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Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Although opening an occluded infarct-related artery >24 hours after myocardial infarction in stable patients in the Occluded Artery Trial (OAT) did not reduce events over 7 years, there was a suggestion that the effect of treatment might differ by patient age. Baseline characteristics and outcomes by treatment with percutaneous coronary intervention (PCI) versus optimal medical therapy alone were compared by prespecified stratification at age 65 years. A p value <0.01 was prespecified as significant for OAT secondary analyses. The primary outcome was death, myocardial infarction, or New York Heart Association class IV heart failure. Patients aged >65 years (n = 641) were more likely to be female, to be nonsmokers, and to have hypertension, lower estimated glomerular filtration rates, and multivessel disease compared to younger patients (aged ≤65 years, n = 1,560) (p <0.001). There was no significant observed interaction between treatment assignment and age for the primary outcome after adjustment (p = 0.10), and there was no difference between PCI and optimal medical therapy observed in either age group. At 7-year follow-up, younger patients tended to have angina more often compared to the older group (hazard ratio 1.21, 99% confidence interval 1.00 to 1.46, p = 0.01). The 7-year composite primary outcome was more common in older patients (p <0.001), and age remained significant after covariate adjustment (hazard ratio 1.42, 99% confidence interval 1.09 to 1.84). The rate of early PCI complications was low in the 2 age groups. The trend toward a differential effect of PCI in the young versus the old for the primary outcome was likely driven by measured and unmeasured confounders and by chance. PCI reduces angina to a similar degree in the young and old. In conclusion, there is no indication for routine PCI to open a persistently occluded infarct-related artery in stable patients after myocardial infarction, regardless of age. [ABSTRACT FROM AUTHOR]

This study examined a ready-to-eat breakfast cereal, CHEERIOS, made of whole grain oats, containing 8 grams of oat bran per oz., for its cholesterol-lowering effect. This was a randomized, double-blind study, with forty-three subjects (21 men and 22 women) who had mild to moderate hypercholesterolemia (mean baseline value 5.94 +/- 0.65 mmol/L [230.8 +/- 25.3 mg/dL]). Subjects followed medical nutrition therapy and ate either 3 oz. of Country CORNFLAKES, with essentially no bran or germ or CHEERIOS for 4 weeks. Compared with the control, those consuming oat cereal achieved a 4.4 % reduction in total cholesterol and a 4.9% reduction in low-density lipoprotein cholesterol compared with baseline. Copyright © 2000 by Aspen Publishers, Inc. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether stable, high-risk patients with persistent total occlusion of the infarct-related coronary artery identified after the currently accepted period for myocardial salvage has passed should undergo percutaneous coronary intervention (PCI) in addition to receiving optimal medical therapy to reduce the risk of subsequent events.Methods: We conducted a randomized study involving 2166 stable patients who had total occlusion of the infarct-related artery 3 to 28 days after myocardial infarction and who met a high-risk criterion (an ejection fraction of <50% or proximal occlusion). Of these patients, 1082 were assigned to routine PCI and stenting with optimal medical therapy, and 1084 were assigned to optimal medical therapy alone. The primary end point was a composite of death, myocardial reinfarction, or New York Heart Association (NYHA) class IV heart failure.Results: The 4-year cumulative primary event rate was 17.2% in the PCI group and 15.6% in the medical therapy group (hazard ratio for death, reinfarction, or heart failure in the PCI group as compared with the medical therapy group, 1.16; 95% confidence interval [CI], 0.92 to 1.45; P=0.20). Rates of myocardial reinfarction (fatal and nonfatal) were 7.0% and 5.3% in the two groups, respectively (hazard ratio, 1.36; 95% CI, 0.92 to 2.00; P=0.13). Rates of nonfatal reinfarction were 6.9% and 5.0%, respectively (hazard ratio, 1.44; 95% CI, 0.96 to 2.16; P=0.08); only six reinfarctions (0.6%) were related to assigned PCI procedures. Rates of NYHA class IV heart failure (4.4% vs. 4.5%) and death (9.1% vs. 9.4%) were similar. There was no interaction between treatment effect and any subgroup variable (age, sex, race or ethnic group, infarct-related artery, ejection fraction, diabetes, Killip class, and the time from myocardial infarction to randomization).Conclusions: PCI did not reduce the occurrence of death, reinfarction, or heart failure, and there was a trend toward excess reinfarction during 4 years of follow-up in stable patients with occlusion of the infarct-related artery 3 to 28 days after myocardial infarction. (ClinicalTrials.gov number, NCT00004562 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: Whether revascularisation (REV) improves outcomes in patients with three-vessel coronary artery disease (3V-CAD) is uncertain., Aims: Our objective was to evaluate outcomes with REV (percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]) versus medical therapy in patients with 3V-CAD., Methods: ISCHEMIA participants with 3V-CAD on coronary computed tomography angiography without prior CABG were included. Outcomes following initial invasive management (INV) with REV (PCI or CABG) versus initial conservative management (CON) with medical therapy alone were evaluated. Regression modelling was used to estimate the outcomes if all participants were to undergo prompt REV versus those assigned to CON. Outcomes were cardiovascular (CV) death/myocardial infarction (MI), death, CV death, and quality of life. Bayesian posterior probability for benefit (Pr [benefit]) for 1 percentage point lower 4-year rates with REV versus CON were evaluated., Results: Among 1,236 participants with 3V-CAD (612 INV/624 CON), REV was associated with lower 4-year CV death/MI (adjusted 4-year difference: -4.4, 95% credible interval [CrI] -8.7 to -0.3 percentage points, Pr [benefit]=94.8%) when compared with CON, with similar results for PCI versus CON (-5.8, 95% CrI: -10.8 to -0.5 percentage points, Pr [benefit]=96.4%) and CABG versus CON (-3.7, 95% CrI: -8.8 to 1.5 percentage points, Pr [benefit]=84.7%). Adjusted 4-year REV versus CON differences were as follows: death -1.2 (95% CrI: -4.7 to 2.2) percentage points, CV death -2.3 (95% CrI: -5.5 to 0.8) percentage points, with similar results for PCI and for CABG. The Pr (benefit) for death with REV (PCI or CABG) versus CON was 49-63%. The adjusted 12-month Seattle Angina Questionnaire-7 summary score differences favoured REV: REV versus CON 4.6 (95% CrI: 2.7-6.4) percentage points; PCI versus CON 3.6 (95% CrI: 1.2-5.8) percentage points and CABG versus CON 4.3 (95% CrI: 1.5-6.9) percentage points with high Pr (benefit)., Conclusions: In participants with 3V-CAD, REV (either PCI or CABG) was associated with a lower 4-year CV death/MI rate and improved quality of life, with similar results for PCI versus CON and CABG versus CON. The differences in all-cause mortality between REV and CON were small with wide confidence intervals. (ClinicalTrials.gov: NCT01471522).

Introduction: Electronic health record (EHR)-embedded tools are known to improve prescribing of guideline-directed medical therapy (GDMT) for patients with heart failure. However, physicians may perceive EHR tools to be unhelpful and be hesitant to implement these in their practice., Methods: The BETTER CARE-HF trial (NCT05275920) ran from April 28, 2022 to October 26, 2022 at NYU Langone Health outpatient clinics being seen by 180 cardiologists. The trial compared the effectiveness of an Alert during visits, Messages between visits, or usual care with the primary outcome of MRA prescribing. In this study, we sent surveys via electronic mail to cardiologists who either received an Alert or a Message during BETTER CARE-HF (60 cardiologists per survey)., Results: Of the 120 cardiologists who were sent the survey, response rate was 27% in the Alert group and 33% in the Message group. A majority of respondents in both the alert and message groups agreed that EHR tools were easy to use (Alert 79%; Message 69%), served as a reminder to prescribe therapy (Alert 77%; Message 77%;), and that the underlying evidence (Alert 86%; Message 62%) and clinical information (Alert 86%; Message 69%) were trustworthy. Overall, 54% agreed with continued use of the Alert, while 31% agreed with continued use of the Message., Conclusion: Cardiologists perceived the EHR tools to be easy to use, helpful, and improve the overall management of their patients with heart failure., Competing Interests: Conflict of interest There are no conflicts of interest to disclose related to the work in this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 6-15 % of MI patients. Cardiac magnetic resonance (CMR) imaging identifies MINOCA etiologies, but access may be limited., Methods: We assessed associations between the index electrocardiogram (ECG) and CMR in MINOCA. Women with MI and < 50 % angiographic stenosis in all vessels were prospectively enrolled at 16 sites. CMR (median 6d from MI) was analyzed for late gadolinium enhancement (LGE), myocardial edema, and wall motion. We assessed ECGs for T-wave inversions (TWI), Q-waves (QW), ST-elevations (STE), ST-depressions (STD), and fragmented QRS complexes (fQRS). We calculated the DETERMINE score (# leads TWI + # fQRS +2*[# QW], excluding aVR, V1)., Results: Among 112 women with interpretable ECG, 81.3 % (91/112) had abnormal ECG; 50 % (56/112) had ≥1 TWI. CMR was abnormal in 74.1 % (83/112), with LGE in 49.1 % (55/112) and myocardial edema in 61.6 % (69/112). DETERMINE score ≥ 3 was associated with abnormal CMR (adjusted odds ratio [aOR] aOR 6.06 [1.89, 24.6], p = 0.002) and LGE (aOR 3.10 [1.26, 8.00], p = 0.013), but not edema (aOR 1.86 [0.80, 4.43], p = 0.152). TWI was also associated with abnormal CMR and LGE after adjustment (aOR 3.13 [1.08, 10.1], p = 0.036, aOR 3.23 [1.27, 8.63], p = 0.013, respectively), but not edema (aOR 1.26 [0.54, 2.96], p = 0.589). Specificity for abnormal CMR was 0.83 for DETERMINE score ≥ 3 and 0.75 for TWI. No other ECG findings were associated with CMR abnormality., Conclusion: DETERMINE score ≥ 3 and the presence of any TWI were associated with abnormal CMR and with LGE in MINOCA. Our findings demonstrate that the index ECG can provide insight on CMR findings but without sensitivity or specificity required to forgo the CMR. We reaffirm the central role of CMR in elucidating MINOCA pathophysiology., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) demonstrated greater health status benefits with an initial invasive strategy, as compared with a conservative one, for patients with chronic coronary disease and moderate or severe ischemia. Whether these benefits vary globally is important to understand to support global adoption of the results., Methods: We analyzed participants' disease-specific health status using the validated 7-item Seattle Angina Questionnaire (SAQ: >5-point differences are clinically important) at baseline and over 1-year follow-up across 37 countries in 6 international regions. The average effect of initial invasive versus conservative strategies on 1-year SAQ scores was estimated using Bayesian proportional odds regression and compared across regions., Results: Considerable regional variation in baseline health status was observed among 4617 participants (mean age=64.4±9.5 years, 24% women), with the mean SAQ summary scores of 67.4±19.5 in Eastern Europe participants (17% of the total), 71.4±15.4 in Asia-Pacific (18%), 74.9±16.7 in Central and South America (10%), 75.5±19.5 in Western Europe (26%), and 78.6±19.2 in North America (28%). One-year improvements in SAQ scores were greater in regions with lower baseline scores with initial invasive management (17.7±20.9 in Eastern Europe and 11.4±19.3 in North America), but similar in the conservative arm. Adjusting for baseline SAQ scores, similar health status benefits of an initial invasive strategy on 1-year SAQ scores were observed (ranging from 2.38 points [95% CI, 0.04-4.50] in North America to 4.66 points [95% CI, 2.46-6.94] in Eastern Europe), with an 88.3% probability that the difference in benefit across regions was <5 points., Conclusions: In patients with chronic coronary disease and moderate or severe ischemia, initial invasive management was associated with a consistent health status benefit across regions, with modest regional variability, supporting the international generalizability of health status benefits from invasive management of chronic coronary disease., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522., Competing Interests: Dr Ikemura received an unrestricted research grant for the Department of Cardiology, Keio University School of Medicine from Bristol Myer Squibb. Dr Spertus discloses providing consultative services on patient-reported outcomes and evidence evaluation to Alnylam, AstraZeneca, Bayer, Merck, Janssen, Bristol Meyers Squibb, Edwards, Kineksia, 4DT Medical, Terumo, Cytokinetics, Imbria, and United Healthcare. He holds research grants from Bristol Meyers Squibb, Abbott Vascular, and Janssen. He owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire and serves on the Board of Directors for Blue Cross Blue Shield of Kansas City. Dr Nguyen is currently supported by the National Heart, Lung, and Blood Institute under Award Number T32HL110837. Dr Reynolds reports grants from National Heart, Lung, and Blood Institute, during the conduct of the study, she received 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 Bangalore reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants and personal fees from Abbott Vascular; personal fees from Biotronik, Pfizer, Amgen, and Reata outside the submitted work. Dr Bhargava reports grants from the National Heart, Lung and Blood Institute, during the conduct of the study. Dr Senior reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and speaker fees from Bracco, Lantheus Medical Imaging Boston USA, and Philips Healthcare outside the submitted work. A. Elghamaz reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) and speaker/consulting honoraria (eg, advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, CYTE Ltd., Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research center and MD Primer, Canadian VIGOUR center, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating center, PERFUSE Research Institute, TIMI Study Group (Brigham Health). Dr Lopes reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; other from Bayer and Boehringer Ingelheim; grants and other from Bristol-Myers Squibb; other from Daiichi Sankyo; grants and other from GlaxoSmithKline and Medtronic; other from Merck; grants and other from Pfizer; other from Portola; and grants and other from Sanofi, outside the submitted work. Dr Pracon reports grants from National Heart, Lung, and Blood Institute, during the conduct of the study and research grant honoraria from NYU. Dr Lopez-Sendon reports grants from National Heart, Lung and Blood Institute, during the conduct of the study; other from Bayer, other from Boehringer Ingleheim, grants and other from Bristol-Myers Squibb, other from Daiichi Sankyo, grants and other from Glaxo Smith Kline, grants and other from Medtronic, other from Merck, grants and other from Pfizer, other from Portola, grants and other from Sanofi, outside the submitted work. Dr Maggioni reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and personal fees from Bayer, AstraZeneca, Sanofi and Novartis, outside the submitted work. Dr Kohsaka has received grant support paid to the institution and fees from Novartis and AstraZeneca. Dr White has received grant support paid to the institution and fees for serving on Steering Committees of the ODYSSEY trial from Sanofi and Regeneron Pharmaceuticals, the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) and MINT study from the National Institutes of Health, the STRENGTH trial from Omthera Pharmaceuticals, the HEART-FID study from American Regent, the DAL-GENE study from DalCor Pharma UK Inc., the AEGIS-II study from CSL Behring, the CLEAR OUTCOMES study from Esperion Therapeutics Inc, and the SOLIST-WHF and SCOREDS trials from Sanofi Aventis Australia Pty Ltd. Dr Mavromatis reports grants from the National Heart, Lung, and Blood Institute; grants from National Heart, Blood, and Lung Institute (CV Inflammation Reduction Trial and GMCSF in PAD-3 Trial), grants from CSL Behring, St Jude’s Medical, Medtronic, DalCor Pharmaceuticals, AstraZeneca, Novartis, Regeneron, and Member of American College of Cardiology and Society of Cardiovascular Angiography and Interventions. Dr Boden reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants from Abbvie, grants from Amarin, grants from Amgen, personal fees from Amgen, personal fees from Cleveland Clinic Clinical Coordinating Center, personal fees from Janssen, outside the submitted work. Dr Fatima Rodriguez reports consulting fees from Novartis, NovoNordisk, AstraZeneca, and Health Pals, and research support from the National Institutes of Health, the American Heart Association, and the Doris Duke Foundation. Dr Hochman is PI for the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) 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.; Omron Healthcare Inc, and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. She is also the PI for ISCHEMIA-EXTEND. Dr Maron reports grants from National Heart, Lung, and Blood Institute, during the conduct of the study. The other authors report no conflicts.

Background: Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19., Methods: This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774., Findings: The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis., Interpretation: SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19., Funding: National Institutes of Health., Competing Interests: Declaration of interests MNK has received research grant support from University of Pittsburgh, AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Regeneron, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca and Vifor Pharma; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He holds stock options from Artera Health and Saghmos Therapeutics. OV has received institutional research support from AstraZeneca, Bayer, and Cardurion, and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi. JSB reports research grants from National Institutes of Health and American Heart Association and has consulted for Janssen. HRR reports receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study, as well as nonfinancial support from Abbott Vascular, SHL Telemedicine, Siemens, and Phillips outside the submitted work. ADA is an employee of Medtronic. SDS has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. ASB has received research grant support to his institution from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention. AP reports a research grant from the German Research Foundation. MNG reports receiving grants from National Institutes of Health, Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention and receiving personal fees from Regeneron for serving on the data safety monitoring board for monoclonal antibody trials in COVID-19. LZK reports receiving personal fees from Cerus Corp, University of Maryland, Coagulant Therapeutics, Haemonetics, and Gamma Diagnostics. PK receives grant funding as a principal investigator from NIH and Cerenovus; consulting fees as a scientific advisor to Basking Biosciences, Bayer, Lumosa, and Shionogi; and royalties for online publication from UpToDate. KSK reports grants from National Institutes of Health during the conduct of the study, funding from Eisai outside the submitted work, and personal fees from National Institutes of Health for committee service indirectly related to the research. LBK reports that her institution received funding from National Institutes of Health to perform the study. AJ reports receiving funding from AstraZeneca to study mechanisms of action of dapagliflozin. LW reports funding from the National Institutes of Health for ACTIV-4A and ACTIV-4C. JLSM reports receiving honoraria from Roche la Hoffman and Novartis. MQH reports receiving research funding from National Institutes of Health and NIAID. JLS reports research grants or contracts from Amgen, BMS, GSK, Medtronic, Pfizer, Sanofi-Aventis; funding for educational activities or lectures from Pfizer, BMS, Novo Nordisk, AstraZeneca, and funding for consulting from Bayer, Boehringer Ingelheim, BMS, Novo Nordisk, and AstraZeneca. RDL has received grants from Amgen, BMS, and GSK; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, and NovoNordisk; and Honoraria from AstraZeneca, Daiichi Sankyo, NovoNordisk and Pfizer. JLC reports direct support for this project from National Institutes of Health/National Heart, Lung, and Blood Institute; grants from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/NIAID, the Department of Defense, the Department of Veterans Affairs, and the COPD Foundation, outside of this project; and support paid to his institution outside this project from CDL Behring, LLC, AstraZeneca, and Novartis, GBMH. B-AK (through SOCAR Research) received grants from National Institutes of Health. MWG reports funding in part by the National Institutes of Health Agreement 1OT2HL156812 through the National Heart, Lung, and Blood Institute CONNECTS programme. MDN serves as chief medical officer for Haima Therapeutics and has received grants from the National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, Department of Defense, Haemonetics, and Instrumentation Laboratories. He has received personal fees from Haemonetics, Takeda, CSL Behring, and Janssen Pharmaceuticals. JSH is the study chair for ACTIV-4a under a National Heart, Lung, and Blood Institute–University of Pittsburgh grant subaward. SLW, SB, JFL, ESL, ALK, MC, CC, and AA declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Aims: The aim of this study was to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA., Methods: Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or myocardial infarction over a median follow-up of 3.3 (interquartile range 2.2-4.4) years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis., Results: Analysable CCTA data were available from 3711 participants (mean age 64 years, 21% female, 79% multivessel coronary artery disease). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted hazard ratio 1.56, 95% confidence interval 1.25-1.97 per interquartile range increase [559 mm3]; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model's predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002). The findings were similar for the other reported outcomes., Conclusions: In ISCHEMIA, total plaque volume was associated with cardiovascular death or myocardial infarction. In this highly diseased, high-risk population, enhanced assessment of atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improved event prediction., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The coronavirus disease 2019 pandemic highlighted the need to conduct efficient randomized clinical trials with interim monitoring guidelines for efficacy and futility. Several randomized coronavirus disease 2019 trials, including the Multiplatform Randomized Clinical Trial (mpRCT), used Bayesian guidelines with the belief that they would lead to quicker efficacy or futility decisions than traditional "frequentist" guidelines, such as spending functions and conditional power. We explore this belief using an intuitive interpretation of Bayesian methods as translating prior opinion about the treatment effect into imaginary prior data. These imaginary observations are then combined with actual observations from the trial to make conclusions. Using this approach, we show that the Bayesian efficacy boundary used in mpRCT is actually quite similar to the frequentist Pocock boundary., Methods: The mpRCT's efficacy monitoring guideline considered stopping if, given the observed data, there was greater than 99% probability that the treatment was effective (odds ratio greater than 1). The mpRCT's futility monitoring guideline considered stopping if, given the observed data, there was greater than 95% probability that the treatment was less than 20% effective (odds ratio less than 1.2). The mpRCT used a normal prior distribution that can be thought of as supplementing the actual patients' data with imaginary patients' data. We explore the effects of varying probability thresholds and the prior-to-actual patient ratio in the mpRCT and compare the resulting Bayesian efficacy monitoring guidelines to the well-known frequentist Pocock and O'Brien-Fleming efficacy guidelines. We also contrast Bayesian futility guidelines with a more traditional 20% conditional power futility guideline., Results: A Bayesian efficacy and futility monitoring boundary using a neutral, weakly informative prior distribution and a fixed probability threshold at all interim analyses is more aggressive than the commonly used O'Brien-Fleming efficacy boundary coupled with a 20% conditional power threshold for futility. The trade-off is that more aggressive boundaries tend to stop trials earlier, but incur a loss of power. Interestingly, the Bayesian efficacy boundary with 99% probability threshold is very similar to the classic Pocock efficacy boundary., Conclusions: In a pandemic where quickly weeding out ineffective treatments and identifying effective treatments is paramount, aggressive monitoring may be preferred to conservative approaches, such as the O'Brien-Fleming boundary. This can be accomplished with either Bayesian or frequentist methods., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: In myocardial infarction with nonobstructive coronary arteries (MINOCA), there are limited patient-level data on outcomes by sex and race., Objective: The aim of this study was to assess baseline demographics and 3-year outcomes by sex and race for MINOCA patients., Methods: Patients admitted to a single center with acute myocardial infarction (MI) between 1 January 2012 and 31 December 2018, were identified by chart and angiographic review. The primary outcome was nonfatal MI with secondary outcomes including nonfatal cerebrovascular accident (CVA), chest pain readmission, and repeat coronary angiography., Results: During the study period, 304 patients were admitted with MINOCA. The cohort was predominantly female (66.4%), and women were significantly older (64.6 vs. 59.2). One-sixth of the total population were Black patients, and nearly half of Black patients (47.2%) were male. Prior CVA (19.7%) and comorbid anxiety, depression, or post-traumatic stress disorder (41.1%) were common. Rates of nonfatal MI were 6.3% without difference by sex or race. For secondary outcomes, rates of CVA were 1.7%, chest pain readmission was 22.4%, and repeat angiography was 8.9%. Men were significantly more likely to have repeat angiography (13.7 vs. 6.4%), and Black patients were more likely to be readmitted for angina (34.0 vs. 19.1%). Over one-quarter of patients underwent repeat stress testing, with 8.9% ultimately undergoing repeat angiograms and low numbers (0.7%) undergoing revascularization. Men were more likely to be referred for a repeat angiogram (13.7 vs. 6.4%, P  = 0.035). In multivariate analysis, Black race [odds ratio (OR), 2.31; 95% confidence interval (CI), 1.06-5.03] was associated with an increased risk of readmission for angina, while female sex was associated with decreased odds of repeat angiography (OR, 0.36; 95% CI, 0.14-0.90) and current smoking was associated with increased odds of repeat angiography (OR, 4.07; 95% CI, 1.02-16.29)] along with hyperlipidemia (OR, 4.65; 95% CI, 1.22-17.7)., Conclusion: White women presented more frequently with MINOCA than White men, however, Black men are equally as affected as Black women. Rates of nonfatal MI were low without statistical differences by sex or race., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cardiometabolic co-morbidities, diabetes (DM), hypertension (HTN), and obesity contribute to cardiovascular disease. Circulating biomarkers facilitate prognostication for patients with cardiovascular disease. We explored the relation between cardiometabolic co-morbidity burden in patients with chronic coronary disease and biomarkers of myocardial stretch, injury, inflammation, and platelet activity. We analyzed participants from the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trials biorepository with plasma biomarkers (N-terminal probrain natriuretic peptide, high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein, interleukin-6, soluble CD40 ligand, and growth differentiation factor-15) and clinical risk factors (hemoglobin A1c [HbA1c], systolic blood pressure [SBP], and body mass index [BMI]) at baseline. We defined cardiometabolic co-morbidities as DM, HTN, and obesity at baseline. Co-morbidity burden is characterized by the number and severity of co-morbidities. Controlled co-morbidities were defined as HbA1c <7% for those with DM, SBP <130 mm Hg for those with HTN, and BMI <30 kg/m 2 . Severely uncontrolled was defined as HbA1c ≥8%, SBP ≥160 mm Hg, and BMI ≥35 kg/m 2 . We performed linear regression analyses to examine the association between co-morbidity burden and log-transformed biomarker levels, adjusting for age, gender, estimated glomerular filtration rate controlled for hemodialysis, and left ventricular ejection fraction. A total of 752 participants (mean age 66 years, 19% women, 84% White) were included in this analysis. Self-reported Black race, current smokers, history of myocardial infarction, and heart failure had a greater cardiometabolic co-morbidity burden. The presence of ≥1 severely uncontrolled co-morbidity was associated with significantly higher baseline levels of high-sensitivity cardiac troponin T, high-sensitivity C-reactive protein, interleukin-6, and growth differentiation factor-15 than participants with no co-morbidities. In conclusion, increasing cardiometabolic co-morbidity burden in patients with chronic coronary disease is associated with higher levels of circulating biomarkers of myocardial injury and inflammation., Competing Interests: Declaration of competing interest Dr. Bangalore reports grants from National Heart, Lung, and Blood Institute during the conduct of the study; grants and personal fees from Abbott Vascular; personal fees from Biotronik, Pfizer, Amgen, and Reata outside the submitted work. Dr. Mavromatis reports grants from National Heart, Lung, and Blood Institute (NHLBI); grants from NHLBI (CV Inflammation Reduction Trial and GMCSF in PAD-3 Trial), grants from CSL Behring, St Jude's Medical, Medtronic, DalCor Pharmaceuticals, AstraZeneca, Novartis, Regeneron, and Member of American College of Cardiology and Society of Cardiovascular Angiography and Interventions. Dr. Newby reports grants from the National Institutes of Health/NHLBI, AstraZeneca Healthcare Foundation, Boehringer Ingelheim (Ingelheim, Germany), CSL, and Medtronic. Dr. Reynolds reports grants from NHLBI, during the conduct of the study, she receives support from Abbott Vascular (donation of optical coherence tomography catheters for an unrelated research study), Biotelemetry Inc. (donation of telemetry monitors for an unrelated research study), and Siemens. Dr. Hochman is principal investigators for the ISCHEMIA trial for which, in addition to support by 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 (Wilmington, Delaware); Merck Sharp & Dohme Corp.; Omron Healthcare, Inc, Sunovion Pharmaceuticals, Inc. Espero BioPharma; and Amgen, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr. Hochman is also the PI for ISCHEMIA-EXTEND. Drs. Anthopolos, Maron, Newman, and Berger reports grants from the NHLBI during the conduct of the study. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.

The working diagnosis Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA) is being increasingly recognized with the common use of high-sensitivity troponins and coronary angiography, accounting for 5% to 10% of all acute myocardial infarction presentations. Cardiac magnetic resonance (CMR) imaging is pivotal in patients presenting with suspected MINOCA, mainly to delineate those with a nonischemic cause, for example, myocarditis and Takotsubo syndrome, from those with true ischemic myocardial infarction, that is, MINOCA. The optimal timing for CMR imaging in patients with suspected MINOCA has been uncertain and, until recently, not been examined prospectively. Previous retrospective studies have indicated that the diagnostic yield decreases with time from the acute event. The SMINC studies (Stockholm Myocardial Infarction with Normal Coronaries) show that CMR should be performed early in all patients with the working diagnosis of MINOCA, with the possible exception of patients who are clearly identified as having Takotsubo syndrome as determined by echocardiography. In addition to CMR imaging, other investigations of importance in selected patients may be pulmonary artery computed tomography to exclude pulmonary embolism, optical coherence tomography to identify plaque disruption, and acetylcholine provocation to identify coronary artery spasm. Imaging of patients with the working diagnosis MINOCA, which is centered on CMR together with supplemental investigations, results in a clear diagnosis in approximately three-quarters of the patients. This is a good example of personalized medicine, because a correct diagnosis will not only increase the satisfaction of the individual patient but also result in optimizing treatment without harming the patient., Competing Interests: Dr Reynolds has received unrestricted donations from Abbott and Siemens. Dr Nickander received speaker fees from Sanofi Genzyme.

Background: Coronary slow flow (CSF) by invasive coronary angiography is frequently understood to be an indicator of coronary microvascular dysfunction (CMD) in patients with ischemia with nonobstructive coronary arteries. However, the relationship between visual estimates of CSF and quantitative wire-based invasive diagnosis of CMD is uncertain., Methods: We prospectively enrolled adults aged ≥18 years with stable ischemic heart disease who were referred for invasive coronary angiography. Individuals with ≥50% epicardial coronary artery stenosis were excluded. Invasive coronary angiography was reviewed for CSF, defined as ≥3 cardiac cycles to opacify distal vessels with contrast. Coronary function testing was performed in the left anterior descending coronary artery using bolus coronary thermodilution techniques to measure coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR). Invasively determined CMD was defined as abnormal CFR (<2.5), abnormal IMR (≥25), or both., Results: Among 104 participants, the median age was 61.5 years and 79% were female. The median CFR was 3.6 (interquartile range, 2.5-4.7) and the median IMR was 21 (interquartile range, 13.3-28.0). Overall, 24.0% of participants had abnormal CFR, 34.6% had abnormal IMR, and 48.1% had a final diagnosis of invasively determined CMD. CSF was present in 23 participants (22.1%). The proportions of patients with CMD (56.5% versus 45.7%; P =0.36), abnormal CFR (17.4% versus 25.9%; P =0.40), and abnormal IMR (43.5% versus 32.1%; P =0.31) were not different in patients with versus without CSF., Conclusions: Among patients with ischemia with nonobstructive coronary artery, CSF was not associated with abnormal CFR, IMR, or either abnormal CFR or IMR. CSF is not a reliable angiographic surrogate of abnormal CFR or IMR as determined by invasive, wire-based physiology testing., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03537586., Competing Interests: Disclosures Dr Smilowitz has served on an advisory board for Abbott Vascular. Dr Reynolds reports in-kind donations from Abbott Vascular, Philips, SHL Telemedicine, and Siemens. Dr Serrano-Gomez reports speaking arrangements with AstraZeneca and Terumo. The other authors report no conflicts.

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 low-density 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., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522., Competing Interests: Disclosures Dr Pracoń reports grants from the National Heart, Lung, and Blood Institute (NHLBI), during the conduct of the study. Dr Spertus reports grants from the NHLBI, during the conduct of the study; personal fees from Bayer, Novartis, AstraZeneca, Amgen, Janssen, and United Healthcare; grants from the American College of Cardiology; and personal fees from Blue Cross Blue Shield of Kansas City, outside the submitted work. In addition, Dr Spertus has a patent Copyright to the Seattle Angina Questionnaire with royalties paid and Equity in Health Outcomes Sciences. Dr Bangalore reports grants from the NHLBI, during the conduct of the study; grants and personal fees from Abbott; and personal fees from Biotronik, Pfizer, Amgen, and Reata outside the submitted work. Dr Rockhold receives research support from the National Institutes of Health, Patient-Centered Outcomes Research Institute (PCORI), BMS, AstraZeneca, American Regent, the Gates Foundation, and Eidos; consulting fees from Janssen, Clover, Doctor Evidence, Resolve, and Intercept; is on the data safety and monitoring boards (DSMBs) for Lilly, AstraZeneca, Merck, Gilead, Novartis, Icosavax, Sanofi, Union Chimique Belge (UCB), Amgen, Biogen, BMS, Pulmocide, Alkermes, and Diurnal; is the nonprofit chairman of the board (unpaid) of the Frontier Science Foundation; and has stock/stock options in GSK, Clover, Athira, Doctor Evidence, DataVant, Spencer Health Solutions, and Adaptic Health. Dr Mavromatis reports grants from the NHLBI; grants from NHLBI (Cardiovascular Inflammation Reduction Trial and GMCSF in PAD-3 trial [Granulocyte-Macrophage Stimulating Factor (GM-CSF) in Peripheral Arterial Disease (GPAD-3)]); grants from CSL Behring, St Jude’s Medical, Medtronic, DalCor Pharmaceuticals, AstraZeneca, Novartis, and Regeneron; and is a member of the American College of Cardiology and the Society of Cardiovascular Angiography and Interventions. Dr Manjunath reports grants from NHLBI during the conduct of the study. Dr Stone reports grants from NHLBI during the conduct of the study; has received speaker honoraria from Pulnovo and Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Vascular Dynamics, Shockwave, V-Wave, Cardiomech, Gore, and Amgen; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar Family of Funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Stone’s daughter is an employee at Medtronic. Dr Stone’s employer, Mount Sinai Hospital, receives research support from Abbott, Bioventrix, Cardiovascular Systems, Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, and V-Wave. Dr Mancini reports grants from NHLBI, during the conduct of the study; grants and personal fees from Amgen, Sanofi, Boehringer Ingelheim, AstraZeneca, Bayer, Janssen, and Novo Nordisk; grants from Novartis; and grants and personal fees from HLS Therapeutics, outside the submitted work. Dr Boden reports grants from NHLBI, during the conduct of the study; grants from Abbvie, Amarin, and Amgen; and personal fees from Amgen, the Cleveland Clinic Clinical Coordinating Center, and Janssen, outside the submitted work. Dr Newman reports grants from NHLBI, during the conduct of the study. Dr Reynolds reports grants from NHLBI, during the conduct of the study, and 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 Hochman is a primary investigator for the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) for which, in addition to support by NHLBI 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 Corporation, Omron Healthcare, Inc, Sunovion Pharmaceuticals, Inc, Espero BioPharma, and Amgen, Inc, and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Hochman is also a primary investigator for the ISCHEMIA-EXTEND trial (The International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA] Extended Follow-Up). Dr Maron reports grants from NHLBI, during the conduct of the study. The other authors report no conflicts.

Background: The ISCHEMIA trial found that patients with chronic coronary disease randomized to invasive strategy had better health status than those randomized to conservative strategy. It is unclear how best to translate these population-level results to individual patients., Objectives: The authors sought to identify patient characteristics associated with health status from invasive and conservative strategies, and develop a prediction algorithm for shared decision-making., Methods: One-year disease-specific health status was assessed in ISCHEMIA with the Seattle Angina Questionnaire (SAQ) Summary Score (SAQ SS) and Angina Frequency, Physical Limitations (PL), and Quality of Life (QL) domains (range 0-100, higher = less angina/better health status)., Results: Among 4,617 patients from 320 sites in 37 countries, mean SAQ SS was 74.1 ± 18.9 at baseline and 85.7 ± 15.6 at 1 year. Lower baseline SAQ SS and younger age were associated with better 1-year health status with invasive strategy (P interaction = 0.009 and P interaction = 0.004, respectively). For the individual domains, there were significant treatment interactions for baseline SAQ score (Angina Frequency, PL), age (PL, QL), anterior ischemia (PL), and number of baseline antianginal medications (QL), with more benefit of invasive in patients with worse baseline health status, younger age, anterior ischemia, and on more antianginal medications. Parsimonious prediction models were developed for 1-year SAQ domains with invasive or conservative strategies to support shared decision-making., Conclusions: In the management of chronic coronary disease, individual patient characteristics are associated with 1-year health status, with younger age and poorer angina-related health status showing greater benefit from invasive management. This prediction algorithm can support the translation of the ISCHEMIA trial results to individual patients. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)., Competing Interests: Funding Support and Author Disclosures The research reported in this paper was funded through grants from National Institutes of Health/National Heart, Lung, and Blood Institute grants U01HL105907, U01HL105462, U01HL105561, and U01HL105565, Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, and Clinical and Translational Science Awards from the National Center for Advancing Translational Sciences (11UL1 TR001445 and UL1 TR002243). Devices or medications were provided by Abbott Vascular, Medtronic, St Jude Medical, Volcano, Amgen, Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, Espero Pharmaceuticals, Merck Sharp & Dohme, Omron Healthcare, and Sunovion Pharmaceuticals. Contents of this paper are solely the responsibility of the authors and do not necessarily represent official views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Department of Health and Human Services. Dr Cohen has received research grant support from Abbott, Boston Scientific, Edwards Lifesciences, Philips, CathWorks, Zoll Medical, and I-Rhythm; and has received consulting income from Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic. Dr Reynolds has received in-kind support for unrelated research from Abbott Vascular, Siemens, and BioTelemetry. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; has been a consultant to Abbott, Daiichi-Sankyo, Ablative Solutions, CorFlow, Apollo Therapeutics, Cardiomech, Gore, Robocath, Miracor, Vectorious, Abiomed, Valfix, TherOx, HeartFlow, Neovasc, Ancora, Elucid Bio, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, Cardiac Success, and HighLife; holds equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; and receives institutional research grants from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr Spertus owns the copyright to the Seattle Angina Questionnaire; has received consulting income from Janssen, Bayer, AstraZeneca, Novartis, and Merck; serves on the cardiovascular scientific advisory board of United Healthcare; is on the board of directors for Blue Cross Blue Shield of Kansas City; and holds equity interest in Health Outcomes Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain., Objectives: The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD., Methods: Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent., Results: Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80)., Conclusions: Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD., Competing Interests: Funding Support and Author Disclosures Dr Reynolds is supported by in-kind donations for research from Abbott Vascular, Philips, SHL Telemedicine, and Siemens. Dr McCarthy has received speaking honoraria and payments as a content expert for educational materials from Abbott Vascular. Dr Smilowitz is supported in part by the National Heart, Lung, and Blood Institute of the National Institutes of Health (award K23HL150315); and has served on an advisory board and as a consultant for Abbott Vascular. Dr Miner has received unrestricted research grants and speaking honoraria from Abbott Vascular. Dr Blair has served on an advisory board, as a consultant, and on the Speakers Bureau for Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Electronic health record (EHR) tools can improve prescribing of guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF), but their effectiveness may vary by physician workload., Objectives: This paper aims to assess whether physician workload modifies the effectiveness of EHR tools for HFrEF., Methods: This was a prespecified subgroup analysis of the BETTER CARE-HF (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure) cluster-randomized trial, which compared effectiveness of an alert vs message vs usual care on prescribing of mineralocorticoid antagonists (MRAs). The trial included adults with HFrEF seen in cardiology offices who were eligible for and not prescribed MRAs. Visit volume was defined at the cardiologist-level as number of visits per 6-month study period (high = upper tertile vs non-high = remaining). Analysis at the patient-level used likelihood ratio test for interaction with log-binomial models., Results: Among 2,211 patients seen by 174 cardiologists, 932 (42.2%) were seen by high-volume cardiologists (median: 1,853; Q1-Q3: 1,637-2,225 visits/6 mo; and median: 10; Q1-Q3: 9-12 visits/half-day). MRA was prescribed to 5.5% in the high-volume vs 14.8% in the non-high-volume groups in the usual care arm, 10.3% vs 19.6% in the message arm, and 31.2% vs 28.2% in the alert arm, respectively. Visit volume modified treatment effect (P for interaction = 0.02) such that the alert was more effective in the high-volume group (relative risk: 5.16; 95% CI: 2.57-10.4) than the non-high-volume group (relative risk: 1.93; 95% CI: 1.29-2.90)., Conclusions: An EHR-embedded alert increased prescribing by >5-fold among patients seen by high-volume cardiologists. Our findings support use of EHR alerts, especially in busy practice settings. (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure [BETTER CARE-HF]; NCT05275920)., Competing Interests: Funding Support and Author Disclosures This study was funded by the National Center for Advancing Translational Sciences (NIH/NCATS UL1TR001445). Dr Mukhopadhyay is supported by an American Heart Association Career Development Award (23CDA1042602), outside the scope of the present work. Dr Reynolds has received in-kind donations for unrelated research from Abbott Vascular, Philips, SHL Telemedicine, and Siemens. Dr Phillips has received consulting fees from Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear., Research Question: In the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days?, Study Design and Methods: This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed., Results: Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR [aOR], 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96)., Interpretation: In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04505774; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: Y. Y. G. is the founder and CEO of Sabra Medical, Inc outside the submitted work. J. S. B. received grants from the National Heart, Lung, and Blood Institute and American Heart Association and personal fees from Jannssen and Amgen, outside the submitted work. L. Z. K. received consulting fees from Cerus, Gamma Diagnostics, and University of Maryland, outside the submitted work. P. R. L. received grants from the National Institutes of Health during the conduct of the study. R. D. L. receive consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi, outside the submitted work. H. R. R. received nonfinancial support from Siemens, Philips, and Abbott Vascular and grants from the National Heart, Lung, and Blood Institute, outside the submitted work. M. D. N. received personal fees from Haemonetics and Takeda, grants from Instrumentation Laboratories and Haemonetics, and serves on the advisory board for and has equity stake in Haima Therapeutics, outside the submitted work. M. N. G. received grants from the National Institutes of Health and the Centers for Disease Control and Prevention, outside the submitted work. None declared (K. H., J. F., S. R. W., V. V., Y. L., S. Y. C., C. C., F. S., M. G., R. M. G., W. N., J. S. A., L. W., A. Z., E. C. G., R. Z., E. L., D. T. H., J. S. H., M. C.)., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management., Methods and Results: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial randomized patients with moderate or severe ischemia to invasive management with angiography, revascularization, and guideline-directed medical therapy, or initial conservative management with guideline-directed medical therapy alone. We evaluated the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) and other end points, by sex, in 1168 (22.6%) women and 4011 (77.4%) men. Invasive group catheterization rates were similar, with less revascularization among women (73.4% of invasive-assigned women revascularized versus 81.2% of invasive-assigned men; P <0.001). Women had less coronary artery disease: multivessel in 60.0% of invasive-assigned women and 74.8% of invasive-assigned men, and no ≥50% stenosis in 12.3% versus 4.5% ( P <0.001). In the conservative group, 4-year catheterization rates were 26.3% of women versus 25.6% of men ( P =0.72). Guideline-directed medical therapy use was lower among women with fewer risk factor goals attained. There were no sex differences in the primary outcome (adjusted hazard ratio [HR] for women versus men, 0.93 [95% CI, 0.77-1.13]; P =0.47) or the major secondary outcome of cardiovascular death/myocardial infarction (adjusted HR, 0.93 [95% CI, 0.76-1.14]; P =0.49), with no significant sex-by-treatment-group interactions., Conclusions: Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial., Registration: URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.

Background: Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation., Objectives: The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin., Methods: Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21., Results: Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low., Conclusions: Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis., Competing Interests: The ACTIV-4a platform was sponsored by the 10.13039/100000050National Heart, Lung, and Blood Institute, 10.13039/100000002National Institutes of Health, Bethesda and administered through OTA-20 to 011. The research was, in part, funded by the 10.13039/100000002National Institutes of Health (NIH) Agreement 1OT2HL156812 through the 10.13039/100000050National Heart, Lung, and Blood Institute (NHLBI) CONNECTS program. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH. The ATTACC platform was supported by grants from the 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100012357LifeArc, Thistledown Foundation, Peter Munk Cardiac Centre, 10.13039/100008794Research Manitoba, 10.13039/100009395CancerCare Manitoba Foundation, 10.13039/501100023238Victoria General Hospital Foundation, and the 10.13039/501100000226Ontario Ministry of Health. The REMAP-CAP platform was supported by the European Union—through FP7-HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re)emerging Epidemics (PREPARE) consortium (602525), and 10.13039/100010661Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium (101003589)—and by the Australian 10.13039/501100000925National Health and Medical Research Council (APP1101719), the 10.13039/501100001505Health Research Council of New Zealand (16/631), the 10.13039/501100000024Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant - 158584, and COVID-19 Rapid Research Operating Grant - 447335), the U.K. NIHR and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Learning While Doing Program, the Translational Breast Cancer Research Consortium, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Amgen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). Dr Godoy is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the 10.13039/501100000024Canadian Institutes of Health Research. Dr Neal has received grants from the 10.13039/100000002National Institutes of Health and 10.13039/100000005United States Department of Defense; has received research support from Haemonetics, Janssen and Instrumentation Laboratories; has received honoraria from Haemonetics, 10.13039/100005565Janssen, and 10.13039/501100014255CSL Behring; and serves on the Scientific Advisory Board of Haima Therapeutics. Dr Goligher has received personal fees and nonfinancial support from Getinge, nonfinancial support from Timpel, outside the submitted work. Dr Cushman has received personal fees from the 10.13039/100000002National Institutes of Health, during the conduct of the study. Dr Bradbury has received personal fees from BMS Pfizer; nonfinancial support from 10.13039/100002429Amgen; personal fees and nonfinancial support from Bayer; personal fees and nonfinancial support from 10.13039/100004336Novartis; personal fees from Janssen; personal fees from Portola; and personal fees from Ablynx, outside the submitted work. Dr Tritschler is a member of the Canadian Venous Thromboembolism Research Network (CanVECTOR); the network receives grant funding from the 10.13039/501100000024Canadian Institutes of Health Research (CDT-142654). Dr Kahn is supported by a Tier 1 10.13039/501100001804Canada Research Chair. Dr L. Berry has received grants from PREPARE Network, 10.13039/501100000780European Commission through University Antwerp, grants from OPTIMISE CAP. She reports Australia funding through Monash University; grants from REMAP-CAP; New Zealand funding through Medical Research Institute of New Zealand; grants from Global Coalition for Adaptive Research (GCAR); United States funding through grants from ATTACC; Canada funding through 10.13039/100009663University Health Network, grants from ACTIV-4; and reports IP funding, 10.13039/100007921University of Pittsburgh, during the conduct of the study. Dr Lorenzi has received grants from PREPARE in EU (University Antwerp), grants from OPTIMISE-CAP in Australia (Monash University), grants from REMAP-CAP in New Zealand (Medical Research Institute of New Zealand (MRINZ)), grants from REMAP-COVID in the US (GCAR), grants from ATTACC in Canada (10.13039/100009663University Health Network), grants from ACTIV-4 IP in the U.S. (10.13039/100007125University of Pittsburgh), during the conduct of the study. Dr Higgins has received grants from 10.13039/501100000925National Health and Medical Research Council, grants from 10.13039/501100016056Minderoo Foundation, during the conduct of the study. Dr Berger has received grants from 10.13039/100000002National Institutes of Health - 10.13039/100000050NHLBI, during the conduct of the study; personal fees from Astra Zeneca, personal fees from Janssen, personal fees from Amgen, outside the submitted work. Dr Gong has received grants from 10.13039/100000050NHLBI, during the conduct of the study. Dr Castellucci has received unrelated honoraria received from Bayer, BMS-Pfizer Alliance, The Academy, LEO Pharma, Sanofi, Servier, and Valeo; and holds a Heart and Stroke Foundation of Canada National New Investigator Award, and a Tier 2 research Chair in Thrombosis and Anticoagulation Safety from the University of Ottawa. Dr Le Gal holds a Heart and Stroke Foundation of Canada National Clinician-Scientist Award, and the Chair on Diagnosis of Venous Thromboembolism from the University of Ottawa. Dr Rosenson has a patent EFSID 40934007 pending. Dr Derde has received grants from EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, grants from H2020 RECOVER grant agreement No 101003589, during the conduct of the study; COVID-19 guideline committee SCCM/ESICM/ SSC, ESICM COVID-19 taskforce, Dutch intensivists (NVIC) taskforce infectious threats, outside the submitted work. Dr Kumar has received grants from Merck, outside the submitted work. Dr McVerry has received grants from 10.13039/100000002NIH - National Heart, Lung and Blood Institute, during the conduct of the study; grants from Bayer Pharmaceuticals, Inc, outside the submitted work. Dr Nicolau has received personal fees from AMGEN, grants from 10.13039/100004325AstraZeneca, grants and personal fees from Bayer, grants from 10.13039/501100022336Esperion, grants from CLS Behring, personal fees from Daiichi-Sankyo, grants from Dalcor, grants from Janssen, grants and personal fees from Novartis, grants from NovoNordisk, grants and personal fees from Sanofi, personal fees from Servier, grants from Vifor, outside the submitted work. Dr Huang has received grants from the 10.13039/100000002NIH, during the conduct of the study. Dr Reynolds has received grants from 10.13039/100000050National Heart, Lung and Blood Institute, during the conduct of the study; nonfinancial support from 10.13039/100011949Abbott Vascular, nonfinancial support from BioTelemetry Inc, nonfinancial support from 10.13039/100004340Siemens, outside the submitted work. Dr Carrier has received grants from 10.13039/100004319Pfizer, grants from 10.13039/501100000024Canadian Institutes of Health Research, grants from 10.13039/100002491BMS, during the conduct of the study; grants and personal fees from Leo Pharma, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Bayer, personal fees from Sanofi Aventis, personal fees from Pfizer, outside the submitted work. Dr S. Berry reports grants from PREPARE Network, grants from Optimise-CAP, grants from REMAP-CAP, grants from GCAR, grants from 10.13039/100009663University Health Network, grants from 10.13039/100007125University of Pittsburgh, during the conduct of the study. Dr Webb reports grants from 10.13039/501100000925National Health and Medical Research Council, grants from 10.13039/501100016056Minderoo Foundation, during the conduct of the study. Dr Turgeon reports grants from 10.13039/100022992Canadian Institutes of Health Research, during the conduct of the study. Dr McArthur has received grants from 10.13039/501100001505Health Research Council of New Zealand, during the conduct of the study. Dr Farkouh has received grants from 10.13039/100002429Amgen, grants from Novo Nordisk, grants from 10.13039/100004336Novartis, outside the submitted work. Dr Hochman is a principal investigator for the ISCHEMIA trial which, in addition to funding by 10.13039/100000002NIH, received support in the form of devices and medications 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 financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Zarychanski has received unrelated grant funding from the 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100009395CancerCare Manitoba Foundation, and 10.13039/100008794Research Manitoba and receives operating support as the Lyonel G. Israels Research Chair in Hematology at the 10.13039/100010318University of Manitoba. Dr Lawler has received unrelated consulting fees from Novartis, CorEvitas, and Brigham and Women’s Hospital, and unrelated royalties from McGraw-Hill Publishing; and is supported by a Heart and Stroke Foundation of Canada National New Investigator career award. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The 24-hour day consists of physical activity (PA), sedentary behavior, and sleep, and changing the time spent on one activity affects the others. Little is known about the impact of such changes on cardiovascular risk, particularly in Asian American immigrant (AAI) women, who not only have a higher cardiovascular risk but also place greater cultural value on family and domestic responsibilities compared to other racial/ethnic groups. The purpose of this study was to evaluate the effects of reallocating 30 minutes of each 24-hour activity component for another on BMI, waist circumference, and blood pressure in AAI women. Seventy-five AAI women completed 7 days of hip and wrist actigraphy monitoring and were included in the analysis (age = 61.5±8.0 years, BMI = 25.5±3.6 kg/m2, waist circumference = 85.9±10.2 cm). Sleep was identified from wrist actigraphy data, and moderate-to-vigorous PA (MVPA), light PA, and sedentary behavior identified from hip actigraphy data. On average, the women spent 0.5 hours in MVPA, 6.2 hours in light PA, 10 hours in sedentary activities, and 5.3 hours sleeping within a 24-hour day. According to the isotemporal substitution models, replacing 30 minutes of sedentary behavior with MVPA reduced BMI by 1.4 kg/m2 and waist circumference by 4.0 cm. Replacing that same sedentary time with sleep reduced BMI by 0.5 kg/m2 and waist circumference by 1.4 cm. Replacing 30 minutes of light PA with MVPA decreased BMI by 1.6 kg/m2 and waist circumference by 4.3 cm. Replacing 30 minutes of light PA with sleep also reduced BMI by 0.8 kg/m2 and waist circumference by 1.7 cm. However, none of the behavioral substitutions affected blood pressure. Considering AAI women's short sleep duration, replacing their sedentary time with sleep might be a feasible strategy to reduce their BMI and waist circumference., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Global longitudinal strain (GLS) is a sensitive marker for identifying subclinical myocardial dysfunction in obstructive coronary artery disease (CAD). Little is known about the relationship between GLS and ischemia in patients with myocardial ischemia and no obstructive CAD (INOCA)., Objectives: To investigate the relationship between resting GLS and ischemia on stress echocardiography (SE) in patients with INOCA., Methods: Left ventricular GLS was calculated offline on resting SE images at enrollment (n = 144) and 1-year follow-up (n = 120) in the CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial screen failures with no obstructive CAD on computed tomography [CT] angiography) study, which enrolled participants with moderate or severe ischemia by local SE interpretation (≥3 segments with new or worsening wall motion abnormality and no obstructive (<50% stenosis) on coronary computed tomography angiography., Results: Global longitudinal strain values were normal in 83.3% at enrollment and 94.2% at follow-up. Global longitudinal strain values were not associated with a positive SE at enrollment (GLS = -21.5% positive SE vs GLS = -19.9% negative SE, P = .443) or follow-up (GLS = -23.2% positive SE vs GLS = -23.1% negative SE, P = .859). Significant change in GLS was not associated with positive SE in follow-up (P = .401). Regional strain was not associated with colocalizing ischemia at enrollment or follow-up. Changes in GLS and number of ischemic segments from enrollment to follow-up showed a modest but not clinically meaningful correlation (β = 0.41; 95% CI, 0.16, 0.67; P = .002)., Conclusions: In this cohort of INOCA patients, resting GLS values were largely normal and did not associate with the presence, severity, or location of stress-induced ischemia. These findings may suggest the absence of subclinical myocardial dysfunction detectable by echocardiographic strain analysis at rest in INOCA., Competing Interests: Conflicts of Interest J.P. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. J.L.-S. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; grants from Bayer; grants and personal fees from Pfizer; personal fees from Menarini; grants and personal fees from Sanofi; grants from Merck; grants and personal fees from Boeringher Infleheim; and grants from Amgen outside the submitted work. R.S. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study; he also reports speaker fees from Lantheus Medical Imaging, Bracco, and Philips Healthcare. M.D.S. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. He also serves on the Scientific Advisory Board for Regeneron and Amgen. P.A.P. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. K.A. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. K.A.-N. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. R.A. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Y.X. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. D.M.K. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. J.A.S. reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; personal fees from Bayer, Novartis, AstraZeneca, Amgen, Janssen, and United Healthcare; and grants from the American College of Cardiology, outside the submitted work. In addition, he has a patent Copyright to Seattle Angina Questionnaire with royalties paid and is on the Board of Directors for Blue Cross Blue Shield of Kansas City and Equity in Health Outcomes Sciences. J.H. 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, Abbott Laboratories (formerly St. Jude Medical), Royal Philips NV (formerly Volcano Corporation), Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, Merck Sharp & Dohme, Omron Healthcare, Sunovion Pharmaceuticals, Espero BioPharma; financial donations were provided by Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. D.M. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. M.H.P. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. H.R.R. reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study, nonfinancial support from Abbott Vascular, Philips, SHL Telemedicine, and Siemens outside the submitted work. The remaining authors report no conflicts of interest., (Copyright © 2023 American Society of Echocardiography. All rights reserved.)

Importance: Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown., Objectives: To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia., Design and Setting: The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository., Main Outcome Measures: Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA)., Exposures: Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3)., Results: Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity., Conclusions and Relevance: Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Women with myocardial infarction (MI) are more likely to have elevated stress levels and depression than men with MI., Objectives: We investigated psychosocial factors in women with myocardial infarction with nonobstructive coronary arteries (MINOCA) and those with MI and obstructive coronary artery disease (CAD)., Methods: Women with MI enrolled in a multicenter study and completed measures of perceived stress (Perceived Stress Scale-4) and depressive symptoms (Patient Health Questionnaire-2) at the time of MI (baseline) and 2 months later. Stress, depression, and changes over time were compared between MI subtypes., Results: We included 172 MINOCA and 314 MI-CAD patients. Women with MINOCA were younger (age 59.4 years vs 64.2 years; P < 0.001) and more diverse than those with MI-CAD. Women with MINOCA were less likely to have high stress (Perceived Stress Scale-4 ≥6) at the time of MI (51.0% vs 63.0%; P = 0.021) and at 2 months post-MI (32.5% vs 46.3%; P = 0.019) than women with MI-CAD. There was no difference in elevated depressive symptoms (Patient Health Questionnaire-2 ≥2) at the time of MI (36% vs 43%; P = 0.229) or at 2 months post-MI (39% vs 40%; P = 0.999). No differences in the rate of 2-month decline in stress and depression scores were observed between groups., Conclusions: Stress and depression are common among women at the time of and 2 months after MI. MINOCA patients were less likely to report high stress compared with MI-CAD patients, but the frequency of elevated depressive symptoms did not differ between the 2 groups. Stress and depressive symptoms decreased in both MI-CAD and MINOCA patients over time., Competing Interests: Funding Support and Author Disclosures This study was funded by American Heart Association Go Red for Women Strategically Focused Research Network grant 16SFRN27810006. Dr. Hausvater is supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) (NIH T32HL098129). Dr Smilowitz is supported, in part, by the NIH/NHLBI under Award Number K23HL150315; and has served on an advisory board as a consultant to Abbott Vascular. Dr Shah receives grant funding from the NIH/NHLBI (1R01HL146206, 3R01HL146206-02S1) and VA Office of Research and Development (CSP 2002, I01CX002358); has served on the advisory boards for Philips Volcano and Horizons Therapeutics; has served as a consultant for Terumo medical; has served on the data safety monitoring board for Heartflow’s PRECISE trial (Cardiovascular Research Foundation) and Encompass ET02; and has served on the Clinical Events Committees for Abbott’s SPIRIT-48 and Concept Medical’s ABILITY-DM trials (Icahn School of Medicine at Mount Sinai). Dr Wei has served as a consultant for an Abbott advisory board on coronary microvascular dysfunction (paid to institution). Dr Har has served as a speaker for Abbott. Dr Hochman has served as Principal Investigator for the ISCHEMIA trial, for which, in addition to support by an NHLBI 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 and Dohme Corp, and Omron Healthcare, Inc, and financial donations were provided by Arbor Pharmaceuticals, LLC, and AstraZeneca Pharmaceuticals, LP; and has served as Principal Investigator for ISCHEMIA-EXTEND. Dr Reynolds has received grants from the NHLBI during the conduct of the study; and has received 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). 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.)

Centers specializing in coronary function testing are critical to ensure a systematic approach to the diagnosis and treatment of angina with nonobstructive coronary arteries (ANOCA). Management leveraging lifestyle, pharmacology, and device-based therapeutic options for ANOCA can improve angina burden and quality of life in affected patients. Multidisciplinary care teams that can tailor and titrate therapies based on individual patient needs are critical to the success of comprehensive programs. As coronary function testing for ANOCA is more widely adopted, collaborative research initiatives will be fundamental to improve ANOCA care. These efforts will require standardized symptom assessments and data collection, which will propel future large-scale clinical trials., Competing Interests: Funding Support and Author Disclosures Dr Smilowitz has served on an advisory board for Abbott Vascular and is supported, in part, by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL150315. Dr Prasad has served on an advisory board and/or as a consultant for Abbott Vascular, Boston Scientific, Cardinol, CONAVI, Chiesi, and Neovasc. Dr Widmer has served on advisory boards for Abbott Vascular, Philips, and Medtronic; and has received research support from Cardiol Therapeutics. Dr Quesada is supported, in part, by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL151867. Dr Sutton has received honoraria for speaking or consulting from Abbott, Philips, Zoll, and Shockwave. Dr Lerman has served on an advisory board for Philips/Volcano. Dr Reynolds has received research support from Abbott Vascular, Philips, and Siemens. Dr Kesarwani has a consulting agreement with Abbott Vascular. Dr Sweeny has received honoraria from Abbott Vascular. Dr Park has received honoraria from Abbott Vascular and CSI. Dr Blair has received research support from Abbott Vascular and Philips; and is on a Speakers Bureau for Abbott Vascular. Dr Jeremias has consulting agreements with Philips, Abbott Vascular, ACIST, Neovasc, and CathWorks. Dr Kearney has consulting agreements with Abbott Vascular, Abiomed, Boston Scientific, CSI, Medtronic, Teleflex, and Philips. Dr Kobayashi has a consulting agreement with Abbott Vascular. Dr Miner has received investigator-initiated research support from Abbott Vascular. Dr Samuels has served as a consultant and has served on a Speaker’s Bureau for Abbott Vascular and Philips. Dr Shah has received research support from Abbott Vascular and the FDA of the U.S. Department of Health and Human Services (HHS). Dr Wei has served on an advisory board for Abbott Vascular. Dr Fearon has received institutional research support from Abbott Vascular, Medtronic, and the NIH (5R33HL139929-05); has a consulting agreement with CathWorks and Siemens; and has stock options with HeartFlow. Dr Henry has received research support and honoraria from Neovasc. Dr Moses has served as a consultant for Covanos; and has equity in Orchestra BioMed and Covanos. Dr Tremmel has received honoraria from and served on advisory boards for Abbott Vascular; has received honoraria and research funding from Boston Scientific; and has received honoraria from Shockwave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

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.)

Angina with nonobstructive coronary arteries (ANOCA) is increasingly recognized and may affect nearly one-half of patients undergoing invasive coronary angiography for suspected ischemic heart disease. This working diagnosis encompasses coronary microvascular dysfunction, microvascular and epicardial spasm, myocardial bridging, and other occult coronary abnormalities. Patients with ANOCA often face a high burden of symptoms and may experience repeated presentations to multiple medical providers before receiving a diagnosis. Given the challenges of establishing a diagnosis, patients with ANOCA frequently experience invalidation and recidivism, possibly leading to anxiety and depression. Advances in scientific knowledge and diagnostic testing now allow for routine evaluation of ANOCA noninvasively and in the cardiac catheterization laboratory with coronary function testing (CFT). CFT includes diagnostic coronary angiography, assessment of coronary flow reserve and microcirculatory resistance, provocative testing for endothelial dysfunction and coronary vasospasm, and intravascular imaging for identification of myocardial bridging, with hemodynamic assessment as needed., Competing Interests: Funding Support and Author Disclosures Dr Samuels has served as a consultant and on a Speakers Bureau for Abbott Vascular and Philips. Dr Shah has received research support from Abbott Vascular and the Food and Drug Administration of the U.S. Department of Health and Human Services. Dr Widmer has served on advisory boards for Abbott Vascular, Philips, and Medtronic; and has received research support from Cardiol Therapeutics. Dr Kobayashi has served as a consultant for Abbott Vascular. Dr Miner has received investigator-initiated research support from Abbott Vascular. Dr Jeremias has served as a consultant for Philips, Abbott Vascular, ACIST, Neovasc, and CathWorks. Dr Blair has received research support from Abbott Vascular and Philips; and is on a Speakers Bureau for Abbott Vascular. Dr Kearney has served as a consultant for Abbott Vascular, Abiomed, Boston Scientific, CSI, Medtronic, Teleflex, and Philips. Dr Wei has served on an advisory board for Abbott Vascular. Dr Park has received honoraria from Abbott Vascular and CSI. Dr Kesarwani has served as a consultant for Abbott Vascular. Dr Lerman has served on an advisory board for Philips/Volcano. Dr Prasad has served on an advisory board and/or as a consultant for Abbott Vascular, Boston Scientific, Cardiol Therapeutics, Conavi, Chiesi, and Neovasc. Dr Quesada has received partial support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) (award K23HL151867). Dr Reynolds has received research support from Abbott Vascular, Philips, and Siemens. Dr Smilowitz has served on an advisory board for Abbott Vascular; and has received partial support from the National Heart, Lung, and Blood Institute of the NIH (award K23HL150315). Dr Sutton has received honoraria for speaking or consulting from Abbott, Philips, Zoll, and Shockwave. Dr Sweeny has received honoraria from Abbott Vascular. Dr Henry has received research support and honoraria from Neovasc. Dr Moses has served as a consultant for Covanos; and has held equity in Orchestra BioMed and Covanos. Dr Fearon has received institutional research support from Abbott Vascular, Medtronic, and the NIH (5R33HL139929-05); has served as a consultant for CathWorks and Siemens; and has held stock options with HeartFlow. Dr Tremmel has received honoraria from and served on advisory boards for Abbott Vascular; has received honoraria and research funding from Boston Scientific; and has received honoraria from Shockwave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: Disclosures Dr Reynolds received National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) research grant support for ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and ISCHEMIA EXTEND (ISCHEMIA EXTEND [Extended Follow-up]) clinical trials; in-kind research support from Abbott Vascular. Dr Hochman received NIH/NHLBI research grant support for ISCHEMIA and ISCHEMIA EXTEND clinical trials. Dr Rao reports no conflict.

Background: Acute kidney injury (AKI) in patients with COVID-19 is partly mediated by thromboinflammation. In noncritically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support., Objectives: We investigated whether therapeutic-dose heparin reduces the incidence of AKI or death in noncritically ill patients hospitalized for COVID-19., Methods: We report a prespecified secondary analysis of the ACTIV4a and ATTACC open-label, multiplatform randomized trial of therapeutic-dose heparin vs usual-care pharmacologic thromboprophylaxis on the incidence of severe AKI (≥2-fold increase in serum creatinine or initiation of kidney replacement therapy (KDIGO stage 2 or 3) or all-cause mortality in noncritically ill patients hospitalized for COVID-19. Bayesian statistical models were adjusted for age, sex, D-dimer, enrollment period, country, site, and platform., Results: Among 1922 enrolled, 23 were excluded due to pre-existing end stage kidney disease and 205 were missing baseline or follow-up creatinine measurements. Severe AKI or death occurred in 4.4% participants assigned to therapeutic-dose heparin and 5.5% assigned to thromboprophylaxis (adjusted relative risk [aRR]: 0.72; 95% credible interval (CrI): 0.47, 1.10); the posterior probability of superiority for therapeutic-dose heparin (relative risk < 1.0) was 93.6%. Therapeutic-dose heparin was associated with a 97.7% probability of superiority to reduce the composite of stage 3 AKI or death (3.1% vs 4.6%; aRR: 0.64; 95% CrI: 0.40, 0.99) compared to thromboprophylaxis., Conclusion: Therapeutic-dose heparin was associated with a high probability of superiority to reduce the incidence of in-hospital severe AKI or death in patients hospitalized for COVID-19., (© 2023 Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19., Methods: An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry., Results: The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio <1.2) of 98% and a posterior probability of inferiority (odds ratio <1.0) of 91%. Overall, there were 37 deaths (17.5%) in the crizanlizumab arm and 27 deaths (12.8%) in the standard-of-care arm (hazard ratio, 1.33 [95% CrI, 0.85-2.21]; [probability of hazard ratio>1] = 0.879)., Conclusions: Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04505774., Competing Interests: Disclosures Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Dr Solomon has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Akros. Dr Lowenstein has received research grants from Novartis and NIH/National Heart, Lung, and Blood Institute (R01 HL134894, R33 HL14179, 1OT2HL156812, and R01 HL139553). Dr Peikert reports a research grant from the German Research Foundation. Dr Vardeny has received institutional research support from AstraZeneca, Bayer, and Cardurion and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi-Pasteur. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He holds stock options from Artera Health and Saghmos Therapeutics. Dr Berger reports research grants from NIH and American Heart Association and has consulted for Janssen, Amgen, and Amarin. Dr Reynolds reports receiving grants from the National Heart, Lung and Blood Institute during the conduct of the study, as well as nonfinancial support from Abbott Vascular, Siemens, and Royal Phillips outside the submitted work. Dr Althouse is an employee of Medtronic. Dr Gong reports receiving grants from NIH, Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention and receiving personal fees from Regeneron for serving on the data safety monitoring board for monoclonal antibody trials in COVID-19. Dr Kornblith reports receiving personal fees from Cerus Corp, University of Maryland, Coagulant Therapeutics, and Gamma Diagnostics. Dr Khatri receives grant funding as a principal investigator from NIH and Cerenovus; consulting fees as a scientific advisor to Basking Biosciences, Bayer, Diamedica, Lumosa, and Shionogi; and royalties for online publication from UpToDate. Dr Kim reports grants from NIH during the conduct of the study, funding from Eisai outside the submitted work, and personal fees from NIH for committee service indirectly related to the research. Dr Baumann Kreuziger reports that her institution received funding from NIH to perform the study. Dr Kirwan (through SOCAR Research) received grants from NIH. Dr Neal serves as chief medical officer for Haima Therapeutics and has received grants from the National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences , Department of Defense, Haemonetics, and Instrumentation Laboratories. He has received personal fees from Haemonetics, Takeda, CSL Behring, and Janssen Pharmaceuticals. Dr Hochman reports receiving research support for the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) from Merck Sharp & Dohme, Omron Healthcare Inc, Amgen, Espero BioPharma, Sunovion Pharmaceuticals, AstraZeneca Pharmaceuticals, LP, Arbor Pharmaceuticals, NIH, Medtronic, Royal Philips NV (formerly Volcano Corp), and Abbott Vascular Inc (formerly St. Jude Medical Inc) and receiving financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals, LP. She is study chair for ACTIV-4a under a National Heart, Lung, and Blood Institute–University of Pittsburgh grant subaward. The other authors report no conflicts.

Background: The impact of complete revascularization (CR) on angina-related health status (symptoms, function, quality of life) in chronic coronary disease (CCD) has not been well studied., Objectives: Among patients with CCD randomized to invasive (INV) vs conservative (CON) management in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), we compared the following: 1) the impact of anatomic and functional CR on health status compared with incomplete revascularization (ICR); and 2) the predicted impact of achieving CR in all INV patients compared with CON., Methods: Multivariable regression adjusting for patient characteristics was used to compare 12-month health status after independent core laboratory-defined CR vs ICR in INV patients who underwent revascularization. Propensity-weighted modeling was then performed to estimate the treatment effect had CR or ICR been achieved in all INV patients, compared with CON., Results: Anatomic and functional CR were achieved in 43.3% and 57.8% of 1,641 INV patients, respectively. Among revascularized patients, CR was associated with improved Seattle Angina Questionnaire Angina Frequency compared with ICR after adjustment for baseline differences. After modeling CR and ICR in all INV patients, patients with CR and ICR each had greater improvements in health status than CON, with better health status with CR than ICR. The projected benefits of CR were most pronounced in patients with baseline daily/weekly angina and not seen in those with no angina., Conclusions: Among patients with CCD in ISCHEMIA, health status improved more with CR compared with ICR or CON, particularly in those with frequent angina. Anatomic and functional CR provided comparable improvements in quality of life. (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, and T32 HL079896. This project was supported in part by Clinical Translational Science Award Nos. 11UL1 TR001445 and UL1 TR002243 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 and Dohme Corp, and Sunovion Pharmaceuticals. Dr Mavromatis has received grants from the 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 Ali has received institutional grant support from Abbott, Abiomed, Acist Medical, Boston Scientific, Cardiovascular Systems Inc, Medtronic Inc, National Institutes 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 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 Bangalore has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; has received grants and personal fees from Abbott Vascular; and has received personal fees from Biotronik, Pfizer, Amgen, and Reata outside of the submitted work. Dr Genereux has served as a consultant for, advisor for, and received speaker fees from Abbott Vascular, Abiomed, BioTrace Medical, and Medtronic; has served as a consultant for Boston Scientific, CARANX Medical, Cardiovascular System Inc (PI Eclipse Trial), GE Healthcare, iRhythm Technologies, Opsens, Siemens Teleflex, and 4C Medical (PI Feasibility study); has served as a consultant for, advisor for, proctor for, and received speaker fees and institutional research grant from Edwards Lifesciences (PI EARLY-TAVR trial, PI PROGRESS trial); has equity in and is a consultant for Pi-Cardia, Puzzle Medical, Saranas, and Soundbite Medical Inc; and has served as a consultant for and received speaker fees from Shockwave. Dr Goodman has received grants and personal fees from the National Heart, Lung, and Blood Institute, during the conduct of the study, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, CSL Behring/PERFUSE, Daiichi-Sankyo/American Regent/DCRI, Ferring, Novartis, and Regeneron/Sanofi; and has received personal fees from Esperion/C5, Boehringer Ingelheim/Eli Lilly, GlaxoSmithKline, HLS Therapeutics, Merck, Novo Nordisk, and Servier, outside of the submitted work. Drs Alexander and Chen have received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. 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 outside of the submitted work. Dr Reynolds has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and has received 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 Maron has received grants from the the National Heart, Lung, and Blood Institute during the conduct of the study. 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 and Dohme Corp, Omron Healthcare, Inc, Sunovion Pharmaceuticals, Inc, Espero BioPharma, and Amgen Inc; and financial donations were provided by Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr Spertus has provided consultative services on patient-reported outcomes and evidence valuation to Alnylam, AstraZeneca, Bayer, Merck, Janssen, Bristol Myers Squibb, Edwards, Kineksia, 4DT Medical, Terumo, Imbria, and United Healthcare; holds research grants from Bristol Myers Squibb, Abbott Vascular, and Janssen; owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire; and serves on the Board of Directors for Blue Cross Blue Shield of Kansas City. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The contents of this paper 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., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Adverse pregnancy outcomes (APOs), hypertensive disorders of pregnancy, gestational diabetes mellitus, and preterm birth are associated with ischemic heart disease in later life., Objectives: The authors aimed to study the features of premature myocardial infarction (MI) among women with and without prior APOs., Methods: We performed a retrospective analysis of women with premature MI (<65 years of age) referred for left heart catheterization matched with a database of abstracted pregnancy data. We compared MI characteristics and epicardial coronary anatomy between women with and without APOs during their index pregnancy and evaluated time from delivery to MI., Results: Of 391 women with premature MI and associated coronary angiography (age: 49 ± 8 years), 154 (39%) had a prior APO (hypertensive disorders of pregnancy n = 78, preeclampsia n = 35, gestational diabetes mellitus n = 28, and preterm birth n = 48). Women with APO history had a higher prevalence of diabetes (33% vs 16% without APO; P = 0.001) and presented earlier with MI following delivery (19.6 [IQR: 14.3-23.5] years vs those without APO 21.5 [IQR: 17.0-25.4] years; P = 0.012), driven by preeclampsia (17.1 [IQR: 12.7-22.4] years, P = 0.010). Women with and without APOs had similar MI features including rates of ST-segment elevation MI, obstructive and multi-vessel coronary artery disease, percutaneous coronary intervention, and shock., Conclusions: Among women with premature MIs, 39% had a history of an APO. Women with APO history presented sooner after pregnancy but had similar MI characteristics vs those without APOs. Pregnancy history may identify women who warrant early, aggressive cardiovascular disease prevention.

Background: Psoriasis is an inflammatory skin disease associated with increased cardiovascular (CV) risk, whose pathogenesis is not fully known., Objective: We identified a transcriptomic signature in psoriasis and investigated its association with prevalent and future risk of a CV event to understand the connection between psoriasis and CV disease (CVD)., Methods: Psoriasis patients (n = 37) with a history of moderate-severe skin disease without CVD and 11 matched controls underwent whole blood RNA sequencing. This transcriptomic signature in psoriasis versus controls was evaluated in two CVD cohorts: Women referred for cardiac catheterization with (n = 76) versus without (n = 97) myocardial infarction (MI), and patients with peripheral artery disease (n = 106) followed over 2.5 years for major adverse CV or limb events (MACLE). The association between genes differentially expressed in psoriasis and prevalent and incident CV events was assed., Results: In psoriasis, median age was 44 (IQR; 34-51) years, 49% male and ACC/AHA ASCVD Risk Score of 1.0% (0.6-3.4) with no significant difference versus controls. The median psoriasis area and severity index score (PASI) was 4.0 (IQR 2.9-8.2) with 36% on biologic therapy. Overall, 247 whole blood genes were upregulated and 228 downregulated in psoriasis versus controls (p < 0.05), and 1302 genes positively and 1244 genes negatively correlated with PASI (p < 0.05). Seventy-three genes overlapped between psoriasis prevalence and PASI with key regulators identified as IL-6, IL-1β and interferon gamma. In the CVD cohorts, 50 of 73 genes (68%) identified in psoriasis associated with prevalent MI, and 29 (40%) with incident MACLE. Key regulator transcripts identified in psoriasis and CVD cohorts included SOCS3, BCL3, OSM, PIM2, PIM3 and STAT5A., Conclusions: A whole blood transcriptomic signature of psoriasis diagnosis and severity associated with prevalent MI and incident MACLE. These data have implications for better understanding the link between psoriasis, systemic inflammation and CVD., (© 2023 European Academy of Dermatology and Venereology.)

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.)

Women who present with myocardial infarction (MI) are more likely to be diagnosed with nonobstructive coronary arteries (MINOCAs), spontaneous coronary artery dissection (SCAD), and takotsubo syndrome (TS) than men. Malignancy may predispose to MI and TS through shared risk factors and inflammatory mediators. This study aimed to determine the prevalence of cancer in women presenting with clinical syndrome of MI and the association between cancer and mechanism of MI presentation. Among 520 women with MI who underwent coronary angiography at NYU Langone Health from March 2016 to March 2020 or September 2020 to September 2021, 122 (23%) had a previous diagnosis of cancer. Patients with cancer were older at MI presentation but had similar co-morbidity to those without a cancer history. The most common cancers were breast (39%), gynecologic (15%), and gastrointestinal (13%). Women with cancer history were more likely to have TS (17% vs 11% without cancer history p = 0.049). Among women with a final diagnosis of MI, the type of MI (MINOCA, MI-coronary artery disease, or SCAD) was not significantly different between groups (p = 0.374). History of cancer was present in nearly a quarter of women presenting with MI and was associated with a greater likelihood of TS than MI. MINOCA and SCAD were not more common among women with a cancer history., Competing Interests: Disclosures Dr. Reynolds reports in-kind donations from Abbott Vascular, Siemens, and Philips for related research. Dr. Smilowitz reports advisory board membership for Medyria. Dr. Hausvater is supported by National Institutes of Health T32HL098129. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19., Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19., Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients., Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor., Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis., Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77)., Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.