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

Abstract

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 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did.

Results: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P<0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 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 1 year was not significantly correlated with change in angina (ρ=0.029).

Conclusions: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02347215.

Keywords: coronary artery disease; exercise test; ischemia; microvascular angina.

Figure 1.. CONSORT diagram.

CIAO eligibility was restricted to stress echocardiography to avoid the additional radiation exposure required for stress nuclear imaging in follow up. Stress CMR was used infrequently in ISCHEMIA and was not included in CIAO to minimize heterogeneity. The most common reasons for clinical ineligibility were prior revascularization indicating history of obstructive CAD (n=12), normal stress echocardiogram (n=10) and no ischemic symptoms (n=7). ISCHEMIA stress echocardiography participants were enrolled between July 2012-January 2018 in 21 (of 37 total) countries. Most, but not all ISCHEMIA participants had CCTA done before randomization. Among 1,081 randomized participants who had stress echo, 865 had CCTA showing obstructive CAD and 216 did not undergo CCTA. Recruitment was completed when all candidates for CIAO enrollment among ISCHEMIA trial screen failures had been considered. SAQ was missing at baseline in 5 and at 1 year in 11. 1-year stress echocardiography was missing in 16 (not mutually exclusive from missing SAQ).

Figure 2.. Ischemia severity, angina severity and their correlation in INOCA and CAD at enrollment.

Panels A–B. Distribution of the number of ischemic segments on enrollment stress echocardiography for CIAO participants with INOCA (A) and ISCHEMIA participants with CAD on study coronary CT angiogram (B). Panels C–D. Distribution of Angina Frequency (AF) scores on the Seattle Angina Questionnaire (SAQ) at enrollment in participants with INOCA (C) and CAD (D) Panels E–F. Distribution of Seattle Angina Questionnaire (SAQ) summary scores at enrollment in participants with INOCA (E) and CAD (F). Panels G–H. Distribution of ischemia severity categories as compared with SAQ AF score categories in participants with INOCA (G) and CAD (H). When SAQ AF was analyzed as a continuous variable, there was also no significant correlation: rho=0.105, p=0.15 for INOCA and rho=0.027, p=0.42, respectively. Only ISCHEMIA participants who qualified for the trial based on stress echocardiography and underwent coronary CT angiography showing at least 1 vessel with ≥50% stenosis are included here. Number of ischemic segments reflects core laboratory determination. Ischemia severity was mild if there were 1–2 ischemic segments, moderate if there were 3 ischemic segments, and severe if there were 4 or more ischemic segments. Participants in ISCHEMIA were permitted to enroll in CIAO before core laboratory confirmation of ischemia severity, to be consistent with the main trial, so some INOCA participants had less than 3 ischemic segments per core laboratory assessment. The interpretation of SAQ scores is depicted on the figure. The median time between stress echocardiography and angina assessment was similar for INOCA and CAD participants (Table 1). ISCHEMIA stress echocardiography participants with CAD had similar angina frequency (median 90, IQR 70–100, p=0.22, Figure 2 and Table 3) but poorer SAQ summary scores (ISCHEMIA median 77, IQR 63–92, CIAO median 83, IQR 66–93, p=0.019) at baseline. Median overall health status was rated by INOCA participants as 75 (IQR 60,81) on a scale of 100 on the EQ-5D, indicating, on average, good health status. There was also no correlation between SAQ summary score or angina frequency score and number of ischemic segments when considering SAQ scores as continuous rather than categorical measures.

Figure 3.. Change in number of ischemic segments from enrollment to 1 year in INOCA.

Panel A. Change in the number of ischemic segments on stress echocardiography from enrollment to 1 year. Panel B. Number of ischemic segments at enrollment. Panel C. Number of ischemic segments at 1 year.

Figure 4.. Change in angina vs. change in ischemia in INOCA, in relation to 1-year stress echo findings

Panels A and B show SAQ scores at enrollment (SAQ AF score, panel A, and SAQ summary score, panel B), 6 months, and 1 year in relation to improvement in the number of ischemic segments on stress echocardiography by at least 2 segments from enrollment to 1 year. Panels C and D. Correlation between change in the number of ischemic segments and change in SAQ angina frequency (C); and change in SAQ summary score (D). The median SAQ summary score was 90 (IQR 77–100) and median angina frequency score was 100 at 1 year (IQR 80–100, p<0.001 across all 3 time points, Table 3). Overall health status was rated similarly to that at enrollment, median 80 of 100 (IQR 70–90, p=<0.001 across all 3 time points). There was no correlation between the SAQ physical limitation subscale score and the number of ischemic segments at enrollment (rho =−0.03, p=0.69). There was no significant correlation between the SAQ summary score or any subscale score at 1 year and the number of ischemic segments at 1 year.