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Background: Type 2 diabetes mellitus (T2DM) significantly worsens heart failure (HF) prognosis., Objectives: This study sought to investigate the impact of T2DM on outcomes in patients enrolled in VICTORIA and assess the efficacy of vericiguat in patients with and without T2DM., Methods: Patients with HF with reduced ejection fraction were randomized to receive vericiguat or placebo in addition to standard therapy. The primary outcome was a composite of cardiovascular death or first heart failure hospitalization (HFH). A Cox proportional hazards model was used to calculate HRs and 95% CIs to assess if the effect of vericiguat differed by history of T2DM., Results: Of 5,050 patients enrolled, 3,683 (72.9%) had glycosylated hemoglobin (HbA 1c ) measured at baseline. Of these, 2,270 (61.6%) had T2DM, 741 (20.1%) had pre-T2DM, 449 (12.2%) did not have T2DM, and 178 (4.8%) had undiagnosed T2DM. The risks of the primary outcome, HFH, and all-cause and cardiovascular mortality were high across all categories. The efficacy of vericiguat on the primary outcome did not differ in patients stratified by T2DM by history (HR: 0.92; 95% CI: 0.81-1.04), T2DM measured by HbA 1c (HR: 0.77; 95% CI: 0.49-1.20), and pre-T2DM measured by HbA 1c (HR: 0.88; 95% CI: 0.68-1.13) and in those with normoglycemia (HR: 1.02: 95% CI: 0.75-1.39; P for interaction = 0.752). No significant differences were observed in subgroups with respect to the efficacy of vericiguat on HFH and all-cause or cardiovascular death., Conclusions: In this post hoc analysis of VICTORIA, vericiguat compared with placebo significantly reduced the risk of cardiovascular death or HFH in patients with worsening HF with reduced ejection fraction regardless of T2DM status. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [Mk-1242-001] [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures VICTORIA was funded by Bayer and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA. Dr Khan has served as an Advisory Board Member for Bayer. Dr Butler has received consulting fees from 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, Roche, and Vifor. Dr Roessig has been an employee of Bayer AG. Dr Blaustein has been an employee of Merck & Co, Inc. Dr Lam has received research grants from Bayer, National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, Radcliffe Group Ltd, and Corpus; has patent PCT/SG2016/050217 pending and patent 16/216929 pending; and is cofounder and nonexecutive director of eKo.ai. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics and consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, MyoKardia, Novartis, Servier, and Roche Diagnostics. Dr Ponikowski has received research grants, has received consulting fees, and has served on the Speakers Bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd, BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr Anstrom has received research grants from Merck and the National Institutes of Health. Dr Armstrong has received consulting fees from Merck, Bayer, Boehringer Ingelheim, and Novo Nordisk and research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly, and CSL Limited. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C., Methods: Overall, 18,219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n=15,731)., Results: As baseline LDL-C increased, risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days (hazard ratio 0.69 [0.53-0.90], 0.71 [0.57-0.88], and 0.78 [0.65-0.93]). In contrast, there was no difference between treatment groups among those with LDL-C <100 mg/dL at baseline., Conclusions: In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analysed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety., Methods: We conducted a systematic search and meta-analysis of observational and randomized data comparing DOACs vs. VKAs in patients with LVT. Endpoints of interest were stroke or systemic embolism, thrombus resolution, all-cause death, and a composite bleeding endpoint. Estimates were pooled using a random-effects model meta-analysis, and their robustness was investigated using sensitivity and influential analyses., Results: We identified 22 articles (18 observational studies, 4 small randomized clinical trials) reporting on a total of 3587 patients (2489 VKA vs. 1098 DOAC therapy). The pooled estimates for stroke or systemic embolism [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.57, 1.15] and thrombus resolution (OR: 1.12; 95% CI: 0.86, 1.46) were comparable, and there was low heterogeneity overall across the included studies. The use of DOACs was associated with lower odds of all-cause death (OR: 0.65; 95% CI: 0.46, 0.92) and a composite bleeding endpoint (OR: 0.67; 95% CI: 0.47, 0.97). A risk of bias was evident particularly for observational reports, with some publication bias suggested in funnel plots., Conclusion: In this comprehensive analysis of mainly observational data, the use of DOACs was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution, compared with VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Adequately sized randomized clinical trials are needed to confirm these findings, which could allow a wider adoption of DOACs in patients with LVT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk., Methods: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years., Conclusion: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter., Trial Registration: ClinicalTrials.gov NCT05757869., Competing Interests: Disclosures SSJ reports consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. KWM’s financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey. KSP is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc. WS has received honoraria (>10K USD) from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Pfizer Japan, and research grants (>50K USD) from Daiichi Sankyo and Nippon Boehringer Ingelheim. CTR reports Research Grants through Institution from: Athos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. Honoraria for scientific ad boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. He is a member of The TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Abiomed, Inc, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research & Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Saghmos Therapeutics, Inc, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc, Zora Biosciences. PRK reports consultancy from Anthos, J&J, BMS and Bayer. GS has received research grants from Amarin, AstraZeneca, and Sanofi; has participated in clinical trials, consulting, or speaking for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Novo Nordisk, PhaseBio, Pfizer, and Sanofi; is a Senior Associate Editor at Circulation; and serves as the CMO for Bioquantis. RM reports 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; consultant to Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, 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., Radcliffe and honoararia from AMA and ACC. SCJ has received research support from Jansen, BMS, and AstraZeneca. GJH reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention). RAH has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor Xia inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai. The remaining authors report no relevant disclosures or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI., Objectives: This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of cardiovascular (CV) death and recurrent MI., Methods: The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6 g CSL112) or placebo., Results: The incidence of the composite of CV death and type 1 MI was 11% to 16% lower in the CSL112 group over the study period (HR: 0.84; 95% CI: 0.7-1.0; P = 0.056 at day 90; HR: 0.86; 95% CI: 0.74-0.99; P = 0.048 at day 180; and HR: 0.89; 95% CI: 0.79-1.01; P = 0.07 at day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112-treated patients throughout the follow-up period (HR: 0.92; 95% CI: 0.80-1.05 at day 90, HR: 0.89; 95% CI: 0.79-0.996 at day 180, HR: 0.91; 95% CI: 0.83-1.01 at day 365). The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis)., Conclusions: Although CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared with placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations., Competing Interests: Funding Support and Author Disclosures This study was funded by CSL Behring. Dr Povsic has received research funding paid to his institution from CSL Behring; has received research funding from Xylocor Inc, Ionis, Bayer, Roche, and the National Institutes of Health (NIH); and has received consulting income from Novo Nordisk, Corvia, and Boehringer Ingelheim. Dr Korjian has received research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from CSL Behring. Dr Bahit has received modest honorarium from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr Chi has received research grant support paid to the Beth Israel Deaconess Medical Center, Harvard Medical School from Bayer, Janssen Scientific Affairs, and CSL Behring. Dr Duffy is an employee of CSL Behring. Dr Alexander has received research grants from Artivion/CryoLife, Bayer, Bristol Myers Squibb, CSL Behring, Ferring, the U.S. Food and Drug Administration, Humacyte, and the NIH; and has received advisory board/consulting payments from AbbVie, Artivion/CryoLife, AtriCure, Bayer, Bristol Myers Squibb, Eli Lilly, Ferring, GlaxoSmithKline, Janssen, Novostia, Pfizer, Portola, Theravance, and Veralox. Dr Vinereanu has received research grants from CSL Behring, Bayer, Novartis, Amgen, and Boehringer Ingelheim; and has received consultancy fees from Bayer, Novartis, Amgen, and Boehringer Ingelheim. Dr Tricoci, Ms Mears, and Dr Deckelbaum are employees of CSL Behring. Dr Bonaca is the Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant/consulting funding between August 2021 and the present from Abbott Laboratories, Agios Pharmaceuticals, Inc, Alexion Pharma, Alnylam Pharmaceuticals, Inc, Amgen Inc, Angionetics, Inc, Anthos Therapeutics, ARCA Biopharma, Inc, Array BioPharma, Inc, AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc, Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc, Boston Clinical Research Institute, Bristol Myers Squibb Company, Cambrian Biopharma, Inc, Cardiol Therapeutics Inc, CellResearch Corp, Cleerly Inc, Cook Regentec LLC, CSL Behring LLC, Eidos Therapeutics, Inc, EP Trading Co Ltd, EPG Communication Holdings Ltd, Epizon Pharma, Inc, Esperion Therapeutics, Inc, Everly Well, Inc, Exicon Consulting Pvt Ltd, Faraday Pharmaceuticals, Inc, Foresee Pharmaceuticals Co Ltd, Fortress Biotech, Inc, HDL Therapeutics Inc, HeartFlow Inc, Hummingbird Bioscience, Insmed Inc, Ionis Pharmaceuticals, IQVIA Inc, Janssen and Affiliates, Kowa Research Institute, Inc, Kyushu University, Lexicon Pharmaceuticals, Inc, Medimmune Ltd, Medpace, Merck & Affiliates, Nectero Medical Inc, Novartis Pharmaceuticals Corp, Novo Nordisk, Inc, Osiris Therapeutics Inc, Pfizer Inc, PhaseBio Pharmaceuticals, Inc, PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Inc, Saint Luke’s Hospital of Kansas City, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stanford Center for Clinical Research, Stealth BioTherapeutics Inc, State of Colorado CCPD Grant, The Brigham & Women's Hospital, Inc, The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, Worldwide Clinical Trials Inc, WraSer, LLC, and Yale Cardiovascular Research Group. Dr Ridker has received institutional research grant support from Kowa, Novartis, Amarin, Pfizer, Esperion, Novo Nordisk, and the National Heart, Lung, and Blood Institute (NHLBI); during the past 5 years has served as a consultant to 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; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and has received 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 Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and 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, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, and TIMI Study Group (Brigham Health). Dr Cornel has served on advisory boards for Amgen and AstraZeneca. Dr Lewis has received consulting fees from Janssen R&D and Idorsia. Prof Parkhomenko has received research grants from CSL Behring, Amgen, Novo Nordisk, and Boehringer Ingelheim; and has received consulting or speaking fees from Novo Nordisk, AstraZeneca, Pfizer, Sanofi, and Boehringer Ingelheim. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Aylward has received research support from CSL and Janssen Advisory Board; and has received honoraria and speaker fees from Novartis, Boehringer Ingelheim, Amgen, and AstraZeneca. Dr Lincoff has received honoraria for consulting activities from Novo Nordisk, Eli Lilly, Akebia, Ardelyx, Becton Dickson, Endologix, Fibrogen, GlaxoSmithKline, Medtronic, Neovasc, Provention Bio, ReCor, Brainstorm Cell, Alnylam, and Intarcia; and has received research funding to his institution from AbbVie, Esperion, AstraZeneca, CSL Behring, Novartis, and Eli Lilly. Dr Heise is an employee of CSL Behring. Dr Sacks has received support from CSL Behring. Dr Nicolau is recipient of a scholarship from National Council of Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq) # 303448/2021-0; 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. Prof Merkely has received direct personal payment (speaker fees, studies) from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Medtronic, and Novartis; and has received institutional grants (for the Heart and Vascular Center of Semmelweis University) from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and Vifor Pharma. Dr Trebacz has received research support from CSL Behring. Dr Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; and is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech, Inc; has received research funding to his laboratory in the past 2 years from Novartis, Novo Nordisk, and Genentech; is on the Board of Directors of XBiotech, Inc; has a financial interest in XBiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics; and has received funding support from the NHLBI (1R01HL134892 and 1R01HL163099-01), the RRM Charitable Fund, and the Simard Fund. Dr Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx, and Sanofi-Regeneron; and has served as a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Vaxxinity, CSL Sequiris, and Novo Nordisk. Dr Pocock has served as a consultant for CSL Behring as a member of executive and publications committees. Dr Bhatt discloses the following relationships: Advisory Board: 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, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; Data Monitoring Committees: 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; Rutgers University (for the NIH-funded MINT Trial); Honoraria: 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), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham & Women's Hospital who assigned to Lexicon; neither I nor Brigham & Women's Hospital receive any income from this patent); research funding: 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, 89Bio; royalties: Elsevier (Editor, Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; trustee: American College of Cardiology; unfunded research: FlowCo. Dr Kastelein has served on a clinical trials steering committee for Novartis, NewAmsterdam Pharma, and CSL Behring; has served as a consultant or speaker for Scribe, CiVi Biotech, Draupnir, 89Bio, and Esperion Therapeutics; and is Chief Science Officer at NewAmsterdam Pharma. Dr Bode has received research support from CSL Behring. Dr Mahaffey has received research funding from the American Heart Association, Apple, Inc, Bayer, California Institute of Regenerative medicine, CLS Behring, Eidos, Ferring, Gilead, Google (Verily), Idorsia, Johnson & Johnson, Luitpold, Novartis, PAC-12, Predordior, and Sanifit; has served as a consultant for Applied Therapeutics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson & Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, and Theravance; and has equity in Human, Medeloop, Precordior, and Regencor. Dr Steg has received research grants from Amarin and Sanofi; has served on clinical trials (steering committee, clinical events committee, data and safety monitoring board [DSMB]) for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, CSL Behring, Idorsia, Janssen, Novartis, Novo Nordisk, Pfizer, and Sanofi; has served as a consultant or speaker for Amarin, Amgen, BMS, and Novo Nordisk; and is Senior Associate Editor at Circulation. Dr Tendera has received consultation fees from the PERFUSE Group for participation in the executive committee, sponsored by CSL Behring for meetings of the study; has received consultation fees from Bayer, Janssen-Cilag, Kowa, and Servier for activities unrelated to the study; and has received a lecture honorarium from Bayer. Dr Bainey has received research support from CSL Behring. Dr Harrington has research relationships with Baim Institute (DSMB), CSL (Randomized Controlled Trial [RCT] Executive Committee), Janssen (RCT Chair), NHLBI (RCT Executive Committee; DSMB Chair), PCORI (RCT Co-Chair), and DCRI; has served as a consultant for Atropos Health, Bitterroot Bio, BMS, BridgeBio, Element Science, Edwards Lifesciences, Foresite Labs, and Medscape/WebMD; and has served on the board of directors for American Heart Association, College of the Holy Cross, and Cytokinetics. Dr Mehran has received institutional research payments from Abbott, Abiomed, Affluent Medical, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, AtriCure Inc, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, CERC, Chiesi, Cleerly Health Inc, Concept Medical, Cytosorbents, Daiichi-Sankyo, Duke, Element Science, Essential Medical, Faraday, Idorsia Pharmaceuticals, Janssen, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Population Health Research Institute, Protembis, RecCor Medical Inc, RenalPro, RM Global, Sanofi, Shockwave, Vivasure, and Zoll; has received personal fees from Affluent Medical, Boehringer Ingelheim, Cardiovascular Research Foundation (CRF), Cordis, Daiichi-Sankyo Brasil, E.R. Squibb & Sons, Esperion Science/Innovative Biopharma, Europa Group/Boston Scientific, Gaffney Events, Educational Trust, Henry Ford Health Cardiology, Ionis Pharmaceuticals, Lilly and Company, MedCon International, Novartis, Novo Nordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Vectura, VoxMedia, WebMD, IQVIA, Radcliffe, and TARSUS Cardiology; has served on the Scientific Advisory Board fpr AMA; has served as a Women in Innovations Committee Member for SCAI; has received faculty CRF honorarium from JAMA Cardiology (Associate Editor), ACC (BOT Member, SC Member CTR Program); and has equity <1% in Applied Therapeutics, Elixir Medical, Stel, CntrolRad (spouse). Dr Duerschmied has received speaker honoraria from Daiichi-Sankyo, Bayer Healthcare, Boston Scientific, Pfizer, and AOP Health; and has received consulting fees from Boston Scientific, CSL Behring, and Johnson & Johnson. Dr Kingwell is an employee and shareholder of CSL Ltd. Dr Gibson has received research funding from CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson Corporation, and SCAD Alliance; has received consulting from 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, Fortress Biotech; and has received royalties as contributor to UpToDate., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear., Methods: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up., Results: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group., Conclusions: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment., Methods and Results: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P <0.0001)., Conclusions: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Despite the atherosclerotic cardiovascular disease (ASCVD) risk reduction achieved by low-density lipoprotein cholesterol (LDL-C) lowering therapy, residual ASCVD risk still exists. Previous epidemiological studies have suggested high plasma triglyceride (TG) levels as a risk factor or risk marker for ASCVD independent of LDL-C levels. In this review, we highlighted the underlying pathophysiology of hypertriglyceridaemia, the mechanistic action of therapeutic agents, the interpretation of conflicting results on recent clinical trials, and the present options for primary and secondary prevention. The benefits of fibrates-induced reduction in TG and increase in high-density lipoprotein cholesterol might outweigh the disadvantages of increasing LDL-C levels in primary prevention. In secondary CVD prevention, using eicosapentaenoic acid without docosahexaenoic acid, in addition to statins, will be beneficial. This comprehensive review may prove useful for the development of novel approaches that target hypertriglyceridaemia in future., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence., Methods and Results: RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE ( n = 9), patients with moderate or severe pericardial LGE ( n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence., Conclusions: Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered., Clinicaltrialsgov Identifier: NCT03737110., Competing Interests: P.C. Cremer: Cremer reports grants and personal fees from Kiniksa Pharmaceuticals; grants from Novartis Pharmaceuticals; and personal fees from SOBI Pharmaceuticals outside the submitted work. D. Lin: None. S.A. Luis: Luis reports consultant fees for Kiniksa Pharmaceuticals, SOBI Pharmaceuticals, and Medtronic. J. Petersen: None. A. Abbate: Abbate reports grants and personal fees from Kiniksa Pharmaceuticals during the conduct of the study; grants and personal fees from Olatec, Serpin, Novartis, and Janssen; and personal fees from Novo-Nordisk and Cromos Pharma outside the submitted work. C.L. Jellis: None. D. Kwon: None. A. Brucato: Brucato reports institutional funding from Kiniksa Pharmaceuticals as an investigative site; an unrestricted research grant from SOBI and ACARPIA; and travel and accommodation for the advisory committee from SOBI and Kiniksa Pharmaceuticals. F. Fang: Fang reports personal fees and others from Kiniksa Pharmaceuticals outside the submitted work at the time the study was conducted. A. Insalaco: Insalaco reports personal fees from SOBI. M. LeWinter: LeWinter reports grants and advisory board, consulting, and other fees from Kiniksa Pharmaceuticals outside the submitted work and consulting fees from SOBI Pharmaceuticals outside the submitted work. B.S. Lewis: Lewis reports personal fees from Kiniksa Pharmaceuticals during the conduct of the study. L. Zou: Zou reports personal fees and others from Kiniksa Pharmaceuticals outside the submitted work. S.J. Nicholls: Nicholls reports grants and personal fees from Kiniksa Pharmaceuticals during the conduct of the study; grants and personal fees from AstraZeneca, Anthera, Resverlogix, Sanofi-Regeneron, and Esperion; personal fees from Akcea, Eli Lilly, Omthera, Merck, Takeda, CSL Behring, and Boehringer Ingelheim; and grants from Amgen, Novartis, Abionyx (formerly Cerenis), The Medicines Company, Liposcience, Roche, and InfraReDx outside the submitted work. A.L. Klein: Klein reports grants and others from Kiniksa Pharmaceuticals during the conduct of the study and other fees from Cardiol Therapeutics, SOBI Pharmaceuticals, and Pfizer Pharmaceuticals outside the submitted work. M. Imazio: Imazio reports no disclosures. J.F. Paolini: Paolini reports personal fees and others from Kiniksa Pharmaceuticals outside the submitted work and is a patent inventor on pending patent applications licensed to Kiniksa Pharmaceuticals covering methods of using rilonacept for treating RP., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Polypharmacy management of recurrent pericarditis (RP) often involves long-term therapies, often with negative effects. Slow tapering of oral therapies is often required to avoid recurrence. A post hoc analysis of the phase III trial Rilonacept inHibition of interleukin-1 Alpha and beta for recurrent Pericarditis: a pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated investigator approaches to transitioning to IL-1 blockade monotherapy with rilonacept, which was hypothesised to allow accelerated withdrawal of common multidrug pericarditis regimens., Methods: RHAPSODY was a multicentre (Australia, Israel, Italy, USA), double-blind, placebo-controlled, randomised-withdrawal trial in adults and adolescents with RP. Investigators initiated rilonacept at the labelled dose level and discontinued oral pericarditis therapies during the 12-week run-in; randomised patients received study drug as monotherapy. Time to rilonacept monotherapy was quantified in patients receiving multidrug regimens at baseline who achieved rilonacept monotherapy during run-in., Results: In 86 enrolled patients, mean time to rilonacept monotherapy was 7.9 weeks, with no recurrences. Of these, 64% (n=55) entered on multidrug regimens: non-steroidal anti-inflammatory drugs (NSAIDs) plus colchicine (44% (24/55)), colchicine plus glucocorticoids (24% (13/55)), or NSAIDs, colchicine, plus glucocorticoids (33% (18/55)). Investigators transitioned patients receiving colchicine and glucocorticoids at baseline to rilonacept monotherapy without recurrence regardless of taper approach: sequential (n=14; median, 7.7 weeks) or concurrent (n=17; median, 8.0 weeks). Median time to rilonacept monotherapy was similar regardless of glucocorticoid dose and duration: ≤15 mg/day (n=21): 7.3 weeks; >15 mg/day (n=18): 8.0 weeks; long-term (≥28 days): 7.6 weeks., Conclusions: Rapid discontinuation of oral RP therapies while transitioning to rilonacept monotherapy was feasible without triggering pericarditis recurrence., Trial Registration Number: NCT03737110., Competing Interests: Competing interests: AB reports institutional funding from Kiniksa Pharmaceuticals as an investigative site; an unrestricted research grant from Sobi and Acarpia; and travel and accommodation for advisory committee from Sobi and Kiniksa Pharmaceuticals. AW reports personal fees from Kiniksa Pharmaceuticals during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. AW is a former employee of Kiniksa Pharmaceuticals; the work here was completed during his employment. SAL reports consultant fees for Kiniksa Pharmaceuticals, Sobi Pharmaceuticals and Medtronic. AA reports grants and personal fees from Kiniksa Pharmaceuticals during the conduct of the study; grants and personal fees from Olatec, Serpin, Novartis and Janssen; and personal fees from Novo-Nordisk and Cromos Pharma outside the submitted work. PCC reports grants and personal fees from Kiniksa Pharmaceuticals; grants from Novartis Pharmaceuticals; and personal fees from Sobi Pharmaceuticals outside the submitted work. LZ reports personal fees and other from Kiniksa Pharmaceuticals outside the submitted work. ML reports grants and advisory board, consulting, and other fees from Kiniksa Pharmaceuticals outside the submitted work and consulting fees from Sobi Pharmaceuticals outside the submitted work. BSL reports personal fees from Kiniksa Pharmaceuticals during the conduct of the study. DL reports personal fees from Regeneron outside the submitted work. SN reports grants and personal fees from Kiniksa Pharmaceuticals during the conduct of the study; grants and personal fees from AstraZeneca, Anthera, Resverlogix, Sanofi-Regeneron and Esperion; personal fees from Akcea, Eli Lilly, Omthera, Merck, Takeda, CSL Behring and Boehringer Ingelheim; and grants from Amgen, Novartis, Cerenis, The Medicines Company, Liposcience, Roche and InfraReDx outside the submitted work. ALK reports grants and other from Kiniksa Pharmaceuticals during the conduct of the study and other fees from Cardiol Therapeutics, Sobi Pharmaceuticals and Pfizer Pharmaceuticals outside the submitted work. MI reports other fees from Kiniksa Pharmaceuticals and Sobi outside the submitted work. JFP reports personal fees and other from Kiniksa Pharmaceuticals outside the submitted work and is a patent inventor on pending patent applications licensed to Kiniksa Pharmaceuticals covering methods of using rilonacept for treating recurrent pericarditis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Aims: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE)., Methods and Results: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination., Conclusion: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Awareness of racial/ethnic disparities represents a key challenge for healthcare systems that attempt to provide effective healthcare and to reduce existing inequalities in the use of and adherence to guideline-recommended cardiovascular drugs to improve clinical outcomes for cardiovascular disease (CVD). In this review, we describe important racial/ethnic differences between and within ethnic groups in the prevalence, risk factors, haemostatic factors, anti-inflammatory and endothelial markers, recurrence, and outcomes of CVD. We discuss important differences in the selection, doses, and response [efficacy and adverse drug reactions (ADRs)] in ethnically diverse patients treated with antithrombotics or lipid-lowering drugs. Differences in drug response are mainly related to racial/ethnic differences in the frequency of polymorphisms in genes encoding drug-metabolizing enzymes (DMEs) and drug transporters. These polymorphisms markedly influence the pharmacokinetics, dose requirements, and safety of warfarin, clopidogrel, and statins. This review aims to support a better understanding of the genetic differences between and among populations to identify patients who may experience an ADR or a lack of drug response, thus optimizing therapy and improving outcomes. The greater the understanding of the differences in the genetic variants of DMEs and transporters that determine the differences in the exposure, efficacy, and safety of cardiovascular drugs between races/ethnicities, the greater the probability that personalized medicine will become a reality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Whether diabetes without insulin therapy is an independent cardiovascular (CV) risk factor in atrial fibrillation (AF) has recently been questioned. We investigated the prognostic relevance of diabetes with or without insulin treatment in patients in the ARISTOTLE trial., Methods and Results: Patients with AF and increased stroke risk randomized to apixaban vs. warfarin were classified according to diabetes status: no diabetes; diabetes on no diabetes medications; diabetes on non-insulin antidiabetic drugs only; or insulin-treated. The associations between such patient subgroups and stroke/systemic embolism (SE), myocardial infarction (MI), and CV death were examined by Cox proportional hazard regression, both unadjusted and adjusted for other prognostic variables. Patients with diabetes were younger and had a higher body mass index. Median CHA2DS2VASc score was 4.0 in patients with diabetes and 3.0 in patients without diabetes. We found no significant difference in stroke/SE incidence across patient subgroups. Compared with no diabetes, only insulin-treated diabetes was significantly associated with higher risk. When adjusted for clinical variables, compared with no diabetes, the hazard ratios (HRs) for MI (95% confidence intervals) were for diabetes on no medication: 1.15 (0.62-2.14); for diabetes on non-insulin antidiabetic drugs: 1.32 (0.90-1.94); for insulin-treated diabetes: 2.34 (1.43-3.82); interaction P = 0.008. HRs for CV death were for diabetes on no medication: 1.19 (0.86-166); for diabetes on non-insulin antidiabetic drugs: 1.12 (0.88-1.42); for insulin-treated diabetes 1.85 (1.36-2.53), interaction P = 0.001., Conclusion: In anticoagulated patients with AF, a higher risk of MI and CV death is largely confined to diabetes treated with insulin., (© The Author(s) 2020. Published on behalf of the European Society of Cardiology.)

Aims: Coronary artery disease (CAD) portends worse outcomes in heart failure (HF). We aimed to characterize patients with CAD and worsening HF with reduced ejection fraction (HFrEF) and evaluate post hoc whether vericiguat treatment effect varied according to CAD., Methods and Results: Cox proportional hazards were generated for the primary endpoint of cardiovascular death or HF hospitalization (CVD/HFH). CAD was defined as previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. Of 5048 patients in VICTORIA with available data on CAD status, 2704 had CAD and were older, were more frequently male, diabetic, and had a lower glomerular filtration rate than those without CAD (all p <0.0001). Use of implantable cardioverter defibrillators and cardiac resynchronization therapy (CRT) was higher in patients with versus without CAD (33.5% vs. 21.1%; p <0.0001 and 16.3% vs. 12.8%; p = 0.0006). The primary endpoint of CVD/HFH was higher in those with versus without CAD (40.6 vs. 30.1/100 patient-years; adjusted hazard ratio [HR] 1.23; p <0.001) as was all-cause mortality (17.9% vs. 12.7%; adjusted HR 1.32; p <0.001). The primary outcome of CVD/HFH associated with vericiguat in patients with or without CAD was 38.8 versus 27.6 per 100 patient-years and for placebo was 42.6 versus 32.7 per 100 patient-years (interaction p = 0.78)., Conclusion: In this post hoc study, CAD was associated with more CVD and HFH in patients with HFrEF and worsening HF. Vericiguat was beneficial and safe regardless of concomitant CAD., (© 2022 European Society of Cardiology.)

Heart failure (HF) is a chronic debilitating and potentially life-threatening condition. HF patients are usually at high risk of polypharmacy and consequently, potentially inappropriate prescribing leading to poor clinical outcomes. Based on the published literature, a comprehensive HF-specific prescribing review tool is compiled to avoid medications that may cause HF or harm HF patients and to optimize the prescribing practice of HF guideline-directed medical therapies. Recommendations are made in line with the last versions of European Society of Cardiology (ESC) guidelines, ESC position papers, scientific evidence, and experts' opinions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

There is a strong and ever-growing body of evidence regarding the use of pharmacogenomics to inform cardiovascular pharmacology. However, there is no common position taken by international cardiovascular societies to unite diverse availability, interpretation, and application of such data, nor is there recognition of the challenges of variation in clinical practice between countries within Europe. Aside from the considerable barriers to implementing pharmacogenomic testing and the complexities of clinically actioning results, there are differences in the availability of resources and expertise internationally within Europe. Diverse legal and ethical approaches to genomic testing and clinical therapeutic application also require serious thought. As direct-to-consumer genomic testing becomes more common, it can be anticipated that data may be brought in by patients themselves, which will require critical assessment by the clinical cardiovascular prescriber. In a modern, pluralistic and multi-ethnic Europe, self-identified race/ethnicity may not be concordant with genetically detected ancestry and thus may not accurately convey polymorphism prevalence. Given the broad relevance of pharmacogenomics to areas, such as thrombosis and coagulation, interventional cardiology, heart failure, arrhythmias, clinical trials, and policy/regulatory activity within cardiovascular medicine, as well as to genomic and pharmacology subspecialists, this position statement attempts to address these issues at a wide-ranging level., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources, and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on pharmacogenomics implementation. Clinical workforce upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hypokalaemia is common in patients with cardiovascular disease. In this review, we emphasize the importance of tight potassium regulation in patients with cardiovascular disease based on findings from observational studies. To enhance the understanding, we also describe the mechanisms of potassium homeostasis maintenance, the most common causes of hypokalaemia and present strategies for monitoring and management of low potassium levels. We propose elevation of potassium in asymptomatic patients with lower normal concentrations and concurrent cardiovascular disease. These proposals are intended to assist clinicians until more evidence is available., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

The aim of this collaborative document is to provide an update for clinicians on best antithrombotic strategies in patients with aortic and/or peripheral arterial diseases. Antithrombotic therapy is a pillar of optimal medical treatment for these patients at very high cardiovascular risk. While the number of trials on antithrombotic therapies in patients with aortic or peripheral arterial diseases is substantially smaller than for those with coronary artery disease, recent evidence deserves to be incorporated into clinical practice. In the absence of specific indications for chronic oral anticoagulation due to concomitant cardiovascular disease, a single antiplatelet agent is the basis for long-term antithrombotic treatment in patients with aortic or peripheral arterial diseases. Its association with another antiplatelet agent or low-dose anticoagulants will be discussed, based on patient's ischaemic and bleeding risk as well therapeutic paths (e.g. endovascular therapy). This consensus document aims to provide a guidance for antithrombotic therapy according to arterial disease localizations and clinical presentation. However, it cannot substitute multidisciplinary team discussions, which are particularly important in patients with uncertain ischaemic/bleeding balance. Importantly, since this balance evolves over time in an individual patient, a regular reassessment of the antithrombotic therapy is of paramount importance., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

This review article aims to explain the important issues that data safety monitoring boards (DSMB) face when considering early termination of a trial and is specifically addressed to the needs of clinical and research cardiologists. We give an insight into the overall background and then focus on the three principal reasons for stopping trials, i.e. efficacy, futility, and harm. The statistical essentials are also addressed to familiarize clinicians with the key principles. The topic is further highlighted by numerous examples from lipid trials and antithrombotic trials. This is followed by an overview of regulatory aspects, including an insight into industry-investigator interactions. To conclude, we summarize the key elements that are the basis for a decision to stop a randomized clinical trial (RCT)., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Aims: Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. There was no benefit of blood pressure (BP) lowering treatment in the overall group, but a reduction in events in the third of participants with elevated systolic BP. After cessation of all the trial medications, we examined whether the benefits observed during the active treatment phase were sustained, enhanced, or attenuated., Methods and Results: After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up. During 3.1 years of post-trial observation (total follow-up of 8.7 years), participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64-0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68-1.01). Therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69-0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69-0.89, P = 0.002). There was no benefit of BP lowering in the overall study either during the active or post-trial observation period, however, a 24% reduction in MACE-1 was observed over 8.7 years., Conclusion: The CV benefits of rosuvastatin, and BP lowering in those with elevated systolic BP, compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect., Trial Registration Number: NCT00468923., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population., Methods and Results: The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM., Conclusion: In iron-deficient patients with HF and left ventricular ejection fraction <50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Purpose: The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups., Methods: Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed., Results: Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72])., Conclusions: Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00468923.

Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels., Methods and Results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026)., Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels., (© 2020 European Society of Cardiology.)

Aims: The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug., Methods/results: We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation., Conclusion: Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation., Competing Interests: Competing interests: AC reports grant funding from the National Institutes of Health. SMA-K reports grants and personal fees from Medtronic, grants and personal fees from Abbott, personal fees from Bristol Myer Squibb, personal fees from Pfizer, outside the submitted work. DX reports grants from Cadila Pharmaceuticals, grants from Boehringer Ingelheim, grants from Astra Zeneca India, grants from Sanofi Aventis, grants from Pfizer, grants from Bristol Myers Squibb, grants from United Kingdom Medical Research Council, grants from Wellcome Trust, outside the submitted work. BSL reports grants and personal fees from Pfizer, personal fees from BMS, during the conduct of the study; grants from Bayer Healthcare, grants from Daiichi Sankyo, outside the submitted work. MH reports other from BRISTOL-MYERS SQUIBB, during the conduct of the study; other from BRISTOL-MYERS SQUIBB, outside the submitted work. JHA reports grants from Bristol-Myers Squibb during the conduct of the study; personal fees from AbbVie, grants from Astra Zeneca, grants and personal fees from Bayer, grants from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from CryoLife, grants and personal fees from CSL Behring, grants from Ferring, grants from GlaxoSmithKline, personal fees from Novo Nordisk, personal fees from Pfizer, personal fees from Portola, grants and personal fees from XaTek outside the submitted work. RDL reports other from Bayer, other from Boehringer Ingleheim, grants and other from Bristol-Myers Squibb, other from Daiichi Sankyo, grants and other from Glaxo Smith Kline, grants and other from Medtronic, other from Merck, grants and other from Pfizer, other from Portola, grants and other from Sanofi, outside the submitted work. LW reports grants from Bristol-Myers Squibb/Pfizer, during the conduct of the study; grants from AstraZeneca, grants from GlaxoSmithKline, grants from Merck & Co, from Abbott, grants from Roche, grants from Boehringer Ingelheim, outside the submitted work; In addition, LW has a patent EP2047275B1 licensed to Roche Diagnostics, and a patent US8951742B2 licensed to Roche Diagnostics. CBG reports grants and personal fees from Bristol Myers Squibb, grants and personal fees from Pfizer, during the conduct of the study; personal fees from Abbvie, grants from AKROS, grants from Apple, grants from AstraZeneca, personal fees from Bayer Corporation US, grants and personal fees from Boehringer Ingelheim, personal fees from Boston Scientific Corporation, personal fees from CeleCor Therapeutics, personal fees from Correvio, grants from Daiichi Sankyo, personal fees from Espero BioPharma, grants from Glaxo SmithKline, grants and personal fees from Janssen Pharaceutica Products, LP, personal fees from Medtronic Inc, grants from Medtronic Foundation, personal fees from Merck, personal fees from Novo Nordisk, grants from Novartis Pharmaceutical Company, personal fees from Rhoshan Pharmaceuticals, personal fees from Roche Diagnostics, outside the submitted work. For complete disclosures, see https://dcri.org/about-us/conflict-of-interest/., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis., Methods: We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed., Results: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections., Conclusions: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.)., (Copyright © 2020 Massachusetts Medical Society.)

Introduction: Coronary artery disease and malignancy occur more frequently in patients with type 2 diabetes. They may share inflammation as a possible common pathogenetic mechanism, but it is unclear whether a clinical correlation exists between them., Methods: This prospective cohort study followed 735 asymptomatic diabetics, aged 63.4 ± 5.3 years (mean ± standard deviation) for 12.2 ± 0.6 years after baseline coronary artery calcium scoring and cardiac computed tomography angiography. We examined extent and nature of coronary atherosclerosis and incidence of clinical cardiovascular (CV) events (death or myocardial infarction) and sought a relation to incidence of malignancy and malignancy mortality., Results: Total mortality was 16.5% (121/735 patients): malignancy was cause of death in 48/121 (39.7%) of these and CV events in 44/121 (36.3%). There was no relation between extent of coronary atherosclerosis and incident malignancy (plaque volume 127 [21, 427] mm3 (median [interquartile range]) for incident malignancy versus 153 [24, 427] mm3 no malignancy, p = 0.71) or death from malignancy (plaque volume 176 [26, 646] versus 144 [22, 411] mm3, p = 0.32). There was also no relation between presence of high-risk plaque and incident malignancy (high-risk plaque in 27.1% with malignancy vs. 21.6% without, p = 0.18) or fatal malignancy (p = 0.16). Incident and fatal malignancy were not related to clinical CV events. Independent predictors of incident and fatal malignancy were age, smoking at baseline, and elevated C-reactive protein., Conclusion: This study found no relation between extent of coronary atherosclerosis or incidence of CV events and malignancy. Malignancy surpassed CV disease as the commonest long-term cause of mortality in middle-aged and older diabetics., (© 2021 S. Karger AG, Basel.)

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure., Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed., Findings: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group., Interpretation: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death., Funding: Vifor Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: The 2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol identified patients with recent (past 12 months) myocardial infarction (MI) as very high risk, in whom a PCSK9 inhibitor is reasonable to add to maximally tolerated statin combined with ezetimibe if their low-density lipoprotein cholesterol level is 70 mg/dL or greater or non-high-density lipoprotein cholesterol level is 100 mg/dL or greater., Objective: To examine the clinical efficacy of evolocumab in patients with recent MI., Design, Setting, and Participants: This was a prespecified secondary analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, in which 27 564 patients with atherosclerotic cardiovascular disease treated with a statin were randomized to evolocumab vs placebo. Patients with prior MI with a known date (n = 22 320) were stratified as having a recent MI (within 12 months of randomization) or a remote MI (more than 12 months prior to randomization). Per protocol, patients with MI within 4 weeks prior to randomization were excluded from the FOURIER trial. Data were collected from February 2013 to November 2016, and data were analyzed from May 2019 to February 2020., Main Outcomes and Measures: The primary composite end point was cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary composite end point was cardiovascular death, MI, or stroke., Results: Of 22 320 included patients, 17 516 (78.5%) were male, and the mean (SD) age was 62.2 (9.0) years. Compared with 16 609 patients with a remote MI, 5711 patients with a recent MI were younger and more likely to be treated with high-intensity statin (77.3% [4415] vs 69.3% [11 506]). In the placebo arm, the 3-year Kaplan-Meier rate for the primary end point was 17.2% in patients with recent MI compared with 14.4% in those with remote MI (adjusted HR, 1.45; 95% CI, 1.29-1.64; P < .001). Similarly, the 3-year Kaplan-Meier rates for the key secondary end point was also higher in those with recent MI (10.9% vs 9.5%; adjusted HR, 1.45; 95% CI, 1.24-1.69; P < .001). In patients with a recent MI, evolocumab reduced the risk of the primary and key secondary end points by 19% (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93) and 25% (HR, 0.75; 95% CI, 0.62-0.91), respectively. In patients with a remote MI, evolocumab reduced the risk of the primary and key secondary end points by 8% (HR, 0.92; 95% CI, 0.84-1.01; P for interaction = .13) and 15% (HR, 0.85; 95% CI, 0.76-0.96; P for interaction = .24), respectively. Given the higher event rates in patients with a recent MI, the absolute risk reductions over 3 years with evolocumab were 3.7% in those with recent MI vs 1.1% in those with remote MI for the primary end point and 3.2% vs 1.3%, respectively, for the key secondary end point., Conclusions and Relevance: Patients with a recent MI were at higher risk of cardiovascular events and tended to experience greater absolute risk reductions with evolocumab than those with remote MIs. These findings support the concept in US and European guidelines to aggressively lower low-density lipoprotein cholesterol levels in very high-risk patients, such as those with a recent MI., Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Importance: The PCSK9 inhibitor evolocumab reduced major vascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, yet the types and sizes of myocardial outcomes in FOURIER have not been previously explored., Objective: To assess the types and sizes of myocardial infarction (MI) and the effect of evolocumab on MI by subtype., Design, Setting, and Participants: A prespecified analysis of a multicenter double-blind randomized clinical trial. Patients were randomized to evolocumab or placebo and followed up for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Clinical end points were evaluated by the Thrombolysis in Myocardial Infarction clinical events committee. Rates presented are 3-year Kaplan-Meier estimates. Data were collected from 2013 to 2016 and analyzed from June 2017 to December 2019., Main Outcomes and Measures: Myocardial infarction was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass, ST-segment elevation myocardial infarction [STEMI] vs non-STEMI) and by MI size (determined by peak troponin level)., Results: A total of 27 564 patients were randomized, with a mean (SD) age of 62.5 (9.0) years, and 20 795 (75%) were male. Of these, 1107 patients experienced a total of 1288 MIs. Most MIs (68%) were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention-related (type 4). Sudden death (type 3) and coronary artery bypass grafting-related (type 5) accounted for a total of 21 MIs (<2%). Evolocumab significantly reduced the risk of first MI by 27% (4.4% vs 6.3%; hazard ratio [HR], 0.73; 95% CI, 0.65-0.82; P < .001), type 1 by 32% (2.9% vs 4.5%; HR, 0.68; 95% CI, 0.59-0.79; P < .001), and type 4 by 35% (0.8% vs 1.1%; HR, 0.65; 95% CI, 0.48-0.87; P = .004), with no effect on type 2 (0.9% vs 0.8%; HR, 1.09; 95% CI, 0.82-1.45; P = .56). Most MIs (688 [59.8%]) had troponin levels greater than or equal to 10 times the upper limit of normal. The benefit was highly significant and consistent regardless of the size of MI with a 34% reduction in MIs with troponin level greater than or equal to 10 times the upper limit of normal (2.6% vs 3.7%; HR, 0.66; 95% CI, 0.56-0.77; P < .001) and a 36% reduction in the risk of STEMI (1.0% vs 1.5%; HR, 0.64; 95% CI, 0.49-0.84; P < .001)., Conclusions and Relevance: Low-density lipoprotein cholesterol lowering with evolocumab was highly effective in reducing the risk of MI. This reduction with evolocumab included benefit across multiple subtypes of MI related to plaque rupture, smaller and larger MIs, and both STEMI and non-STEMI. These data are consistent with the known benefit of low-density lipoprotein cholesterol lowering and underscore the reduction in clinically meaningful events., Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events., Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding., Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P =0.002; and hazard ratio, 0.77, P =0.005, respectively, P interaction =0.77) and all-cause mortality (hazard ratio, 0.81, P =0.05; and hazard ratio, 0.84, P =0.09, respectively; P interaction =0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative P interaction <0.0001; 1.9% versus 0.6% for all-cause mortality, P interaction =0.02; 2.7% versus 1.7% for major vascular events, P interaction <0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative P interaction =0.001)., Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%., Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease., Interventions: Patients were randomized 1:1 to evolocumab or placebo., Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020., Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model., Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment., Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial., Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Background: The COMPASS trial (Cardiovascular Outcomes for People using Anticoagulation Strategies) demonstrated that dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily reduced the primary major adverse cardiovascular event (MACE) outcome of cardiovascular death, myocardial infarction, or stroke, as well as, mortality, in patients with chronic coronary syndromes or peripheral arterial disease. Whether this remains true in patients with a history of percutaneous coronary intervention (PCI) is unknown., Methods: In a prespecified subgroup analysis from COMPASS, we examined the outcomes of patients with chronic coronary syndrome with or without a previous PCI treated with DPI versus aspirin alone. Among patients with a previous PCI, we studied the effects of treatment according to the timing of the previous PCI., Results: Of the 27 395 patients in COMPASS, 16 560 patients with a chronic coronary syndrome were randomly assigned to DPI or aspirin, and, of these, 9862 (59.6%) had previous PCI (mean age 68.2±7.8, female 19.4%, diabetes mellitus 35.7%, previous myocardial infarction 74.8%, multivessel PCI 38.0%). Average time from PCI to randomization was 5.4 years (SD, 4.4) and follow-up was 1.98 (SD, 0.72) years. Regardless of previous PCI, DPI versus aspirin produced consistent reductions in MACE (PCI: 4.0% versus 5.5%; hazard ratio [HR], 0.74 [95% CI, 0.61-0.88]; no PCI: 4.4% versus 5.7%; HR, 0.76 [95% CI, 0.61-0.94], P -interaction=0.85) and mortality (PCI: 2.5% versus 3.5%; HR, 0.73 [95% CI, 0.58-0.92]; no PCI: 4.1% versus 5.0%; HR, 0.80 [95% CI, 0.64-1.00], P -interaction=0.59), but increased major bleeding (PCI: 3.3% versus 2.0%; HR, 1.72 [95% CI, 1.34-2.21]; no PCI: 2.9% versus 1.8%; HR, 1.58 [95% CI, 1.15-2.17], P -interaction=0.68). In those with previous PCI, DPI compared with aspirin produced consistent (robust) reductions in MACE irrespective of time since previous PCI (as early as 1 year and as far as 10 years; P -interaction=0.65), irrespective of having a previous myocardial infarction ( P -interaction=0.64)., Conclusions: DPI compared with aspirin produced consistent reductions in MACE and mortality but with increased major bleeding with or without previous PCI. Among those with previous PCI 1 year and beyond, the effects on MACE and mortality were consistent irrespective of time since last PCI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Randomized clinical trials (RCTs) are important and the Gold Standard for drugs in modern cardiovascular (CV) therapy. The cornerstone of RCTs is the recording of hard clinical endpoints instead of surrogates. It is important to select an appropriate endpoint. Efficacy endpoints must be clinically relevant and can be hierarchically divided. A very interesting innovation in endpoint acquisition is the total event paradigm., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: The role and selection of antithrombotic therapy to improve limb outcomes in chronic lower extremity artery disease (LEAD) is still debated. We conducted a meta-analysis to examine the efficacy and safety of antithrombotic and more intense antithrombotic therapy on limb outcomes and limb salvage in patients with chronic LEAD., Methods and Results: Study inclusion criteria were: enrolment of patients with LEAD, randomized allocation to more vs. less intense antithrombotic therapy [more vs. less intense single-antiplatelet therapy (SAPT); dual-antiplatelet therapy vs. SAPT; dual antithrombotic therapy vs. SAPT or oral anticoagulant]; enrolment of ≥200 patients; reporting of at least one of following outcomes: limb amputation or revascularization. Seven randomized studies enrolling 30 447 patients were included. Over a median follow-up of 24 months, more vs. less intense antithrombotic therapy or placebo significantly reduced the risk of limb revascularization [relative risk (RR) 0.89, 95% confidence interval (CI) 0.83-0.94] and limb amputation (RR 0.63, 95% CI 0.46-0.86), as well as stroke (RR 0.82, 95% CI 0.70-0.97). There was no statistically significant effect on the risk of myocardial infarction (RR 0.98, 95% CI 0.87-1.11), all-cause (RR 0.93, 95% CI 0.86-1.01), and cardiovascular death (RR 0.97, 95% CI 0.86-1.08). Risk of major bleeding increased (RR 1.23, 95% CI 1.04-1.44)., Conclusion: In patients with LEAD, more intense antithrombotic therapy reduces the risk of limb amputation and revascularization as well as stroke with an increase in the risk of bleeding events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: The COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI) trial demonstrated that staged nonculprit lesion percutaneous coronary intervention (PCI) reduced major cardiovascular (CV) events in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD)., Objectives: The purpose of this study was to determine the effect of nonculprit-lesion PCI timing on major CV outcomes and also the time course of the benefit of complete revascularization., Methods: Following culprit-lesion PCI, 4,041 patients with STEMI and multivessel CAD were randomized to staged nonculprit-lesion PCI or culprit-lesion only PCI. Randomization was stratified according to investigator-planned timing of nonculprit-lesion PCI: during or after the index hospitalization. The first coprimary outcome was the composite of CV death or myocardial infarction (MI). In pre-specified analyses, hazard ratios (HRs) were calculated for each time stratum. Landmark analyses of the entire population were performed within 45 days and after 45 days., Results: For nonculprit-lesion PCI planned during the index hospitalization (actual time: median 1 day), CV death or MI was reduced with complete revascularization compared with culprit-lesion only PCI (HR: 0.77; 95% confidence interval [CI]: 0.59 to 1.00). For nonculprit lesion PCI planned to occur after hospital discharge (actual time: median 23 days), CV death or MI was also reduced with complete revascularization (HR: 0.69; 95% CI: 0.49 to 0.97; interaction p = 0.62). Landmark analyses demonstrated an HR of 0.86 (95% CI: 0.59 to 1.24) during the first 45 days and 0.69 (95% CI: 0.54 to 0.89) from 45 days to the end of follow-up for intended nonculprit lesion PCI versus culprit lesion only PCI., Conclusions: Among STEMI patients with multivessel disease, the benefit of complete revascularization over culprit-lesion only PCI was consistent irrespective of the investigator-determined timing of nonculprit-lesion intervention. The benefit of complete revascularization on hard clinical outcomes emerged mainly over the long term., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI., Methods: Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y 12 inhibitor. We explored bleeding, death and hospitalization, as well as death and ischemic events, by antithrombotic strategy in 3 prespecified subgroups: patients with ACS treated medically, patients with ACS treated with PCI, and those undergoing elective PCI., Results: Of 4614 patients enrolled, 1097 (23.9%) had ACS treated medically, 1714 (37.3%) had ACS treated with PCI, and 1784 (38.8%) had elective PCI. Apixaban compared with vitamin K antagonist reduced International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding in patients with ACS treated medically (hazard ratio [HR], 0.44 [95% CI, 0.28-0.68]), patients with ACS treated with PCI (HR, 0.68 [95% CI, 0.52-0.89]), and patients undergoing elective PCI (HR, 0.82 [95% CI, 0.64-1.04]; P interaction =0.052) and reduced death or hospitalization in the ACS treated medically (HR, 0.71 [95% CI, 0.54-0.92]), ACS treated with PCI (HR, 0.88 [95% CI, 0.74-1.06]), and elective PCI (HR, 0.87 [95% CI, 0.72-1.04]; P interaction =0.345) groups. Compared with vitamin K antagonists, apixaban resulted in a similar effect on death and ischemic events in the ACS treated medically, ACS treated with PCI, and elective PCI groups ( P interaction =0.356). Aspirin had a higher rate of bleeding than did placebo in patients with ACS treated medically (HR, 1.49 [95% CI, 0.98-2.26]), those with ACS treated with PCI (HR, 2.02 [95% CI, 1.53-2.67]), and those undergoing elective PCI (HR, 1.91 [95% CI, 1.48-2.47]; P interaction =0.479). For the same comparison, there was no difference in outcomes among the 3 groups for the composite of death or hospitalization ( P interaction =0.787) and death and ischemic events ( P interaction =0.710)., Conclusions: An antithrombotic regimen consisting of apixaban and a P2Y 12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have ACS, whether managed medically or with PCI, and those undergoing elective PCI compared with regimens that include vitamin K antagonists, aspirin, or both., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02415400.

The European Society of Cardiology (ESC) has published a series of guidelines on heart failure (HF) over the last 25 years, most recently in 2016. Given the amount of new information that has become available since then, the Heart Failure Association (HFA) of the ESC recognized the need to review and summarise recent developments in a consensus document. Here we report from the HFA workshop that was held in January 2019 in Frankfurt, Germany. This expert consensus report is neither a guideline update nor a position statement, but rather a summary and consensus view in the form of consensus recommendations. The report describes how these guidance statements are supported by evidence, it makes some practical comments, and it highlights new research areas and how progress might change the clinical management of HF. We have avoided re-interpretation of information already considered in the 2016 ESC/HFA guidelines. Specific new recommendations have been made based on the evidence from major trials published since 2016, including sodium-glucose co-transporter 2 inhibitors in type 2 diabetes mellitus, MitraClip for functional mitral regurgitation, atrial fibrillation ablation in HF, tafamidis in cardiac transthyretin amyloidosis, rivaroxaban in HF, implantable cardioverter-defibrillators in non-ischaemic HF, and telemedicine for HF. In addition, new trial evidence from smaller trials and updated meta-analyses have given us the chance to provide refined recommendations in selected other areas. Further, new trial evidence is due in many of these areas and others over the next 2 years, in time for the planned 2021 ESC guidelines on the diagnosis and treatment of acute and chronic heart failure., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)