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Randomized Controlled Trial
. 2025 Sep;18(9):943-955.
doi: 10.1016/j.jcmg.2025.03.016. Epub 2025 Jul 9.

Comparative Prognosis by Stress ECG and Stress Imaging: Results From the ISCHEMIA Trial

Leslee J Shaw  1 , Lawrence M Phillips  2 , Jonathon Leipsic  3 , Samuel Broderick  4 , Jennifer H Mieres  5 , Thomas H Marwick  6 , Matthias G Friedrich  7 , Todd Miller  8 , Renato D Lopes  4 , Benjamin Chow  9 , Rodrigo Cerci  10 , Ron Blankstein  11 , Marcelo DiCarli  11 , David J Maron  12 , Judith S Hochman  2 , Karen P Alexander  4 , Gregg W Stone  13 , Sean O'Brien  4 , Bernard R Chaitman  14 , Raymond Y Kwong  11 , Michael H Picard  15 , Daniel S Berman  16 , Harmony R Reynolds  2 ; ISCHEMIA Research Group
Affiliations
Randomized Controlled Trial

Comparative Prognosis by Stress ECG and Stress Imaging: Results From the ISCHEMIA Trial

Leslee J Shaw et al. JACC Cardiovasc Imaging. 2025 Sep.

Abstract

Background: Limited contemporary evidence exists on risk prediction by stress imaging and exercise electrocardiography (ECG) among patients with chronic coronary syndromes (CCS). Objectives From the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) study, prognosis was examined by core laboratory-defined stress imaging and exercise ECG findings in CCS patients.

Methods: A total of 5,179 patients (qualifying by stress nuclear imaging [n = 2,567], echocardiography [n = 1,085], cardiac magnetic resonance [CMR] [n = 257], and ECG [n = 1,270]) were randomized. Cox models assessed associations between trial endpoints and the number of scarred and ischemic segments, rest/stress left ventricular ejection fraction (LVEF), and ST-segment depression. HRs and 95% CIs were calculated per millimeter, segment, or 5% of LVEF. We examined prognostic models for the following trial endpoints: 1) the trial's primary endpoint of cardiovascular (CV) death, myocardial infarction (MI), resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure; 2) CV death; 3) spontaneous MI; 4) procedural MI; and 5) type 2 MI.

Results: The number of scarred segments (HR: 1.07 [95% CI: 1.02-1.13]; P = 0.0209), rest LVEF (HR: 0.88 [95% CI: 0.83-0.93]; P < 0.001), and stress LVEF (HR: 0.87 [95% CI: 0.83-0.91]; P < 0.001) predicted the trial's primary endpoint of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure. The extent of scar and rest/stress LVEF on echocardiography and nuclear imaging predicted several trial endpoints. The number of ischemic segments predicted spontaneous (HR: 1.08 [95% CI: 1.03-1.14]; P = 0.0104) and procedural MI (HR: 1.14 [95% CI: 1.03-1.25]; P = 0.0015) but was of borderline significance for the trial's primary endpoint (P = 0.0746). Ischemia extent by CMR predicted the trial's primary endpoint (P = 0.0068) and spontaneous MI (P = 0.0042).

Conclusions: ISCHEMIA trial findings from 320 worldwide centers revealed that stress imaging and exercise ECG measures exhibited a variable association with key trial endpoints delineating risk patterns for ischemia and infarction. Stress CMR ischemia predicted several trial endpoints, supporting an expanded role in the evaluation of patients with CCS (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).

Keywords: chronic coronary syndromes; ischemia; multimodality imaging; prognosis.

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Conflict of interest statement

Funding Support and Author Disclosures This work has been supported by National Institutes of Health (NIH) grants U01HL105907, U01HL105462, U01HL105561, and U01HL105565. Dr Shaw has received grants from the National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the trial and currently. Dr Leipsic has received consulting fees and has stock options with HeartFlow and Circle CVI; and a research grant from GE Healthcare outside of the submitted work. Dr Maron has received grants from the NHLBI during the conduct of the trial. Dr Hochman is the primary investigator for the ISCHEMIA trial for which, in addition to support from the NHLBI, devices and medications were provided by Abbott Vascular, Medtronic Inc, Abbott Laboratories (formerly St. Jude Medical Inc), Royal Philips NV (formerly Volcano Corporation), Arbor Pharmaceuticals LLC, AstraZeneca Pharmaceuticals LP, Merck Sharp and Dohme Corp, Omron Healthcare Inc, Sunovion Pharmaceuticals Inc, Espero BioPharma, and Amgen Inc; and has received financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Stone has received grants from the NHLBI during the conduct of the study; personal fees from Terumo, Amaranth, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Vectorious, Matrizyme, Miracor, Neovasc, SpectraWave, Orchestra Biomed, V-wave, Abiomed, Claret, Sirtex, MAIA Pharmaceuticals, Ancora, and Qool Therapeutics; and other support from Cagent, Applied Therapeutics, Aria, Biostar family of funds, Cardiac Success, and MedFocus family of funds, outside of the submitted work. Dr O’Brien has received grants from the NHLBI during the conduct of the trial. Dr Chaitman has received grants from the NHLBI during the conduct of the trial; and personal fees from Merck, NovoNordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor outside of the conduct of the trial. Dr Kwong has received grants from the NHLBI during the conduct of the trial. Dr Berman has received software royalties from Cedars-Sinai Medical Center outside of the submitted work; and grants from the NHLBI during the conduct of the trial. Dr Picard has received grants from the NHLBI during the conduct of the trial. Dr Reynolds has received grants from the NHLBI during the conduct of the trial; and has also received in-kind support for unrelated research from Abbott Vascular, Philips, SHL Telemedicine, and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

References

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