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Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined., Objectives: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure., Methods: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously., Results: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same., Conclusions: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977)., Competing Interests: Funding Support and Author Disclosures The authors met criteria for authorship as described by the International Committee of Medical Journal Editors (ICMJE). No author received payment related to the development of the manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The study was supported and funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. To ensure independent interpretation of clinical trial results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically 1 year after the approval has been granted by major regulatory authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information. Dr Packer has received consulting fees from 89bio, Abbvie, Actavis, Altimmune, Ardelyx, ARMGO Pharma, Attralus, Amgen, Alnylam, AstraZeneca, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, Cytokinetics, Eli Lilly & Company, Imara, Moderna, Medtronic, Novartis, Pharmacosmos, Reata, Regeneron, and Salamandra. Dr Ferreira has served as consultant for Boheringer Ingelheim and AstraZeneca. Dr Butler has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Filippatos has received consulting fees from Bayer, Boehringer Ingelheim, and Servier; has received lecture fees from Novartis; has received trial committee membership fees from Impulse Dynamics, Vifor, and Medtronic; has served on trial committee for Cardior; and has received consulting fees from Novo Nordisk. Dr Maldonado has received consulting fees from Boehringer Ingelheim Pharma GmbH & Co KG. Dr Saadati has served as freelance statistician for Boehringer. Dr Sattar has served in advisory positions for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics; has received consulting fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novo Nordisk, Pfizer, and Sanofi; has received speaker fees from Abbott Laboratories, AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; and has received research grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Dr Anker has received grants and personal fees from Vifor and Abbott Laboratories; has received personal fees for consultancies, trial committee work and lectures from Actimed, AstraZeneca, Bayer, Bioventrix, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Occlutech, Pfizer, Regeneron, Relaxera, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is named co-inventor of 2 patent applications regarding MR-proANP (DE 102007010834 & DE 102007022367), but he does not benefit personally from the related issued patents. Drs Gonzalez Maldonado, Panova-Noeva, Prochaska, Saadati, and Sumin are employees of Boehringer Ingelheim. Dr Zannad has served on the Steering Committee or Data Safety Monitoring Board for or served as a consultant to 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Cardior, Cereno, Cellprothera, CEVA, Merck, Northsea, Novartis, NovoNordisk, Otsuka, Owkin, Salubris, and Servier; has equity in Cardior, G3Pharmaceutical, Cereno Pharmaceutical, and CVCT; and has lectured for Bayer, Boehringer Ingelheim, CVRx, CEVA, Merck, and Novartis. All other authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

During patient follow-up in a randomized trial, some deaths may occur. Where death (or noncardiovascular death) is not part of an outcome of interest it is termed a competing risk. Conventional analyses (eg, Cox proportional hazards model) handle death similarly to other censored follow-up. Patients still alive are unrealistically assumed to be representative of those who died. The Fine and Gray model has been used to handle competing risks, but is often used inappropriately and can be misleading. We propose an alternative multiple imputation approach that plausibly accounts for the fact that patients who die tend also to be at high risk for the (unobserved) outcome of interest. This provides a logical framework for exploring the impact of a competing risk, recognizing that there is no unique solution. We illustrate these issues in 3 cardiovascular trials and in simulation studies. We conclude with practical recommendations for handling competing risks in future trials., Competing Interests: Funding Support and Author Disclosures Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to Boehringer Ingelheim substances, as well as intellectual property considerations. Boehringer Ingelheim had no role in the design, analysis, or interpretation of the results in this study. Dr Gregson has received consultancy fees from Boehringer Ingelheim, Amarin, and Vifor Pharma; and has received research grants from AstraZeneca. Dr Pocock has received grants and personal fees from AstraZeneca; and has received personal fees from Boehringer Ingelheim, Vifor, Abbott Vascular, Amarin, Novartis, Abiomed, Edwards, Janssen, and Medtronic. Dr Anker has received grants and personal fees from Vifor and Abbott Vascular; has received personal fees for consultancies, trial committee work, and/or lectures from Actimed, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bioventrix, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Edwards, Farraday, Impulse Dynamics, Janssen, Novartis, Occlutech, Pfizer, Respicardia, Servier, Vectorious, and V-Wave; and is named coinventor of 2 patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but he does not benefit personally from the related issued patents. Dr Bhatt has served on the Advisory Board of Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; serves on the Board of Directors of American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on Data Monitoring Committees of Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); has served as Deputy Editor of Clinical Cardiology; is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (neither he nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as Site Co-Investigator of Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo. Dr Packer has received consultancy fees from Abbvie, Altimmune, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Moderna, Novartis, Reata, Regeneron, Relypsa, and Salamandra. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Amgen, and Boehringer Ingelheim; has served as a consultant to Abbott, Daiichi-Sankyo, Ablative Solutions, CorFlow, Cardiomech, Robocath, Miracor, Vectorious, Apollo Therapeutics, Elucid Bio, Cardiac Success, Valfix, TherOx, HeartFlow, Neovasc, Ancora, Occlutech, Impulse Dynamics, Adona Medical, Millennia Biopharma, Oxitope, HighLife, Elixir, Remote Cardiac Enablement, and Aria; has equity/options from Cardiac Success, Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Valfix, and Xenter; and his employer, Mount Sinai Fuster Heart Hospital, receives research grants from Shockwave, Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense Webster, Vascular Dynamics, Pulnovo, and V-wave. Dr Cordula is an employee of Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim, Germany., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Following an acute myocardial infarction (AMI), patients remain at risk for subsequent cardiovascular (CV) events. In the AEGIS-II trial, CSL112, a human apolipoprotein A-I derived from plasma that enhances cholesterol efflux, did not significantly reduce the first occurrence of CV death, myocardial infarction (MI), or stroke through 90 days compared with placebo. However, an analysis involving only the first event may not capture the totality of the clinical impact of an intervention because patients may experience multiple events., Objectives: This prespecified exploratory analysis examines the effect of CSL112 on total burden of nonfatal ischemic events (ie, recurrent MI and stroke) and CV death., Methods: A total of 18,219 patients with AMI, multivessel coronary artery disease, and additional CV risk factors were randomized to either 4 weekly infusions of 6 g CSL112 (n = 9,112) or matching placebo (n = 9,107). A negative binomial regression model was applied to estimate the effect of CSL112 compared with placebo on the rate ratio (RR) of ischemic events., Results: For CV death, MI, and stroke, there were numerically fewer total events at 90 days (503 vs 545 events; rate ratio [RR]: 0.88; 95% CI: 0.76-1.03, P = 0.11), and nominally significantly fewer total events at 180 days (745 vs 821 events, RR: 0.87; 95% CI: 0.77-0.99; P = 0.04) and 365 days (1,120 vs 1,211 events; RR 0.89; 95% CI: 0.80-0.99; P = 0.04). Subsequent events constituted 13% of events at 90 days, 17% at 180 days, and 22% at 1 year. Similar findings were seen with the total occurrence of nonfatal MI and CV death. When type II MIs, unlikely to be modified by enhancing cholesterol efflux, were excluded, there were nominally significant reductions in the total occurrence of nonfatal MI (excluding type 2) and CV death at all timepoints (90 days: RR: 0.81; 95% CI: 0.68-0.97; P = 0.02; 180 days: RR: 0.82; 95% CI: 0.71-0.95; P < 0.01; 365 days: RR: 0.86; 95% CI: 0.76-0.98; P = 0.02)., Conclusions: In this prespecified exploratory analysis of the AEGIS-II trial, 4 weekly infusions of CSL112 among high-risk patients after AMI significantly reduced the total burden of nonfatal ischemic events and CV death at 180 and 365 days compared with placebo. (AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome]; NCT03473223)., Competing Interests: Funding Support and Author Disclosures The study was sponsored by CSL Behring. CSL Behring was involved in the study design, data collection, data analysis, data interpretation, and the preparation, review, and approval of the manuscript. The decision to submit the manuscript for publication was made by the academic leadership of the steering committee. Dr Gibson has received research funding from CSL Behring, Janssen Pharmaceuticals, Johnson and Johnson Corporation, and SCAD Alliance; has been a consultant for Angel/Avertix Medical Corporation, AstraZeneca, Bayer Corporation, Beren Therapeutics, Boehringer Ingelheim, Boston Clinical Research Institute, Boston Scientific, Bristol Myers Squibb, Cardiovascular Research Foundation, CeleCor Therapeutics, CSL Behring, DCRI, Esperion, EXCITE International ($0 received), Fortress Biotech, Gilead Sciences Inc., Janssen, Pharmaceuticals, Johnson & Johnson Corporation, MashUp MD, MD Magazine, Microport, MJHealth, Novartis, NovoNordisk, Pfizer, PHRI, PLxPharma, SCAI, Solstic Health/New Amsterdam Pharma, Somahlution/Marizyme, Vectura, Web MD, and Women as One; has equity in nference, Dyad Medical, Absolutys, and Fortress Biotech; and has received royalties as a contributor to UpToDate. Dr Chi has received research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from Bayer, CSL Behring, Janssen Scientific Affairs, and SCAD Alliance. Dr Duffy has received salary as an employee of CSL Behring. Dr Bahit has received honoraria from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr White has received grant support to institution from Sanofi, Regeneron Pharmaceuticals, Eli Lilly, Omthera Pharmaceuticals, American Regent, Eisai Inc, DalCor Pharma UK Inc., CSL Behring, NHI, Sanofi-Aventis Australia Pty Ltd, Esperion Therapeutics Inc, and National Institutes of Health; has received fees for serving on Steering Committees of the ODYSSEY trial from Sanofi and Regeneron Pharmaceuticals, the ISCHEMIA and the MINT studies 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 SCORED trial and the SOLOIST-WHF trial from Sanofi Australia Pty Ltd, and the CLEAR OUTCOMES study from Esperion Therapeutics. Dr Korjian has received research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from CSL Behring. Dr Alexander has received research grants through Duke University from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, the U.S. FDA, Humacyte, and the U.S. NIH; has served as advisory board member or received honoraria or consulting payments from AbbVie, Artivion/CryoLife, AtriCure, Bayer, Bristol Myers Squibb, Curis, Eli Lilly, Ferring, GlaxoSmithKline, Janssen, Novostia, Pfizer, Portola, Theravance, and Veralox. Dr Lincoff has received research funding from Esperion, Eli Lilly, Novartis, AstraZeneca, AbbVie; and has been a consultant for Novo Nordisk, Eli Lilly, Glaxo, Akebia, Endologix, Fibrogen, Provention, Becton Dickson, Brainstorm Cell, Intarcia, Medtronic, and Recor. Dr Anschuetz has received a salary as an employee of CSL Behring. Dr Girgis has received a salary as an employee of CSL Behring. Dr Nicolau has received a scholarship from the National Council of Scientific and Technological Development (CNPq) #303448/2021-0 and has received research grants from Amgen, AstraZeneca, Bayer, CSL Behring, Daiichi-Sankyo, Dalcor, Esperion, Ionis, Janssen, Novartis, Novo Nordisk, Sanofi, and Vifor; and has received consulting fees from Libbs. Dr Lopes has received grant support from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has been a consultant for AstraZeneca, Bayer, Boehringer, Bristol Myers Squibb, and Novo Nordisk; and has participated in educational activities for Daiichi-Sankyo, AstraZeneca, Novo Nordisk, and Pfizer. Dr Bainey has received research support from CSL Behring. Dr Libby has served on a scientific advisory board for Amgen, Kowa Pharmaceuticals, Novo Nordisk, Caristo, CSL Behring, DalCor, Dewpoint, Euclid Bioimaging, Xbiotech, Olatec, Medimmune, PlaqueTec, Polygon Therapeutics, TenSixteen Bio, Soley Therapeutics; and has been a consultant for Amgen, Baim Institute Beren, Esperion, Genentech, Kancera, Kowa Pharmaceuticals, Novo Nordisk, Novartis, and Sanofi-Regeneron. Dr Sacks has received support from CSL Behring. Dr Ridker has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, NovoNordisk, and the NHLBI; has served as a consultant to numerous companies including Novartis, Flame, Agepha, Ardelyx, Arrowhead, AstraZeneca, CSL Behring, Janssen, Civi Biopharm, GlaxoSmithKline, SOCAR, Novo Nordisk, Health Outlook, Montai Health, Eli Lilly, New Amsterdam, Boehringer Ingelheim, RTI, Zomagen, Cytokinetics, Horizon Therapeutics, and Cardio Therapeutics; holds minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and receives compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation (Paris, FR), and the Baim Institute (Boston, Massachusetts). Dr Goodman has received research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from Alnylam, 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, Roche, Sanofi, Servier, Tolmar Pharmaceuticals, Valeo Pharma; has received 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, Jewish General Hospital∖CIUSSS Centre-Ouest-de-l'Ile-de-Montreal, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, Ted Rogers Centre for Heart Research, and TIMI Study Group (Brigham Health). Dr Mahaffey has received grants from AHA, Apple Inc, Bayer, California Institute Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google (Verily), Idorsia, Johnson & Johnson, Luitpold, Novartis, PAC-12, Precordior, Sanifit; consulting fees from applied Therapeutics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson & Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, Theravance; has received payment or honoraria from CSL Behring; and has stock or stock options in Human, Medeloop, Precordior, and Regencor. Dr Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron; and has been a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Novo Nordisk, CSL Sequiris, and Vaxxinity. Dr Pocock has been a consultant to CSL Behring. Dr Mehran has received institutional research payments from Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi-Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; has received personal fees from Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Daiichi-Sankyo, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., and Radcliffe; has held equity <1% in Elixir Medical, Stel, ControlRad (spouse); has received an honorarium from AMA; is associate editor of JAMA Cardiology; and is a BOT Member, SC Member CTR Program of ACC. Dr Harrington has research relationships with Baim Institute, CSL, Janssen, NHLBI, PCORI, DCRI; has consulting relationships with Atropos Health, Bitterroot Bio, BMS, BridgeBio, Element Science, Edwards Lifesciences, Foresite Labs, Medscape/WebMD; and serves on boards of directors for the American Heart Association, College of the Holy Cross, and Cytokinetics. Dr Cornel has reported that he has 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.)

Many randomized trials in cardiovascular disease have repeat nonfatal events (such as hospitalizations) occurring during patient follow-up; yet, it remains common practice to have time-to-first event as the primary outcome. We explore the value of analyses that include repeat events. Do they help us understand the effect of treatment and total disease burden? Do they enhance statistical power? Should they become a trial's primary analysis? It may also be difficult to choose which of the various statistical methods for analyzing repeat events to use, and we provide a nontechnical guide to what each method is doing. We compare several methods for repeat events: Lin Wei Yang Ying, negative binomial, joint frailty, win ratio, and area under the curve. We illustrate their performance in 5 large cardiovascular trials and compare them with time-to-first-event analyses. We review their use in recently published heart failure trials and make recommendations for their use in future trials., Competing Interests: Funding Support and Author Disclosures This work was funded by the British Heart Foundation. Dr Gregson has received consultancy fees from Boehringer Ingelheim, Amarin, and Vifor Pharma; and has received research grants from AstraZeneca. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, Abbott, Amgen, and Boehringer Ingelheim; has served as a consultant to 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, and Oxitope; has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; 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; and his daughter is an employee at IQVIA. Dr Bhatt has served on the Advisory Board of Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on the Board of Directors of Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, and TobeSoft; has served as Inaugural Chair of the American Heart Association Quality Oversight Committee; has served as a consultant for Broadview Ventures and Hims; has served on Data Monitoring Committees of Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), and Wiley (steering committee); has served as Deputy Editor of Clinical Cardiology; has served as Chair of the NCDR-ACTION Registry Steering Committee and VA CART Research and Publications Committee; has a patent for Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither he nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has served as a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo and Takeda. Dr Packer has received personal fees from Abbvie, Altimmune, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Lilly, Moderna, Novartis, Reata, Regeneron, Relypsa, and Salamandra. Ms Zeller is an employee of Boehringer Ingelheim Pharma GmbH and Co KG. Dr Anker has received grants and personal fees from Vifor and Abbott Vascular; has received personal fees for consultancies, trial committee work and/or lectures from Actimed, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bioventrix, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Edwards, Farraday, Impulse Dynamics, Janssen, Novartis, Occlutech, Pfizer, Respicardia, Servier, Vectorious, and V-Wave; and is named coinventor of 2 patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but he does not benefit personally from the related issued patents. Dr Pocock has received grants and personal fees from AstraZeneca; and has received personal fees from Boehringer Ingelheim, Vifor, Abbot Vascular, Amarin, and Novartis. 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: It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF)., Objectives: In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF., Methods: In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models., Results: The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; P interaction  = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration., Conclusions: Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180)., Competing Interests: Funding Support and Author Disclosures The EMPHASIS-HF trial was sponsored by Pfizer. Drs Jhund and McMurray are supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217 and the Vera Melrose Heart Failure Research Fund. Dr Matsumoto has received research grants and personal fees from Abott, Bayer Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic, Novartis, Ono Pharma, Orbus Neich, Otsuka Pharma, and the Uehara Memorial Foundation. Dr Kondo has received speaker fees from Abbott, Ono Pharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, and Abiomed. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, and Analog Devices; is a director of Global Clinical Trial Partners; and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk. Dr Campbell has received consultancy honoraria from Bayer and speaking honoraria from AstraZeneca. Dr Swedberg has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novartis. Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speaker Bureau, manuscript writing, and educational events from Boehringer Ingelheim. Dr Pitt has served as a consultant for Bayer, AstraZeneca, Boehringer Ingelheim, Merck, Lexicon, KBP BioSciences (with stock options), Vifor (with stock options), Sarfez (with stock options), scPharmaceuticals (with stock options), SQ Innovation (with stock options), G3 Pharmaceuticals, Proton Intel (with stock options), Cereno Scientific (with stock options), and Brainstorm Medical (with stock options); has U.S. patent 9931422 (site-specific delivery of eplerenone to the myocardium); and has U.S. patent pending 63/045783 (histone acetylation modulating agents for the protection and treatment of organ damage). Dr Zannad has received personal fees from Boehringer Ingelheim during the conduct of the study; has received personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera; and is cofounder of CVCT and Cardiorenal, outside the submitted work. Dr McMurray has received payments through Glasgow University for work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; has received personal consultancy fees from Alnylam Pharma, Bayer, Bristol Myers Squibb, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, and River 2 Renal Corporation; and has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica health, Intas Pharma, J.B. Chemicals & Pharma, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, and Translational Medicine Academy; and is a director of Global Clinical Trial Partners., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Empagliflozin reduces the risk of major heart failure outcomes in heart failure with reduced or preserved ejection fraction., Objectives: The goal of this study was to evaluate the effect of empagliflozin across the spectrum of chronic kidney disease in a pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced or Preserved Ejection Fraction, respectively)., Methods: A total of 9,718 patients were grouped into Kidney Disease Improving Global Outcomes (KDIGO) categories based on estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio into low-, moderate-, high-, and very-high-risk categories, comprising 32.0%, 29.1%, 21.9%, and 17.0% of the participants, respectively., Results: In the placebo arm, when compared with lower risk categories, patients at higher risk experienced a slower rate of decline in eGFR, but a higher risk of a composite kidney event. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalizations similarly in all KDIGO categories (HR: 0.81; 95% CI: 0.66-1.01 for low-; HR: 0.63; 95% CI: 0.52-0.76 for moderate-; HR: 0.82; 95% CI: 0.68-0.98 for high-; and HR: 0.84; 95% CI: 0.71-1.01 for very-high-risk groups; P trend = 0.30). Empagliflozin reduced the rate of decline in eGFR whether it was estimated by chronic slope, total slope, or unconfounded slope. When compared with the unconfounded slope, the magnitude of the effect on chronic slope was larger, and the effect on total slope was smaller. In EMPEROR-Reduced, patients at lowest risk experienced the largest effect of empagliflozin on eGFR slope; this pattern was not observed in EMPEROR-Preserved., Conclusions: The benefit of empagliflozin on major heart failure events was not influenced by KDIGO categories. The magnitude of the renal effects of the drug depended on the approach used to calculate eGFR slopes., Competing Interests: Funding Support and Author Disclosures Boehringer Ingelheim and Eli Lilly and Company funded EMPEROR-Reduced and EMPEROR-Preserved. The manuscript was sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Butler has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor; and is a Trial Executive Committee member of Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Packer has received consulting fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Verma has received research and/or speaking honoraria from Amgen, Amarin, AstraZeneca, Bayer, CMS, Janssen, HLS, Sanofi, Novo Nordisk, Novartis, Merck, and PhaseBio; has received personal fees from Boehringer Ingelheim; is president of the Canadian Medical and Surgical Knowledge Translation Research Group; and holds the Tier 1 Canada Research Chair in Cardiovascular Surgery. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly and Company, GSK, Gilead, MSD, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius. Dr Ferreira has received consulting fees from Boehringer Ingelheim; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Filippatos has received payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim, Medtronic, Vifor, Servier, and Novartis; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Anker has received grants from Abbott Vascular and Vifor (International) Ltd; has received consulting fees from Abbott Vascular, Bayer, Brahms GmbH, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor (International) Ltd; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Zannad has recieved payment or honoraria for lectures, presentations, Speakers Bureau, manuscript writing, or educational events from Boehringer Ingelheim, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, and Bayer; other financial or nonfinancial interests in CVCT and Cardiorenal; and is a Trial Executive Committee member of the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance (trial sponsor). Drs Brueckmann and Gergei, and Tomoko Iwata are employees of Boehringer Ingelheim, the manufacturer of empagliflozin. Dr Siddiqi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results., Objectives: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19., Methods: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group., Results: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent., Conclusions: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079)., Competing Interests: Funding Support and Author Disclosures Dr Stone has received speaker honoraria from Medtronic, Pulnovo, Infraredx, Abiomed, and Abbott; has served as a consultant to Daiichi-Sankyo, 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; and 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 Farkouh has received institutional research grants from Amgen, AstraZeneca, Novo Nordisk, and Novartis; has received consulting fees from Otitopic; and has received honoraria from Novo Nordisk. Dr Lala has received consulting fees from Merck and Bioventrix; has received honoraria from Zoll Medical and Novartis; has served on an advisory board for Sequana Medical; and is the Deputy Editor for the Journal of Cardiac Failure. Dr Moreno has received honoraria from Amgen, Cuquerela Medical, and Gafney; has received payment for expert testimony from Koskoff, Koskoff & Dominus, Dallas W. Hartman, and Riscassi & Davis PC; and has stock options in Provisio. Dr Goodman has received institutional research grants from Bristol Myers Squibb/Pfizer Alliance, Bayer, and Boehringer Ingelheim; has received consulting fees from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Ferring Pharmaceuticals, HLS Therapeutics, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, and Sanofi; has received honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, and Servier; has served on Data Safety and Monitoring boards for Daiichi-Sankyo/American Regent and Novo Nordisk A/C; has served on advisory boards for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, and Tolmar Pharmaceuticals; has a leadership role in the Novartis Council for Heart Health (unpaid); and otherwise has received salary support or honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, 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, and the TIMI Study Group (Brigham Health). Dr Ricalde has received consulting fees from Medtronic, Servier, and Boston Scientific; has received honoraria from Medtronic, Pfizer, Merck, Boston Scientific, Biosensors, and Bayer; has served on an advisory board for Medtronic; and has leadership roles in SOLACI and Kardiologen. Dr Payro has received consulting fees from Bayer Mexico; has received honoraria from Bayer, Merck, AstraZeneca, Medtronic, and Viatris; has received payments for expert testimony from Bayer; has received travel support from AstraZeneca; has served on an advisory board for Bayer; and his institution has received equipment donated from AstraZeneca. Dr Castellano has received consulting fees and honoraria from Ferrer International, Servier, and Daiichi-Sankyo; and has received travel support from Ferrer International. Dr Hung has served as an advisory board member for Pfizer, Merck, AstraZeneca, Fosun, and Gilead. Dr Nadkarni has received consulting fees from Renalytix, Variant Bio, Qiming Capital, Menarini Health, Daiichi-Sankyo, BioVie, and Cambridge Health; has received honoraria from Daiichi-Sankyo and Menarini Health; has patents for automatic disease diagnoses using longitudinal medical record data, methods, and apparatus for diagnosis of progressive kidney function decline using a machine learning model, electronic phenotyping technique for diagnosing chronic kidney disease, deep learning to identify biventricular structure and function, fusion models for identification of pulmonary embolism, and SparTeN: a novel spatio-temporal deep learning model; has served on a Data Safety and Monitoring Board for CRIC OSMB; has leadership roles for Renalytix scientific advisory board, Pensive Health scientific advisory board, and ASN Augmented Intelligence and Digital Health Committee; has ownership interests in Renalytix, Data2Wisdom LLC, Verici Dx, Nexus I Connect, and Pensieve Health; and his institution receives royalties from Renalytix. Dr Goday has received the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. Dr Furtado has received institutional research grants from AstraZeneca, CytoDin, Pfizer, Servier, Amgen, Alliar Diagnostics, and the Brazilian Ministry of Health; has received consulting fees from Biomm and Bayer; has received honoraria from AstraZeneca, Bayer, Servier, and Pfizer; and has received travel support from Servier, AstraZeneca, and Bayer. Dr Granada has received consulting fees, travel support, and stock from Cogent Technologies Corp; and has received stock from Kutai. Dr Contreras has served as a consultant for Merck, CVRx, Novodisk, and Boehringer Ingelheim; and has received educational grants from Alnylam Pharmaceuticals and AstraZeneca. Dr Bhatt has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89bio; has received royalties from Elsevier; has received consultant fees from Broadview Ventures and McKinsey; has received honoraria from the American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, WebMD, Wiley, Society of Cardiovascular Patient Care; has received fees from expert testimony from the Arnold and Porter law firm; has received travel support from the American College of Cardiology, Society of Cardiovascular Patient Care, American Heart Association; has a patent for otagliflozin assigned to Brigham and Women’s Hospital who assigned to Lexicon; has participated on a data safety monitoring board or advisory board for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, AngioWave, Baim Institute, Bayer, Boehringer Ingelheim, Boston Scientific, Cardax, CellProthera, Cereno Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Elsevier Practice Update Cardiology, Janssen, Level Ex, Mayo Clinic, Medscape Cardiology, Merck, Mount Sinai School of Medicine, MyoKardia, NirvaMed, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Population Health Research Institute, and Stasys; serves as a trustee or director for American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, and TobeSoft; has ownership interests in AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; has other interests in Clinical Cardiology, the NCDR-ACTION Registry Steering Committee; has conducted unfunded research with FlowCo and Takeda, Contego Medical, American Heart Association Quality Oversight Committee, Inaugural Chair, VA CART Research and Publications Committee; and has been a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), Phillips SpectraWAVE, Svelte, and Vascular Solutions. Dr Fuster declares that he raised $7 million from patients for this study granted to Mount Sinai Heart, unrelated to industry. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The impact of transcatheter edge-to-edge repair (TEER) on the rate and prognostic impact of hospitalizations in patients with heart failure (HF) and severe secondary mitral regurgitation is unknown., Objectives: This study sought to evaluate the effect of the MitraClip percutaneous edge-to edge repair system on fatal and nonfatal hospitalizations and their relationship with mortality in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial., Methods: Patients with HF (n = 614) with severe secondary mitral regurgitation were randomized to TEER plus guideline-directed medical therapy (GDMT) versus GDMT alone. Hospitalizations were classified as fatal if death occurred during that hospitalization or nonfatal if the patient was discharged alive., Results: At 2 years, TEER treatment, compared with GDMT alone, resulted in lower time-to-first-event rates of any heart failure hospitalization (HFH) (34.8% vs 56.4%; HR: 0.51; 95% CI: 0.39-0.66) and fatal HFH (6.5% vs 12.6%; HR: 0.47; 95% CI: 0.26-0.85). TEER also resulted in lower rates of all-cause nonfatal and fatal hospitalizations. During the 2-year follow-up period, patients who underwent TEER spent an average of 2 more months alive and out of the hospital than did patients treated with GDMT alone (581 ± 27 days vs 519 ± 26 days; P = 0.002). All HFHs (adjusted HR: 6.37; 95% CI: 4.63-8.78) and nonfatal HFHs (adjusted HR: 1.78; 95% CI: 1.27-2.49) were consistently independently associated with increased 2-year mortality in both the TEER and GDMT groups (P interaction  = 0.34 and 0.39, respectively)., Conclusions: In the COAPT trial, compared with GDMT alone, patients with HF and severe secondary mitral regurgitation undergoing TEER with the percutaneous edge-to edge repair system had lower 2-year rates of fatal and nonfatal all-cause hospitalizations and HFH and spent more time alive and out of the hospital. HFHs were strongly associated with mortality, irrespective of treatment. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT]; NCT01626079)., Competing Interests: Funding Support and Author Disclosures The COAPT trial was sponsored by Abbott. Dr Giustino has received consulting fees (Advisory Board) from Bristol Myers Squibb/Pfizer. Dr Kapadia has received stock options from Navigate Cardiac Structures, Inc. Dr Kar has received consulting fees and served on the advisory board of Boston Scientific; has received consulting fees/stock equity from Valcare; and has received consulting fees from W.L. Gore and Medtronic. Dr Abraham has received research grant support from Abbott Vascular; and has received consulting fees from Abbott Vascular. Dr Lindenfeld has received research grant support from AstraZeneca; and has received consulting fees from Abbott Vascular, AstraZeneca, CVRx, Edwards Lifesciences, Impulse Dynamics, Boehringer Ingelheim, and V-Wave. Dr Lim has received research grant support from Abbott, Edwards, Medtronic, and Gore; has served as a consultant to Abbott, Edwards, Keystone Heart, Pipeline, Siemens, Valgen, and Venus; has served on the advisory boards of Ancora and Venus; and holds equity in 510Kardiac and Venus. Dr Grayburn has received consulting fees from Abbott Vascular, Edwards Lifesciences, W.L. Gore, Medtronic, and 4C Medical; and has received grant support from Abbott Vascular, Boston Scientific, Cardiovalve, Edwards Lifesciences, W.L. Gore, Medtronic, and Neochord. Dr Cohen has received research grant support from Abbott, Medtronic, Edwards Lifesciences, and Boston Scientific; and has received consulting fees from Abbott, Medtronic, Edwards Lifesciences, and Boston Scientific. Dr Asch has institutional contracts with Abbott, Neovasc, Ancora, Mitralign, Medtronic, Boston Scientific, Edwards Lifesciences, Biotronik, and Livanova. Dr Mack has served as coprimary investigator of the PARTNER Trial for Edwards Lifesciences and of COAPT trial for Abbott; and served as study chair for the APOLLO trial for Medtronic. Dr Stone has received speaker honoraria from Medtronic, Pulnovo, 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 received equity/options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter; his employer, Mount Sinai Hospital, has received research support from Abbott, Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, Biosense-Webster, Shockwave, Vascular Dynamics, and V-wave; and his daughter is an employee at Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Empagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied., Objectives: The purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction)., Methods: We grouped patients (n = 5,988) according to their baseline age (<65 years [n = 1,199], 65-74 years [n = 2,214], 75-79 years [n = 1,276], ≥80 years [n = 1,299]). We explored the influence of age on empagliflozin effects on CVD or HFH (primary outcome), total HFH, rate of decline in estimated glomerular filtration rate, health-related quality of life with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and frequency of adverse events., Results: Considering only patients on placebo, the incidence of primary outcomes (P trend = 0.02) and CVD (P trend = 0.003) increased with age. Empagliflozin reduced primary outcomes (P trend = 0.33), first HFH (P trend = 0.22), and first and recurrent HFH (P trend = 0.11) across all age groups with an effect being similar at ≥75 years (P interaction = 0.22) or >80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups., Conclusions: Empagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT0305951)., Competing Interests: Funding Support and Author Disclosures All authors were involved in the EMPEROR-Preserved trial, which was funded by Boehringer Ingelheim and Eli Lilly. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd, and Vifor; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Filippatos has received Committee Member contributions in trials and personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Mahfoud has received grants and personal fees from Medtronic; and has received personal fees from Recor, Boehringer Ingelheim, and Berlin Chemie. Dr Brueckmann is an employee of Boehringer Ingelheim. Dr Gollop is an employee of Boehringer Ingelheim. Ms Iwata is an employee of Boehringer Ingelheim. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Gilead, Merck Sharp & Dohme, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work. Dr Zannad has received Steering Committee or Advisory Board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Packer has received consulting fees from Boehringer Ingelheim during the conduct of the study; and has received consulting fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and Novo Nordisk, outside the submitted work. Dr Anker has received grants and personal fees from Vifor International, and Abbott Vascular; has received personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Abdin has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known., Objectives: The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)., Methods: Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin's effects and significance on SBP., Results: Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension., Conclusions: Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures All authors were involved in the EMPEROR trial, which was funded by Boehringer Ingelheim and Eli Lilly. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Anker has received grants and personal fees from Vifor Int and Abbott Vascular; has received personal fees from Bayer, Brahms GmbH, Boehringer Ingelheim, Cardiac Dimensions, Cordio, Novartis, and Servier; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Butler has received consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr Filippatos reports Committee Member contributions in trials; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Mahfoud has received grants and personal fees from Medtronic; and has received personal fees from ReCor, Boehringer Ingelheim, and Berlin Chemie, outside the submitted work. Dr Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, BMS, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Drs Ofstad, Jamal, and Brueckmann are employees of Boehringer Ingelheim. Dipl Math Schüler is an employee of mainanalytics, contracted by Boehringer Ingelheim. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GSK, Gilead, MSD, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Packer has received consulting fees from Boehringer Ingelheim during the conduct of the study; and has received consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Eli Lily & Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between the benefits of empagliflozin in heart failure with reduced ejection fraction (HFrEF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) has not been reported., Objectives: The authors sought to evaluate the relationship between NT-proBNP and empagliflozin effects in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)., Methods: Patients with HFrEF were randomly assigned to placebo or empagliflozin 10 mg daily. NT-proBNP was measured at baseline, 4 weeks, 12 weeks, 52 weeks, and 100 weeks. Patients were divided into quartiles of baseline NT-proBNP., Results: Incidence rates for each study outcome were 4- to 6-fold higher among those in the highest versus lowest NT-proBNP quartiles (≥3,480 vs <1,115 pg/mL). Study participants with higher NT-proBNP had 2- to 3-fold total hospitalizations higher than the lowest NT-proBNP quartile. Empagliflozin reduced risk for major cardiorenal events without heterogeneity across NT-proBNP quartiles (primary endpoint P interaction  = 0.94; renal composite endpoint P interaction  = 0.71). Empagliflozin treatment significantly reduced NT-proBNP at all timepoints examined; by 52 weeks, the adjusted mean difference from placebo was 13% (P < 0.001). An NT-proBNP in the lowest quartile (<1,115 pg/mL) 12 weeks after randomization was associated with lower risk for subsequent cardiovascular death or heart failure hospitalization regardless of baseline concentration. Treatment with empagliflozin resulted in 27% higher adjusted odds of an NT-proBNP concentration of <1,115 pg/mL by 12 weeks compared with placebo (P = 0.01)., Conclusions: In EMPEROR-Reduced, higher baseline NT-proBNP concentrations were associated with greater risk for adverse heart failure or renal outcomes, but empagliflozin reduced risk regardless of baseline NT-proBNP concentration. The NT-proBNP concentration after treatment with empagliflozin better informs subsequent prognosis than pretreatment concentrations. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures The EMPEROR-Reduced trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Dr Januzzi is supported in part by the Hutter Family Professorship at Harvard Medical School; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in Clinical Endpoint Committees/Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Zannad has recently received Steering Committee or Advisory Board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and has received grant support from Abbott and Vifor Pharma. Dr Butler is a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, V-Wave Limited, and Vifor. Dr Filippatos has lectured for and/or has Committee Member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim. Dr Pocock is a consultant for Boehringer Ingelheim. Dr Ferreira is a consultant for Boehringer Ingelheim. Dr Sattar has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Novo Nordisk, Novartis, Sanofi, and Pfizer; and has received grant support from Boehringer Ingelheim. Drs Vedin and Schnee, Mr Cotton, and Ms Iwata are employees of Boehringer Ingelheim Pharmaceuticals. Dr Packer has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Lilly, Novartis, ParatusRx, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Consensus as to best practices for the selection, reporting, and interpretation of primary and secondary outcomes of randomized controlled trials is lacking. We reviewed the strategies adopted in publications of randomized controlled trials (RCTs) for the analysis, presentation, and interpretation of efficacy outcomes from a survey of all cardiovascular RCTs published in the New England Journal of Medicine, Lancet, and the Journal of the American Medical Association during 2019. We focus on the choice of primary outcomes, the variety of approaches to selecting secondary outcomes, the options sometimes used to control type I error, and the common practice to not correct for multiple testing in reporting secondary outcomes. We comment on current practice across journals in the reporting of P values and also how conclusions in trial reports frequently adhere to an undue reliance on P < 0.05 as a basis for positive claims of treatment efficacy. We conclude with recommendations for how future RCT reports could best select, report, and interpret their findings on primary and secondary outcomes., Competing Interests: Funding Support and Author Disclosures Dr Pocock has served as a consultant for AstraZeneca, Boehringer Ingelheim, Boston Scientific, Edwards, Medtronic, and Vifor. Dr Stone has received speaker honoraria from Cook and Terumo; has served as a consultant for Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals, Vectorious, Reva, and Matrizyme; and owns equity/options in Ancora, Qool Therapeutics, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, the MedFocus family of funds, and Valfix. Dr Rockhold has received personal fees from Novartis, Eli Lilly, Amgen, Sanofi, NovoNordisk, Merck Research Labs, UCB, Tolerion, Rhythm, KLSMC Stem Cell, Merck KGaA, Janssen, Phathom, Clover Biopharma, Sarepta, Eidos, and Icosavax outside of the submitted work; has received grants and personal fees from AstraZeneca outside of the submitted work; and has equity interest in GlaxoSmithKline, Athira, DataVant, and Spencer Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction., Objectives: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)., Methods: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization., Results: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group., Conclusions: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly. Dr. Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr. Zannad has received personal fees from Boehringer Ingelheim during the conduct of the study; has received personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera outside the submitted work; and has received other support from CardioVascular Clinical Trialists and Cardiorenal, outside the submitted work. Dr. Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Anker has received grants from Vifor; has received personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo Fisher Scientific; and has received grants and personal fees from Abbott Vascular, outside the submitted work. Dr. Butler has received consultancy fees from Boehringer Ingelheim during the conduct of the study; and has received consultancy fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave, and Vifor, outside the submitted work. Dr. Filippatos has received payment for being a trial committee member from Boehringer Ingelheim during the conduct of the study; and has received payment for being a trial committee member from Medtronic, Vifor, Servier, and Novartis, outside the submitted work. Dr. Brueckmann has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and Novo Nordisk, outside the submitted work. Drs. Brueckmann, Steubl, Jamal, and Steubl are employees of Boehringer Ingelheim. Dr. Schueler is an employee of mainanalytics, contracted by Boehringer Ingelheim. Dr. Packer has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention., Objectives: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload., Methods: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment., Results: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients., Conclusions: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures The EMPEROR-Reduced trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Dr. Packer has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Abbvie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and NovoNordisk outside the submitted work. Dr. Anker has received grants and personal fees from Vifor Int. and Abbott Vascular; has received personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor Int.; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Ltd., and Vifor; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Fillipatos has provided Committee Member contributions in trials; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Ferreira is a consultant for Boehringer Ingelheim. Dr. Pocock is a consultant for Boehringer Ingelheim; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Sattar has consulted for or has received lecture fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and has received grant support through his institution from Boehringer Ingelheim. Drs. Brueckmann and Jamal, Mr. Cotton, and Ms. Iwata are employees of Boehringer Ingelheim. Dr. Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and has received personal fees from Boehringer Ingelheim during the conduct of the study., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Varying definitions of procedural myocardial infarction (PMI) are in widespread use., Objectives: This study sought to determine the rates and clinical relevance of PMI using different definitions in patients with left main coronary artery disease randomized to percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG) surgery in the EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial., Methods: The pre-specified protocol definition of PMI (PMI Prot ) required a large elevation of creatine kinase-MB (CK-MB), with identical threshold for both procedures. The Third Universal Definition of MI (types 4a and 5) (PMI UD ) required lesser biomarker elevations but with supporting evidence of myocardial ischemia, different after PCI and CABG. For the PMI UD , troponins were used preferentially (available in 49.5% of patients), CK-MB otherwise. The multivariable relationship between each PMI type and 5-year mortality was determined., Results: PMI Prot occurred in 34 of 935 (3.6%) patients after PCI and 56 of 923 (6.1%) patients after CABG (difference -2.4%; 95% confidence interval [CI]: -4.4% to -0.5%; p = 0.015). The corresponding rates of PMI UD were 37 (4.0%) and 20 (2.2%), respectively (difference 1.8%; 95% CI: 0.2% to 3.4%; p = 0.025). Both PMI Prot and PMI UD were associated with 5-year cardiovascular mortality (adjusted hazard ratio [HR]: 2.18 [95% CI: 1.13 to 4.23] and 2.87 [95% CI: 1.44 to 5.73], respectively). PMI Prot was associated with a consistent hazard of cardiovascular mortality after both PCI and CABG (p interaction  = 0.86). Conversely, PMI UD was strongly associated with cardiovascular mortality after CABG (adjusted HR: 11.94; 95% CI: 4.84 to 29.47) but not after PCI (adjusted HR: 1.14; 95% CI: 0.35 to 3.67) (p interaction  = 0.004). Results were similar for all-cause mortality and with varying PMI UD biomarker definitions. Only large biomarker elevations (CK-MB ≥10× upper reference limit and troponin ≥70× upper reference limit) were associated with mortality., Conclusions: The rates of PMI after PCI and CABG vary greatly with different definitions. In the EXCEL trial, the pre-specified PMI Prot was associated with similar hazard after PCI and CABG, whereas PMI UD was strongly associated with mortality after CABG but not after PCI. (EXCEL Clinical Trial [EXCEL]; NCT01205776)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Investigating the balance of risk for thrombotic and bleeding events after percutaneous coronary intervention (PCI) is especially relevant for patients at high bleeding risk (HBR). The Academic Research Consortium for HBR recently proposed a consensus definition in an effort to standardize the patient population included in HBR trials. The aim of this consensus-based document, the second initiative from the Academic Research Consortium for HBR, is to propose recommendations to guide the design of clinical trials of devices and drugs in HBR patients undergoing PCI. The authors discuss the designs of trials in HBR patients undergoing PCI and various aspects of trial design specific to HBR patients, including target populations, intervention and control groups, primary and secondary outcomes, and timing of endpoint reporting., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The majority of stent-related major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) are believed to occur within the first year. Very-late (>1-year) stent-related MACE have not been well described., Objectives: The purpose of this study was to assess the frequency and predictors of very-late stent-related events or MACE by stent type., Methods: Individual patient data from 19 prospective, randomized metallic stent trials maintained at a leading academic research organization were pooled. Very-late MACE (a composite of cardiac death, myocardial infarction [MI], or ischemia-driven target lesion revascularization [ID-TLR]), and target lesion failure (cardiac death, target-vessel MI, or ID-TLR) were assessed within year 1 and between 1 and 5 years after PCI with bare-metal stents (BMS), first-generation drug-eluting stents (DES1) and second-generation drug-eluting stents (DES2). A network meta-analysis was performed to evaluate direct and indirect comparisons., Results: Among 25,032 total patients, 3,718, 7,934, and 13,380 were treated with BMS, DES1, and DES2, respectively. MACE rates within 1 year after PCI were progressively lower after treatment with BMS versus DES1 versus DES2 (17.9% vs. 8.2% vs. 5.1%, respectively, p < 0.0001). Between years 1 and 5, very-late MACE occurred in 9.4% of patients (including 2.9% cardiac death, 3.1% MI, and 5.1% ID-TLR). Very-late MACE occurred in 9.7%, 11.0%, and 8.3% of patients treated with BMS, DES1, and DES2, respectively (p < 0.0001), linearly increasing between 1 and 5 years. Similar findings were observed for target lesion failure in 19,578 patients from 12 trials. Findings were confirmed in the network meta-analysis., Conclusions: In this large-scale, individual patient data pooled study, very-late stent-related events occurred between 1 and 5 years after PCI at a rate of ∼2%/year with all stent types, with no plateau evident. New approaches are required to improve long-term outcomes after PCI., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The relationship between in-hospital coronary revascularization rate (CRR) and post-discharge mortality rates in survivors of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) at a system level is unclear., Objectives: The purpose of this study was to evaluate CRR and 2-year post-discharge mortality rate (2YMR) in NSTE-ACS., Methods: CRR and 2YMR were analyzed by hospital rate of CRR (in deciles), by country, and by world region in 11,931 patients with NSTE-ACS who survived to discharge and were enrolled in the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) and EPICOR Asia: twin multinational, observational, prospective cohort studies., Results: Significant differences in patient baseline characteristics, medical therapies, CRR, and 2YMR were found. Mean CRR ranged from 0.0% to 96.8% in the first and tenth decile, respectively (p < 0.001); from 12.3% in Romania to 92.4% in Slovenia (p < 0.001); and from 53.9% in South East Asia (SEAsia) to 90.4% in South Korea-Singapore-Hong Kong. 2YMR varied significantly between hospital deciles of CRR (3.6% in tenth decile vs. 9.2% in first decile; p < 0.001), countries (lowest 1.5% in Slovenia, highest 19.4% in Malaysia; p < 0.001), and regions (lowest 3.8% in South Korea-Singapore-Hong Kong, highest 11.7% in SEAsia; p < 0.001). Poisson regression models, adjusted for 15 mortality predictors, showed a significant inverse association between CRR and 2YMR for hospitals (r = -0.90; p < 0.001), countries (r = -0.65; p < 0.001), and regions (r = -0.87; p = 0.005)., Conclusions: Higher CRRs at the hospital, country, and world region levels are strongly associated with higher post-discharge survival, suggesting CRR as a marker of higher system quality., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events., Objectives: Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events., Methods: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl) and low-density lipoprotein cholesterol >40 and ≤100 mg/dl (median baseline of 75 mg/dl), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4 g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint frailty analysis., Results: In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.70; 95% confidence interval: 0.62 to 0.78; p < 0.0001). Icosapent ethyl also reduced totals for each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 vs. 44 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.72; 95% confidence interval: 0.63 to 0.82; p < 0.0001)., Conclusions: Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events. (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial [REDUCE-IT]; NCT01492361)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

In the past 12 months, many important new clinical trials in cardiology have had their first conference presentation and publication. This paper presents a constructive critical appraisal of 6 key studies. In time order of first presentation, they are CABANA, ATTR-ACT, COAPT, DECLARE, REDUCE-IT, and AUGUSTUS. For each study, the aim herein is to document and interpret the main findings, paying attention to new findings, their research context, and study limitations. These topical examples also provide methodological insights pertinent to future clinical trials research., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The randomized EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial reported a similar rate of the 3-year composite primary endpoint of death, myocardial infarction (MI), or stroke in patients with left main coronary artery disease (LMCAD) and site-assessed low or intermediate SYNTAX scores treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). Whether these results are consistent in high-risk patients with diabetes, who have fared relatively better with CABG in most prior trials, is unknown., Objectives: In this pre-specified subgroup analysis from the EXCEL trial, the authors sought to examine the effect of diabetes in patients with LMCAD treated with PCI versus CABG., Methods: Patients (N = 1,905) with LMCAD and site-assessed low or intermediate CAD complexity (SYNTAX scores ≤32) were randomized 1:1 to PCI with everolimus-eluting stents versus CABG, stratified by the presence of diabetes. The primary endpoint was the rate of a composite of all-cause death, stroke, or MI at 3 years. Outcomes were examined in patients with (n = 554) and without (n = 1,350) diabetes., Results: The 3-year composite primary endpoint was significantly higher in diabetic compared with nondiabetic patients (20.0% vs. 12.9%; p < 0.001). The rate of the 3-year primary endpoint was similar after treatment with PCI and CABG in diabetic patients (20.7% vs. 19.3%, respectively; hazard ratio: 1.03; 95% confidence interval: 0.71 to 1.50; p = 0.87) and nondiabetic patients (12.9% vs. 12.9%, respectively; hazard ratio: 0.98; 95% confidence interval: 0.73 to 1.32; p = 0.89). All-cause death at 3 years occurred in 13.6% of PCI and 9.0% of CABG patients (p = 0.046), although no significant interaction was present between diabetes status and treatment for all-cause death (p = 0.22) or other endpoints, including the 3-year primary endpoint (p = 0.82) or the major secondary endpoints of death, MI, or stroke at 30 days (p = 0.61) or death, MI, stroke, or ischemia-driven revascularization at 3 years (p = 0.65)., Conclusions: In the EXCEL trial, the relative 30-day and 3-year outcomes of PCI with everolimus-eluting stents versus CABG were consistent in diabetic and nondiabetic patients with LMCAD and site-assessed low or intermediate SYNTAX scores.(Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization [EXCEL]; NCT01205776)., (Copyright © 2019. Published by Elsevier Inc.)

Background: The optimal revascularization strategy for patients with left main coronary artery disease (LMCAD) and chronic kidney disease (CKD) remains unclear., Objectives: This study investigated the comparative effectiveness of percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery in patients with LMCAD and low or intermediate anatomical complexity according to baseline renal function from the multicenter randomized EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial., Methods: CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m 2 using the CKD Epidemiology Collaboration equation. Acute renal failure (ARF) was defined as a serum creatinine increase ≥5.0 mg/dl from baseline or a new requirement for dialysis. The primary composite endpoint was the composite of death, myocardial infarction (MI), or stroke at 3-year follow-up., Results: CKD was present in 361 of 1,869 randomized patients (19.3%) in whom baseline estimated glomerular filtration rate was available. Patients with CKD had higher 3-year rates of the primary endpoint compared with those without CKD (20.8% vs. 13.5%; hazard ratio [HR]: 1.60; 95% confidence interval [CI]: 1.22 to 2.09; p = 0.0005). ARF within 30 days occurred more commonly in patients with compared with those without CKD (5.0% vs. 0.8%; p < 0.0001), and was strongly associated with the 3-year risk of death, stroke, or MI (50.7% vs. 14.4%; HR: 4.59; 95% CI: 2.73 to 7.73; p < 0.0001). ARF occurred less commonly after revascularization with PCI compared with CABG both in patients with CKD (2.3% vs. 7.7%; HR: 0.28; 95% CI: 0.09 to 0.87) and in those without CKD (0.3% vs. 1.3%; HR: 0.20; 95% CI: 0.04 to 0.90; p interaction  = 0.71). There were no significant differences in the rates of the primary composite endpoint after PCI and CABG in patients with CKD (23.4% vs. 18.1%; HR: 1.25; 95% CI: 0.79 to 1.98) and without CKD (13.4% vs. 13.5%; HR: 0.97; 95% CI: 0.73 to 1.27; p interaction  = 0.38)., Conclusions: Patients with CKD undergoing revascularization for LMCAD in the EXCEL trial had increased rates of ARF and reduced event-free survival. ARF occurred less frequently after PCI compared with CABG. There were no significant differences between PCI and CABG in terms of death, stroke, or MI at 3 years in patients with and without CKD. (EXCEL Clinical Trial [EXCEL]; NCT01205776)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The late-breaking clinical trials presentations at the American College of Cardiology Scientific Sessions in March 2018 are an important contribution to the field of cardiology. This paper presents a constructive critical appraisal of 7 key studies: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), VEST (Vest Prevention of Early Sudden Death Trial), SECURE-PCI (Statins Evaluation in Coronary Procedures and Revascularization), TREAT (Ticagrelor in Patients with ST-Elevation Myocardial Infarction treated with Pharmacological Thrombolysis), POISE (PeriOperative ISchemic Evaluation), SMART-DATE (Safety of 6-Month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome), and CVD-REAL 2 (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors). For each study, our aim is to document and interpret the main findings, noting particularly when "positive spin" appears to occur, and to provide a balanced account of each study, paying attention to both constructive new findings and study limitations. These topical examples also provide useful general insights on what to look for when critiquing clinical trial presentations and publications., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The risk of recurrent ischemic and bleeding events after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) may not be uniform over time, which may affect the benefit-to-risk ratio of guideline-recommended antithrombotic therapies in different intervals., Objectives: This study sought to characterize the average daily ischemic rates (ADIRs) and average daily bleeding rates (ADBRs) within the first year after primary PCI for STEMI., Methods: Among 3,602 patients with STEMI who were enrolled in the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, all ischemic and bleeding events, including recurrent events, were classified according to the timing of their occurrence as acute (≤24 h after PCI), subacute (1 day to 30 days), and late (30 days to 1 year). Patients were treated with aspirin and clopidogrel for the entire year. ADIRs included cardiac death, reinfarction, and definite stent thrombosis. ADBRs included non-coronary artery bypass graft-related Thrombolysis In Myocardial Infarction major and minor bleeding. ADIRs and ADBRs were calculated as the total number of events divided by the number of patient-days of follow-up in each interval assuming a Poisson distribution. Generalized estimating equations were used to test the absolute least square mean differences (LSMD) between ADIRs and ADBRs., Results: The ADIR and ADBR both exponentially decreased from the acute to the late periods (p < 0.0001). Although there were no significant differences in ADIR and ADBR in the acute phase (LSMD: +0.11%; 95% confidence interval [CI]: -0.35% to 0.58%; p = 0.63), the ADBR was greater than the ADIR in the subacute phase (LSMD: -0.39%; 95% CI: -0.58% to -0.20%; p < 0.0001). In the late phase, the ADIR exceeded the ADBR (LSMD: +1.51%; 95% CI: 1.04% to 1.98%; p < 0.0001)., Conclusions: After primary PCI, the ADIR and ADBR both markedly decreased over time. Although the rates for bleeding exceeded those for ischemia within 30 days, the daily risk of ischemia significantly exceeded the daily risk of bleeding beyond 30 days, supporting the use of intensified platelet inhibition during the first year after STEMI., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The noninferiority design is used extensively in current clinical research, but its complex features may hamper the appropriate interpretation of such trials. Thus, understanding the pillars of noninferiority design is indispensable. The authors discuss fundamental concepts regarding the design and interpretation of noninferiority trials and then explore some common methodological criticism by analyzing a sample of contemporary coronary stent trials. Finally, the authors give an overall perspective to enhance the design and conduct of future trials., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Propensity scores (PS) are an increasingly popular method to adjust for confounding in observational studies. Propensity score methods have theoretical advantages over conventional covariate adjustment, but their relative performance in real-word scenarios is poorly characterized. We used datasets from 4 large-scale cardiovascular observational studies (PROMETHEUS, ADAPT-DES [the Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents], THIN [The Health Improvement Network], and CHARM [Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity]) to compare the performance of conventional covariate adjustment with 4 common PS methods: matching, stratification, inverse probability weighting, and use of PS as a covariate. We found that stratification performed poorly with few outcome events, and inverse probability weighting gave imprecise estimates of treatment effect and undue influence to a small number of observations when substantial confounding was present. Covariate adjustment and matching performed well in all of our examples, although matching tended to give less precise estimates in some cases. PS methods are not necessarily superior to conventional covariate adjustment, and care should be taken to select the most suitable method., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: A 1-year follow-up, polymer-free metallic stent coated with biolimus-A9 followed by 1-month dual antiplatelet therapy is safer and more effective than a bare-metal stent (BMS) for patients with high risk of bleeding., Objectives: This study analyzed 2-year outcomes to determine whether these benefits are maintained., Methods: In a prospective, multicenter, double-blind trial, we randomized 2,466 high bleeding risk patients to receive a drug-coated stent (DCS) or a BMS followed by 1-month dual antiplatelet therapy. The primary safety endpoint was a composite of cardiac death, myocardial infarction, or stent thrombosis. The primary efficacy endpoint was clinically driven target lesion revascularization., Results: At 2 years, the primary safety endpoint had occurred in 147 DCS and 180 BMS patients (15.3%) (hazard ratio: 0.80; 95% confidence interval: 0.64 to 0.99; p = 0.039). Clinically driven target lesion revascularization occurred for 77 DCS and 136 BMS patients (12.0%) (hazard ratio: 0.54; 95% confidence interval: 0.41 to 0.72; p < 0.0001). Major bleeding occurred in 8.9% of DCS and 9.2% of BMS patients (p = 0.95), and a coronary thrombotic event (myocardial infarction and/or stent thrombosis) occurred in 8.2% of DCS and 10.6% of BMS patients (p = 0.045). One-year mortality was 27.1% for a major bleed and 26.3% for a thrombotic event. At 2 years, multivariate correlates of major bleeding were age >75 years, anemia, raised plasma creatinine, and planned long-term anticoagulation. Correlates of the primary safety endpoint were age, anemia, congestive heart failure, multivessel disease, number of stents implanted, and use of a BMS rather than a DCS., Conclusions: Safety and efficacy benefits of DCS over BMS were maintained for 2 years in high bleeding risk patients. Rates of major bleeding and coronary thrombotic events were no different and were associated with a substantial and comparable mortality risk. (A Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug Coated Stent Versus the Gazelle Bare Metal Stent in Patients With High Risk of Bleeding [LEADERS FREE]; NCT01623180)., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Upstream administration of antithrombotic drugs to patients with non-ST-segment elevation acute coronary syndromes before coronary angiography is a common practice despite an incomplete understanding of the risks and benefits., Objectives: The authors analyzed the incidence of bleeding and ischemic events occurring before angiography and assessed their association with antithrombotic drugs and mortality risk., Methods: All patients from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial with planned angiography after enrollment were included. Bleeding events were classified according to the ACUITY scale as major or nonmajor bleeding. Kaplan-Meier and Cox proportional hazards analyses were performed., Results: Of 13,726 patients, 275 (2.0%) bled before angiography, including 52 (0.4%) with major bleeding. Forty-four (0.3%) experienced myocardial infarction. The median time from randomization to coronary angiography was 4.5 h (interquartile ratio [IQR]: 1.7 to 19.7 h) for patients who did not bleed while waiting for angiography and 27.9 h (IQR: 21.9 to 65.6 h) for patients who bled while waiting for angiography (p < 0.001). Bleeding events accrued linearly over time, reaching 10.4% at 96 h post-randomization. Independent predictors of bleeding before angiography included age (adjusted hazard ratio [HR]: 1.03 per year of age; 95% confidence interval [CI]: 1.01 to 1.04; p < 0.001), renal insufficiency (adjusted HR: 1.48; 95% CI: 1.07 to 2.04; p = 0.02), and use of multiple antithrombotic drugs (adjusted HR: 1.33; 95% CI: 1.14 to 1.56; p < 0.001). Bleeding before coronary angiography was associated with longer hospitalization (4.8 days [IQR: 3.0 to 8.9 days] vs. 3.0 days [IQR: 1.9 to 5.9 days]; p < 0.001). Patients who bled before angiography were more likely to die within 1 year than patients who did not bleed (8.5% vs. 4.1%; p < 0.001; adjusted HR: 1.89 (95% CI: 1.23 to 2.90; p = 0.004)., Conclusions: Upstream antithrombotic treatment of patients with non-ST-segment elevation acute coronary syndromes awaiting coronary angiography is associated with excess bleeding with mortality implications. Bleeding avoidance strategies before angiogram, including early angiography, may negate the need to prolong upstream antithrombotic treatment and improve the overall risk-benefit balance for these patients. (Acute Catheterization and Urgent Intervention Triage Strategy [ACUITY]; NCT00093158)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Regression to the mean (RTM) describes the tendency for an extreme measurement on 1 occasion to become less extreme when measured again. RTM may affect clinical trial data interpretation when the outcome measure has high variability. We investigated RTM in the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial of renal denervation versus a sham procedure. Analysis of covariance was performed on the 6-month change in systolic blood pressure, estimating a mean treatment difference of -4.11 mm Hg (95% confidence interval: -8.44 to 0.22 mm Hg; p = 0.064), which was similar to the unadjusted difference but with a smaller confidence interval. RTM occurred in both arms, but it had a negligible effect on the observed treatment difference. A second example concerns changes in hemoglobin A1c in a nonrandomized study. These findings emphasize the importance of incorporating RTM and analysis of covariance into the design and reporting of clinical studies of how treatments affect time changes in quantitative outcomes. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

As a sequel to last week's paper on the fundamentals of clinical trial design, this paper tackles related controversial issues: noninferiority trials, the value of factorial designs, the importance and challenges of strategy trials, Data Monitoring Committees (including when to stop a trial early), and the role of adaptive designs. All topics are illustrated by relevant examples from cardiology trials., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This paper provides practical guidance on the fundamentals of design for major randomized controlled trials. Topics covered include the choice of patients, choice of treatment and control groups, choice of primary and secondary endpoints, methods of randomization, appropriate use of blinding, and determination of trial size. Insights are made with reference to contemporary major trials in cardiology., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This paper tackles several statistical controversies that are commonly faced when reporting a major clinical trial. Topics covered include: multiplicity of data, interpreting secondary endpoints and composite endpoints, the value of covariate adjustment, the traumas of subgroup analysis, assessing individual benefits and risks, alternatives to analysis by intention to treat, interpreting surprise findings (good and bad), and the overall quality of clinical trial reports. All is put in the context of topical cardiology trial examples and is geared to help trialists steer a wise course in their statistical reporting, thereby giving readers a balanced account of trial findings., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This paper is a practical guide to the essentials of statistical analysis and reporting of randomized clinical trials (RCTs). It is the first in a series of 4 educational papers on statistical issues for RCTs, which will also include statistical controversies in RCT reporting and interpretation, the fundamentals of design for RCTs, and statistical challenges in the design and monitoring of RCTs. Here, we concentrate on displaying results in tables and figures, estimating treatment effects, expressing uncertainty using confidence intervals, and using p values wisely to assess the strength of evidence for a treatment difference. The various methods and their interpretation are illustrated by recent, topical cardiology trial results., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Little is known about the benefits and risks of the long-term use of cardiovascular drugs. Evidence from randomized clinical trials (RCTs) rarely goes beyond a few years of follow-up, but patients are often given continuous treatment with multiple drugs well into old age. We focus on 4 commonly used cardiovascular drug classes: aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors given to patients after myocardial infarction. However, the issues raised apply more broadly to all long-term medications across cardiovascular diseases and the whole of medicine. The evidence and limitations of RCTs are addressed, as well as current practice in pre-licensing trials, the increasing problems of polypharmacy (especially in the elderly), the lack of trial evidence for withdrawal of drugs, the role of regulatory authorities and other stakeholders in this challenging situation, and the potential educational solutions for the medical profession. We conclude with a set of recommendations on how to improve the situation of long-term drug use., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The RITA-3 (Third Randomised Intervention Treatment of Angina) trial compared outcomes of a routine early invasive strategy (coronary arteriography and myocardial revascularization, as clinically indicated) to those of a selective invasive strategy (coronary arteriography for recurrent ischemia only) in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). At a median of 5 years' follow-up, the routine invasive strategy was associated with a 24% reduction in the odds of all-cause mortality., Objectives: This study reports 10-year follow-up outcomes of the randomized cohort to determine the impact of a routine invasive strategy on longer-term mortality., Methods: We randomized 1,810 patients with NSTEACS to receive routine invasive or selective invasive strategies. All randomized patients had annual follow-up visits up to 5 years, and mortality was documented thereafter using data from the Office of National Statistics., Results: Over 10 years, there were no differences in mortality between the 2 groups (all-cause deaths in 225 [25.1%] vs. 232 patients [25.4%]: p = 0.94; and cardiovascular deaths in 135 [15.1%] vs. 147 patients [16.1%]: p = 0.65 in the routine invasive and selective invasive groups, respectively). Multivariate analysis identified several independent predictors of 10-year mortality: age, previous myocardial infarction, heart failure, smoking status, diabetes, heart rate, and ST-segment depression. A modified post-discharge Global Registry of Acute Coronary Events (GRACE) score was used to calculate an individual risk score for each patient and to form low-risk, medium-risk, and high-risk groups. Risk of death within 10 years varied markedly from 14.4 % in the low-risk group to 56.2% in the high-risk group. This mortality trend did not depend on the assigned treatment strategy., Conclusions: The advantage of reduced mortality of routine early invasive strategy seen at 5 years was attenuated during later follow-up, with no evidence of a difference in outcome at 10 years. Further trials of contemporary intervention strategies in patients with NSTEACS are warranted. (Third Randomised Intervention Treatment of Angina trial [RITA-3]; ISRCTN07752711)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is unclear, and its risks and benefits may vary according to DES generation., Objectives: The goal of this study was to evaluate the efficacy and safety of DAPT after DES implantation., Methods: We included randomized controlled trials that tested different durations of DAPT after DES implantation: shorter dual antiplatelet therapy (S-DAPT) was defined as the per-protocol minimum duration of DAPT after the procedure, and longer dual antiplatelet therapy (L-DAPT) was defined as the per-protocol period of more prolonged DAPT. The primary efficacy and safety outcomes were definite/probable stent thrombosis and clinically significant bleeding (CSB), respectively., Results: Ten randomized controlled trials (N = 32,135) were included. Compared with L-DAPT, S-DAPT had an overall higher rate of stent thrombosis (odds ratio [OR]: 1.71 [95% confidence interval (CI): 1.26 to 2.32]; p = 0.001). The effect of S-DAPT on stent thrombosis was attenuated with the use of second-generation DES (OR: 1.54 [95% CI: 0.96 to 2.47]) compared with the use of first-generation DES (OR: 3.94 [95% CI: 2.20 to 7.05]; p for interaction = 0.008). S-DAPT had an overall significantly lower risk of CSB (OR: 0.63 [95% CI: 0.52 to 0.75]; p < 0.001). Finally, a numerically lower all-cause mortality rate was observed with S-DAPT (OR: 0.87 [95% CI: 0.74 to 1.01]; p = 0.073)., Conclusions: S-DAPT had overall lower rates of bleeding yet higher rates of stent thrombosis compared with L-DAPT; the latter effect was significantly attenuated with the use of second-generation DES, although the analysis may have been limited by the varying DAPT durations among studies. All-cause mortality was numerically higher with L-DAPT without reaching statistical significance. Prolonging DAPT requires careful assessment of the trade-off between ischemic and bleeding complications., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) treated with bivalirudin had lower bleeding and mortality rates, but higher acute stent thrombosis rates compared with heparin + a glycoprotein IIb/IIIa inhibitor (GPI). Subsequent changes in primary PCI, including the use of potent P2Y12 inhibitors, frequent radial intervention, and pre-hospital medication administration, were incorporated into the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, which assigned 2,218 patients to bivalirudin versus heparin ± GPI before primary PCI., Objectives: The goal of this study was to examine the outcomes of procedural anticoagulation with bivalirudin versus heparin ± GPI for primary PCI, given the evolution in primary PCI., Methods: Databases from HORIZONS-AMI and EUROMAX were pooled for patient-level analysis. The Breslow-Day test evaluated heterogeneity between trials., Results: A total of 5,800 patients were randomized to bivalirudin (n = 2,889) or heparin ± GPI (n = 2,911). The radial approach was used in 21.3% of patients, prasugrel/ticagrelor was used in 18.1% of patients, and GPI was used in 84.8% of the control group. Bivalirudin compared with heparin ± GPI resulted in reduced 30-day rates of major bleeding (4.2% vs. 7.8%; relative risk [RR]: 0.53; 95% confidence interval [CI]: 0.43 to 0.66; p < 0.0001), thrombocytopenia (1.4% vs. 2.9%, RR: 0.48; 95% CI: 0.33 to 0.71; p = 0.0002), and cardiac mortality (2.0% vs. 2.9%; RR: 0.70; 95% CI: 0.50 to 0.97; p = 0.03), with nonsignificantly different rates of reinfarction, ischemia-driven revascularization, stroke, and all-cause mortality. Bivalirudin resulted in increased acute (<24 h) stent thrombosis rates (1.2% vs. 0.2%; RR: 6.04; 95% CI: 2.55 to 14.31; p < 0.0001), with nonsignificantly different rates of subacute stent thrombosis. Composite net adverse clinical events were lower with bivalirudin (8.8% vs. 11.9%; RR: 0.74; 95% CI: 0.63 to 0.86; p < 0.0001). There was no significant heterogeneity between the 2 trials for these outcomes, and results were consistent across major subgroups., Conclusions: Despite increased acute stent thrombosis, primary PCI with bivalirudin improved 30-day net clinical outcomes, with significant reductions in major bleeding, thrombocytopenia, and transfusions compared with heparin ± GPI, results that were consistent with evolution in PCI technique and pharmacotherapy. (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966) (European Ambulance Acute Coronary Syndrome Angiography [EUROMAX]; NCT01087723)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

This paper describes some important controversies regarding the current state of clinical trials research in cardiology. Topics covered include the inadequacy of trial research on medical devices, problems with industry-sponsored trials, the lack of head-to-head trials of new effective treatments, the need for wiser handling of drug safety issues, the credibility (or lack thereof) of trial reports in medical journals, problems with globalization of trials, the role of personalized (stratified) medicine in trials, the need for new trials of old drugs, the need for trials of treatment withdrawal, the importance of pragmatic trials of treatment strategies, and the limitations of observational comparative effectiveness studies. All issues are illustrated by recent topical trials in cardiology. Overall, we explore the extent to which clinical trials, as currently practiced, are successful in meeting society's expectations., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to determine whether, in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), the reduction in cardiac mortality in those taking bivalirudin compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (UFH+GPI) can be fully attributed to reduced bleeding., Background: The association between hemorrhagic complications and mortality may explain the survival benefit with bivalirudin., Methods: A total of 3,602 STEMI patients undergoing primary PCI were randomized to bivalirudin versus UFH+GPI. Three-year cardiac mortality was analyzed in patients with and without major bleeding., Results: When compared with UFH+GPI, bivalirudin resulted in lower 3-year rates of major bleeding (6.9% vs. 10.5%, hazard ratio [HR]: 0.64 [95% confidence interval (CI): 0.51 to 0.80], p < 0.0001) and cardiac mortality (2.9% vs. 5.1%, HR: 0.56 [95% CI: 0.40 to 0.80], p = 0.001). Three-year cardiac mortality was reduced in bivalirudin-treated patients with major bleeding (20 fewer deaths with bivalirudin; 5.8% vs. 14.6%, p = 0.025) and without major bleeding (18 fewer deaths with bivalirudin; 2.6% vs. 3.8%, p = 0.048). In a fully-adjusted multivariable model accounting for major bleeding and other adverse events, bivalirudin was still associated with a 43% reduction in 3-year cardiac mortality (adjusted HR: 0.57 [95% CI: 0.39 to 0.83], p = 0.003)., Conclusions: Bivalirudin reduces cardiac mortality in patients with STEMI undergoing primary PCI, an effect that can only partly be attributed to prevention of bleeding. Further studies are required to identify the nonhematologic benefits of bivalirudin. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; NCT00433966)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2) and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion., Background: Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients., Methods: This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients ≥ 75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m(2), and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality)., Results: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups., Conclusions: In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m(2) and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess whether patient age modifies the comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI)., Background: Increasingly, CABG and PCI are performed in older patients to treat multivessel disease, but their comparative effectiveness is uncertain., Methods: Individual data from 7,812 patients randomized in 1 of 10 clinical trials of CABG or PCI were pooled. Age was analyzed as a continuous variable in the primary analysis and was divided into tertiles for descriptive purposes (≤56.2 years, 56.3 to 65.1 years, ≥65.2 years). The outcomes assessed were death, myocardial infarction and repeat revascularization over complete follow-up, and angina at 1 year., Results: Older patients were more likely to have hypertension, diabetes, and 3-vessel disease compared with younger patients (p < 0.001 for trend). Over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age (interaction p < 0.01), with adjusted CABG-to-PCI hazard ratios and 95% confidence intervals (CI) of 1.23 (95% CI: 0.95 to 1.59) in the youngest tertile; 0.89 (95% CI: 0.73 to 1.10) in the middle tertile; and 0.79 (95% CI: 0.67 to 0.94) in the oldest tertile. The CABG-to-PCI hazard ratio of less than 1 for patients 59 years of age and older. A similar interaction of age with treatment was present for the composite outcome of death or myocardial infarction. In contrast, patient age did not alter the comparative effectiveness of CABG and PCI on the outcomes of repeat revascularization or angina., Conclusions: Patient age modifies the comparative effectiveness of CABG and PCI on hard cardiac events, with CABG favored at older ages and PCI favored at younger ages., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to develop a practical risk score to predict the risk and implications of major bleeding in acute coronary syndromes (ACS)., Background: Hemorrhagic complications have been strongly linked with subsequent mortality in patients with ACS., Methods: A total of 17,421 patients with ACS (including non-ST-segment elevation myocardial infarction [MI], ST-segment elevation MI, and biomarker negative ACS) were studied in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) and the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trials. An integer risk score for major bleeding within 30 days was developed from a multivariable logistic regression model., Results: Non-coronary artery bypass graft surgery (CABG)-related major bleeding within 30 days occurred in 744 patients (7.3%) and had 6 independent baseline predictors (female sex, advanced age, elevated serum creatinine and white blood cell count, anemia, non-ST-segment elevation MI, or ST-segment elevation MI) and 1 treatment-related variable (use of heparin + a glycoprotein IIb/IIIa inhibitor rather than bivalirudin alone) (model c-statistic = 0.74). The integer risk score differentiated patients with a 30-day rate of non-CABG-related major bleeding ranging from 1% to over 40%. In a time-updated covariate-adjusted Cox proportional hazards regression model, major bleeding was an independent predictor of a 3.2-fold increase in mortality. The link to mortality risk was strongest for non-CABG-related Thrombolysis In Myocardial Infarction (TIMI)-defined major bleeding followed by non-TIMI major bleeding with or without blood transfusions, whereas isolated large hematomas and CABG-related bleeding were not significantly associated with subsequent mortality., Conclusions: Patients with ACS have marked variation in their risk of major bleeding. A simple risk score based on 6 baseline measures plus anticoagulation regimen identifies patients at increased risk for non-CABG-related bleeding and subsequent 1-year mortality, for whom appropriate treatment strategies can be implemented., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study was designed to determine: 1) whether a routine invasive (RI) strategy reduces the long-term frequency of cardiovascular death or nonfatal myocardial infarction (MI) using a meta-analysis of individual patient data from all randomized studies with 5-year outcomes; and 2) whether the results are influenced by baseline risk., Background: Pooled analyses of randomized trials show early benefit of routine intervention, but long-term results are inconsistent. The differences may reflect differing trial design, adjunctive therapies, and/or limited power. This meta-analysis (n = 5,467 patients) is designed to determine whether outcomes are improved despite trial differences., Methods: Individual patient data, with 5-year outcomes, were obtained from FRISC-II (Fragmin and Fast Revascularization during Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Randomized Trial of a Conservative Treatment Strategy Versus an Interventional Treatment Strategy in Patients with Unstable Angina) trials for a collaborative meta-analysis. A Cox regression analysis was used for a multivariable risk model, and a simplified integer model was derived., Results: Over 5 years, 14.7% (389 of 2,721) of patients randomized to an RI strategy experienced cardiovascular death or nonfatal MI versus 17.9% (475 of 2,746) in the selective invasive (SI) strategy (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.71 to 0.93; p = 0.002). The most marked treatment effect was on MI (10.0% RI strategy vs. 12.9% SI strategy), and there were consistent trends for cardiovascular deaths (HR: 0.83, 95% CI: 0.68 to 1.01; p = 0.068) and all deaths (HR: 0.90, 95% CI: 0.77 to 1.05). There were 2.0% to 3.8% absolute reductions in cardiovascular death or MI in the low- and intermediate-risk groups and an 11.1% absolute risk reduction in highest-risk patients., Conclusions: An RI strategy reduces long-term rates of cardiovascular death or MI and the largest absolute effect in seen in higher-risk patients.

The completion and proper assessment of prospective, randomized controlled trials is essential for best medical practice. However, even though randomized trials are generally considered the pinnacle of evidence-based medicine, they are not infrequently poorly designed, implemented with inadequate quality control, and/or are subject to inappropriate interpretation or generalization, resulting in suboptimal clinical care and/or future investigative directions. The present report describes the most common and egregious misrepresentations from randomized trials, many of which may be attributed to the fallacies that arise from underpowered studies, resulting in overly optimistic or unwarranted conclusions. Caution is necessary when assessing composite outcomes, secondary end points, subgroup analyses, and the results of meta-analysis and meta-regression. Sponsors and investigators must accept responsibility for optimizing the design and execution of clinical trials, and practitioners, guidelines committees, editors, and regulators must critically interpret the data and literature arising from such studies. It is hoped that the principles embodied in the present commentary will spur improved design of future randomized trials and thoughtful critical appraisal by health care providers., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the relative impact of spontaneously occurring and periprocedural myocardial infarction (MI) on survival after percutaneous coronary intervention (PCI)., Background: The clinical significance of periprocedural MI after PCI remains uncertain., Methods: Outcomes during a 1-year follow-up were evaluated among 7,773 patients enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial with a non-ST-segment elevation acute coronary syndrome in whom PCI was performed., Results: Periprocedural MI developed in 466 patients (6.0%), and spontaneous MI unrelated to PCI subsequently developed in 200 patients (2.6%). Patients developing spontaneous and periprocedural MI compared with those patients without MI had significantly greater unadjusted rates of mortality at 30 days (5.0% vs. 3.2% vs. 0.8%, respectively, p < 0.0001) and at 1 year (16.0% vs. 6.0% vs. 2.6%, respectively, p < 0.0001). In a time-updated multivariable analysis, after adjusting for differences in baseline and procedural characteristics between the groups, we found that spontaneous MI was a powerful independent predictor of subsequent mortality (hazard ratio: 7.49, 95% confidence interval: 4.95 to 11.33, p < 0.0001), whereas periprocedural MI was not a significant predictor of mortality (hazard ratio: 1.30, 95% confidence interval: 0.85 to 1.98, p = 0.22)., Conclusions: Among patients with acute coronary syndrome undergoing PCI, the spontaneous development of an MI unrelated to PCI is a powerful predictor of subsequent mortality. In contrast, periprocedural MI is a marker of baseline risk, atherosclerosis burden, and procedural complexity but in most cases does not have independent prognostic significance. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158).