Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe AS (EVoLVeD)

Early Valve Replacement Guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients With Severe Aortic Stenosis

Aortic stenosis is the most common valvular disease in the Western world. It is caused by progressive narrowing of the aortic valve leading to increased strain on the heart muscle which has to work increasingly hard to pump blood through the narrowed valve. Over time the heart muscle thickens to generate more force, but eventually the heart fails leading to death if the valve is not replaced with an operation. No medical treatments exist to stop or reverse the heart valve narrowing. Current clinical guidelines suggest that an operation should be performed only when symptoms develop or the heart muscle is visibly weak on cardiac ultrasound scanning. However, symptoms can be difficult to interpret and in many patients the heart muscle has become irreversibly damaged and the heart fails to recover following surgery.

Using MRI scans of the heart, the investigators have identified heart scarring which seems to develop as the heart muscle thickens. Several studies now show that people who have developed this scarring are more likely to suffer poor outcomes including death. The investigators have also identified clinical risks that predict the presence of scarring.

The investigators propose a study where patients with severe aortic stenosis but no indications for valve replacement as per current guidelines are assessed for those clinical risks. If a participant's risk of having scarring is higher they will undergo a cardiac MRI scan. If scarring is present participants will be randomised to routine clinical care, or referral for valve replacement surgery. Participants with no evidence of scarring will be randomised routine care with study follow or not. The investigators of this study hypothesize that early surgery will lead to fewer complications and reduced risk of death compared to standard care.

Study Overview

• Status: Active, not recruiting
• Conditions: Aortic Valve Stenosis; Hypertrophy, Left Ventricular
• Intervention / Treatment: Procedure: Aortic valve intervention

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom
    • Nhs Lothian

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Severe aortic stenosis (aortic valve jet velocity ≥4.0 m/s, or aortic valve area indexed to body surface area <0.6cm2/m2 with aortic jet velocity ≥3.5m/s)
2. Age over 18 years
3. No symptoms attributable to aortic stenosis that require aortic valve replacement

Exclusion Criteria:

1. Deemed lower risk for mid-wall fibrosis on screening
2. Planned cardiac surgery
3. Previous valve replacement
4. Severe hypertension (systolic >180 or diastolic >110 mmHg)
5. Acute pulmonary oedema or cardiogenic shock
6. Left ventricular ejection fraction <50% on cardiac MRI
7. Significant abnormalities on cardiac MRI that would prevent enrolment
8. Coexistent severe aortic regurgitation or mitral regurgitation
9. Coexistent mitral stenosis greater than mild in severity
10. Coexistent hypertrophic cardiomyopathy or cardiac amyloidosis
11. Any contraindication to MRI scanning (such as permanent pacemaker)
12. Advanced renal impairment (glomerular filtration rate <30 mL/min/1.73 m2)
13. Pregnancy or breast feeding
14. Patient judged to be unfit to be considered for aortic valve replacement or transcatheter aortic valve implantation
15. Patient declines to consider undergoing valve replacement surgery or transcatheter aortic valve implantation
16. Inability to give informed consent
17. Previous randomisation into this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Early intervention; Patients will be referred immediately for aortic valve intervention.	Procedure: Aortic valve intervention; The choice of either surgical aortic valve replacement or transcatheter aortic valve implantation (TAVI) will be made by the local clinical team according to local policies. In patients undergoing surgical replacement the choice of surgical technique and type of valve replacement used will be at the discretion of the operating surgeon. Patients found to have significant coronary artery disease requiring concomitant coronary artery bypass surgery will not be excluded. Similarly the choice of TAVI valve and need for percutaneous coronary intervention will be made by the TAVI heart team. The procedure should be performed as soon as possible and ideally within four months of randomisation and allocation to group A.
No Intervention: Group B: Routine care; Patients will be invited back for clinical follow up according to local policy. Decision making regarding future aortic valve intervention will be taken by the participant's clinical team (cardiologist and cardiac surgeon).
No Intervention: Group C: Routine care; Patients will be invited back for clinical follow up according to local policy. Decision making regarding future aortic valve intervention will be taken by the patient's clinical team (cardiologist and cardiac surgeon). Group C will appear identical to Group B
No Intervention: Group D: No further study follow up; Patients will be invited back for clinical follow up according to local policy. Decision making regarding future aortic valve intervention will be taken by the patient's clinical team (cardiologist and cardiac surgeon). No further study follow up will take place but personal data will be retained for future data linkage.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of all-cause mortality or unplanned aortic stenosis-related hospitalisation	The first event of all-cause mortality or unplanned aortic stenosis-related hospitalisation Unplanned aortic stenosis-related hospitalisation is defined as an unplanned admission with syncope, heart failure, chest pain or arrhythmia (ventricular arrhythmia or second or third degree heart block) attributed to aortic stenosis. This endpoint will be adjudicated by two independent investigators blinded to the details of randomisation following review of the case notes and hospital records.	Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality		Randomisation through to study completion, an average of 2.75 years
Cardiovascular death		Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
AS-related death	AS-related death is a death where aortic stenosis has been listed as a contributory cause by the clinical care team on the patient's official death certificate.	Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Sudden cardiac death		Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Unplanned aortic-stenosis related hospitalisation	Unplanned aortic stenosis-related hospitalisation is defined as an unplanned admission with syncope, heart failure, chest pain or arrhythmia (ventricular arrhythmia or second or third degree heart block) attributed to aortic stenosis.	Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
WHODAS 2.0 (12 item)	The World Health Organization Disability Assessment Schedule (WHODAS 2.0) is a generic assessment instrument developed by WHO to provide a standardized method for measuring health and disability across cultures.	At study completion (mean follow up is expected to be an average of 2.75 years)
LV systolic function	The development of LV systolic dysfunction (EF <50% quantitatively or at least mild LV dysfunction qualitatively)	Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
NYHA status	Self reported patient symptoms on a scale of I-IV (I = No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, IV = Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.)	At study completion (mean follow up is expected to be an average of 2.75 years)
Permanent pacemaker insertion, cardiac resynchronisation therapy or automated implantable cardioverter defibrillator	To compare between study arms the number of participants who have had a permanent pacemaker insertion, cardiac resynchronisation therapy or automated implantable cardioverter defibrillator	Randomisation to through to study completion (mean follow up is expected to be an average of 2.75 years)
Stroke		Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Endocarditis	To compare between study arms the number of participants who have endocarditis	Randomisation to through to study completion (mean follow up is expected to be an average of 2.75 years)
Post-operative complications following aortic valve intervention		30 days post aortic valve intervention

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: Sir Jules Thorn Charitable Trust
• Investigators: Principal Investigator: Marc Dweck, University of Edinburgh

Publications and helpful links

General Publications

• Zelis JM, Tonino PAL, Pijls NHJ, De Bruyne B, Kirkeeide RL, Gould KL, Johnson NP. Coronary Microcirculation in Aortic Stenosis: Pathophysiology, Invasive Assessment, and Future Directions. J Interv Cardiol. 2020 Jul 22;2020:4603169. doi: 10.1155/2020/4603169. eCollection 2020.
• Di Pietro E, Frittitta V, Motta S, Strazzieri O, Valvo R, Reddavid C, Costa G, Tamburino C. Treatment in patients with severe asymptomatic aortic stenosis: is it best not to wait? Eur Heart J Suppl. 2022 Nov 12;24(Suppl I):I170-I174. doi: 10.1093/eurheartjsupp/suac089. eCollection 2022 Nov.
• Bing R, Everett RJ, Tuck C, Semple S, Lewis S, Harkess R, Mills NL, Treibel TA, Prasad S, Greenwood JP, McCann GP, Newby DE, Dweck MR. Rationale and design of the randomized, controlled Early Valve Replacement Guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients with Severe Aortic Stenosis (EVOLVED) trial. Am Heart J. 2019 Jun;212:91-100. doi: 10.1016/j.ahj.2019.02.018. Epub 2019 Mar 15.
• Loganath K, Craig NJ, Everett RJ, Bing R, Tsampasian V, Molek P, Botezatu S, Aslam S, Lewis S, Graham C, White AC, MacGillivray T, Tuck CE, Rayson P, Cranley D, Irvine S, Armstrong R, Milne L, Chin CWL, Hillis GS, Fairbairn T, Greenwood JP, Steeds R, Leslie SJ, Lang CC, Bucciarelli-Ducci C, Joshi NV, Kunadian V, Vassiliou VS, Dungu JN, Hothi SS, Boon N, Prasad SK, Keenan NG, Dawson D, Treibel TA, Motwani M, Miller CA, Mills NL, Rajani R, Ripley DP, McCann GP, Prendergast B, Singh A, Newby DE, Dweck MR; EVOLVED investigators. Early Intervention in Patients With Asymptomatic Severe Aortic Stenosis and Myocardial Fibrosis: The EVOLVED Randomized Clinical Trial. JAMA. 2025 Jan 21;333(3):213-221. doi: 10.1001/jama.2024.22730.
• Patel KP, Scully PR, Saberwal B, Sinha A, Yap-Sanderson JJL, Cheasty E, Mullen M, Menezes LJ, Moon JC, Pugliese F, Klotz E, Treibel TA. Regional Distribution of Extracellular Volume Quantified by Cardiac CT in Aortic Stenosis: Insights Into Disease Mechanisms and Impact on Outcomes. Circ Cardiovasc Imaging. 2024 May;17(5):e015996. doi: 10.1161/CIRCIMAGING.123.015996. Epub 2024 May 21.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2017
• Primary Completion (Actual): July 1, 2024
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: March 10, 2017
• First Submitted That Met QC Criteria: March 22, 2017
• First Posted (Actual): March 29, 2017

Study Record Updates

• Last Update Posted (Estimated): September 8, 2025
• Last Update Submitted That Met QC Criteria: September 1, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Aortic Valve Disease; Cardiovascular Diseases; Pathological Conditions, Anatomical; Heart Diseases; Heart Valve Diseases; Ventricular Outflow Obstruction; Cardiomegaly; Hypertrophy; Pathological Conditions, Signs and Symptoms; Aortic Valve Stenosis; Hypertrophy, Left Ventricular
• Other Study ID Numbers: 15/JTA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: It is planned that an anonymised raw dataset will be shared under a controlled access model. It will be available following primary publication. Requests will be made in accordance with Edinburgh Clinical Trials Unit policy at the time of release.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No