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AbstractIn response to the Covid-19 pandemic, the National Heart, Lung, and Blood Institute launched five multisite clinical trials testing candidate host tissue-directed medical interventions to hasten recovery, improve function, and reduce morbidity and mortality. Speed, flexibility, and collaboration were essential. This article from the Steering and Executive committees describes the Collaborating Network of Networks for Evaluating Covid-19 and Therapeutic Strategies (CONNECTS) research program that enrolled 6690 participants and evaluated 18 intervention strategies using 10 molecular agents across the care continuum (outpatient, inpatient, and post discharge), and reports lessons learned from this initiative. Successes include rapid trial execution through collaboration and adaptive platform designs. Challenges that impeded efficiency included time required to execute subcontracts, constraints on clinical research workforce, and limited research infrastructure in nonacademic settings.

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).

Background: Pursuing initial invasive or conservative management of chronic coronary disease (CCD) is a preference-sensitive decision that should include shared decision-making. Communicating the benefits of either approach is challenging, as individual patients rarely achieve the population-averaged outcomes reported in clinical trials. Our objective was to develop a patient decision aid (PDA) with patient-specific estimates of outcomes for initial invasive versus conservative management of CCD, based on the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches)., Methods: This was a multiphase mixed-methods study using focus groups of outpatients with CCD, caregivers, clinicians, and researchers. Focus groups were held in Kansas City, MO and New York City, NY between September 2021 and June 2022. Patients with CCD were included if they had a positive stress test within 1 year. Phase 1 focused on patient priorities for outcomes to guide treatment decisions. Phase 2 involved PDA development and refinement. Phase 3 involved further refinement and member checking. Key themes involving shared decision-making and treatment preferences were elicited from focus groups using a deductive approach to develop a PDA representing the outcomes most important to patients., Results: Of 46 patient and caregiver participants, the mean age was 63.5 years, 53% were female, 61% were White, 24% were Black, and 9% were Hispanic. When deciding between treatments, participants valued shared decision-making but generally deferred decisions to clinicians. The outcomes most important to participants were survival and quality of life, followed by physical functioning and symptoms. To represent these outcomes, participants favored simple visualizations, such as a speedometer or health meter. When deciding between treatment options, participants preferred to use the PDA collaboratively with a clinician instead of as a stand-alone tool., Conclusions: Our novel, patient-centered approach to developing a PDA for CCD with patient-specific outcomes has the potential to rapidly translate clinical trial results to individual patients and support shared decision-making., Competing Interests: Dr Spertus 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, Dr Spertus has a patent copyright to SAQ (Seattle Angina Questionnaire) with royalties paid, and is on the Board of Directors for Blue Cross Blue Shield of Kansas City, and reports equity in Health Outcomes Sciences. Mr. Jones reports employment by the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Maron reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Hochman is the principal investigator 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, Sunovion Pharmaceuticals, Inc, Espero BioPharma, and Amgen, Inc, and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The other authors report no conflicts.

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.)

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction., (© 2024. The Author(s).)

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.

Background: Cardiogenic shock is a morbid complication of heart disease that claims the lives of more than 1 in 3 patients presenting with this syndrome. Supporting a unique collaboration across clinical specialties, federal regulators, payors, and industry, the American Heart Association volunteers and staff have launched a quality improvement registry to better understand the clinical manifestations of shock phenotypes, and to benchmark the management patterns, and outcomes of patients presenting with cardiogenic shock to hospitals across the United States., Methods: Participating hospitals will enroll consecutive hospitalized patients with cardiogenic shock, regardless of etiology or severity. Data are collected through individual reviews of medical records of sequential adult patients with cardiogenic shock. The electronic case record form was collaboratively designed with a core minimum data structure and aligned with Shock Academic Research Consortium definitions. This registry will allow participating health systems to evaluate patient-level data including diagnostic approaches, therapeutics, use of advanced monitoring and circulatory support, processes of care, complications, and in-hospital survival. Participating sites can leverage these data for onsite monitoring of outcomes and benchmarking versus other institutions. The registry was concomitantly designed to provide a high-quality longitudinal research infrastructure for pragmatic randomized trials as well as translational, clinical, and implementation research. An aggregate deidentified data set will be made available to the research community on the American Heart Association's Precision Medicine Platform. On March 31, 2022, the American Heart Association Cardiogenic Shock Registry received its first clinical records. At the time of this submission, 100 centers are participating., Conclusions: The American Heart Association Cardiogenic Shock Registry will serve as a resource using consistent data structure and definitions for the medical and research community to accelerate scientific advancement through shared learning and research resulting in improved quality of care and outcomes of shock patients., Competing Interests: Dr Jessup, S. Costello, Jennifer Hall, M. Isler, C. Rutan are employees of the American Heart Association. A. Aringo is a recent employee of the American Heart Association. David Morrow is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals Inc., Roche, Siemens Healthcare Diagnostics Inc., Softcell Medical Limited, The Medicines Company, Zora Biosciences; as well he has received consulting fees from Abbott, ARCA Biopharma, InCarda, Inflammatix, Merck, Novartis, and Roche Diagnostics. Dr Drakos serves as a consultant for Abbott Laboratories and is receiving research support from Novartis, National Heart Lung and Blood Institute, AHA, US Department of Veterans Affairs Merit and the Nora Eccles Treadwell Foundation. Dr Kilic serves as a speaker/consultant for Abiomed, Abbott, Livanova, and 3ive. Dr Kormos is an employee of Abbott Laboratories. Dr Lindenfeld is receiving research support from AstraZeneca and Volumetrix and consulting fees from Abbott, Alleviant,AstraZeneca, Axon, Boston Scientific, CVRx, Merck, Medtronic, Whiteswell, Vascular Dynamics, VWave. Dr Lombardi is an employee of Getinge.

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: 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.

Objective: This study aimed to assess whether an obesity paradox (lower event rates with higher body mass index [BMI]) exists in participants with advanced chronic kidney disease (CKD) and chronic coronary disease in the International Study of Comparative Health Effectiveness of Medical and Invasive Approaches (ISCHEMIA)-CKD, and whether BMI modified the effect of initial treatment strategy., Methods: Baseline BMI was analyzed as both a continuous and categorical variable (< 25, ≥ 25 to < 30, ≥ 30 kg/m 2 ). Associations between BMI and the primary outcome of all-cause death or myocardial infarction (D/MI), and all-cause death, cardiovascular death, and MI individually were estimated. Associations with health status were also evaluated using the Seattle Angina Questionnaire-7, the Rose Dyspnea Scale, and the EuroQol-5D Visual Analog Scale., Results: Body mass index ≥ 30 kg/m 2 vs < 25 kg/m 2 demonstrated increased risk for MI (hazard ratio [HR] [95% confidence interval] = 1.81 [1.12-2.92]) and for D/MI (HR 1.45 [1.06-1.96]) with a HR for MI of 1.22 (1.05-1.40) per 5 kg/m 2 increase in BMI in unadjusted analysis. In multivariate analyses, a BMI ≥ 30 kg/m 2 was marginally associated with D/MI (HR 1.43 [1.00-2.04]) and greater dyspnea throughout follow-up (P < .05 at all time points). Heterogeneity of treatment effect between baseline BMI was not evident for any outcome., Conclusions: In the ISCHEMIA-CKD trial, an obesity paradox was not detected. Higher BMI was associated with worse dyspnea, and a trend toward increased D/MI and MI risk. Larger studies to validate these findings are warranted., (Published by Elsevier Inc.)

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.)