Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) Trial

Coronary Artery Disease Clinical Trial

— CorCMR  

Official title:

The Clinical Utility Of Cardiac Magnetic Resonance Imaging in Patients With Angina But No Obstructive Coronary Disease (CorCMR): A Diagnostic Study And Nested Randomised Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04805814
• Other study ID #: 281128
• Status: Recruiting
• Phase: N/A
• Start date: February 9, 2021
• Est. completion date: February 2024

Study information

• Verified date: March 2021
• Source: NHS National Waiting Times Centre Board
• Contact: Colin Berry, MBChB, PhD
• Phone: +44 141 951 5180
• Email: colin.berry[@]glasgow.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Anginal symptoms due to ischaemia with no obstructive coronary arteries (INOCA) is a common clinical problem, however, diagnosis and onward management is heterogeneous, and prognosis is affected. Recent advances in quantifying myocardial blood flow using stress perfusion cardiac magnetic resonance imaging (CMR) has potential for accurate detection coronary microvascular dysfunction.

The CorCMR diagnostic study involves stress perfusion CMR in patients with suspected INOCA to clarify the prevalence of subgroups of patients with underlying problems, such as microvascular disease or undisclosed obstructive coronary artery disease, that might explain their anginal symptoms.

A nested, prospective, randomised, controlled, double-blind trial will determine whether stratified medical therapy guided by the results of the stress perfusion CMR improves symptoms, well-being, cardiovascular risk and health and economic outcomes.

Description:

Background:

There are approximately 2 million men and women living with angina in the UK. In 2014, there were ~247,000 coronary angiograms performed, mostly for the investigation of known or suspected angina. However, obstructive CAD is detected in only 1 in 2 patients. The explanation for the cause(s) of the chest pain are often unclear. Microvascular or vasospastic angina may be one explanation.

Adjunctive tests of coronary artery function to diagnose these problems are rarely used during coronary angiography in the NHS, meaning that patient management may be empirical and heterogeneous. The lack of adoption of these novel tests in the NHS reflects key gaps in the clinical evidence. It is these gaps, coupled with the increasing adoption of anatomical coronary artery imaging with CT coronary angiography (CTCA), which stimulate this research. In recent large clinical trials, CT coronary angiography has been shown not to reduce the rate of invasive angiography. In fact, compared to standard care based on stress testing, CTCA is associated with less improvement in anginal symptoms and in quality of life (PUBMED ID: 28246175). Anatomical tests, such as CTCA and invasive angiography, do not provide information on myocardial blood flow. New evidence that addresses these gaps might inform therapy development and future trials.

Current gaps in evidence and guidelines point to a problem of unmet need in the NHS care pathway. Stress perfusion CMR has potential diagnostic value for microvascular disease, but whether it might discriminate clinical endotypes in a relatively unselected population of patients in daily practice, is uncertain. Further, access to stress perfusion CMR varies widely not least because evidence from randomised trials supporting clinical and economic benefits from a CMR-guided approach is lacking. CorCMR is a clinical strategy trial that is designed to address this evidence gap.

Hypothesis:

In patients with angina in whom obstructive disease in the epicardial coronary arteries has been ruled out by coronary angiography ± FFR, stress perfusion CMR will reclassify the diagnosis leading to changes in treatment (start or stop therapy), improvements in health and economic outcomes, as compared to decisions based standard care (CMR not disclosed).

Design:

We propose that an observational, diagnostic study involving stress CMR will provide information on the prevalence of microvascular disease in a population with anginal symptoms potentially attributable to myocardial ischaemia with no obstructive coronary arteries (INOCA). Each diagnosis is linked to a guideline-directed treatment plan.The potential value of this strategy can only be confirmed if it is associated with patient benefits, which is why we propose a nested, randomised, controlled, double-blind trial of routine disclosure of stress perfusion CMR vs. angiography-guided management

Methods:

Patients undergoing invasive coronary angiography for the investigation of known or suspected angina and who do not have either structural heart disease or a systemic health problem that would explain those symptoms will be invited to participate. Written informed consent is required for participation. Eligibility is further confirmed at the time of the coronary angiogram by exclusion of obstructive (stenosis >70% in a single segment or 50 - 70% in 2 adjacent segments in an artery >2.5 mm, or FFR ≤0.80) coronary artery disease (CAD). Angina symptoms will be confirmed by the completion of validated questionnaires and patients will be invited to attend for a stress perfusion CMR within 3 months of the original coronary angiogram.

On arrival for the CMR, patients will be randomised (1:1) to either the intervention (CMR guided, results disclosed) or blinded control group (CMR undertaken but results not disclosed, standard of care) group.

Trial participants will be blinded to treatment group. The clinicians responsible for on-going care will also be blinded. The design is therefore 'double-blind'. Following the CMR, patients and clinicians will be advised of the diagnosis (endotype) but not the randomised group. The endotype will be informed by the CMR in the intervention group but not in the control group (CMR results not disclosed, angiography-guided). Medical therapy and lifestyle measures are linked to the endotype and informed by contemporary practice guidelines. Therefore, optimal guideline-directed medical care according to the endotype is intended to be the same, regardless of the group allocation.

The sample size is 280 randomised participants. The minimum follow-up duration is 12 months from the last participant recruitment. Follow-up will continued in the longer term including, where feasible, electronic case record linkage.

The primary outcome of the diagnostic study is the reclassification of the initial diagnosis based on findings from the cardiac MRI scan. The primary outcome of the nested randomised trial is the within-subject change at 6 months from baseline for the domains of the Seattle Angina Questionnaire.

Secondary outcomes include other Patient Reported Outcome Measures (PROMS) to describe other aspects of health and wellbeing. These include EQ-5D-5L, Illness perception (Brief IPQ), Treatment satisfaction (TSQM), Duke Activity Status Index (DASI), the International Physical Activity Questionnaire (IPAQ-SF) short-form and a pain questionnaire.

There is preliminary evidence that small vessel disease can be a systemic problem affecting different organs. Whether small vessel disease in the heart might associate with small vessel disease in the brain or retina is unknown. In the CorMicA pilot study, studies of small vessels isolated from biopsies found evidence of endothelial dysfunction and increased responsiveness of the blood vessels to naturally-occurring, constriction-inducing peptides such as endothelin and thromboxane. For these reasons, we plan heart-brain-retina and peripheral vascular substudies.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 280
• Est. completion date: February 2024
• Est. primary completion date: February 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years

2. Symptoms of angina or angina-equivalent informed by the Rose Angina questionnaire.

3. Coronary angiography =3 months with a plan for medical management.

Exclusion Criteria:

1. Obstructive coronary artery disease i.e. a stenosis >70% in a single segment or 50 - 70% in 2 adjacent segments in an artery >2.5 mm, or FFR =0.80.

2. Coronary revascularization by percutaneous coronary intervention or coronary artery bypass graft surgery following the index angiogram.

3. Prior coronary artery bypass surgery

4. A diagnosis that would explain the angina e.g. anaemia, aortic stenosis, hypertrophic cardiomyopathy,

5. Contra-indication to contrast-enhanced CMR e.g. eGFR < 30mL/min/1.73m2.

6. Contra-indication to intravenous adenosine, i.e. severe asthma; long QT syndrome; second- or third-degree AV block and sick sinus syndrome.

7. Lack of informed consent.

Related Conditions & MeSH terms

• Angina Pectoris
• Angina, Stable
• Atherosclerosis
• Cerebral Small Vessel Diseases
• Cerebrovascular Disorders
• Coronary Artery Disease
• Microvascular Angina
• Myocardial Ischemia
• Non-Obstructive Coronary Atherosclerosis
• Small Vessel Cerebrovascular Disease

Intervention

Diagnostic Test:
• CMR results disclosed
The results of the CMR are disclosed, and used to guide management
• CMR performed but results not disclosed
The results of the CMR are not disclosed, and management is angiography-guided

Locations

Country	Name	City	State
United Kingdom	Golden Jubilee National Hospital	Glasgow	Scotland

Sponsors (4)

Lead Sponsor	Collaborator
NHS National Waiting Times Centre Board	British Heart Foundation, Chief Scientist Office of the Scottish Government, University of Glasgow

Country where clinical trial is conducted

United Kingdom, 

References & Publications (12)

Berry C, Sidik N, Pereira AC, Ford TJ, Touyz RM, Kaski JC, Hainsworth AH. Small-Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need, and Future Directions. J Am Heart Assoc. 2019 Feb 5;8(3):e011104. doi: 10.1161/JAHA.118.011104. Review. — View Citation

Corcoran D, Ford T, Hsu LY, Orchard V, Oldroyd KG, Arai AE, Berry C, on behalf of the CorMicA Investigators. The diagnostic utility of multiparametric CMR in patients with angina and non-obstructive coronary artery disease. Eur Heart J. 2020;

Ford TJ, Berry C. Angina: contemporary diagnosis and management. Heart. 2020 Mar;106(5):387-398. doi: 10.1136/heartjnl-2018-314661. Epub 2020 Feb 12. Review. — View Citation

Ford TJ, Rocchiccioli P, Good R, McEntegart M, Eteiba H, Watkins S, Shaukat A, Lindsay M, Robertson K, Hood S, Yii E, Sidik N, Harvey A, Montezano AC, Beattie E, Haddow L, Oldroyd KG, Touyz RM, Berry C. Systemic microvascular dysfunction in microvascular and vasospastic angina. Eur Heart J. 2018 Dec 7;39(46):4086-4097. doi: 10.1093/eurheartj/ehy529. — View Citation

Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sidik N, McCartney P, Corcoran D, Collison D, Rush C, McConnachie A, Touyz RM, Oldroyd KG, Berry C. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018 Dec 11;72(23 Pt A):2841-2855. doi: 10.1016/j.jacc.2018.09.006. Epub 2018 Sep 25. — View Citation

Ford TJ, Stanley B, Sidik N, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, McCartney P, Corcoran D, Collison D, Rush C, Sattar N, McConnachie A, Touyz RM, Oldroyd KG, Berry C. 1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA). JACC Cardiovasc Interv. 2020 Jan 13;13(1):33-45. doi: 10.1016/j.jcin.2019.11.001. Epub 2019 Nov 11. — View Citation

Hsu LY, Jacobs M, Benovoy M, Ta AD, Conn HM, Winkler S, Greve AM, Chen MY, Shanbhag SM, Bandettini WP, Arai AE. Diagnostic Performance of Fully Automated Pixel-Wise Quantitative Myocardial Perfusion Imaging by Cardiovascular Magnetic Resonance. JACC Cardiovasc Imaging. 2018 May;11(5):697-707. doi: 10.1016/j.jcmg.2018.01.005. Epub 2018 Feb 14. — View Citation

Knott KD, Seraphim A, Augusto JB, Xue H, Chacko L, Aung N, Petersen SE, Cooper JA, Manisty C, Bhuva AN, Kotecha T, Bourantas CV, Davies RH, Brown LAE, Plein S, Fontana M, Kellman P, Moon JC. The Prognostic Significance of Quantitative Myocardial Perfusion: An Artificial Intelligence-Based Approach Using Perfusion Mapping. Circulation. 2020 Apr 21;141(16):1282-1291. doi: 10.1161/CIRCULATIONAHA.119.044666. Epub 2020 Feb 14. — View Citation

Kotecha T, Martinez-Naharro A, Boldrini M, Knight D, Hawkins P, Kalra S, Patel D, Coghlan G, Moon J, Plein S, Lockie T, Rakhit R, Patel N, Xue H, Kellman P, Fontana M. Automated Pixel-Wise Quantitative Myocardial Perfusion Mapping by CMR to Detect Obstructive Coronary Artery Disease and Coronary Microvascular Dysfunction: Validation Against Invasive Coronary Physiology. JACC Cardiovasc Imaging. 2019 Oct;12(10):1958-1969. doi: 10.1016/j.jcmg.2018.12.022. Epub 2019 Feb 13. — View Citation

Kunadian V, Chieffo A, Camici PG, Berry C, Escaned J, Maas AHEM, Prescott E, Karam N, Appelman Y, Fraccaro C, Buchanan GL, Manzo-Silberman S, Al-Lamee R, Regar E, Lansky A, Abbott JD, Badimon L, Duncker DJ, Mehran R, Capodanno D, Baumbach A. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. EuroIntervention. 2021 Jan 20;16(13):1049-1069. doi: 10.4244/EIJY20M07_01. — View Citation

Ludman P on behalf of the British Cardiovascular Intervention Society (BCIS). BCIS Audit Returns for Adult Interventional Procedures (Jan - Dec 2016). October 2017. https://www.bcis.org.uk/resources/audit-results/

Williams MC, Hunter A, Shah A, Assi V, Lewis S, Mangion K, Berry C, Boon NA, Clark E, Flather M, Forbes J, McLean S, Roditi G, van Beek EJ, Timmis AD, Newby DE; Scottish COmputed Tomography of the HEART (SCOT-HEART) Trial Investigators. Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial. Heart. 2017 Jul;103(13):995-1001. doi: 10.1136/heartjnl-2016-310129. Epub 2017 Feb 28. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Small vessel substudy	Sub-study of small vessel function using myography in arterioles isolated from gluteal skin biopsies.; Standard pharmacological read-outs include the drug concentration required to achieve 50% of the maximum contraction and/or relaxation (wire myography) and structure/function relationships (pressure myography).	0-12 months
Other	Retinal imaging substudy	Retinal vascular imaging by optical coherence tomography (OCT) to assess for the presence or absence of small vessel disease.	0-12 months
Primary	Reclassification of the initial diagnosis	The reclassification of the initial diagnosis based on invasive management following multi-parametric stress perfusion CMR. The diagnostic groups (endotypes) are: Anginal symptoms with a myocardial perfusion defect indicative of obstructive CAD; Anginal symptoms associated with a myocardial perfusion defect indicative of microvascular disease; Vasospastic angina; Incidental finding that is actionable e.g. aortic stenosis, cardiomyopathy, lung cancer; or; No clinically significant finding or normal.	Day 1
Primary	Seattle Angina Questionnaire (SAQ) Summary Score	The 7-item version of the SAQ reflects the frequency of angina (SAQ Angina Frequency score) and the disease-specific effect of angina on patients' physical function (SAQ Physical Limitation score) and quality of life (Quality of Life score) over the previous 4 weeks; these scores are averaged to obtain the SAQ Summary score, which is an overall measure of patients' stable ischaemic heart disease-specific health status. SAQ scores range from 0 to 100, with higher scores indicating less frequent angina, improved function, and better quality of life.	6 months
Secondary	Compliance with the protocol	Assess feasibility of the clinical strategy by measuring compliance with the protocol and, specifically, rate of enrolment, % of patients who drop-out, % of patients who complete the diagnostic MRI protocol.	0-36 months
Secondary	Integrity of blinding in the Radiology Department and during follow-up	Assess the integrity and feasibility of blinding by administering patient and clinician questionnaires to determine if both groups have been successfully blinded	0-36 months
Secondary	Diagnostic utility	To assess % of patients with a change in diagnosis following disclosure of the cardiac MRI results, and relatedly, the level of certainty reported by the physicians for the diagnosis (diagnostic utility). This will be assessed by a questionnaire completed by the clinician before the MRI, and then again after the MRI results are disclosed.	0-36 months
Secondary	Clinical Utility	To assess impact of disclosure of the cardiac MRI results on clinical management (including treatment and investigations). This will be measured by asking clinicians to complete a questionnaire on ongoing clinical management following disclosure of the MRI result	0-36 months
Secondary	Abnormal myocardial perfusion	Assess the prevalence of abnormal blood flow in the heart muscle, as defined by a minimum of 2 adjacent cardiac segments each with =50% deficit in myocardial perfusion at peak stress revealed by (1) visual assessment of the dynamic stress perfusion CMR scan and (2) pixel mapping of myocardial blood flow (< 2.0 ml/min/g tissue).	Day 1
Secondary	Myocardial blood flow	Assess the associations between myocardial blood flow (ml/min/g) and invasive measures of coronary function (where available) that might be implicated in the pathophysiology of abnormal coronary vascular function.	Day 1
Secondary	Myocardial tissue characteristics	Assess the correlation between myocardial blood flow (ml/min/g) and myocardial tissue characteristics as revealed by MRI T1- and T2- relaxation times (ms) and extracellular volume fraction.	Day 1
Secondary	Cardiovascular risk	Assess the correlation between cardiovascular risk factors, reflected by validated risk scores (e.g. ASSIGN, JBS3), and myocardial blood flow (ml/min/g) in medically managed patients.	Day 1
Secondary	Within subject change in myocardial blood flow	Assess the within-subject change in cardiac MRI findings during 12-months. This will be done by measuring the within-subject change in peak, global, myocardial blood flow over 12 months.	0-12 months
Secondary	Between-group, within subject change in myocardial blood flow	Assess the between-group, within-subject change in cardiac MRI findings over 12 months. This outcome will provide insights into the effect of the study intervention on MRI findings. This will be done by measuring the within-subject, between group change in peak, global, myocardial blood flow over 12 months.	0-12 months
Secondary	Health Status: EQ5D-5L Questionnaire	The 5-item EuroQol Group EQ5D-5L is a validated questionnaire comprising mobility, self-care, usual activities, pain/discomfort and anxiety/depression to quantitatively assess patient's self-reported health status and will be administered at each study visit.	0-36 months
Secondary	Health Status: Seattle Angina Questionnaire	Seattle Angina Questionnaire (SAQ) Summary Score and component scores (Angina Limitation, Angina Stability, Angina Frequency, Treatment Satisfaction and Quality of Life) will be recorded at all study visits.	0-36 months
Secondary	Health Status: Illness Perception - Brief IPQ	Brief Illness Perception Questionnaire (Brief IPQ), a nine-item scale designed to rapidly assess the cognitive and emotional representations of illness taken at all study visits.	0-36 months
Secondary	Health Status: Treatment satisfaction - TSQM	The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) is a reliable and valid instrument to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction and will administered at all study visits.	0-36 months
Secondary	Health Status: Duke Activity Status Index	The 12 point Duke Activity Status Index (DASI) is a validated questionnaire to assess functional capacity and will be administered at all study visits.	0-36 months
Secondary	Health Status: International Physical Activity Questionnaire- Short Form (IPAQ-SF)	The 4 point IPAQ-SF is a validated questionnaire to assess functional ability and activuty levels and will be administered at all study visits.	0-36 months
Secondary	Health Status: Montreal Cognitive Assessment (MOCA)	The MOCA is an internationally validated 30 point assessment of cognitive function, and will be administered on all study visits.	0-36 months
Secondary	Correlation between myocardial blood flow and health status	Assess the correlation between myocardial blood flow (ml/min/g) and health status, as measured by validated questionnaires.	0-36 months
Secondary	Long term prognosis	Assess the long-term prognostic significance of between myocardial perfusion (ml/min/g).	0-20 years
Secondary	Health Outcomes: Major Adverse Cardiovascular Events	MACE including death, re-hospitalisation for cardiovascular events including myocardial infarction, heart failure, stroke/ TIA, unstable angina and coronary revascularisation. Unscheduled hospital visits for chest pain that have not led to hospital admission will also be documented.	0-20 years
Secondary	Angina events	Anginal episodes based on completion of a chest symptoms log and adjudicated by a clinical event committee.	0-3 years
Secondary	Brain small vessel disease	Quantify small vessel disease score in the brain using the The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) guidelines.	0-36 months
Secondary	Correlation between small vessel disease in the brain and myocardial perfusion	Assess the correlation between MRI features of small vessel disease in the brain and myocardial perfusion.	0-36 months
Secondary	Health economics: Inpatients visits	Health resource utilisation will also be assessed by recording the number of inpatient visits in the follow-up period	0-20 years
Secondary	Health economics: Cardiac procedures	Health resource utilisation will also be assessed by recording the number of repeat cardiac procedures performed in the follow up period	0-20 years
Secondary	Health economics: Medication use	Health resource utilisation will also be assessed by recording the medication used in the follow up period	0-20 years
Secondary	Work limitation	Use the 8-item Work limitation Questionnaire to estimate productivity loss and time lost from work, where appropriate.	0-36 months