CORonary MICrovascular Angina (CorMicA)

Study Overview
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Brief Summary
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Angina is form of chest pain that is due to a lack of blood to the heart muscle. Angina is commonly triggered by stress and exertion, and is a common health problem worldwide. The diagnosis and treatment of angina is usually focused on detection of blockages in heart arteries, and relief of this problem with drugs, stents or bypass surgery. However, about one third of all invasive angiograms that are performed in patients with angina do not reveal any blockages. Many of such patients may have symptoms due to narrowings in the very small micro vessels (too small to be seen on an angiogram). The purpose of this research is to undertake a 'proof-of-concept' clinical trial to gather information as to whether routine tests of small vessel function in the heart might help identify patients with a stable coronary syndrome due to a disorder of coronary function (vasospastic or microvascular angina), and appropriately rule out this problem in patients with normal test results. The diagnostic strategy enables stratification of patient sub-groups to optimized therapy (personalised medicine). Evidence of patient benefits in this study would support the plan for a larger study that would be designed to impact on healthcare costs and patient reported outcome measures (PROMS).

Detailed Description
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Background: Patients with a stable coronary syndromes include those with obstructive coronary artery disease (CAD) or ischaemia with no obstructive CAD (INOCA). Disorders of coronary vasomotion leading to microvascular and vasospastic angina are debilitating, prognostically important health problems. Use of coronary function tests with thresholds (normal/abnormal) that are linked to evidence-based treatment (start/stop) could be useful to diagnose (rule-in/rule-out) these conditions, but, evidence is lacking. Design: (1) A proof-of-concept, randomised controlled stratified medicine trial of a clinical strategy informed by invasive tests of coronary function and linked guideline-based treatment decisions vs. standard care using angiography only in 150 patients; (2) A nested observational imaging sub-study using quantitative stress perfusion cardiac magnetic resonance (CMR). CONSORT guidelines will be followed. Objectives: (1) To assess whether a diagnostic strategy involving tests of coronary function changes the diagnosis and treatment and improves health and economic outcomes; (2) To assess the diagnostic accuracy of novel MRI methods for abnormal perfusion due to microvascular disease. 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 (>50% stenosis, fractional flow reserve <=0.80) coronary artery disease (CAD). After the angiogram, eligible participants will be randomised immediately in the catheter laboratory to test disclosure (intervention group) or measurement without disclosure (control group). Coronary function will be assessed using a diagnostic guidewire and intra-coronary infusions of acetylcholine (10-6M, 10-5M, -10-4M) and a bolus of glyceryl trinitrate (300 micrograms). The guidewire-derived parameters include fractional flow reserve (FFR), coronary flow reserve (CFR), index of microvascular resistance (IMR) and the resistance reserve ratio (RRR). Participants who are enrolled but not randomised will enter a follow-up registry. The endotypes (diagnostic strata) are: obstructive CAD, coronary vasospastic angina, microvascular angina, endothelial dysfunction (no angina), normal (non-cardiac, normal coronary function results, no angina). Thus, a diagnosis may be ruled-in or ruled-out based on the test results. Microvascular disease will be characterised as structural (abnormal IMR) and/or functional (abnormal CFR, RRR). Primary outcome: Between-group difference in Seattle Angina Questionnaire (SAQ) scores at 6 months; Secondary: Reclassification of the treatment decision; certainty of the diagnosis; health status (EQ-5D, Illness Perception, Treatment Satisfaction & Patient Health questionnaires); angina medication and adherence; health economics; reference clinical decisions as evaluated by an independent expert panel of clinicians. Follow-up will continue in the longer term, including through electronic health record linkage. Value: To our knowledge, the study is the first to assess the clinical value of invasive management guided by routine use of adjunctive tests of coronary function in appropriately selected patients. The study will provide new insights into disease mechanisms and provide pilot data to inform the rationale and design of a larger clinical trial. The CMR substudy will provide information on the diagnostic utility of quantitative non-invasive imaging methods in this patient population. Should our hypotheses be confirmed, the research will bring new knowledge with potential benefits to patients and healthcare providers.

Official Title
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CORonary MICrovascular Angina (CorMicA): a Randomised, Controlled, Pilot Trial

Conditions
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Angina, Stable, Coronary Vasospasm, Coronary Circulation, Coronary Syndrome, Microvascular Angina, Coronary Disease

Intervention / Treatment
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* Diagnostic Test: Stratified medicine involving a diagnostic intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A clinically-indicated plan for invasive coronary angiography. Symptoms of angina or angina-equivalent (according to the Rose- and Seattle Angina questionnaires). Exclusion Criteria: A non-coronary indication for invasive angiography e.g. valve disease During the angiogram: obstructive disease evident in a main coronary artery (diameter >2.5 mm), i.e. a coronary stenosis>50% or a fractional flow reserve (FFR) ≤0.80 Lack of informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, parallel group, prospective
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention group (coronary function test results disclosed)<br>In the intervention group, coronary function tests are measured and disclosed to the attending clinician permitting re-evaluation of the initial diagnosis and treatment as compared with initial angiography-guided decisions. The intervention involves measurement of CFR, IMR and RRR in a target, major coronary artery followed by coronary reactivity testing using incremental doses of acetylcholine (10-4M, 10-5M, 10-6M) to assess endothelial function, bolus infusion of ACh (10-4M) for vasospasm provocation testing, followed by administration of a bolus dose (300 micrograms) of glyceryl trinitrate. Endotypes are identified based on established criteria for abnormalities in coronary vasodilator function, vasospasm and microvascular resistance. The endotypes (diagnostic strata) are: obstructive CAD, coronary artery spasm, microvascular angina, endothelial dysfunction (no angina), normal (non-cardiac). A diagnosis may be ruled-in or ruled-out based on the test results. | Diagnostic Test: Stratified medicine involving a diagnostic intervention<br>* Adjunctive tests of coronary artery function at the time of invasive coronary angiography. Diagnostic groups: stable coronary syndromes in patients with no-obstructive coronary artery disease including the following sub-groups (coronary artery vasospasm, microvascular spasm, impaired vasorelaxation due to (1) endothelial dysfunction and/or (2) non-endothelial dysfunction, or unaffected (normal test results). Medical management is linked to contemporary clinical guidelines for the management of patients with stable coronary artery disease (European Society of Cardiology (2013)).<br>|
| Sham Comparator: Usual care group (coronary function results not disclosed)<br>Coronary function tests are measured but not disclosed to the attending clinician or the participant. The same coronary function tests are undertaken as in the intervention group. Masking is achieved by obscuring the catheter laboratory monitors from the attending clinician and participant. The effectiveness of masking is prospectively monitored. | Diagnostic Test: Stratified medicine involving a diagnostic intervention<br>* Adjunctive tests of coronary artery function at the time of invasive coronary angiography. Diagnostic groups: stable coronary syndromes in patients with no-obstructive coronary artery disease including the following sub-groups (coronary artery vasospasm, microvascular spasm, impaired vasorelaxation due to (1) endothelial dysfunction and/or (2) non-endothelial dysfunction, or unaffected (normal test results). Medical management is linked to contemporary clinical guidelines for the management of patients with stable coronary artery disease (European Society of Cardiology (2013)).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health status (Seattle Angina Score) | Health status and symptoms will be assessed at baseline and again at 6 months using the Seattle Angina Questionnaire. The primary outcome is the within-subject change in SAQ score at 6 months from baseline. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of the stratified medicine approach defined by protocol compliance as measured by deviations from the protocol. | Feasibility will be assessed in terms of enrolment rates and protocol compliance relating to enrolment, cross-over, integrity of blinding, adherence with therapy during follow-up, and compliance with follow up assessments | Through study completion, 3 years | 
| Procedure-related serious adverse events | Safety as reflected by the occurrence of procedure-related serious adverse events | Day 1 (index coronary angiogram procedure) | 
| Prevalence of endotypes | Diagnosis of endotypes (disease strata): obstructive CAD, coronary vasospastic angina, microvascular angina, endothelial dysfunction (no angina), normal (non-cardiac, normal coronary function results, no angina). | Day 1 | 
| Diagnostic utility of the diagnostic intervention | Impact of disclosure of the coronary function test results on the diagnosis and certainty of the diagnosis (diagnostic utility) | Day 1 | 
| Clinical utility of the stratified approach | Impact of disclosure of the coronary function test results on medical decisions (including treatment and investigations), and to compare these decisions against a medical decisions formed by an independent panel of experts (reference dataset) | Day 1 | 
| Cardiovascular risk factors | Assess the relationships between cardiovascular risk factors, reflected by validated risk scores (e.g. ASSIGN, JBS3), and parameters of coronary function, in medically managed patients. | Day 1 | 
| Anxiety and depression | Assess the participants' self-reported levels of anxiety and depression using the Patient Health Questionnaire-4 (PHQ-4) | Through study completion, 3 years | 
| Treatment satisfaction | Assess the participants' self-reported levels of treatment satisfaction using the Treatment Satisfaction Questionnaire for Medication (TSQM) | Through study completion, 3 years | 
| Illness perception | Assess the participants' perception of their illness using the brief Illness Perception Questionnaire | Through study completion, 3 years | 
| Health status EQ5D | Assess the participants' general health status and self reported quality of life using the EQ5D questionnaire. | Through study completion, 3 years | 
| Health status (Seattle Angina Score) | Health status and symptoms will be assessed at baseline and again at 6 months, 12 months and close-out using the Seattle Angina Questionnaire. The secondary outcome is the within-subject change in SAQ score over time. | Through study completion, 3 years | 
| Biomarkers | Assess associations between circulating molecules that are implicated in the pathophysiology of disorders of coronary function. | 36 months | 
| Health economics | Assess resource utilisation including primary and secondary care costs for tests, procedures and out-patient visits, and medicines, between the randomised groups | 36 months | 
| Myocardial perfusion | Assess the diagnostic accuracy of stress perfusion magnetic resonance imaging for identification of endotypes based on reference tests of coronary function. | 42 days | 
| Incidental findings | Detection of clinically significant (actionable) incidental findings using magnetic resonance imaging. The incidental findings may be cardiac or non-cardiac. | 42 days | 
| Myocardial tissue characterisation | Detection of myocardial pathology using multiparametric CMR | 42 days |