Coronary Microvascular Function and CT Coronary Angiography (CorCTCA)
Coronary Microvascular Function and CT Coronary Angiography (CorCTCA)
Angina in patients without obstructive coronary artery disease (CAD) is a clinical conundrum
 and patient management is heterogeneous. Hypothesis: Abnormal coronary function is common and
 clinically relevant in this population. Design: An observational cohort study and nested
 randomised controlled diagnostic strategy trial. Methods: 250 patients with known or
 suspected angina informed by validated questionnaires but without obstructive CAD (<70%
 stenosis) in an artery >=2.5 mm or structural heart disease, as revealed by CT coronary
 angiography (CTCA), will be invited to undergo coronary function testing (FFR, CFR, IMR;
 intra-coronary ACh) during invasive angiography. Patients will be randomised following
 angiography but before testing coronary function to disclosure of the coronary function test
 results or not. Treatment decisions by the attending cardiologist will be recorded before and
 after disclosure of results. Outcomes: Primary: The between-group difference in the
 reclassification rate of the initial diagnosis using logistic regression, adjusted for
 baseline factors associated with the likelihood of reclassification of the initial diagnosis.
 Secondary: Prevalence of microvascular or vasospastic angina; health status reflected by the
 EuroQol group 5-Dimensions (EQ-5D), Seattle Angina Questionnaire, Illness perception,
 treatment satisfaction questionnaires and functional status questionnaires; angina medication
 and adherence. Value: This research will provide new insights into the conundrum of angina in
 patients without obstructive CAD or structural heart disease.
According to information provided by the British Heart Foundation, there are approximately
 2.3 million men and women living with angina in the United Kingdom (UK). In 2014, there were
 ~247,363 coronary angiograms performed, mostly for the investigation of known or suspected
 angina, but only about half of the patients have obstructive coronary artery disease (CAD)
 identified by the angiogram. Considering CT coronary angiography (CTCA), <=1 in 4 patients
 referred to the Chest Pain Clinic with chest pain of suspected cardiac origin have
 obstructive CAD identified by the CTCA scan. The explanation for the cause(s) of the chest
 pain are often unclear, which can be frustrating to patients and clinicians. Small vessel
 disease, i.e. microvascular or vasospastic angina may be one explanation.

 Anatomical imaging of the coronary arteries non-invasively by CTCA or invasively is an
 insensitive approach for the assessment of coronary function, and even visual assessment of
 the angiogram for obstructive CAD by invasive angiography or CTCA, may sometimes lead to
 mis-diagnosis and sub-optimal outcomes. Novel adjunctive tests of coronary function may have
 incremental diagnostic value to further inform medical decisions. Taken together, the
 literature and practice guidelines suggest a clinical problem of unmet need, with the
 potential for benefits to patients and healthcare providers if the diagnostic management can
 be improved. Our proposal addresses the evidence gap, by exploiting advances in diagnostic
 tests to gather information on the prevalence of microvascular and vasospastic disorders in
 patients with angina in whom obstructive CAD has been ruled out. By implementing a diagnostic
 management strategy in the context of a randomised, blinded, controlled trial, the
 investigators aim to determine whether use of coronary function tests in relevant patients
 might be beneficial.

 Angina in patients without obstructive CAD and insights from contemporary clinical trials:
 The Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME-2),
 Scottish COmputed Tomography of the HEART (SCOT-HEART), Prospective Multicenter Imaging Study
 for Evaluation of Chest Pain (PROMISE), and Clinical Evaluation of Magnetic Resonance Imaging
 in Coronary Heart Disease 2 (CE-MARC 2) 2 trials focused on the diagnosis and treatment of
 angina due to obstructive CAD. Paradoxically, the findings in these trials have diagnosed
 considerable numbers of patients with angina without obstructive CAD. In FAME-2, of 1220
 patients with stable CAD, 332 (27%) had non-flow limiting (FFR>0.80) CAD. The distribution of
 the Canadian Cardiovascular Society angina classes was similar between the randomised
 patients and those in the registry (p=0.64), as was the prevalence of silent ischaemia (16%;
 p=0.96). The registry patients were treated with medical therapy and the MACE rate was 9% at
 2 years.

 In SCOT-HEART, of 4146 patients with suspected angina assessed at the Chest Pain Clinic, 2450
 (59%) had confirmed angina (typical or atypical), yet considering the prevalence of
 obstructive CAD as revealed by CTCA (>70% stenosis in ≥1 major branches or 50% in the left
 main stem), just 25% had obstructive CAD. In the PROMISE trial, 10,003 participants (n=8939
 (89.4%) with typical or atypical angina) were randomised to a strategy of initial anatomical
 testing with CTCA or to a strategy of functional testing (exercise ECG or stress imaging).
 Using similar diagnostic criteria as in SCOT-HEART, only 517 (10.7%) of the 4996 participants
 in the CTCA group had a 'positive' result. No further data were provided to explain the
 aetiology of the angina in the patients without obstructive CAD.

 Most recently, the CE-MARC 2 trial compared diagnostic strategies in patients referred to the
 Chest Pain Clinic with a pre-test likelihood of CAD of 10% to 90%. All (n=1202) of the
 participants had a history of angina, with 401 (33.4%) having typical angina. Only a minority
 of participants had a positive non-invasive test (12.4% in the CMR group, 18.2% in the
 myocardial perfusion scintigraphy (MPS) group and 13.4% in the NICE Guideline group).
 Invasive coronary angiography was performed within 12 months of randomisation in 265 (22%)
 patients. The primary outcome of unnecessary angiography (defined as an FFR>0.8 or
 quantitative coronary analysis showing no stenosis ≥70% in 1 view or ≥50% in 2 orthogonal
 views in all coronary vessels ≥2.5 mm diameter), occurred in 139 subjects (12%): 7.5% in the
 CMR group, 7.1% in the MPS group and 28.8% of participants in the NICE guidelines group.
 CEMARC 2 was a pragmatic trial and since invasive angiography was not performed in all of the
 subjects, the causes of the angina in patients with 'negative' non-invasive imaging tests
 were unclear. Finally, the ISCHEMIA trial investigators have observed that some of the
 participants enrolled with moderate-severe myocardial ischemia on stress testing (% left
 ventricular (LV) mass) do not have obstructive CAD. The Changes in Ischemia and Angina over
 One year among ISCHEMIA trial screen failures with no obstructive coronary artery disease on
 coronary CT angiography (CIAO-ISCHEMIA) study has been instigated to investigate these
 patients in greater detail.

 In the SCOT-HEART trial, symptoms and quality of life assessed at baseline and 6 months
 improved less in patients assigned to the CTCA-guided strategy as compared to standard care.
 This analysis refuted the hypothesis that symptoms and quality of life would improve with a
 CTCA-guided strategy and it conflicts with the NICE-95 guideline recommendations. Patients in
 the CTCA group with a change in diagnosis confirming obstructive CAD or excluding CAD had the
 greatest improvement in symptoms. By contrast, patients with non-obstructive CAD had the
 least improvement in symptoms. There could be several reasons to explain this finding.
 Firstly, patient satisfaction may be greater with a definitive diagnosis and treatment plan
 i.e. 1) normal coronaries - stop treatment, 2) obstructive CAD - percutaneous coronary
 intervention (PCI) or coronary artery bypass surgery (CABG), while a result of intermediate
 CAD with no change in treatment may result in lower patient satisfaction. Secondly, a false
 negative CTCA result may have occurred in some patients with flow limiting CAD (since
 objective assessments of flow limiting CAD and/or ischaemia were not performed). Finally,
 some patients with non-obstructive CAD may have had microvascular disease. Since clinicians
 may have stopped angina treatment in patients without obstructive CAD, the symptoms of
 patients who had microvascular angina (and a negative CTCA scan) may have deteriorated.

 The design of our study includes a multicentre, observational study involving novel
 diagnostic tests of coronary function in order to provide information on the prevalence of
 microvascular and/or vasospastic disease in patients with angina but non obstructive CAD as
 revealed by CTCA. The CTCA protocol will be undertaken according optimal standards i.e. heart
 rate control with beta-blocker medication, administration of sublingual nitrate before the
 CTCA scan, etc. The clinical relevance of additional tests of coronary function will be
 assessed through a nested randomised strategy trial of management (diagnosis and treatment)
 guided by the coronary function test results versus standard care guided by angiography. The
 possibility of occasional CAD misclassification by CTCA (i.e. false negative, obstructive
 CAD) will also be assessed. Follow-up will include assessments of health, well-being and
 treatment satisfaction. The wider adoption of anatomical imaging with CTCA as a first-line
 diagnostic test for the assessment of stable chest pain (NICE-95 guideline update, November
 2016), supports the rationale for this research.
Inclusion Criteria:

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

 2. Intermediate or no obstructive coronary disease i.e. no coronary stenosis >70% in an
 artery >2.5 mm, as revealed by CT coronary angiography.

 Exclusion Criteria:

 1. A health problem that would explain the angina, e.g. anaemia, moderate-severe aortic
 stenosis, hypertrophic obstructive cardiomyopathy

 2. Obstructive disease evident in a coronary artery (diameter >2.5 mm), i.e. >50 - 70%
 circumferential plaque extending for ≥2 coronary segments, or a stenosis>70% as
 revealed by CT coronary angiography

 3. Lack of informed consent.

 Exclusion from randomisation in the catheter laboratory:

 4. Flow-limiting coronary disease defined by a fractional flow reserve (FFR) ≤0.80 in an
 artery>2.5 mm.