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1. Continuous Infusion of Angiotensin IV Protects against Acute Myocardial Infarction via the Inhibition of Inflammation and Autophagy.

Author

Bai WW, Wang H, Gao CH, Liu KY, Guo BX, Jiang F, Zhang MX, Li C, and Qin WD

Subjects
Angiotensin II administration & dosage, Angiotensin II pharmacology, Animals, Apoptosis, Cardiomyopathies etiology, Cardiomyopathies metabolism, Cardiomyopathies pathology, Cells, Cultured, Inflammation etiology, Inflammation metabolism, Inflammation pathology, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction etiology, Myocardial Infarction metabolism, Myocardial Infarction pathology, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Oxidative Stress, Rats, Angiotensin II analogs & derivatives, Autophagy, Cardiomyopathies prevention & control, Inflammation drug therapy, Myocardial Infarction prevention & control, Myocytes, Cardiac drug effects, Protective Agents pharmacology
Abstract

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Angiotensin (Ang) IV possesses many biological properties that are not yet completely understood. Therefore, we investigated the function and mechanism of Ang IV in AMI in in vivo and in vitro conditions. AMI was performed by ligation of the left anterior descending coronary artery (LAD) in male C57 mice. Ang IV was continuously infused by a minipump 3 d before AMI for 33 d. The neonatal rat ventricular myocytes (NRVCs) were stimulated with Ang IV and cultured under hypoxic conditions. In vivo , Ang IV infusion significantly reduced the mortality after AMI. By the 7 th day after AMI, compared with the AMI group, Ang IV reduced the inflammatory cytokine expression. Moreover, terminal deoxyribonucleotidyl transferase- (TDT-) mediated dUTP nick-end labeling (TUNEL) assay showed that Ang IV infusion reduced AMI-induced cardiomyocyte apoptosis. Compared with AMI, Ang IV reduced autophagosomes in cardiomyocytes and improved mitochondrial swelling and disarrangement, as assessed by transmission electron microscopy. By 30 th day after AMI, Ang IV significantly reduced the ratio of heart weight to body weight. Echocardiography showed that Ang IV improved impaired cardiac function. Hematoxylin and eosin (H&E) and Masson staining showed that Ang IV infusion reduced the infarction size and myocardial fibrosis. In vitro , dihydroethidium (DHE) staining and comet assay showed that, compared with the hypoxia group, Ang IV reduced oxidative stress and DNA damage. Enzyme-linked immunosorbent assay (ELISA) showed that Ang IV reduced hypoxia-induced secretion of the tumor necrosis factor- (TNF-) ɑ and interleukin- (IL-) 1 β . In addition, compared with the hypoxia group, Ang IV reduced the transformation of light chain 3- (LC3-) I to LC3-II but increased p62 expression and decreased cardiomyocyte apoptosis. Overall, the present study showed that Ang IV reduced the inflammatory response, autophagy, and fibrosis after AMI, leading to reduced infarction size and improved cardiac function. Therefore, administration of Ang IV may be a feasible strategy for the treatment of AMI., Competing Interests: There were no competing financial interests in relation to the work., (Copyright © 2021 Wen-wu Bai et al.)

Published
2021
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2. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE) : an international, randomised, placebo-controlled trial

Author

P J Devereaux, Emmanuelle Duceppe, Gordon Guyatt, Vikas Tandon, Reitze Rodseth, Bruce M Biccard, Denis Xavier, Wojciech Szczeklik, Christian S Meyhoff, Jessica Vincent, Maria Grazia Franzosi, Sadeesh K Srinathan, Jason Erb, Patrick Magloire, John Neary, Mangala Rao, Prashant V Rahate, Navneet K Chaudhry, Bongani Mayosi, Miriam de Nadal, Pilar Paniagua Iglesias, Otavio Berwanger, Juan Carlos Villar, Fernando Botto, John W Eikelboom, Daniel I Sessler, Clive Kearon, Shirley Pettit, Mukul Sharma, Stuart J Connolly, Shrikant I Bangdiwala, Purnima Rao-Melacini, Andreas Hoeft, Salim Yusuf, P.J. Devereaux, Shrikant I. Bangdiwala, Stuart Connolly, John Eikelboom, Janice Pogue, Daniel I. Sessler, Sara Di Diodato, Zora Gasic, Louise J. Mastrangelo, Sarah H. Molnar, Jennifer L. Swanson, Makayla L. Tosh, Jennifer R. Wells, Rafael Diaz, Clara K. Chow, Beatriz Gonzales, Skarlet Vásquez, Petr Jansky, Radovan Dušek, Christian S. Meyhoff, Pierre Coriat, Maria Wittmann, Gerald Yonga, Nandini Mathur, Elena Seletti, German Malaga, Bernadette A. Tumanan-Mendoza, Maria Pamela A. Tagle, Bruce M. Biccard, Pablo Alonso-Coello, Ekaterine Popova, Martin Shields, Yannick Le Manach, Paul Moayyedi, Sander van Zanten, Edith Fleischmann, Amit Garg, Kamilu Karaye, Edward McFalls, Alben Sigamani, Emilie Belley-Côté, Grzegorz Biedroń, Flavia Borges, Steffan Frosi Stella, Christian Haarmark Nielsen, Darryl P. Leong, Jessica Spence, Allen Tran, Katarzyna Wawrzycka-Adamczyk, Stephen S. Yang, Terence Yung, D. George Wyse, Davy Cheng, David E. Johnstone, George A. Wells, Philip Joseph, Ameen Patel, Krysten Gregus, Kelly Lawrence, Lindsay Doharris, David Conen, Jason Cheung, Jim Douketis, Douglas Wright, Spencer Wikkerink, William Dechert, Mohamed Panju, Khalid Azzam, Theodore Rapanos, Tomas Van Helder, Anjali Shroff, Jacqueline Hare, Biniam Kidane, Thang Nguyen, Larissa Leydier, Vanessa Bayaraa, Joel Parlow, Deborah A. DuMerton, Amar Thakrar, Jessica Shelley, Benoit Deligne, Roberta Daila Carling, Marko Mrkobrada, George K. Dresser, Michael J. Jacka, David Hornstein, Gerrit B. Winkelaar, Zoeb Hussain Haider, Pravina Prashant Lanjewar, Valsamma Varughese, Rajneesh Calton, Hemani Ahuja, Preetha George, Ambika Sharma, Keyur Sureshchandra Bhatt, Dhaval Odhavajibhai Mangukiya, Karshan Vira Nandaniya, Viral Vasantrai Parekh, Ashok Bhaskaran Pillai, Vidya P. Menon, Sanjay Channappa Desai, Ravinder Singh Sidhu, Sandeep Kumar Gupta, Robbie K. George, T.R. Gurunath, Leanne W. Drummond, Alexandra M. Torborg, Belinda S. Küsel, Prebashini Naidoo, Datshana P. Naidoo, Chantal Rajah, Zane Farina, Richard Peter von Rahden, Simphiwe Gumede, Chishala Chishala, Ettienne Coetzee, Robert A. Dyer, Johan Diedericks, Piotr Bielański, Bogusz Kaczmarek, Dorota Studzińska, Maciej Zaniewski, Marek Józef Libura, Tomasz Mikołaj Zacharias-Nalichowski, Aurelia A.S. Sega, Jakub Salwa, Mateusz Kózka, Jacek Górka, Anna Wludarczyk, Ilona Nowak-Kózka, Paweł Szczepan Grudzień, Jaroslaw W. Gucwa, Michał Piotr Słowiaczek, Paweł P.D. Dobosz, Ismail Gögenur, Jens Ravn Eriksen, Tine Borup, Tove Kirkegaard, Dan Isbye, Asger Sonne, Lars S. Rasmussen, Sofie Pedersen, Hannibal Troensegaard, Camilla L. Duus, Benedikte M. Halle, Ossian N. Gundel, Katrine F. Bernholm, Kristian Rønsholt Martinsen, Søren Pedersen, Theis S. Itenov, Elena Camio, Carles Vázquez, Silvia Matarin, Esther Cano, Jesús Álvarez-García, Inmaculada India, Aránzazu González-Osuna, Marc Vives, Elena Rosselló, Ana B. Serrano, Maurizio Turiel, Lorenzo Drago, Chiara Colombo, Federica Marra, Lucio Mos, Franco Arteni, Rosalba Lembo, Alessandro Ortalda, Simonetta Passarani, Zhirajr Mokini, Estevao Lanna Figueiredo, Gustavo Fonseca Werner, Joao Luiz Petriz, Lilia Nigro Maia, Ricardo R. Bergo, Dalton Bertolim Precoma, José Francisco Kerr Saraiva, Oscar Gomez Vilamajo, Eduardo Allegrini, Mariano Benzadón, Maria Leonor Parody, Ernesto A. Duronto, Adrián C. Ingaramo, Gustavo Adolfo Parra, Danny Novoa, Scott A. Miller, Sabu Thomas, Sudhakar P. Karlapudi, Mohamad H. Bourji, Subhash Banerjee, Anita Gupta, Isaac O. Opole, Michal Fischer, Victor Lecaros Mendoza, Eugenio Borja Reyes, Richard J. Pierson, Martin O. Shields, Vincent Piriou, Kai Zacharowski, Aida Rotta-Rotta, Main Paper, Sadeesh K. Srinathan, Prashant Rahate, Navneet Chaudhry, Bogani Mayosi, and Mike Sharma

Subjects
Male, medicine.medical_specialty, Myocardial Infarction, Placebo-controlled study, Hemorrhage, 030204 cardiovascular system & hematology, Placebo, Antithrombins, Dabigatran, law.invention, Peripheral Arterial Disease, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, 030202 anesthesiology, law, Internal medicine, medicine, Humans, Perioperative Period, Stroke, Aged, Aged, 80 and over, business.industry, Hazard ratio, Proton Pump Inhibitors, Thrombosis, Venous Thromboembolism, General Medicine, Perioperative, Placebo Effect, medicine.disease, Troponin, Clinical trial, Treatment Outcome, Female, business, Omeprazole, medicine.drug
Abstract

Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

Published
2018

3. Blunting periprocedural myocardial necrosis: Rationale and design of the randomized ALPHEUS study

Author

François Jourda, Christophe Saint-Etienne, Luc Christiaens, Grégoire Rangé, Benoit Lattuca, Philippe Brunel, Paul Guedeney, Hervé Le Breton, Marie Hauguel-Moreau, Eric Vicaut, Anne Bellemain-Appaix, Jean-Louis Georges, Guillaume Cayla, Christophe Pouillot, Christophe Caussin, Gregory Ducrocq, Ziad Boueri, Farzin Beygui, Johanne Silvain, Thibault Lhermusier, Gilles Montalescot, Jean-Noël Labèque, Jean-Philippe Collet, Zuzana Motovska, Franck Boccara, Mohamad El Kasty, Raphaelle Dumaine, Jean-Guillaume Dillinger, Mikael Laredo, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de cardiologie et de pathologie vasculaire [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de cardiologie [Chartres], Les hôpitaux de Chartres [Chartres], Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Hôpital de Bastia, Service de Cardiologie [Hôpital privé Dijon Bourgogne], Hôpital privé Dijon Bourgogne, Clinique Sainte Clotilde, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de cardiologie [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de cardiologie [Centre Hospitalier de la Côte Basque, Bayonne], Centre Hospitalier de la Côte Basque, CHU Toulouse [Toulouse], Centre Hospitalier de Versailles André Mignot (CHV), Cardiology Department, Centre Hospitalier d'Antibes Juan les Pins, Antibes, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Institut Mutualiste de Montsouris (IMM), Hôpital d'Auxerre, Partenaires INRAE, Grand Hôpital de l'Est Francilien (GHEF), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, AstraZeneca France Novartis Daiichi-Sankyo Bristol-Myers Squibb, BMS Eli Lilly and Company Bayer AstraZeneca France Boston Scientific Corporation, BSC Abbott Laboratories Medtronic Biotronik Fédération Française de Cardiologie, FFC, The ALPHEUS and the Bio-ALPHEUS studies are funded by the Fond de dotation ACTION ( www.action-fonds.org ) and a grant from AstraZeneca . The Bio-ALPHEUS study is also funded by the Institute of Cardiometabolism and Nutrition . The first draft of the paper was developed by Dr Silvain and Dr Montalescot, and all authors subsequently contributed to its development and final content and are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. AstraZeneca reviewed the manuscript and was allowed to make suggestions, but final content was determined by the authors., Dr Silvain reports receiving consulting and lecture or travel support from AstraZeneca, Bayer HealthCare SAS, Biotronik, BPI France, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, Sanofi-Aventis France, Terumo France SAS, Abbott Medical France SAS, and Zoll and is a stockholder of Pharmaseeds. Dr Cayla reports speaker or congress fees and has received research grants/consultant fees/lectures fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis. Dr Beygui reports receiving consulting and lecture fees from Astrazeneca, Bristol-Myers Squibb, Medtronic, Biosensors, Boston Scientific Institutional and research grants from Medtronic, Biosensors, Acist, and Boston scientific. Dr Rangé reports receiving speaker’s and/or consulting fees from Abbott. Dr Lattuca has received research grants from Biotronik, Boston Scientific, Daiichi-Sankyo, Fédération Française de Cardiologie, and Institute of CardioMetabolism and Nutrition, consultant fees from Daiichi-Sankyo and Eli Lilly, and lecture fees from AstraZeneca, Medtronic, and Novartis. Dr Collet reports receiving consulting and lecture fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Fédération Française de Cardiologie, Lead-Up, Medtronic, MSD, Sanofi-Aventis, and WebMD. Dr Dillinger reports receiving consulting and lecture fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, and Sanofi and grants from Bayer, Bristol-Myers Squibb/Pfizer, and Biosensors. Dr Boueri reports receiving consulting and lecture fees from Novartis and Astra Zeneca. Dr Boccara reports consulting or speaker fees from Amgen, Gilead, ViiV Healthcare, Amgen, Sanofi, MSD, and Servier outside the submitted work. Dr Christiaens reports consulting or speaker fees from Astra Zeneca. Dr Lhermusier reports consulting or speaker fees from Astra Zeneca, Boston Scientifics, and Abbott and a research grant from Astra Zeneca. Dr Georges reports consulting or speaker fees from AstraZeneca France, Sanofi-Aventis, Amgen, and Merck Sharpe and Dohme. Dr Bellemain-Appaix reports consulting or speaker fees from Astra Zeneca, Novartis, and Pfizer. Dr Saint-Etienne reports consulting or speaker fees from Abbott, Medtronic, Edwards, and Biotronik. Dr Motovska reports consulting or speaker fees from Astrazeneca. Dr Laredo reports fellowship grants from Medtronic, Biotronik, and Boston Scientific. Dr Ducrocq reports consulting or speaker fees from Amgen, Astra Zeneca, Bayer, BMS, Janssen, Sanofi, and Terumo, proctoring: Boston scientific, CEC: Novo Nordisk, and travel fees: Astra Zeneca, Bayer, and BMS. Dr Vicaut reports consulting or speaker fees from Abbott, Bristol Myers Squibb, Celgene, Edwards, Pfizer, Sanofi, and Novartis. Dr Montalescot reports consulting or speaker fees from Abbott, AIM group, Amgen, Actelion, American College of Cardiology Foundation, Astrazeneca, Axis-Santé, Bayer, Boston-Scientific, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Fréquence Médicale, ICOM, Idorsia, Elsevier, Fédération Française de Cardiologie, Fréquence Médicale, Institute of Cardiometabolism and Nutrition, Lead-Up, Menarini, Medtronic, MSD, Novo-Nordisk, Pfizer, Quantum Genomics, Sanofi-Aventis, SCOR global life, Servier, and WebMD. Other authors have no conflict of interest to report., Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier d'Auxerre (CHA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord

Subjects
medicine.medical_specialty, Ticlopidine, medicine.medical_treatment, Myocardial Infarction, Coronary Disease, 030204 cardiovascular system & hematology, Coronary Angiography, Loading dose, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Percutaneous Coronary Intervention, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, cardiovascular diseases, Aged, Aspirin, business.industry, Percutaneous coronary intervention, medicine.disease, Clopidogrel, 3. Good health, Conventional PCI, Cardiology, Purinergic P2Y Receptor Antagonists, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Cardiology and Cardiovascular Medicine, business, Ticagrelor, Platelet Aggregation Inhibitors, medicine.drug
Abstract

International audience; Background: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting. Methods: Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier). Conclusion: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality.

Published
2020

4. Impact of Geographic Region on the COMMANDER-HF Trial

Author

João Pedro Ferreira, John G.F. Cleland, Carolyn S.P. Lam, Dirk J. van Veldhuisen, William M. Byra, David A. La Police, Stefan D. Anker, Mandeep R. Mehra, Céline Leroy, Valerie Eschwege, Marie Toussaint-Hacquard, Patrick Rossignol, Barry Greenberg, Faiez Zannad, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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 ), University of Glasgow, National Heart Centre Singapore (NHCS), Duke-National University of Singapore Graduate Medical School, University Medical Center Groningen [Groningen] (UMCG), Janssen Research & Development, Berlin-Brandenburg Center for Regenerative Therapies, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Brigham and Women's Hospital [Boston], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of California [San Diego] (UC San Diego), University of California, Funding Support and Author Disclosures The COMMANDER-HF trial was supported by Janssen Research and Development. Drs. Ferreira, Rossignol, and Zannad are supported by Reseau Hospitalo-Universitaire Fight-HF, a public grant overseen by the French National Research Agency as part of the second 'Investissements d’Avenir' program (reference: ANR-15-RHUS-0004) and by the French Investments for the Future Program project 'Lorraine Université d’Excellence' (reference: ANR-15-IDEX-04-LUE). The biobanking for rivaroxaban dosages is managed by Biological Resource Center Lorrain BB-0033-00035. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), and Cardiovascular Centre (CVC)

Subjects
Latin Americans, [SDV]Life Sciences [q-bio], Psychological intervention, heart failure, 030204 cardiovascular system & hematology, Lower risk, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Stroke, rivaroxaban, Clinical Trials as Topic, Rivaroxaban, business.industry, Patient Selection, Stroke Volume, medicine.disease, 3. Good health, Latin America, [SDU]Sciences of the Universe [physics], Cardiology and Cardiovascular Medicine, business, Regional differences, Demography, medicine.drug, regional differences
Abstract

OBJECTIVES This study sought to compare patient characteristics, outcomes, and treatment effects among regions in the COMMANDER-HF trial.BACKGROUND Globalization of cardiovascular trials increases generalizability. However, regional differences may also introduce heterogeneity in results.METHODS Incidence rates and interactions with treatment were recorded in pre-specified regions: Eastern Europe, Western Europe and South Africa, North America, Asia-Pacific, and Latin America.RESULTS Most patients (n = 3,224; 64.2%) were from Eastern Europe; 458 (9.1%) were from Western Europe and South Africa; 149 (3.0%) were from North America; 733 (14.6%) were from Asia-Pacific; and 458 (9.1%) were from Latin America. Compared with patients from Eastern Europe, patients from Western Europe and South Africa, North America, and Asia-Pacific were older and more likely to have coronary interventions and cardiac devices. Patients from Eastern Europe had the lowest event rates. For the primary outcome of myocardial infarction (MI), stroke, or all-cause death, event rates (100/year) were 11.6 in Eastern Europe (10.8 to 12.5); 19.5 (16.5 to 23.0) in Western Europe and South Africa; 14.2 (10.5 to 19.2) in North America; 17.7 (15.4 to 20.3) in Asia-Pacific; and 18.6 (15.6 to 22.1) in Latin America. There was a lower incidence of bleeding in Eastern Europe. Blood concentrations of rivaroxaban (Xarelto, Titusville, New Jersey) at 4 weeks were undetectable in 21% patients from Eastern Europe (n = 128) compared to 5% in other regions (n = 42). There was no evidence of treatment-by-region heterogeneity for the primary outcome (interaction(p) = 0.14), but a favorable effect on the secondary outcome of MI, stroke, or cardiovascular death was observed in Western Europe and South Africa, North America, and Latin America but not in Eastern Europe and Asia-Pacific (interaction(p) = 0.017).CONCLUSIONS In the COMMANDER-HF study, patients from Eastern Europe had a lower risk profile and fewer cardiovascular and bleeding events, possibly related to lower treatment adherence. Those differences might have influenced the effect of rivaroxaban therapy. (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure [COMMANDER HF]; NCT01877915) (c) 2021 by the American College of Cardiology Foundation.

Published
2021

5. Randomised, double-blind, placebo-controlled clinical trial for evaluating the efficacy of intracoronary injection of autologous bone marrow mononuclear cells in the improvement of the ventricular function in patients with idiopathic dilated myocardiopathy: a study protocol

Author

Miguel Romero, José Suárez-de-Lezo, Concha Herrera, Manuel Pan, José López-Aguilera, Flor Baeza-Garzón, Francisco Javier Hidalgo-Lesmes, Olga Fernández-López, Juliana Martínez-Atienza, Eva Cebrián, Vanesa Martín-Palanco, Rosario Jiménez-Moreno, Rosario Gutiérrez-Fernández, Sonia Nogueras, Maria Dolores Carmona, Soledad Ojeda, Natividad Cuende, Rosario Mata, [Romero,M, Suárez-de-Lezo, Pan,M, López-Aguilera,J, Suárez-de-Lezo Jr,J, Baeza-Garzón,F, Hidalgo-Lesmes,FJ, Cebrián,E, Ojeda,S] Cardiology Unit, Reina Sofía University Hospital, Córdoba, Spain. [Herrera,C, Martín-Palanco,V, Jiménez-Moreno,R, Gutiérrez-Fernández,R, Nogueras,S, Carmona,MD] Cell Production Unit, Reina Sofía University Hospital, Córdoba, Spain. [Fernández-López,O, Martínez-Atienza,J, Cuende,N, Mata,R] Andalusian Initiative for Advanced Therapies, Andalusian Public Foundation Progress and Health, Seville, Spain., and This paper presents an investigator-driven Clinical trial partially funded by research grant provided by the Regional Ministry of Health of Andalusia (Grant Reference Number salud-201600073587-tra).

Subjects
Male, lcsh:Diseases of the circulatory (Cardiovascular) system, Time Factors, Ensayo clínico controlado aleatorio, 030204 cardiovascular system & hematology, Cell therapy, Ventricular Function, Left, law.invention, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Study Protocol, Cardiomiopatía dilatada, 0302 clinical medicine, Randomized controlled trial, law, Dilated myocardiopathy, Multicenter Studies as Topic, 030212 general & internal medicine, Myocardial infarction, Diseases::Cardiovascular Diseases::Heart Diseases::Cardiomyopathies::Cardiomyopathy, Dilated [Medical Subject Headings], Bone Marrow Transplantation, Randomized Controlled Trials as Topic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Evaluation Studies as Topic::Clinical Trials as Topic::Controlled Clinical Trials as Topic::Randomized Controlled Trials as Topic [Medical Subject Headings], Diseases::Cardiovascular Diseases::Vascular Diseases::Myocardial Ischemia::Myocardial Infarction [Medical Subject Headings], Ejection fraction, Middle Aged, Treatment Outcome, Disciplines and Occupations::Natural Science Disciplines::Science::Research::Biomedical Research [Medical Subject Headings], Female, Cardiology and Cardiovascular Medicine, Adult, Cardiomyopathy, Dilated, medicine.medical_specialty, Information Science::Information Science::Communications Media::Publications [Medical Subject Headings], Adolescent, Cell- and tissue-based therapy, Células de la médula ósea, Bone Marrow Cells, Placebo, Transplantation, Autologous, Young Adult, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Double-Blind Method, Tratamiento basado en trasplante de células y tejidos, Internal medicine, medicine, Humans, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Cell- and Tissue-Based Therapy [Medical Subject Headings], Aged, Angiology, Anatomy::Cells::Bone Marrow Cells [Medical Subject Headings], business.industry, Consolidated Standards of Reporting Trials, Recovery of Function, medicine.disease, Interim analysis, Clinical trial, lcsh:RC666-701, Spain, Bone marrow mononuclear cells, business
Abstract

Cellular therapies have been increasingly applied to diverse human diseases. Intracoronary infusion of bone marrow-derived mononuclear cells (BMMNC) has demonstrated to improve ventricular function after acute myocardial infarction. However, less information is available about the role of BMMNC therapy for the treatment of dilated myocardiopathies (DCs) of non-ischemic origin. This article presents the methodological description of a study aimed at investigating the efficacy of intracoronary injection of autologous BMMNCs in the improvement of the ventricular function of patients with DC. This randomised, placebo-controlled, double-blinded phase IIb clinical trial compares the improvement on ventricular function (measured by the changes on the ejection fraction) of patients receiving the conventional treatment for DC in combination with a single dose of an intracoronary infusion of BMMNCs, with the functional recovery of patients receiving placebo plus conventional treatment. Patients assigned to both treatment groups are monitored for 24 months. This clinical trial is powered enough to detect a change in Left Ventricular Ejection Fraction (LVEF) equal to or greater than 9%, although an interim analysis is planned to re-calculate sample size. The study protocol was approved by the Andalusian Coordinating Ethics Committee for Biomedical Research (Comite Coordinador de Etica en Investigacion Biomedica de Andalucia), the Spanish Medicines and Medical Devices Agency (Agencia Espanola de Medicamentos y Productos Sanitarios), and is registered at the EU Clinical Trials Register (EudraCT: 2013–002015-98). The publication of the trial results in scientific journals will be performed in accordance with the applicable regulations and guidelines to clinical trials. ClinicalTrials.gov Identifier NCT02033278 (First Posted January 10, 2014): https://clinicaltrials.gov/ct2/show/NCT02033278 ; EudraCT number: 2013–002015-98, EU CT Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002015-98 . Trial results will also be published according to the CONSORT statement at conferences and reported peer-reviewed journals.

Published
2019