Clinical trial NCT04805814: Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) Trial
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Microvascular Angina
Angina Pectoris
Angina, Stable
Non-Obstructive Coronary Atherosclerosis
Small Vessel Cerebrovascular Disease
Coronary Artery Disease
Lead sponsor: NHS National Waiting Times Centre Board
Sponsor class: OTHER
Collaborators: name: University of Glasgow
name: British Heart Foundation
name: Chief Scientist Office of the Scottish Government
First posted: 2021-03-18
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Reclassification of the initial diagnosis
timeFrame: Day 1
measure: Seattle Angina Questionnaire (SAQ) Summary Score
timeFrame: 6 months
Secondary outcomes:
measure: Compliance with the protocol
timeFrame: 0-36 months
measure: Integrity of blinding in the Radiology Department and during follow-up
timeFrame: 0-36 months
measure: Diagnostic utility
timeFrame: 0-36 months
measure: Clinical Utility
timeFrame: 0-36 months
measure: Abnormal myocardial perfusion
timeFrame: Day 1
measure: Myocardial blood flow
timeFrame: Day 1
measure: Myocardial tissue characteristics
timeFrame: Day 1
measure: Cardiovascular risk
timeFrame: Day 1
measure: Within subject change in myocardial blood flow
timeFrame: 0-12 months
measure: Between-group, within subject change in myocardial blood flow
timeFrame: 0-12 months
measure: Health Status: EQ5D-5L Questionnaire
timeFrame: 0-36 months
measure: Health Status: Seattle Angina Questionnaire
timeFrame: 0-36 months
measure: Health Status: Illness Perception - Brief IPQ
timeFrame: 0-36 months
measure: Health Status: Treatment satisfaction - TSQM
timeFrame: 0-36 months
measure: Health Status: Duke Activity Status Index
timeFrame: 0-36 months
measure: Health Status: International Physical Activity Questionnaire- Short Form (IPAQ-SF)
timeFrame: 0-36 months
measure: Health Status: Montreal Cognitive Assessment (MOCA)
timeFrame: 0-36 months
measure: Correlation between myocardial blood flow and health status
timeFrame: 0-36 months
measure: Long term prognosis
timeFrame: 0-20 years
measure: Health Outcomes: Major Adverse Cardiovascular Events
timeFrame: 0-20 years
measure: Angina events
timeFrame: 0-3 years
measure: Brain small vessel disease
timeFrame: 0-36 months
measure: Correlation between small vessel disease in the brain and myocardial perfusion
timeFrame: 0-36 months
measure: Health economics: Inpatients visits
timeFrame: 0-20 years
measure: Health economics: Cardiac procedures
timeFrame: 0-20 years
measure: Health economics: Medication use
timeFrame: 0-20 years
measure: Work limitation
timeFrame: 0-36 months
Other outcomes:
measure: Small vessel substudy
timeFrame: 0-12 months
measure: Retinal imaging substudy
timeFrame: 0-12 months
Locations:
city: East Kilbride
country: United Kingdom
facility: University Hospital Hairmyres
state: Glasgow
city: Ayr
country: United Kingdom
facility: University Hospital Ayr
state: Scotland
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital
state: Scotland
Study officials:
affiliation: Univerisity of Glasgow
name: Colin Berry, MBChB, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bradley CP, Berry C. Microvascular arterial disease of the brain and the heart: a shared pathogenesis. QJM. 2023 Oct 23;116(10):829-834. doi: 10.1093/qjmed/hcad158.
citation: Bradley CP, Orchard V, McKinley G, Heggie R, Wu O, Good R, Watkins S, Lindsay M, Eteiba H, McGowan J, McGeoch R, Corcoran D, Kellman P, McConnachie A, Berry C. The coronary microvascular angina cardiovascular magnetic resonance imaging trial: Rationale and design. Am Heart J. 2023 Nov;265:213-224. doi: 10.1016/j.ahj.2023.08.067. Epub 2023 Aug 30.
citation: Bradley C, Berry C. Definition and epidemiology of coronary microvascular disease. J Nucl Cardiol. 2022 Aug;29(4):1763-1775. doi: 10.1007/s12350-022-02974-x. Epub 2022 May 9.
citation: Sidik NP, Stanley B, Sykes R, Morrow AJ, Bradley CP, McDermott M, Ford TJ, Roditi G, Hargreaves A, Stobo D, Adams J, Byrne J, Mahrous A, Young R, Carrick D, McGeoch R, Corcoran D, Lang NN, Heggie R, Wu O, McEntegart MB, McConnachie A, Berry C. Invasive Endotyping in Patients With Angina and No Obstructive Coronary Artery Disease: A Randomized Controlled Trial. Circulation. 2024 Jan 2;149(1):7-23. doi: 10.1161/CIRCULATIONAHA.123.064751. Epub 2023 Oct 5.
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/
citation: 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.
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.
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.
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.
citation: 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. No abstract available.
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;
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.
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.
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.
citation: 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. No abstract available.
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.