Clinical trial NCT03094143: Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients with Severe AS
Official title: Early Valve Replacement Guided by Biomarkers of Left Ventricular Decompensation in Asymptomatic Patients with Severe Aortic Stenosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Aortic Valve Stenosis
Hypertrophy, Left Ventricular
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: Sir Jules Thorn Charitable Trust
First posted: 2017-03-29
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: \~1000 patients with asymptomatic severe aortic stenosis will be screened across the sites (this is how we have defined enrollment below). Patients at high risk of left ventricular decompensation based on high-sensitivity troponin or ECG will proceed to CMR. 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).
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Composite of all-cause mortality or unplanned aortic stenosis-related hospitalisation
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
Secondary outcomes:
measure: All-cause mortality
timeFrame: Randomisation through to study completion, an average of 2.75 years
measure: Cardiovascular death
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: AS-related death
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: Sudden cardiac death
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: Unplanned aortic-stenosis related hospitalisation
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: WHODAS 2.0 (12 item)
timeFrame: At study completion (mean follow up is expected to be an average of 2.75 years)
measure: LV systolic function
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: NYHA status
timeFrame: At study completion (mean follow up is expected to be an average of 2.75 years)
measure: Permanent pacemaker insertion, cardiac resynchronisation therapy or automated implantable cardioverter defibrillator
timeFrame: Randomisation to through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: Stroke
timeFrame: Randomisation through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: Endocarditis
timeFrame: Randomisation to through to study completion (mean follow up is expected to be an average of 2.75 years)
measure: Post-operative complications following aortic valve intervention
timeFrame: 30 days post aortic valve intervention
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
Study officials:
affiliation: University of Edinburgh
name: Marc Dweck
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.