title: Stratified medicine in angina with no obstructive coronary artery disease on computed tomography coronary angiography
Creators: name: Purnama Sidik, Novalia
Publisher: name: University of Glasgow
Year: 2023

description: Introduction Angina and no obstructive coronary artery disease (ANOCA) is increasingly recognised as part of a spectrum of conditions underlying chronic coronary syndromes, reflected in changes in recent ischaemic heart disease (IHD) guidelines. A considerable proportion of patients referred for coronary angiography have unobstructed coronary arteries. In patients referred for computed tomography coronary angiography (CTCA), who are typically a lower risk population, the proportion of patients with unobstructed artery may be as high as 75%. Although anatomical tests such as CTCA enable confirmation or exclusion of an obstructive coronary artery disease (CAD) diagnosis, conditions such as microvascular or vasospastic angina (endotypes of ANOCA) are systematically overlooked and underdiagnosed. Patients with ANOCA endure a substantial symptom burden and prior studies have shown that they have increased long-term risk of cardiovascular events. Contemporary international guidelines have identified ANOCA as an area of unmet need. The rationale for this study was to characterise the prevalence, clinical significance and management of ANOCA in ambulatory patients referred for the investigation of angina. The specific questions were, firstly, what is the prevalence of coronary microvascular dysfunction in a relatively unselected population of patients with a history of stable angina and no obstructive coronary arteries, as revealed by CTCA. Secondly, does a clinical strategy of stratified medicine, involving tests of coronary microvascular function and coronary spasm to define endotypes and linked therapy, improve wellbeing. Finally, does this strategy improve the burden of cardiovascular risk factors. Methods The overall objective was to undertake a prospective observational study with a nested multicentre, randomised, sham-controlled, clinical trial with blind outcome assessments. Patients referred for clinically-indicated CTCA for the investigation of suspected coronary artery disease were screened in 3 regional centres. Following informed consent, they were enrolled before CTCA and remained eligible if obstructive disease was excluded. Chest symptoms were assessed using the Rose Angina and Seattle Angina Questionnaires (SAQ). Invasive angiography involving adjunctive coronary vascular function tests was undertaken to assess for endotypes defined by guideline criteria. The interventional diagnostic procedure (IDP) protocol involved measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microvascular resistance (IMR) using a diagnostic guidewire followed by intracoronary infusion of incremental doses of acetylcholine (0.182μg/ml, 1.82μg/ml, 18.2μg/ml) sequentially infused (2 ml/minute) to assess for microvascular and/or coronary spasm. Participants were randomised to stratified medicine (Intervention group) or angiography-guided usual care (Control group, blinded). The primary outcome was the mean within-individual change in SAQ Summary Score during follow-up. Patient reported outcome measures included the 5-level EQ-5D health-related quality of life questionnaire, the Brief Illness Perception Questionnaire (BIPQ), the Patient Health Questionnaire-4 (PHQ-4), the Duke Activity Status Index (DASI) and the Treatment Satisfaction Questionnaire for Medication (TSQM-9). Cardiovascular risk factors (modifiable and non-modifiable), including body mass index, blood pressure, lipids and cigarette smoking, were measured at baseline and at the final visit, intended for 12 months post-randomisation. Results In summary, the main findings of this study are: 1) ANOCA was prevalent and occurred in three quarters of outpatients with suspected angina and no obstructive coronary artery disease on CTCA. 2) Stratified medicine guided by an IDP to evaluate coronary microvascular function changed the initial diagnosis in 68.7% of patients in the intervention group and improved the attending cardiologist’s certainty of the diagnosis. 3) Stratified medicine increased the frequency of a diagnosis of microvascular and/or vasospastic angina. 4) Stratified medicine increased the frequency of prescription of angina therapy for disorders of coronary function. 5) Stratified medicine improved blood pressure and treatment satisfaction but did not improve angina or health-related quality of life or other modifiable cardiovascular risk factors. However, medical management was disrupted by the pandemic. Conclusion ANOCA endotypes are common in outpatients with angina and no obstructive coronary artery disease, as defined by CTCA. There is a substantial health burden in this population, with one in four patients having an unplanned episode of hospital care for chest pain. However, a routine invasive strategy with medical management led by the standard care clinicians during a pandemic did not improve health status. Further clinical trials of patients stratified by endotype should improve our understanding of this condition and clarify effective treatment strategies.