Mechanisms of Excess Risk in Aortic Stenosis

Heart Failure Clinical Trial

— MASTER  

Official title:

Mechanisms of Excess Risk in Aortic STEnosis After Aortic Valve Replacement

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04627987
• Other study ID #: 125312
• Status: Recruiting
• Start date: March 23, 2021
• Est. completion date: December 1, 2025

Study information

• Verified date: April 2021
• Source: University College, London
• Contact: Thomas A Treibel, MBBS PhD
• Phone: 020 3416 5000
• Email: thomas.treibel.12[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Aortic stenosis (AS) is caused by narrowing of one of the main heart valves. Replacing the valve is the only treatment to prevent the heart from failing or death. The timing of replacement is currently often too late - half of patients are left with permanent scarring and a quarter die within 3.5 years.

Studies are underway to see if earlier replacement makes a difference. But for those with scarring of the heart, there is currently no tailored treatment. I want to change this by understanding why and how patients with scar are dying and what the investigators can do to prevent this.

In this study, the investigators will use a heart scan (MRI) to detect scarring before valve replacement. After replacement, patients will receive a tiny monitor (paper clip size), which the investigators inject underneath the skin. This monitor continuously checks the heartbeat and can detect increased body fluid due to heart failure. The investigators will monitor patients for an average of 3 years to see if scarring is linked to abnormal heart rhythms and heart failure.

Once the investigators know how and why, the investigators can target patients with available medications and design studies using specialised treatments, eg defibrillator implantation, to protect patients with scar from dying.

Description:

Valvular heart disease (VHD) affects around 1.5 million people above the age of 65 across the UK and is set to nearly double by 2050. Aortic Stenosis (AS) is the most common VHD in the UK, affecting 3% of those over 75 with more than 11,000 people requiring aortic valve replacement (AVR) in the UK each year (>100,000 world-wide). Current guidelines recommend AVR to improve survival and symptom status when AS symptoms emerge or there is a reduction in left ventricle (LV) function (1), but years of excessive haemodynamic load result in an "AS cardiomyopathy" with LV hypertrophy, remodelling, diffuse and focal scar. The investigators, and others, have shown that these changes lead to an excess in morbidity and mortality, but the mechanisms of increased risk is unclear.

Patients undergoing aortic valve replacement for severe aortic stenosis have a shorter life expectancy compared with the general population (2). Years of excessive haemodynamic load result in an "AS cardiomyopathy" with LV hypertrophy, remodelling, diffuse and focal scar. The investigators and others have shown that these changes to the heart muscle are associated with poor outcome. But the mechanism of how heart muscle damage leads to excess mortality is poorly understood.

The proposed study will enhance our understanding of the residual risk after AVR and reveal the modes and substrate of mortality. Heart failure and heart rhythm disturbances (arrhythmias) are likely downstream effects of heart muscle damage, but without understanding the mode of death (heart failure, arrhythmia or other), the investigators are unable to target therapeutic strategies to improve outcomes.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 192
• Est. completion date: December 1, 2025
• Est. primary completion date: December 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with symptomatic severe aortic stenosis referred for surgical or transcatheter AVR (one out of: effective orifice area [EOA] <1.0 cm2 , indexed EOA of 0.6cm/m2, peak velocity >4.0 m/s or mean gradient >40mmHg).

Exclusion Criteria:

• More than moderate valve disease other than AS

• Diagnosis of dilated or hypertrophic cardiomyopathy, pregnancy/breast feeding

• eGFR <30ml/min, CMR incompatible devices

• Inability to complete the protocol

• Other conditions that would prevent participation in the study.

• Adenosine perfusion will not be performed in patients with AV block, severe asthma/COPD or LVEF<40%.

Related Conditions & MeSH terms

• Aortic Stenosis
• Aortic Valve Stenosis
• Constriction, Pathologic
• Heart Failure
• Non-Sustained VT

Intervention

Diagnostic Test:
• Cardiac MRI scan
Cardiac MRI scan pre- and post- aortic valve replacement to assess degree of left ventricular remodelling, fibrosis and myocardial blood flow.
• Serum biomarkers (High sensitivity troponin, NT-proBNP
Blood tests looking evidence of cardiac structural remodelling and function.

Procedure:
• Implantable Loop Recorder
Determine post-AVR arrhythmia burden

Diagnostic Test:
• 6 minute walk test
Validated assessment of functional capacity - distance walked over 6 minute time frame.
• Echocardiogram
Ultrasound assessment of heart structure and function. Standard of care in valve surgery pathway.

Locations

Country	Name	City	State
United Kingdom	Barts Heart Centre	London

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	Barts & The London NHS Trust

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Heart failure death or hospitalisation for heart failure.		5 years after aortic valve replacement
Primary	Burden of non-sustained VT	As assessed on implantable cardiac monitor (approximate battery life 2.5 years)	2.5 years after aortic valve replacement.
Secondary	All-cause mortality (all-cause and cardiovascular via NHS spine/death registration)		5 years after aortic valve replacement
Secondary	change in functional capacity (6-minute walk test)		At 6 weeks and 12 months after aortic valve replacement.
Secondary	Heart failure symptoms	New York Heart Association (NYHA) functional classification (NYHA 1 least symptomatic, 4 most symptomatic)	At 6 weeks and 12 months post aortic valve surgery
Secondary	Heart failure symptoms	World Health Organisation Disability Assessment Schedule 2.0 (Higher score indicates greater disability)	At 6 weeks and 12 months post aortic valve surgery
Secondary	Burden of other serious arrhythmias requiring change in management	Participants with complete heart block, Mobitz 2 AV block, new onset atrial fibrillation	2.5 years after aortic valve replacement