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.