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Study Summary

The ISCHEMIA Trial was a landmark trial presented in 2019 which studied whether medical management or revascularization was preferable for the treatment of stable obstructive coronary artery disease and moderate-to-severe ischemia. The CIAO-ISCHEMIA Subtrial looked further at 208 patients with angina and ischemia (diagnosed by echocardiogram stress test), but without corresponding obstructive coronary disease on CT angiography, defined as no lesions >50% (INOCA). These patients were compared with 865 similar patients who had obstructive coronary disease and echocardiogram stress tests as part of the main ISCHEMIA Trial (see accompanying Hurst's Central Illustration). Patients with INOCA were younger (63 versus 66 years), more likely female (66% versus 22%), less likely to have diabetes and /or be smokers, and had less anterior ischemia on stress testing, but had more frequent anginal symptoms compared with ISCHEMIA trial matched cohort. Medical management, for which there was no specific protocol, was associated with improvement in symptoms in 42%, stress echo improved in 50% and was same or worse in 45% at 1 year. There was no correlation between change in angina and change in ischemia.

Commentary

Study Strengths: This is an important study focused on a subgroup usually excluded from interventional trials.

Study Limitations: This small trial was purely a descriptive trial. There was no invasive testing to elucidate the mechanism of INOCA — i.e. epicardial vasospastic disease (ergotamine challenge) versus microvascular dysfunction (adenosine infusion) — and no randomized treatment strategy was tested.

Next Steps/Clinical Perspective: Clearly, INOCA is a poorly understood chest pain syndrome that primarily affects women and is associated with documented myocardial ischemia despite a lack of epicardial obstructive atherosclerotic disease. Depression, which has been associated with INOCA but is not well defined, could be a therapeutic target. The pathophysiological mechanisms of this process may be in part due to epicardial vasospasm or microvascular dysfunction. Randomized, controlled trials need to be completed to further discern the underlying mechanisms and potential efficacious treatments of this disease, since current medical management only ameliorated symptoms in about half of the subjects of this study. Moreover, heart failure with preserved ejection fraction and takatsubo's cardiomyopathy (broken heart syndrome) are other poorly understood cardiac syndromes that largely affect women and are also hypothesized to be driven by microvascular dysfunction. Perhaps CT-FFR, in angiographically indeterminate disease, can be utilized to better define the pathophysiology of these syndromes leading to improvements in management, morbidity, and mortality.

Trial Reference

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Reynolds H for the CIAO-ISCHEMIA Investigators. Natural History Of Symptoms And Stress Echo Findings In Patients With Moderate Or Severe Ischemia And No Obstructive CAD (INOCA): The NHLBI Funded CIAO Ancillary Study To The ISCHEMIA Trial. [Presentation at ACC.20 Together With World Congress of Cardiology, 30 March 2020]

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