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BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14–2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78–12.86] and 2.63 [95% CI, 1.51–4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23–3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34–2.40]). Baseline lowdensity lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46–0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease. [ABSTRACT FROM AUTHOR]

Competing Interests: Dr Fleg reports employment by the National Heart, Lung, and Blood Institute during the conduct of the study. Drs O’Brien, Berger, Kwong, and Maron and Z. Huang report grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Reynolds reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. She receives support from Abbott Vascular (donation of optical coherence tomography catheters for an unrelated research study) and Biotelemetry Inc (donation of telemetry monitors for an unrelated research study). Dr Reynolds is also a consultant for HeartFlow. Dr Chaitman reports grants from the National Heart, Lung, and Blood Institute, and personal fees from Merck, NovoNordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor outside the submitted work. Dr Berman receives software royalties from Cedars-Sinai Medical Center outside the submitted work. Dr Min reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; other from Cleerly Inc, grants and other from GE Healthcare, and other from Arineta outside the submitted work. Dr Bangalore reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants and personal fees from Abbott Vascular; and personal fees from Biotronik, Pfizer, Amgen, and Reata outside the submitted work. Dr Hochman is principal investigator for the ISCHEMIA trial for which, in addition to support by the National Heart, Lung, and Blood Institute grant, 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 & Dohme Corp, and Omron Healthcare, Inc, and financial donations were provided by Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Hochman is also the PI of ISCHEMIA-EXTEND. The other authors report no conflicts. The content of this article is solely the responsibility of the authors and does not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the United States Department of Health and Human Services.

Background: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported., Objectives: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management., Methods: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management., Results: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference -3.5; 95% CI: -7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was -2.4%. Results were similar but less pronounced with FCR., Conclusions: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)., Competing Interests: Funding Support and Author Disclosures This work was supported by National Institutes of Health grants U01HL105907, U01HL105462, U01HL105561, U01HL105565, T32 HL079896. This project was also supported in part by Clinical Translational Science Award No. 11UL1 TR001445 from the National Center for Advancing Translational Sciences and by grants from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Devices or medications were provided by Abbott Vascular (previously St Jude Medical, Inc), Medtronic, Inc, Phillips (previously Volcano Corporation), and Omron Healthcare, Inc; and medications were provided by Amgen Inc, Arbor Pharmaceuticals, LLC, AstraZeneca Pharmaceuticals, LP, Espero Pharmaceuticals, Merck Sharp & Dohme Corp, and Sunovion Pharmaceuticals. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the 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. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, and Abbott; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, Amgen, Adona Medical, and Millennia Biopharma; has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; his daughter is an employee at IQVIA; and his employer, Mount Sinai Hospital, receives research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr Ali has received institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems Inc, Medtronic Inc, National Institute of Health, Opsens Medical, Philips, and Teleflex; has received consulting fees from AstraZeneca, Philips, and Shockwave; and has equity in Elucid, Spectrawave, Shockwave, and VitalConnect. Dr Genereux has received consulting, advisory, and speaker fees from Abbott Vascular, Abiomed, Edwards Lifesciences, Medtronic, and BioTrace Medical; has served as a consultant for Boston Scientific, CARANX Medica, Cardiovascular System Inc (PI Eclipse Trial), GE Healthcare, iRythm Technologies, Opsens, Siemens, Teleflex, and 4C Medical (PI Feasibility study); has equity in and served as a consultant for Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc; has served as a consultant for and received speaker fees from Shockwave; and has served as a proctor for, received an institutional research grant from, and served as PI for the EARLY-TAVR and PROGRESS trials for Edwards Lifesciences. Dr Bangalore has received grants from the National Heart, Lung, and Blood Institute; has received grants and personal fees from Abbott Vascular; and has received personal fees from Biotronik, Pfizer, Amgen, and Reata. Dr Mavromatis has received grants from the National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute (CV Inflammation Reduction Trial and GMCSF in PAD-3 Trial), CSL Behring, St Jude Medical, Medtronic, DalCor Pharmaceuticals, AstraZeneca, Novartis, and Regeneron; and is a Member of the American College of Cardiology and Society of Cardiovascular Angiography and Interventions. Dr Dwivedi has received grants from the National Heart, Lung, and Blood Institute. Dr Chen has received grants from the National Heart, Lung, and Blood Institute. Dr Chaitman has received grants from the National Heart, Lung, and Blood Institute; and has received personal fees from Merck, Novo Nordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi-Sankyo, Tricida, Relypsa, Imbria, and Xylocor outside the submitted work. Dr Berman has received royalties for nuclear cardiology software from Cedars-Sinai Medical Center. Dr Boden has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received grants from Abbvie, Amarin, and Amgen; and has received personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen. Dr White has received grant support paid to the institution and fees for serving on Steering Committees from Sanofi, Regeneron Pharmaceuticals, Eli Lilly, Omthera Pharmaceuticals, American Regent, Eisai Inc, DalCor Pharma UK, Inc, CSL Behring, NHI, Sanofi Australia Pty Ltd, Esperion Therapeutics, Inc, and the National Institutes of Health; and has served on the Advisory Board for Genentech, Inc (an affiliate of F. Hoffmann-La Roche Ltd, ‘Roche’; Lytics Post-PCI Advisory Board at European Society of Cardiology). Dr Fremes has received NPI CIHR funding for the ROMA and STICH3C studies. Dr Reynolds has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and has received nonfinancial support from Abbott Vascular, Siemens, and BioTelemetry. Dr Spertus has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received personal fees from Bayer, Novartis, AstraZeneca, Amgen, Janssen, and United Healthcare; has received grants from American College of Cardiology; has received personal fees from Blue Cross Blue Shield of Kansas City; and has a patent Copyright to Seattle Angina Questionnaire, with royalties paid and Equity in Health Outcomes Sciences. Dr Hochman is PI for the ISCHEMIA trial for which, in addition to support by the National Heart, Lung, and Blood Institute grant, devices and medications were provided by Medtronic, Inc, Abbott Vascular, Inc (formerly St Jude Medical, Inc), Royal Philips NV (formerly Volcano Corporation), Arbor Pharmaceuticals, LLC, AstraZeneca Pharmaceuticals, LP, Merck Sharp & 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 Maron has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown., Objectives: The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial., Methods: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure., Results: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (P interaction  = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (P interaction  = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (P interaction  = 0.29)., Conclusions: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)., Competing Interests: Funding Support and Author Disclosures This project was supported in part by National Institutes of Health grants U01HL105907, U01HL105462, U01HL105561, and U01HL105565; and in part by Clinical Translational Science Award numbers 11UL1 TR001445 and UL1 TR002243 from the National Center for Advancing Translational Sciences. The contents of this project 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. Dr Nguyen is currently supported by the National Heart, Lung, and Blood Institute under Award Number T32HL110837. Dr Spertus has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received personal fees from Bayer, Novartis, AstraZeneca, Amgen, Janssen, and United Healthcare; has received grants from the American College of Cardiology, outside the submitted work; has a patent copyright to SAQ with royalties paid; is on the Board of Directors for Blue Cross Blue Shield of Kansas City; and has equity in Health Outcomes Sciences. Dr Newman, Dr Alexander, Mrs Stevens, Dr O'Brien, Dr Gamma, Dr Perna, Dr Garg, Dr Vertes, Dr Smanio, Dr Senior, Dr Held, and Dr Maron have received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Mr Jones reports employment by the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; receives research support from TD Bank, CV Diagnostix, AusculSciences, and Siemens Healthineers; and has equity interest in General Electric. Dr White has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received grant support paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial from Sanofi and Regeneron Pharmaceuticals, for the ACCELERATE study from Eli Lilly, for the STRENGTH trial from Omthera Pharmaceuticals, for the HEART-FID study from American Regent, for the CAMELLIA-TIMI study from Eisai Inc, for the dal-GenE study from DalCor Pharma UK Inc, for the AEGIS-II study from CSL Behring, for the SCORED trial and the SOLOIST-WHF trial from Sanofi Australia Pty Ltd, and for the CLEAR Outcomes Study from Esperion Therapeutics Inc. Dr White was on the Advisory Board for Genentech, Inc; and has received lecture fees from AstraZeneca. Dr Boden has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received grants from AbbVie, Amarin, and Amgen; and has received personal fees from Amgen, the Cleveland Clinic Clinical Coordinating Center, and Janssen, outside the submitted work. Dr Mark has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and has received grants from HeartFlow and Merck, outside the submitted work. Dr Reynolds has received funding for this research from the National Heart, Lung, and Blood Institute; and has received in-kind donations for unrelated research from Abbott Vascular, Siemens, and Philips. Dr Bangalore has received grants from the National Heart, Lung, and Blood Institute and Abbott Vascular; and serves on the advisory board for Abbott Vascular, Pfizer, Amgen, Biotronik, Meril, and Reata. Dr Chan has received funding from the American Heart Association; and is a consultant for Optum Rx. Dr Stone has received grants and personal fees from the National Heart, Lung, and Blood Institute during the conduct of the study; has received personal fees from Terumo, Amaranth, Shockwave, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-Wave, Abiomed, Claret, Sirtex, MAIA Pharmaceuticals, and Vectorious; has received personal fees and has equity/options from VALFIX, Ancora, Qool Therapeutics, SpectraWave, and Orchestra Biomed; has equity/options from Cagent, Applied Therapeutics, BioStar family of funds, MedFocus family of funds, and Aria; and has equity/options from Cardiac Success, outside the submitted work. Dr Hochman is Principal Investigator for the ISCHEMIA trial for which, in addition to support by a National Heart, Lung, and Blood Institute grant, 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 & Dohme Corp, Omron Healthcare, Inc, Sunovion Pharmaceuticals, Inc, Espero BioPharma, and Amgen, Inc, as well as financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy., Methods: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory-interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest)., Results: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61-1.30]; severe ischemia HR, 0.83 [95% CI, 0.57-1.21]; P =0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86-1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98-1.91]; P =0.04 for trend, P =NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06-6.98]) and MI (HR, 3.78 [95% CI, 1.63-8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%-12.4%]), but 4-year all-cause mortality was similar., Conclusions: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01471522.

Background: It is advisable that the intensity of the exercises for rehabilitation of patients with coronary artery disease does not cause myocardial ischemia., Objective: Compare the capacity of myocardial tomographic scintigraphy with the electrocardiogram capacity in ischemia detection during rehabilitation session., Methods: Twenty six patients with coronary artery disease, undergoing the rehabilitation program and with previous scintigraphy, with transient hypo-uptake have been administered a new injection of MIBI-Tc-99m during a training session when they were also monitored with dynamic electrocardiography. The rest scintigraphies, after ergometric treadmill test and rehabilitation session, were assessed in a semi-quantitative way using scores from 0 to 4 to classify each one of the chosen segments (0 = normal; 1 = discrete hypo-uptake; 2 = moderate; 3 = intense; 4 = lack of uptake)., Results: The means of the total scores found were: at rest = 12.9; after treadmill test = 19.3; after rehabilitation session = 15.1. There were statistically significant differences among them. An individual assessment showed that in 14 cases (53.8 %) hypo-uptake to some degree was identified during rehabilitation and in 12 cases (46.6%) it was not. Monitoring with the Holter system didn't show in any of the cases a ST segment depression equal or greater than 1mm., Conclusion: The exercises prescribed for patients with coronary artery disease, according to recommendations found in the literature, may trigger myocardial ischemia, assessed by scintigraphy during a rehabilitation session.

Objective: To correlate myocardial perfusion scintigraphy (MPS) with Tc-99m-MIBI and adenosine infusion using quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS)., Methods: Seventy patients with coronary artery disease (CAD) referred for myocardial perfusion scintigraphy (MPS) with MIBI and adenosine were studied. Clinical, electrocardiographic (ECG), and scintigraphic findings were correlated with variables of visual and quantitative angiographic analysis, as well as to those of IVUS., Results: The mean age of patients was 60.6 years, and 39 were male. Coronary angiography showed percentage of diameter stenosis (% DS) of 49.94% in 105 arteries, 83 of which were re-evaluated by QCA (79%), mean of 44.20%, p<0.05. ST-segment depression during adenosine infusion was associated with higher degrees of % DS (55.0% vs. 47.8%), p<0.05). Scintigraphic ischemia was correlated with greater cross-sectional area of lumen obstruction by IVUS (% CSA). Clinical, ECG, and IVUS findings were considered together and expressed as global ischemic versus non-ischemic responses. Ischemia was associated with lower values of minimal lumen diameter (MLD) and minimal lumen area (MLA) determined by QCA and IVUS., Conclusion: Tc-99m-MIBI and adenosine myocardial SPECT is correlated with % CSA on IVUS, perfusion images considered. Global results assessment showed association between lumen diameter and area at obstructed sites as determined by QCA and IVUS.