Clinical trial NCT03674255: Echocardiography: Value and Accuracy at REst and STress
Official title: Use of Imaging and Blood Biomarkers to Improve the Diagnostic Accuracy of Cardiac Assessment by Stress Echocardiogram
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Coronary Artery Disease
Ischaemic Heart Disease
Angina Pectoris
Keywords: Stress Echocardiography
Blood Biomarkers
Extracellular Vesicles
Imaging Biomarkers
Machine Learning
Artificial Intelligence
Ischaemic Heart Disease
Coronary Artery Disease
Angina Pectoris
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Oxford University Hospitals NHS Trust
name: Royal United Hospital Bath NHS Trust
name: Tameside Hospital NHS Foundation Trust
name: Royal Berkshire NHS Foundation Trust
name: East Lancashire Hospitals NHS Trust
name: Bradford Teaching Hospitals NHS Foundation Trust
name: Calderdale and Huddersfield NHS Foundation Trust
name: Great Western Hospitals NHS Foundation Trust
name: Mid Essex Hospital NHS Trust
name: Buckinghamshire Healthcare NHS Trust
name: Wrightington, Wigan and Leigh NHS Foundation Trust
name: Chelsea and Westminster NHS Foundation Trust
name: Milton Keynes University Hospital NHS Foundation Trust
name: University Hospitals Bristol and Weston NHS Foundation Trust
name: North Middlesex University Hospital
name: Northumbria Healthcare NHS Foundation Trust
name: London North West Healthcare NHS Trust
name: St George's University Hospitals NHS Foundation Trust
name: Ultromics Ltd
name: National Institute for Health Research, United Kingdom
name: King's College Hospital NHS Trust
name: Guy's and St Thomas' NHS Foundation Trust
name: Poole Hospital NHS Foundation Trust
name: Blackpool Teaching Hospitals NHS Foundation Trust
name: Mid Yorkshire Teaching NHS Trust
name: Northampton General Hospital NHS Trust
name: North West Anglia NHS Foundation Trust
name: Yeovil District Hospital NHS Foundation Trust
name: East Suffolk and North Essex NHS Foundation Trust
name: Nottingham University Hospitals NHS Trust
name: Hampshire Hospitals NHS Foundation Trust
name: Lantheus Medical Imaging
First posted: 2018-09-17
Enrollment: 23000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: For phases 1 - 3, patients will be recruited when attending hospital for a stress echocardiogram to investigate the presence of ischaemic heart disease. For phase 4, patients attending hospital for a stress echocardiogram, for any investigation, will be recruited.

Brief summary: EVAREST will identify and validate novel blood and imaging biomarkers of potential value for consistent and accurate interpretation of stress echocardiography. During phase one, blood samples will be collected to assess the impact of cardiac stress on levels of circulating biomarkers and examine whether the measurement of these biomarkers can provide additional prognostic information. Phases one, two and three will also determine whether novel imaging biomarkers can be identified in the echocardiograms that can be used for objective interpretation of the stress echocardiograms. EVAREST will recruit up to 8000 patients (First 500 during phase one, an additional 500 during phase two and an additional 7000 during phase three) from multiple hospitals across United Kingdom, who have been referred for a stress echocardiogram as part of their investigations into ischaemic heart disease. Phase four of the study will continue into a clinical study cohort phase to capture information from all patients referred for a stress echocardiogram in the UK, regardless of the reason for investigation.This registry phase will run for 2 years, recruiting up to 15000 participants.

Detailed description: Study Overview:

• Design

EVAREST is a multi-centre observational study comparing accuracy of novel quantitative stress echocardiography biomarkers for prediction of 12 month outcome against standard clinical interpretation.

• Scientific Justification

Coronary artery disease affects 2.3 million people in the UK and is responsible for 66 000 deaths each (BHF, 2018). As such, early diagnosis and intervention is crucial for saving lives and improving people's quality of life. Stress echocardiography is a commonly used, non-invasive imaging test used for detection of prognostically significant coronary artery disease. It allows the detection of regional wall motion abnormalities (RWMAs) which develop when the myocardium is not receiving adequate perfusion and, as such, indicates obstructive coronary artery disease. Average sensitivity and specificity for stress echocardiography is estimated at 81% and 82%, respectively (Geleijnse et al., 2009) in meta-analysis but remains highly subjective (Hoffmann et al., 1996) and subject to operator skill (Picano et al., 1991). Objective, quantifiable biomarkers in blood samples, or from images, acquired during the stress echocardiogram, which predict outcome of patients, could be used to reduce variability of stress echocardiography and ensure consistent and accurate results.

Aims

* To establish whether the measurement of specific blood biomarkers, in particular, extracellular vesicles, during a stress echocardiogram, can give additional prognostic information to stress echocardiography.
* To establish whether imaging biomarkers can provide additional prognostic information to stress echocardiography.

Phase One

Phase one will investigate the impact of cardiac stress on the levels of circulating biomarkers, in particular, extracellular vesicles. This phase will also assess whether they provide further prognostic information in addition to the echocardiogram. Blood samples will be collected from a cannula (inserted for the standard clinical procedure) before stress, during peak stress and during recovery and analysed to determine whether there were any changes in circulating extracellular vesicles during these three stages and whether these differ between patients with and without ischaemic heart disease.

Phase Two

Phase two continues recruitment for collection of stress echocardiogram images. Data collected during this phase will be compared with the data obtained during phase one to assess the usefulness of incorporating blood biomarkers into assessment of stress echocardiograms. In addition, the images obtained during phase two will be combined with the images collected during phase one to allow for the identification of novel imaging biomarkers which can be used to assist in the identification of patients with prognostically significant coronary disease.

Phase Three

Phase three will expand recruitment to allow evaluation of the generalisability of the imaging biomarkers identified in phase one and two across different healthcare settings, operators, stress protocols, machines and patient groups.

Phase Four

The fourth phase of the study allows for an assessment of all stress echocardiography practise in the UK and the demographics of patients being referred for stress echocardiogram. Phase four will investigate the use of stress echocardiography as a clinical procedure in the UK.

• Recruitment, Consent and Data Collection

Patients who have been scheduled a stress echocardiogram (using either pharmacological or exercise stress) as part of clinical investigations will be sent a participant information leaflet to read prior to their clinic appointment. When they are in the department, they will be approached by a study investigator to see whether they would be interested in taking part in the study and have the opportunity to ask the investigator any questions so that they fully understand the study. If they are interested in taking part, the process of obtaining informed consent will take place.

Following consent, the images acquired during the stress echocardiogram will be downloaded and anonymised with the participant's unique study ID number. These images will be transferred to the Oxford Research Echocardiography Core Laboratory (ORECL) for further analysis. Relevant medical history will be obtained for each participant as well as the clinician's interpretation of the echocardiogram. One year after the initial stress echocardiogram (range: 11-18 months), the participant will be followed-up to determine whether they underwent any further investigations for ischaemic heart disease (such as coronary angiography, cardiac magnetic resonance imaging, myocardial perfusion scintigraphy or repeat stress echocardiography) or had any coronary events. The participant may also be contacted via telephone to find out whether they were admitted to any other hospital for investigations. For phase one participants only, three blood samples (totalling approximately 40 ml) will be obtained before, at peak stress and after a recovery period, for the assessment of blood biomarkers. These samples will be taken through the cannula inserted as is routine during stress echocardiography. Participants will also give consent for follow-up information to be accessed for up to ten years after their initial stress echocardiogram.

• Outcome Assessment

Patient outcomes will be examined by an adjudication committee, blinded to the results of the stress echocardiograms. This committee will be led by a cardiologist and will examine all information obtained for a participant after the follow-up period has concluded. The criteria for confirming the presence of significant coronary artery disease include \> 70% stenosis (assessed either via invasive coronary angiography or CT coronary angiography), an FFR \< 0.85 or disease requiring intervention (either by percutaneous coronary intervention (PCI) or coronary artery bypass grafts (CABG)). Other end-points include coronary events (such as myocardial infarction) or death (attributed to coronary artery disease). If a patient has had no further investigations or events since their stress echocardiogram, their outcome will be recorded as normal.

• Confidentiality

All data obtained will be securely stored in accordance with the General Data Protection Regulations and Data Protection Act (2018) and Caldicott Principles.

Eligibility criteria: Inclusion Criteria:

* Patients must be undergoing a stress echocardiogram to investigate the presence of ischaemic heart disease (groups 1-3).
* Patients must be able to provide informed consent.
* Patients must be aged over 18 years of age.

Exclusion Criteria:

* Patients undergoing stress echocardiography to assess valvular function.
* Patients who are unwilling or unable to provide informed consent.
* Patients aged under 18 years of age.

Primary outcomes:
measure: Assessment of Prognostically Significant CAD
timeFrame: Data will be collected for ten years after the patient undergoes the stress echocardiogram.
measure: Examination of Medical Records
timeFrame: Data will be collected for ten years after the patient undergoes the stress echocardiogram.
Secondary outcomes:
measure: Quantification of Extracellular Vesicles (obtained from blood samples) by Flow Cytometry
timeFrame: Blood samples will be obtained before and after the stress echocardiogram. Analysis will be complete one year from the date of the stress echocardiogram
measure: Assessment of Time to Diagnosis
timeFrame: Data will be collected for ten years after the patient undergoes the stress echocardiogram.
measure: Analysis of Potential Cost Savings Through the Use of Novel Biomarkers By the Reduction in Unnecessary Procedures
timeFrame: Data will be collected for ten years after the patient undergoes the stress echocardiogram.
measure: Investigation into the use of stress echocardiography as a clinical procedure in the UK.
timeFrame: Data will be collected for ten years after the patient undergoes the stress echocardiogram.
Other outcomes:
Locations:
Study officials:
affiliation: Cardiovascular Clinical Research Facility, University of Oxford
name: Paul Leeson
role: PRINCIPAL_INVESTIGATOR
References:
citation: Alsharqi M, Upton R, Mumith A, Leeson P. Artificial intelligence: a new clinical support tool for stress echocardiography. Expert Rev Med Devices. 2018 Aug;15(8):513-515. doi: 10.1080/17434440.2018.1497482. Epub 2018 Jul 19. No abstract available.
citation: Augustine D, Ayers LV, Lima E, Newton L, Lewandowski AJ, Davis EF, Ferry B, Leeson P. Dynamic release and clearance of circulating microparticles during cardiac stress. Circ Res. 2014 Jan 3;114(1):109-13. doi: 10.1161/CIRCRESAHA.114.301904. Epub 2013 Oct 18.
citation: Ayers L, Nieuwland R, Kohler M, Kraenkel N, Ferry B, Leeson P. Dynamic microvesicle release and clearance within the cardiovascular system: triggers and mechanisms. Clin Sci (Lond). 2015 Dec;129(11):915-31. doi: 10.1042/CS20140623.