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

Primary Purpose

Aortic Valve Stenosis, Hypertrophy, Left Ventricular

Status
Active
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
Aortic valve intervention
Sponsored by
University of Edinburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aortic Valve Stenosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • NHS Lothian

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

No Intervention

No Intervention

No Intervention

Arm Label

Group A: Early intervention

Group B: Routine care

Group C: Routine care

Group D: No further study follow up

Arm Description

Patients will be referred immediately for aortic valve intervention.

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).

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

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

All-cause mortality
Cardiovascular death
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.
Sudden cardiac death
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.
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.
LV systolic function
The development of LV systolic dysfunction (EF <50% quantitatively or at least mild LV dysfunction qualitatively)
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.)
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
Stroke
Endocarditis
To compare between study arms the number of participants who have endocarditis
Post-operative complications following aortic valve intervention

Full Information

First Posted
March 10, 2017
Last Updated
November 16, 2022
Sponsor
University of Edinburgh
Collaborators
Sir Jules Thorn Charitable Trust
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1. Study Identification

Unique Protocol Identification Number
NCT03094143
Brief Title
Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients With Severe AS
Acronym
EVoLVeD
Official Title
Early Valve Replacement Guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients With Severe Aortic Stenosis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 21, 2017 (Actual)
Primary Completion Date
October 1, 2024 (Anticipated)
Study Completion Date
October 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Edinburgh
Collaborators
Sir Jules Thorn Charitable Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aortic Valve Stenosis, Hypertrophy, Left Ventricular

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Participants are randomised based on the result of the cardiac MRI. Participants who have mid wall fibrosis (heart scarring) are randomised to receive either early surgical intervention (group A) or routine care (group B). Participants who have no mid wall fibrosis are randomised to routine care with study follow up (group C) or without study follow up (group D).
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The result of the cardiac MRI will be blinded to care provider, participant and investigator. Group A will be unblinded, as participants can only enter group A if mid-wall fibrosis is present. Groups B and C will appear identical and the groups combined so the presence of mid-wall fibrosis will be blinded. Group D will be unblinded, as participants can only enter group D if mid-wall fibrosis is not present. Outcome assessors will be blinded to allocation in all groups where outcome is adjudicated (groups A, B and C)
Allocation
Randomized
Enrollment
1000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group A: Early intervention
Arm Type
Experimental
Arm Description
Patients will be referred immediately for aortic valve intervention.
Arm Title
Group B: Routine care
Arm Type
No Intervention
Arm Description
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).
Arm Title
Group C: Routine care
Arm Type
No Intervention
Arm Description
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
Arm Title
Group D: No further study follow up
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Aortic valve intervention
Intervention Description
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.
Primary Outcome Measure Information:
Title
Composite of all-cause mortality or unplanned aortic stenosis-related hospitalisation
Description
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.
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Secondary Outcome Measure Information:
Title
All-cause mortality
Time Frame
Randomisation through to study completion, an average of 2.75 years
Title
Cardiovascular death
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
AS-related death
Description
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.
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
Sudden cardiac death
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
Unplanned aortic-stenosis related hospitalisation
Description
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.
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
WHODAS 2.0 (12 item)
Description
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.
Time Frame
At study completion (mean follow up is expected to be an average of 2.75 years)
Title
LV systolic function
Description
The development of LV systolic dysfunction (EF <50% quantitatively or at least mild LV dysfunction qualitatively)
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
NYHA status
Description
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.)
Time Frame
At study completion (mean follow up is expected to be an average of 2.75 years)
Title
Permanent pacemaker insertion, cardiac resynchronisation therapy or automated implantable cardioverter defibrillator
Description
To compare between study arms the number of participants who have had a permanent pacemaker insertion, cardiac resynchronisation therapy or automated implantable cardioverter defibrillator
Time Frame
Randomisation to through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
Stroke
Time Frame
Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
Endocarditis
Description
To compare between study arms the number of participants who have endocarditis
Time Frame
Randomisation to through to study completion (mean follow up is expected to be an average of 2.75 years)
Title
Post-operative complications following aortic valve intervention
Time Frame
30 days post aortic valve intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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) Age over 18 years No symptoms attributable to aortic stenosis that require aortic valve replacement Exclusion Criteria: Deemed lower risk for mid-wall fibrosis on screening Planned cardiac surgery Previous valve replacement Severe hypertension (systolic >180 or diastolic >110 mmHg) Acute pulmonary oedema or cardiogenic shock Left ventricular ejection fraction <50% on cardiac MRI Significant abnormalities on cardiac MRI that would prevent enrolment Coexistent severe aortic regurgitation or mitral regurgitation Coexistent mitral stenosis greater than mild in severity Coexistent hypertrophic cardiomyopathy or cardiac amyloidosis Any contraindication to MRI scanning (such as permanent pacemaker) Advanced renal impairment (glomerular filtration rate <30 mL/min/1.73 m2) Pregnancy or breast feeding Patient judged to be unfit to be considered for aortic valve replacement or transcatheter aortic valve implantation Patient declines to consider undergoing valve replacement surgery or transcatheter aortic valve implantation Inability to give informed consent Previous randomisation into this study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marc Dweck
Organizational Affiliation
University of Edinburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
NHS Lothian
City
Edinburgh
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
36380774
Citation
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.
Results Reference
derived
PubMed Identifier
32774184
Citation
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.
Results Reference
derived
PubMed Identifier
30978556
Citation
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.
Results Reference
derived

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

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