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1. Development and validation of a quantitative Proximity Extension Assay instrument with 21 proteins associated with cardiovascular risk (CVD-21).

Author: Agneta Siegbahn, Niclas Eriksson, Erika Assarsson, Martin Lundberg, Andrea Ballagi, Claes Held, Ralph A H Stewart, Harvey D White, Mikael Åberg, and Lars Wallentin
Subjects: Medicine, Science
Abstract: BackgroundTreatment of cardiovascular diseases (CVD) is a substantial burden to healthcare systems worldwide. New tools are needed to improve precision of treatment by optimizing the balance between efficacy, safety, and cost. We developed a high-throughput multi-marker decision support instrument which simultaneously quantifies proteins associated with CVD.Methods and findingsCandidate proteins independently associated with different clinical outcomes were selected from clinical studies by the screening of 368 circulating biomarkers. We then custom-designed a quantitative PEA-panel with 21 proteins (CVD-21) by including recombinant antigens as calibrator samples for normalization and absolute quantification of the proteins. The utility of the CVD-21 tool was evaluated in plasma samples from a case-control cohort of 4224 patients with chronic coronary syndrome (CCS) using multivariable Cox regression analyses and machine learning techniques. The assays in the CVD-21 tool gave good precision and high sensitivity with lower level of determination (LOD) between 0.03-0.7 pg/ml for five of the biomarkers. The dynamic range for the assays was sufficient to accurately quantify the biomarkers in the validation study except for troponin I, which in the modeling was replaced by high-sensitive cardiac troponin T (hs-TnT). We created seven different multimarker models, including a reference model with NT-proBNP, hs-TnT, GDF-15, IL-6, and cystatin C and one model with only clinical variables, for the comparison of the discriminative value of the CVD-21 tool. All models with biomarkers including hs-TnT provided similar discrimination for all outcomes, e.g. c-index between 0.68-0.86 and outperformed models using only clinical variables. Most important prognostic biomarkers were MMP-12, U-PAR, REN, VEGF-D, FGF-23, TFF3, ADM, and SCF.ConclusionsThe CVD-21 tool is the very first instrument which with PEA simultaneously quantifies 21 proteins with associations to different CVD. Novel pathophysiologic and prognostic information beyond that of established biomarkers were identified by a number of proteins.
Published: 2023
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2. Type 2 MI and Myocardial Injury in the Era of High-sensitivity Troponin

Author: Rifly Rafiudeen, Peter Barlis, Harvey D White, and William van Gaal
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Troponin has been the cornerstone of the definition of MI since its introduction to clinical practice. High-sensitivity troponin has allowed clinicians to detect degrees of myocardial damage at orders of magnitude smaller than previously and is challenging the definitions of MI, with implications for patient management and prognosis. Detection and diagnosis are no doubt enhanced by the greater sensitivity afforded by these markers, but perhaps at the expense of specificity and clarity. This review focuses on the definitions, pathophysiology, prognosis, prevention and management of type 2 MI and myocardial injury. The five types of MI were first defined in 2007 and were recently updated in 2018 in the fourth universal definition of MI. The authors explore how this pathophysiological classification is used in clinical practice, and discuss some of the unanswered questions in this era of availability of high-sensitivity troponin.
Published: 2022
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3. Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective

Author: Gerald F. Watts, David R. Sullivan, David L. Hare, Karam M. Kostner, Ari E. Horton, Damon A. Bell, Tom Brett, Ronald J. Trent, Nicola K. Poplawski, Andrew C. Martin, Shubha Srinivasan, Robert N. Justo, Clara K. Chow, Jing Pang, Zanfina Ademi, Justin J Ardill, Wendy Barnett, Timothy R Bates, Lawrence J Beilin, Warrick Bishop, J Andrew Black, Alex Brown, John R Burnett, Christina A Bursill, Alison Colley, Peter M Clifton, Elif I Ekinci, Gemma A Figtree, Brett H Forge, Jacquie Garton-Smith, Dorothy F Graham, Ian Hamilton-Craig, Christian R Hamilton-Craig, Clare Heal, Charlotte M Hespe, Amanda J Hooper, Laurence G Howes, Jodie Ingles, Edward D Janus, Nadarajah Kangaharan, Anthony C Keech, Andrew B Kirke, Leonard Kritharides, Campbell V Kyle, Paul Lacaze, Stephen CH Li, Stjepana Maticevic, Brendan M McQuillan, Sam Mirzaee, Trevor A Mori, Allison C Morton, David M Colquhoun, Joanna C Moullin, Paul J Nestel, Kristen J Nowak, Richard C O'Brien, Nicholas Pachter, Michael M Page, Peter J Psaltis, Jan Radford, Nicola J Reid, Elizabeth N Robertson, Jacqueline DM Ryan, Mitchell N Sarkies, Carl J Schultz, Russell S Scott, Christopher Semsarian, Leon A Simons, Catherine Spinks, Andrew M Tonkin, Frank van Bockxmeer, Kathryn E Waddell-Smith, Natalie C Ward, Harvey D White, Andrew M Wilson, Ingrid Winship, Ann Marie Woodward, Stephen J Nicholls, Peter Brett, Luke Elias, Wynand Malan, John Irvin, Kirsten Lambert, and Annette Pedrotti
Subjects: Familial hypercholesterolaemia, Guidance, Care, Management, Adults, Children, Diseases of the circulatory (Cardiovascular) system, RC666-701, Public aspects of medicine, RA1-1270
Abstract: Summary: Introduction: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations: Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH: These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.
Published: 2021
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4. Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study.

Author: Lars Wallentin, Niclas Eriksson, Maciej Olszowka, Tanja B Grammer, Emil Hagström, Claes Held, Marcus E Kleber, Wolfgang Koenig, Winfried März, Ralph A H Stewart, Harvey D White, Mikael Åberg, and Agneta Siegbahn
Subjects: Medicine
Abstract: BackgroundCirculating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.Methods and findingsThe derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.ConclusionsProfiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.Trial registrationClinicalTrials.gov NCT00799903.
Published: 2021
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5. Pharmacogenetic meta-analysis of baseline risk factors, pharmacodynamic, efficacy and tolerability endpoints from two large global cardiovascular outcomes trials for darapladib.

Author: Astrid Yeo, Li Li, Liling Warren, Jennifer Aponte, Dana Fraser, Karen King, Kelley Johansson, Allison Barnes, Colin MacPhee, Richard Davies, Stephanie Chissoe, Elizabeth Tarka, Michelle L O'Donoghue, Harvey D White, Lars Wallentin, and Dawn Waterworth
Subjects: Medicine, Science
Abstract: Darapladib, a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, failed to demonstrate efficacy for the primary endpoints in two large phase III cardiovascular outcomes trials, one in stable coronary heart disease patients (STABILITY) and one in acute coronary syndrome (SOLID-TIMI 52). No major safety signals were observed but tolerability issues of diarrhea and odor were common (up to 13%). We hypothesized that genetic variants associated with Lp-PLA2 activity may influence efficacy and tolerability and therefore performed a comprehensive pharmacogenetic analysis of both trials. We genotyped patients within the STABILITY and SOLID-TIMI 52 trials who provided a DNA sample and consent (n = 13,577 and 10,404 respectively, representing 86% and 82% of the trial participants) using genome-wide arrays with exome content and performed imputation using a 1000 Genomes reference panel. We investigated baseline and change from baseline in Lp-PLA2 activity, two efficacy endpoints (major coronary events and myocardial infarction) as well as tolerability parameters at genome-wide and candidate gene level using a meta-analytic approach. We replicated associations of published loci on baseline Lp-PLA2 activity (APOE, CELSR2, LPA, PLA2G7, LDLR and SCARB1) and identified three novel loci (TOMM5, FRMD5 and LPL) using the GWAS-significance threshold P≤5E-08. Review of the PLA2G7 gene (encoding Lp-PLA2) within these datasets identified V279F null allele carriers as well as three other rare exonic null alleles within various ethnic groups, however none of these variants nor any other loci associated with Lp-PLA2 activity at baseline were associated with any of the drug response endpoints. The analysis of darapladib efficacy endpoints, despite low power, identified six low frequency loci with main genotype effect (though with borderline imputation scores) and one common locus (minor allele frequency 0.24) with genotype by treatment interaction effect passing the GWAS-significance threshold. This locus conferred risk in placebo subjects, hazard ratio (HR) 1.22 with 95% confidence interval (CI) 1.11-1.33, but was protective in darapladib subjects, HR 0.79 (95% CI 0.71-0.88). No major loci for tolerability were found. Thus, genetic analysis confirmed and extended the influence of lipoprotein loci on Lp-PLA2 levels, identified some novel null alleles in the PLA2G7 gene, and only identified one potentially efficacious subgroup within these two large clinical trials.
Published: 2017
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6. Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease

Author: Dan D. Nguyen, John A. Spertus, Karen P. Alexander, Jonathan D. Newman, John A. Dodson, Philip G. Jones, Susanna R. Stevens, Sean M. O’Brien, Reto Gamma, Gian P. Perna, Pallav Garg, João V. Vitola, Benjamin J.W. Chow, Andras Vertes, Harvey D. White, Paola E.P. Smanio, Roxy Senior, Claes Held, Jianghao Li, William E. Boden, Daniel B. Mark, Harmony R. Reynolds, Sripal Bangalore, Paul S. Chan, Gregg W. Stone, Suzanne V. Arnold, David J. Maron, and Judith S. Hochman
Subjects: Cardiology and Cardiovascular Medicine
Published: 2023
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7. Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations

Author: Natalie C. Ward, Gerald F. Watts, Warrick Bishop, David Colquhoun, Christian Hamilton-Craig, David L. Hare, Nadarajah Kangaharan, Karam M. Kostner, Leonard Kritharides, Richard O’Brien, Trevor A. Mori, Paul J. Nestel, Stephen J. Nicholls, Peter J. Psaltis, Natalie Raffoul, Harvey D. White, and David R. Sullivan
Subjects: Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine
Published: 2023
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8. Survival After Invasive or Conservative Management of Stable Coronary Disease

Author: Judith S. Hochman, Rebecca Anthopolos, Harmony R. Reynolds, Sripal Bangalore, Yifan Xu, Sean M. O’Brien, Stavroula Mavromichalis, Michelle Chang, Aira Contreras, Yves Rosenberg, Ruth Kirby, Balram Bhargava, Roxy Senior, Ann Banfield, Shaun G. Goodman, Renato D. Lopes, Radosław Pracoń, José López-Sendón, Aldo Pietro Maggioni, Jonathan D. Newman, Jeffrey S. Berger, Mandeep S. Sidhu, Harvey D. White, Andrea B. Troxel, Robert A. Harrington, William E. Boden, Gregg W. Stone, Daniel B. Mark, John A. Spertus, David J. Maron, Shari Esquenazi-Karonika, Margaret Gilsenan, Ewelina Gwiszcz, Patenne Mathews, Samaa Mohamed, Anna Naumova, Arline Roberts, Kerrie VanLoo, Ying Lu, Zhen Huang, Samuel Broderick, Luis Guzmán, Joseph Selvanayagam, Gabriel Steg, Jean-Michel Juliard, Rolf Doerr, Matyas Keltai, Boban Thomas, Tali Sharir, Eugenia Nikolsky, Aldo P. Maggioni, Shun Kohsaka, Jorge Escobedo, Olga Bockeria, Claes Held, Leslee J. Shaw, Lawrence Phillips, Daniel Berman, Raymond Y. Kwong, Michael H. Picard, Bernard R. Chaitman, Ziad Ali, James Min, G.B. John Mancini, Jonathon Leipsic, Graham Hillis, Suku Thambar, Majo Joseph, John Beltrame, Irene Lang, Herwig Schuchlenz, Kurt Huber, Kaatje Goetschalckx, Whady Hueb, Paulo Ricardo Caramori, Alexandre de Quadros, Paola Smanio, Claudio Mesquita, João Vitola, José Marin-Neto, Expedito Ribeiro da Silva, Rogério Tumelero, Marianna Andrade, Alvaro Rabelo Alves, Frederico Dall’Orto, Carisi Polanczyk, Estevão Figueiredo, Andrew Howarth, Gilbert Gosselin, Asim Cheema, Kevin Bainey, Denis Phaneuf, Ariel Diaz, Pallav Garg, Shamir Mehta, Graham Wong, Andy Lam, James Cha, Paul Galiwango, Amar Uxa, Benjamin (Ben) Chow, Adnan Hameed, Jacob Udell, Magdy Hamid, Marie Hauguel-Moreau, Alain Furber, Pascal Goube, Philippe-Gabriel Steg, Gilles Barone-Rochette, Christophe Thuaire, Michel Slama, Georg Nickenig, Raffi Bekeredjian, P. Christian Schulze, Bela Merkely, Geza Fontos, András Vértes, Albert Varga, Ajit Kumar, Rajesh G. Nair, Purvez Grant, Cholenahally Manjunath, Nagaraja Moorthy, Santhosh Satheesh, Ranjit Kumar Nath, Gurpreet Wander, Johann Christopher, Sudhanshu Dwivedi, Abraham Oomman, Atul Mathur, Milind Gadkari, Sudhir Naik, Eapen Punnoose, Ranjan Kachru, Upendra Kaul, Arthur Kerner, Giuseppe Tarantini, Gian Piero Perna, Emanuela Racca, Andrea Mortara, Lorenzo Monti, Carlo Briguori, Gianpiero Leone, Roberto Amati, Mauro Salvatori, Antonio Di Chiara, Paolo Calabro, Marcello Galvani, Stefano Provasoli, Keiichi Fukuda, Shintaro Nakano, Aleksandras Laucevicius, Sasko Kedev, Ahmad Khairuddin, Robert Riezebos, Jorik Timmer, Spencer Heald, Ralph Stewart, Walter Mogrovejo Ramos, Marcin Demkow, Tomasz Mazurek, Jarozlaw Drozdz, Hanna Szwed, Adam Witkowski, Nuno Ferreira, Fausto Pinto, Ruben Ramos, Bogdan Popescu, Calin Pop, Leo Bockeria, Elena Demchenko, Alexander Romanov, Leonid Bershtein, Ahmed Jizeeri, Goran Stankovic, Svetlana Apostolovic, Nada Cemerlic Adjic, Marija Zdravkovic, Branko Beleslin, Milica Dekleva, Goran Davidovic, Terrance Chua, David Foo, Kian Keong Poh, Mpiko Ntsekhe, Alessandro Sionis, Francisco Marin, Vicente Miró, Montserrat Gracida Blancas, José González-Juanatey, Francisco Fernández-Avilés, Jesús Peteiro, Jose Enrique Castillo Luena, Johannes Aspberg, Mariagrazia Rossi, Srun Kuanprasert, Sukit Yamwong, Nicola Johnston, Patrick Donnelly, Andrew Moriarty, Ahmed Elghamaz, Sothinathan Gurunathan, Nikolaos Karogiannis, Benoy N. Shah, Richard H.J. Trimlett, Michael B. Rubens, Edward D. Nicol, Tarun K. Mittal, Reinette Hampson, Reto Gamma, Mark De Belder, Thuraia Nageh, Steven Lindsay, Kreton Mavromatis, Todd Miller, Subhash Banerjee, Harmony Reynolds, Khaled Nour, and Peter Stone
Subjects: Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract: Background: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes during a median of 3.2 years. Extended follow-up for mortality is ongoing. Methods: ISCHEMIA participants were randomized to an initial invasive strategy added to guideline-directed medical therapy or a conservative strategy. Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and noncardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models, and Bayesian methods. Undetermined deaths were classified as cardiovascular as prespecified in the trial protocol. Results: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23% women, 16% Hispanic, 4% Black, 42% with diabetes, and median ejection fraction 0.60. A total of 557 deaths accrued during a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 noncardiovascular deaths, and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate, 12.7% in invasive strategy, 13.4% in conservative strategy; adjusted hazard ratio, 1.00 [95% CI, 0.85–1.18]). There was a lower 7-year rate cardiovascular mortality (6.4% versus 8.6%; adjusted hazard ratio, 0.78 [95% CI, 0.63–0.96]) with an initial invasive strategy but a higher 7-year rate of noncardiovascular mortality (5.6% versus 4.4%; adjusted hazard ratio, 1.44 [95% CI, 1.08–1.91]) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. Conclusions: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of noncardiovascular mortality with an initial invasive strategy during a median follow-up of 5.7 years. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04894877.
Published: 2023
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9. Does it Matter What the Cause of Death Is in Revascularization Trials?

Author: Harvey D. White
Subjects: Cardiology and Cardiovascular Medicine
Published: 2023
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10. Morphine and clinical outcomes in patients with ST segment elevation myocardial infarction treated with fibrinolytic and antiplatelet therapy: Insights from the TREAT trial

Author: Warren J. Cantor, Mary Tan, Otavio Berwanger, Shahar Lavi, Harvey D. White, Jose C. Nicolau, Payam Dehghani, Carlos D. Tajer, Renato D. Lopes, Diogo D.F. Moia, Stephen J. Nicholls, Alexander Parkhomenko, Oleg Averkov, Neil Brass, Sohrab Lutchmedial, Germán Malaga, Lucas P. Damiani, Leopoldo S. Piegas, Christopher B. Granger, and Shaun G. Goodman
Subjects: Ticagrelor, Morphine, fibrinolytic, Hemorrhage, patients, clinical outcomes, antiplatelet therapy, Clopidogrel, Percutaneous Coronary Intervention, Treatment Outcome, myocardial infarction, ST segment, Humans, ST Elevation Myocardial Infarction, Thrombolytic Therapy, Cardiology and Cardiovascular Medicine, Platelet Aggregation Inhibitors
Abstract: Background: Morphine is commonly used to relieve pain, anxiety and dyspnea in STEMI but it lowers blood pressure and delays the activity of oral antiplatelet agents. The impact of morphine on clinical outcomes remains unknown. This analysis was performed to determine if morphine use was associated with increased risk of adverse clinical events among STEMI patients treated with fibrinolytic therapy and clopidogrel or ticagrelor. Methods: In the Ticagrelor in Patients with ST Elevation Myocardial Infarction Treated with Pharmacological Thrombolysis (TREAT) study, 3799 STEMI patients treated with fibrinolysis were randomized to receive clopidogrel or ticagrelor. Morphine use was left to the discretion of the treating physicians. In this pre-specified analysis, we evaluated clinical outcomes based on the use and timing of morphine administration. Outcomes were stratified by randomized treatment group. Multivariable analysis was performed using Inverse Probability Treatment Weighting (IPTW) weighting. Results: Morphine was used in 53% of patients. After adjustment using IPTW weighting, morphine use was associated with higher hazard of reinfarction at 7 days (HR 4.9, P = .0006) and 30 days (HR 1.7, P = .04), and lower hazard of major bleeding (HR 0.37, P = .006). There was no significant difference in mortality at any time point. Conclusions: Among patients with STEMI treated with fibrinolytic therapy, morphine use was associated with a higher risk of early reinfarction and a lower risk of major bleeding but no difference in mortality.
Published: 2022
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11. Heparin use in acute coronary syndromes and cardiovascular interventions: habit or evidence based?

Author: Sean Tan, Harvey D. White, and Jamie Layland
Subjects: Habits, Heparin, Anticoagulants, Humans, Acute Coronary Syndrome, Cardiology and Cardiovascular Medicine
Published: 2022
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12. Lipoprotein(a) and the Effect of Alirocumab on Revascularization Following Acute Coronary Syndrome

Author: P. Gabriel Steg, Michael Szarek, Marco Valgimigli, Shahidul Islam, Andreas M. Zeiher, Deepak L. Bhatt, Vera A. Bittner, Chern-En Chiang, Rafael Diaz, Shaun G. Goodman, Nina Gotcheva, Robert A. Harrington, J. Wouter Jukema, Hyo-Soo Kim, Sang-Hyun Kim, Joao Morais, Robert Pordy, Michel Scemama, Harvey D. White, and Gregory G. Schwartz
Subjects: Cardiology and Cardiovascular Medicine, 610 Medicine & health
Abstract: BACKGROUND Many patients require revascularization after an index acute coronary syndrome (ACS). Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In ODYSSEY OUTCOMES, alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a) levels. We explored whether risk of revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo. METHODS ODYSSEY OUTCOMES compared alirocumab with placebo in 18 924 patients with ACS and elevated atherogenic lipoproteins despite optimized statin treatment. In this post hoc analysis, treatment effects are summarized by competing-risks proportional hazard models. RESULTS A total of 1559 (8.2%) patients had coronary, 204 (1.1%) had limb, and 40 (0.2%) had carotid revascularization. Alirocumab reduced coronary revascularization (2.8 versus 3.2 events per 100 patient-years; HR, 0.88 [95% CI, 0.80-0.97]; P=0.01) and any revascularization (3.2 versus 3.7 events per 100 patient-years; HR, 0.85 [95% CI, 0.78-0.94]; P=0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm and inversely related to treatment HRs (all Ptrend
Published: 2023
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13. Elevated C-Reactive Protein Amplifies Association of Lipoprotein(a) With Cardiovascular Risk and Clinical Benefit of Alirocumab

Author: Gregory G. Schwartz, Michael Szarek, Andreas Zeiher, Harvey D. White, J. Wouter Jukema, Robert A. Harrington, Shaun G. Goodman, Rafael Diaz, Vera Bittner, Deepak L. Bhatt, and Ph. Gabriel Steg
Subjects: C-Reactive Protein, Cardiovascular Diseases, Risk Factors, Heart Disease Risk Factors, Humans, Cardiology and Cardiovascular Medicine, Lipoprotein(a)
Published: 2022

14. B‐Type Natriuretic Peptide and Long‐Term Cardiovascular Mortality in Patients With Coronary Heart Disease

Author: Ralph A. H. Stewart, Adrienne Kirby, Harvey D. White, Simone L. Marschner, Malcolm West, Peter L. Thompson, David Sullivan, Edward Janus, David Hunt, Leonard Kritharides, Anthony Keech, John Simes, and Andrew M. Tonkin
Subjects: Predictive Value of Tests, Risk Factors, Natriuretic Peptide, Brain, Myocardial Infarction, Humans, Coronary Disease, Prognosis, Cardiology and Cardiovascular Medicine, Biomarkers
Abstract: Background The plasma concentration of B‐type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured. Methods and Results Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to P Conclusions BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long‐term risk prediction.
Published: 2022
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15. Excessive daytime sleepiness, morning tiredness and major adverse cardiovascular events in patients with chronic coronary syndrome

Author: Stability Investigators, Harvey D. White, Nermin Hadziosmanovic, Emil Hagström, Athanasios J. Manolis, Stephan Denchev, Lars Wallentin, R. Stewart, M Olszowka, and Claes Held
Subjects: Male, cardiovascular risk factors, 0301 basic medicine, medicine.medical_specialty, Excessive daytime sleepiness, Disorders of Excessive Somnolence, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Surveys and Questionnaires, Internal medicine, Oximes, Internal Medicine, medicine, Humans, Cardiac and Cardiovascular Systems, Prospective Studies, Myocardial infarction, Aged, Proportional Hazards Models, Morning, Kardiologi, Proportional hazards model, business.industry, Hazard ratio, Middle Aged, coronaryheart disease, medicine.disease, mortality, Confidence interval, myocardial infarction, 030104 developmental biology, Cardiovascular Diseases, Benzaldehydes, Chronic Disease, Cardiology, Female, sleep disorders, medicine.symptom, Choking, business, Mace
Abstract: Background Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS). Methods Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference. Results During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes. Conclusions In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality.
Published: 2021
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16. Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol

Author: Michael Szarek, J. Wouter Jukema, Qian H Li, Harvey D. White, Investigators, Rafael Diaz, Deepak L. Bhatt, Robert Pordy, Shaun G. Goodman, Garen Manvelian, Timothée Sourdille, Gregory G. Schwartz, Philippe Gabriel Steg, Yong-Un Kim, and Vera Bittner
Subjects: Male, PCSK9 protein, human, medicine.medical_specialty, Acute coronary syndrome, Low density lipoprotein cholesterol, Antibodies, Monoclonal, Humanized, LDL, acute coronary syndrome, Risk Factors, lipoprotein(a), Original Research Articles, Physiology (medical), Internal medicine, medicine, PCSK9 protein, Humans, human, Prospective Studies, Clinical efficacy, Propensity Score, lipoproteins, LDL, Aged, Lipoprotein cholesterol, Alirocumab, biology, business.industry, PCSK9 Inhibitors, Cholesterol, LDL, Lipoprotein(a), Middle Aged, medicine.disease, lipoproteins, Propensity score matching, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, hydroxymethylglutaryl-CoA reductase inhibitors, Very high risk
Abstract: Supplemental Digital Content is available in the text., Background: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score–matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment. Methods: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: 50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching. Results: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C 50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73–1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels
Published: 2021
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17. INTERNATIONAL COMPARISONS OF HEALTH STATUS OUTCOMES IN PATIENTS UNDERGOING INITIAL INVASIVE VERSUS CONSERVATIVE MANAGEMENT FOR CHRONIC CORONARY DISEASE: INSIGHTS FROM THE ISCHEMIA TRIAL

Author: Nobuhiro Ikemura, John A. Spertus, Dan Nguyen, Zhuxuan Fu, Philip Jones, Harmony R. Reynolds, Sripal Bangalore, Balram Bhargava, Roxy Senior, Ahmed Elghamaz, Shaun G. Goodman, Renato D. Lopes, Radoslaw M. Pracon, Jose Lopez-Sendon, Aldo Pietro Maggioni, Harvey D. White, Kreton Mavromatis, William E. Boden, Fatima Rodriguez, Judith S. Hochman, and David Joel Maron
Subjects: Cardiology and Cardiovascular Medicine
Published: 2023
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18. LIPOPROTEIN(A) AND CARDIOVASCULAR OUTCOMES IN WOMEN AND MEN AFTER AN ACUTE CORONARY SYNDROME: A POST HOC ODYSSEY OUTCOMES TRIAL ANALYSIS

Author: Vera Bittner, Gregory G. Schwartz, Deepak L. Bhatt, Rafael Diaz, Geneviève Garon, Shaun G. Goodman, Robert A. Harrington, Johan Wouter Jukema, Robert Pordy, Michael Szarek, Harvey D. White, Andreas M. Zeiher, Philippe Gabriel Steg, and ODYSSEY OUTCOMES Investigators
Subjects: Cardiology and Cardiovascular Medicine
Published: 2023
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19. SHORT-DURATION, VERY HIGH-INTENSITY LIPID-LOWERING THERAPY RESULTS IN PROLONGED REDUCTION OF CARDIOVASCULAR EVENTS FOLLOWING ACUTE CORONARY SYNDROME

Author: Gregory G. Schwartz, Michael Szarek, Deepak L. Bhatt, Vera Bittner, Maja Bujas-Bobanovic, Rafael Diaz, Sergio Fazio, Shaun G. Goodman, Robert A. Harrington, Johan Wouter Jukema, Robert Pordy, Michel Scemama, Harvey D. White, Andreas M. Zeiher, and Philippe Gabriel Steg
Subjects: Cardiology and Cardiovascular Medicine
Published: 2023
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20. Meta-Analysis of Bleeding Scores Performance for Acute Coronary Syndrome

Author: Ojas Hrakesh Mehta, Tom Kai Ming Wang, Yi-Wen Becky Liao, Michael T.M. Wang, Harvey D. White, and Ralph A.H. Stewart
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Acute coronary syndrome, business.industry, Unstable angina, MEDLINE, Hemorrhage, 030204 cardiovascular system & hematology, medicine.disease, Risk Assessment, Triage, Confidence interval, 03 medical and health sciences, 0302 clinical medicine, Meta-analysis, Internal medicine, medicine, Humans, Registries, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Cardiology and Cardiovascular Medicine, business, Complication
Abstract: Background Bleeding is a common and frequently devastating complication in acute coronary syndrome (ACS). It is critical to evaluate in the current era of ACS management involving invasive strategies and potent anti-thrombotics. Risk models remain under-utilised in this setting but may guide the choice and duration of therapy. We compared their performances for predicting bleeding in ACS patients in this meta-analysis. Methods Medline, EMBASE, Cochrane and Scopus were searched for relevant articles from 1980 to 31 December 2017 assessing external validation of risk scores for bleeding after ACS. Two (2) authors independently reviewed the searched studies for eligibility, followed by pooled analyses using random effects models. Results Amongst 1,843 articles searched, 73 full-texts were reviewed and 17 studies totalling 18,155 patients were included for analysis. C-statistics (95% confidence interval) for predicting in-hospital major bleeding by risk model were Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) 0.714 (0.659–0.779), Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) 0.711 (0.626–0.797), Acute Coronary Treatment and Intervention Outcomes Network (ACTION) 0.767 (0.737–0.797), Global Registry of Acute Coronary Events (GRACE) 0.689 (0.473–0.905) and HAS-BLED 0.636 (0.460–0.812). CRUSADE also predicted bleeding during medium-term follow-up c=0.704 (0.644–0.765). It performed better for radial versus femoral access (c=0.826 and 0.734), invasive versus non-invasive strategy (c=0.752 and 0.625) and similarly for ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) (c=0.791 and 0.760). Heterogeneities of studies and paucity of studies assessing risk scores beyond CRUSADE were important limitations. Conclusions Acute coronary syndrome-specific bleeding scores had moderate discrimination for bleeding, while the GRACE and HAS-BLED scores could not. The ACTION score had the highest pooled c-statistic, while the CRUSADE score was the most widely studied, and also performed better for invasive strategy and radial access subgroups.
Published: 2020
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21. Effect of Platelet Inhibition by Cangrelor Among Obese Patients Undergoing Coronary Stenting: Insights From CHAMPION

Author: Benjamin E. Peterson, Robert A. Harrington, Gregg W. Stone, Ph. Gabriel Steg, C. Michael Gibson, Christian W. Hamm, Matthew J. Price, Renato D. Lopes, Sergio Leonardi, Jayne Prats, Efthymios N. Deliargyris, Kenneth W. Mahaffey, Harvey D. White, and Deepak L. Bhatt
Subjects: Percutaneous Coronary Intervention, Treatment Outcome, Myocardial Infarction, Purinergic P2Y Receptor Antagonists, Humans, Hemorrhage, Stents, Obesity, Cardiology and Cardiovascular Medicine, Adenosine Monophosphate, Platelet Aggregation Inhibitors
Abstract: Background: In randomized trials, cangrelor reduced periprocedural ischemic events related to percutaneous coronary intervention without increasing GUSTO severe bleeding. However, some antiplatelet agents have shown a differential treatment effect by body mass index (BMI). Methods: Patients from the 3 CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) who were randomized to cangrelor versus clopidogrel during percutaneous coronary intervention were stratified by BMI. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis within 48 hours. The principal safety outcome was GUSTO moderate or severe bleeding at 48 hours, although more sensitive bleeding measures such as Thrombolysis in Myocardial Infarction major bleeding were also assessed. We examined obese patients (defined as BMI≥30) versus nonobese patients. Results: There were 24 893 patients, with 8979 (36.1%) having BMI of ≥30. There was no significant difference in the primary efficacy end point among obese versus nonobese patients (4.3% versus 4.2%; rate ratio, 1.01 [95% CI, 0.89–1.15]; P =0.82). There was a consistent benefit in the primary efficacy end point in patients who received cangrelor versus placebo who were obese (3.9% versus 4.7%, rate ratio, 0.83 [95% CI, 0.68–1.02]; P =0.07) and not obese (3.8% versus 4.7%; rate ratio, 0.81 [95% CI, 0.69–0.94]; P =0.0053); interaction P =0.77. There was no difference in GUSTO moderate or severe bleeding among patients who received cangrelor versus placebo who were obese (0.6% versus 0.6%; rate ratio, 0.99 [95% CI, 0.58–1.67]; P =0.96). Conclusions: Cangrelor at the time of percutaneous coronary intervention is effective and safe in obese and nonobese patients. There was no difference in short-term efficacy between obese and nonobese patients. Periprocedural cangrelor is an effective and safe antiplatelet agent, irrespective of BMI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01156571, NCT00385138, NCT00305162.
Published: 2022
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22. Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial

Author: Rafael Diaz, Michael Szarek, Christian Mueller, Shaun G. Goodman, Yong-Un Kim, J. Wouter Jukema, Odyssey Outcomes Investigators, José Tuñón, Andreas M. Zeiher, Gregory G. Schwartz, Philippe Gabriel Steg, Deepak L. Bhatt, Vera Bittner, Alexander Parkhomenko, Robert Pordy, Qian H Li, Harvey D. White, Piyamitr Sritara, and UAM. Departamento de Medicina
Subjects: medicine.medical_specialty, Acute coronary syndrome, Medicina, Renal function, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Brain Ischemia, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Clinical Research, Internal medicine, Chronic kidney disease, medicine, Humans, AcademicSubjects/MED00200, Low-density lipoprotein cholesterol, 030212 general & internal medicine, Myocardial infarction, Renal Insufficiency, Chronic, Adverse effect, Alirocumab, business.industry, Anticholesteremic Agents, PCSK9, medicine.disease, PCSK9 inhibition, Lipids, Stroke, Treatment Outcome, Relative risk, Major adverse cardiovascular events, Cardiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Proprotein Convertase 9, Intensive Cardiac Care and Acute Coronary Syndromes, Glomerular filtration rate, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Statins reduce cardiovascular risk in patients with acute coronary syndrome (ACS) and normal-to-moderately impaired renal function. It is not known whether proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide similar benefit across a range of renal function. We determined whether effects of the PCSK9 inhibitor alirocumab to reduce cardiovascular events and death after ACS are influenced by renal function. ................................................................................................................................................................................................... Methods ODYSSEY OUTCOMES compared alirocumab with placebo in patients with recent ACS and dyslipidaemia despite and results intensive statin treatment. Estimated glomerular filtration rate (eGFR) _90 mL/min/1.73 m (n = 7470; hazard ratio 0.784, 95% confidence interval 0.670–0.919; P = 0.003) and 60 to 60 mL/min/1.73 m 2 2 2 2, The trial was funded by Sanofi and Regeneron Pharmaceuticals, Inc.
Published: 2020

23. Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes

Author: Deepak L. Bhatt, Andrew H. Briggs, Shelby D. Reed, Lieven Annemans, Michael Szarek, Vera A. Bittner, Rafael Diaz, Shaun G. Goodman, Robert A. Harrington, Keiko Higuchi, Florence Joulain, J. Wouter Jukema, Qian H. Li, Kenneth W. Mahaffey, Robert J. Sanchez, Matthew T. Roe, Renato D. Lopes, Harvey D. White, Andreas M. Zeiher, Gregory G. Schwartz, Ph. Gabriel Steg, Pierluigi Tricoci, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, Robert Pordy, William J. Sasiela, and Jean-François Tamby
Subjects: medicine.medical_specialty, Acute coronary syndrome, Apolipoprotein B, Cost effectiveness, Population, 030204 cardiovascular system & hematology, Placebo, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, education, Alirocumab, education.field_of_study, biology, business.industry, Cholesterol, medicine.disease, chemistry, biology.protein, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: Background Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain. Objectives This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy. Methods A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non–high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were Results Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C Conclusions In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C NCT01663402 )
Published: 2020
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24. Sustained Low-Density Lipoprotein Cholesterol Lowering With Alirocumab in ODYSSEY OUTCOMES

Author: Gregory G. Schwartz, Rafael Diaz, Michael Szarek, Harvey D. White, Vera Bittner, Shaun G. Goodman, Deepak L. Bhatt, Philippe Gabriel Steg, J. Wouter Jukema, Robert A. Harrington, Andreas M. Zeiher, and Odyssey Outcomes Investigators
Subjects: Acute coronary syndrome, medicine.medical_specialty, Time Factors, Low density lipoprotein cholesterol, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Placebo, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Humans, Medicine, 030212 general & internal medicine, Acute Coronary Syndrome, Alirocumab, business.industry, Cholesterol, Anticholesteremic Agents, Cholesterol, LDL, medicine.disease, Treatment Outcome, chemistry, Monoclonal, Statin therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business, Follow-Up Studies
Abstract: In the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, 18,924 patients with a recent acute coronary syndrome (ACS) not at lipid goals despite maximally tolerated statin therapy were randomized to alirocumab or placebo
Published: 2020
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25. Circulating Cystatin C Is an Independent Risk Marker for Cardiovascular Outcomes, Development of Renal Impairment, and Long-Term Mortality in Patients With Stable Coronary Heart Disease: The LIPID Study

Author: Malcolm West, Adrienne Kirby, Ralph A. Stewart, Stefan Blankenberg, David Sullivan, Harvey D. White, David Hunt, Ian Marschner, Edward Janus, Leonard Kritharides, Gerald F. Watts, John Simes, Andrew M. Tonkin, Neil Anderson, Ralph Stewart, Harvey White, Paul Nestel, Paul Glasziou, Marian Gandy, Jeannie Joughin, Jennifer Seabrook, Jenny Stephenson, Alison Clague, Stephen MacMahon, Philip Aylward, Malcolm Whiting, John McNeil, Andrew Tonkin, Craig Anderson, Jenny Baker, Elizabeth Barnes, Wendy Hague, Anthony Keech, Li‐Ping Li, Sarah Mulray, Helen Pater, Kristy Robledo, R. John Simes, Paul Magnus, John Shaw, Rory Collins, Andrew Thomson, Phillip Harris, Norman Sharpe, Paul Meier, Philip Barter, John Watson, Lawrence Beilin, Graeme Hankey, Michael Hobbs, Peter Thompson, Gerald Watts, and David Colquhoun
Subjects: Creatinine, Myocardial Infarction, Humans, Coronary Disease, Renal Insufficiency, Cystatin C, Renal Insufficiency, Chronic, Cardiology and Cardiovascular Medicine, Lipids, Biomarkers, Glomerular Filtration Rate
Abstract: Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long‐term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow‐up, 6 years) and long‐term (median follow‐up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR‐creatinine, then GFR‐creatinine‐cystatin C). Over 6 years, in fully adjusted multivariable time‐to‐event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07–1.74; P =0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19–1.82; P P Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all‐cause mortality. Prediction of long‐term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au ; Unique identifier: ACTRN12616000535471.
Published: 2022

26. Body Mass Index and Association With Cardiovascular Outcomes in Patients With Stable Coronary Heart Disease – A STABILITY Substudy

Author: Claes Held, Nermin Hadziosmanovic, Philip E. Aylward, Emil Hagström, Judith S. Hochman, Ralph A. H. Stewart, Harvey D. White, and Lars Wallentin
Subjects: Male, obesity, Kardiologi, Coronary Disease, Middle Aged, Prognosis, Peptide Fragments, Body Mass Index, Risk Factors, RC666-701, Natriuretic Peptide, Brain, risk factors, Diseases of the circulatory (Cardiovascular) system, Humans, Cardiac and Cardiovascular Systems, Female, Prospective Studies, Cardiology and Cardiovascular Medicine, coronary artery disease, Biomarkers, Aged
Abstract: BACKGROUND The obesity paradox states that patients with higher body mass index (BMI) and cardiovascular disease may experience better prognosis. However, this is less clear in patients with coronary heart disease. METHODS AND RESULTS The prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial included 15 828 patients with stable coronary heart disease with 3 to 5 years’ follow‐up on optimal secondary preventive treatment. BMI was measured at baseline (n=15 785). Associations between BMI and cardiovascular outcomes were evaluated by Cox regression analyses with multivariable adjustments. Mean age was 64±9 years and 19% women. Most risk markers (diabetes, hypertension, inflammatory biomarkers, triglycerides) showed a graded association with higher BMI. The frequency of smoking, levels of high‐density lipoprotein, growth differentiation factor 15, and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were higher at lower BMI. Low BMI (2 ; n=244 [1.5%]) was associated with doubled risk of total death (hazard ratio [HR], 2.27; 95% CI, 1.60–3.22), cardiovascular death (HR, 2.26; 95% CI, 1.46–3.49), and heart failure (HR, 2.51; 95% CI, 1.35–4.68) compared with BMI of 25 to 2 (n=6752 [42.8%]) as reference. Similarly, high BMI of ≥35 kg/m 2 (n=1768 [11.2%]) was associated with increased risk of the same outcomes. A BMI between 20 and 2 was associated with increased risk of cardiovascular death (HR, 1.26; 95% CI, 1.03–1.54) and total death (HR, 1.21; 95% CI, 1.03–1.42). CONCLUSIONS Patients with stable coronary heart disease showed a graded increase in cardiometabolic and inflammatory risk factors with increasing BMI category >25 kg/m 2 . All‐cause and cardiovascular mortality were lowest at BMI of 25 to 35 kg/m 2 . Underweight with BMI of 2 and very high BMI of ≥35 kg/m 2 were strong risk markers for poor prognosis. REGISTRATION URL: https://clinicaltrials.gov/ ; Unique identifier NCT00799903.
Published: 2022
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27. Effect of Alirocumab on Incidence of Atrial Fibrillation After Acute Coronary Syndromes: Insights from the ODYSSEY OUTCOMES Trial

Author: Renato D. Lopes, Patrícia O. Guimarães, Gregory G. Schwartz, Deepak L. Bhatt, Vera A. Bittner, Andrzej Budaj, Anthony J. Dalby, Rafael Diaz, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Robert Gabor Kiss, Megan Loy, Robert Pordy, Yann Poulouin, Michael Szarek, Harvey D. White, and Philippe Gabriel Steg
Subjects: Treatment Outcome, Risk Factors, Incidence, Atrial Fibrillation, Myocardial Infarction, Humans, General Medicine, Acute Coronary Syndrome, Antibodies, Monoclonal, Humanized
Abstract: Using data from the ODYSSEY OUTCOMES trial (NCT01663402), we sought to identify factors associated with the development of incident atrial fibrillation in patients with recent acute coronary syndrome without prior atrial fibrillation and to determine whether alirocumab treatment influenced risk of incident atrial fibrillation.ODYSSEY OUTCOMES compared alirocumab treatment with placebo in 18,924 patients with recent acute coronary syndrome and dyslipidemia despite high-intensity or maximum-tolerated statin therapy. The primary outcome of major adverse cardiovascular events (MACE) comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Patients were classified as having previous atrial fibrillation (present prior to or at randomization) or no previous atrial fibrillation. A multivariable model was used to determine factors associated with incident atrial fibrillation.Among 18,262 participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (hazard ratio 0.91; 95% confidence interval, 0.77-1.09). Patients with vs without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs 3.7 events per 100 patient-years), without significant interaction between atrial fibrillation and randomized treatment on risk of MACE (PWhile alirocumab did not modify risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history. History of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.
Published: 2022

28. Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab

Author: Emil Hagström, P. Gabriel Steg, Michael Szarek, Deepak L. Bhatt, Vera A. Bittner, Nicolas Danchin, Rafael Diaz, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Evangelos Liberopoulos, Nikolaus Marx, Jennifer McGinniss, Garen Manvelian, Robert Pordy, Michel Scemama, Harvey D. White, Andreas M. Zeiher, Gregory G. Schwartz, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, William J. Sasiela, Jean-François Tamby, Philip E Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N Gotcheva, Juan-Carlos Prieto, Huo Yong, Patricio López-Jaramillo, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Steen Hvitfeldt Poulsen, Margus Viigimaa, Markku S Nieminen, Vakhtang Chumburidze, Pablo Carlos, Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M Correa Flores, Rody G. Sy, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Jan Murin, Zlatko Fras, Anthony J Dalby, José Tuñón, H. Asita de Silva, Ulf Landmesser, Christian Müller, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean F.P. van Diepen, Matthew D. Wilson, Andrew Tze-Kay Yan, Lilia B Schiavi, Marcelo Garrido, Andrés F Alvarisqueta, Sonia A Sassone, Anselmo P Bordonava, Alberto E Alves De Lima, Jorge M Schmidberg, Ernesto A Duronto, Orlando C Caruso, Leonardo P Novaretto, Miguel Angel Hominal, Oscar R Montaña, Alberto Caccavo, Oscar A Gomez Vilamajo, Alberto J Lorenzatti, Luis R Cartasegna, Gustavo A Paterlini, Ignacio J Mackinnon, Guillermo D Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R Codutti, Horacio O Jure, Julio OE Bono, Adrian D Hrabar, Julio A Vallejos, Rodolfo A Ahuad Guerrero, Federico Novoa, Cristian A Patocchi, Cesar J Zaidman, Maria E Giuliano, Ricardo D Dran, Marisa L Vico, Gabriela S Carnero, Pablo N Guzman, Juan C Medrano Allende, Daniela F Garcia Brasca, Miguel H Bustamante Labarta, Sebastian Nani, Eduardo DS Blumberg, Hugo R Colombo, Alberto Liberman, Victorino Fuentealba, Hector L Luciardi, Gabriel D Waisman, Mario A Berli, Ruben O Garcia Duran, Horacio G Cestari, Hugo A Luquez, Jorge A Giordano, Silvia S 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Blok, William Sheldon, Masoud M Azizad, Carsten Schmalfuss, Mark Picone, Robert Pederson, William Herzog, Keith Friedman, Jason Lindsey, Eichenlaub Timothy, Parilak Leonard, Norman Lepor, Mahfouz El Shahawy, Howard Weintraub, Anand Irimpen, Alvaro Alonso, Wade May, Daniels Christopher, Thomas Galski, Alan Chu, Freny Mody, Ebrahimi Ramin, Zachary Hodes, Joseph Rossi, Gregory Rose, James Fairlamb, Charles Lambert, Ajit Raisinghani, Antonio Abbate, George Vetrovec, Marilyn King, Charles Carey, Jaime Gerber, Liwa Younis, Hyeun (Tom) Park, Mladen Vidovich, Thomas Knutson, Dennis Friedman, Fred Chaleff, Arthur Loussararian, Phillip Rozeman, Carey Kimmelstiel, Jeffrey Kuvin, Kevin Silver, Malcolm Foster, Glen Tonnessen, Andrey Espinoza, Mohamadali Amlani, Andreas Wali, Christopher Malozzi, Geert T Jong, Clara Massey, Keattiyoat Wattanakit, Philip J. O’Donnell, Dinesh Singal, Naseem Jaffrani, Sridhar Banuru, Daniel Fisher, Mark Xenakis, Neal Perlmutter, Ravi Bhagwat, James Strader, Ronald Blonder, Ayim Akyea-Djamson, Ajay Labroo, Kwan Lee, H. John Marais, Edmund Claxton, Robert Weiss, Rohr Kathryn, Martin Berk, Peter Rossi, Parag Joshi, Amit Khera, Ajit S Khaira, Greg Kumkumian, Steven Lupovitch, Joshua Purow, Stephen Welka, David Hoffman, Stuart Fischer, Eugene Soroka, Donald Eagerton, Samir Pancholy, Michael Ray, Norman Erenrich, Michael Farrar, Stewart Pollock, William J French, Steve Diamantis, Douglas Guy, Lawrence Gimple, Mark Neustel, Steven Schwartz, Edward Pereira, Seals Albert, Douglas Spriggs, Janet Strain, Suneet Mittal, Anthony Vo, Majed Chane, Jason Hall, Nampalli Vijay, Kapildeo Lotun, F. Martin Lester, Ahed Nahhas, Theodore Pope, Paul Nager, Rakesh Vohra, Mukesh Sharma, Riyaz Bashir, Hinan Ahmed, Michael Berlowitz, Robert Fishberg, Robert Barrucco, Eric Yang, Michael Radin, Daniel Sporn, Dwight Stapleton, Steven Eisenberg, Joel Landzberg, Martin Mcgough, Samir Turk, Michael Schwartz, P. Sandy Sundram, Diwakar Jain, Mark Zainea, Carlos Bayron, Ronald Karlsberg, Suhail Dohad, Henry Lui, William Keen, Donald Westerhausen, Sandeep Khurana, Himanshu Agarwal, Jessica Birchem, William Penny, Mark Chang, Sherrill Murphy, John Henry, Branislav Schifferdecker, John M Gilbert, Gopal Chalavarya, Charles Eaton, John F Schmedtje, Stuart Christenson, Imran Dotani, Douglas Denham, Alexander Macdonell, Paul Gibson, Aref Rahman, Tammam Al Joundi, Nizar Assi, Gary Conrad, Purushotham Kotha, Michael Love, Gregory Giesler, Howard Rubenstein, Dawood Gamil, Laura Akright, Justine Krawczyk, Joanne Cobler, Terry Wells, James Welker, Robert Foster, Richard Gilmore, Jay Anderson, Douglas Jacoby, Bill Harris, Geraldine Gardner, Ramprasad Dandillaya, Kishor Vora, John Kostis, John Hunter, David Laxson, Eric Ball, Flavia Egydio, Anelise Kawakami, Janaina Oliveira, Julianna Wozniak, Alexander Matthews, Caroline Ratky, Janine Valiris, Lisa Berdan, Anita Hepditch, Kirby Quintero, Tyrus Rorick, Melissa Westbrook, Madeleine Bezault, Elodie Drouet, Tabassome Simon, Caroline Alsweiler, Anne Luyten, Julie Butters, Liddy Griffith, Michelle Shaw, Lena Grunberg, Shahidul Islam, Marie-France Brégeault, Nathalie Bougon, Douglas Faustino, Sylvie Fontecave, Judith Murphy, Jean- Francois Tamby, Melanie Verrier, Veronique Agnetti, Dorthe Andersen, Emmy Badreddine, Mhamed Bekkouche, Cecile Bouancheau, Imane Brigui, Maddy Brocklehurst, Joseph Cianciarulo, Dawn Devaul, Szilvia Domokos, Cecile Gache, Caroline Gobillot, Severine Guillou, Jan Healy, Megan Heath, Gayatri Jaiwal, Carine Javierre, Julien Labeirie, Myriam Monier, Ulises Morales, Asmaa Mrabti, Bicky Mthombeni, Betim Okan, Lucile Smith, Jennifer Sheller, Sebastien Sopena, Valerie Pellan, Fadela Benbernou, Nafissa Bengrait, Maud Lamoureux, Katarina Kralova, Raphael Bejuit, Anthony Coulange, Christelle Berthou, Jérôme Repincay, Christelle Lorenzato, Alexis Etienne, Valerie Gouet, Virginie Loizeau, Mickael Normand, Anne Ourliac, Christelle Rondel, Antony Adamo, Pascale Beltran, Pauline Barraud, Helene Dubois-Gache, Benjamin Halle, Lamia Metwally, Maxime Mourgues, Marc Sotty, Marion Vincendet, Raluca Cotruta, Zhu Chengyue, Dominique Fournie-Lloret, Christine Morrello, Aurelie Perthuis, Patrick Picault, Isabelle Zobouyan, Helen M. 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McClanahan, Roe, Matthew T., Blicharski, Tomasz, Bystryk, Leszek, Szpajer, Michal, Korol, Marek, Czerski, Tomasz, Gniot, Jacek, Lubinski, Andrzej, Gorny, Jerzy, Franek, Edward, Raczak, Grzegorz, Vogel, Robert, Szwed, Hanna, Monteiro, Pedro, Mesquita Bastos, Jose, Pereira, Helder H., Morais, Joao, Seixo, Filipe, Mendonça, Carlos, Botelho, Ana, Caetano, Francisca, Minescu, Bogdan, Chaitman, Bernard, Istratoaie, Octavian, Tesloianu, Dan N., Dorobantu, Maria, Cristian, Gabriel, Dumitrescu, Silviu, Podoleanu, Cristian Gc, Constantinescu, Mircea Ca, Bengus, Cristina M., Militaru, Constantin, Rosu, Doina, Kelsey, Sheryl F., Parepa, Irinel R., Matei, Adrian V., Alexandru, Tom M., Malis, Mihaela, Coman, Ioan, Shvarts, Yury, Orlikova, Olga, Kobalava, Zhanna, Barbarash, Olga L., Markov, Valentin, Olsson, Anders G., Lyamina, Nadezhda, Gordienko, Alexander, Zrazhevsky, Konstantin, Vishnevsky, Alexander Y., Gurevich, Victor, Stryuk, Raisa, Lomakin, Nikita V., Bokarev, Igor, Khlevchuk, Tatiana, Shalaev, Sergey, Rouleau, Jean-Lucien, Khaisheva, Larisa, Chizhov, Petr, Viktorova, Inna, Osokina, Natalya, Shchekotov, Vladimir, Akatova, Evgenia, Chumakova, Galina, Libov, Igor, Voevoda, Mikhail I., Tretyakova, Tatyana V., Simoons, Maarten L., Baranov, Evgeny, Shustov, Sergey, Yakushin, Sergey, Gordeev, Ivan, Khasanov, Niiaz, Reshetko, Olga, Sotnikova, Tatiana, Molchanova, Olga, Nikolaev, Konstantin, Gapon, Liudmila, Alexander, Karen, Baranova, Elena, Kosmachova, Elena, Karpov, Yuriy, Karpov, Yuri, Povzun, Anton, Egorova, Liudmila, Tyrenko, Vadim V., Ivanov, Igor G., Ilya, Masterov, Kanorsky, Sergey, Meloni, Chiara, Simic, Dragan, Ivanovic, Nikola, Davidovic, Goran, Tasic, Nebojsa, Asanin, Milika R., Stojic, Stevo, Apostolovic, Svetlana R., Ilic, Stevan, Tosic, Biljana Putnikovic, Stankovic, Aleksandar, Rosenson, Robert, Arandjelovic, Aleksandra, Radovanovic, Slavica, Todic, Branislava, Ristic, Arsen D., Balinovac, Jovan, Dincic, Dragan V., Seferovic, Petar, Karadzic, Ana, Dodic, Slobodan, Dimkovic, Sinisa, Sijbrands, Eric J. G., Jakimov, Tamara, Poh, Kian-Keong, Yee Ong, Hean, Tang I-Shing, Justin, Micko, Karol, Nociar, Jan, Pella, Daniel, Fulop, Peter, Hranai, Marian, Palka, Juraj, Tricoci, Pierluigi, Mazur, Juraj, Majercák, Ivan, Dzupina, Andrej, Fazekas, František, Gonsorcik, Jozef, Bugan, Viliam, Murin, Jan, Selecky, Juraj, Kamensky, Gabriel, Strbova, Jaroslava, Alexander, John H., Smik, Rudolf, Dukat, Andrej, Olexa, Peter, Žuran, Ivan, Poklukar, Janez, Šuligoj, Nataša Černič, Cevc, Matija, Fras, Zlatko, Cyster, Henry P., Ranjith, Naresh, Armaganijan, Luciana, Corbett, Clive, Bayat, Junaid, Makoali Makotoko, Ellen, du Toit Theron, Hendrik, Kapp, Ilse E., de V Basson, Matthys M., Lottering, Hanlie, Van Aswegen, Dina, Van Zyl, Louis J., Sebastian, Peter J., Bagai, Akshay, Pillay, Thayabran, Saaiman, Jan A., Commerford, Patrick J., Cassimjee, Soraya, Riaz, Garda, Ebrahim, Iftikhar O., Sarvan, Mahomed, Mynhardt, Joseph H., Dalby, Anthony J., Reuter, Helmuth, Bahit, Maria Cecilia, Moodley, Rajendran, Vida, Manuel, Fillat, Angel R. 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Matthew, Worner Diz, Fernando, Garcia-Dorado, David, Iñiguez, Andres, Gonzalez-Juanatey, Jose R., Portales, Javier Fernandez, Murillo, Fernando Civeira, Pericas, Laia Matas, Zamorano, Jose Luis, De Mora Martin, Manuel, Cortada, Jordi Bruguera, Clifton, Shaun, Alonso Martin, Joaquin J., Serrano Antolin, Jose Maria, De Berrazueta Fernández, José R., Vázquez de Prada, José Antonio, Díaz Fernández, Jose Francisco, García Lledó, José Alberto, Cosín Sales, Juan, Rodriguez, Javier Botas, Tragant, Gabriel Gusi, Benedicto, Amparo, DeVore, Adam D., Gonzalez-Juanatey, Carlos, Camprubí Potau, Mercedes, Perez, Ignacio Plaza, De La Tassa, César Morís, Rincon, Pablo Loma-Osorio, Recena, Javier Balaguer, Escudier, Juan M., Payeras, Antonio Coca, Orcajo, Norberto Alonso, Constantine, Godwin, Deloatch, Shalonda, Haniffa, Ruvaiz, Tissera, Nirmali, Amarasekera, Stanley, Ponnamperuma, Chandrike, Fernando, Nimali, Fernando, Kaputella, Jayawardena, Jayanthimala, Wijeyasingam, Santharaj, Ranasinghe, Gotabhaya, Ekanayaka, Ruvan, Dickey, Sheila, Mendis, Sepalika, Senaratne, Vajira, Mayurathan, Gnanamoorthy, Rajapaksha, Ajantha, Sirisena, Thilak, Herath, Jagath I., Amarasena, Naomali, Berglund, Stefan, Rasmanis, Gundars, Hagström, Emil, Dombrowski, Keith, Vedin, Ola, Witt, Nils, Mourtzinis, Georgios, Nicol, Peter, Hansen, Ole, Romeo, Stefano, Jensen, Steen Agergaard, Torstensson, Ingemar, Ahremark, Ulf, Sundelin, Torbjörn, Ducrocq, Grégory, Moccetti, Tiziano, Müller, Christian, Mach, Francois, Binde, Ronald, Landmesser, Ulf, Gämperli, Oliver, Chiang, Chern-En, Tsai, Wei-Chuan, Ueng, Kwo-Chang, Lai, Wen-Ter, Eapen, Zubin, Liu, Ming-En, Hwang, Juey-Jen, Yin, Wei-Hsian, Hsieh, I.-Chang, Hsieh, Ming-Jer, Hsiang Lin, Wei, Kuo, Jen-Yuan, Huang, Tsuei-Yuan, Fang, Chih-Yuan, Kaewsuwanna, Pinij, Endsley, Patricia, Soonfuang, Wasant, Jintapakorn, Woravut, Sukonthasarn, Apichard, Sritara, Piyamitr, Wongpraparut, Nattawut, Sastravaha, Krisada, Sansanayudh, Nakarin, Kehasukcharoen, Wirash, Piyayotai, Dilok, Chotnoparatpat, Paiboon, Eppinger, Arleen, Camsari, Ahmet, Kultursay, Hakan, Guneri, Sema, Mutlu, Bulent, Ersanli, Murat, Demirtas, Mustafa, Kirma, Cevat, Ural, Ertan, Koldas, Lale, Karpenko, Oleksandr, Harrison, Robert W., Prokhorov, Alexander, Vakaluyk, Ihor, Myshanych, Halyna, Reshotko, Dmytro, Batushkin, Valeriy, Rudenko, Leonid, Kovalskyi, Ihor, Kushnir, Mykola, Tseluyko, Vira, Mostovoy, Yuriy, Hess, Connie Ng, Stanislavchuk, Mykola, Kyiak, Yulian, Karpenko, Yuriy, Malynovsky, Yaroslav, Klantsa, Andriy, Kutniy, Oles, Amosova, Ekaterina, Tashchuk, Viktor, Leshchuk, Oleh, Parkhomenko, Alexander, Hlatky, Mark A., Rishko, Mykola, Kopytsya, Mykola, Yagensky, Andriy, Vatutin, Mykola, Bagriy, Andriy, Barna, Olga M., Ushakov, Olexiy, Dzyak, Georgiy, Goloborodko, Borys, Rudenko, Anatolii, Jordan, Joseph Dedrick, Zheleznyy, Volodymyr, Trevelyan, Jasper, Zaman, Azfar, Lee, Kaeng, Moriarty, Andrew, Aggarwal, Rajesh K., Clifford, Piers, Wong, Yuk-ki, Iqbal, Syed Mr, Subkovas, Eduardas, Knowles, Joshua W., Braganza, Denise, Sarkar, David, Storey, Robert, Griffiths, Huw, Mcclure, Sam, Muthusamy, Rangasamy, Smith, Simon, Kurian, John, Levy, Terry, Barr, Craig, Kolls, Bradley J., Kadr, Honer, Gerber, Robert, Simaitis, Audrius, Soran, Handrean, Brodison, Adrian, Ayaz, Mohammad, Cheema, Muhammad, Oliver, Richard, Thackray, Simon, Mudawi, Telal, Kong, David F., Rahma, Gohar, Sultan, Ayyaz, Reynolds, Timothy, Sharman, David, Spriging, David, Butler, Rob, Wilkinson, Peter, Lip, Gregory Yh, Ossei-Gerning, Nicholas, Vardi, Gil, Leonardi, Sergio, Baldari, Duccio, Brabham, David, Treasure Ii, Charles, Dahl, Charles, Palmer, Bruce, Wiseman, Alan, Khan, Abul, Puri, Sanjeev, Mohart, Ann Elizabeth, Ince, Carlos, Lillis, Linda, Flores, Enrique, Wright, Scott, Cheng, Shi-Chi, Rosenberg, Michael, Rogers, William, Kosinski, Edward, Forgosh, Les, Waltman, Jonathan, Shoukfeh, Mohammad, Dagher, Georges, Lopes, Renato D., Cambier, Patrick, Lieber, Ira, Kumar, Priya, East, Cara, Krichmar, Perry, Hasan, Mian, White, Lindsey, Knickelbine, Thomas, Haldis, Thomas, Gillespie, Eve, Maron, David J., Amidon, Thomas, Suh, David, Arif, Imran, Abdallah, Mouhamad, Akhter, Faiq, Carlson, Eric, D'Urso, Michael, El-Ahdab, Fadi, Nelson, William, Moriarty, Katie, Mahaffey, Kenneth W., Harris, Barry, Cohen, Steven, Carter, Luther, Doty, Daniel, Sabatino, Kenneth, Haddad, Tariq, Rao, Sunder, Mulkay, Angel, Jovin, Ion, Klancke, Kim, Marcus, Jill, Malhotra, Vinay, Devarapalli, Sai K., Koren, Michael, Chandna, Harish, Dodds Iii, George, Goraya, Tauqir, Bengston, James, Janik, Matthew, Moran, Joseph, Sumner, Andrew, Mathews, Robin, Kobayashi, John, Davis, William, Yazdani, Shahram, Pasquini, John, Thakkar, Maitreya, Vedere, Amarnath, Leimbach, Wayne, Rider, James, Fenton, Sarah, Singh, Narendra, Mehta, Rajendra H., Shah, Anil V., Moriarty, Patrick M., Janosik, Denise, Pepine, Carl, Berman, Brett, Gelormini, Joseph, Daniels, Christopher, Richard, Kerensky, Keating, Friederike, Kondo, Nicholas I., Mentz, Robert J., Shetty, Sanjay, Levite, Howard, Waider, Winfried, Takata, Theodore, Abu-Fadel, Mazen, Shah, Vipul, Aggarwal, Rahul, Kumar, Anil, Hattler, Brack, Do, Rose, Moreira, Humberto Graner, Link, Chad, Bortnick, Anna, Kinzfogl Iii, George, Ghitis, Arnold, Larry, John, Teufel, Edward, Kuhlman, Peter, Mclaurin, Brent, Zhang, Wenwu, Thew, Stephen, Patel, Chetan B., Abbas, Jalal, White, Matthew, Islam, Othman, Subherwal, Sumeet, Ranadive, Nandkishore, Vakili, Babak, Gring, Christian, Henderson, David, Schuchard, Timothy, Farhat, Naim, Pereira, Sabrina Bernardez, Kline, Geoffrey, Mahal, Sharan, Whitaker, Jack, Speirs, Shawn, Andersen, Rolf, Daboul, Nizar, Horwitz, Phillip, Zahr, Firas, Ponce, George, Jafar, Zubair, Perkins, Lynn, Mcgarvey, Joseph, Panchal, Vipul, Voyce, Stephen, Blok, Thomas, Sheldon, William, Azizad, Masoud M., Schmalfuss, Carsten, Picone, Mark, Pederson, Robert, Herzog, William, Povsic, Thomas J., Friedman, Keith, Lindsey, Jason, Timothy, Eichenlaub, Leonard, Parilak, Lepor, Norman, El Shahawy, Mahfouz, Weintraub, Howard, Irimpen, Anand, Alonso, Alvaro, May, Wade, Puymirat, Etienne, Christopher, Daniels, Galski, Thomas, Chu, Alan, Mody, Freny, Ramin, Ebrahimi, Hodes, Zachary, Rossi, Joseph, Rose, Gregory, Fairlamb, James, Lambert, Charles, Raisinghani, Ajit, Abbate, Antonio, Vetrovec, George, King, Marilyn, Carey, Charles, Gerber, Jaime, Younis, Liwa, Park, Hyeun Tom, Vidovich, Mladen, Knutson, Thomas, Jones, William Schuyler, Friedman, Dennis, Chaleff, Fred, Loussararian, Arthur, Rozeman, Phillip, Kimmelstiel, Carey, Kuvin, Jeffrey, Silver, Kevin, Foster, Malcolm, Tonnessen, Glen, Espinoza, Andrey, Shah, Bimal R., Amlani, Mohamadali, Wali, Andreas, Malozzi, Christopher, Jong, Geert T., Massey, Clara, Wattanakit, Keattiyoat, O'Donnell, Philip J., Singal, Dinesh, Jaffrani, Naseem, Banuru, Sridhar, Sherwood, Matthew W., Fisher, Daniel, Xenakis, Mark, Perlmutter, Neal, Bhagwat, Ravi, Strader, James, Blonder, Ronald, Akyea-Djamson, Ayim, Labroo, Ajay, Lee, Kwan, Marais, H. John, Stringfellow, Kenya, Claxton, Edmund, Weiss, Robert, Kathryn, Rohr, Berk, Martin, Rossi, Peter, Joshi, Parag, Khera, Amit, Khaira, Ajit S., Kumkumian, Greg, Lupovitch, Steven, Sujjavanich, Darin, Purow, Joshua, Welka, Stephen, Hoffman, David, Fischer, Stuart, Soroka, Eugene, Eagerton, Donald, Pancholy, Samir, Ray, Michael, Erenrich, Norman, Farrar, Michael, Toma, Mustafa, Pollock, Stewart, French, William J., Diamantis, Steve, Guy, Douglas, Gimple, Lawrence, Neustel, Mark, Schwartz, Steven, Pereira, Edward, Albert, Seals, Spriggs, Douglas, Trotter, Charlene, Strain, Janet, Mittal, Suneet, Vo, Anthony, Chane, Majed, Hall, Jason, Vijay, Nampalli, Lotun, Kapildeo, Lester, F. Martin, Nahhas, Ahed, Pope, Theodore, van Diepen, Sean F. 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Andreas M, Roe, Matthew T, Mahaffey, Kenneth W, Edelberg, Jay M, Sasiela, William J, Aylward, Philip E, Lopes, Renato D, Gotcheva, Nina N, Nieminen, Markku S, Laucevičius, Aleksandras, Correa Flores, Roger M, Sy, Rody G, Ristic, Arsen D, Dalby, Anthony J, de Silva, H Asita, Ray, Kausik K, Moriarty, Patrick M, Kelsey, Sheryl F, Olsson, Anders G, Simoons, Maarten L, Sijbrands, Eric J G, Alexander, John H, Brennan, J Matthew, DeVore, Adam D, Harrison, Robert W, Hlatky, Mark A, Knowles, Joshua W, Kolls, Bradley J, Kong, David F, Maron, David J, Mehta, Rajendra H, Mentz, Robert J, Patel, Chetan B, Povsic, Thomas J, Shah, Bimal R, Sherwood, Matthew W, van Diepen, Sean F P, Wilson, Matthew D, Schiavi, Lilia B, Alvarisqueta, Andrés F, Sassone, Sonia A, Bordonava, Anselmo P, Alves De Lima, Alberto E, Schmidberg, Jorge M, Duronto, Ernesto A, Caruso, Orlando C, Novaretto, Leonardo P, Montaña, Oscar R, Gomez Vilamajo, Oscar A, Lorenzatti, Alberto J, Cartasegna, Luis R, Paterlini, Gustavo A, Mackinnon, Ignacio J, Caime, Guillermo D, Codutti, Oscar R, Jure, Horacio O, Hrabar, Adrian D, Vallejos, Julio A, Ahuad Guerrero, Rodolfo A, Patocchi, Cristian A, Zaidman, Cesar J, Giuliano, Maria E, Dran, Ricardo D, Vico, Marisa L, Carnero, Gabriela S, Guzman, Pablo N, Medrano Allende, Juan C, Garcia Brasca, Daniela F, Bustamante Labarta, Miguel H, Colombo, Hugo R, Luciardi, Hector L, Waisman, Gabriel D, Berli, Mario A, Garcia Duran, Ruben O, Cestari, Horacio G, Luquez, Hugo A, Giordano, Jorge A, Saavedra, Silvia S, Waites, Jonathon H, Arstall, Margaret A, Rogers, James F, Oqueli Flores, Romulo E, Lehman, Sam J, Garrahy, Paul J, Carroll, Patrick A, Wolf, Luc De, Nicolau, Jose C, Giorgeto, Flavio E, Silva, Ricardo P, Abrantes, José Antonio M, Bodanese, Luiz C, Michalaros, Yorghos L, Eliaschewitz, Freddy G, Vidotti, Maria H, Leaes, Paulo E, Botelho, Roberto V, Manenti, Euler Roberto F Fernandes, Precoma, Dalton B, Moura Jorge, Jose C, Silveira, Jose A, Neto, Jose A Marin, Feitosa, Gilson S, Ritt, Luiz Eduardo F, de Souza, Juliana A, Todorov, Georgi V, Nikolov, Fedya P, Velcheva, Elena S, Tzekova, Maria L, Benov, Haralambi O, Petranov, Stanislav L, Tumbev, Haralin S, Shehova-Yankova, Nina S, Markov, Dimitar T, Raev, Dimitar H, Mollov, Mihail N, Kichukov, Kostadin N, Ilieva-Pandeva, Katya A, Mincheva, Valentina M, Lazov, Petar V, Dimov, Bojidar I, Prieto, Juan C, Raffo, Carlos A, Luna Botia, Diana C, De Salazar, Dora I Molina, Bonfanti, Alberto J Cadena, Barrera Silva, Sandra I, Garcia Lozada, Henry J, Coronel Arroyo, Julian A, Accini Mendoza, Jose L, Fernandez Ruiz, Ricardo L, Quintero Ossa, Alvaro M, Manzur Jatin, Fernando G, Urina Triana, Miguel A, Trujillo, Angela M Fernandez, Poulsen, Steen H, Bang, Lia E, Hove, Jens D, Kristensen, Kjeld S, Lomholdt, Jens D, Klausen, Ib C, Fausto Ovando, Sergio R, Arango Benecke, Juan L, Rodriguez De Leon, Edgar R, Premchand, Rajendra K, Abhyanakar, Atul D, Govinda, Ravishankar A, Patil, Sachin N, Joshi, Abhijeet B, Pothineni, Ramesh B, Monteiro, Minguel R, Iyengar, Shamanna S, Fulwani, Mahesh C, Chopra, Vijay K, Goyal, Naresh K, Manakshe, Gajendra V, Pellegrin, Annamaria De, De Cesare, Nicoletta B, Piatti, Piermarco, Luca, Giuseppe De, Leo, Alessandro De, Petrulionienė, Žaneta, Šakalytė, Gintarė, Šlapikas, Rimvydas, Liew, Houng B, Breedveld, Robert W, Wiersma, Jacobijne J, Troquay, Roland PTh, Viergever, Eric P, Bartels, Gerard L, Cornel, Jan H, Bos, Robert J, Van Der Zwaan, Coenraad C, Groenemeijer, Bjorn E, Willems, Frank F, Munk, Peter S, Calderon Ticona, Jorge R, Durand Velasquez, Julio R, Negron Miguel, Sandra A, Sanabria Perez, Enrique S, Carrion Chambilla, Jesus M, Chavez Ayala, Carlos A, Castillo Leon, Reynaldo P, Vargas GonzalesC, Rolando J, Hernandez Zuniga, Jose D, Camacho Cosavalente, Luis A, Bravo Mannucci, Jorge E, Llerena Navarro, Nassip C, Roldan Concha, Yudy M, Rodriguez Chavez, Víctor E, Anchante Hernandez, Henry A, Zea Nunez, Carlos A, Sy, Rosa Allyn G, Morales, Dante D, Pereira, Helder H, Tesloianu, Dan N, Bengus, Cristina M, Parepa, Irinel R, Matei, Adrian V, Alexandru, Tom M, Barbarash, Olga L, Vishnevsky, Alexander Y, Lomakin, Nikita V, Voevoda, Mikhail I, Tretyakova, Tatyana V, Tyrenko, Vadim V, Ivanov, Igor G, Asanin, Milika R, Apostolovic, Svetlana R, Dincic, Dragan V, Cyster, Henry P, Kapp, Ilse E, de V Basson, Matthys M, Aswegen, Dina Van, Van Zyl, Louis J, Sebastian, Peter J, Saaiman, Jan A, Commerford, Patrick J, Ebrahim, Iftikhar O, Mynhardt, Joseph H, Fillat, Angel R Cequier, Cruz Fernández, Jose M, Gonzalez-Juanatey, Jose R, Alonso Martin, Joaquin J, De Berrazueta Fernández, José R, Escudier, Juan M, Herath, Jagath I, Hsieh, I-Chang, Barna, Olga M, Aggarwal, Rajesh K, Wong, Yuk-Ki, Devarapalli, Sai K, Shah, Anil V, Kondo, Nicholas I, Azizad, Masoud M, Jong, Geert T, O'Donnell, Philip J, Marais, H John, Khaira, Ajit S, French, William J, Lester, F Martin, Sundram, P Sandy, Gilbert, John M, Schmedtje, John F, Colhoun, Helen M, Dempsey, Michael A, and McClanahan, Mark A
Subjects: Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Anticholesteremic Agents/adverse effects, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], prevention & control, heart disease risk factors, diagnosis [Cardiovascular Diseases], Antibodies, Monoclonal, Humanized, PCSK9 inhibitors, acute coronary syndrome, apolipoproteins B, LDL cholesterol, Antibodies, acute coronary syndrome, LDL, drug therapy [Atherosclerosis], Risk Factors, Physiology (medical), therapeutic use [Hydroxymethylglutaryl-CoA Reductase Inhibitors], Monoclonal, Humans, Cardiac and Cardiovascular Systems, Humanized, Cardiovascular Diseases/diagnosis, Apolipoproteins B, Kardiologi, diagnosis [Acute Coronary Syndrome], Anticholesteremic Agents, PCSK9 inhibitors, apolipoproteins B, cholesterol, LDL, cholesterol, Atherosclerosis/drug therapy, Cholesterol, LDL, Atherosclerosis, Acute Coronary Syndrome/diagnosis, drug therapy, Cholesterol, Treatment Outcome, Cardiovascular Diseases, Heart Disease Risk Factors, epidemiology, adverse effects [Anticholesteremic Agents], Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine
Abstract: Circulation : an official journal of the American Heart Association / ed.-in-chief Ephraim Donosco 146(9), 657-672 (2022). doi:10.1161/CIRCULATIONAHA.121.057807, Published by Ovid, [Erscheinungsort nicht ermittelbar]
Published: 2022
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29. High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality

Author: P J, Devereaux, Andre, Lamy, Matthew T V, Chan, René V, Allard, Vladimir V, Lomivorotov, Giovanni, Landoni, Hong, Zheng, Domenico, Paparella, Michael H, McGillion, Emilie P, Belley-Côté, Joel L, Parlow, Malcolm J, Underwood, Chew Yin, Wang, Nazari, Dvirnik, Marat, Abubakirov, Evgeny, Fominskiy, Stephen, Choi, Stephen, Fremes, Fabrizio, Monaco, Gerard, Urrútia, Marialuz, Maestre, Ludhmila A, Hajjar, Graham S, Hillis, Nicholas L, Mills, Vito, Margari, Joseph D, Mills, J Stephen, Billing, Emily, Methangkool, Carisi A, Polanczyk, Roberto, Sant'Anna, Dmitry, Shukevich, David, Conen, Peter A, Kavsak, Matthew J, McQueen, Katheryn, Brady, Jessica, Spence, Yannick, Le Manach, Rajibul, Mian, Shun Fu, Lee, Shrikant I, Bangdiwala, Sara, Hussain, Flavia K, Borges, Shirley, Pettit, Jessica, Vincent, Gordon H, Guyatt, Salim, Yusuf, Joseph S, Alpert, Harvey D, White, Richard P, Whitlock, Allison, Serra, Devereaux, P. J., Lamy, A., Chan, M. T. V., Allard, R. V., Lomivorotov, V. V., Landoni, G., Zheng, H., Paparella, D., Mcgillion, M. H., Belley-Cote, E. P., Parlow, J. L., Underwood, M. J., Wang, C. Y., Dvirnik, N., Abubakirov, M., Fominskiy, E., Choi, S., Fremes, S., Monaco, F., Urrutia, G., Maestre, M., Hajjar, L. A., Hillis, G. S., Mills, N. L., Margari, V., Mills, J. D., Billing, J. S., Methangkool, E., Polanczyk, C. A., Sant'Anna, R., Shukevich, D., Conen, D., Kavsak, P. A., Mcqueen, M. J., Brady, K., Spence, J., Le Manach, Y., Mian, R., Lee, S. F., Bangdiwala, S. I., Hussain, S., Borges, F. K., Pettit, S., Vincent, J., Guyatt, G. H., Yusuf, S., Alpert, J. S., White, H. D., and Whitlock, R. P.
Subjects: Male, heart infarction, adverse event, Myocardial Infarction, surgery, Postoperative Complications, blood, coronary artery bypass graft, Reference Values, Humans, postoperative complication, human, Prospective Studies, Cardiac Surgical Procedures, Coronary Artery Bypass, Aged, Troponin I, reference value, clinical trial, General Medicine, Middle Aged, biological marker, mortality, heart surgery, multicenter study, Aortic Valve, Female, Biomarkers, prospective study
Abstract: BACKGROUND Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to >= 70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.)
Published: 2022
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30. Cardiac death should be the primary endpoint for revascularization trials and meta-analyses

Author: Harvey D. White
Subjects: medicine.medical_specialty, business.industry, medicine.medical_treatment, Revascularization, Death, Percutaneous Coronary Intervention, Internal medicine, Cardiology, Clinical endpoint, Medicine, Humans, ST Elevation Myocardial Infarction, Cardiology and Cardiovascular Medicine, business
Published: 2021

31. The genomics of heart failure: design and rationale of the HERMES consortium

Author: Svati H. Shah, Olle Melander, Neneh Sallah, Quinn S. Wells, Jerome I. Rotter, Faye Zhao, Charlotte Andersson, Guðmundur Thorgeirsson, Ghazaleh Fatemifar, Alex S. F. Doney, Michael E. Dunn, David E. Lanfear, Ian Ford, Eric Boersma, Sonia Shah, Christopher Newton-Cheh, Douglas L. Mann, Niek Verweij, Carolina Roselli, Laura M. Yerges-Armstrong, Jian Yang, Christian Torp-Pedersen, Veikko Salomaa, Mary L. Biggs, Alaa Shalaby, Christoph Nowak, Stefan Gross, Patrick T. Ellinor, Mari Liis Tammesoo, Diane T. Smelser, Peter M. Visscher, Hans L. Hillege, Ruth C. Lovering, Honghuang Lin, Colin N. A. Palmer, Louis Philippe Lemieux Perreault, Jeffrey Brandimarto, Uwe Völker, Perttu Salo, Andrea Koekemoer, Rebecca Gutmann, Åsa K. Hedman, Nilesh J. Samani, Heming Xing, Faiez Zannad, Jaison Jacob, Harry Hemingway, Michael R. Brown, Franco Giulianini, Anubha Mahajan, Xing Chen, Alexander Niessner, Peter Almgren, Daniel I. Swerdlow, Gunnar Engström, Lars Lind, Tõnu Esko, Tomasz Czuba, Anna Helgadottir, Harvey D. White, David J. Stott, Johan Ärnlöv, Lars Køber, Chim C. Lang, Krishna G. Aragam, Kent D. Taylor, Anders Mälarstig, Frederick K. Kamanu, Kenneth B. Margulies, Michelle L. O'Donoghue, Andrew D. Morris, Sahar Ghasemi, J. Wouter Jukema, Jessica van Setten, Abbas Dehghan, Guillaume Paré, Luca A. Lotta, Giorgio E. M. Melloni, Albert Henry, Bruce M. Psaty, Paul M. Ridker, David J. Carey, Marie-Pierre Dubé, John S. Gottdiener, Xiaosong Wang, Per H. Svensson, Xu Chen, Patrik K. E. Magnusson, Claudia Langenberg, Alexander Teumer, Vilmantas Giedraitis, Simon de Denus, Michael W. Nagle, Marcus Dörr, Thomas P. Cappola, André G. Uitterlinden, Michael Morley, Eliana Portilla-Fernandez, J. Gustav Smith, Abirami Veluchamy, Peter Weeke, Ify R. Mordi, Unnur Thorsteinsdottir, Naveed Sattar, Folkert W. Asselbergs, Daniel I. Chasman, Daníel F. Guðbjartsson, Jonathan H. Chung, Marcus E. Kleber, Raul Weiss, Christopher P. Nelson, Spiros Denaxas, Bing Yu, Simon P. R. Romaine, Nicholas A Marston, Anjali T. Owens, Cecilia M. Lindgren, John J.V. McMurray, Joshua D. Backman, Michael V. Holmes, Stella Trompet, Hilma Holm, Kerri L. Wiggins, Jian'an Luan, Stephan B. Felix, Yifan Yang, Jemma B. Wilk, Maryam Kavousi, Markus Perola, Christian T. Ruff, Jean-Claude Tardif, G Sveinbjörnsson, Samuel C. Dudley, Nicholas J. Wareham, Teemu J. Niiranen, Andrew P. Morris, Danny Tuckwell, Maris Teder-Laving, R. Thomas Lumbers, James P. Cook, Géraldine Asselin, William A. Chutkow, Winfried März, Steven A. Lubitz, John G.F. Cleland, Bill Kraus, Ramachandran S. Vasan, Christopher M. Haggerty, Olympe Chazara, Chris Finan, Heather L. Bloom, Hans-Peter Brunner-La Rocca, Francoise Fougerousse, Kenneth Rice, Craig L. Hyde, Graciela E. Delgado, Mark Chaffin, Marc S. Sabatine, Alanna C. Morrison, Kay-Tee Khaw, Kari Stefansson, Felix Vaura, Barry London, Isabella Kardys, Aroon D. Hingorani, Hongsheng Gui, Steen Stender, René Fouodjio, Mohsen Ghanbari, Pim van der Harst, Nicholas L. Smith, Karoline Kuchenbaecker, Adriaan A. Voors, Benoit Tyl, University College of London [London] (UCL), University College London Hospitals (UCLH), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Lund University [Lund], Pfizer, Karolinska Institutet [Stockholm], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Groningen [Groningen], University of Oxford [Oxford], Dalarna University, Massachusetts General Hospital [Boston], Montreal Heart Institute - Institut de Cardiologie de Montréal, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, University of Washington [Seattle], Emory University [Atlanta, GA], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Pennsylvania [Philadelphia], The University of Texas Health Science Center at Houston (UTHealth), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), AstraZeneca, Novartis Institutes for BioMedical Research (NIBR), University of Glasgow, University of Liverpool, Université de Montréal (UdeM), Imperial College London, University of Heidelberg, Medical Faculty, University of Dundee, Universität Greifswald - University of Greifswald, University of Minnesota Medical School, University of Minnesota System, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Institut de Recherches Internationales Servier [Suresnes] (IRIS), Uppsala University, University of Maryland School of Medicine, University of Maryland System, University of Iceland [Reykjavik], deCODE genetics [Reykjavik], Henry Ford Hospital, Carver College of Medicine, University of Iowa, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), ICIN - Netherlands Heart Institute, Leiden University Medical Center (LUMC), Netherlands Heart Institute, Partenaires INRAE, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, University of Leicester, Duke University [Durham], University of Iowa [Iowa City], Genentech, Inc., Genentech, Inc. [San Francisco], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Skane University Hospital [Malmo], University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, University of Turku, National Institute for Health and Welfare [Helsinki], McMaster University [Hamilton, Ontario], Kaiser Permanente Washington Health Research Institute [Seattle] (KPWHRI), Harbor UCLA Medical Center [Torrance, Ca.], University Medical Center [Utrecht], University of Pittsburgh Medical Center [Pittsburgh, PA, États-Unis] (UPMC), University of Tartu, Aalborg University [Denmark] (AAU), Leiden University, University of Queensland [Brisbane], Ohio State University [Columbus] (OSU), Auckland City Hospital, GlaxoSmithKline, Glaxo Smith Kline, University of Texas Health Science Center, Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Duke University Medical Center, Regeneron Pharmaceuticals [Tarrytown], Vanderbilt University [Nashville], European Project, Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Kidney Center (GKC), Cardiology, University of Oxford, University of Pennsylvania, Universiteit Leiden, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Epidemiology, and Internal Medicine
Subjects: Male, Study Designs, Cardiomyopathy, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, AFRICAN ANCESTRY, Epidemiology, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, Cardiac and Cardiovascular Systems, AGING RESEARCH, RISK, Aged, 80 and over, 0303 health sciences, Kardiologi, Genomics, Middle Aged, Prognosis, 3. Good health, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Heart failure, CLASSIFICATION, Heart Failure/genetics, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetic model, medicine, Genetics, Diseases of the circulatory (Cardiovascular) system, Humans, Allele frequency, Genotyping, METAANALYSIS, 030304 developmental biology, Aged, Association studies, Study Design, business.industry, Odds ratio, ADULTS, COHORTS, medicine.disease, RC666-701, REPLICATION, business, Biomarkers, Genome-Wide Association Study
Abstract: Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
Published: 2021
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32. Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol

Author: Gregory G. Schwartz, Michael Szarek, Vera A. Bittner, Rafael Diaz, Shaun G. Goodman, J. Wouter Jukema, Ulf Landmesser, Patricio López-Jaramillo, Garen Manvelian, Robert Pordy, Michel Scemama, Peter R. Sinnaeve, Harvey D. White, Ph Gabriel Steg, P.h. Gabriel Steg, Deepak L. Bhatt, Robert A. Harrington, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, William J. Sasiela, Jean-François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilic, Renato D. Lopes, Nina N. Gotcheva, Juan-Carlos Prieto, Huo Yong, Ivan Pećin, Zeljko Reiner, Petr Ostadal, Steen Hvitfeldt Poulsen, Margus Viigimaa, Markku S. Nieminen, Nicolas Danchin, Vakhtang Chumburidze, Nikolaus Marx, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung-Fat Tse, Robert Gabor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang-Hyun Kim, Andrejs Erglis, Aleksandras Laucevicius, Sasko Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Rody G. Sy, Andrzej Budaj, Joao Morais, Maria Dorobantu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Jan Murin, Zlatko Fras, Anthony J. Dalby, José Tuñón, H. Asita de Silva, Emil Hagström, Christian Müller, Chern-En Chiang, Piyamitr Sritara, Sema Guneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders G. Olsson, Jean-Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert Rosenson, Eric J.G. Sijbrands, John H. Alexander, Luciana Armaganijan, Akshay Bagai, Maria Cecilia Bahit, J. Matthew Brennan, Shaun Clifton, Adam D. DeVore, Shalonda Deloatch, Sheila Dickey, Keith Dombrowski, Grégory Ducrocq, Zubin Eapen, Patricia Endsley, Arleen Eppinger, Robert W. Harrison, Connie Ng Hess, Mark A. Hlatky, Joseph Dedrick Jordan, Joshua W. Knowles, Bradley J. Kolls, David F. Kong, Sergio Leonardi, Linda Lillis, David J. Maron, Jill Marcus, Robin Mathews, Rajendra H. Mehta, Robert J. Mentz, Humberto Graner Moreira, Chetan B. Patel, Sabrina Bernardez Pereira, Lynn Perkins, Thomas J. Povsic, Etienne Puymirat, William Schuyler Jones, Bimal R. Shah, Matthew W. Sherwood, Kenya Stringfellow, Darin Sujjavanich, Mustafa Toma, Charlene Trotter, Sean F.P. van Diepen, Matthew D. Wilson, Andrew Tze-Kay Yan, Lilia B. Schiavi, Marcelo Garrido, Andrés F. Alvarisqueta, Sonia A. Sassone, Anselmo P. Bordonava, Alberto E. Alves De Lima, Jorge M. Schmidberg, Ernesto A. Duronto, Orlando C. Caruso, Leonardo P. Novaretto, Miguel Angel Hominal, Oscar R. Montaña, Alberto Caccavo, Oscar A. Gomez Vilamajo, Alberto J. Lorenzatti, Luis R. Cartasegna, Gustavo A. Paterlini, Ignacio J. Mackinnon, Guillermo D. Caime, Marcos Amuchastegui, Oscar Salomone, Oscar R. Codutti, Horacio O. Jure, Julio O.E. Bono, Adrian D. Hrabar, Julio A. Vallejos, Rodolfo A. Ahuad Guerrero, Federico Novoa, Cristian A. Patocchi, Cesar J. Zaidman, Maria E. Giuliano, Ricardo D. Dran, Marisa L. Vico, Gabriela S. Carnero, Pablo N. Guzman, Juan C. Medrano Allende, Daniela F. Garcia Brasca, Miguel H. Bustamante Labarta, Sebastian Nani, Eduardo D.S. Blumberg, Hugo R. Colombo, Alberto Liberman, Victorino Fuentealba, Hector L. Luciardi, Gabriel D. Waisman, Mario A. Berli, Ruben O. Garcia Duran, Horacio G. Cestari, Hugo A. Luquez, Jorge A. Giordano, Silvia S. Saavedra, Gerardo Zapata, Osvaldo Costamagna, Susana Llois, Jonathon H. Waites, Nicholas Collins, Allan Soward, Chris L.S. Hii, James Shaw, Margaret A. Arstall, John Horowitz, Daniel Ninio, James F. Rogers, David Colquhoun, Romulo E. Oqueli Flores, Philip Roberts-Thomson, Owen Raffel, Sam J. Lehman, Constantine Aroney, Steven G.M. Coverdale, Paul J. Garrahy, Gregory Starmer, Mark Sader, Patrick A. Carroll, Ronald Dick, Robert Zweiker, Uta Hoppe, Kurt Huber, Rudolf Berger, Georg Delle-Karth, Bernhard Frey, Dirk Faes, Kurt Hermans, Bruno Pirenne, Attilio Leone, Etienne Hoffer, Mathias C.M. Vrolix, Luc De Wolf, Bart Wollaert, Marc Castadot, Karl Dujardin, Christophe Beauloye, Geert Vervoort, Harry Striekwold, Carl Convens, John Roosen, Emanuele Barbato, Marc Claeys, Frank Cools, Ibrahim Terzic, Fahir Barakovic, Zlatko Midzic, Belma Pojskic, Emir Fazlibegovic, Azra Durak-Nalbantic, Mehmed Kulić, Dusko Vulic, Adis Muslibegovic, Boris Goronja, Gilmar Reis, Luciano Sousa, Jose C. Nicolau, Flavio E. Giorgeto, Ricardo P. Silva, Lilia Nigro Maia, Rafael Rech, Paulo R.F. Rossi, Maria José A.G. Cerqueira, Norberto Duda, Renato Kalil, Adrian Kormann, José Antonio M. Abrantes, Pedro Pimentel Filho, Ana Priscila Soggia, Mayler O.N. de Santos, Fernando Neuenschwander, Luiz C. Bodanese, Yorghos L. Michalaros, Freddy G. Eliaschewitz, Maria H. Vidotti, Paulo E. Leaes, Roberto V. Botelho, Sergio Kaiser, Euler Roberto F. Fernandes Manenti, Dalton B. Precoma, Jose C. Moura Jorge, Pedro Silva, Jose A. Silveira, Wladmir Saporito, Jose A. Marin Neto, Gilson S. Feitosa, Luiz Eduardo F. Ritt, Juliana A. de Souza, Fernando Costa, Weimar K.S.B. Souza, Helder J.L. Reis, Leandro Machado, José Carlos Aidar Ayoub, Georgi V. Todorov, Fedya P. Nikolov, Elena S. Velcheva, Maria L. Tzekova, Haralambi O. Benov, Stanislav L. Petranov, Haralin S. Tumbev, Nina S. Shehova-Yankova, Dimitar T. Markov, Dimitar H. Raev, Mihail N. Mollov, Kostadin N. Kichukov, Katya A. Ilieva-Pandeva, Raya Ivanova, Maryana Gospodinov, Valentina M. Mincheva, Petar V. Lazov, Bojidar I. 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Raffo, Claudia Olivares, Leonardo Nahuelpan, Humberto Montecinos, Jiyan Chen, Yugang Dong, Weijian Huang, Jianzhong Wang, Shi'An Huang, Zhuhua Yao, Xiang Li, Lan Cui, Wenhua Lin, Yuemin Sun, Jingfeng Wang, Jianping Li, Xuelian Zhang, Hong Zhu, Dandan Chen, Lan Huang, Shaohong Dong, Guohai Su, Biao Xu, Xi Su, Xiaoshu Cheng, Jinxiu Lin, Wenxia Zong, Huanming Li, Yi Feng, Dingli Xu, Xinchun Yang, Yuannan Ke, Xuefeng Lin, Zheng Zhang, Zeqi Zheng, Zhurong Luo, Yundai Chen, Chunhua Ding, Yi Zhong, Yang Zheng, Xiaodong Li, Daoquan Peng, Shuiping Zhao, Ying Li, Xuebo Liu, Meng Wei, Shaowen Liu, Yihua Yu, Baiming Qu, Weihong Jiang, Yujie Zhou, Xingsheng Zhao, Zuyi Yuan, Ying Guo, Xiping Xu, Xubo Shi, Junbo Ge, Guosheng Fu, Feng Bai, Weiyi Fang, Xiling Shou, Xiangjun Yang, Jian'An Wang, Meixiang Xiang, Yingxian Sun, Qinghua Lu, Ruiyan Zhang, Jianhua Zhu, Yizhou Xu, Zhongcai Fan, Tianchang Li, Chun Wu, Nicolas Jaramillo, Gregorio Sanchez Vallejo, Diana C. Luna Botia, Rodrigo Botero Lopez, Dora I. Molina De Salazar, Alberto J. Cadena Bonfanti, Carlos Cotes Aroca, Juan Diego Higuera, Marco Blanquicett, Sandra I. Barrera Silva, Henry J. Garcia Lozada, Julian A. Coronel Arroyo, Jose L. Accini Mendoza, Ricardo L. Fernandez Ruiz, Alvaro M. Quintero Ossa, Fernando G. Manzur Jatin, Aristides Sotomayor Herazo, Jeffrey Castellanos Parada, Rafael Suarez Arambula, Miguel A. Urina Triana, Angela M. Fernandez Trujillo, Maja Strozzi, Siniša Car, Melita Jerić, Davor Miličić, Martina Lovrić Benčić, Hrvoje Pintarić, Đeiti Prvulović, Jozica Šikić, Viktor Peršić, Dean Mileta, Kresimir Štambuk, Zdravko Babić, Vjekoslav Tomulic, Josip Lukenda, Stanka Mejic-Krstulovic, Boris Starcevic, Jindrich Spinar, David Horak, Zdenek Velicka, Josef Stasek, David Alan, Vilma Machova, Ales Linhart, Vojtech Novotny, Vladimir Kaucak, Richard Rokyta, Robert Naplava, Zdenek Coufal, Vera Adamkova, Ivo Podpera, Jiri Zizka, Zuzana Motovska, Ivana Marusincova, Premysl Svab, Petr Heinc, Jiri Kuchar, Petr Povolny, Jiri Matuska, Steen H. Poulsen, Bent Raungaard, Peter Clemmensen, Lia E. Bang, Ole May, Morten Bøttcher, Jens D. Hove, Lars Frost, Gunnar Gislason, John Larsen, Peter Betton Johansen, Flemming Hald, Peter Johansen, Jørgen Jeppesen, Tonny Nielsen, Kjeld S. Kristensen, Piotr Maria Walichiewicz, Jens D. Lomholdt, Ib C. Klausen, Peter Kaiser Nielsen, Flemming Davidsen, Lars Videbaek, Mai Soots, Veiko Vahula, Anu Hedman, Üllar Soopõld, Kaja Märtsin, Tiina Jurgenson, Arved Kristjan, Heikki Huikuri, Juhani Airaksinen Pierre Coste, Emile Ferrari, Olivier Morel, Gilles Montalescot, Jacques Machecourt, Gilles Barone-Rochette, Jacques Mansourati, Yves Cottin, Florence Leclercq, Abdelkader Belhassane, Nicolas Delarche, Franck Boccara, Franck Paganelli, Jérôme Clerc, Francois Schiele, Victor Aboyans, Vincent Probst, Jacques Berland, Thierry Lefèvre, Bernard Citron, Irakli Khintibidze, Tamaz Shaburishvili, Zurab Pagava, Ramaz Ghlonti, Zaza Lominadze, George Khabeishvili, Rayyan Hemetsberger, Kemala Edward, Ursula Rauch-Kröhnert, Matthias Stratmann, Karl-Friedrich Appel, Ekkehard Schmidt, Heyder Omran, Christoph Stellbrink, Thomas Dorsel, Emmanouil Lianopoulos, Hans Friedrich Vöhringer, Roger Marx, Andreas Zirlik, Detlev Schellenberg, Thomas Heitzer, Ulrich Laufs, Christian Werner, Stephan Gielen, Sebastian Nuding, Bernhard Winkelmann, Steffen Behrens, Karsten Sydow, Mahir Karakas, Gregor Simonis, Thomas Muenzel, Nikos Werner, Stefan Leggewie, Dirk Böcker, Rüdiger Braun-Dullaeus, Nicole Toursarkissian, Michael Jeserich, Matthias Weißbrodt, Tim Schaeufele, Joachim Weil, Heinz Völler, Johannes Waltenberger, Mohammed Natour, Susanne Schmitt, Dirk Müller-Wieland, Stephan Steiner, Lothar Heidenreich, Elmar Offers, Uwe Gremmler, Holger Killat, Werner Rieker, Sotiris Patsilinakos, Athanasios Kartalis, Athanassios Manolis, Dimitrios Sionis, Geargios Chachalis, Ioannis Skoumas, Vasilios Athyros, Panagiotis Vardas, Frangkiskos Parthenakis, John Lekakis, Apostolos Hatzitolios, Sergio R. Fausto Ovando, Juan L. Arango Benecke, Edgar R. Rodriguez De Leon, Bryan P.Y. Yan, David C.W. Siu, Tibor Turi, Bela Merkely, Imre Ungi, Geza Lupkovics, Lajos Nagy, András Katona, István Édes, Gábor Müller, Iván Horvath, Tibor Kapin, Zsolt Szigeti, József Faluközy, Mukund Kumbla, Manjinder Sandhu, Sharath Annam, Naveen Reddy Proddutur, Reddy Regella, Rajendra K. Premchand, Ajaykumar Mahajan, Sudhir Pawar, Atul D. Abhyanakar, Prafulla Kerkar, Ravishankar A. Govinda, Abraham Oomman, Dhurjati Sinha, Sachin N. Patil, Dhiman Kahali, Jitendra Sawhney, Abhijeet B. Joshi, Sanjeev Chaudhary, Pankaj Harkut, Santanu Guha, Sanjay Porwal, Srimannarayana Jujjuru, Ramesh B. Pothineni, Minguel R. Monteiro, Aziz Khan, Shamanna S. Iyengar, Jasprakash Singh Grewal, Manoj Chopda, Mahesh C. Fulwani, Aparna Patange, Patil Sachin, Vijay K. Chopra, Naresh K. Goyal, Rituparna Shinde, Gajendra V. Manakshe, Nitin Patki, Sumeet Sethi, Vengatesh Munusamy, Sunil Karnaand Sunil Thanvi, Srilakshmi Adhyapak, Chandrakant Patil, Ulhas Pandurangi, Rishabh Mathur, Jugal Gupta, Suhas Kalashetti, Ajit Bhagwat, Bagirath Raghuraman, Shiv Kumar Yerra, Prasant Bhansali, Rohidas Borse, Patil Rahul, Srihari Das, Vinay Kumar, Jabir Abdullakutty, Shireesh Saathe, Priya Palimkar, Jabir Abdullkutty, Shireesh Sathe, Shaul Atar, Michael Shechter, Morris Mosseri, Yaron Arbel, Chorin Ehud, Havakuk Ofer, Chaim Lotan, Uri Rosenschein, Amos Katz, Yaakov Henkin, Adi Francis, Marc Klutstein, Eugenia Nikolsky, Robert Zukermann, Yoav Turgeman, Majdi Halabi, Alon Marmor, Ran Kornowski, Michael Jonas, Offer Amir, Yonathan Hasin, Yoseph Rozenman, Shmuel Fuchs, Vered Zvi, Osamah Hussein, Dov Gavish, Zvi Vered, Yoseph Caraco, Mazen Elias, Naveh Tov, Efrat Wolfovitz, Michael Lishner, Nizar Elias, Giancarlo Piovaccari, Annamaria De Pellegrin, Raffaella Garbelotto, Gabriele Guardigli, Valgimigli Marco, Giovanni Licciardello, Carla Auguadro, Filippo Scalise, Claudio Cuccia, Alessandro Salvioni, Giuseppe Musumeci, Michelle Senni, Paolo Calabrò, Salvatore Novo, Pompilio Faggiano, Marco Metra, Nicoletta B. De Cesare, Sergio Berti, Claudio Cavallini, Enrico Puccioni, Marcello Galvani, Maurizio Tespili, Piermarco Piatti, Michela Palvarini, Giuseppe De Luca, Roberto Violini, Alessandro De Leo, Zoran Olivari, Pasquale Perrone Filardi, Maurizio Ferratini, Vittorio Racca, Kazuoki Dai, Yuji Shimatani, Haruo Kamiya, Kenji Ando, Yoshihiro Takeda, Yoshihiro Morino, Yoshiki Hata, Kazuo Kimura, Koichi Kishi, Ichiro Michishita, Hiroki Uehara, Toshinori Higashikata, Atsushi Hirayama, Keiji Hirooka, Yasuji Doi, Satoru Sakagami, Shuichi Taguchi, Akihiro Koike, Hiroyuki Fujinaga, Shinji Koba, Ken Kozuma, Tomohiro Kawasaki, Yujiro Ono, Masatoshi Shimizu, Yousuke Katsuda, Atsuyuki Wada, Toshiro Shinke, Junya Ako, Kenshi Fujii, Toshiyuki Takahashi, Tomohiro Sakamoto, Koichi Nakao, Yutaka Furukawa, Hiroshi Sugino, Ritsu Tamura, Toshiaki Mano, Masaaki Uematsu, Noriaki Utsu, Kashima Ito, Takuya Haraguchi, Katsuhiko Sato, Yasunori Ueda, Akira Nishibe, Kazuteru Fujimoto, Motomaru Masutani, Jung Han Yoon, Hack-Lyoung Kim, Hun Sik Park, In-Ho Chae, Moo Hyun Kim, Myung Ho Jeong, Seungwoon Rha, Chongjin Kim, Hae Young Kim, Taekjong Hong, Seung-Jea Tahk, Youngkwon Kim, Arija Busmane, Natalija Pontaga, Aldis Strelnieks, Iveta Mintale, Iveta Sime, Zaneta Petrulioniene, Roma Kavaliauskiene, Ruta Jurgaitiene, Gintare Sakalyte, Rimvydas Slapikas, Sigute Norkiene, Nerijus Misonis, Aleksandras Kibarskis, Raimondas Kubilius, Stojko Bojovski, Nensi Lozance, Aleksandar Kjovkaroski, Snezana Doncovska, Tiong Kiam Ong, Sazzli Kasim, Oteh Maskon, Balachandran Kandasamy, Houng B. Liew, Wan Mohd Izani Wan Mohamed, Armando García Castillo, Jorge Carrillo Calvillo, Pedro Fajardo Campos, Juan Carlos Núñez Fragoso, Edmundo Alfredo Bayram Llamas, Marco Antonio Alcocer Gamba, Jaime Carranza Madrigal, Luis Gerardo González Salas, Enrique López Rosas, Belinda González Díaz, Eduardo Salcido Vázquez, Alfredo Nacoud Ackar, Guillermo Antonio Llamas Esperón, Carlos Rodolfo Martínez Sánchez, María Guerrero De Leon, Rodrigo Suarez Otero, Guillermo Fanghänel Salmón, Jesús Antonio Pérez Ríos, José Angel Garza Ruíz, Robert W. Breedveld, Margriet Feenema-Aardema, Alida Borger-Van Der Burg, Pieter A.M. Hoogslag, Harry Suryapranata, Antonius Oomen, Paulus Van Haelst, Margriet Feenema-Aradema, Jacobijne J. Wiersma, Dirk Basart, Ruud M.A. Van Der Wal, Peter Zwart, Pascalle Monraats, Henricus Van Kesteren, Ioannis Karalis, Johan Jukema, Gerardus J.E. Verdel, Bart R.G. Brueren, Roland PTh Troquay, Eric P. Viergever, Nadea Y.Y. Al-Windy, Gerard L. Bartels, Jan H. Cornel, Walter R.M. 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Bravo Mannucci, Javier Heredia Landeo, Nassip C. Llerena Navarro, Yudy M. Roldan Concha, Víctor E. Rodriguez Chavez, Henry A. Anchante Hernandez, Carlos A. Zea Nunez, Walter Mogrovejo Ramos, Arthur Ferrolino, Rosa Allyn G. Sy, Louie Tirador, Generoso Matiga, Raul Martin Coching, Alisa Bernan, Gregorio Rogelio, Dante D. Morales, Edgar Tan, Dennis Jose Sulit, Adrian Wlodarczak, Krystyna Jaworska, Grzegorz Skonieczny, Lidia Pawlowicz, Pawel Wojewoda, Benita Busz-Papiez, Janusz Bednarski, Aleksander Goch, Pawel Staneta, Elzbieta Dulak, Krzysztof Saminski, Wlodzimierz Krasowski, Wanda Sudnik, Aleksander Zurakowski, Marcin Skorski, Roman Lysek, Beata Miklaszewicz, Jacek Kubica, Jan Andrzej Lipko, Edyta Kostarska-Srokosz, Marek Piepiorka, Anna Drzewiecka, Ryszard Sciborski, Arkadiusz Stasiewski, Tomasz Blicharski, Leszek Bystryk, Michal Szpajer, Marek Korol, Tomasz Czerski, Ewa Mirek-Bryniarska, Jacek Gniot, Andrzej Lubinski, Jerzy Gorny, Edward Franek, Grzegorz Raczak, Hanna Szwed, Pedro Monteiro, Jose Mesquita Bastos, Helder H. Pereira, Dinis Martins, Filipe Seixo, Carlos Mendonça, Ana Botelho, Francisca Caetano, Bogdan Minescu, Octavian Istratoaie, Dan N. Tesloianu, Gabriel Cristian, Silviu Dumitrescu, Cristian G.C. Podoleanu, Mircea C.A. Constantinescu, Cristina M. Bengus, Constantin Militaru, Doina Rosu, Irinel R. Parepa, Adrian V. Matei, Tom M. Alexandru, Mihaela Malis, Ioan Coman, Rodica Stanescu-Cioranu, Doina Dimulescu, Yury Shvarts, Olga Orlikova, Zhanna Kobalava, Olga L. Barbarash, Valentin Markov, Nadezhda Lyamina, Alexander Gordienko, Konstantin Zrazhevsky, Alexander Y. Vishnevsky, Victor Gurevich, Raisa Stryuk, Nikita V. Lomakin, Igor Bokarev, Tatiana Khlevchuk, Sergey Shalaev, Larisa Khaisheva, Petr Chizhov, Inna Viktorova, Natalya Osokina, Vladimir Shchekotov, Evgenia Akatova, Galina Chumakova, Igor Libov, Mikhail I. Voevoda, Tatyana V. Tretyakova, Evgeny Baranov, Sergey Shustov, Sergey Yakushin, Ivan Gordeev, Niiaz Khasanov, Olga Reshetko, Tatiana Sotnikova, Olga Molchanova, Konstantin Nikolaev, Liudmila Gapon, Elena Baranova, Zaur Shogenov, Elena Kosmachova, Yuriy Karpov, Anton Povzun, Liudmila Egorova, Vadim V. Tyrenko, Igor G. Ivanov, Masterov Ilya, Sergey Kanorsky, Dragan Simic, Nikola Ivanovic, Goran Davidovic, Nebojsa Tasic, Milika R. Asanin, Stevo Stojic, Svetlana R. Apostolovic, Stevan Ilic, Biljana Putnikovic Tosic, Aleksandar Stankovic, Aleksandra Arandjelovic, Slavica Radovanovic, Branislava Todic, Jovan Balinovac, Dragan V. Dincic, Petar Seferovic, Ana Karadzic, Slobodan Dodic, Sinisa Dimkovic, Tamara Jakimov, Kian-Keong Poh, Hean Yee Ong, Justin Tang I-Shing, Karol Micko, Jan Nociar, Daniel Pella, Peter Fulop, Marian Hranai, Juraj Palka, Juraj Mazur, Ivan Majercák, Andrej Dzupina, František Fazekas, Jozef Gonsorcik, Viliam Bugan, Juraj Selecky, Gabriel Kamensky, Jaroslava Strbova, Rudolf Smik, Andrej Dukat, Peter Olexa, Ivan Žuran, Janez Poklukar, Nataša Černič Šuligoj, Matija Cevc, Henry P. Cyster, Naresh Ranjith, Clive Corbett, Junaid Bayat, Ellen Makoali Makotoko, Hendrik du Toit Theron, Ilse E. Kapp, Matthys M. de V Basson, Hanlie Lottering, Dina Van Aswegen, Louis J. Van Zyl, Peter J. 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Devarapalli, Michael Koren, Harish Chandna, George Dodds, Tauqir Goraya, James Bengston, Matthew Janik, Joseph Moran, Andrew Sumner, John Kobayashi, William Davis, Shahram Yazdani, John Pasquini, Maitreya Thakkar, Amarnath Vedere, Wayne Leimbach, James Rider, Sarah fenton, Narendra Singh, Anil V. Shah, Denise Janosik, Carl Pepine, Brett Berman, Joseph Gelormini, Christopher Daniels, Kerensky Richard, Friederike Keating, Nicholas I. Kondo, Sanjay Shetty, Howard Levite, Winfried Waider, Theodore Takata, Mazen Abu-Fadel, Vipul Shah, Rahul Aggarwal, Mark Izzo, Anil Kumar, Brack Hattler, Rose Do, Chad Link, Anna Bortnick, George Kinzfogl, Arnold Ghitis, John Larry, Edward Teufel, Peter Kuhlman, Brent Mclaurin, Wenwu Zhang, Stephen Thew, Jalal Abbas, Matthew White, Othman Islam, Sumeet Subherwal, Nandkishore Ranadive, Babak Vakili, Christian Gring, David Henderson, Timothy Schuchard, Naim Farhat, Geoffrey Kline, Sharan Mahal, Jack Whitaker, Shawn Speirs, Rolf Andersen, Nizar Daboul, Phillip Horwitz, Firas Zahr, George Ponce, Zubair Jafar, Joseph Mcgarvey, Vipul Panchal, Stephen Voyce, Thomas Blok, William Sheldon, Masoud M. Azizad, Carsten Schmalfuss, Mark Picone, Robert Pederson, William Herzog, Keith Friedman, Jason Lindsey, Rosemary Nowins, Eichenlaub Timothy, Parilak Leonard, Norman Lepor, Mahfouz El Shahawy, Howard Weintraub, Anand Irimpen, Alvaro Alonso, Wade May, Daniels Christopher, Thomas Galski, Alan Chu, Freny Mody, Ebrahimi Ramin, Zachary Hodes, Joseph Rossi, Gregory Rose, James Fairlamb, Charles Lambert, Ajit Raisinghani, Antonio Abbate, George Vetrovec, Marilyn King, Charles Carey, Jaime Gerber, Liwa Younis, Hyeun Park, Mladen Vidovich, Thomas Knutson, Dennis Friedman, Fred Chaleff, Arthur Loussararian, Phillip Rozeman, Carey Kimmelstiel, Jeffrey Kuvin, Kevin Silver, Malcolm Foster, Glen Tonnessen, Andrey Espinoza, Mohamadali Amlani, Andreas Wali, Christopher Malozzi, Geert T. Jong, Clara Massey, Keattiyoat Wattanakit, Philip J. O'Donnell, Dinesh Singal, Naseem Jaffrani, Sridhar Banuru, Daniel Fisher, Mark Xenakis, Neal Perlmutter, Ravi Bhagwat, James Strader, Ronald Blonder, Ayim Akyea-Djamson, Ajay Labroo, Kwan Lee, H. John Marais, Edmund Claxton, Robert Weiss, Rohr Kathryn, Martin Berk, Peter Rossi, Parag Joshi, Amit Khera, Ajit S. Khaira, Greg Kumkumian, Steven Lupovitch, Joshua Purow, Stephen Welka, David Hoffman, Stuart Fischer, Eugene Soroka, Donald Eagerton, Samir Pancholy, Michael Ray, Norman Erenrich, Michael Farrar, Stewart Pollock, William J. French, Steve Diamantis, Douglas Guy, Lawrence Gimple, Mark Neustel, Steven Schwartz, Edward Pereira, Seals Albert, Douglas Spriggs, Janet Strain, Suneet Mittal, Anthony Vo, Majed Chane, Jason Hall, Nampalli Vijay, Kapildeo Lotun, F. Martin Lester, Ahed Nahhas, Theodore Pope, Paul Nager, Rakesh Vohra, Mukesh Sharma, Riyaz Bashir, Hinan Ahmed, Michael Berlowitz, Robert Fishberg, Robert Barrucco, Eric Yang, Michael Radin, Daniel Sporn, Dwight Stapleton, Steven Eisenberg, Joel Landzberg, Martin Mcgough, Samir Turk, Michael Schwartz, P. Sandy Sundram, Diwakar Jain, Mark Zainea, Carlos Bayron, Ronald Karlsberg, Suhail Dohad, Henry Lui, William Keen, Donald Westerhausen, Sandeep Khurana, Himanshu Agarwal, Jessica Birchem, William Penny, Mark Chang, Sherrill Murphy, John Henry, Branislav Schifferdecker, John M Gilbert, Gopal Chalavarya, Charles Eaton, John F. Schmedtje, Stuart Christenson, Imran Dotani, Douglas Denham, Alexander Macdonell, Paul Gibson, Aref Rahman, Tammam Al Joundi, Nizar Assi, Gary Conrad, Purushotham Kotha, Michael Love, Gregory Giesler, Howard Rubenstein, Dawood Gamil, Laura Akright, Justine Krawczyk, Joanne Cobler, Terry Wells, James Welker, Robert Foster, Richard Gilmore, Jay Anderson, Douglas Jacoby, Bill Harris, Geraldine Gardner, Ramprasad Dandillaya, Kishor Vora, John Kostis, John Hunter, David Laxson, Eric Ball, Flavia Egydio, Anelise Kawakami, Janaina Oliveira, Julianna Wozniak, Alexander Matthews, Caroline Ratky, Janine Valiris, Lisa Berdan, Anita Hepditch, Kirby Quintero, Tyrus Rorick, Melissa Westbrook, Andrea Pascual, Carla Rovito, Madeleine Bezault, Elodie Drouet, Tabassome Simon, Caroline Alsweiler, Anne Luyten, Julie Butters, Liddy Griffith, Michelle Shaw, Lena Grunberg, Shahidul Islam, Marie-France Brégeault, Nathalie Bougon, Douglas Faustino, Sylvie Fontecave, Judith Murphy, Melanie Verrier, null Veronique Agnetti, Dorthe Andersen, Emmy Badreddine, Mhamed Bekkouche, Cecile Bouancheau, Imane Brigui, Maddy Brocklehurst, Joseph Cianciarulo, Dawn Devaul, Szilvia Domokos, Cecile Gache, Caroline Gobillot, Severine Guillou, Jan Healy, Megan Heath, Gayatri Jaiwal, Carine Javierre, Julien Labeirie, Myriam Monier, Ulises Morales, Asmaa Mrabti, Bicky Mthombeni, Betim Okan, Lucile Smith, Jennifer Sheller, Sebastien Sopena, Valerie Pellan, Fadela Benbernou, Nafissa Bengrait, Maud Lamoureux, Katarina Kralova, Raphael Bejuit, Anthony Coulange, Christelle Berthou, Jérôme Repincay, Christelle Lorenzato, Alexis Etienne, Valerie Gouet, Virginie Loizeau, Mickael Normand, Anne Ourliac, Christelle Rondel, Antony Adamo, Pascale Beltran, Pauline Barraud, Helene Dubois-Gache, Benjamin Halle, Lamia Metwally, Maxime Mourgues, Marc Sotty, Marion Vincendet, Raluca Cotruta, Zhu Chengyue, Dominique Fournie-Lloret, Christine Morrello, Aurelie Perthuis, Patrick Picault, Isabelle Zobouyan, Helen M. Colhoun, Michael A. Dempsey, Mark A. McClanahan, Masira, and Laucevičius, Aleksandras
Subjects: Male, Acute coronary syndrome, medicine.medical_specialty, Cardiac & Cardiovascular Systems, Randomization, PCSK9 inhibitor, LOW-DENSITY-LIPOPROTEIN, Antibodies, Monoclonal, Humanized, acute coronary syndrom, Placebo, Gastroenterology, lipoprotein(a), Internal medicine, medicine, Humans, Low-density lipoprotein cholesterol, Aged, Alirocumab, RISK, low-density lipoprotein cholesterol, Science & Technology, biology, business.industry, PCSK9, PCSK9 Inhibitors, Hazard ratio, ALIROCUMAB, acute coronary syndrome, Cholesterol, LDL, Lipoprotein(a), Middle Aged, EFFICACY, medicine.disease, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, SAFETY, Cardiovascular System & Cardiology, biology.protein, Female, lipids (amino acids, peptides, and proteins), STATIN, low-density lipoprotein, cholesterol PCSK9 inhibitor, CORONARY, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine, Mace
Abstract: Digital, Background Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402), Ciencias Médicas y de la Salud
Published: 2021
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33. Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome

Author: Harvey D. White, Paul W. Armstrong, E. Magnus Ohman, Lenden M. Bowsman, Mark Y. Chan, Svati H. Shah, Simon G. Gregory, Kevin L. Duffin, Joseph V. Haas, Keith A.A. Fox, Megan L. Neely, Elizabeth Grass, Matthew T. Roe, and Lydia Coulter Kwee
Subjects: Male, 0301 basic medicine, Circulating mirnas, Acute coronary syndrome, Protein biomarkers, Physiology, 030204 cardiovascular system & hematology, Biology, acute coronary syndrome, Cohort Studies, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Natriuretic Peptide, Brain, microRNA, Genetics, medicine, Humans, Circulating MicroRNA, Osteopontin, Aged, Sequence Analysis, RNA, biomarkers, High-Throughput Nucleotide Sequencing, Middle Aged, Prognosis, medicine.disease, Peptide Fragments, Phenotype, 030104 developmental biology, Immunology, biology.protein, Female, Research Article
Abstract: The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH2-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. P = 7.5 × 10−4) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. P = 1.6 × 10−6). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.
Published: 2019
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34. Sitagliptin does not reduce the risk of cardiovascular death or hospitalization for heart failure following myocardial infarction in patients with diabetes: observations from TECOS

Author: Timo E. Strandberg, Michael A. Nauck, Tuncay Delibasi, Russell S. Scott, Harvey D. White, Rury R. Holman, Eric D. Peterson, Karen S. Pieper, Yuliya Lokhnygina, Darren K. McGuire, Axel Riefflin, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Helsinki University Hospital Area, and Clinicum
Subjects: Male, lcsh:Diseases of the circulatory (Cardiovascular) system, Time Factors, Endocrinology, Diabetes and Metabolism, Myocardial Infarction, Type 2 diabetes, 030204 cardiovascular system & hematology, MELLITUS, 0302 clinical medicine, Risk Factors, Case fatality rate, IMPROVES, REPERFUSION, Myocardial infarction, Original Investigation, OUTCOMES, GLUCAGON-LIKE PEPTIDE-1, Incidence, Middle Aged, ISCHEMIA, 3. Good health, Hospitalization, Treatment Outcome, Sitagliptin, Female, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Cardiovascular outcomes, 030209 endocrinology & metabolism, Acute myocardial infarction, Placebo, Risk Assessment, 03 medical and health sciences, CARDIAC-FUNCTION, Double-Blind Method, Internal medicine, Diabetes mellitus, medicine, Humans, Aged, Heart Failure, Dipeptidyl-Peptidase IV Inhibitors, Proportional hazards model, business.industry, Sitagliptin Phosphate, medicine.disease, RECEPTOR AGONISTS, SIZE, Diabetes Mellitus, Type 2, lcsh:RC666-701, LIRAGLUTIDE, 3121 General medicine, internal medicine and other clinical medicine, Heart failure, business
Abstract: Background To examine the effects of the DPP-4i sitagliptin on CV outcomes during and after incident MI in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Methods TECOS randomized 14,671 participants with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD) to sitagliptin or placebo, in addition to usual care. For those who had a within-trial MI, we analyzed case fatality, and for those with a nonfatal MI, we examined a composite cardiovascular (CV) outcome (CV death or hospitalization for heart failure [hHF]) by treatment group, using Cox proportional hazards models left-censored at the time of the first within-trial MI, without and with adjustment for potential confounders, in intention-to-treat analyses. Results During TECOS, 616 participants had ≥ 1 MI (sitagliptin group 300, placebo group 316, HR 0.95, 95% CI 0.81–1.11, P = 0.49), of which 25 were fatal [11 and 14, respectively]). Of the 591 patients with a nonfatal MI, 87 (15%) died subsequently, with 66 (11%) being CV deaths, and 57 (10%) experiencing hHF. The composite outcome occurred in 58 (20.1%; 13.9 per 100 person-years) sitagliptin group participants and 50 (16.6%; 11.7 per 100 person-years) placebo group participants (HR 1.21, 95% CI 0.83–1.77, P = 0.32, adjusted HR 1.23, 95% CI 0.83–1.82, P = 0.31). On-treatment sensitivity analyses also showed no significant between-group differences in post-MI outcomes. Conclusions In patients with type 2 diabetes and ASCVD experiencing an MI, sitagliptin did not reduce subsequent risk of CV death or hHF, contrary to expectations derived from preclinical animal models. Trial registration clinicaltrials.gov no. NCT00790205
Published: 2019
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35. Effect of Alirocumab on Mortality After Acute Coronary Syndromes

Author: Philippe Gabriel, Steg, Michael, Szarek, Deepak L, Bhatt, Vera A, Bittner, Marie-France, Brégeault, Anthony J, Dalby, Rafael, Diaz, Jay M, Edelberg, Shaun G, Goodman, Corinne, Hanotin, Robert A, Harrington, J Wouter, Jukema, Guillaume, Lecorps, Kenneth W, Mahaffey, Angèle, Moryusef, Petr, Ostadal, Alexander, Parkhomenko, Robert, Pordy, Matthew T, Roe, Pierluigi, Tricoci, Robert, Vogel, Harvey D, White, Andreas M, Zeiher, and Gregory G, Schwartz
Subjects: Male, Injections, Subcutaneous, Hypercholesterolemia, alirocumab, Antibodies, Monoclonal, Humanized, Corrections, acute coronary syndrome, Double-Blind Method, Original Research Articles, Humans, PCSK9 protein, Aged, cholesterol, Cholesterol, LDL, Middle Aged, mortality, Treatment Outcome, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Drug Therapy, Combination, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Follow-Up Studies
Abstract: Supplemental Digital Content is available in the text., Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P
Published: 2019

36. Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis

Author: Carlos Tajer, Shaun G. Goodman, Stephen J. Nicholls, Germán Málaga, Harvey D. White, Jose C. Nicolau, Lucas P. Damiani, Denise M. Paisani, Renato D. Lopes, Francisco Antonio Helfenstein Fonseca, Otavio Berwanger, Alexander Parkhomenko, Lixin Jiang, Pedro Gabriel Melo de Barros e Silva, Leopoldo S. Piegas, Nanci Valeis, Tamiris A Miranda, Renato Hideo Nakagawa Santos, Hélio Penna Guimarães, Christopher B. Granger, Oleg Averkov, José Francisco Kerr Saraiva, and Diogo D.F. Moia
Subjects: medicine.medical_specialty, business.industry, medicine.medical_treatment, 030204 cardiovascular system & hematology, medicine.disease, Clopidogrel, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Fibrinolysis, medicine, Cardiology, In patient, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Fibrinolytic therapy, Cardiology and Cardiovascular Medicine, business, Ticagrelor, medicine.drug
Abstract: Background: The efficacy of ticagrelor in the long-term post–ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain.Objectives: The purpose o...
Published: 2019
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37. The efficacy and safety of cangrelor in single vessel vs multivessel percutaneous coronary intervention: Insights from CHAMPION PHOENIX

Author: Christoph B. Olivier, Harvey D. White, Champion Phoenix Investigators, Gregg W. Stone, Robert A. Harrington, Vandana Sundaram, Kenneth W. Mahaffey, Christian W. Hamm, Freddy Abnousi, Matthew J. Price, Efthymios N. Deliargyris, C. Michael Gibson, Celina M. Yong, Jaden Yang, Philippe Gabriel Steg, Jayne Prats, and Deepak L. Bhatt
Subjects: medicine.medical_specialty, Streptokinase, medicine.medical_treatment, Population, Clinical Investigations, multivessel percutaneous coronary intervention, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, P2Y12, Cangrelor, Internal medicine, medicine, 030212 general & internal medicine, Myocardial infarction, cardiovascular diseases, education, education.field_of_study, clopidogrel, business.industry, Percutaneous coronary intervention, General Medicine, Clopidogrel, medicine.disease, chemistry, Conventional PCI, Cardiology, Cardiology and Cardiovascular Medicine, business, medicine.drug, cangrelor
Abstract: Background The intravenous, rapidly acting P2Y12 inhibitor cangrelor reduces the rate of ischemic events during PCI with no significant increase in severe bleeding. However, the efficacy and safety of cangrelor compared with clopidogrel in patients treated with single vessel (SV)-percutaneous coronary intervention (PCI) or multivessel (MV)-PCI remains unexplored. Methods We studied the modified intention-to-treat population of patients from the CHAMPION PHOENIX trial who were randomized to either cangrelor or clopidogrel. We used logistic regression and propensity score matching to evaluate the effect of cangrelor compared with clopidogrel on the primary efficacy outcome (composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) at 48 hours. The safety outcome was moderate or severe Global Utilization of Streptokinase and tPA for Occluded Arteries bleeding at 48 hours. Hypothesis Cangrelor is as efficacious and safe as clopidogrel in both SV and MV PCI. Results Among 10 854 patients, 9204 (85%) underwent SV- and 1650 (15%) MV-PCI. After adjustment, cangrelor was associated with similar reductions vs clopidogrel in the primary efficacy outcome in patients undergoing SV-PCI (4.5% vs 5.2%; odds ratio [OR] 0.81 [0.66-0.98]) or MV-PCI (6.1% vs 9.8%, OR 0.59 [0.41-0.85]; Pint 0.14). Similar results were observed after propensity score matching (SV-PCI: 5.5% vs 5.9%, OR 0.93 [0.74-1.18]; MV-PCI: 6.2% vs 8.9%, OR 0.67 [0.44-1.01]; Pint 0.17). There was no evidence of heterogeneity in the treatment effect of cangrelor compared with clopidogrel for the safety outcome. Conclusions In patients undergoing SV- or MV-PCI, cangrelor was associated with similar relative risk reductions in ischemic complications and no increased risk of significant bleeding compared with clopidogrel, which highlights the expanding repertoire of options for use in complex PCI.
Published: 2019

38. Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials

Author: Dawn Waterworth, Nicholas Galwey, Gurparkash Singh, Geert Byttebier, William Alazawi, Elisa Fabbrini, Derek J. Nunez, Bart Vannieuwenhuyse, Laura M. Yerges-Armstrong, Gary Meininger, Stuart Kendrick, Myriam Alexander, Lars Wallentin, Naveed Sattar, Ele Ferrannini, and Harvey D. White
Subjects: Adult, Male, medicine.medical_specialty, Physiology, 030209 endocrinology & metabolism, Placebo, Gastroenterology, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Physiology (medical), Internal medicine, Liver enzyme, Epidemiology, medicine, Humans, Aspartate Aminotransferases, Obesity, Alanine aminotransferase, Aged, Glycated Hemoglobin, Hepatology, business.industry, Body Weight, Alanine Transaminase, Middle Aged, Clinical trial, Diabetes Mellitus, Type 2, Liver, Female, 030211 gastroenterology & hepatology, business
Abstract: Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy (“STABILITY”) trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A1clevels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, 60 ml·min−1·1.73 m−2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA1con ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials.NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.
Published: 2019
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39. Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial

Author: Michael, Szarek, Harvey D, White, Gregory G, Schwartz, Marco, Alings, Deepak L, Bhatt, Vera A, Bittner, Chern-En, Chiang, Rafael, Diaz, Jay M, Edelberg, Shaun G, Goodman, Corinne, Hanotin, Robert A, Harrington, J Wouter, Jukema, Takeshi, Kimura, Robert Gabor, Kiss, Guillaume, Lecorps, Kenneth W, Mahaffey, Angèle, Moryusef, Robert, Pordy, Matthew T, Roe, Pierluigi, Tricoci, Denis, Xavier, Andreas M, Zeiher, Ph Gabriel, Steg, and Rushton-Smith, Sophie
Subjects: Male, total events, Antibodies, Monoclonal, food and beverages, alirocumab, Middle Aged, Antibodies, Monoclonal, Humanized, acute coronary syndrome, Humans, Drug Therapy, Combination, Female, ddc:610, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Aged, Follow-Up Studies
Abstract: Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18, 924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. Results: With 3, 064 first and 5, 425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
Published: 2019

40. The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design

Author: Derek P. Chew, David Brieger, Michael E. Farkouh, John K. French, Harvey D. White, Erin Morton, Stephen Quinn, Anthony Chuang, Ian A Scott, Matthew Horsfall, Kathryn Tiver, Tom Briffa, Billingsley Kaambwa, and Kristina Lambrakis
Subjects: Acute coronary syndrome, medicine.medical_specialty, Cost effectiveness, Myocardial Infarction, Context (language use), 030204 cardiovascular system & hematology, Coronary Angiography, law.invention, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Risk of mortality, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Intensive care medicine, Rupture, Framingham Risk Score, biology, business.industry, medicine.disease, Troponin, Plaque, Atherosclerotic, Heart Injuries, Sample Size, biology.protein, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract: Background Elevated troponin level findings among patients presenting with suspected acute coronary syndrome (ACS) or another intercurrent illness undeniably identifies patients at increased risk of mortality. Whilst enhancing our capacity to discriminate risk, the use of high-sensitivity troponin assays frequently identifies patients with myocardial injury (i.e. troponin rise without acute signs of myocardial ischemia) or type 2 myocardial infarction (T2MI; oxygen supply-demand imbalance). This leads to the clinically challenging task of distinguishing type 1 myocardial infarction (T1MI; coronary plaque rupture) from myocardial injury and T2MI in the context of concurrent acute illness. Diagnostic discernment in this context is crucial because MI classification has implications for further investigation and care. Early invasive management is of well-established benefit among patients with T1MI. However, the appropriateness of this investigation in the heterogeneous context of T2MI, where there is high competing mortality risk, remains unknown. Although coronary angiography in T2MI is advocated by some, there is insufficient evidence in existing literature to support this opinion as highlighted by current national guidelines. Objective The objective is to evaluate the clinical and economic impact of early invasive management with coronary angiography in T2MI in terms of all-cause mortality and cost effectiveness. Design This prospective, pragmatic, multicenter, randomized trial among patients with suspected supply demand ischemia leading to troponin elevation (n=1,800; T2MI [1,500], chronic myocardial injury [300]) compares the impact of invasive angiography (or computed tomography angiography as per local preference) within 5 days of randomization versus conservative management (with or without functional testing at clinician discretion) on all-cause mortality by 2 years. Randomized treatment allocation will be stratified by baseline estimated risk of mortality using the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III risk score. Cost-effectiveness will be evaluated by follow-up on clinical events, quality of life, and resource utilization over 24 months. Summary Ascertaining the most appropriate first-line investigative strategy for these commonly encountered high-risk T2MI patients in a randomized comparative study will be pivotal in informing evidence-based guidelines that lead to better patient and health care outcomes.
Published: 2019
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41. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality

Author: A. Mark Richards, W.H. Wilson Tang, Julie A. Johnson, Stanley L. Hazen, Danilo Fliser, Heribert Schunkert, Yan Gong, Andreas Martinsson, Peter Lipp, Yi-An Ko, Stephen Zewinger, Andrej Teren, Marcus E. Kleber, Ian Ford, Sarah Triem, David J. Stott, Matthias C. Reichert, Hannah Campbell, Dawn M. Waterworth, Ulrich Laufs, Caitrin W. McDonough, Stefan Wagenpfeil, Marcin Krawczyk, Michael Böhm, J. Wouter Jukema, Naveed Sattar, Shichao Pang, Markus Scholz, Rafael Kramann, Stella Trompet, Philipp Ege, Niclas Eriksson, David Schmit, Christie M. Ballantyne, Claes Held, Marie-Pierre Dubé, Winfried März, Thimoteus Speer, Jörn Walter, Stefan James, Maxine Sun, Hooman Allayee, Lars Wallentin, Harvey D. White, Vicky A. Cameron, Stefan J Schunk, Sharon Cresci, Barbara A. Niemeyer, Susanne N. Weber, Anna P. Pilbrow, Emmanuel Ampofo, J. Gustav Smith, Sascha Tierling, Jean-Claude Tardif, Robert N. Doughty, Rhonda M. Cooper-DeHoff, Arshed A. Quyyumi, Ralph Burkhardt, John A. Spertus, Chang Liu, Eric Boerwinkle, Wolfgang Koenig, Tamim Sarakpi, Yassamin Feroz-Zada, Jaana Hartiala, Isabella Jaumann, Vinicius Tragante, and Megan L. Grove
Subjects: Inflammasomes, Inflammation, 030204 cardiovascular system & hematology, Systemic inflammation, Coronary artery disease, Inflammasome, 03 medical and health sciences, 0302 clinical medicine, NLRP3, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Humans, Cardiac and Cardiovascular Systems, Serum amyloid A, Allele, 030304 developmental biology, 0303 health sciences, Kardiologi, biology, integumentary system, business.industry, C-reactive protein, R1, 3. Good health, Minor allele frequency, Cardiovascular diseases, Immunology, biology.protein, Leukocytes, Mononuclear, Apolipoprotein C3, medicine.symptom, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
Published: 2021

42. Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

Author: the ODYSSEY OUTCOMES Committees and Investigators, Ph. Gabriel Steg, Harvey D. White, Robert Pordy, Garen Manvelian, Megan Loy, J. Wouter Jukema, Shaun G. Goodman, Rafael Diaz, Deepak L. Bhatt, Vera A. Bittner, Michael Szarek, and Gregory G. Schwartz
Abstract: OBJECTIVE Observational data associate greater prevalence of type 2 diabetes (T2D) with lower lipoprotein(a) levels. Whether pharmacologic lowering of lipoprotein(a) influences incident T2D is unknown. We determined the relationship of lipoprotein(a) concentration to incident T2D and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS The ODYSSEY OUTCOMES trial compared alirocumab with placebo in patients with acute coronary syndrome (ACS). Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS Among 13,480 patients without diabetes at baseline, 1324 developed T2D over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio (HR) 1.04 (95% CI 1.02-1.06, PAlirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident T2D (HR 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels alirocumab tended to reduce incident T2D, while at high baseline lipoprotein(a) alirocumab tended to increase incident T2D compared to placebo (treatment-baseline lipoprotein(a) interaction P=0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with HR 1.07 (95% CI 1.03−1.12; P=0.0002) for incident T2D. CONCLUSIONS In patients with ACS, baseline lipoprotein(a) concentration associated inversely with incident T2D. Alirocumab had neutral overall effect on incident T2D. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident T2D. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
Published: 2021
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43. High flow oxygen and risk of mortality in patients with a suspected acute coronary syndrome: pragmatic, cluster randomised, crossover trial

Author: Peter A. Jones, Bridget Dicker, John Edmond, Andrew Swain, David J. Smyth, Harvey D. White, Yannan Jiang, A. Ranchord, Mark Webster, Tony Scott, Martin Than, Ralph A.H. Stewart, Tony Smith, Andrew Kerr, and Gerard Devlin
Subjects: Male, Acute coronary syndrome, medicine.medical_specialty, law.invention, Randomized controlled trial, Clinical Protocols, law, Internal medicine, medicine, Risk of mortality, Cluster Analysis, Humans, Acute Coronary Syndrome, Survival rate, Oxygen saturation (medicine), Aged, Cross-Over Studies, business.industry, Research, Oxygen Inhalation Therapy, General Medicine, Odds ratio, Middle Aged, medicine.disease, Crossover study, Hospitalization, Survival Rate, Cohort, Female, business, New Zealand
Abstract: Objective To determine the association between high flow supplementary oxygen and 30 day mortality in patients presenting with a suspected acute coronary syndrome (ACS). Design Pragmatic, cluster randomised, crossover trial. Setting Four geographical regions in New Zealand. Participants 40 872 patients with suspected or confirmed ACS included in the All New Zealand Acute Coronary Syndrome Quality Improvement registry or ambulance ACS pathway during the study periods. 20 304 patients were managed using the high oxygen protocol and 20 568 were managed using the low oxygen protocol. Final diagnosis of ST elevation myocardial infarction (STEMI) and non-STEMI were determined from the registry and ICD-10 discharge codes. Interventions The four geographical regions were randomly allocated to each of two oxygen protocols in six month blocks over two years. The high oxygen protocol recommended oxygen at 6-8 L/min by face mask for ischaemic symptoms or electrocardiographic changes, irrespective of the transcapillary oxygen saturation (SpO 2 ). The low oxygen protocol recommended oxygen only if SpO 2 was less than 90%, with a target SpO 2 of less than 95%. Main outcome measure 30 day all cause mortality determined from linkage to administrative data. Results Personal and clinical characteristics of patients managed under both oxygen protocols were well matched. For patients with suspected ACS, 30 day mortality for the high and low oxygen groups was 613 (3.0%) and 642 (3.1%), respectively (odds ratio 0.97, 95% confidence interval 0.86 to 1.08). For 4159 (10%) patients with STEMI, 30 day mortality for the high and low oxygen groups was 8.8% (n=178) and 10.6% (n=225), respectively (0.81, 0.66 to 1.00) and for 10 218 (25%) patients with non-STEMI was 3.6% (n=187) and 3.5% (n=176), respectively (1.05, 0.85 to 1.29). Conclusion In a large patient cohort presenting with suspected ACS, high flow oxygen was not associated with an increase or decrease in 30 day mortality. Trial registration ANZ Clinical Trials ACTRN12616000461493.
Published: 2021

44. Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial

Author: Elena A Demchenko, Gurpreet Singh Wander, Mandeep S. Sidhu, Karen P. Alexander, Bernard R. Chaitman, Milind Gadkari, Judith S. Hochman, Matyas Keltai, William E. Boden, Thuraia Nageh, Daniel B. Mark, Reto Gamma, Derek D. Cyr, Jesús Peteiro, Rajesh Goplan Nair, Zhen Huang, Jianghao Li, David J. Maron, Sean M. O'Brien, Harmony R. Reynolds, Jose Lopez-Sendon, Jonathan D. Newman, Sripal Bangalore, Marcin Demkow, Peter Stone, Harvey D. White, and Kian Keong Poh
Subjects: medicine.medical_specialty, Unstable angina, business.industry, Myocardial Ischemia, Ischemia, Coronary Artery Disease, Conservative Treatment, medicine.disease, Coronary artery disease, Heart failure, Internal medicine, medicine, Clinical endpoint, Cardiology, Humans, Cumulative incidence, Angina, Unstable, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, Stroke
Abstract: Aims The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. Methods and results Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh–Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8–20.9] and 19.7 in CON (95% CI 17.5–22.2), difference −1.5 (95% CI −5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. Conclusions In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. Clinical trial registration ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.
Published: 2021
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45. The universal definition of myocardial infarction

Author: Kristian Thygesen, Joseph S Alpert, Allan S Jaffe, and Harvey D White
Subjects: cardiovascular system, cardiovascular diseases
Abstract: Myocardial infarction is defined by the presence of myocardial injury detected by abnormal cardiac biomarkers in the setting of acute clinical myocardial ischaemia. These conditions are met when there is a detection of a rise and/or fall of cardiac biomarkers, preferably cardiac troponins, with at least one value above the 99th percentile of the upper reference limit together with evidence of acute clinical myocardial ischaemia as recognized by at least one of the following: symptoms of ischaemia, ECG changes of new ischaemia, development of pathological Q waves, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, or identification of an intracoronary thrombus by angiography or autopsy.
Published: 2021
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46. Diabetes status modifies the long-term effect of lipoprotein-associated phospholipase A2 on major coronary events

Author: Lars Wallentin, Pamela L. St. Jean, Moneeza K. Siddiqui, Enrique Soto-Pedre, Gwen Kennedy, Samira Bell, Colin H. Macphee, Harvey D. White, Fiona Carr, Colin N. A. Palmer, Gillian Smith, Dawn M. Waterworth, and Adem Y. Dawed
Subjects: medicine.medical_specialty, Epidemiology, Endocrinology, Diabetes and Metabolism, Lipoproteins, Type 2 diabetes, Placebo, Article, Risk Factors, Darapladib, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, Humans, Cardiac and Cardiovascular Systems, Major coronary events, Retrospective Studies, Kardiologi, Proportional hazards model, business.industry, Confounding, Precision medicine, Retrospective cohort study, medicine.disease, Prognosis, Lipids, Diabetes Mellitus, Type 2, Cohort, 1-Alkyl-2-acetylglycerophosphocholine Esterase, lipids (amino acids, peptides, and proteins), business, Biomarkers, Clinical diabetes
Abstract: Aims/hypothesis Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor. Methods A retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations. Results In GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous and quartile divided) and diabetes control status was observed in the prediction of MCE (p p p p p = 0.008). In contrast, Lp-PLA2 inhibitor showed no efficacy in individuals with low activity, regardless of diabetes status, or among those with no baseline diabetes and high Lp-PLA2 activity. Conclusions/interpretation These results support the hypothesis that diabetes status modifies the association between Lp-PLA2 activity and MCE. These results suggest that cardiovascular morbidity and mortality associated with Lp-PLA2 activity is especially important in patients with type 2 diabetes, particularly those with worse glycaemic control. Further investigation of the effects of Lp-PLA2 inhibition in diabetes appears warranted. Data availability STABILITY trial data are available from clinicaltrials.gov repository through the GlaxoSmithKline clinical study register https://clinicaltrials.gov/ct2/show/NCT00799903. GoDARTS datasets generated during and/or analysed during the current study are available following request to the GoDARTS Access Managements Group https://godarts.org/scientific-community/. Graphical abstract
Published: 2021

47. Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline

Author: Lukas Habegger, Charumathi Sabanayagam, Michael Preuss, Laura M. Raffield, Mary F. Feitosa, Bamidele O. Tayo, Kevin Ho, Leo-Pekka Lyytikäinen, Florian Kronenberg, Valencia Hui Xian Foo, Adrienne Tin, Michael Cantor, Nisha Bansal, Tarunveer S. Ahluwalia, Melanie Waldenberger, Sarah A. Pendergrass, Behrooz Z. Alizadeh, Wolfgang Koenig, Qiong Yang, Xiaodong Bai, Christoph Wanner, Ben Schöttker, Giovanni Coppola, A. R. Shuldiner, Leslie A. Lange, Piyush Gampawar, Markus Scholz, Tien Yin Wong, Mary L. Biggs, Morris Swertz, Alicia Hawes, Girish N. Nadkarni, Christina-Alexandra Schulz, Chiea Chuen Khor, Ricardo H. Ulloa, Jeffrey C. Staples, Miao-Li Chee, Laura M. Yerges-Armstrong, Andrew Blumenfeld, Karlhans Endlich, Bernhard Banas, Bruce H.R. Wolffenbuttel, Kai-Uwe Eckardt, Pavel Hamet, Carsten A. Böger, Harold Snieder, Marcus B. Jones, Judy Wang, Shih-Jen Hwang, Mathias Gorski, Anselm Hoppmann, Josyf C. Mychaleckyj, Bernd Holleczek, Pamela R. Matias-Garcia, Rainer Rettig, Karsten B. Sieber, Manasi Pradhan, Pashupati P. Mishra, Peter Rossing, Matthias Wuttke, Miao-Ling Chee, H. Marike Boezen, Yong Li, M. Arfan Ikram, Jeffrey G. Reid, Teresa Nutile, Maria Sotiropoulos Padilla, Lude Franke, Robert J. Carroll, Luca A. Lotta, Bernhard K. Krämer, Kjell Nikus, Jerome I. Rotter, Thomas Meitinger, Lars Wallentin, Cisca Wijmenga, Kent D. Taylor, Holly Kramer, Louis Widom, Olli T. Raitakari, Marcus E. Kleber, Man Li, Nina Hutri-Kähönen, Massimiliano Cocca, Reinhold Schmidt, John D. Overton, Cristian Pattaro, Michael Lattari, Sarah E. Wolf, Jin-Fang Chai, Karina Toledo, Brigitte Kühnel, Zhenhua Gu, Peter Almgren, Caitlin Forsythe, Yuri Milaneschi, Stephan J. L. Bakker, Layal Chaker, Dawn M. Waterworth, Silke Szymczak, James G. Wilson, Peter J. van der Most, Michelle L. O'Donoghue, William Salerno, Masayuki Yasuda, Sahar Ghasemi, Eric Boerwinkle, Josef Coresh, Ilja M. Nolte, Kia Manoochehri, Konstantin Strauch, Thomas D. Schleicher, Myriam Rheinberger, Audrey Y. Chu, Sanaz Sedaghat, Sandra Freitag-Wolf, Boting Ning, Matthias Nauck, Christina Beechert, Helena Schmidt, Harvey D. White, Nina Mononen, Johanne Tremblay, Navya Shilpa Josyula, Mika Kähönen, Katrin Horn, Andre Franke, Marianne Rots, Bettina Jung, Alexander R. Rosenkranz, Christian M. Shaffer, Mary Ann Lukas, Gerjan Navis, Christian Gieger, John Chalmers, Shareef Khalid, Uwe Völker, Marju Orho-Melander, Iris M. Heid, Brenda W.J.H. Penninx, A. Baras, Alexander Lopez, Evan Maxwell, Ruth J. F. Loos, Erin D. Fuller, Christa Meisinger, Gonçalo R. Abecasis, Suganthi Balasubramanian, Chris H. L. Thio, Martin H. de Borst, Stefan Coassin, Ching-Yu Cheng, Wolfgang Lieb, Kenneth Rice, Alexander Teumer, Mark Woodward, Gisu Eom, Hermann Brenner, Thomas W. Winkler, Anna Köttgen, Edith Hofer, Aris Economides, Ron T. Gansevoort, Pim van der Harst, Lyndon J. Mitnaul, Bruce M. Psaty, Erwin P. Bottinger, Olle Melander, Niek Verweij, Frauke Degenhardt, Yan Zhang, Mohsen Ghanbari, Veronika Wanner, Terho Lehtimäki, Leland Barnard, Tampere University, Primary Health Care, Department of Paediatrics, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Department of Marketing Management, Epidemiology, Internal Medicine, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, and APH - Digital Health
Subjects: 0301 basic medicine, medicine.medical_specialty, Genome-wide association study, 030232 urology & nephrology, Protein Disulfide-Isomerases, Hasso-Plattner-Institut für Digital Engineering GmbH, Renal function, Locus (genetics), Biology, AMP-Activated Protein Kinases, Kidney, 3121 Internal medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, end-stage kidney disease, rapid eGFRcrea decline, Urologi och njurmedicin, medicine, Humans, Urology and Nephrology, ddc:610, Allele, Genetic association, Genetics, Creatinine, genome-wide association study, Acute kidney injury, acute kidney injury, medicine.disease, United Kingdom, ddc, 030104 developmental biology, chemistry, Nephrology, Medical genetics, 3111 Biomedicine, 610 Medizin und Gesundheit, Glomerular Filtration Rate
Abstract: Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function., Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät; 19
Published: 2021
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48. Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study

Author: M Olszowka, Marcus E. Kleber, Tanja B. Grammer, Ralph A.H. Stewart, Winfried März, Wolfgang Koenig, Lars Wallentin, Niclas Eriksson, Agneta Siegbahn, Harvey D. White, Mikael Åberg, Emil Hagström, and Claes Held
Subjects: Male, Myocardial Infarction, Coronary Disease, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Biochemistry, Vascular Medicine, 0302 clinical medicine, Medical Conditions, Risk Factors, Medicine and Health Sciences, Coronary Heart Disease, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, Immune Response, Kardiologi, Eukaryota, General Medicine, Blood Proteins, Plants, Brain natriuretic peptide, Prognosis, Legumes, Cardiovascular Diseases, Cohort, Biomarker (medicine), Medicine, Female, medicine.symptom, Research Article, Signal Transduction, medicine.medical_specialty, Transmembrane Receptors, Immunology, Cardiology, 03 medical and health sciences, Signs and Symptoms, Diabetes mellitus, Darapladib, Internal medicine, medicine, Humans, Aged, Retrospective Studies, Inflammation, Proportional hazards model, business.industry, Organ dysfunction, Organisms, Peas, Biology and Life Sciences, Proteins, Retrospective cohort study, Cell Biology, Cardiovascular Disease Risk, medicine.disease, Atherosclerosis, Fibroblast Growth Factor-23, Clinical Medicine, business, Biomarkers
Abstract: Background Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD. Methods and findings The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3–5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799–2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491–1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527–1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362–1.775), renin HR 1.501 (95% CI 1.305–1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297–1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307–1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243–1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131–1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226–1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255–1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316–1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134–1.396), spondin-1 HR 1.295 (95% CI 1.156–1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237–1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129–1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307–1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490–2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events. Conclusions Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD. Trial registration ClinicalTrials.gov NCT00799903., Niclas Eriksson and colleagues report associations between 157 cardiovascular plasma biomarkers and cardiovascular death in patients., Author summary Why was this study done? There are many reports on associations between biomarkers and outcomes in patients with chronic coronary artery disease (CAD). New analytical technologies allow concurrent measurement of hundreds of protein biomarkers in small volumes of plasma. The value of multiplex protein analyses has rarely been evaluated in cohorts with adequate numbers of patients and outcome events. What did the researchers do and find? We investigated the associations between the levels of multiple proteins and the occurrence of cardiovascular (CV) death during 3–12 years follow-up of 2 cohorts of 3,393 and 1,287 patients with chronic CAD. The biomarkers were measured with the OLINK Proximity Extension Assay (PEA) panels CVD I and Inflammation and/or conventional immunoassays. The analyses identified 18 biomarkers with confirmed independent associations with CV death. What do these findings mean? Measurements of levels of plasma protein profiles can be useful for the identification of pathophysiological pathways associated with an increased risk of CV death in patients with chronic coronary heart disease (CHD). Measurements of these profiles might be useful for the identification of new treatment targets and to balance different treatments and treatment responses in patients with chronic CHD.
Published: 2021

49. Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective

Author: Nicholas Pachter, Annette Pedrotti, Allison C Morton, Michael M. Page, David R. Sullivan, Ann Marie Woodward, Amanda J Hooper, Stjepana Maticevic, Luke Elias, Peter M Clifton, Shubha Srinivasan, Zanfina Ademi, Natalie C Ward, Gemma A. Figtree, Christian R Hamilton-Craig, Christina A Bursill, Kathryn E Waddell-Smith, Trevor A Mori, John R Burnett, Catherine Spinks, Elif I Ekinci, John Irvin, Jing Pang, Sam Mirzaee, Ronald J. Trent, Peter Brett, Carl J Schultz, Paul Lacaze, Anthony C Keech, David M Colquhoun, Russell S Scott, Ari Horton, Ingrid Winship, Justin J Ardill, Gerald F. Watts, Nicola K. Poplawski, Peter J Psaltis, Edward D Janus, Charlotte Hespe, Andrew Wilson, Christopher Semsarian, Joanna C Moullin, Jan Radford, Jacqueline Dm Ryan, Jacquie Garton-Smith, Clara K Chow, Frank van Bockxmeer, Clare Heal, Alex Brown, Stephen J. Nicholls, Stephen Ch Li, Dorothy F Graham, Andrew B Kirke, David L Hare, Lawrence J Beilin, Timothy R Bates, Brett H Forge, Nadarajah Kangaharan, Laurence G. Howes, Leon A Simons, Tom Brett, Damon A. Bell, Elizabeth N Robertson, Mitchell Sarkies, Warrick Bishop, Robert N. Justo, Nicola J Reid, Jodie Ingles, Paul J. Nestel, Harvey D White, Wendy Barnett, Richard C O'Brien, Kirsten Lambert, Karam Kostner, Campbell V Kyle, J Andrew Black, Alison Colley, Ian Hamilton-Craig, Brendan M McQuillan, W. L. Malan, Andrew Tonkin, Kristen J. Nowak, Leonard Kritharides, and Andrew J. Martin
Subjects: medicine.medical_specialty, Care, Health care, medicine, Adults, Diseases of the circulatory (Cardiovascular) system, PCSK9 Inhibitors, Children, Genetic testing, Government, medicine.diagnostic_test, business.industry, Prevention, PCSK9, Public health, Service design, Perspective (graphical), General Medicine, Management, Practice Guideline, Family medicine, RC666-701, Guidance, Public aspects of medicine, RA1-1270, business, Familial hypercholesterolaemia, Corrigendum
Abstract: Summary Introduction Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. Main recommendations Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. Potential impact on care of FH These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.
Published: 2020

50. Waiting room computer tablets to improve health literacy and cardiovascular outcomes

Author: Harvey D. White
Subjects: Medical education, Computers, business.industry, media_common.quotation_subject, Patient portal, Health literacy, Cardiovascular System, Waiting Rooms, Health Literacy, Clinical trial, Numeracy, Reading (process), Health care, Humans, Medicine, Social media, The Internet, Cardiology and Cardiovascular Medicine, business, Tablets, media_common
Abstract: Poor health literacy is common occurring in a third of the adult population.1 Rates of low health literacy are higher in the elderly, those with limited education, lower income, chronic medical conditions and those who are non-native English speakers. Low health literacy is associated with limited knowledge of health conditions and increased likelihood of poor adherence, rehospitalisation, morbidity and mortality.2–4 Limited health literacy has also been associated with approximately double the risk of not achieving guideline blood pressure recommendations.5 Health literacy as defined by the American Heart Association is the degree to which individuals can access and process basic health information and services and thereby participate in health-related decisions.3 Improved health literacy may be achieved by various education tools. There are increasing amounts and increasing complexity of cardiac educational material provided to patients, including electronic patient portals and other internet-based tools. There is also increasing capture of the young by computer devices. Greater health literacy is required to navigate these. Health literacy requires multiple skills beyond reading, writing and numeracy and includes interpretation of images, oral communication and may include social networking. As many as 11 fundamental and inter-related skills have been reported to make up and define health literacy (table 1).3 View this table: Table 1 Health literacy skills and competency domains3 The increasing health information that comes via the internet and social media will not reach the many older people without access to technology and will also exclude those without understanding of how to access and interpret the information. There is also the increasing challenge of sifting ‘false information’ from facts on these platforms. In this issue of the journal,6 McIntyre and colleagues6 describe the results of a randomised single centre clinical trial with 330 participants …
Published: 2021
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