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Background and Aims: Cardiogenic shock (CS) remains the primary cause of in-hospital death after acute coronary syndromes (ACS), with its plateauing mortality rates approaching 50%. To test novel interventions, personalized risk prediction is essential. The ORBI (Observatoire Régional Breton sur l'Infarctus) score represents the first-of-its-kind risk score to predict in-hospital CS in ACS patients undergoing percutaneous coronary intervention (PCI). However, its sex-specific performance remains unknown, and refined risk prediction strategies are warranted., Methods: This multinational study included a total of 53 537 ACS patients without CS on admission undergoing PCI. Following sex-specific evaluation of ORBI, regression and machine-learning models were used for variable selection and risk prediction. By combining best-performing models with highest-ranked predictors, SEX-SHOCK was developed, and internally and externally validated., Results: The ORBI score showed lower discriminative performance for the prediction of CS in females than males in Swiss (area under the receiver operating characteristic curve [95% confidence interval]: 0.78 [0.76-0.81] vs. 0.81 [0.79-0.83]; P =.048) and French ACS patients (0.77 [0.74-0.81] vs. 0.84 [0.81-0.86]; P = .002). The newly developed SEX-SHOCK score, now incorporating ST-segment elevation, creatinine, C-reactive protein, and left ventricular ejection fraction, outperformed ORBI in both sexes (females: 0.81 [0.78-0.83]; males: 0.83 [0.82-0.85]; P < .001), which prevailed following internal and external validation in RICO (females: 0.82 [0.79-0.85]; males: 0.88 [0.86-0.89]; P < .001) and SPUM-ACS (females: 0.83 [0.77-0.90], P = .004; males: 0.83 [0.80-0.87], P = .001)., Conclusions: The ORBI score showed modest sex-specific performance. The novel SEX-SHOCK score provides superior performance in females and males across the entire spectrum of ACS, thus providing a basis for future interventional trials and contemporary ACS management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS)., Methods: Plasma cDPP3 levels were assessed at baseline and 12-24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787)., Results: Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05-1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36-2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28-2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12-24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86-37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70-12.42, P < .001). Results were consistent across various patient subgroups., Conclusions: This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets., Methods and Results: Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid., Conclusion: The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown., Methods and Results: An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200-1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17-1.31 and HR: 1.16, 95% CI: 1.05-1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90-1.06 and HR: 0.87, 95% CI: 0.39-1.92, respectively)., Conclusion: Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS., Competing Interests: Conflict of interest: E.T.K. reports receiving lecture fees from Astellas, Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly Japan KK, Daiichi-Sankyo, Menarini, Ono Pharmaceutical, Ootsuka Pharmaceutical, MSD KK, Takeda Pharmaceutical, Tanabe-Mitsubishi, Bayer, Pfizer; consultant fee from Boehringer Ingelheim and Daiichi-Sankyo; research fund from Abbott, Ono Pharmaceutical, and Tanabe-Mitsubishi; D.M. reports grants to the Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, AstraZeneca, Eisai, Medicines Co., Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; and consultant fees from InCardia, Inflammatix, Merck & Co, Novartis, and Roche Diagnostics. D.M. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, The Medicines Company, and Zora Biosciences; J.G. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s from Abbott Laboratories, Amgen; AstraZeneca; Critical Diagnostics, Daiichi-Sankyo; Eisai; Genzyme; Gilead; GlaxoSmithKline; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Poxel; Roche Diagnostics; and Takeda; D.D.B. is supported by Harvard Catalyst KL2/CMeRIT (NIH/NCATS grant UL 1TR002541). He has received research grant support to his institution from AstraZeneca and Pfizer; consulting fees from AstraZeneca; and participates on a clinical endpoint committee for a study sponsored by Kowa Pharmaceuticals. M.B. has no conflict of interest; E.A.B. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., The Medicines Company, Zora Biosciences. E.A.B. has received personal fees from Servier, Kowa, Medscape, Novo Nordisk, Amgen, PriMed and Merck; M.P.B. is the Executive Director of CPC, a non-profit academic research organization affiliated with the University of Colorado, that receives research grant/consulting funding from: Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AstraZeneca, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, Bristol-Myers Squibb, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, NovoNordisk, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Ciosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, Yale Cardiovascular Research Group. M.P.B. also reports stock in Medtronic and Pfizer and consulting fees from Audent; C.P.C. reports research grants from: Amgen, Better Therapeutics, Boehringer-Ingelheim (BI), Bristol-Myers Squibb (BMS), Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer, Consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, and Sanofi. C.P.C. serve on Data and Safety Monitoring Boards for the Veteran’s Administration, Applied Therapeutics and NovoNordisk; J.A.d.L reports grant support from Roche Diagnostics and Abbott Diagnostics, consulting fees from Ortho Clinical Diagnostics, Siemen’s Health Care Diagnostics, Beckman Coulter, and Quidel; R.P.G. reports clinical trials/research support from Amgen, Anthos Therapeutics, Daiichi Sankyo, honoraria for Lectures/CME Programs for Amgen, Centrix, Daiichi Sankyo, Dr. Reddy’s Laboratories, Medical Education Resources (MER), Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, Voxmedia, Consultant fee from Amarin, Amgen, Boston Scientific, CryoLife, CSL Behring, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Lukes, Samsung; P.J. reports research support from Abbott Laboratories, Amgen, Inc., AstraZeneca, LP, Daiichi-Sankyo, Inc., GlaxoSmithKline, Merck & Co., Inc., Regeneron, Roche Diagnostics Corporation, and Siemens Healthineers; T.K. has been a paid consultant for and/or received honoraria payments from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Edwards, Novartis, Pharmacosmos, and Vifor and has received research support from Vifor; K.N. reports research funding through Duke University from Roche Diagnostics; Consulting honoraria from Beckman-Coulter; M.O’. reports Grants via Brigham and Women’s Hospital from Amgen, Novartis, AstraZeneca, Janssen, Intarcia, Merck, Pfizer. Honararia from Novartis, AstraZeneca, Amgen, Janssen; M.A.P. reports Research Grant Support from Novartis; consultant to AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, DalCor, GlaxoSmithKline, Lexicon, NHLBI CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge and Sanofi; and has equity in DalCor; N.R. has no conflic of interest; S.D.W. reports research grants from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Janssen, and Merck. He reports consulting fees from AstraZeneca, Boston Clinical Research Institute, ICON Clinical, Novo Nordisk. Spouse, Dr. Caroline Fox is an employee of Merck. S.D.W. is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences; S.D.W. has been a paid consultant for and has received research support from Boehringer Ingelheim, and has received honoraria payments from Roche Diagnostics. T.K. and S.D.W. hold patents (EP 2047275 B1 and US 8951742) and have a licensing contract with Roche Diagnostics related to GDF-15; E.B. reports research grants through his institution from Astra Zeneca, Daiichi Sankyo, Merck and Novartis, and consultancies with Amgen, Boehringer-Ingelheim/Lilly, Bristol Myers Squibb, Cardurion, Novo Nordisk, and Verve; M.S. report research grant support through Brigham and Women’s Hospital from Amgen; Anthos Therapeutics; AstraZeneca; Bayer; Daiichi-Sankyo; Eisai; Intarcia; Ionis; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Quark Pharmaceuticals. Consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Bristol-Myers Squibb; DalCor; Dr. Reddy’s Laboratories; Fibrogen; Intarcia; Merck; Moderna; Novo Nordisk; Silence Therapeutics. Additionally, M.S. is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, ARCA Biopharma, Inc., Janssen Research and Development, LLC, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, Regeneron, Roche, and Zora Biosciences., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial. Recent randomized controlled trials (RCTs) and long-term follow-up data have yet to be included in a contemporary meta-analysis., Methods and Results: A systematic review of RCTs that compared an early IS vs. delayed IS for NSTE-ACS was conducted by searching MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. A meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. This study was registered with PROSPERO (CRD42021246131). Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality [RR: 0.90, 95% confidence interval (CI): 0.78-1.04], MI (RR: 0.86, 95% CI: 0.63-1.16), admission for HF (RR: 0.66, 95% CI: 0.43-1.03), repeat re-vascularization (RR: 1.04, 95% CI: 0.88-1.23), major bleeding (RR: 0.86, 95% CI: 0.68-1.09), or stroke (RR: 0.95, 95% CI: 0.59-1.54) were observed. Recurrent ischaemia (RR: 0.57, 95% CI: 0.40-0.81) and length of stay (median difference: -22 h, 95% CI: -36.7 to -7.5 h) were reduced with an early IS., Conclusion: In all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, or increase major bleeding or stroke when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS., Competing Interests: Conflict of interest: S.A.K. reports personal fees from Bayer. C.P.G. reports personal fees from AstraZeneca, personal fees from Amgen, personal fees from Bayer, grants from BMS, personal fees from Boehrinher-Ingelheim, personal fees from Chiesi, personal fees from Daiichi Sankyo, personal fees from Vifor Pharma, grants from Abbott, personal fees from Menarini, personal fees from Wondr Medical, personal fees from Raisio Group, personal fees from Zydus, personal fees from Oxford University Press, grants from Abbott Diabetes, grants from BMS grants from British Heart Foundation, grants from NIHR, grant from Horizon 2020, grants from ESC, outside the submitted work. N.C. reports unrestricted research grants from Boston Scientific, HeartFlow, Beckman Coulter, and speaker/consultancy fees from Boston, Abbott, HeartFlow outside the submitted work. A.P.B. reports speaker fees from Boston Scientific, Medtronic, Abbott, and Miracor. G.P.M. reports research grants from NIHR, BHF, MRC, and AstraZeneca outside the submitted the work. The remaining authors have no conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo., Methods and Results: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF., Conclusion: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention., (© 2019 The Authors. The European Heart Journal is published on behalf of the European Society of Cardiology, Inc., by Oxford University Press. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is non-commercial, and no modifications or adaptations are made.)

Aims: After percutaneous coronary intervention (PCI) in patients with atrial fibrillation, safety and efficacy with dabigatran dual therapy were evaluated in pre-specified subgroups of patients undergoing PCI due to acute coronary syndrome (ACS) or elective PCI, and those receiving ticagrelor or clopidogrel treatment., Methods and Results: In the RE-DUAL PCI trial, 2725 patients were randomized to dabigatran 110 mg or 150 mg with P2Y12 inhibitor, or warfarin with P2Y12 inhibitor and aspirin. Mean follow-up was 14 months, 50.5% had ACS, and 12% received ticagrelor. The risk of the primary endpoint, major or clinically relevant non-major bleeding event, was reduced with both dabigatran dual therapies vs. warfarin triple therapy in patients with ACS [hazard ratio (95% confidence interval), 0.47 (0.35-0.63) for 110 mg and 0.67 (0.50-0.90) for 150 mg]; elective PCI [0.57 (0.43-0.76) for 110 mg and 0.76 (0.56-1.03) for 150 mg]; receiving ticagrelor [0.46 (0.28-0.76) for 110 mg and 0.59 (0.34-1.04) for 150 mg]; or clopidogrel [0.51 (0.41-0.64) for 110 mg and 0.73 (0.58-0.91) for 150 mg], all interaction P-values >0.10. Overall, dabigatran dual therapy was comparable to warfarin triple therapy for the composite endpoint of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization, with minor variations across the subgroups, all interaction P-values >0.10., Conclusion: The benefits of both dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy in reducing bleeding risks were consistent across subgroups of patients with or without ACS, and patients treated with ticagrelor or clopidogrel., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS)., Methods and Results: Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events., Conclusion: Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

Aims: Near-infrared spectroscopy (NIRS) is able to quantify cholesterol within coronary arteries by the lipid core burden index (LCBI). We studied the prognostic value of NIRS-derived LCBI in patients with coronary artery disease (CAD) for adverse cardiac outcome during long-term follow-up., Methods and Results: During 2009-2013, NIRS was performed in a non-culprit artery of 275 patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina. LCBI was quantified by an independent corelab for the region of interest (LCBIROI) and the 4 and 10 mm long segment with the maximum LCBI (MaxLCBI4mm and MaxLCBI10mm). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, non-fatal ACS, or unplanned revascularization. Hazard ratios (HR) were adjusted for age, gender, clinical risk factors, and segment plaque burden based on intravascular ultrasound. During a median follow-up of 4.1 years, 79 patients (28.7%) had MACE. There was a statistically significant and independent continuous relationship between higher MaxLCBI4mm values and a higher risk of MACE. Each 100 units increase of MaxLCBI4mm was associated with a 19% increase in MACE [hazard ratios (HR) 1.19, 95% confidence intervals (95% CI): 1.07-1.32, P = 0.001]. Continuous MaxLCBI4mm remained independently associated with MACE after exclusion of target lesion-related events (HR 1.21, 95% CI: 1.08-1.35), as well as after exclusion of adverse events related to the NIRS-imaged coronary segment (HR 1.19, 95% CI: 1.06-1.34). Results for MaxLCBI10mm were comparable., Conclusion: NIRS-derived LCBI is associated with adverse cardiac outcome in CAD patients during long-term follow-up independent of clinical risk factors and plaque burden., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L)., Methods and Results: The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91)., Conclusion: Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed., Trial No: UMIN000002742, registered as an International Standard Randomized Controlled Trial., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology)

Aims: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS., Methods and Results: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79)., Conclusions: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel., Trial Registration: ClinicalTrials.gov identifier: NCT00699998., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: We aimed to assess the prevalence and management of clinical familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS)., Methods and Results: We studied 4778 patients with ACS from a multi-centre cohort study in Switzerland. Based on personal and familial history of premature cardiovascular disease and LDL-cholesterol levels, two validated algorithms for diagnosis of clinical FH were used: the Dutch Lipid Clinic Network algorithm to assess possible (score 3-5 points) or probable/definite FH (>5 points), and the Simon Broome Register algorithm to assess possible FH. At the time of hospitalization for ACS, 1.6% had probable/definite FH [95% confidence interval (CI) 1.3-2.0%, n = 78] and 17.8% possible FH (95% CI 16.8-18.9%, n = 852), respectively, according to the Dutch Lipid Clinic algorithm. The Simon Broome algorithm identified 5.4% (95% CI 4.8-6.1%, n = 259) patients with possible FH. Among 1451 young patients with premature ACS, the Dutch Lipid Clinic algorithm identified 70 (4.8%, 95% CI 3.8-6.1%) patients with probable/definite FH, and 684 (47.1%, 95% CI 44.6-49.7%) patients had possible FH. Excluding patients with secondary causes of dyslipidaemia such as alcohol consumption, acute renal failure, or hyperglycaemia did not change prevalence. One year after ACS, among 69 survivors with probable/definite FH and available follow-up information, 64.7% were using high-dose statins, 69.0% had decreased LDL-cholesterol from at least 50, and 4.6% had LDL-cholesterol ≤1.8 mmol/L., Conclusion: A phenotypic diagnosis of possible FH is common in patients hospitalized with ACS, particularly among those with premature ACS. Optimizing long-term lipid treatment of patients with FH after ACS is required., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: While prior work has suggested that a high-grade atrioventricular block (HAVB) in the setting of an acute coronary syndrome (ACS) is associated with in-hospital death, limited information is available on the incidence of, and death associated with, HAVB in ACS patients receiving contemporary management., Methods and Results: The incidence of HAVB was determined within The Global Registry of Acute Coronary Events (GRACE). The clinical characteristics, in-hospital therapies, and outcomes were compared between patients with and without HAVB. Factors associated with death in patients with HAVB were determined. A total of 59 229 patients with ACS between 1999 and 2007 were identified; 2.9% of patients had HAVB at any point during the index hospitalization; 22.7% of whom died in hospital [adjusted odds ratio (OR) = 4.2, 95% confidence interval (CI), 3.6-4.9, P < 0.001]. The association between HAVB and in-hospital death varied with type of ACS [OR: ST-segment elevation myocardial infarction (STEMI) = 3.0; non-STEMI = 6.4; unstable angina = 8.2, P for interaction < 0.001]. High-grade atrioventricular block present at the time of presentation to hospital (vs. occurring in-hospital) and early (<12 h) percutaneous coronary intervention or fibrinolysis (vs.>12 h or no intervention) were associated with improved in-hospital survival, whereas temporary pacemaker insertion was not. Patients with HAVB surviving to discharge had similar adjusted survival at 6 months compared with those without HAVB. A reduction in the rate of, but not in-hospital mortality associated with, HAVB was noted over the study period., Conclusion: Although the incidence of HAVB is low and decreasing, this complication continues to have a high risk of in-hospital death., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: The obesity paradox refers to the epidemiological evidence that obesity compared with normal weight is associated with counter-intuitive improved health in a variety of disease conditions. The aim of this study was to investigate the relationship between body mass index (BMI) and mortality in patients with acute coronary syndromes (ACSs)., Methods and Results: We extracted data from the Swedish Coronary Angiography and Angioplasty Registry and identified 64 436 patients who underwent coronary angiography due to ACSs. In 54 419 (84.4%) patients, a significant coronary stenosis was identified, whereas 10 017 (15.6%) patients had no significant stenosis. Patients were divided into nine different BMI categories. The patients with significant stenosis were further subdivided according to treatment received such as medical therapy, percutaneous coronary intervention (PCI), or coronary artery by-pass grafting. Mortality for the different subgroups during a maximum of 3 years was compared using Cox proportional hazards regression with the lean BMI category (21.0 to <23.5 kg/m(2)) as the reference group. Regardless of angiographic findings [significant or no significant coronary artery disease (CAD)] and treatment decision, the underweight group (BMI <18.5 kg/m(2)) had the greatest risk for mortality. Medical therapy and PCI-treated patients with modest overweight (BMI category 26.5-<28 kg/m(2)) had the lowest risk of mortality [hazard ratio (HR) 0.52; 95% CI 0.34-0.80 and HR 0.64; 95% CI 0.50-0.81, respectively]. When studying BMI as a continuous variable in patients with significant CAD, the adjusted risk for mortality decreased with increasing BMI up to ~35 kg/m(2) and then increased. In patients with significant CAD undergoing coronary artery by-pass grafting and in patients with no significant CAD, there was no difference in mortality risk in the overweight groups compared with the normal weight group., Conclusion: In this large and unselected group of patients with ACSs, the relation between BMI and mortality was U-shaped, with the nadir among overweight or obese patients and underweight and normal-weight patients having the highest risk. These data strengthen the concept of the obesity paradox substantially.

Bleeding has recently emerged as an important outcome in the management of acute coronary syndromes (ACS), which is relatively frequent compared with ischaemic outcomes and has important implications in terms of prognosis, outcomes, and costs. In particular, there is evidence that patients experiencing major bleeding in the acute phase are at higher risk for death in the following months, although the causal nature of this relation is still debated. This position paper aims to summarize current knowledge regarding the epidemiology of bleeding in ACS and percutaneous coronary intervention, including measurement and definitions of bleeding, with emphasis on the recent consensus Bleeding Academic Research Consortium (BARC) definitions. It also provides an European perspective on management strategies to minimize the rate, extent, and consequences of bleeding. Finally, the research implications of bleeding (measuring and reporting bleeding in trials, the importance of bleeding as an outcome measure, and bleeding as a subject for future research) are also discussed.

Aims There is increasing evidence that immune mechanisms are involved in the pathogenesis of heart failure (HF). The relationship between neopterin and the risk of HF has yet to be investigated on a large scale. We assessed the relationship between neopterin, a novel marker of monocyte activation, and risk of hospitalization for HF. Methods and results Among the subjects of Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial, 3946 had neopterin levels measured at study entry, on average 7 days after acute coronary syndrome (ACS). We assessed the relationship between neopterin and hospitalization for HF, and for death or HF over 2 years mean follow-up in a post hoc analysis using Cox regression models. Unadjusted hospitalization rates for HF increased across quartiles of neopterin, from 0.66 to 3.97 per 100 person-years. Per 1SD increment in log (neopterin), the adjusted risk of HF increased by 34% [hazard ratio (HR) 1.34, CI 1.10-1.64; P = 0.004]. Even after excluding individuals with a prior history of HF or recurrent ischaemic events, the relationship between neopterin and HF hospitalization remained significant. When added to a multivariable Cox model of HF-risk containing traditional risk factors, C-reactive protein and brain natriuretic protein (BNP), the further addition of neopterin significantly improved the HF-risk prediction model by likelihood ratio test analysis (P = 0.005), C-statistic (increasing from 0.743 to 0.773; P = 0.027), integrated discrimination improvement (IDI) analysis (P = 0.001), but not net reclassification improvement (NRI) analysis (P = 0.406). Similar results were obtained for the endpoint of death or HF. Conclusion Neopterin levels are an independent predictor of HF hospitalization, and improve risk prediction over and above conventional biomarkers.

Aims: Natural history and prognosis of acute coronary syndrome (ACS) in HIV-infected patients remain to be determined. We sought to compare coronary risk factors, angiographic features, acute results of percutaneous coronary intervention, in-hospital outcomes, and pre-specified 1 year prognosis of HIV-infected and HIV-uninfected patients with ACS., Methods and Results: HIV-infected and HIV-uninfected patients with a first episode of ACS were matched for age (±5 years), sex, and type of ACS. The primary endpoint was the rate of major adverse cardiac and cerebral events (MACCE), comprising cardiac death, recurrent ACS, recurrent coronary revascularization, and stroke. Overall, 103 HIV-infected and 195 HIV-uninfected patients were enrolled (mean age 49.0 ± 9.4 years, 94% men). Coronary risk factors were well balanced, but HIV-infected patients more frequently used illicit drugs (23 vs. 6%, P = 0.001) and had higher triglyceride concentrations (246 ± 189 vs. 170 ± 139 mg/dL, P = 0.002) compared with HIV-uninfected patients. Angiographic features of coronary artery disease were similar (multivessel disease 41 vs. 39%, P = 0.96; ACC/AHA type culprit lesion ≥B2, both 77%, P = 0.83). At 1 year, the rate of occurrence of first MACCE did not differ between groups [hazard ratio (HR) 1.4, 95% CI 0.6-3.0]. Recurrent ACS was more frequent in HIV-infected patients (HR 6.5, 95% CI 1.7-23.9) with no difference in the rate of clinical restenosis., Conclusions: These results suggest that the acute management of ACS in HIV-infected patients can routinely be the same as that of HIV-uninfected patients, but that specific secondary prevention measures are needed to alleviate the increased risk of recurrent ACS.

Aims: To determine the incidence and factors associated with heart rupture (HR) in acute coronary syndrome (ACS) patients., Methods and Results: Among 60 198 patients, 273 (0.45%) had HR (free wall rupture, n = 118; ventricular septal rupture, n = 155). Incidence was 0.9% for ST-segment elevation myocardial infarction (STEMI), 0.17% for non-STEMI, and 0.25% for unstable angina. Hospital mortality was 58 vs. 4.5% in patients without HR (P < 0.001). The incidence was lower in STEMI patients with primary percutaneous coronary intervention (PCI) than in those without (0.7 vs. 1.1%; P = 0.01), but primary PCI was not independently related to HR in adjusted analysis (P = 0.20). Independent variables associated with HR included: ST-segment elevation (STE)/left bundle branch block; ST-segment deviation; female sex; previous stroke; positive initial cardiac biomarkers; older age; higher heart rate; systolic blood pressure/30 mmHg decrease. Conversely, previous MI and the use of low-molecular-weight heparin and beta-blockers during first 24 h were identified as protective factors for HR., Conclusion: The incidence of HR is low in patients with ACS, although its incidence is probably underestimated. Heart rupture occurs more frequently in ACS with STE and is associated with high hospital mortality. A number of variables are independently related to HR.

Aims: To examine: (i) the temporal changes in the management pattern; (ii) the reasons for any treatment disparities; (iii) the relationship between invasive treatment and outcome, among acute coronary syndrome (ACS) patients with vs. without kidney dysfunction., Methods and Results: Canadian ACS I, ACS II registries and Global Registry of Acute Coronary Events (GRACE) were prospective, multi-centre, observational studies of patients with ACS. From 1999 to 2007, non-ST elevation (NSTE) ACS patients were recruited in ACS I (n = 3295; 1999-2001), ACS II (n = 1956; 2002-2003), and GRACE (n = 6491; 2004-2007) in Canada. Using the four-variable Modified Diet in Renal Disease equation, we stratified the study population (n = 11,377) into three groups based on their estimated glomerular filtration rate (eGFR), and examined their treatment and outcome. While in-hospital use of coronary angiography and revascularization increased over time in all groups (P < 0.001), patients with kidney dysfunction were less likely to undergo invasive management (P < 0.001). Unadjusted 1 year mortality was lower among patients receiving in-hospital coronary angiography within all eGFR categories (> or =60 mL/min/1.73 m(2): 2.5 vs. 7.6%, P < 0.001; 30-59 mL/min/1.73 m(2): 8.0 vs. 14.6%, P < 0.001; <30 mL/min/1.73 m(2): 27.5 vs. 41.5%, P = 0.043). In-hospital revascularization was independently associated with lower 1-year mortality (adjusted OR = 0.52, 95% CI 0.36-0.77, P = 0.001), irrespective of eGFR (P for heterogeneity = 0.39). Underestimation of patient risk was the most common barrier to an invasive treatment strategy., Conclusion: Despite temporal increases in invasive management of NSTE-ACS, patients with kidney dysfunction are more commonly treated conservatively, with an associated worse outcome. In-hospital revascularization was independently associated with improved survival, irrespective of eGFR. Randomized controlled trials involving patients with kidney dysfunction are needed to confirm whether more aggressive treatment will improve their poor outcome.

Aims: We explored the impact of having a hospital admission for an acute coronary syndrome (ACS) on the subsequent prognosis among patients with chronic heart failure (CHF)., Methods and Results: A total of 7599 patients with CHF, New York Heart Association Classes II-IV, were randomly assigned to candesartan or placebo. We assessed the risk of death after a first ACS using time-updated Cox proportional hazard models adjusted for baseline predictors. During a mean follow-up of 3.3 years, 1174 patients experienced at least one ACS. Myocardial infarction (MI) was the first ACS in 442 subjects and unstable angina (UA) in 732. After these events, 219 (49.5%) and 167 (22.8%) patients died during follow-up. The early risk of death was more pronounced after MI: 30.2% died within 30 days compared with 3.6% after UA. After an ACS event, the risk of death declined steadily over time, although 18 months after an MI the risk was still twice that of patients without an ACS., Conclusion: Patients with CHF, who develop an ACS, have markedly increased subsequent mortality, particularly in the early phase after an MI.

Aims: Functional mitral regurgitation (MR) is a frequent complication after the acute phase of a myocardial infarction and plays an important role in the development of congestive heart failure (CHF) after a Q-wave myocardial infarction. Nevertheless, until now, the relevance of functional MR after a non-ST-segment elevation acute coronary syndrome (NSTSEACS) has been poorly addressed. Our aim was to assess the relationship between the presence or absence and the severity of functional MR after a first NSTSEACS and the development of CHF., Methods and Results: Two hundred and seventy-nine patients discharged from hospital in NYHA functional classes I and II (71.7% men; mean age 66.3 +/- 13.2 years) after a first NSTSEACS were studied. Every patient underwent an echocardiographic study during the first week after the index NSTSEACS and were clinically followed-up. MR was detected in 40.1% patients. Patients were followed-up for a median time of 418 days (inter-quartile range: 295-561). Six patients (3.6%) in the group without MR and 15 patients (13.4%) in the group with MR required hospitalization due to CHF during follow-up. Only MR was found as an independent predictor of CHF development (HR = 1.8; 95% CI = 1.1-3.1; P = 0.02) and CHF development or cardiac death (HR = 2.1; 95% CI = 1.3-3.3; P = 0.01) in the long-term follow-up multivariable Cox regression analysis., Conclusion: There is an increased risk for subsequent CHF in patients with MR after a first NSTSEACS. The risk of CHF is closely related to the MR presence and severity. Thus, the detection of MR by means of Doppler echocardiography after a first episode of NSTSEACS is crucial.

Antithrombotic therapy and invasive risk stratification in selected high-risk patients have improved outcomes from non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but carry a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e. clinical trial vs. registry), the definition used, and the use of invasive procedures, it is becoming clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death. Blood transfusion itself may carry a risk for ischaemic outcomes that is independent of bleeding. Therefore, therapies that provide an adequate level of anticoagulation to reduce ischaemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with NSTE-ACS. Anticoagulants studied in recent clinical trials that have focused on bleeding reduction include fondaparinux and bivalirudin. In this review, we discuss the clinical trial evidence for these agents, the association between bleeding and clinical outcomes, the biology of blood transfusion and potential mechanisms underlying its association with adverse outcomes, and propose strategies to deal with bleeding complications. Future directions for research and clinical practice are also discussed.