fraction. J Am Coll Cardiol. 2016 — View Citation

Michelena HI, Prakash SK, Della Corte A, Bissell MM, Anavekar N, Mathieu P, Bosse Y, Limongelli G, Bossone E, Benson DW, Lancellotti P, Isselbacher EM, Enriquez-Sarano M, Sundt TM 3rd, Pibarot P, Evangelista A, Milewicz DM, Body SC; BAVCon Investigators. — View Citation

Myerson SG, d'Arcy J, Mohiaddin R, Greenwood JP, Karamitsos TD, Francis JM, Banning AP, Christiansen JP, Neubauer S. Aortic regurgitation quantification using cardiovascular magnetic resonance: association with clinical outcome. Circulation. 2012 Sep 18;1 — View Citation

Steeds RP, Myerson SG. Imaging assessment of mitral and aortic regurgitation: current state of the art. Heart. 2020 Nov;106(22):1769-1776. doi: 10.1136/heartjnl-2019-316216. Epub 2020 Aug 17. No abstract available. — View Citation

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Vecera J, Bartunek J, Vanderheyden M, Kotrc M, Kockova R, Penicka M. Three-dimensional echocardiography-derived vena contracta area at rest and its increase during exercise predicts clinical outcome in mild-moderate functional mitral regurgitation. Circ J — View Citation

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* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite safety and efficacy endpoint at 12 months post-randomization (all 3 criteria must be fulfilled):	Reverse LV remodelling (CMR-derived EDVI decrease >15% compared to baseline); LV ejection fraction >50%; Absence of MACE (cardiovascular mortality, stroke, myocardial infarction, hospitalization for heart failure, infective endocarditis)	12 months
Secondary	Change in comparison to baseline:	1) Quality of life questionnaire >10%	12 months
Secondary	Change in comparison to baseline:	2) Spiroergometry - maximal oxygen consumption (VO2 max) >10% and/or >3 ml/kg/min	12 months
Secondary	Normalization of N-terminal pro B-natriuretic peptide serum level	NT-proBNP <112 ng/L	12 months
Secondary	In hospital and 30 days mortality	Perioperative and/or early postoperative mortality	30 day postoperatively
Secondary	Time to cardiovascular death	Death due to myocardial infarction, death due to heart failure, death due to stroke, death due to CV procedures, death due to CV hemorrhage, and sudden cardiac death.	12 months
Secondary	Time to first heart failure hospitalization	Heart failure symptoms that require hospitalization.	12 months
Secondary	Number of Participants with Major bleeding	Fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding leading to transfusion of two or more units of whole blood or red cells.	12 months