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Context: Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events.Objective: To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events.Design and Setting: A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia.Patients: A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction.Interventions: Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission.Main Outcome Measures: Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization.Results: A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001).Conclusion: For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the efficacy and safety of ranolazine in a larger and more diverse group of patients with angina than previously studied.Background: Ranolazine is an antianginal shown to reduce angina and improve exercise performance in selected patients with early-positive exercise testing and those with frequent angina.Methods: We investigated the antianginal effects of ranolazine in the subgroup of patients with prior chronic angina (n = 3,565, 54%) enrolled in the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 36 trial of patients with acute coronary syndrome. Follow-up was a median of 350 days.Results: Patients with prior angina received evidence-based therapy (95% aspirin, 78% statins, 89% beta-blockers, average 2.9 antianginal agents). The primary end point (cardiovascular death, myocardial infarction, recurrent ischemia) was less frequent with ranolazine (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.75 to 0.97; p = 0.017), due entirely to a significant reduction in recurrent ischemia (HR: 0.78; 95% CI: 0.67 to 0.91; p = 0.002). Ranolazine also reduced worsening angina (HR: 0.77; 95% CI: 0.59 to 1.00; p = 0.048) and intensification of antianginal therapy (HR: 0.77; 95% CI: 0.64 to 0.92, p = 0.005). Exercise duration at 8 months was greater with ranolazine (514 s vs. 482 s, p = 0.002). Cardiovascular death or myocardial infarction did not differ between treatment groups (HR: 0.97; 95% CI: 0.80 to 1.16; p = 0.71). Symptomatic documented arrhythmias (2.9% vs. 2.9%, p = 0.92) and total mortality (6.2% vs. 6.4%, p = 0.96) were similar with ranolazine or placebo.Conclusions: In this largest study of ranolazine in patients with established coronary artery disease, ranolazine was effective in reducing angina with favorable safety in a substantially broader group of patients with angina than previously studied. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788). [ABSTRACT FROM AUTHOR]

Background: In patients with stable coronary artery disease, it remains unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events.Methods: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6).Results: There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P=0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P=0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P=0.33).Conclusions: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is associated with higher risk of myocardial infarction and anemia. Among patients with anemia and CKD who experience myocardial infarction, it remains uncertain if a liberal red blood cell transfusion threshold strategy (hemoglobin cutoff [Hgb] < 10 g/dL) is superior to a restrictive transfusion threshold (Hgb 7-8 g/dL) strategy., Methods: Among the 3,504 patients enrolled in the Myocardial Ischemia and Transfusion (MINT) trial with non-missing creatinine, we compared baseline characteristics and 30-day and 6-month outcomes of patients without CKD (N = 1279), CKD with eGFR 30-60 mL/min/1.73 m2 (N = 999), CKD with eGFR < 30 mL/min/1.73 m2 (N = 802), and CKD requiring dialysis (N = 415) by assigned transfusion strategy., Results: No statistically significant interactions were observed between CKD stage and assigned transfusion strategy. Among non-dialysis dependent patients with an eGFR < 30 mL/min/1.73 m2, a restrictive transfusion strategy was associated with a higher risk of 30-day death or recurrent myocardial infarction (risk difference [RD], 5.8%, 95% CI 0.4% to 11.2%) compared to a liberal transfusion strategy. Among patients with an eGFR 30-60 mL/min/1.73 m2, a restrictive strategy was associated with a similar risk of 30-day death or recurrent myocardial infarction (RD, 3.7%, 95% CI -0.9% to 8.2%) compared to a liberal transfusion strategy. Among patients with CKD requiring dialysis, a restrictive strategy was also associated with a similar risk of 30-day death or recurrent myocardial infarction (RD, -2.6%, 95% CI -10.0% to 4.8%) compared to a liberal transfusion strategy., Conclusions: In patients with CKD included in this MINT subgroup analysis, a liberal transfusion strategy was not worse than a restrictive transfusion strategy and was associated with less harm in subgroups not receiving dialysis., (Copyright © 2025 by the American Society of Nephrology.)

Background: The MINT trial (Myocardial Ischemia and Transfusion) raised concern for harm from a restrictive versus liberal transfusion strategy in patients with acute myocardial infarction (MI) and anemia. Type 1 and type 2 MI are distinct pathophysiologic entities that may respond differently to blood transfusion. This analysis sought to determine whether the effects of transfusion varied among patients with a type 1 or a type 2 MI and anemia. The authors hypothesized that the liberal transfusion strategy would be of greater benefit in type 2 than in type 1 MI., Methods: The authors compared rates of death or MI at 30 days in patients with type 1 (n=1460) and type 2 (n=1955) MI and anemia who were randomly allocated to a restrictive (threshold, 7-8 g/dL) or a liberal (threshold, 10 g/dL) transfusion strategy., Results: The primary outcome of death or MI was observed in 16% of type 1 MI and 15.4% of type 2 MI patients. The rate of death or MI was higher in patients with type 1 MI randomized to a restrictive (18.2%) versus liberal (13.8%) transfusion strategy (relative risk [RR], 1.32 [95% CI, 1.04-1.67]) with no difference observed between the restrictive (15.8%) and liberal (15.1%) transfusion strategies in patients with type 2 MI (RR, 1.05 [95% CI, 0.85-1.29]). The test for a differential effect of transfusion strategy by MI type was not statistically significant ( P interaction = 0.16)., Conclusions: The concern for harm with a restrictive transfusion strategy in patients with acute MI and anemia raised in the MINT primary outcome manuscript may be more apparent in patients with type 1 than type 2 MI., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02981407., Competing Interests: Dr DeFilippis reports research grants from Ionis Pharmaceutical; and consulting for Velkor, Inc and Novo Nordisk. Dr Abbott reports consulting for Abbott, Medtronic, Penumbra. Research Boston Scientific, Recor, Med Alliance, Shockwave, and Microport. Dr White reports grant support paid to the institution for: ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; from Sanofi and Regeneron Pharmaceuticals); STRENGTH trial (Long-Term Outcomes Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia; Omthera Pharmaceuticals); HEART-FID Study (Ferric Carboxymaltose in Heart Failure With Iron Deficiency; American Regent); Dal GenE study (Study Effect of Dalcetrapib Versus Placebo on CV Risk in a Genetically Defined Population With a Recent ACS; DalCor Pharma UK Inc); AEGIS II study (CSL Behring); Clear Outcomes Study (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen; Esperion Therapeutics); SOLIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) and SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) studies (Sanofi Aventis Australia Pty Ltd); Librexia AF (A Study of Milvexian Versus Apixaban in Participants With Atrial Fibrillation) and ACS (A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome) studies (Janssen); and ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and MINT ([Myocardial Ischemia and Transfusion] National Institutes of Health); and personal fees as a steering committee member from DalCor Pharma UK, CSL Behring, Sanofi Australia Pty Ltd, Janssen, and Esperion Therapeutics; as well as membership on advisory boards for CSL Behring and Genentech. Dr Lopes reports grant support or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Alexander reports grant support (to Duke University) from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, United States Food and Drug Administration, Humacyte, and National Institutes of Health; and advisory board or consulting payments from AbbVie, Artivion/CryoLife, AtriCure, Bayer, Bristol-Myers Squibb, Eli Lilly, Ferring, GlaxoSmithKline, Janssen, Novostia, Pfizer, Portola, Theravance, and Veralox. Drs Carson and Hébert report participation on the data safety monitoring board for Cerus. Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) and/or 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, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and salary support/honoraria from the Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, and Thrombolysis in Myocardial Infarction Study Group (Brigham Health). The other authors report no conflicts.

Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography., Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test. Among those with preserved renal function who underwent coronary computed tomography angiography, we examined relationships between ischemia and CAD by coronary computed tomography angiography, overall, and by stress test modality, regardless of subsequent randomization. Core laboratories categorized ischemia as severe, moderate, mild, or none, while the extent and severity of anatomic CAD were categorized based on the modified Duke prognostic index., Results: Among 3601 participants with interpretable stress tests and coronary computed tomography angiography, ischemia severity was weakly associated with CAD extent/severity (r=0.27), with modest variability in strength of association by modality: nuclear (n=1532; r=0.40), echocardiography (n=827; r=0.15), cardiac magnetic resonance imaging (n=108; r=0.31), and exercise tolerance test (n=1134; r=0.18). The extent of infarction on nuclear imaging and echocardiography was weakly associated with CAD extent/severity., Conclusions: Overall, ischemia severity on stress testing showed weak to moderate associations with the anatomic extent of CAD in this cohort with moderate or severe ischemia on local interpretation and controlled symptoms., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522., Competing Interests: Dr Reynolds reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study, and consulting fees from HeartFlow; 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 Berman receives software royalties from Cedars-Sinai Medical Center, outside the submitted work. Dr Chaitman reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and personal fees from Merck, Novo Nordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor, outside the submitted work. Dr Kwong reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. 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 Arineta, outside the submitted work. Dr Leipsic is a consultant and has stock options in HeartFlow and Circle CVI and received research grant from GE Healthcare, outside the submitted work. Dr Mancini reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants and personal fees from Amgen, grants and personal fees from Sanofi, Boehringer Ingelheim, AstraZeneca, Bayer, Janssen, Novo Nordisk, and HLS Therapeutics; and grants from Novartis, outside the submitted work. Dr Budoff reports grant support from General Electric, outside the submitted work. Dr Hague 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. Dr Bhargava reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Dr Celutkiene reported personal fees from Boehringer Ingelheim, AstraZeneca, Bayer, and Novartis. Dr Bainey received unrestricted research grant support from the Heart and Stroke Foundation of Canada, AstraZeneca, and Bayer; speaker honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Boehringer Ingelheim-Eli Lilly Alliance; consultancy and advisory board memberships in AstraZeneca, Abbott Vascular, Bayer, Bristol-Myers Squibb-Pfizer Alliance, and Boehringer Ingelheim-Eli Lilly Alliance; and proctorship honoraria from Abbott Vascular. Dr Doerr reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Ong reports speaker honoraria from Abbott Medical, Phillips, Bayer Healthcare, Pfizer, and Medtronic and research funding from the Berthold Leibinger Foundation, Ditzingen, Germany. Dr Steg reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study and research grants from Amarin, Bayer, Sanofi, and Servier; he serves as a member of the Steering Committee, Clinical Events Committee, or Data and Safety Monitoring Board for clinical trials conducted in Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Myokardia, Novartis, Pfizer, Sanofi, and Servier; consulting or speaker’s fees from Amgen, Novo Nordisk, and Regeneron. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; receives research support from TD Bank, CV Diagnostix and AusculSciences, and Siemens Healthineers; and has equity interest in General Electric. Dr Phillips has served as a consultant for Novo Nordisk. Dr Mark reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study, and grants from HeartFlow and Merck, outside the submitted work. 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; 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 Seattle Angina Questionnaire with royalties paid and Equity in Health Outcomes Sciences. Dr O’Brien reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Boden reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; grants from Abbvie, Amarin, and Amgen; and personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen, 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 Stone reports grants and personal fees from the National Heart, Lung, and Blood Institute during the conduct of the study; speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; is 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; and equity/options in Ancora, Cagent, Applied Therapeutics, Biostar Family of Funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Institutional disclosures: Dr Stone’s employer, Mount Sinai Hospital; Dr Stone receives research grants from Abbott, Abiomed, Bioventrix, Cardiovascular Systems, Inc, Phillips, Biosense Webster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Family disclosure: Dr Stone’s daughter is an employee at IQVIA. Dr Maron reports grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Hochman was the 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 Corporation; and Omron Healthcare, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. She is a PI for ISCHEMIA-EXTEND (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches Extended Follow-Up). The other authors report no conflicts.

Background: The optimal hemoglobin threshold to guide red blood cell (RBC) transfusion for patients with acute myocardial infarction (MI) and anemia is uncertain., Objective: To estimate the efficacy of 4 individual hemoglobin thresholds (<10 g/dL [<100 g/L], <9 g/dL [<90 g/L], <8 g/dL [<80 g/L], and <7 g/dL [<70 g/L]) to guide transfusion in patients with acute MI and anemia., Design: Prespecified secondary analysis of the MINT (Myocardial Ischemia and Transfusion) trial using target trial emulation methods. (ClinicalTrials.gov: NCT02981407)., Setting: 144 clinical sites in 6 countries., Participants: 3492 MINT trial participants with acute MI and a hemoglobin level below 10 g/dL., Intervention: Four transfusion strategies to maintain patients' hemoglobin concentrations at or above thresholds of 10, 9, 8, or 7 g/dL. Protocol exceptions were permitted for specified adverse clinical events., Measurements: Data from the MINT trial were leveraged to emulate 4 transfusion strategies and estimate per protocol effects on the composite outcome of 30-day death or recurrent MI (death/MI) and 30-day death using inverse probability weighting., Results: The 30-day risk for death/MI was 14.8% (95% CI, 11.8% to 18.4%) for a <10-g/dL strategy, 15.1% (CI, 11.7% to 18.2%) for a <9-g/dL strategy, 15.9% (CI, 12.4% to 19.0%) for a <8-g/dL strategy, and 18.3% (CI, 14.6% to 22.0%) for a <7-g/dL strategy. Absolute risk differences and risk ratios relative to the <10-g/dL strategy for 30-day death/MI increased as thresholds decreased, although 95% CIs were wide. Findings were similar and imprecise for 30-day death., Limitation: Unmeasured confounding may have persisted despite adjustment., Conclusion: The 30-day risks for death/MI and death among patients with acute MI and anemia seem to increase progressively with lower hemoglobin concentration thresholds for transfusion. However, the imprecision around estimates from this target trial analysis precludes definitive conclusions about individual hemoglobin thresholds., Primary Funding Source: National Heart, Lung, and Blood Institute., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M24-0571.

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: Current risk stratification tools for acute myocardial infarction (AMI) have limitations, particularly in predicting mortality. This study utilizes cardiac ultrasound radiomics (i.e., ultrasomics) to risk stratify AMI patients when predicting all-cause mortality., Results: The study included 197 patients: (a) retrospective internal cohort (n = 155) of non-ST-elevation myocardial infarction (n = 63) and ST-elevation myocardial infarction (n = 92) patients, and (b) external cohort from the multicenter Door-To-Unload in ST-segment-elevation myocardial infarction [DTU-STEMI] Pilot Trial (n = 42). Echocardiography images of apical 2, 3, and 4-chamber were processed through an automated deep-learning pipeline to extract ultrasomic features. Unsupervised machine learning (topological data analysis) generated AMI clusters followed by a supervised classifier to generate individual predicted probabilities. Validation included assessing the incremental value of predicted probabilities over the Global Registry of Acute Coronary Events (GRACE) risk score 2.0 to predict 1-year all-cause mortality in the internal cohort and infarct size in the external cohort. Three phenogroups were identified: Cluster A (high-risk), Cluster B (intermediate-risk), and Cluster C (low-risk). Cluster A patients had decreased LV ejection fraction (P < 0.01) and global longitudinal strain (P = 0.03) and increased mortality at 1-year (log rank P = 0.05). Ultrasomics features alone (C-Index: 0.74 vs. 0.70, P = 0.04) and combined with global longitudinal strain (C-Index: 0.81 vs. 0.70, P < 0.01) increased prediction of mortality beyond the GRACE 2.0 score. In the DTU-STEMI clinical trial, Cluster A was associated with larger infarct size (> 10% LV mass, P < 0.01), compared to remaining clusters., Conclusions: Ultrasomics-based phenogroup clustering, augmented by TDA and supervised machine learning, provides a novel approach for AMI risk stratification., (© 2024. The Author(s).)

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: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina., Methods: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×10 11 viral particles) via transepicardial delivery., Results: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months., Conclusions: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732., Competing Interests: Disclosures Dr Nakamura received institutional research support from XyloCor Therapeutics and consulting fees from XyloCor Therapeutics and Sana Biotechnology. Dr Henry received consulting fees (Steering Committee) from XyloCor Therapeutics. Dr Latter received consulting fees from and is a data and safety monitoring board (DSMB) member of XyloCor Therapeutics. Dr Mokadam received consulting fees from Abbott, Medtronic, SynCardia, and XyloCor Therapeutics and is a DSMB member of XyloCor Therapeutics, Medtronic, and Carmat. Dr Williams received consulting fees from XyloCor Therapeutics. Dr Sun received consulting fees from Abbott Vascular and is a DSMB member of 4C Medical and Abbott. Dr DiCarli received institutional research support from XyloCor Therapeutics and Gilead Sciences, consulting fees from Sanofi and MedTrace Pharma, and institutional in-kind research support from Amgen. Dr Chaitman received consulting fees and institutional research support from XyloCor Therapeutics. M.W. Peterson is an employee of XyloCor Therapeutics. D.G. Byrnes is an employee of XyloCor Therapeutics. Dr Ohman is an employee of Amgen. Dr Pepine received institutional research support from XyloCor Therapeutics, BioCardia, Caladrius, Duke Clinical Research Institute, the Gatorade Foundation, the McJunkin Family Foundation Trust, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute/National Patient-Centered Clinical Research Network, Pfizer, Sanofi, University of Florida Clinical and Translational Science Institute, and US Department of Defense and consulting fees from AbbVie, Akros, BioCardia, Bloomer Tech, Caladrius, Imbria Pharmaceuticals, Ironwood Pharmaceuticals, Milestone Pharmaceuticals, and Verily Life Sciences LLC. Dr Crystal received consulting fees from and has equity in XyloCor Therapeutics. Dr Rosengart is an advisor of, is a board of directors member of, and received consulting fees, royalties, and honoraria from XyloCor Therapeutics. Dr Kowalewski received institutional research support from XyloCor Therapeutics. Dr Koch received institutional research support from XyloCor Therapeutics. Dr Dittrich is an employee of XyloCor Therapeutics. Dr Povsic received institutional research support from XyloCor Therapeutics, CSL Behring, Priovant, Bayer, Ionis Pharmaceuticals, UCB Biopharma SRL, BodyPort, and Merck Pharmaceuticals; consulting fees from AstraZeneca, Biocardia, Boehringer Ingelheim, Caladrius Biosciences, Recardio, Veralox Therapeutics, Sana Biotechnology, Inc, Guidepoint Global LLC, and the Gerson Lehrman Group; is a DSMB member of Corvia, Novo Nordisk, and Parexel International; and has leadership or fiduciary role in the American Heart Association and the American College of Cardiology.

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: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level., Methods: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days., Results: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49)., Conclusions: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.)., (Copyright © 2023 Massachusetts Medical Society.)

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

Background: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy., Methods: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points., Conclusions: The MINT trial will inform RBC transfusion practice in patients with acute MI., Competing Interests: Disclosures JLC: DSMB member for Cerus Corporation project. MMB: DSMB member for Cerus Corporation project. JDA: Research funding MicroPort, Boston Scientific. Advisory Boards Philips, Medtronic. Consulting Abbott, Shockwave, Penumbra, Recor. SGG: Research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from: Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, 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 Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, TIMI Study Group (Brigham Health). AMG: None. MHB: None. Philippe Gabriel Steg: has received research grants from Bayer, Merck, Sanofi, Servier; has been a speaker or consultant for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers-Squibb, Janssen, Lexicon, Merck, Novartis, Novo-Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, Servier. He is a Senior Associate Editor for Circulation. APD: Consultant Velakor Biotherapeutics Inc. RDL: Grants from Bristol-Myers Squibb, GlaxoSmithKline plc., Medtronic, Pfizer, Bayer, Sanofi; consulting fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novo Nordisk, GlaxoSmithKline plc., Medtronic, Merck, Pfizer, Portola, Sanofi; and honoraria for lectures from Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Novo Nordisk, and Bayer. PCH: DSMB member of Cerus Corporation project., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively)., Objectives: This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death., Methods: Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified., Results: A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy., Conclusions: In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360)., Competing Interests: Funding Support and Author Disclosures This project was supported by grants from the National Institutes of Health grants U01H117904 and U01HL117905; 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); Omron Healthcare, Inc; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Espero Pharmaceuticals; Merck Sharp and Dohme Corp; and Sunovion Pharmaceuticals. The manuscript contents 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 United States Department of Health and Human Services. Dr Sidhu has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and has received personal fees from AstraZeneca and Sanofi-Regeneron outside the submitted work. Dr Alexander has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Mr Huang has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Mathew has received grants from National Heart, Lung, and Blood Institute, during the conduct of the study. Dr Newman has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr O’Brien has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Pellikka has received grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr Bockeria has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Briguori has received grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Dr Kretov has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Mazurek has received grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Dr Orso has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Roik has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Sajeev has received grants from National Heart, Lung, and Blood Institute, during the conduct of the study. Dr Shutov has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Rockhold reports grants from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, Bristol Myers Squibb, AstraZeneca, American Regent, Gates Foundation, and Eidos during the conduct of the study; has received consulting fees from Janssen, Clover, Doctor Evidence, and Intercept; and equity ownership in GlaxoSmithKline, Clover, Athira, Doctor Evidence, DataVant, Spencer Health Solutions, and Adaptic Health. Dr Borrego has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Balter has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Stone has received grants from the National Heart, Lung, and Blood Institute 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 Chaitman has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study; and has received personal fees from Merck, NovoNordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor outside the submitted work. Dr Goodman has received grants and personal fees from the National Heart, Lung, and Blood Institute during the conduct of the study; has received grants and personal fees from Amgen; AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, 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, GlaxoSmithKline, HLS Therapeutics, Merck, NovoNordisk, and Servier outside the submitted work. Dr Fleg has reports employment by the National Heart, Lung, and Blood Institute during the conduct of the study. 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 outside the submitted work. Dr Maron has received 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 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 and Dohme Corp; Omron Healthcare, Inc, Sunovion Pharmaceuticals, Inc Espero BioPharma; and Amgen, Inc; and has received financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. Dr 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 the submitted work. Dr Lyubarova has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background: Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown., Objectives: The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA., Methods: Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia., Results: Among 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2])., Conclusions: Among participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)., Competing Interests: Funding Support and Author Disclosures This project was supported by National Institutes of Health grants (U01HL105907, U01HL105462, U01HL105561, and U01HL105565) and supported in part by Clinical Translational Science Award (11UL1 TR001445 and UL1 TR002243) from the National Center for Advancing Translational Sciences and by grants from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The manuscript contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Department of Health and Human Services. Devices or medications were provided by Abbott Vascular (previously St. Jude Medical, Inc); Medtronic, Inc; Phillips (previously Volcano Corporation); and Omron Healthcare, Inc; medications were provided by Amgen Inc; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Espero Pharmaceuticals; Merck, Sharp & Dohme Corp; and Sunovion Pharmaceuticals. All authors have received funding from the National Heart, Lung and Blood Institute for the study. Dr Reynolds has received nonfinancial support from Abbott Vascular, Siemens, BioTelemetry, and Leipsic; is a consultant and holder of stock options from Circle CVI and HeartFlow; is the recipient of research grants from GE Healthcare and Edwards; and serves on speakers bureaus for Philips and GE Healthcare. Dr Budoff has received grant support from General Electric; has been on the Medical Advisory Board of Arineta; and has received salary from and has ownership interest in Cleerly, Inc. Dr Berman has received software royalties from Cedars-Sinai Medical Center. Dr Lopes has received grants and other support from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, and Glaxo Smith Kline; and has received grants from Medtronic, Merck, Pfizer, Portola, and Sanofi. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; has received research support from TD Bank, CV Diagnostix and AusculSciences, and Siemens Healthineers; and has equity interest in General Electric. Dr Stone has received personal fees from Terumo, Amaranth, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-wave, SpectreWave, MAIA Pharmaceuticals, Orchestra Biomed, Vectorious Abiomed, Claret, Sirtex, Ancora, and Qool Therapeutics; other considerations from Cagent, Applied Therapeutics, Biostar family of funds; support from MedFocus family of funds, Aria; and personal fees from Cardiac Success work. Dr Boden has received support from Abbvie and Amarin; grants from Amgen; and personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen. Dr Bangalore has received grants and personal fees from Abbott Vascular; and personal fees from Biotronik, Pfizer, and Amgen. Dr Hochman is principal investigator for the ISCHEMIA trial, for which grant, devices, and medications were provided by Abbott Vascular; Medtronic, Inc; St. Jude Medical, Inc; Volcano Corporation; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; Omron Healthcare, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Randomized clinical trials have not demonstrated a survival benefit with percutaneous coronary intervention in stable ischemic heart disease (SIHD). We evaluated the generalizability of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial findings to the broader population of veterans with SIHD. Veterans who underwent coronary angiography between 2005 and 2013 for SIHD were identified from the Veterans Affairs Clinical Assessment, Reporting and Tracking Program (VA CART). Patient-level comparisons were made between patients from VA CART who met the eligibility criteria for COURAGE and veterans enrolled in COURAGE between 1999 and 2004. All-cause mortality over long-term follow-up was assessed using Cox proportional hazards models. COURAGE-eligible patients from VA CART (n = 59,758) were older, had a higher body mass index, a greater prevalence of co-morbidities, but fewer diseased vessels on index coronary angiography, and were less likely to be on optimal medical therapy at baseline and on 1-year follow-up compared with VA COURAGE participants (n = 968). Patients from VA CART (median follow-up 6.5 years) had higher all-cause mortality (adjusted hazard ratio [aHR] 1.98 [1.61 to 2.43]) than participants from VA COURAGE (median follow-up: 4.6 years). Risks of mortality were greater in the 56.4% patients from CART who were medically managed (aHR 1.94 [1.49 to 2.53]) and in the 43.6% who underwent percutaneous coronary intervention (aHR 1.99 [1.45 to 2.74]), compared with their respective VA COURAGE arms. In conclusion, in this noncontemporaneous patient-level analysis, veterans in the randomized COURAGE trial had more favorable outcomes than the population of veterans with SIHD at large., Competing Interests: Disclosures Dr. Smilowitz serves on an advisory board for Abbott Vascular. Dr. Shah serves on an advisory board for Philips Volcano and Terumo Medical. The remaining authors have no conflicts of interest to declare., (Published by Elsevier Inc.)

Background: ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) reported an initial invasive treatment strategy did not reduce the risk of death or nonfatal myocardial infarction (MI) compared with a conservative treatment strategy in patients with advanced chronic kidney disease, stable coronary disease, and moderate or severe myocardial ischemia. The cumulative frequency of different MI type after randomization and subsequent prognosis have not been reported., Methods: MI classification was based on the Third Universal Definition for MI. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary MI definition used cTn (cardiac troponin); both definitions included elevated biomarker-only events with higher thresholds than nonprocedural MIs. The cumulative frequency of MI type according to treatment strategy was determined. The association of MI with subsequent all-cause death and new dialysis initiation was assessed by treating MI as a time-dependent covariate., Results: The 3-year incidence of type 1 or 2 MI with the primary MI definition was 11.2% in invasive treatment strategy and 13.6% in conservative treatment strategy (hazard ratio [HR], 0.66 [95% CI, 0.42-1.02]). Procedural MIs were more frequent in invasive treatment strategy and accounted for 9.8% and 28.3% of all MIs with the primary and secondary MI definitions, respectively. Patients had an increased risk of all-cause death after type 1 MI (adjusted HR, 4.35 [95% CI, 2.73-6.93]) and after procedural MI with the primary (adjusted HR, 2.75 [95% CI, 0.99-7.60]) and secondary MI definitions (adjusted HR, 2.91 [95% CI, 1.73-4.88]). Dialysis initiation was increased after a type 1 MI (HR, 6.45 [95% CI, 2.59-16.08]) compared with patients without an MI., Conclusions: In ISCHEMIA-CKD, the invasive treatment strategy had higher rates of procedural MIs, particularly with the secondary MI definition, and lower rates of type 1 and 2 MIs. Procedural MIs, type 1 MIs, and type 2 MIs were associated with increased risk of subsequent death. Type 1 MI increased the risk of dialysis initiation., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01985360.

Background: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial demonstrated no overall difference in the composite primary endpoint and the secondary endpoints of cardiovascular (CV) death/myocardial infarction or all-cause mortality between an initial invasive or conservative strategy among participants with chronic coronary disease and moderate or severe myocardial ischemia. Detailed cause-specific death analyses have not been reported., Methods: We compared overall and cause-specific death rates by treatment group using Cox models with adjustment for pre-specified baseline covariates. Cause of death was adjudicated by an independent Clinical Events Committee as CV, non-CV, and undetermined. We evaluated the association of risk factors and treatment strategy with cause of death., Results: Four-year cumulative incidence rates for CV death were similar between invasive and conservative strategies (2.6% vs 3.0%; hazard ratio [HR] 0.98; 95% CI [0.70-1.38]), but non-CV death rates were higher in the invasive strategy (3.3% vs 2.1%; HR 1.45 [1.00-2.09]). Overall, 13% of deaths were attributed to undetermined causes (38/289). Fewer undetermined deaths (0.6% vs 1.3%; HR 0.48 [0.24-0.95]) and more malignancy deaths (2.0% vs 0.8%; HR 2.11 [1.23-3.60]) occurred in the invasive strategy than in the conservative strategy., Conclusions: In International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, all-cause and CV death rates were similar between treatment strategies. The observation of fewer undetermined deaths and more malignancy deaths in the invasive strategy remains unexplained. These findings should be interpreted with caution in the context of prior studies and the overall trial results., (Copyright © 2022. Published by Elsevier Inc.)

Importance: Clinical events adjudication is pivotal for generating consistent and comparable evidence in clinical trials. The methodology of event adjudication is evolving, but research is needed to develop best practices and spur innovation., Observations: A meeting of stakeholders from regulatory agencies, academic and contract research organizations, pharmaceutical and device companies, and clinical trialists convened in Chicago, IL, for Clinical Events Classification (CEC) Summit 2018 to discuss key topics and future directions. Formal studies are lacking on strategies to optimize CEC conduct, improve efficiency, minimize cost, and generally increase the speed and accuracy of the event adjudication process. Major challenges to CEC discussed included ensuring rigorous quality of the process, identifying safety events, standardizing event definitions, using uniform strategies for missing information, facilitating interactions between CEC members and other trial leadership, and determining the CEC's role in pragmatic trials or trials using real-world data. Consensus recommendations from the meeting include the following: (1) ensure an adequate adjudication infrastructure; (2) use negatively adjudicated events to identify important safety events reported only outside the scope of the primary endpoint; (3) conduct further research in the use of artificial intelligence and digital/mobile technologies to streamline adjudication processes; and (4) emphasize the importance of standardizing event definitions and quality metrics of CEC programs., Conclusions and Relevance: As novel strategies for clinical trials emerge to generate evidence for regulatory approval and to guide clinical practice, a greater understanding of the role of the CEC process will be critical to optimize trial conduct and increase confidence in the data generated., Competing Interests: Declaration of competing interest Sharma: reports receiving support from the Canada Institute for Health Research – 175095; Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars program, Alberta Innovates Health Solution, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer-Ingelheim, Novartis, and Takeda. Mahaffey: disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Gibson: no relevant disclosures. Hicks: no relevant disclosures. Alexander: no disclosures reported. Ali: no disclosures reported. Chaitman: grants from National Heart, Lung and Blood Institute, Department of Defense, and personal fees from Merck, NovoNordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor for DSMB/CEC work within 3 years and outside the submitted manuscript. Held: Institutional research grants from AstraZeneca, Pfizer, GlaxoSmithKline. Advisory board for AstraZeneca, Boehringer Ingelheim, Coala Life. Hlatky: no disclosures reported. Jones: research grants from Abbott, AstraZeneca, Bayer, Luitpold, Merck, Boehringer Ingelheim, National Institutes of Health, Patient Centered Outcomes Research Institute. Mehran: no disclosures reported. Menon: no disclosures reported. Rockhold: no relevant disclosures. Seltzer: no relevant disclosures. Spitzer: no relevant disclosures. Wilson: no disclosures reported. Lopes: disclosures can be viewed at https://scholars.duke.edu/person/renato.lopes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)