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Randomized Controlled Trial
. 2023 Jan;16(1):63-74.
doi: 10.1016/j.jcmg.2022.06.015. Epub 2022 Sep 14.

Ischemia With Nonobstructive Coronary Arteries: Insights From the ISCHEMIA Trial

Harmony R Reynolds  1 , Ariel Diaz  2 , Derek D Cyr  3 , Leslee J Shaw  4 , G B John Mancini  5 , Jonathon Leipsic  5 , Matthew J Budoff  6 , James K Min  7 , Cameron J Hague  5 , Daniel S Berman  8 , Bernard R Chaitman  9 , Michael H Picard  10 , Sean W Hayes  8 , Marielle Scherrer-Crosbie  11 , Raymond Y Kwong  12 , Renato D Lopes  3 , Roxy Senior  13 , Sudhanshu K Dwivedi  14 , Todd D Miller  15 , Benjamin J W Chow  16 , Ramesh de Silva  17 , Gregg W Stone  18 , William E Boden  19 , Sripal Bangalore  20 , Sean M O'Brien  3 , Judith S Hochman  20 , David J Maron  21 ; ISCHEMIA Research Group
Affiliations
Randomized Controlled Trial

Ischemia With Nonobstructive Coronary Arteries: Insights From the ISCHEMIA Trial

Harmony R Reynolds et al. JACC Cardiovasc Imaging. 2023 Jan.

Abstract

Background: Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown.

Objectives: The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA.

Methods: Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia.

Results: Among 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2]).

Conclusions: Among participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Keywords: coronary CT angiography; ischemia; ischemia with nonobstructive coronary arteries; stress testing.

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Conflict of interest statement

Funding Support and Author Disclosures This project was supported by National Institutes of Health grants (U01HL105907, U01HL105462, U01HL105561, and U01HL105565) and supported in part by Clinical Translational Science Award (11UL1 TR001445 and UL1 TR002243) from the National Center for Advancing Translational Sciences and by grants from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The manuscript contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Department of Health and Human Services. Devices or medications were provided by Abbott Vascular (previously St. Jude Medical, Inc); Medtronic, Inc; Phillips (previously Volcano Corporation); and Omron Healthcare, Inc; medications were provided by Amgen Inc; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Espero Pharmaceuticals; Merck, Sharp & Dohme Corp; and Sunovion Pharmaceuticals. All authors have received funding from the National Heart, Lung and Blood Institute for the study. Dr Reynolds has received nonfinancial support from Abbott Vascular, Siemens, BioTelemetry, and Leipsic; is a consultant and holder of stock options from Circle CVI and HeartFlow; is the recipient of research grants from GE Healthcare and Edwards; and serves on speakers bureaus for Philips and GE Healthcare. Dr Budoff has received grant support from General Electric; has been on the Medical Advisory Board of Arineta; and has received salary from and has ownership interest in Cleerly, Inc. Dr Berman has received software royalties from Cedars-Sinai Medical Center. Dr Lopes has received grants and other support from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, and Glaxo Smith Kline; and has received grants from Medtronic, Merck, Pfizer, Portola, and Sanofi. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; has received research support from TD Bank, CV Diagnostix and AusculSciences, and Siemens Healthineers; and has equity interest in General Electric. Dr Stone has received personal fees from Terumo, Amaranth, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-wave, SpectreWave, MAIA Pharmaceuticals, Orchestra Biomed, Vectorious Abiomed, Claret, Sirtex, Ancora, and Qool Therapeutics; other considerations from Cagent, Applied Therapeutics, Biostar family of funds; support from MedFocus family of funds, Aria; and personal fees from Cardiac Success work. Dr Boden has received support from Abbvie and Amarin; grants from Amgen; and personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen. Dr Bangalore has received grants and personal fees from Abbott Vascular; and personal fees from Biotronik, Pfizer, and Amgen. Dr Hochman is principal investigator for the ISCHEMIA trial, for which grant, devices, and medications were provided by Abbott Vascular; Medtronic, Inc; St. Jude Medical, Inc; Volcano Corporation; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; Omron Healthcare, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
This analysis included participants enrolled in the ISCHEMIA trial. Those without a coronary CT angiogram (CCTA) were excluded. We excluded participants with prior coronary artery bypass grafting (CABG) or prior percutaneous coronary intervention (PCI), because they had obstructive coronary artery disease (CAD) at one time. We compared participants with no obstructive CAD, defined as all stenoses on CCTA <50%, who were excluded from randomization in the trial, to randomized trial participants with at least one stenosis of ≥50% on CCTA, termed obstructive CAD. The final cohort for analysis consisted only of participants with moderate or severe ischemia as determined by core laboratories.
Figure 2.
Figure 2.. Likelihood of INOCA based on ischemia severity and stress imaging modality
See Supplemental Table 1 for definitions of moderate and severe ischemia.
Figure 3.
Figure 3.. Ischemia severity in patients with no obstructive CAD vs. obstructive CAD, including those rated by core laboratories as showing no or mild ischemia.
See Supplemental Table 1 for definitions of moderate and severe ischemia. Note that in the remainder of analyses in this article, INOCA is defined as moderate or severe ischemia with <50% stenosis in all major epicardial vessels.
Figure 4.
Figure 4.. Relationship between severity of ischemia and extent and severity of non-obstructive stenosis on CCTA
The bean plots show the severity of non-obstructive atherosclerosis as measured by the segment stenosis score (left) and the segment involvement score (right). For each bean, patients with moderate ischemia as determined by core laboratories are shown on the left in blue and those with severe ischemia in gray on the right. The median value is shown with a horizontal black line, and the width illustrates the frequency of each value on the y-axis. To calculate the segment stenosis score, each individual coronary segment was graded as having no to severe plaque (i.e., scores from 0–4) based on extent of obstruction of coronary luminal diameter. Then the extent scores of all 16 individual segments were summed to yield a total score ranging from 0–64. The segment involvement score was defined as the total number of coronary artery segments exhibiting plaque, irrespective of the degree of luminal stenosis within each segment (minimum=0; maximum=16). Data are presented for each stress testing modality. P-values comparing segment stenosis score between participants with moderate vs. severe ischemia overall for each modality were all >0.05. The same was true for segment involvement score.
Central Illustration
Central Illustration
We analyzed the prevalence of INOCA, defined as coronary CT angiogram (CCTA) showing < 50% diameter stenosis in all coronary arteries, among participants enrolled in ISCHEMIA. Participants with INOCA identified on CCTA were excluded from randomization in the trial. Clinical and stress test variables associated with INOCA are shown. Female sex was strongly associated with INOCA on multivariable analysis. Ischemia severity and extent of non-obstructive coronary artery disease (CAD) on CCTA were not correlated, whether CAD was assessed based on the number of segments with plaque, or incorporated the severity of plaque and the number of segments affected, in the segment stenosis score.
See this image and copyright information in PMC

Comment in

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