Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study

Background: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. Methods: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in ISCHEMIA trial screen failures with INOCA) was an international cohort study conducted from 2014-2019 involving angina assessments (Seattle Angina Questionnaire [SAQ]) and stress echocardiograms 1-year apart. This was an ancillary study that included patients with history of angina who were not randomized in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease (CAD) status and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between changes in SAQ Angina Frequency score and change in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and compared CIAO participants with ISCHEMIA participants with obstructive CAD who had stress echocardiography before enrollment, as CIAO participants did. Results: INOCA participants in CIAO were more often female (66% of 208 vs. 26% of 865 ISCHEMIA participants with obstructive CAD, p\u3c0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [IQR 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (p=0.46) or ISCHEMIA stress echocardiography participants (p=0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over one year was not significantly correlated with change in angina (rho=0.029). Conclusions: Improvement in ischemia and improvement in angina were common in INOCA, but not correlated. Our INOCA cohort had a similar degree of inducible wall motion abnormalities to concurrently enrolled ISCHEMIA participants with obstructive CAD. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina

Global Longitudinal Strain as Predictor of Inducible Ischemia in No Obstructive Coronary Artery Disease in the CIAO-ISCHEMIA study

BACKGROUND: Global longitudinal strain (GLS) is a sensitive marker for identifying subclinical myocardial dysfunction in obstructive coronary artery disease (CAD). Little is known about the relationship between GLS and ischemia in patients with myocardial ischemia and no obstructive CAD (INOCA). OBJECTIVES: To investigate the relationship between resting GLS and ischemia on stress echocardiography (SE) in patients with INOCA. METHODS: Left ventricular GLS was calculated offline on resting SE images at enrollment (n=144) and 1-year follow-up (n=120) in the CIAO-ISCHEMIA study, which enrolled participants with moderate or severe ischemia by local SE interpretation (\u3e3 segments with new or worsening wall motion abnormality and no obstructive (\u3c50% stenosis) CAD on coronary CT angiography. RESULTS: GLS values were normal in 83.3% at enrollment and 94.2% at follow-up. GLS values were not associated with a positive SE at enrollment (GLS -21.5% positive SE vs. GLS -19.9% negative SE, p=0.443), or follow-up (GLS -23.2% positive SE vs. GLS -23.1% negative SE, p=0.859). Significant change in GLS was not associated with positive SE in follow-up (p=0.401). Regional strain was not associated with co-localizing ischemia at enrollment or follow-up. Changes in GLS and number of ischemic segments from enrollment to follow-up showed a modest but not clinically meaningful correlation (β=0.41, 95% CI 0.16, 0.67, p=0.002). CONCLUSIONS: In this cohort of INOCA patients, resting GLS values were largely normal and did not associate with the presence, severity or location of stress-induced ischemia. These findings may suggest the absence of subclinical myocardial dysfunction detectable by echocardiographic strain analysis at rest in INOCA

Outcomes of participants with diabetes in the ISCHEMIA trials

BACKGROUND: Among patients with diabetes mellitus (diabetes) and chronic coronary disease (CCD), it is unclear if invasive management improves outcomes when added to medical therapy. METHODS: The ISCHEMIA Trials (ISCHEMIA and ISCHEMIA CKD) randomized CCD patients to an invasive (medical therapy + angiography and revascularization if feasible) or a conservative approach (medical therapy alone with revascularization if medical therapy failed). Cohorts were combined after no trial-specific effects were observed. Diabetes was defined by history, HbA1c ≥6.5%, or use of glucose-lowering medication. The primary outcome was all-cause death or myocardial infarction (MI). Heterogeneity of effect of invasive management on death or MI was evaluated using a Bayesian approach to protect against random high or low estimates of treatment effect for patients with vs. without diabetes and for diabetes subgroups of clinical (female sex and insulin use) and anatomic features (coronary artery disease [CAD] severity or left ventricular function). RESULTS: Of 5,900 participants with complete baseline data, the median age was 64 years interquartile range (IQR) [57–70], 24% were female, and the median estimated glomerular filtration was 80 ml/min/1.73(2) IQR [64–95]. Among the 2,553 (43%) of participants with diabetes, median percent hemoglobin A1c was 7% IQR [7–8%], and 30% were insulin treated. Participants with diabetes had a 49% increased hazard of death or MI (HR 1.49; 95% CI: 1.31–1.70, P<0.001). At median 3.1-year follow-up the adjusted event-free survival was 0.54 (95% bootstrapped CI: 0.48, 0.60) and 0.66 (95% bootstrapped CI: 0.61, 0.71) for patients with vs. without diabetes – a 12% (95% bootstrapped CI: 4%, 20%) absolute decrease in event-free survival among participants with diabetes. Female and male patients with insulin-treated diabetes had an adjusted event-free survival of 0.52 (95% bootstrapped CI: 0.42, 0.56) and 0.49 (95% bootstrapped CI: 0.42, 0.56), respectively. There was no difference in death or MI between strategies for patients with vs. without diabetes, or for clinical (female sex or insulin use) or anatomic features (CAD severity or left ventricular function) of patients with diabetes. CONCLUSIONS: Despite higher risk for death or MI, CCD patients with diabetes did not derive incremental benefit from routine invasive management compared with initial medical therapy alone