1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CorMicA)

Objectives The aim of this study was to test the hypothesis that invasive coronary function testing at time of angiography could help stratify management of angina patients without obstructive coronary artery disease. Background Medical therapy for angina guided by invasive coronary vascular function testing holds promise, but the longer-term effects on quality of life and clinical events are unknown among patients without obstructive disease. Methods A total of 151 patients with angina with symptoms and/or signs of ischemia and no obstructive coronary artery disease were randomized to stratified medical therapy guided by an interventional diagnostic procedure versus standard care (control group with blinded interventional diagnostic procedure results). The interventional diagnostic procedure–facilitated diagnosis (microvascular angina, vasospastic angina, both, or neither) was linked to guideline-based management. Pre-specified endpoints included 1-year patient-reported outcome measures (Seattle Angina Questionnaire, quality of life [EQ-5D]) and major adverse cardiac events (all-cause mortality, myocardial infarction, unstable angina hospitalization or revascularization, heart failure hospitalization, and cerebrovascular event) at subsequent follow-up. Results Between November 2016 and December 2017, 151 patients with ischemia and no obstructive coronary artery disease were randomized (n = 75 to the intervention group, n = 76 to the control group). At 1 year, overall angina (Seattle Angina Questionnaire summary score) improved in the intervention group by 27% (difference 13.6 units; 95% confidence interval: 7.3 to 19.9; p < 0.001). Quality of life (EQ-5D index) improved in the intervention group relative to the control group (mean difference 0.11 units [18%]; 95% confidence interval: 0.03 to 0.19; p = 0.010). After a median follow-up duration of 19 months (interquartile range: 16 to 22 months), major adverse cardiac events were similar between the groups, occurring in 9 subjects (12%) in the intervention group and 8 (11%) in the control group (p = 0.803). Conclusions Stratified medical therapy in patients with ischemia and no obstructive coronary artery disease leads to marked and sustained angina improvement and better quality of life at 1 year following invasive coronary angiography. (Coronary Microvascular Angina [CorMicA]; NCT03193294)

In the intervention group, the cardiologist reappraised the initial diagnosis on the basis of coronary angiography and could change the diagnosis with linked therapy decisions. In the control group, management was guided by coronary angiography and all of the other available medical information, but not the IDP results. Written guidance informed by practice guidelines was provided to physicians in both groups allowing treatment on the basis of the physicians' working diagnoses. This included using results of the IDP if available (Online Table 1) (10).
BLINDING AND ADHERENCE. Patients in the control group had their IDPs performed in the same way as those in the intervention group, except that the results were not disclosed to the treating cardiologists.
Details of the blinding procedure have been described Dr. Touyz has acted as an advisor for Novartis. Dr. McEntegart has a proctoring agreement with Boston Scientific and Vascular (7,8). The outcome assessors and statisticians were blinded to treatment group allocation.
IDP. The purpose of the IDP was to identify disorders of coronary vasomotion: MVA, VSA, both, or none.   (9). Diagnosis of coronary microvascular spasm required provocation and reproduction of anginal symptoms, ischemic electrocardiographic shifts, but no epicardial spasm during ACh testing (11). A diagnosis of noncardiac chest pain required no obstructive epicardial CAD (FFR >0.80) and an absence of evidence of any coronary vasomotion disorder (CFR $2.0, index of microcirculatory resistance <25, and negative results on ACh testing). STRATIFIED MEDICAL THERAPY. After randomization and completion of the diagnostic intervention, research staff members invited the cardiologists to consider the new findings and re-evaluate the diagnosis and treatment plan initially made on the basis of angiography alone. The attending cardiologists in both of the groups were provided with written management guidance specific for each endotype and informed by practice guidelines to facilitate personalized treatment that was specifically aligned to their final diagnosis (Online Appendix) (10). For example, the first-line therapy for MVA incorporates betablockers, and nitrates were not recommended, whereas calcium-channel blockers and consideration of long-acting nitrates were advocated for VSA. The total number of patients randomized was 151 with analysis according to intention-to-treat. There was 98% completion of the primary efficacy endpoint assessment at 6 months and 94% at one year.  Table 1.
The majority of the participants were women   likely to be taking beta-blockers and angiotensinconverting enzyme inhibitors at 12 months compared with those in the control arm (Table 3).
The estimated treatment effect in units is stated with 95% confidence intervals at 6 and 12 months (intervention group and control group).
Repeated-measures linear mixed model adjusting for baseline differences between the groups. The relative percentage change represents the

P h y s i c a l a c t i v i t y a n d f u n c t i o n a l c a p a c i t y.
Physical activity assessed using the International Physical Activity Questionnaire-Short Form at 12 months was numerically higher in the intervention group at follow-up, but the differences were not sta-  Treatment effect represents adjusted mean difference at follow-up derived using linear mixed model (intervention À control). *Illness perception. A higher score reflects a more threatening view of the illness.
BIPQ ¼ Brief Illness Perception Score; BMI ¼ body mass index; BP ¼ blood pressure; CI ¼ confidence interval; QoL ¼ quality of life; SAQ ¼ Seattle Angina Questionnaire (lower scores represent worse angina symptoms); VAS ¼ visual analogue score of EQ-5D validated quality-of-life tool (higher scores indicate better quality of life).   were hospitalized for heart failure, and 9 (6%) experienced unstable angina requiring urgent revascularization or hospitalization. Causes of death were cardiac (heart failure, n ¼ 1) and noncardiac (malignancy, n ¼ 1). These events are detailed in Table 4.
There were no between-group differences in any of the MACE subtypes during longer term follow-up.

DISCUSSION
We found that angina severity, quality of life, treatment satisfaction, and illness perception improved at 1 year in the stratified therapy intervention group relative to control. We observed mechanistic differences that help explain the treatment effect, notably appropriate stratification of therapy, lower systolic and diastolic BPs relative to control, enhanced participation in cardiac rehabilitation, and nonsignificant trends toward improved functional capacity and physical activity levels in the intervention group (Central Illustration). There were no procedural safety concerns, and MACE were appreciable in the randomized population, with no significant betweengroup differences.   Tables 1 and 3.  Patients with newly diagnosed angina or ischemic heart disease may benefit from cardiac rehabilitation, and we observed more than 2-fold use in the inter-