Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) Trial

NHS National Waiting Times Centre Board

Status: Active, not recruiting

Conditions: Coronary Artery Disease; Microvascular Angina; Angina, Stable; Small Vessel Cerebrovascular Disease; Angina Pectoris; Non-Obstructive Coronary Atherosclerosis

Treatments: Diagnostic Test: CMR results disclosed; Diagnostic Test: CMR performed but results not disclosed

Study type: Interventional

Funder types: Other

Identifiers

NCT04805814

281128

Details and patient eligibility

About

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.

Full 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.

Enrollment: 280 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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280 participants in 2 patient groups

Intervention Group

Active Comparator group

Description:

All randomised participants will receive stratified medicine. The subjects will undergo stress perfusion CMR as an adjunct to invasive coronary angiography. The CMR results will be disclosed to the clinician to clarify endotypes and re-evaluate the clinical diagnosis. Linked guideline-directed medical therapy and lifestyle measures will be recommended based on the endotype. The patient and clinicians responsible for downstream care will not be informed of the randomised group but they will be informed of the endotype and linked treatment plan, in the same way as in the Standard Care control group. They will be blinded to the allocated study arm and CMR findings.

Treatment:

Diagnostic Test: CMR results disclosed

Standard Care Group

Sham Comparator group

Description:

All randomised participants in this arm will receive standard angiography-guided care. The endotype will be determined based on the angiogram and all of the available clinical information. The participants in this group will also undergo stress perfusion CMR but the results will not be disclosed. Management of the patient is as per standard of care, with therapy linked to the diagnosis (endotype). The patient and clinicians responsible for downstream care will not be informed of the randomised group but they will be informed of the endotype and linked treatment plan in the same way as in the Intervention Group. They will be blinded to the allocated study arm and CMR findings.

Treatment:

Diagnostic Test: CMR performed but results not disclosed