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Abdulla A, Donahue KR, Hall C, Culver LG, Morton C. Incidence of Venous Thromboembolism Post-Oral Anticoagulation Reversal in Intracranial Hemorrhage Patients. Ann Pharmacother 2025; 59:501-510. [PMID: 39563016 DOI: 10.1177/10600280241297701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Rates of in-hospital venous thromboembolism (VTE) in the intracranial hemorrhage (ICH) population post oral anticoagulation (AC) reversal are as high as 10%. Guidelines recommend the initiation of prophylactic AC 24 to 48 hours post ICH; however, there is no guidance regarding optimal VTE prophylaxis post-reversal. OBJECTIVE This study aimed to identify the incidence of thromboembolism post oral AC reversal in patients presenting with ICH and describe VTE prophylaxis timing and agent selection. METHODS This was a retrospective, descriptive study conducted within a single health system. Patients on AC who received reversal agents 4-factor prothrombin complex concentrate (4F-PCC) with or without vitamin K, andexanet alfa, and/or idarucizumab for AC-associated ICH were included. The primary endpoint was incidence of in-hospital VTE post-reversal. Secondary endpoints included AC utilization specifications, length of stay, and in-hospital mortality. RESULTS There were 118 patients (57%) who received 4F-PCC and 89 patients (43%) who received andexanet alfa for reversal post-ICH. Overall, 195 patients (94.2%) achieved hemostasis. Eight patients had incidence of VTE (3.9%), and of those, 6 patients (75%) were reinitiated on AC, all of which utilized prophylactic heparin. The median time from reversal to VTE was 55.9 days (interquartile range [IQR] = 21.2-72.4). For all patients on AC, the median time to initiation from reversal was 3.98 days (IQR = 2.5-6.01), and for those with incidence of thrombosis, the median time to AC initiation was 6.4 days (IQR = 2.6-13.1). Mortality occurred in 13 patients (6.3%). CONCLUSION AND RELEVANCE This patient population is complex in that the need to achieve hemostasis with AC reversal must be balanced with the risk of VTE. Further studies are needed to determine the ideal timing and agent selection for VTE prophylaxis initiation post ICH reversal.
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Affiliation(s)
- Aliya Abdulla
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Kevin R Donahue
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Courtney Hall
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Lauren G Culver
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Celia Morton
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
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Morello G, Alampi D, Aspide R, Beretta A, Bertuetti R, Bilotta F, Brogi E, Buscema G, Caricato A, Caruzzo D, Castioni CA, Chieregato A, Cortegiani A, De Cassai A, Fabbri A, Gelormini D, Gritti P, Guadrini L, Librizzi A, Latronico N, Limbucci N, Munari M, Picetti E, Pipitone G, Pucciarelli G, Robba C, Toni D, Sardo S, Zerbi SM, Zugni N, Rasulo F. Golden hour management in the patient with intraparenchymal cerebral hemorrhage: an Italian intersociety document. JOURNAL OF ANESTHESIA, ANALGESIA AND CRITICAL CARE 2025; 5:25. [PMID: 40346657 PMCID: PMC12065239 DOI: 10.1186/s44158-025-00244-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Accepted: 04/16/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Spontaneous intracerebral hemorrhage (ICH) accounts for 9-27% of all strokes worldwide and is associated with high mortality and disability. The main causes include vascular malformations, small- and large-vessel angiopathies, and coagulation disorders. Mortality rates reach approximately 40% at 1 month and 54% at 1 year, largely influenced by early management decisions. Rapid intervention, particularly within the first hour, is crucial, especially for patients initially treated in peripheral hospitals. This consensus document, developed by SIAARTI with the endorsement of multiple medical societies, aims to standardize ICH management based on hospital capabilities, aligning with the "time is brain" principle and the 2022 AHA guidelines. METHODS A multidisciplinary panel of experts-including neurointensivists, neuroanesthesiologists, neurologists, neuroradiologists, emergency physicians, and neuroscience nurses-developed this consensus document. The process combined a systematic literature review with a modified Delphi method, prioritizing clinical questions using the UCLA-RAND appropriateness methodology. Literature searches were conducted on PubMed following PRISMA 2020 guidelines. Statements were formulated based on both evidence and expert consensus, and the final document underwent external peer review. RESULTS Computer tomography (CT) angiography, with over 90% sensitivity and specificity, is a key tool for identifying macrovascular abnormalities and detecting active bleeding, a critical factor in poor outcomes. Prognostic models, such as the ICH score, assist in clinical decision-making. Strict blood pressure control (target 130-140 mmHg) and early intubation in appropriate cases help mitigate hematoma expansion. Anticonvulsants are recommended only for patients with documented seizures. In cases of anticoagulant-related hemorrhage, prothrombin complex concentrates are effective for rapid reversal, though their long-term impact remains uncertain. Intensive care unit (ICU) admission is determined by ICH severity, with severe cases benefiting from specialized neurocritical care. CONCLUSION A multidisciplinary and inter-societal discussion provided key recommendations for the immediate management of ICH, based on the available literature. While only a few topics are supported by robust evidence, experts strongly recommend early brain angio CT, risk stratification using scoring systems, clear communication of patient data, and intubation for impaired consciousness. Blood pressure should be controlled with alpha- and beta-blockers, avoiding hypotension. Anticoagulant reversal should be appropriately managed, and eligible patients should be centralized in ICU and neurosurgical centers using dedicated scoring systems.
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Affiliation(s)
- Gianluigi Morello
- ASP Catania, Anesthesia and Intensive Care, Militello Hospital, Catania, Italy
| | - Daniela Alampi
- Unit of Anesthesia, Department of Clinical and Surgical Translational Medicine, Intensive Care and Pain Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Raffaele Aspide
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Anesthesia and Intensive Care Unit, Bologna, Italy.
| | - Alessandra Beretta
- Neurocritical and Postoperative Care, Neuroanesthesia, ASST Spedali Civili Di Brescia, Brescia, Italy
| | - Rita Bertuetti
- Neurocritical and Postoperative Care, Neuroanesthesia, ASST Spedali Civili Di Brescia, Brescia, Italy
| | - Federico Bilotta
- Department of Anesthesiology and Intensive Care Medicine, University of Rome "La Sapienza", Rome, Italy
| | - Etrusca Brogi
- Neuroscience Intensive Care Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giovanni Buscema
- Department of Anesthesia and Intensive Care Unit, Azienda Ospedaliero Universitaria Policlinico"G. Rodolico - San Marco"di, Catania, Italy
| | - Anselmo Caricato
- Terapia Intensiva Neurochirurgica, Fondazione Policlinico Universitario A.Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Davide Caruzzo
- Azienda Sanitaria Universitaria Friuli Centrale Di Udine, Udine, Italy
| | - Carlo Alberto Castioni
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Anesthesia and Intensive Care Unit, Bologna, Italy
| | - Arturo Chieregato
- Neuroscience Intensive Care Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Cortegiani
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, Palermo, Italy
- Department of Anesthesia, Intensive Care and Emergency, University Hospital Policlinico Paolo Giaccone, AnalgesiaPalermo, Italy
| | - Alessandro De Cassai
- University of Padua, Padua, Italy
- Institute of Anesthesia and Intensive Care, University Hospital of Padua, Padua, Italy
| | - Andrea Fabbri
- Emergency Department, Local Health Agency of Romagna, Forlì, FC, Italy
| | - Domenico Gelormini
- Neurocritical and Postoperative Care Unit, Department of Emergency, Anesthesia and Intensive Care, Azienda Ospedaliero Universitaria Integrata Di Verona, Verona, Italy
| | - Paolo Gritti
- Department of Anesthesia and Intensive Care Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Lucrezia Guadrini
- Neurocritical and Postoperative Care, Neuroanesthesia, ASST Spedali Civili Di Brescia, Brescia, Italy
| | - Alberto Librizzi
- Neurocritical and Postoperative Care, Neuroanesthesia, ASST Spedali Civili Di Brescia, Brescia, Italy
| | - Nicola Latronico
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
- Department of Emergency, Spedali Civili University Hospital, Brescia, Italy
| | - Nicola Limbucci
- Interventional Neurovascular Unit, Careggi University Hospital, Florence, Italy
| | - Marina Munari
- Department of Anesthesia, Intensive Care and Neurointensive Care, University Hospital of Padua, Padua, Italy
| | - Edoardo Picetti
- Department of Anesthesia and Intensive Care, Parma University Hospital, Parma, Italy
| | | | - Gianluca Pucciarelli
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Chiara Robba
- Department of Surgical Science and Integrated Diagnostic, University of Genova, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Danilo Toni
- Emergency Department Stroke Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
| | - Salvatore Sardo
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, Italy
| | - Simone Maria Zerbi
- Department of Emergency, Anesthesia and Intensive Care, Neurointensive Care, ASST Lariana Ospedale Sant'Anna, San Fermo Della Battaglia (CO), Como, Italy
| | - Nicola Zugni
- Neurocritical and Postoperative Care, Neuroanesthesia, ASST Spedali Civili Di Brescia, Brescia, Italy
| | - Frank Rasulo
- Dept. of Neuroanesthesia, Neurocritical and Postoperative Care, ASST Spedali Civili University Affiliated Hospital of Brescia, Brescia, Italy
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D’Abrantes S, Male C, Brown N, Bjursell M, Ambery P, Berggren A, Mattsson U. Anticoagulant prescribing trends, bleeding events, and reversal agent use in pediatric patients: A retrospective, real-world study. PLoS One 2025; 20:e0323137. [PMID: 40338907 PMCID: PMC12061172 DOI: 10.1371/journal.pone.0323137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 04/01/2025] [Indexed: 05/10/2025] Open
Abstract
This retrospective real-world study aimed to describe anticoagulant prescribing trends, particularly for factor Xa (FXa) inhibitors, bleeding events, and reversal agent use in pediatric patients to assess potential populations for clinical trials of the FXa inhibitor reversal agent andexanet alfa. Real-world health care data from the TriNetX Global Network and Optum's deidentified Clinformatics® Data Mart Database (CDM) were analyzed to identify patients aged <18 years old who were prescribed a direct oral FXa inhibitor, warfarin, or low-molecular-weight heparins from 2007 through 2024 (TriNetX, N = 59,780) or 2023 (CDM, N = 6470). The only anticoagulants prescribed to children were warfarin and/or low-molecular-weight heparins in 2007 and 2008 in TriNetX and from 2007 through 2010 in CDM. Prescriptions of the FXa inhibitor rivaroxaban increased from 0.4% (2009) to 18.0% (2023) in TriNetX and from 0.8% (2011) to 34.0% (2023) in CDM, with similar trends for apixaban. Relevant bleeding was reported in 9.4% of patients prescribed an FXa inhibitor in TriNetX; ≤ 0.1% of patients received andexanet alfa the day of a bleed. Among patients prescribed an FXa inhibitor, ≤ 0.1% in TriNetX and 0 in CDM received andexanet alfa the day of surgery. Direct oral FXa inhibitor use in children is growing, as is the potential for associated bleeds; however, reversal agent use is rare in this population. Given the possible unmet need and subsequent patient recruitment challenges, designing pediatric clinical trials of reversal agents requires innovative approaches.
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Affiliation(s)
- Sofia D’Abrantes
- Data Sciences and Artificial Intelligence, R&D BioPharmaceuticals, AstraZeneca, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - Christoph Male
- Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Nick Brown
- Department of Women’s and Children’s Health, International Maternal and Child Health (IMCH), Uppsala University, Uppsala, Sweden
- Department of Paediatrics, Länssjukhuset Gävle-Sandviken, Gävle, Sweden
- Department of Child Health, Aga Khan University, Karachi, Pakistan
| | - Mikael Bjursell
- Late-stage Development, Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
| | - Philip Ambery
- Late-stage Development, Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
| | - Anders Berggren
- Late-stage Development, Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
| | - Ulrika Mattsson
- Late-stage Development, Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden
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Griffin M, Kwok CS, Qureshi AI, Lip GYH. The latest therapeutic advances with spontaneous intracerebral hemorrhage. Expert Rev Neurother 2025:1-13. [PMID: 40323128 DOI: 10.1080/14737175.2025.2502048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 05/01/2025] [Indexed: 05/08/2025]
Abstract
INTRODUCTION Intracerebral hemorrhage (ICH) accounts for 10% of strokes; however, compared with ischemic stroke, progress leading to novel treatments and improved patient outcomes has been lacking. Recently, there have been several promising developments and renewed research interest within the field. Positive results from randomized controlled trials have now been reported in multiple domains of care for patients with ICH. Anticoagulation-associated ICH is increasingly frequent, and clinicians deciding on reversal and timing of re-initiation of oral anticoagulation now have more therapeutic agents available and evidence to guide them. Minimally invasive techniques are also added to the neurosurgical arsenal, leading to improvements in functional outcomes. Acute treatment at presentation is best served by bundled care approaches, which ensure goal-directed management of blood pressure, glucose and temperature. AREAS COVERED This narrative review summarizes the recent developments in this area, as well as the current recommendations of key international guidelines. Literature search was carried out using PubMed database with priority given to publications since 2020. EXPERT OPINION There is renewed optimism for innovation in ICH. The standard of care for this condition now leads to improvements in mortality and long-term functional ability. Efforts to improve the patient selection and surgical techniques for operative management are ongoing.
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Affiliation(s)
- Michael Griffin
- Department of Cardiology, Mid Cheshire Hospitals NHS Foundation Trust, Crewe, UK
| | - Chun Shing Kwok
- Department of Cardiology, Mid Cheshire Hospitals NHS Foundation Trust, Crewe, UK
| | - Adnan I Qureshi
- Zeenat Qureshi Stroke Institute, St. Cloud, MN, USA
- Department of Neurology, University of Missouri, Columbia, MO, USA
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK
- Faculty of Health, Liverpool John Moores University, Liverpool, UK
- Department of Cardiology, Liverpool Heart & Chest Hospital, Liverpool, UK
- Danish Centre for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Cardiology, Lipidology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
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5
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Selph L, Allison TA, Samuel S. Blood pressure management in the first 24 hours for intracerebral hemorrhage patients on oral anticoagulant therapy. Curr Med Res Opin 2025:1-8. [PMID: 40257438 DOI: 10.1080/03007995.2025.2495853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/22/2025]
Abstract
OBJECTIVE To investigate the differences in blood pressure (BP) management and outcomes between intracerebral hemorrhage (ICH) patients on oral anticoagulant (OAC) therapy compared to those not on OAC therapy within the first 24 h of hospital admission. METHODS This retrospective cohort study included 165 ICH patients admitted to a comprehensive stroke center between July 1, 2014 and June 30, 2021. Patients were divided into two groups: those on OAC therapy (n = 55) and those not on OAC therapy (n = 110). BP measurements, including systolic BP (SBP) within 24 h of post-admission, were recorded. Clinical outcomes, such as mortality, modified Rankin Scale (mRS) scores, and length of hospital stay, were assessed. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to evaluate the impact of BP management on patient outcomes. RESULTS No significant differences in overall survival were observed between the OAC and non-OAC groups. Although the mean SBP at 24 h was slightly higher in the OAC group (142 mmHg) compared to the non-OAC group (136 mmHg; p = 0.032), this did not translate into differences in mortality or functional outcomes. Higher ICH scores were associated with increased mortality risk (HR 2.01, 95% CI 1.29-3.12, p = 0.002). Higher GCS scores were associated with better functional outcomes (HR 0.92, 95% CI 0.85-0.99, p = 0.035), while BP management strategies did not show a significant impact. CONCLUSION BP management in the first 24 h for ICH patients on OAC may not significantly affect mortality or functional outcomes. Current BP management strategies may be applicable to both OAC and non-OAC patients, though further research is needed to explore tailored approaches.
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Affiliation(s)
- Lindsey Selph
- Department of Pharmacy, Memorial Hermann-Texas Medical Center, Houston, TX, USA
| | - Teresa A Allison
- Department of Pharmacy, Memorial Hermann-Texas Medical Center, Houston, TX, USA
| | - Sophie Samuel
- Department of Pharmacy, Memorial Hermann-Texas Medical Center, Houston, TX, USA
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Mishima Y, Townsend G, Clifton SC, Butt AL, Vandyck KB, Stewart KE, Boylan PM, Tanaka KA. Andexanet-induced heparin resistance in cardiac surgery-a rapid review of case reports and series. J Thromb Haemost 2025; 23:1522-1530. [PMID: 39920998 DOI: 10.1016/j.jtha.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/16/2024] [Accepted: 01/27/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Andexanet alfa, a Food and Drug Administration (FDA)-approved antidote for apixaban and rivaroxaban, is used to manage life-threatening or uncontrolled bleeding. In patients undergoing cardiopulmonary bypass (CPB), preoperative exposure to andexanet can cause severe heparin resistance, necessitating effective mitigation strategies. A comprehensive review of such strategies remains lacking. OBJECTIVES This study aimed to systematically review and characterize cases of andexanet-induced heparin resistance in patients undergoing CPB and to evaluate management strategies. METHODS A systematic search was conducted across multiple databases via the Ovid interface, Cochrane Central Register of Controlled Trials, and the FDA Adverse Event Reporting System. Quality appraisal was performed using a validated instrument for case reports and series describing drug-induced adverse events. RESULTS Fourteen discrete patient cases met inclusion criteria. After andexanet administration, the mean initial activated clotting time (ACT) was 199.5 seconds, falling short of a target of ≥400 seconds despite additional heparin dosing (mean total, 1123 U/kg). Moreover, 35.7% of all cases involved thrombus formation in the reservoir, 2 of which required a circuit replacement. Antithrombin (AT) concentrate was administered to 75% of those received an adjunct therapy. A prophylactic AT use (mean, 49.9 IU/kg) resulted in an ACT over 400 seconds, while its effects in low dose after the occurrence of thrombosis varied on ACT values. Nafamostat mesylate was used in some cases reported from Japan. CONCLUSION Heparin resistance following andexanet exposure poses significant procoagulant risk during CPB. Pre-emptive high-dose AT therapy may improve ACT values. Further studies are needed to understand the mechanisms and optimize management of this condition.
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Affiliation(s)
- Yuko Mishima
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Grace Townsend
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Shari C Clifton
- Reference and Instructional Services, Robert M. Bird Health Sciences Library, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Amir L Butt
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Kofi B Vandyck
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Kenneth E Stewart
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Paul M Boylan
- College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Kenichi A Tanaka
- Department of Anesthesiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
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Maegele M, Ntalouka M. Con: The Patient With Recent Intake of Direct Oral Anticoagulants-Problems Are Not Solved With the Approval of Reversal Agents. J Cardiothorac Vasc Anesth 2025; 39:1348-1351. [PMID: 39952835 DOI: 10.1053/j.jvca.2025.01.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/13/2025] [Accepted: 01/22/2025] [Indexed: 02/17/2025]
Affiliation(s)
- Marc Maegele
- Department of Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), University Witten/Herdecke (UW/H), Campus Cologne-Merheim, Cologne, Germany; Institute for Research in Operative Medicine (IFOM), University Witten/Herdecke (UW/H), Campus Cologne-Merheim, Cologne, Germany.
| | - Maria Ntalouka
- Department of Anesthesiology, Larissa University Hospital, University of Thessaly School of Health Sciences, Thessaly, Greece
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Arnaoutoglou E, Ntalouka MP. Pro: The Patient With the Recent Intake of DOACs Problems Are Solved With the Approval of Reversal Agents. J Cardiothorac Vasc Anesth 2025; 39:1345-1347. [PMID: 39984366 DOI: 10.1053/j.jvca.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/20/2025] [Accepted: 02/02/2025] [Indexed: 02/23/2025]
Affiliation(s)
- Eleni Arnaoutoglou
- Department of Anaesthesiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa University Hospital, Thessaly, Greece.
| | - Maria P Ntalouka
- Department of Anaesthesiology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa University Hospital, Thessaly, Greece
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Gikandi A, Connors JM, Nabzdyk CG, Zenati MA. Perioperative risks associated with administration of andexanet alfa during emergency cardiac surgery with circulatory arrest. Perfusion 2025; 40:1045-1048. [PMID: 39052758 DOI: 10.1177/02676591241268395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
This case report describes the perioperative course of a patient undergoing emergency repair of acute type A thoracic aortic dissection. Andexanet alfa was administered intraoperatively to obtain a dry operative field for right axillary artery exposure and cannulation. Andexanet alfa-induced heparin resistance resulted in cardiopulmonary bypass circuit and pericardial thrombosis requiring more than 400,000 units of unfractionated heparin and antithrombin III to overcome. Postoperatively, excessive chest tube output was observed secondary to protracted heparin rebound requiring continuous dosing of protamine. This case demonstrates the significant challenging perioperative, not just intraoperative, hazards associated with intraoperative andexanet alfa use during emergency cardiac surgery with cardiopulmonary bypass.
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Affiliation(s)
- Ajami Gikandi
- Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jean M Connors
- Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Christoph G Nabzdyk
- Division of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Marco A Zenati
- Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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10
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Eikelboom JW, Sharma M, Xu L, Bamberg K, Beyer-Westendorf J, Falkenberg C, Ladenvall P, Narayan R, Penland RC, Verhamme P, Shoamanesh A. Association of Biomarkers With Intracerebral Hematoma Expansion and Arterial Thromboembolic Events in Patients With Acute Intracranial Hemorrhage: The ANNEXA-I Biomarker Substudy. Stroke 2025. [PMID: 40289797 DOI: 10.1161/strokeaha.124.049966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 03/12/2025] [Accepted: 04/04/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors) was a randomized trial that demonstrated that andexanet compared with usual care in patients with intracranial hemorrhage associated with FXa (factor Xa) inhibitor treatment reduces the risk of hematoma expansion and increases the risk of arterial thromboembolic events. METHODS In a secondary analysis of the ANNEXA-I trial, we compared the effects of andexanet with usual care on change in anti-FXa activity and endogenous thrombin potential (ETP) using Wilcoxon rank-sum test. We examined the associations between 1-hour reduction in anti-FXa and 1-hour increase in ETP and hematoma expansion at 12 hours (≥12.5 mL or percentage volume change ≥35%) using logistic regression, both unadjusted and adjusted for time from symptom onset to baseline scan, baseline diastolic blood pressure, hematoma volume, baseline biomarker level and time from baseline scan to treatment, and association with arterial thromboembolic events (ischemic stroke, myocardial infarction, and systemic embolism) during 30 days of follow-up using Cox regression, both unadjusted and adjusted for age, baseline biomarker level, prior MI, and eligibility for treatment with high-dose andexanet. RESULTS ANNEXA-I enrolled 530 patients. Among 438 patients with baseline anti-FXa results, andexanet compared with usual care reduced anti-FXa activity at 1 hour (median, 8.6 versus 97.5 ng/mL; median reduction from baseline, 98.3 versus 10.9 ng/mL; P<0.001). Among 328 patients with baseline ETP data, andexanet compared with usual care increased ETP at 1 hour (median, 1573.5 versus 874.5 nmol/L-min; median increase, 753.1 versus 126.6 nmol/L-min; P<0.001). In adjusted analyses, reduction in anti-FXa at 1 hour was associated with reduced hematoma expansion (per 100 ng/mL: odds ratio, 0.69 [95% CI, 0.53-0.92]; P=0.010), and increase in ETP at 1 hour was associated with reduced hematoma expansion (per 100 nmol/L-min: odds ratio, 0.94 [95% CI, 0.90-0.99]; P=0.019) and risk of thromboembolic events (per 100 nmol/L-min: odds ratio, 1.08 [95% CI, 1.00-1.16]; P=0.047). CONCLUSIONS In patients with apixaban- or rivaroxaban-associated intracranial hemorrhage, andexanet compared with usual care produces greater reduction in anti-FXa and greater increase in ETP at 1 hour. Reduction in anti-FXa from baseline to 1 hour is independently associated with reduced hematoma expansion, and increase in ETP from baseline to 1 hour is independently associated with both reduced hematoma expansion and increase of thromboembolic events. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661528.
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Affiliation(s)
- John W Eikelboom
- Population Health Research Institute, Hamilton Health Sciences and McMaster University (J.W.E., M.S., L.X., A.S.)
| | - Mukul Sharma
- Population Health Research Institute, Hamilton Health Sciences and McMaster University (J.W.E., M.S., L.X., A.S.)
| | - Lizhen Xu
- Population Health Research Institute, Hamilton Health Sciences and McMaster University (J.W.E., M.S., L.X., A.S.)
| | - Krister Bamberg
- AstraZeneca BioPharmaceuticals R&D (K.B., C.F., P.L., R.N., R.C.P.)
| | - Jan Beyer-Westendorf
- Division Thrombosis and Hemostasis, Department of Medicine I, Dresden University Hospital "Carl Gustav Carus," Technical University Dresden, Germany (J.B.-W.)
| | | | - Per Ladenvall
- AstraZeneca BioPharmaceuticals R&D (K.B., C.F., P.L., R.N., R.C.P.)
| | - Rohit Narayan
- AstraZeneca BioPharmaceuticals R&D (K.B., C.F., P.L., R.N., R.C.P.)
| | - Robert C Penland
- AstraZeneca BioPharmaceuticals R&D (K.B., C.F., P.L., R.N., R.C.P.)
| | - Peter Verhamme
- KU Leuven Department of Cardiovascular Sciences, Belgium (P.V.)
| | - Ashkan Shoamanesh
- Population Health Research Institute, Hamilton Health Sciences and McMaster University (J.W.E., M.S., L.X., A.S.)
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11
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Martyak M, Soult A, Britt LD. Diagnosis and management of gastrointestinal hemorrhage: What you need to know. J Trauma Acute Care Surg 2025:01586154-990000000-00961. [PMID: 40205645 DOI: 10.1097/ta.0000000000004599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
ABSTRACT Acute gastrointestinal (GI) hemorrhage is a common cause for hospital admission that requires prompt diagnosis and multidisciplinary management to optimize clinical outcomes. Acute gastrointestinal bleeding (GIB) includes both upper and lower GI tract sources with an extensive list of differential pathologies. This review provides a systematic approach to both upper and lower GIB management, emphasizing initial resuscitation, stabilization, diagnostic evaluation to identify the source, and treatment modalities. Endoscopy remains the cornerstone for diagnostic and interventional purposes, significantly reducing the need for surgical procedures. However, lower GIB and severe or refractory cases may necessitate additional imaging and interventions, including surgical management. Integrating clinical guidelines, evidence-based strategies, and individualized care, this review delineates what you need to know to diagnose and manage acute GI hemorrhage. LEVEL OF EVIDENCE Therapeutic/Care Management; Level III.
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Affiliation(s)
- Michael Martyak
- From the Surgery Department, Eastern Virginia Medical School, Old Dominion University, Norfolk, Virginia
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12
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Crescioli G, Lombardi N, Arzenton E, Luxi N, Fumagalli S, Bonaiuti R, Cacini C, Mannaioni G, Trifirò G, Moretti U, Vannacci A. Safety of direct oral anticoagulants reversal agents in older patients: an analysis of individual case safety reports of adverse drug reaction from VigiBase ®. Aging Clin Exp Res 2025; 37:120. [PMID: 40192996 PMCID: PMC11976745 DOI: 10.1007/s40520-025-03025-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 03/23/2025] [Indexed: 04/10/2025]
Abstract
BACKGROUND Real-world data on adverse drug reactions (ADRs) associated with idarucizumab and andexanet alfa are limited. AIM This study aimed to assess the frequency, the characteristics and clinical and demographic factors associated with ADRs related to their use. METHODS This is a retrospective analysis of ADR reports collected in Vigibase® until May 31, 2023. Multivariable logistic regression estimated reporting odds ratios (RORs) for serious ADRs, death, and thromboembolic events according to demographical and clinical covariates. RESULTS A total of 1095 Individual Case Safety Reports (ICSRs) reporting idarucizumab (72%) or andexanet alfa (28%) as suspected/interacting agents were collected. Most of the subjects were males (44.5%), with a median age of 78 years, and exposed to only one suspected/interacting medication (73.6%). ADRs were defined as serious in 88.6% of cases, with a total of 614 (56.1%) fatal cases. Compared to patients without concomitant medications, probability of serious ADRs and death were both higher in those receiving ≥ 5 concomitant medications in the idarucizumab subgroup (ROR 4.04 and 1.66, respectively) and in those receiving 1-4 concomitant medications in the andexanet alfa subgroup (ROR 5.66 and 4.80, respectively). Moreover, the probability of thromboembolic events was significantly lower for subjects aged > 75 years (ROR for 75-84 years 0.55; ROR for ≥ 85 years 0.50). DISCUSSION In real-world, ADRs associated with idarucizumab and andexanet alfa use are generally serious, resulting in death in a high percentage of subjects. CONCLUSION Clinicians should pay particular attention when managing individuals needing these drugs, especially if vulnerable and requiring polytherapy.
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Affiliation(s)
- Giada Crescioli
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy.
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy.
| | - Niccolò Lombardi
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy
| | - Elena Arzenton
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Nicoletta Luxi
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Stefano Fumagalli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Roberto Bonaiuti
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy
| | - Costanza Cacini
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy
| | - Guido Mannaioni
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Toxicology Unit, Poison Control Center, Careggi University Hospital, Florence, Italy
| | - Gianluca Trifirò
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Ugo Moretti
- Section of Pharmacology, Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Alfredo Vannacci
- Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy
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13
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Seiffge D, Polymeris A, Pfeilschifter W, Apostolaki-Hansson T, Ip B, Kristoffersen ES, Kuramatsu JB, Siepen BM. Reversal of anticoagulation in patients with intracerebral haemorrhage related to oral anticoagulants: State of the evidence. Eur Stroke J 2025; 10:14-23. [PMID: 40401655 DOI: 10.1177/23969873241281477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
PURPOSE About 20%-25% of all intracerebral haemorrhages are associated with oral anticoagulation therapy. Reflecting changings prescription patterns in the general population, the spectrum of oral anticoagulation-associated intracerebral haemorrhage has substantially changed in the last decade. In many European countries, direct oral anticoagulant-associated intracerebral haemorrhage is now more frequent than vitamin K antagonist-associated intracerebral haemorrhage. Outcome in patients with anticoagulation-associated intracerebral haemorrhage is poor, likely mediated by a high incidence of haematoma expansion. Reversal of anticoagulation is an essential part of current care pathways for hyperacute treatment of intracerebral haemorrhage aiming to limit haematoma expansion and thereby improving outcome. METHODS In this review, we summarise the latest evidence regarding reversal therapy for vitamin K antagonist-, direct thrombin inhibitor- and factor Xa inhibitor-associated intracerebral haemorrhage. FINDINGS Two randomised controlled trials have shown that the use of prothrombin complex concentrate (compared to fresh frozen plasma) for reversing vitamin K antagonist-associated intracerebral haemorrhage and andexanet alfa (compared to usual care, mainly prothrombin complex concentrate) for factor Xa inhibitor-associated intracerebral haemorrhage had superior haemostatic efficacy. However, the incidence of thromboembolic complications was high in both trials. For reversal of Vitamin K antagonist-associated intracerebral haemorrhage, the overall rate was 18% but due to crossovers, it is impossible to determine the rate for any specific treatment. For factor-Xa inhibitor associated intracerebral haemorrhage, andexanet alfa led to an increase in the incidence of thromboembolic events. Moreover, these two randomised controlled trials were not powered to detect differences in mortality or functional outcomes and lacked long-term follow-up. Idarucizumab has shown promising results in a single-arm case series of patients with intracerebral haemorrhage associated with the direct thrombin inhibitor dabigatran, yet no randomised controlled trial is available to support these findings. CONCLUSION Given that haematoma expansion is strongly associated with poor outcome, current evidence underlines the importance of rapid, targeted and effective reversal of anticoagulation in patients with anticoagulation-associated intracerebral haemorrhage. While haematoma expansion is a key prognostic factor, no randomised controlled trial has demonstrated a clear improvement in functional outcome. Future research should weigh the advantages of preventing haematoma expansion against the risks of increased thromboembolic events, and aim to identify the patients who would derive the most benefit from reversal treatments.
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Affiliation(s)
- David Seiffge
- Department of Neurology, Inselspital University Hospital and University of Bern, Bern, Switzerland
| | - Alexandros Polymeris
- Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Waltraud Pfeilschifter
- Department of Neurology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
- Department of Neurology and Clinical Neurophysiology, Städtisches Klinikum Lüneburg, Lüneburg, Germany
| | | | - Bonaventure Ip
- Department of Medicine and Therapeutics, Faculty of Medicine, The Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR
- Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR
| | - Espen Saxhaug Kristoffersen
- Department of Neurology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway
- Department of General Practice, University of Oslo, Oslo, Norway
| | - Joji B Kuramatsu
- Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Bernhard M Siepen
- Department of Neurology, Inselspital University Hospital and University of Bern, Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, Bern, Switzerland
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14
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Sarhan K, Mohamed RG, Elmahdi RR, Mohsen Y, Elsayed A, Zayed DM, Elkholi MA, Gabr N, El-Bialy EM, Serag I. Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Neurocrit Care 2025; 42:701-714. [PMID: 39379749 PMCID: PMC11950062 DOI: 10.1007/s12028-024-02130-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 09/06/2024] [Indexed: 10/10/2024]
Abstract
Factor Xa inhibitors (FXaI) are increasingly used for anticoagulation therapy, yet their association with intracranial hemorrhage poses a significant challenge. Although andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) have shown promise in reversing FXaI effects, their comparative efficacy and safety remain uncertain. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a literature search on electronic databases to obtain the relevant studies until May 16, 2024. Our primary outcomes were successful anticoagulation reversal, overall mortality (including 30-day and in-hospital mortality), and thromboembolic events. Secondary outcomes were length of hospital and intensive care unit stay and hematoma volume expansion. Data were pooled using a random-effects model. We included 16 eligible studies with a total of 2,977 patients. A statistically significant improvement in hemostatic efficacy rates was in favor of the AA group (risk ratio [RR] 1.10, 95% confidence interval [CI] 1.01-1.20, P = 0.02). Lower overall mortality rates were found in the AA group (RR 0.67, 95% CI 0.51-0.88, P = 0.004). However, no difference was found in 30-day mortality rates (RR 0.82, 95% CI 0.58-1.16, P = 0.26). In terms of thromboembolic events, more events were found in the AA group (RR 1.47, 95% CI 1.01-2.15, P = 0.046). AA was associated with a longer duration of hospital stay compared to 4F-PCC (mean difference [MD] 0.64, 95% CI 0.07-1.22, P = 0.03). Neither a significant difference in length of intensive care unit stay (MD 0.25, 95% CI - 0.36 to 0.86, P = 0.41) nor a significant difference in hematoma volume expansion was reported (MD - 0.89, 95% CI - 3.11 to 1.34, P = 0.435). Our results suggest that AA is superior to 4F-PCC in enhancing the hemostatic efficacy and reducing the overall and in-hospital mortality rates. More thromboembolic events are thought to be associated with the use of AA. However, more studies are required to validate whether the better results of AA in improving hemostatic efficacy are enough to make up for their higher cost and their possible risk of thromboembolic events.
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Affiliation(s)
- Khalid Sarhan
- Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Rashad G Mohamed
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Reem Reda Elmahdi
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Youstina Mohsen
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Asmaa Elsayed
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Dania Mosaad Zayed
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Menna A Elkholi
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nagat Gabr
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Enjy M El-Bialy
- Mansoura Manchester Program for Medical Education, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ibrahim Serag
- Faculty of Medicine, Mansoura University, Mansoura, Egypt
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15
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Mehrara S, Patel R, DeRon N. Andexanet alfa for reversal of intracerebral haemorrhage resulting in ST-segment myocardial infarction: a case report. Eur Heart J Case Rep 2025; 9:ytaf136. [PMID: 40201406 PMCID: PMC11975805 DOI: 10.1093/ehjcr/ytaf136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/16/2025] [Accepted: 03/19/2025] [Indexed: 04/10/2025]
Abstract
Background Direct oral anticoagulants, such as direct factor Xa inhibitors, are commonly used to treat and prevent blood clots in patients with atrial fibrillation. Andexanet alfa reverses direct factor Xa inhibitors to help treat various thromboembolic conditions. Although it efficiently reverses anticoagulation by preventing life-threatening bleeding events, the use of andexanet alfa in today's clinical practice is limited due to the risk of thromboembolism and cost. Case summary A 76-year-old male presented with atrial fibrillation with rapid ventricular response and was started on Eliquis after a successful direct current cardioversion. Subsequently, the patient developed intracerebral haemorrhage, which required the administration of andexanet alfa. Ultimately, the patient suffered an ST-segment elevation myocardial infarction from complete occlusion of the mid-left anterior descending artery. His hospital course was complicated by acute hypoxic respiratory failure, septic shock, and renal failure. The family elected for comfort care measures and the patient expired shortly after. Discussion This case emphasizes the need for individualized clinical assessment and collaboration with an interdisciplinary team regarding the use of andexanet alfa, as well as strategies to ensure thrombotic risk is effectively minimized. Current European Society of Cardiology Guidelines do not have recommendations for the use of andexanet alfa for the reversal of anticoagulation due to its uncertain risk profile. This case emphasizes the increased risk of thrombotic complications associated with andexanet alfa and highlights the importance of the continued need to research its use, which may help elucidate or revise current guidelines.
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Affiliation(s)
- Shaheen Mehrara
- Department of Internal Medicine, Methodist Dallas Medical Center, 1441 North Beckley Avenue, Dallas, TX 75203, USA
| | - Ravi Patel
- Department of Internal Medicine, Methodist Dallas Medical Center, 1441 North Beckley Avenue, Dallas, TX 75203, USA
| | - Nathan DeRon
- Department of Internal Medicine, Methodist Dallas Medical Center, 1441 North Beckley Avenue, Dallas, TX 75203, USA
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16
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Nagesh VK, Pulipaka SP, Bhuju R, Martinez E, Badam S, Nageswaran GA, Tran HHV, Elias D, Mansour C, Musalli J, Bhattarai S, Shobana LS, Sethi T, Sethi R, Nikum N, Trivedi C, Jarri A, Westman C, Ahmed N, Philip S, Weissman S, Weinberger J, Bangolo AI. Management of gastrointestinal bleed in the intensive care setting, an updated literature review. World J Crit Care Med 2025; 14:101639. [DOI: 10.5492/wjccm.v14.i1.101639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 11/08/2024] [Accepted: 12/02/2024] [Indexed: 12/11/2024] Open
Abstract
Gastrointestinal (GI) bleeding is a critical and potentially life-threatening condition frequently observed in the intensive care unit (ICU). This literature review consolidates current insights on the epidemiology, etiology, management, and outcomes of GI bleeding in critically ill patients. GI bleeding remains a significant concern, especially among patients with underlying risk factors such as coagulopathy, mechanical ventilation, and renal failure. Managing GI bleeding in the ICU requires a multidisciplinary approach, including resuscitation, endoscopic intervention, pharmacologic therapy, and sometimes surgical procedures. Even with enhanced management strategies, GI bleeding in the ICU is associated with considerable morbidity and mortality, particularly when complicated by multi-organ failure. This review reiterates the need for adequate resuscitation and interventions in managing GI bleeding in critically ill patients, aiming to enhance survival rates and improve the quality of care within the ICU setting.
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Affiliation(s)
- Vignesh K Nagesh
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Sai Priyanka Pulipaka
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Ruchi Bhuju
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Emelyn Martinez
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shruthi Badam
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Gomathy Aarthy Nageswaran
- Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Hadrian Hoang-Vu Tran
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Daniel Elias
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Charlene Mansour
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Jaber Musalli
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Sanket Bhattarai
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Lokeash Subramani Shobana
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Tannishtha Sethi
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Ritvik Sethi
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Namrata Nikum
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Chinmay Trivedi
- Department of Gastroenterology, Hackensack University Medical Center, Hackensack, NJ 07061, United States
| | - Amer Jarri
- Department of Pulmonology and Critical Care, HCA Florida Bayonet Point Hospital, Hudson, FL 34667, United States
| | - Colin Westman
- Department of Gastroenterology, Hackensack University Medical Center, Hackensack, NJ 07061, United States
| | - Nazir Ahmed
- Department of Gastroenterology, Hackensack University Medical Center, Hackensack, NJ 07061, United States
| | - Shawn Philip
- Department of Gastroenterology, Hackensack University Medical Center, Hackensack, NJ 07061, United States
| | - Simcha Weissman
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Jonathan Weinberger
- Department of Gastroenterology, Hackensack University Medical Center, Hackensack, NJ 07061, United States
| | - Ayrton I Bangolo
- Department of Hematology & Oncology, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601, United States
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17
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Alhabeeb W, Tash A, Aljedai A, Morsy A, Khaliel F, Alhazmi I, AlSheef M, Arafah M, Alshammeri O, AlAhmari S. A Saudi Heart Association Position Statement on the use of DOACs in Patients With Arterial and Venous Thrombosis. J Saudi Heart Assoc 2025; 37:2. [PMID: 40134412 PMCID: PMC11932698 DOI: 10.37616/2212-5043.1423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 03/27/2025] Open
Abstract
Background Direct oral anticoagulants (DOACs) have emerged as non-inferior and effective alternatives to traditional anticoagulants in managing thromboembolic risks associated with various cardiovascular conditions. This position statement by the Saudi Heart Association (SHA) aims to provide guidance on the use of DOACs in the context of cardiovascular disease, particularly patients with arterial and venous thrombosis. Methods A multidisciplinary panel of experts reviewed current evidence and international guidelines on DOACs, considering the local healthcare context in Saudi Arabia. The statement addresses the initiation, maintenance, interruption, and re-initiation of DOAC therapy across different patient populations. Results DOACs are effective alternatives to traditional anticoagulants with a comparable or lower risk of bleeding and no requirement for frequent monitoring, making them more convenient for patients. It is important to regularly assess stroke risk (CHA2DS2-VASc score) and bleeding risk (HAS-BLED score) before initiating DOAC therapy and during the course of treatment, particularly in patients with changing clinical conditions. Specific factors warrant careful consideration for the use of DOACs in special patient populations. Recommendations are therefore provided for dosing adjustments in renal and hepatic impairment, alongside considerations for patients in different clinical scenarios such as those undergoing surgery or with malignancies. Conclusion DOACs represent a valuable option for clinicians owing to their efficacy, safety and convenience compared to traditional anticoagulants. DOACs should be used based on individualized patient assessment, particularly regarding bleeding risk, stroke risk, and other comorbidities and clinical factors that may affect clinical outcomes. Adherence to the recommendations and guidance provided in this SHA statement is needed to enhance patient care and outcomes in Saudi Arabia.
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Affiliation(s)
- Waleed Alhabeeb
- Department of Cardiac Sciences, King Saud University, Riyadh,
Saudi Arabia
| | - Adel Tash
- National Heart Center, Saudi Health Council, Riyadh,
Saudi Arabia
| | - Ahmed Aljedai
- Department of Therapeutic Affairs, Ministry of Health, Riyadh,
Saudi Arabia
- Colleges of Medicine and Pharmacy, Alfaisal University, Riyadh,
Saudi Arabia
| | - Ayman Morsy
- Department of Cardiology, Ministry of Health, Al Noor Specialist Hospital, Makkah,
Saudi Arabia
| | - Feras Khaliel
- Department of Cardiac Surgery, King Faisal Specialist Hospital and Research Center, Riyadh,
Saudi Arabia
| | - Iman Alhazmi
- Department of Medicine, King Fahad Armed Forces Hospital, Jeddah,
Saudi Arabia
| | - Mohammed AlSheef
- Department of Medical Specialties, King Fahad Medical City, Riyadh,
Saudi Arabia
| | - Mohammed Arafah
- Department of Cardiac Sciences, King Saud University, Riyadh,
Saudi Arabia
| | - Owayed Alshammeri
- Department of Cardiology, Dr. Sulaiman Alhabib Hospital, Riyadh,
Saudi Arabia
| | - Saeed AlAhmari
- Department of Adult Cardiology, Prince Sultan Cardiac Center, Riyadh,
Saudi Arabia
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18
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Salter B, Moffat K, Carlino S, Dobson-Storr J, Beckett L, Broomhead E, Onelöv L, Ge S, Atalla M, Melika R, Bansal S, Kitchen S, Crowther M, Mithoowani S. Evaluation of the MRX PT DOAC assay for detection of clinically relevant factor Xa inhibitor drug levels. J Thromb Haemost 2025; 23:989-996. [PMID: 39675568 DOI: 10.1016/j.jtha.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 11/19/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Although routine monitoring is not needed for direct oral anticoagulants (DOACs), knowing if a clinically relevant DOAC level is present can be critical, especially in cases of severe bleeding or urgent surgery. Rapid assays to exclude these levels are necessary but not widely available. OBJECTIVES To determine the test performance of MRX PT DOAC for excluding clinically relevant DOAC drug levels. METHODS The MRX PT DOAC (Nordic Biomarker, Umeå, Sweden) assay measures the functional effect of DOACs using the clot-time ratio, a ratio between DOAC-sensitive prothrombin time (PT) and DOAC-insensitive PT. We conducted a multicenter retrospective study of 152 samples from 151 patients with known DOAC levels to assess whether the MRX PT DOAC assay could exclude clinically relevant drug levels >50 ng/mL and whether test performance differed across coagulation analyzers. To assess generalizability, the assay was run on 4 coagulation analyzers: Werfen ACLTOP 750, Diagnostica Stago STACompact MAX, Sysmex CS2500, and Sysmex CN-6000. RESULTS The MRX PT DOAC assay had a sensitivity of 100% with a CI of 70% to 100% and negative predictive value (NPV) of 100% (CI: 57%-100%) for edoxaban drug levels >50 ng/mL. For rivaroxaban, sensitivity was 100% (CI: 61%-100%) and NPV was 100% (CI: 5%-100%). For apixaban, sensitivity ranged from 59% to 83% (CI: 41%-93%) and NPV ranged from 0% to 50% (CI: 0%-69%). The specificity of the assay ranged from 61% to 86% (CI: 36%-97%) for apixaban, 36% to 50% (CI: 2%-97%) for edoxaban, and 75% to 100% (CI: 5%-100%) for rivaroxaban. CONCLUSION The MRX PT DOAC assay reliably excludes clinically relevant levels of edoxaban and rivaroxaban, but not apixaban, across multiple analyzers.
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Affiliation(s)
- Brittany Salter
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
| | - Karen Moffat
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
| | - Stephen Carlino
- Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
| | | | - Lee Beckett
- Coagulation Department, Northern General Hospital, Sheffield, UK
| | - Emma Broomhead
- Coagulation Department, Northern General Hospital, Sheffield, UK
| | | | - Sarah Ge
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Marina Atalla
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Raymond Melika
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Saumya Bansal
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Steven Kitchen
- Coagulation Department, Northern General Hospital, Sheffield, UK
| | - Mark Crowther
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Siraj Mithoowani
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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19
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Bekka E, Liakoni E. Anticoagulation reversal (vitamin K, prothrombin complex concentrates, idarucizumab, andexanet-α, protamine). Br J Clin Pharmacol 2025; 91:604-614. [PMID: 38926082 PMCID: PMC11862798 DOI: 10.1111/bcp.16142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/04/2024] [Accepted: 05/31/2024] [Indexed: 06/28/2024] Open
Abstract
Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K-dependent factors. In cases of life-threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non-specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet-α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant-specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet-α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life-threatening bleeding.
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Affiliation(s)
- Elias Bekka
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
| | - Evangelia Liakoni
- Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
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20
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Tallroth M, Östlundh L, Büki A, Cao Y, von Euler M, Ström JO. Reversal treatment and clinical outcomes in acute intracranial haemorrhage associated with oral anticoagulant use: protocol of a planned systematic review and meta-analysis. BMJ Open 2025; 15:e090357. [PMID: 39965957 PMCID: PMC11836858 DOI: 10.1136/bmjopen-2024-090357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 01/31/2025] [Indexed: 02/20/2025] Open
Abstract
INTRODUCTION Reversal treatment is commonly used for managing oral anticoagulant (OAC)-associated intracranial haemorrhages. Its effects on mortality are still understudied, particularly in various subtypes of intracranial haemorrhages. This systematic review and meta-analysis aims to synthesise the available data to study the impact of reversal therapies on mortality following various OAC-associated acute intracranial haemorrhages. METHODS AND ANALYSIS This protocol follows the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Protocols, and the final review will be reported in accordance with the PRISMA reporting guidelines. This systematic review and meta-analysis will include studies that assess contemporary reversal treatment in comparison to no reversal treatment, in cases of OAC-associated intracranial haemorrhage. Stratification will be performed for the types of bleeding as well as OAC at bleeding onset. Preliminary searches to determine search term inclusions were conducted in May-August 2024 in the electronic databases Embase, PubMed, Scopus and Web of Science without language and publication date restrictions. Randomised controlled studies, non-randomised controlled trials, and observational studies will be considered for the final meta-analysis. Three reviewers (MT, JOS and AB) will screen titles and abstracts, and one reviewer (MT) will subsequently conduct full-text screening.Risks of bias will be assessed by MT using tools such as Risk of Bias 2, Risk Of Bias In Non-randomised Studies - of Interventions and the Newcastle-Ottawa Scale. Heterogeneity among the study results will be assessed using the I² statistic. If appropriate, a random-effects meta-analysis model will be performed. Subgroup analyses and meta-regression (if applicable) will be performed to assess sources of heterogeneity among (1) intracranial haemorrhage types, (2) OAC drugs and (3) study types, with randomised controlled trials being the primary focus. ETHICS AND DISSEMINATION Ethical approval is not needed as this project involves previously published data. We intend to publish the results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER CRD42024556420.
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Affiliation(s)
- Mattias Tallroth
- School of Medical Sciences, Örebro University Faculty of Medicine and Health, Örebro, Sweden
| | | | - András Büki
- Department of Neurosurgery, Örebro University Faculty of Medicine and Health, Örebro, Sweden
| | - Yang Cao
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Unit of Integrative Epidemiology, Institute of Enviromental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Mia von Euler
- Department of Neurology and Rehabilitation, Örebro University Faculty of Medicine and Health, Örebro, Sweden
| | - Jakob O Ström
- Department of Neurology and Rehabilitation, Örebro University Faculty of Medicine and Health, Örebro, Sweden
- Department of General Medicine, Whangarei Hospital, Whangarei, New Zealand
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21
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Fujiwara G, Okada Y, Suehiro E, Yatsushige H, Hirota S, Hasegawa S, Karibe H, Miyata A, Kawakita K, Haji K, Aihara H, Yokobori S, Inaji M, Maeda T, Onuki T, Oshio K, Komoribayashi N, Suzuki M, Shiomi N. Development of Machine-learning Model to Predict Anticoagulant Use and Type in Geriatric Traumatic Brain Injury Using Coagulation Parameters. Neurol Med Chir (Tokyo) 2025; 65:61-70. [PMID: 39721668 PMCID: PMC11891141 DOI: 10.2176/jns-nmc.2024-0066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 10/03/2024] [Indexed: 12/28/2024] Open
Abstract
This study aimed to investigate the patterns of anticoagulation therapy and coagulation parameters and to develop a prediction model to predict the type of anticoagulation therapy in geriatric patients with traumatic brain injury. A retrospective analysis was performed using the nationwide neurotrauma database of Japan. Elderly patients (≥65 years) with traumatic brain injury. Patients were divided into 3 groups based on their daily anticoagulant medication (none, direct oral anticoagulant [DOAC], and vitamin K antagonist [VKA]), and coagulation parameters were compared in each group. We then developed a machine-learning model to predict the anticoagulant using coagulation parameters and visualized the pattern using a heat map. A total of 495 patients were enrolled and divided into 3 groups: none (n = 439), DOACs (n = 37), and VKA (n = 19). Comparing none to DOAC and DOAC to VKA for prothrombin time-international normalized ratio (PT-INR), the mean difference and 95% confidence intervals (CIs) were 0.38 (95% CI: 0.59-0.17) and 1.56 (95% CI: 1.21-1.90), and for activated partial thromboplastin time (APTT), the mean difference between none to DOAC and DOAC to VKA was 3.46 (95% CI: 0.98-5.94) and 95% CI was 7.39 (95% CI: 3.29-11.48). A prediction model for the type of anticoagulant used by PT-INR and APTT was developed using machine-learning methods, and a heat map visually revealed their relationship with acceptable predictive ability. This study revealed the characteristic patterns of coagulation parameters in anticoagulants and a pilot model to predict anticoagulant use.
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Affiliation(s)
- Gaku Fujiwara
- Department of Neurosurgery, Saiseikai Shiga Hospital, Imperial Gift Foundation Inc
| | - Yohei Okada
- Department of Preventive Services, School of Public Health, Kyoto University
- Health Services and Systems Research, Duke-NUS Medical School, National University of Singapore
| | - Eiichi Suehiro
- Department of Neurosurgery, International University of Health and Welfare School of Medicine
| | - Hiroshi Yatsushige
- Department of Neurosurgery, National Hospital Organization Disaster Medical Center
| | - Shin Hirota
- Department of Neurosurgery, Tsuchiura Kyodo General Hospital
| | - Shu Hasegawa
- Department of Neurosurgery, Kumamoto Red Cross Hospital
| | | | - Akihiro Miyata
- Department of Neurosurgery, Chiba Emergency Medical Center
| | | | - Kohei Haji
- Department of Neurosurgery, Yamaguchi University School of Medicine
| | - Hideo Aihara
- Department of Neurosurgery, Hyogo Prefectural Kakogawa Medical Center
| | - Shoji Yokobori
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Nippon Medical School
| | - Motoki Inaji
- Department of Neurosurgery, Institute of Science Tokyo
| | - Takeshi Maeda
- Department of Neurological Surgery, Nihon University School of Medicine
| | - Takahiro Onuki
- Department of Emergency Medicine, Teikyo University School of Medicine
| | - Kotaro Oshio
- Department of Neurosurgery, St. Marianna University School of Medicine
| | | | - Michiyasu Suzuki
- Department of Neurosurgery, Yamaguchi University School of Medicine
| | - Naoto Shiomi
- Department of Critical and Intensive Care Medicine, Shiga University of Medical Science
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22
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Iwasaki YK, Noda T, Akao M, Fujino T, Hirano T, Inoue K, Kusano K, Nagai T, Satomi K, Shinohara T, Soejima K, Sotomi Y, Suzuki S, Yamane T, Kamakura T, Kato H, Katsume A, Kondo Y, Kuroki K, Makimoto H, Murata H, Oka T, Tanaka N, Ueda N, Yamasaki H, Yamashita S, Yasuoka R, Yodogawa K, Aonuma K, Ikeda T, Minamino T, Mitamura H, Nogami A, Okumura K, Tada H, Kurita T, Shimizu W. JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias. Circ J 2025:CJ-24-0073. [PMID: 39956587 DOI: 10.1253/circj.cj-24-0073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Affiliation(s)
- Yu-Ki Iwasaki
- Department of Cardiovascular Medicine, Nippon Medical School
| | - Takashi Noda
- Department of Cardiology, Tohoku University Hospital
| | - Masaharu Akao
- Department of Cardiology, National Hospital Organization Kyoto Medical Center
| | - Tadashi Fujino
- Department of Cardiovascular Medicine, Toho University Faculty of Medicine
| | - Teruyuki Hirano
- Department of Stroke Medicine, Kyorin University School of Medicine
| | - Koichi Inoue
- Department of Cardiology, National Hospital Organization Osaka National Hospital
| | - Kengo Kusano
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Toshiyuki Nagai
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University
| | | | - Tetsuji Shinohara
- Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University
| | - Kyoko Soejima
- Department of Cardiovascular Medicine, Kyorin University School of Medicine
| | - Yohei Sotomi
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
| | - Shinya Suzuki
- Department of Cardiovascular Medicine, The Cardiovascular Institute
| | - Teiichi Yamane
- Department of Cardiology, The Jikei University School of Medicine
| | - Tsukasa Kamakura
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Hiroyuki Kato
- Department of Cardiology, Japan Community Healthcare Organization Chukyo Hospital
| | - Arimi Katsume
- Department of Cardiovascular Medicine, Kyorin University School of Medicine
| | - Yusuke Kondo
- Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine
| | - Kenji Kuroki
- Department of Cardiology, Faculty of Medicine, University of Yamanashi
| | - Hisaki Makimoto
- Division of Cardiovascular Medicine, Department of Internal Medicine, Data Science Center, Jichi Medical University
| | | | - Takafumi Oka
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
| | - Nobuaki Tanaka
- Department of Cardiology, Cardiovascular Center, Sakurabashi Watanabe Hospital
| | - Nobuhiko Ueda
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Hiro Yamasaki
- Department of Cardiology, Institute of Medicine, University of Tsukuba
| | - Seigo Yamashita
- Department of Cardiology, The Jikei University School of Medicine
| | - Ryobun Yasuoka
- Department of Cardiology, Kindai University School of Medicine
| | - Kenji Yodogawa
- Department of Cardiology, Nippon Medical School Hospital
| | | | - Takanori Ikeda
- Department of Cardiology, Toho University Medical Center Omori Hospital
| | - Toru Minamino
- Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine
| | - Hideo Mitamura
- National Public Service Mutual Aid Federation Tachikawa Hospital
| | | | - Ken Okumura
- Department of Cardiology, Cardiovascular Center, Saiseikai Kumamoto Hospital
| | - Hiroshi Tada
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui
| | - Takashi Kurita
- Division of Cardiovascular Center, Kindai University School of Medicine
| | - Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School
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23
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Veltkamp R, Haas K, Rücker V, Malzahn U, Heeger A, Kinzler D, Müller P, Rappard P, Rizos T, Schiefer J, Opherk C, Pfeilschifter W, Althaus K, Schellinger P, Gaida B, Gabriel MM, Royl G, Nabavi DG, Haeusler KG, Nolte CH, Wolf ME, Poli S, Sieber M, Mosimann P, Heuschmann PU, Purrucker JC. Association of oral anticoagulants with risk of brain haemorrhage expansion compared to no-anticoagulation. Neurol Res Pract 2025; 7:12. [PMID: 39934933 PMCID: PMC11921975 DOI: 10.1186/s42466-024-00358-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 11/10/2024] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND The impact of direct oral anticoagulants (DOAC) on haematoma size after intracerebral haemorrhage (ICH) compared to no-anticoagulation is controversial and prospective data are lacking. METHODS The investigator-initiated, multicentre, prospective RASUNOA-prime study enrolled patients with non-traumatic ICH and atrial fibrillation while on a DOAC, vitamin K antagonist (VKA) or no anticoagulation (non-OAC). Neuroimaging was reviewed centrally blinded to group allocation. Primary endpoint was haematoma expansion (≥ 6.5 ml or ≥ 33%, any new intraventricular blood or an increase in modified Graeb score by ≥ 2 points) between baseline and follow-up scan within 72 h after symptom onset. RESULTS Of 1,440 patients screened, 951 patients with ICH symptom onset less than 24 h before admission were enrolled. Baseline scans were performed at a median of 2 h (IQR 1-6) after symptom onset. Neurological deficit and median baseline haematoma volumes (11 ml; IQR 4-39) did not differ among 577 DOAC, 251 VKA and 123 non-OAC patients. Haematoma expansion was observed in DOAC patients in 142/356 (39.9, 95%-CI 34.8-45.0%), VKA in 47/155 (30.3, 95-CI 23.1%-37.6%), versus non-OAC in 22/74 (29.7, 19.3-40.1%). Unspecific reversal agents in DOAC-ICH (212/356, 59.6%) did not affect the haematoma expansion rate compared to no-antagonization. CONCLUSION Baseline haematoma volume and risk of haematoma expansion did not differ statistically significantly in patients with and without DOAC.
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Affiliation(s)
- Roland Veltkamp
- Department of Brain Sciences, Imperial College London, London, UK.
- Department of Neurology, Alfried-Krupp Hospital, Essen, Germany.
- Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
| | - Kirsten Haas
- Institute of Clinical Epidemiology and Biometry, Julius-Maximilians-Universität Würzburg (JMU), Würzburg, Germany
| | - Viktoria Rücker
- Institute of Clinical Epidemiology and Biometry, Julius-Maximilians-Universität Würzburg (JMU), Würzburg, Germany
| | - Uwe Malzahn
- Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany
| | - Adrian Heeger
- Department of Neurology, Alfried-Krupp Hospital, Essen, Germany
| | - David Kinzler
- Department of Neurology, Alfried-Krupp Hospital, Essen, Germany
| | - Patrick Müller
- Department of Neurology, Alfried-Krupp Hospital, Essen, Germany
| | - Pascal Rappard
- Department of Neurology, Alfried-Krupp Hospital, Essen, Germany
| | - Timolaos Rizos
- Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
| | - Johannes Schiefer
- Department of Neurology, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Opherk
- Department of Neurology, SLK-Kliniken Heilbronn, Heilbronn, Germany
| | - Waltraud Pfeilschifter
- Department of Neurology, University Hospital Frankfurt, Goethe-University, Frankfurt Am Main, Germany
- Department of Neurology, Klinikum Lüneburg, Lüneburg, Germany
| | | | - Peter Schellinger
- Department of Neurology and Neurogeriatrics, Johannes Wesling University Hospital Minden, Minden, Germany
- Universitätsklinikum Ruhr-Universität Bochum, Bochum, Germany
| | - Bernadette Gaida
- Department of Neurology, University Medicine Greifswald, Greifswald, Germany
| | | | - Georg Royl
- Neurovascular Center, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
| | | | - Karl Georg Haeusler
- Department of Neurology, Universitätsklinikum Würzburg (UKW), Würzburg, Germany
| | - Christian H Nolte
- Center for Stroke Research Berlin (CSB), Berlin, Germany
- Department of Neurology With Experimental Neurology, Berlin Institute of Health (BIH), Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Marc E Wolf
- Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany
| | - Sven Poli
- Department of Neurology & Stroke, Tübingen University Hospital, Tübingen, Germany
- Hertie Institute for Clinical Brain Research, Tübingen University Hospital, Tübingen, Germany
| | - Marilen Sieber
- Institute of Clinical Epidemiology and Biometry, Julius-Maximilians-Universität Würzburg (JMU), Würzburg, Germany
| | - Pascal Mosimann
- Department of Neuroradiology, Toronto Western Hospital Division of Neuroradiology, Toronto, Canada
| | - Peter U Heuschmann
- Institute of Clinical Epidemiology and Biometry, Julius-Maximilians-Universität Würzburg (JMU), Würzburg, Germany
- Clinical Trial Center Würzburg, University Hospital Würzburg, Würzburg, Germany
- Institute for Medical Data Science, University Hospital Würzburg, Würzburg, Germany
| | - Jan C Purrucker
- Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
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24
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Diener HC, Kuklik N, Hüsing A, Alonso A, Nabavi DG, Poli S, Gabriel MM, Maier IL, Grans J. Andexanet alfa in patients with factor Xa inhibitor-associated intracranial hemorrhage: The prospective observational multicenter ASTRO-DE study. Int J Stroke 2025:17474930251317385. [PMID: 39834067 DOI: 10.1177/17474930251317385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
BACKGROUND Hematoma expansion after intracranial hemorrhage (ICH) in anticoagulated patients significantly influences clinical outcomes and mortality, emphasizing the need for effective reversal agents. Andexanet alfa is a specific reversal agent for factor Xa-associated major bleeding. AIMS The Andexanet alfa: non-interventional study at STROke centers in Germany (Deutschland, DE) (ASTRO-DE) study collected real-world evidence on the effect of andexanet alfa on mitigating hematoma expansion and altering prognosis in rivaroxaban- or apixaban-treated patients with ICH. METHODS ASTRO-DE was a prospective non-interventional cohort study conducted at 25 certified stroke centers in Germany. The primary outcome was the hematoma volume change and the proportion of patients with hematoma growth ⩽33% within 12-72 h or until first control imaging. Secondary endpoints included in-hospital thromboembolic events and mortality up to 90 days. RESULTS A total of 137 patients (47.4% male, mean age = 80.0 years) with ICH (92.6% spontaneous, 87.4% intracerebral), mean National Institutes of Health Stroke Scale (NIHSS) on admission of 11.2 points, and mean initial hematoma volume of 26.5 mL (median = 14.1 mL) were analyzed. Ninety patients (65.7%) suffered ICH while treated with apixaban and 47 (34.3%) with rivaroxaban. The median time between symptom onset and application of andexanet alfa was 3.3 h, door-to-needle time was 1.1 h. The mean change in hematoma volume until the first control imaging, conducted after a median of 15.6 h, was 2.3 mL (95% confidence interval (CI) = 0.4-4.2), while the change within 12-72 h was 1.8 mL (95% CI = 0.4-3.2). Hematoma growth ⩽33% was achieved in 90.3% of the 93 evaluable patients based on first control imaging and in 90.5% of the 63 evaluable patients, considering only imaging performed within the 12-72 h window. During hospitalization, death occurred in 30/137 patients (21.9%) and 17 thromboembolic events in 11/137 (8.0%) patients. The 90-day mortality was 47/128 (36.7%). CONCLUSION ASTRO-DE is the first prospective observational study systematically collecting standardized clinical routine data with andexanet alfa treatment. The study demonstrated favorable hemostasis and minimal mean hematoma volume growth in patients with ICH associated with apixaban or rivaroxaban treatment. DATA ACCESS STATEMENT Data are available upon reasonable request by contacting the corresponding author.
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Affiliation(s)
- Hans-Christoph Diener
- Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Nils Kuklik
- Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Centre for Clinical Trials Essen, University Hospital Essen, Essen, Germany
| | - Anika Hüsing
- Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Angelika Alonso
- Department of Neurology and Mannheim Centre for Translational Neurosciences, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Darius G Nabavi
- Department of Neurology, Vivantes Klinikum Neukölln, Berlin, Germany
| | - Sven Poli
- Department of Neurology and Stroke, University of Tübingen, Tübingen, Germany
- Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Maria M Gabriel
- Department of Neurology, Hannover Medical School, Hannover, Germany
| | - Ilko L Maier
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
| | - Julia Grans
- Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Centre for Clinical Trials Essen, University Hospital Essen, Essen, Germany
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25
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Goldin M, Tsaftaridis N, Jnani J, Spyropoulos AC. Reversal of Direct Oral Anticoagulants (DOACs) for Critical Bleeding or Urgent Procedures. J Clin Med 2025; 14:1013. [PMID: 39941682 PMCID: PMC11818480 DOI: 10.3390/jcm14031013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/23/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
The advent of direct-acting oral anticoagulants (DOACs) has transformed the care of patients requiring prevention and treatment for thrombotic disease. Many randomized clinical trials have demonstrated the efficacy and safety of these agents and their comparative advantages over conventional anticoagulants such as vitamin K antagonists (VKAs). While historically clinicians and patients raised questions about the reversal of DOAC-associated bleeding, federal approval in recent years of targeted DOAC reversal agents, along with adjunctive modalities, has given clinicians reliable pharmacologic options. Yet, optimal reversal strategies for bleeding at specific anatomic locations and in specific clinical scenarios remains uncertain. We present here a narrative review of the literature on the reversal of DOAC-associated bleeding or for urgent procedures. The totality of the reversal literature synthesized here yields several clear conclusions: (1) targeted DOAC reversal with specific agents demonstrates superior efficacy for both bleeding and urgent surgical indications when compared to the use of non-specific agents, such as prothrombin complex concentrates (PCCs); (2) at the same time, high-quality data suggest potentially increased thrombotic risks, particularly for ischemic stroke, when using the specific targeted agent andexanet; (3) in all cases of life-threatening bleeding, timely reversal is of the essence; (4) in particular, there is growing consensus that DOAC-associated intracranial hemorrhage (ICH) should be reversed promptly, with a goal door-to-reversal time of 60 min; (5) future research will focus on optimizing clinical pathways for reversal to address "calls to action" from professional groups on this critical topic.
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Affiliation(s)
- Mark Goldin
- Northwell, 2000 Marcus Ave., Suite 300, New Hyde Park, NY 11042-1069, USA; (M.G.); (N.T.); (J.J.)
- Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell, New Hyde Park, NY 11042-1069, USA
- Institute of Health System Science, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Nikolaos Tsaftaridis
- Northwell, 2000 Marcus Ave., Suite 300, New Hyde Park, NY 11042-1069, USA; (M.G.); (N.T.); (J.J.)
- Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell, New Hyde Park, NY 11042-1069, USA
- Institute of Health System Science, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
| | - Jack Jnani
- Northwell, 2000 Marcus Ave., Suite 300, New Hyde Park, NY 11042-1069, USA; (M.G.); (N.T.); (J.J.)
- Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell, New Hyde Park, NY 11042-1069, USA
- Department of Medicine, North Shore University Hospital, Manhasset, NY 11549, USA
| | - Alex C. Spyropoulos
- Northwell, 2000 Marcus Ave., Suite 300, New Hyde Park, NY 11042-1069, USA; (M.G.); (N.T.); (J.J.)
- Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell, New Hyde Park, NY 11042-1069, USA
- Institute of Health System Science, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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26
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Leafloor C, Green R, Sharif S. Andexanet for factor Xa inhibitor-associated acute intracerebral hemorrhage. CAN J EMERG MED 2025; 27:104-106. [PMID: 39760938 DOI: 10.1007/s43678-024-00845-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 11/21/2024] [Indexed: 01/07/2025]
Affiliation(s)
- Cameron Leafloor
- Department of Critical Care Medicine, University of Calgary, Calgary, AB, Canada.
- Canadian Association of Emergency Physicians Critical Care Committee, Ottawa, ON, Canada.
| | - Robert Green
- Canadian Association of Emergency Physicians Critical Care Committee, Ottawa, ON, Canada
- Department of Critical Care, Emergency Medicine, Anesthesia and Surgery, Trauma Nova Scotia, NSH Trauma Program, Dalhousie University, Halifax, NS, Canada
| | - Sameer Sharif
- Canadian Association of Emergency Physicians Critical Care Committee, Ottawa, ON, Canada
- Division of Critical Care & Emergency Medicine, Department of Medicine, McMaster University, Hamilton, ON, Canada
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27
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Kopp SL, Vandermeulen E, McBane RD, Perlas A, Leffert L, Horlocker T. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (fifth edition). Reg Anesth Pain Med 2025:rapm-2024-105766. [PMID: 39880411 DOI: 10.1136/rapm-2024-105766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 11/14/2024] [Indexed: 01/31/2025]
Abstract
Hemorrhagic complications associated with regional anesthesia are extremely rare. The fifth edition of the American Society of Regional Anesthesia and Pain Medicine's Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy reviews the published evidence since 2018 and provides guidance to help avoid this potentially catastrophic complication.The fifth edition of the American Society of Regional Anesthesia and Pain Medicine's Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy uses similar methodology as previous editions but is reorganized and significantly condensed. Therefore, the clinicians are encouraged to review the earlier texts for more detailed descriptions of methods, clinical trials, case series and pharmacology. It is impossible to perform large, randomized controlled trials evaluating a complication this rare; therefore, where the evidence is limited, the authors continue to maintain an 'antihemorrhagic' approach focused on patient safety and have proposed conservative times for the interruption of therapy prior to neural blockade. In previous versions, the anticoagulant doses were described as prophylactic and therapeutic. In this version, we will be using 'low dose' and 'high dose,' which will allow us to be consistent with other published guidelines and more accurately describe the dose in the setting of specific patient characteristics and indications. For example, the same 'high' dose may be used in one patient as a treatment for deep venous thrombosis (DVT) and in another patient as prophylaxis for recurrent DVT. Due to the increasing ability to obtain drug-specific assays, we have included suggestions for when ordering these tests may be helpful and guide practice. Like previous editions, at the end of each recommendation the authors have clearly noted how the recommendation has changed from previous editions.
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Affiliation(s)
- Sandra L Kopp
- Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Robert D McBane
- Cardiovascular Medicine and Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Anahi Perlas
- Anesthesia and Pain Management, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Lisa Leffert
- Anesthesia, Critical Care & Pain Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Terese Horlocker
- Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA
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Qiu D, Wang L, Wang L, Dong Y. Human platelet lysate: a potential therapeutic for intracerebral hemorrhage. Front Neurosci 2025; 18:1517601. [PMID: 39881806 PMCID: PMC11774881 DOI: 10.3389/fnins.2024.1517601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/30/2024] [Indexed: 01/31/2025] Open
Abstract
Intracerebral hemorrhage (ICH) is a major public health challenge worldwide, and is associated with elevated rates of mortality, disability, and morbidity, especially in low- and middle-income nations. However, our knowledge of the detailed molecular processes involved in ICH remains insufficient, particularly those involved in the secondary injury stage, resulting in a lack of effective treatments for ICH. Human platelet lysates (HPL) are abundant in bioactive factors, and numerous studies have demonstrated their beneficial effects on neurological diseases, including their anti-neuroinflammatory ability, anti-oxidant effects, maintenance of blood-brain barrier integrity, and promotion of neurogenesis. In this review, we thoroughly explore the potential of HPL for treating ICH from three critical perspectives: the rationale for selecting HPL as a treatment for ICH, the mechanisms through which HPL contributes to ICH management, and the additional measures necessary for HPL as a treatment for ICH. We elucidate the role of platelets in ICH pathophysiology and highlight the limitations of the current treatment options and advancements in preclinical research on the application of HPL in neurological disorders. Furthermore, historical developments and preparation methods of HPL in the field of biomedicine are discussed. Additionally, we summarize the bioactive molecules present in HPL and their potential therapeutic effects in ICH. Finally, we outline the issues that must be addressed regarding utilizing HPL as a treatment modality for ICH.
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Affiliation(s)
- Dachang Qiu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lin Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lanlan Wang
- Department of Geriatrics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yongfei Dong
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Simioni P, Cipriano A, D'Angelo A, Giannasi G, Ricci G, Campello E, Susi B, Andreone V, Candelaresi P. The efficacy and safety of andexanet alfa in the treatment of anticoagulation-related major bleedings: An Italian perspective. Thromb Res 2025; 245:109241. [PMID: 39700713 DOI: 10.1016/j.thromres.2024.109241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 12/04/2024] [Accepted: 12/08/2024] [Indexed: 12/21/2024]
Affiliation(s)
- Paolo Simioni
- Department of Medicine (DIMED), University of Padua, Padua, Italy; General Internal Medicine Unit, Padua University-Hospital, Padua, Italy
| | - Alessandro Cipriano
- Emergency Department, Nuovo Santa Chiara Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Armando D'Angelo
- Coagulation Service and Thrombosis Research Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gianfranco Giannasi
- Emergency Medicine Unit, Ospedale San Giovanni di Dio, Emergency Department of Azienda USL Toscana Centro, Florence, Italy
| | - Giorgio Ricci
- Poison Control Center of Verona, Integrated University Hospital of Verona, Verona, Italy
| | - Elena Campello
- Department of Medicine (DIMED), University of Padua, Padua, Italy; General Internal Medicine Unit, Padua University-Hospital, Padua, Italy
| | - Beniamino Susi
- S. Paolo Hospital, Civitavecchia (RM) - ASL, Roma 4, Italy
| | | | - Paolo Candelaresi
- Neurology and Stroke Unit, AORN "Antonio Cardarelli", Naples, Italy.
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Chabata CV, Yu H, Ke L, Frederiksen JW, Patel PA, Sullenger BA, Thalji NK. Andexanet Alfa-Associated Heparin Resistance in Cardiac Surgery: Mechanism and In Vitro Perspectives. Arterioscler Thromb Vasc Biol 2025; 45:144-156. [PMID: 39569519 DOI: 10.1161/atvbaha.124.321650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/04/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND Andexanet alfa (andexanet) is the only Food and Drug Administration-approved antidote for direct FXa (factor Xa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass. The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown. METHODS The effect of andexanet in vitro was determined using activated clotting times and thromboelastography. Ex vivo cardiopulmonary bypass circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of AT (antithrombin) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance. RESULTS Andexanet prevented UFH-mediated prolongation of activated clotting times and thromboelastography times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and thrombin generation assay validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient cardiopulmonary bypass heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require high UFH doses and potentially AT supplementation. CONCLUSIONS Andexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided before heparinization and direct thrombin inhibitors are undesirable, our in vitro study suggests excess UFH should be considered as a potential strategy before AT supplementation.
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Affiliation(s)
- Charlene V Chabata
- Departments of Pharmacology and Cancer Biology (C.V.C., H.Y., B.A.S.), Duke University, Durham, NC
| | - Haixiang Yu
- Departments of Pharmacology and Cancer Biology (C.V.C., H.Y., B.A.S.), Duke University, Durham, NC
- Surgery (H.Y., J.W.F., B.A.S.), Duke University, Durham, NC
| | - Lei Ke
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.K., N.K.T.)
| | | | - Prakash A Patel
- Department of Anesthesiology, Jefferson Abington Hospital, PA (P.A.P.)
| | - Bruce A Sullenger
- Departments of Pharmacology and Cancer Biology (C.V.C., H.Y., B.A.S.), Duke University, Durham, NC
- Surgery (H.Y., J.W.F., B.A.S.), Duke University, Durham, NC
| | - Nabil K Thalji
- Division of Cardiothoracic Anesthesiology, Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (L.K., N.K.T.)
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Buka RJ. Andexanet alfa: trials just leave us with more questions. Res Pract Thromb Haemost 2025; 9:102628. [PMID: 39868401 PMCID: PMC11760292 DOI: 10.1016/j.rpth.2024.102628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 10/27/2024] [Accepted: 11/04/2024] [Indexed: 01/28/2025] Open
Abstract
Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor (ANNEXA-I), the first ever randomized controlled trial of a reversal agent for direct oral anticoagulants, was published in 2024. The trial, which randomized patients with intracranial hemorrhage to andexanet alfa or usual care, was mandated by the United States Food and Drug Administration as part of its conditional approval in 2018. This approval was originally based on the single-arm trial, The Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4). ANNEXA-I was stopped early for benefit and showed a reduction in the number of patients with significant hematoma expansion. However, the study was not powered for clinical endpoints such as disability or death and showed no difference in these outcomes. It did, however, show an increased risk of thrombosis, predominantly stroke with andexanet alfa. In this perspective, I reflect on some of the key criticisms of the trial and the implications for its interpretation.
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Affiliation(s)
- Richard J. Buka
- Department of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
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Frol S, Cortez GM, Pretnar-Oblak J, Ntaios G, Siddiqui AH, Levy EI. Letter: Use of Andexanet Alfa Before Urgent Neurosurgical and Neurointerventional Procedures: An Unresolved Issue. Neurosurgery 2025; 96:e11-e13. [PMID: 39485026 DOI: 10.1227/neu.0000000000003254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 09/13/2024] [Indexed: 11/03/2024] Open
Affiliation(s)
- Senta Frol
- Department of Vascular Neurology, University Medical Center Ljubljana, Ljubljana , Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana , Slovenia
| | - Gustavo M Cortez
- Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo , New York , USA
- Department of Neurosurgery, Gates Vascular Institute at Kaleida Health, Buffalo , New York , USA
| | - Janja Pretnar-Oblak
- Department of Vascular Neurology, University Medical Center Ljubljana, Ljubljana , Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana , Slovenia
| | - George Ntaios
- Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa , Greece
| | - Adnan H Siddiqui
- Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo , New York , USA
- Department of Neurosurgery, Gates Vascular Institute at Kaleida Health, Buffalo , New York , USA
- Department of Radiology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo , New York , USA
- Jacobs Institute, SUNY University at Buffalo and Kaleida Health, Buffalo , New York , USA
| | - Elad I Levy
- Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo , New York , USA
- Department of Neurosurgery, Gates Vascular Institute at Kaleida Health, Buffalo , New York , USA
- Department of Radiology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo , New York , USA
- Jacobs Institute, SUNY University at Buffalo and Kaleida Health, Buffalo , New York , USA
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Mithoowani S, Bungard T, Castellucci L, Crowther M, de Wit K, Dowlatshahi D, Forbes N, Lin K, Siegal DM. Multidisciplinary Expert Guidance for the Management of Severe Bleeding on Oral Anticoagulation: An Algorithm for Practicing Clinicians. Thromb Haemost 2024. [PMID: 39515380 DOI: 10.1055/a-2464-2887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Bleeding complications associated with oral anticoagulant (OAC) frequently lead to emergency department visits and hospitalization. Short-term all-cause mortality after severe bleeding is substantial ranging from approximately 10% for gastrointestinal bleeding (the most frequent single site) to approximately 50% for intracranial bleeding. A protocol for multidisciplinary approach to bleeding is needed to (i) ensure rapid identification of patients at risk of adverse outcomes, (ii) optimize delivery of supportive measures, (iii) treat the source of bleeding, and (iv) administer anticoagulant reversal or hemostatic therapies judiciously for patients most likely to benefit. We convened a multidisciplinary panel of experts (emergency medicine, gastroenterology, general internal medicine, hematology, neurology, pharmacy, thrombosis) to review the literature and provide practical guidance including a corresponding algorithm for use at the point of care to assist clinicians in the management of patients with acute severe OAC-related bleeding.
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Affiliation(s)
| | - Tammy Bungard
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Lana Castellucci
- Department of Medicine, University of Ottawa, Ottawa, Canada
- Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Mark Crowther
- Department of Medicine, McMaster University, Hamilton, Canada
| | - Kerstin de Wit
- Department of Emergency Medicine, Queen's University, Kingston, Canada
| | - Dar Dowlatshahi
- Department of Medicine, University of Ottawa, Ottawa, Canada
- Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Nauzer Forbes
- Department of Medicine, University of Calgary, Calgary, Canada
| | - Katie Lin
- Department of Medicine, University of Calgary, Calgary, Canada
| | - Deborah M Siegal
- Department of Medicine, University of Ottawa, Ottawa, Canada
- Inflammation and Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada
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Mithoowani S, Siegal D. DOACs: role of anti-Xa and drug level monitoring. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:178-185. [PMID: 39643984 DOI: 10.1182/hematology.2024000666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Direct oral anticoagulants (DOACs) do not require routine monitoring of anticoagulant effect, but measuring DOAC activity may be desirable in specific circumstances to detect whether clinically significant DOAC levels are present (eg, prior to urgent surgery) or to assess whether drug levels are excessively high or excessively low in at-risk patients (eg, after malabsorptive gastrointestinal surgery). Routine coagulation tests, including the international normalized ratio (INR) or activated partial thromboplastin time (aPTT), cannot accurately quantify drug levels but may provide a qualitative assessment of DOAC activity when considering the estimated time to drug clearance based on timing of last drug ingestion and renal and hepatic function. Drug-specific chromogenic and clot-based assays can quantify drug levels but they are not universally available and do not have established therapeutic ranges. In this review, we discuss our approach to measuring DOAC drug levels, including patient selection, interpretation of coagulation testing, and how measurement may inform clinical decision-making in specific scenarios.
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Affiliation(s)
- Siraj Mithoowani
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Deborah Siegal
- Department of Medicine, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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35
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Seiffge DJ, Fandler-Höfler S, Du Y, Goeldlin MB, Jolink WMT, Klijn CJM, Werring DJ. Intracerebral haemorrhage - mechanisms, diagnosis and prospects for treatment and prevention. Nat Rev Neurol 2024; 20:708-723. [PMID: 39548285 DOI: 10.1038/s41582-024-01035-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2024] [Indexed: 11/17/2024]
Abstract
Intracerebral haemorrhage (ICH) is a devastating condition associated with high mortality and substantial residual disability among survivors. Effective treatments for the acute stages of ICH are limited. However, promising findings from randomized trials of therapeutic strategies, including acute care bundles that target anticoagulation therapies, blood pressure control and other physiological parameters, and trials of minimally invasive neurosurgical procedures have led to renewed optimism that patient outcomes can be improved. Currently ongoing areas of research for acute treatment include anti-inflammatory and haemostatic treatments. The implementation of effective secondary prevention strategies requires an understanding of the aetiology of ICH, which involves vascular and brain parenchymal imaging; the use of neuroimaging markers of cerebral small vessel disease improves classification with prognostic relevance. Other data underline the importance of preventing not only recurrent ICH but also ischaemic stroke and cardiovascular events in survivors of ICH. Ongoing and planned randomized controlled trials will assess the efficacy of prevention strategies, including antiplatelet agents, oral anticoagulants or left atrial appendage occlusion (in patients with concomitant atrial fibrillation), and optimal management of long-term blood pressure and statin use. Together, these advances herald a new era of improved understanding and effective interventions to reduce the burden of ICH.
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Affiliation(s)
- David J Seiffge
- Department of Neurology, Inselspital University Hospital Bern and University of Bern, Bern, Switzerland
| | - Simon Fandler-Höfler
- Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK
- Department of Neurology, Medical University of Graz, Graz, Austria
| | - Yang Du
- Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Martina B Goeldlin
- Department of Neurology, Inselspital University Hospital Bern and University of Bern, Bern, Switzerland
| | | | - Catharina J M Klijn
- Department of Neurology, Donders Institute of Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - David J Werring
- Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, University College London, London, UK.
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Ageno W, Caramelli B, Donadini MP, Girardi L, Riva N. Changes in the landscape of anticoagulation: a focus on direct oral anticoagulants. Lancet Haematol 2024; 11:e938-e950. [PMID: 39433055 DOI: 10.1016/s2352-3026(24)00281-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/27/2024] [Accepted: 08/30/2024] [Indexed: 10/23/2024]
Abstract
Over the last decade, the advent of direct oral anticoagulants (DOACs) has rapidly changed the landscape of anticoagulation. In the early 2010s, DOACs became widely available for stroke prevention in atrial fibrillation and the treatment of venous thromboembolism. About 10 years later, approximately two-thirds of patients requiring oral anticoagulant treatment were receiving a DOAC. The results of several post-marketing studies consistently confirmed the findings of phase 3 clinical trials, and research has focused on new areas of development, with heterogeneous results. A role for DOACs has emerged for patients with peripheral artery disease and other challenging conditions, such as cancer-associated thrombosis, unusual-site venous thromboembolism, and end-stage renal disease. Conversely, clinical trials showed that DOACs were not efficacious in patients with valvular atrial fibrillation, mechanical heart valves, embolic strokes of undetermined source, or antiphospholipid syndrome. In this Review, we discuss the impact of DOACs in clinical practice over the last decade, new areas under development, and practical issues in the management of these drugs.
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Affiliation(s)
- Walter Ageno
- Department of Internal Medicine, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland; Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Bruno Caramelli
- Unidade de Medicina Interdisciplinar em Cardiologia, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | - Laura Girardi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Nicoletta Riva
- Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
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Dobesh PP, Coleman CI, Danese M, Lesén E, Chang RC, Odelade O, Fermann GJ. Management of factor Xa inhibitor-related traumatic non-intracranial bleeding events with andexanet alfa or four-factor prothrombin complex concentrate in a US multicenter observational study. J Am Coll Emerg Physicians Open 2024; 5:e13333. [PMID: 39524040 PMCID: PMC11543631 DOI: 10.1002/emp2.13333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/18/2024] [Accepted: 09/27/2024] [Indexed: 11/16/2024] Open
Abstract
Objectives This study describes clinical characteristics and management strategies for patients with factor Xa (FXa) inhibitor-related traumatic non-intracranial bleeds who were treated with andexanet alfa or four-factor prothrombin complex concentrate (4F-PCC). Methods An observational cohort study (ClinicalTrials.gov Identifier: NCT05548777) was conducted using electronic health records from 354 US hospitals. Included patients were hospitalized with rivaroxaban- or apixaban-related bleeding, had received andexanet alfa or 4F-PCC treatment during their hospitalization, and were discharged between May 2018 and September 2022. This analysis was performed in the subgroup of patients with traumatic non-intracranial critical compartment/non-compressible bleeds or other traumatic bleeds. Results The study population included 250 patients (andexanet alfa, n = 116; 4F-PCC, n = 134). Critical compartment bleeds were the most common (86.8%), with retroperitoneal bleeds the most common subtype (30.9%). Most patients were admitted via the emergency department (82.0%). The median time from presentation to reversal/replacement treatment was 2.7 (interquartile range, 1.2, 6.6) h. For patients treated with andexanet alfa, 63.8% were administered the low-dose regimen. For 4F-PCC, a median of 2000 total units was administered per patient. Other treatment strategies used included intravenous fluids (26.0%), fresh frozen plasma (16.0%), and packed red blood cells (13.2%). Prior to hospital discharge, oral anticoagulants were restarted in 20.4% of patients. Overall, 25 (10.0%) patients died in hospital. Conclusion This analysis provides insights into the clinical characteristics and management strategies, including time to treatment, for patients treated with andexanet alfa or 4F-PCC while hospitalized for FXa inhibitor-related traumatic bleeds.
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Affiliation(s)
- Paul P. Dobesh
- College of PharmacyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Craig I. Coleman
- University of Connecticut School of PharmacyStorrsConnecticutUSA
- Evidence‐Based Practice CenterHartford HospitalHartfordConnecticutUSA
| | | | | | | | | | - Gregory J. Fermann
- Department of Emergency MedicineUniversity of CincinnatiCincinnatiOhioUSA
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Sin CF, Wong KP, Siu CW, Wong TF, Wong HM. Utilization of international normalized ratio-derived formula to predict plasma rivaroxaban level-Validation study and real-world experience. Int J Lab Hematol 2024; 46:1101-1108. [PMID: 39019497 DOI: 10.1111/ijlh.14347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 06/27/2024] [Indexed: 07/19/2024]
Abstract
INTRODUCTION Specific assays of plasma rivaroxaban level are not always readily available with short turnaround time, which hamper the management of urgent clinical situations. In this study, we aimed to build a predictive formula of plasma rivaroxaban levels from international normalized ratio (INR) value and validated in real world clinical situations. METHODS Ninety-four patients who were taking rivaroxaban participated in the study. Patients were randomized into testing cohort and validation cohorts. The prediction formula was built from the testing cohort and then validated in validation cohort. The predictive performance was further validated on real-world clinical requests. RESULTS The root mean square error (RMSE) of the predictive formula for the testing and validation cohorts were 61.81 and 69.32 ng/mL, respectively. The sensitivity and specificity for the formula to predict the threshold plasma rivaroxaban level of 75 ng/mL were 95% (95% CI: 85.4%-100%) and 87.5% (95% CI: 71.3%-100%), respectively, in real-world clinical situations. CONCLUSION Plasma rivaroxaban level of threshold level of 75 ng/mL can be calculated from prediction formula by INR value with satisfactory accuracy and it can be used to guide the decision for reversal.
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Affiliation(s)
- Chun-Fun Sin
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Ka-Ping Wong
- Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Chun Wah Siu
- Division of Cardiology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Tsz-Fu Wong
- Division of Haematology and Blood Bank, Department of Pathology, Queen Mary Hospital, Hong Kong, China
| | - Hoi-Man Wong
- Division of Haematology and Blood Bank, Department of Pathology, Queen Mary Hospital, Hong Kong, China
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Schönichen C, Sun S, Middelveld H, Huskens D, de Groot PG, Heemskerk JWM, Roest M, de Laat B. Functionally distinct anticoagulant mechanisms of endothelial cells. Thromb Res 2024; 244:109208. [PMID: 39522336 DOI: 10.1016/j.thromres.2024.109208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/29/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Antithrombin and tissue factor pathway inhibitor (TFPI) provide different anticoagulant mechanisms. Having established a potent anticoagulant role of cultured human umbilical vein endothelial cells in vessel-on-a-chip microfluidic models, we now investigated how these cells modulated thrombin generation under stasis through antithrombin and TFPI pathways. We observed that endothelial monolayers in 96 well-plates strongly delayed and suppressed the thrombin generation process induced by tissue factor, regardless of the presence of whole blood, platelet-rich plasma or platelet-free plasma. Intervention studies indicated that the blocking of heparin-like proteoglycans with polybrene or protamine sulphate, similarly as the absence of antithrombin in plasma, reverted the endothelial anticoagulant activity. Heparinase treatment of the cells also reduced the anticoagulant potential. Furthermore, the presence of andexanet-alpha (inactivated factor Xa) and an anti-TFPI antibody were able to revert the endothelial effects. Jointly, these data point to additive anticoagulant mechanisms of endothelial cells through surface-expressed heparin-like proteoglycans and TFPI, both contributing to thrombin inhibition.
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Affiliation(s)
- Claudia Schönichen
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany
| | - Siyu Sun
- Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands
| | - Harmen Middelveld
- Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands
| | - Dana Huskens
- Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands
| | - Philip G de Groot
- Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands
| | - Johan W M Heemskerk
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands.
| | - Mark Roest
- Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands.
| | - Bas de Laat
- Synapse Research Institute Maastricht, Kon. Emmaplein 7, 6217, KD, Maastricht, the Netherlands
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40
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Røed-Undlien H, Schultz NH, Husebråten IM, Wollmann BM, Akerkar RR, Molden E, Amundsen EK, Bjørnstad JL. Apixaban removal during emergency surgery for type A acute aortic dissection: a prospective cohort study. Int J Surg 2024; 110:7782-7790. [PMID: 39806740 PMCID: PMC11634093 DOI: 10.1097/js9.0000000000002137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/05/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Acute type A aortic dissection (ATAAD) has a high mortality, and acute aortic repair is the only curative treatment. In patients treated with factor Xa (FXa) inhibitors, the risk of severe disease-related complications such as cardiac tamponade and hemodynamic shock must be balanced against the potential for severe perioperative bleeding. The aim was to study intraoperative changes in plasma levels of the FXa inhibitor apixaban when using hemoadsorption during acute thoracic aortic repair. MATERIALS AND METHODS This is a single-center prospective cohort study. Eight apixaban-treated patients presenting with ATAAD underwent acute thoracic aortic repair with intraoperative hemoadsorption with CytoSorb. Apixaban concentrations were measured at the start of cardiopulmonary bypass (CPB) and after 5, 15, 30, 60, and 90 min of CPB, at CPB weaning, 30 min after CPB weaning and 24 h postoperatively, using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). RESULTS After 30 min of CPB with hemoadsorption, mean apixaban concentration (±SD) was reduced by 59% from 108 (±69) µg/l to 44 (±20) µg/l (P=0.009). There was a further reduction to 37 (±17) µg/l at CPB weaning (P=0.008). Apixaban concentration displayed an increase to 56 (±29) µg/l 24 h postoperatively (P=0.01). In-hospital mortality was 25%. The mean 24H chest tube drainage volume was 621 (±136) ml. CONCLUSION Intraoperative hemoadsorption lowers apixaban levels in patients undergoing emergency surgery for ATAAD. Further research is needed to determine its impact on perioperative bleeding complications and mortality.
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Affiliation(s)
| | - Nina H. Schultz
- Research Institute for Internal Medicine, Oslo University Hospital
- Department of Hematology, Oslo University Hospital
| | | | | | - Rupali R. Akerkar
- Department of Health Registries, Norwegian Institute of Public Health, Bergen
| | - Espen Molden
- Center for Psychopharmacology, Diakonhjemmet Hospital
- Department of Pharmacy, Section for Pharmacology and Pharmaceutical Biosciences, University of Oslo
| | - Erik K. Amundsen
- Department of Medical Biochemistry, Oslo University Hospital
- Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway
| | - Johannes L. Bjørnstad
- Institute of Clinical Medicine, University of Oslo
- Department of Cardiothoracic Surgery, Oslo University Hospital
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41
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Rodrigues A, Gonçalves LR, Gregório T, Baldaia C, Santo GC, Gouveia J. Urgent Reversal of Direct Oral Anticoagulants in Critical and Life-Threatening Bleeding: A Multidisciplinary Expert Consensus. J Clin Med 2024; 13:6842. [PMID: 39597986 PMCID: PMC11595216 DOI: 10.3390/jcm13226842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/08/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024] Open
Abstract
Direct oral anticoagulants (DOACs) are increasingly being used due to their improved efficacy/safety ratio and lower clinical and economic burden when compared to vitamin K antagonists. However, bleeding is still the most frequent complication associated with DOACs, and although rare, bleeding episodes can be life-threatening or critical. The impact of DOAC anticoagulation activity during a bleeding event must be evaluated according to patient clinical assessment, dosage and time from last intake, the presence of comorbidities (especially kidney and liver dysfunction), and, whenever possible, coagulation tests. Unfortunately, DOACs' anticoagulation activity is not easily or usually detectable in routine common coagulation testing. Specific DOAC tests allow for specific drug monitoring, but they are too time consuming, and are usually unavailable in routine emergency practice. If a clinically relevant DOAC plasma concentration is assumed or proven in a severe bleeding scenario, DOAC reversal is needed to restore hemostasis. This experts' consensus provides a narrative review about DOAC reversal and practical life-threatening bleeding management in several scenarios (trauma, intracranial hemorrhage and gastrointestinal bleeding), focusing on the selection of patients to whom specific reversal agents should be given.
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Affiliation(s)
- Anabela Rodrigues
- Serviço de Imuno-Hemoterapia, Unidade Local de Saúde (ULS) Santa Maria, 1649-028 Lisboa, Portugal
| | - Luciana Ricca Gonçalves
- Serviço de Imuno-Hemoterapia, Unidade Local de Saúde (ULS) São João, 4200-319 Porto, Portugal;
| | - Tiago Gregório
- Serviço de Medicina Interna e Unidade AVC, Unidade Local de Gaia e Espinho, 4434-502 Vila Nova de Gaia, Portugal;
- CINTESIS—Centro de Investigação em Tecnologias e Serviços de Saúde, 4200-450 Porto, Portugal
| | - Cilénia Baldaia
- Serviço de Medicina Intensiva, Unidade Local de Saúde (ULS) Santa Maria, 1649-028 Lisboa, Portugal; (C.B.); (J.G.)
- Serviço de Gastroenterologia, Unidade Local de Saúde (ULS) Santa Maria, 1649-028 Lisboa, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal
| | - Gustavo C. Santo
- Serviço de Neurologia, Hospitais da Universidade de Coimbra, Unidade Local de Saúde (ULS) de Coimbra, 3004-561 Coimbra, Portugal;
- Center for Innovative Biomedicine and Biotechnology (CiBB), Universidade de Coimbra, 3004-561 Coimbra, Portugal
| | - João Gouveia
- Serviço de Medicina Intensiva, Unidade Local de Saúde (ULS) Santa Maria, 1649-028 Lisboa, Portugal; (C.B.); (J.G.)
- Clínica Universitária de Medicina Intensiva, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal
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Wienhold J, Rossaint R, Vandeput E, Grottke O. The Efficacy of Andexanet Alfa for the Reversal of Factor Xa Inhibitors Is Not Influenced by Hemodilution with Different Volume Expanders. J Clin Med 2024; 13:6706. [PMID: 39597850 PMCID: PMC11594903 DOI: 10.3390/jcm13226706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 10/29/2024] [Accepted: 11/02/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Andexanet alfa is a specific antidote for factor Xa (FXa) inhibitors. It is licensed to treat patients under FXa inhibitor therapy with life-threatening bleeding. Concomitantly, volume expanders are used to compensate for blood loss and maintain circulation. The competitive binding of andexanet to FXa inhibitors may be disrupted due to hemodilution, as shown by laboratory assays with high sample dilution. This study investigated the efficacy of andexanet for the reversal of FXa inhibitors under hemodilution. Methods: Blood from 10 healthy volunteers was anticoagulated with rivaroxaban and subsequently treated with four different volume expanders (Ringer's solution, 4% gelatine, 5% and 20% human albumin (HA)) at two dilution levels (20% and 50%). After anticoagulation and hemodilution, andexanet was added according to the high-dose protocol. Blood samples were analyzed using a Russell's viper venom (RVV) test on a Clot Pro® device, a thrombin generation assay, a fully automated coagulation analyzer and a chromogenic anti-FXa activity assay. Results: After anticoagulation, the median rivaroxaban concentration was 272 ng/mL (IQR 254-353). Anticoagulation with rivaroxaban caused a significant impairment of all coagulation parameters, which was further aggravated by hemodilution. After the administration of andexanet, coagulation parameters in anticoagulated samples were reversed to near baseline in all groups. Andexanet administration decreased the rivaroxaban plasma concentration in all groups to a median of <10 ng/mL. In the anticoagulated, non-hemodiluted samples, anti-FXa activity was reduced by 98%. The anti-FXa activity in the anticoagulated, hemodiluted samples was reduced by approximately 96% in the 20% diluted samples and by about 93% in the 50% diluted samples. Conclusions: Our data indicate that FXa inhibitor reversal with andexanet is about 5% less effective with 50% hemodilution than in non-hemodiluted samples.
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Affiliation(s)
- Jan Wienhold
- Department of Anesthesiology, University Hospital RWTH Aachen, 52074 Aachen, Germany
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Gigante B, Tamargo J, Agewall S, Atar D, Ten Berg J, Campo G, Cerbai E, Christersson C, Dobrev D, Ferdinandy P, Geisler T, Gorog DA, Grove EL, Kaski JC, Rubboli A, Wassmann S, Wallen H, Rocca B. Update on antithrombotic therapy and body mass: a clinical consensus statement of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and the European Society of Cardiology Working Group on Thrombosis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2024; 10:614-645. [PMID: 39237457 DOI: 10.1093/ehjcvp/pvae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/16/2024] [Indexed: 09/07/2024]
Abstract
Obesity and underweight are a growing health problem worldwide and a challenge for clinicians concerning antithrombotic therapy, due to the associated risks of thrombosis and/or bleeding. This clinical consensus statement updates a previous one published in 2018, by reviewing the most recent evidence on antithrombotic drugs based on body size categories according to the World Health Organization classification. The document focuses mostly on individuals at the extremes of body weight, i.e. underweight and moderate-to-morbid obesity, who require antithrombotic drugs, according to current guidelines, for the treatment or prevention of cardiovascular diseases or venous thromboembolism. Managing antithrombotic therapy or thromboprophylaxis in these individuals is challenging, due to profound changes in body composition, metabolism and organ function, and altered drug pharmacokinetics and pharmacodynamics, as well as weak or no evidence from clinical trials. The document also includes artificial intelligence simulations derived from in silico pharmacokinetic/pharmacodynamic models, which can mimic the pharmacokinetic changes and help identify optimal regimens of antithrombotic drugs for severely underweight or severely obese individuals. Further, bariatric surgery in morbidly obese subjects is frequently performed worldwide. Bariatric surgery causes specific and additional changes in metabolism and gastrointestinal anatomy, depending on the type of the procedure, which can also impact the pharmacokinetics of antithrombotic drugs and their management. Based on existing literature, the document provides consensus statements on optimizing antithrombotic drug management for underweight and all classes of obese patients, while highlighting the current gaps in knowledge in these complex clinical settings, which require personalized medicine and precision pharmacology.
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Affiliation(s)
- Bruna Gigante
- Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
- Department of Cardiology, Danderyds Hospital, 18288 Stockholm, Sweden
| | - Juan Tamargo
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, de Madrid, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERCV, 28040 Madrid, Spain
| | - Stefan Agewall
- Division of Clinical Science, Danderyds Hospital, Karolinska Institutet, 18288 Stockholm, Sweden
- Institute of Clinical Sciences, University of Oslo, NO-0318 Oslo, Norway
| | - Dan Atar
- Institute of Clinical Sciences, University of Oslo, NO-0318 Oslo, Norway
- Department of Cardiology, Oslo University Hospital Ulleval, N-0450 Oslo, Norway
| | - Jurrien Ten Berg
- St Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands
- Maastricht University Medical Center, P Debyelaan 25, 6229 HX Maastricht, the Netherlands
| | - Gianluca Campo
- Azienda Ospedaliero Universitaria di Ferrara, Via Aldo Moro 8, Cona, FE 44124, Italy
| | - Elisabetta Cerbai
- Department of Neurofarba, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
- Laboratory for Non-Linear Spectroscopy, Via N. Carrara 1, Sesto Fiorentino, 50019 Florence, Italy
| | | | - Dobromir Dobrev
- Institute of Pharmacology, University Duisburg-Essen, 45141 Essen, Germany
- Montréal Heart Institute, Université de Montréal, H3C 3J7 Montréal, Québec, Canada
- Department of Integrative Physiology, Baylor College of Medicine, Houston, 77030 TX, USA
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest 1089, Hungary
- Pharmahungary Group, Szeged 6722, Hungary
| | - Tobias Geisler
- Department of Cardiology and Angiology, University Hospital, 72076 Tübingen, Germany
| | - Diana A Gorog
- Faculty of Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK
- Centre for Health Services and Clinical Research, School of Life and Medical Sciences, Postgraduate Medical School, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, UK
| | - Erik L Grove
- Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Palle Juul-Jensens Boulevard 11, 8200 Aarhus, Denmark
| | - Juan Carlos Kaski
- Molecular and Clinical Sciences Research Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK
- St George's University Hospitals NHS Trust, London SW17 0RE, UK
| | - Andrea Rubboli
- Department of Emergency, Internal Medicine, and Cardiology, Division of Cardiology, S. Maria delle Croci Hospital, Viale Randi 5, 48121 Ravenna, Italy
| | - Sven Wassmann
- Cardiology Pasing, Munich, and Faculty of Medicine, University of the Saarland, 66421 Homburg/Saar, Germany
| | - Håkan Wallen
- Department of Cardiology, Danderyds Hospital, 18288 Stockholm, Sweden
- Department of Clinical Sciences, Danderyds Hospital, Karolinska Institutet, 18288 Stockholm, Sweden
| | - Bianca Rocca
- Department of Neurofarba, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
- Department of Medicine and Surgery, LUM University, S.S. 100 Km. 18, 70010 Casamassima, Bari, Italy
- Department of Healthcare Surveillance and Bioethics, Catholic University School of Medicine, Largo F. Vito 1, 00168 Rome, Italy
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Mair A, Sahli SD, Studt JD, Braun J, Lunkiewicz J, Spahn DR, Kaserer A. Impact of elevated direct factor Xa inhibitor plasma levels on perioperative blood loss in patients undergoing urgent surgery. Transfusion 2024; 64:2114-2123. [PMID: 39319425 DOI: 10.1111/trf.18021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 09/06/2024] [Accepted: 09/07/2024] [Indexed: 09/26/2024]
Abstract
INTRODUCTION Data on the perioperative bleeding risk associated with elevated plasma levels of direct factor Xa inhibitors (FXa inhibitors) are limited. This study examines perioperative red blood cell (RBC) loss in patients undergoing urgent surgery with a residual FXa inhibitor level exceeding 100 mcg/L and without preoperative FXa inhibitor reversal. METHODS This retrospective analysis includes data from 32 patients who underwent urgent noncardiac surgery between 2018 and 2022. This study aims to analyze perioperative RBC loss in patients undergoing urgent surgery with a residual FXa inhibitor level exceeding 100 mcg/L and without preoperative FXa inhibitor antidote-based reversal or unspecific treatment with 4-factor prothrombin complex concentrate (PCC). All patients were managed using a watch-and-wait strategy. RESULTS The last determination of FXa inhibitor plasma concentration prior to surgery showed a median of 245 mcg/L (IQR 144-345), with a median time interval of 3.8 h (IQR 2.4-7.2) before incision. Median RBC loss during surgery was 49 mL (IQR 0-253), 189 mL (IQR 104-217) until POD1 and 254 mL (IQR 58-265) until POD3. Only one patient required intraoperative treatment with 4-factor-PCC and none required reversal with andexanet alfa. Linear regression models found no significant influence of FXa inhibitor plasma levels on intraoperative RBC loss. Rivaroxaban was associated with higher RBC loss until postoperative Day 1 compared with apixaban. No thromboembolic events were observed. CONCLUSION Despite markedly elevated plasma concentrations of residual direct FXa inhibitors, perioperative RBC loss was limited in patients undergoing urgent noncardiac surgery. The intraoperative watch-and-wait strategy with selective intraoperative FXa inhibitor reversal or treatment only when required appears to be an appropriate approach.
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Affiliation(s)
- Alexander Mair
- Institute of Anesthesiology, University and University Hospital Zurich, Zurich, Switzerland
| | - Sebastian D Sahli
- Institute of Anesthesiology, University and University Hospital Zurich, Zurich, Switzerland
| | - Jan-Dirk Studt
- Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland
| | - Julia Braun
- Departments of Biostatistics and Epidemiology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Justyna Lunkiewicz
- Institute of Anesthesiology, University and University Hospital Zurich, Zurich, Switzerland
| | - Donat R Spahn
- Institute of Anesthesiology, University and University Hospital Zurich, Zurich, Switzerland
| | - Alexander Kaserer
- Institute of Anesthesiology, University and University Hospital Zurich, Zurich, Switzerland
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45
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Wilson SJ, Gelovani D, Von A, Kaatz S, Grant PJ. Medical Clinics of North America-Periprocedural Antithrombotics: Prophylaxis and Interruption. Med Clin North Am 2024; 108:1017-1037. [PMID: 39341611 DOI: 10.1016/j.mcna.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Anticoagulation management in the surgical patient requires clinical expertise and careful attention. For patients already receiving anticoagulation for a defined indication (ie, stroke prevention for atrial fibrillation, treatment of venous thromboembolism (VTE), or presence of a mechanical heart valve), understanding how to manage these agents by weighing the risks of thromboembolic events and bleeding is paramount. Additionally, prevention of VTE in the surgical patient involves the identification of patient-specific and procedure-specific risk factors for both VTE and bleeding. With this information, as well as familiarity with the several antithrombotic options available, an appropriate prophylaxis strategy can be employed.
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Affiliation(s)
- Steven J Wilson
- Michigan Medicine, Department of Internal Medicine, 1500 E. Medical Center Drive, UH South, Unit 4, SPC 5220, Ann Arbor, MI 48109, USA.
| | - David Gelovani
- Henry Ford Health, Department of Internal Medicine, 2799 W Grand Boulevard, Detroit, MI 48202, USA
| | - Anna Von
- Emory University School of Medicine, Department of Internal Medicine, 1364 Clifton Road NE, Suite N-305, Atlanta, GA 30322, USA
| | - Scott Kaatz
- Henry Ford Health, Department of Internal Medicine, 2799 W Grand Boulevard, Detroit, MI 48202, USA
| | - Paul J Grant
- Michigan Medicine, Department of Internal Medicine, 1500 E. Medical Center Drive, UH South, Unit 4, SPC 5220, Ann Arbor, MI 48109, USA
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Hou H, Qu Z, Liu R, Jiang B, Wang L, Li A. Traumatic brain injury: Advances in coagulopathy (Review). Biomed Rep 2024; 21:156. [PMID: 39268405 PMCID: PMC11391523 DOI: 10.3892/br.2024.1844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 08/05/2024] [Indexed: 09/15/2024] Open
Abstract
Trauma is a prevalent cause of coagulopathy, with traumatic brain injury (TBI) accompanied by coagulation disorders particularly linked to adverse outcomes. TBI is distinguished by minimal bleeding volume and unique injury sites, which precipitate complex coagulation disturbances. Historically, research into trauma-induced coagulopathy has primarily concentrated on the molecular biology and pathophysiology of endogenous anticoagulation and inflammation. Nonetheless, recognizing that cells are the fundamental units of structure and function in all living organisms, the present review aimed to distill our understanding of coagulopathy post-TBI by elucidating the intricate cellular mechanisms involving endothelial cells, neutrophils and platelets. Additionally, this study evaluates the strengths and weaknesses of various diagnostic tools and discusses the characteristics of pharmacological treatments and potential therapies for patients with TBI and coagulation disorders. The aim of this review is to amalgamate recent updates in mechanistic research and innovative diagnostic and therapeutic methodologies, thereby fostering the progression of precision medicine within this specialized domain.
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Affiliation(s)
- Hongqiao Hou
- Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
| | - Zhe Qu
- Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
| | - Ruping Liu
- Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
| | - Bowen Jiang
- Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
| | - Lanlan Wang
- Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
| | - Aiqun Li
- Department of Emergency, Yantai Affiliated Hospital of Binzhou Medical College, Yantai, Shandong 264100, P.R. China
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von Heymann C, Afshari A, Ahmed A, Arnaoutoglou E, Bolliger D, Fenger-Eriksen C, Grottke O. Commentary on the ANNEXA-I trial from the guideline group of the European Society of Anaesthesiology and Intensive Care (ESAIC) on the reversal of direct oral anticoagulants in patients with life threatening bleeding. Eur J Anaesthesiol 2024; 41:867-868. [PMID: 39514740 DOI: 10.1097/eja.0000000000002061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Affiliation(s)
- Christian von Heymann
- From the Department of Anaesthesia, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Vivantes Klinikum im Friedrichshain, Berlin, Germany (CvH), Department of Paediatric and Obstetric Anaesthesia, Juliane Marie Centre, Rigshospitalet; & Department of Clinical Medicine, Copenhagen University, Denmark (AA), Department of Anaesthesia and Critical Care, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester (AA), Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (AA), Department of Anaesthesiology, Larissa University Hospital, Larissa, Greece (EA), Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital Basel, Spitalstrasse, Basel, Switzerland (DB), Department of Anaesthesiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard, Aarhus, Denmark (CF-E), and Department of Anaesthesiology, RWTH Aachen University Hospital, Pauwelsstrasse, Aachen, Germany (OG)
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Roman C, Mihaila R, Cindea CN, Iliescu A, Roman-Filip I, Stingaciu AR, Breazu A, Saceleanu V. Anticoagulation Reversal in Intracerebral Hemorrhage: A Case Report on the Efficacy of Andexanet Alfa in an Apixaban-Treated Patient. Cureus 2024; 16:e74750. [PMID: 39734980 PMCID: PMC11682709 DOI: 10.7759/cureus.74750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2024] [Indexed: 12/31/2024] Open
Abstract
Intracerebral hemorrhage (ICH) presents complex clinical challenges, particularly in patients receiving anticoagulation therapy. This case report discusses the management of acute ICH in a 60-year-old male patient on long-term apixaban therapy, who arrived at the emergency department with altered consciousness, right-sided hemiplegia, and mixed aphasia. Computed tomography (CT) imaging revealed a 70 ml left lenticular-capsular hematoma with significant mass effect, necessitating rapid intervention. Due to the patient's deteriorating neurological condition, andexanet alfa was administered as a reversal agent for apixaban, effectively reducing anti-factor Xa (FXa) activity and enabling an urgent left temporal craniotomy for hematoma evacuation. Postoperatively, the patient received ICU monitoring, blood pressure management, and supportive care, showing gradual improvement in consciousness and sensory aphasia over several days. Despite initial right hemiplegia and motor aphasia requiring rehabilitation, the patient showed excellent progress at one month, now walking independently and managing daily self-care. This report highlights the potential of andexanet alfa for effective anticoagulation reversal in critical ICH cases while also addressing associated thrombotic risks. It underscores the need for a multidisciplinary approach and emphasizes the importance of further research to refine treatment strategies for anticoagulated patients with ICH.
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Affiliation(s)
- Corina Roman
- Neurology, County Clinical Emergency Hospital of Sibiu, Sibiu, ROU
| | - Romeo Mihaila
- Hematology, Lucian Blaga University of Sibiu, Sibiu, ROU
- Hematology, County Clinical Emergency Hospital of Sibiu, Sibiu, ROU
| | - Cosmin Nicodim Cindea
- Neurosurgery, County Clinical Emergency Hospital of Sibiu, Sibiu, ROU
- Neurosurgery, Lucian Blaga University of Sibiu, Sibiu, ROU
| | | | | | | | - Alexandru Breazu
- Neurosurgery, County Clinical Emergency Hospital of Sibiu, Sibiu, ROU
| | - Vicentiu Saceleanu
- Neurosurgery, County Clinical Emergency Hospital of Sibiu, Sibiu, ROU
- Neurosurgery, Lucian Blaga University of Sibiu, Sibiu, ROU
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Shaw JR, Almujalli AA, Xu Y, Levy JH, Schulman S, Siegal D, Dowlatshahi D, Tokessy M, Buyukdere H, Carrier M, Castellucci LA. Prothrombin complex concentrate for direct factor Xa inhibitor-associated bleeding or before urgent surgery. Thromb Res 2024; 243:109172. [PMID: 39362177 DOI: 10.1016/j.thromres.2024.109172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/20/2024] [Accepted: 09/23/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Factor Xa inhibitor (FXaI)-associated bleeding events are common and associated with substantial morbidity. Systematic evaluation of widely available, effective, and affordable FXaI bleed management strategies is needed. MATERIALS AND METHODS We conducted a single-center retrospective cohort study of FXaI-treated patients presenting to a tertiary academic medical center from January 2018 to May 2019 who received 25-50 IU/kg 4F-PCC for either FXaI-associated major bleeding or urgent surgery. The primary outcome was hemostatic efficacy, and the safety outcome was the 30-day risk of thromboembolism. RESULTS PCC was used to treat FXaI-associated bleeding in 83 cases (79.1 %) and was given before urgent surgery in 22 cases (20.9 %). Sixty-six patients were on apixaban, 38 were on rivaroxaban and one patient was on edoxaban. Intracranial hemorrhage (ICH) and gastrointestinal bleeding accounted for most bleeds (74.7 %). Median interval between last DOAC intake and presentation to triage was 9 h [IQR 5.3-14.8] and median PCC dosing was 40.0 IU/kg [IQR 28.5-46.6]. Forty-two patients (40.0 %) had pre-PCC FXaI levels drawn with median FXaI levels of 114.5 ng/mL [IQR 70.0-175.0]. Effective hemostasis occurred in 66.7 % [95%CI 55.4-76.3] of patients receiving PCC for bleeding and surgical hemostasis was rated as normal in 95.5 % (95%CI 76.5-100.0) for patients having urgent surgery. The 30-day risk of thromboembolism was 7.6 % [95%CI 3.7-14.5] and 22.9 % [95%CI 15.8-31.8] of patients died. CONCLUSIONS PCC for FXaI-associated bleeding was associated with hemostatic efficacy in two-thirds of patients and thromboembolic events were uncommon. PCC represents a promising treatment strategy for FXaI-associated bleeding.
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Affiliation(s)
- Joseph R Shaw
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
| | | | - Yan Xu
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Jerrold H Levy
- Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Sam Schulman
- Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Obstetrics and Gynecology and Perinatal Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Deborah Siegal
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Dar Dowlatshahi
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Melanie Tokessy
- Department of Pathology and Laboratory Medicine, Division of Hematology and Transfusion Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Hakan Buyukdere
- Department of Pathology and Laboratory Medicine, Division of Hematology and Transfusion Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Marc Carrier
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Lana A Castellucci
- Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
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Levy JH, Shaw JR, Castellucci LA, Connors JM, Douketis J, Lindhoff-Last E, Rocca B, Samama CM, Siegal D, Weitz JI. Reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2024; 22:2889-2899. [PMID: 39029742 DOI: 10.1016/j.jtha.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 07/21/2024]
Abstract
The currently approved direct oral anticoagulants (DOACs) are increasingly used in clinical practice. Although serious bleeding risks are lower with DOACs than with vitamin K antagonists, bleeding remains the most frequent side effect. Andexanet alfa and idarucizumab are the currently approved specific reversal agents for oral factor (F)Xa inhibitors and dabigatran, respectively. Our prior guidance document was published in 2016, but with more information available on the utility and increased use of these reversal agents and other bleeding management strategies, we have updated this International Society on Thrombosis and Haemostasis guidance document on DOAC reversal. In this narrative review, we compare the mechanism of action of specific and nonspecific reversal agents, review the clinical data supporting their use, and provide guidance on when reversal is indicated. In addition, we briefly discuss the reversal of oral FXIa inhibitors, a new class of DOACs currently under clinical development.
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Affiliation(s)
- Jerrold H Levy
- Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
| | - Joseph R Shaw
- Department of Medicine, Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada
| | - Lana A Castellucci
- Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada
| | - Jean M Connors
- Hematology Division Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - James Douketis
- Department of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Edelgard Lindhoff-Last
- Department of Vascular Medicine and Hemostaseology, Coagulation Research Centre Bethanien Hospital, Frankfurt, Germany
| | - Bianca Rocca
- Department of Safety and Bioethics-Section of Pharmacology, Catholic University School of Medicine, Rome, Italy; NeuroFarBa Department, University of Florence, Florence, Italy
| | - Charles Marc Samama
- Department of Anaesthesia, Intensive Care and Perioperative Medicine, Groupement Hospitalier Universitaire Assistance Publique - Hôpitaux de Paris Centre, Université Paris Cité, Paris, France
| | - Deborah Siegal
- Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada
| | - Jeffrey I Weitz
- Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
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