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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.)

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.)

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: 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: 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.)