1
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Mestareehi A. Comprehensive and robust stability-indicating reversed phase high performance liquid chromatography (RP-HPLC) method for Rivaroxaban: synergistic integration of infrared spectroscopy and clinical pharmacology insights. Front Chem 2025; 13:1551189. [PMID: 40351528 PMCID: PMC12062752 DOI: 10.3389/fchem.2025.1551189] [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: 01/07/2025] [Accepted: 03/24/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Rivaroxaban is an anticoagulant medication that targets a key stage in the blood clotting process, preventing the formation and growth of clots. It is commonly used to prevent thrombosis or inhibit the enlargement of existing clots. Rivaroxaban functions as a Factor Xa inhibitor and is indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, treating deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as reducing the risk of recurrent DVT and PE, and prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery. Methods A robust, precise, and selective reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated for analyzing Rivaroxaban in raw materials. Isocratic elution at a flow rate of 1 mL/min was performed using a Thermo ODS Hypersil C18 column (4.6 × 250 mm, 5 µm) at ambient temperature. The mobile phase consisted of monobasic potassium phosphate at pH 2.9 and acetonitrile in a 70:30 (v/v) ratio, with UV detection at 249 nm. Results Linearity was established in the concentration range of 50-1,000 ppm (R2 = 0.999), and the retention time for Rivaroxaban was approximately 12 min. The percentage relative standard deviation (RSD) for precision and accuracy was consistently below 2.0%, ensuring method reliability. Solution stability studies confirmed the stability of Rivaroxaban over the analysis period, as no peak loss, degradation, or additional peaks were observed between the first and last injections. Furthermore, forced degradation studies were conducted under various stress conditions, including acid and base hydrolysis, as well as hydrogen peroxide oxidation. The method successfully resolved Rivaroxaban from its degradation products, demonstrating its stability-indicating capability. Conclusion Rivaroxaban is a novel oral anticoagulant that selectively and directly inhibits factor Xa. A method has been developed and validated for its analysis, adhering to guidelines from the International Conference on Harmonisation (ICH) and the U.S. Pharmacopeia (USP). The validation process assessed parameters such as specificity, robustness, linearity, accuracy, precision, limit of detection (LOD), and limit of quantitation (LOQ). The LOD for impurities and degradants was determined to be 0.3 ppm, while the LOQ was 1 ppm. This stability-indicating method is highly suitable for routine quality control and analytical applications in both raw materials and finished drug products, owing to its simplicity, efficiency, and robustness.
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Affiliation(s)
- Aktham Mestareehi
- Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman, Jordan
- Department of Pharmaceutical Sciences, School of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United States
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern Illinois University, Chicago, IL, United States
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2
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Miceli G, Ciaccio AM, Tuttolomondo A. Challenges and Opportunities of Direct Oral Anticoagulant (DOAC) Therapy in Complex Clinical Scenarios: A Comprehensive Review and Practical Guide. J Clin Med 2025; 14:2914. [PMID: 40363949 PMCID: PMC12072619 DOI: 10.3390/jcm14092914] [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: 03/14/2025] [Revised: 04/07/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Direct oral anticoagulants (DOACs) have emerged as a preferred alternative to vitamin K antagonists (VKAs) for the prevention and treatment of thromboembolic disorders, offering improved safety, predictable pharmacokinetics, and ease of administration. Despite these advantages, their use in complex clinical scenarios presents significant challenges that necessitate individualized therapeutic strategies. This comprehensive review explores the efficacy, safety, and limitations of DOAC therapy in special populations, including patients with renal or hepatic impairment, obesity, cancer-associated thrombosis, and antiphospholipid syndrome. Additionally, we examine their role in uncommon thrombotic conditions such as superficial venous thrombosis, embolic stroke of undetermined source, upper extremity vein thrombosis, inferior vena cava thrombosis, pelvic vein thrombosis, and cerebral vein thrombosis. The pharmacokinetic variability of DOACs in renal and hepatic dysfunction requires caution to balance the bleeding and thrombotic risks. In obesity, altered drug distribution and metabolism raise concerns regarding appropriate dosing and therapeutic efficacy. Cancer-associated thrombosis presents a complex interplay of prothrombotic mechanisms, necessitating careful selection of anticoagulant therapy. Furthermore, the use of DOACs in antiphospholipid syndrome remains controversial due to concerns about recurrent thrombotic events. Finally, in some unusual scenarios like inferior vena cava, pelvic vein, and cerebral vein thrombosis, the use of DOACs has scarce evidence. This review aims to guide clinicians in optimizing anticoagulation management in challenging patient populations by synthesizing current evidence and providing practical recommendations.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE) Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Anna Maria Ciaccio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE) Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE) Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90100 Palermo, Italy
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3
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Wu H, Yu Q, Jin P, Huo L, An J. Association of rivaroxaban plasma trough concentrations with clinical characteristics and outcomes. Front Pharmacol 2025; 16:1563745. [PMID: 40170732 PMCID: PMC11958709 DOI: 10.3389/fphar.2025.1563745] [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: 01/20/2025] [Accepted: 02/24/2025] [Indexed: 04/03/2025] Open
Abstract
Background Rivaroxaban use has increased significantly among older adults; however, no definitive plasma concentration thresholds for bleeding or thrombosis have been established. However, dose adjustments for this population remain controversial. Methods Between January 2022 and August 2023, we analyzed trough plasma samples from hospitalized patients treated with rivaroxaban for at least three consecutive days. Clinical data, including demographics, comorbidities, and adverse events, were extracted from electronic medical records. The plasma concentrations of rivaroxaban were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Statistical analyses were performed to identify factors influencing rivaroxaban exposure and clinical outcomes. Results Among 360 plasma samples analyzed (55% male; median age: 72 years), age (P = 0.042) and renal function (P = 0.002) were significant predictors of rivaroxaban concentration-to-dose ratio. Bleeding events were associated with higher trough concentrations (median: 81.85 ng/mL in the bleeding group vs. 26.80 ng/mL in others; P < 0.001) and were more common in patients with malignancies or prior bleeding history. Thrombotic events occurred predominantly in older patients with a history of stroke (P < 0.05). Patients who died were older and had higher CHA2DS2-VASc scores (P < 0.05), prolonged prothrombin times (P < 0.001), and multiple comorbidities. Conclusion Routine monitoring of rivaroxaban plasma concentrations may improve safety in older adults with multiple comorbidities or impaired hepatic, renal, or coagulation functions. Further research is required to establish specific therapeutic thresholds for bleeding and thrombosis.
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Affiliation(s)
- Huizhen Wu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
| | - Qiaoling Yu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
- Graduate School, Hebei Medical University, Shijiazhuang, China
| | - Panpan Jin
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
- Graduate School, Hebei Medical University, Shijiazhuang, China
| | - Lijing Huo
- Department of Laboratory, Hebei General Hospital, Shijiazhuang, China
| | - Jing An
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
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Tombolini E, Squizzato A, Podda GM, Aghemo A, Ferri N, Segato S, Poli D, Donadini MP. Drug-Drug Interactions Between DAAs and Anticoagulants or Antiplatelets: A Position Paper of the Italian Anticoagulation Clinics. Liver Int 2025; 45:e16177. [PMID: 39736105 DOI: 10.1111/liv.16177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/18/2024] [Accepted: 11/09/2024] [Indexed: 01/01/2025]
Abstract
The natural history of chronic hepatitis C virus (HCV) infection has changed after the introduction of direct-acting antiviral agents (DAAs). Screening programs have been ongoing to reach the World Health Organisation's goal of HCV elimination by 2030, and most infected people are eligible for treatment. Given the increased cardiovascular risk in people with HCV infection and the metabolic pathways of DAAs, it is not uncommon to face the issue of drug-drug interactions (DDIs) with antiplatelet or anticoagulant drugs. In the absence of clinical trials, we offer suggestions to deal with DDIs in case of treatment of patients with DAAs who are also receiving antiplatelet or anticoagulant drugs, based on the best available evidence from pharmacodynamics and pharmacokinetics studies in conjunction with clinical experience in the field of haemostasis and thrombosis.
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Affiliation(s)
- Elisabetta Tombolini
- Emergency Medicine and Thrombosis and Haemostasis Center, ASST Sette Laghi, Varese, Italy
| | - Alessandro Squizzato
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
- Research Center on Thromboembolic Disorders and Antithrombotic Therapies, ASST Lariana, University of Insubria, Como, Italy
| | - Gian Marco Podda
- Dipartimento di Scienza della Salute, S.C. Medicina Generale II, Ospedale San Paolo, ASST Santi Paolo e Carlo, Università Degli Studi di Milano, Milano, Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Nicola Ferri
- Department of Medicine, University of Padova, Padova, Italy
| | - Simone Segato
- Gastroenterology and Digestive Endoscopy, ASST Sette Laghi, Varese, Italy
| | - Daniela Poli
- Thrombosis Centre, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy
| | - Marco Paolo Donadini
- Emergency Medicine and Thrombosis and Haemostasis Center, ASST Sette Laghi, Varese, Italy
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
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5
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Liu YB, Liang Y, Liu HC, Feng GX, Zhou XC, Zhang L, Zhang XL, Li Q, Ren BY, Xia X, Zhu J, Wu CT, Jin JD. Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Recombinant Neorudin, a New Anticoagulant Drug in Patients With Acute Coronary Syndrome. Clin Pharmacol Drug Dev 2024; 13:1189-1197. [PMID: 39385558 DOI: 10.1002/cpdd.1478] [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: 03/05/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024]
Abstract
This study evaluated the safety, tolerability, pharmacodynamics, and pharmacokinetics of recombinant neorudin (EPR-hirudin [EH]) in patients with acute coronary syndrome (ACS), providing a basis for further therapeutic research. This open-label, single-center, nonrandomized, nonblinded, and noncontrolled trial categorized 24 patients with nonprogressive ACS who met the screening criteria into 3 groups. They received an intravenous injection of neorudin (0.4 mg/kg), followed by an intravenous drip at doses of 0.15, 0.30, and 0.45 mg/kg/h for 3 days in the low-, medium-, and high-dose groups, respectively. The safety, tolerability, pharmacodynamics, and pharmacokinetics of EH were assessed after treatment, indicating that neorudin was safe and well tolerated in nonprogressive ACS. No serious adverse events or clinical composite end points were observed. The activated partial thromboplastin time and thrombin time increased significantly and dose dependently following EH administration across all groups compared to pretreatment values. Conversely, thrombin activity significantly decreased after drug administration but returned to baseline levels shortly after drug withdrawal. Within the administered dose range, neorudin exposure increased with the dose, and its half-life was approximately 2 hours. Neorudin was found to be safe and tolerable for treating patients with nonprogressive ACS, demonstrating therapeutic efficacy at doses up to 0.45 mg/kg/h over a 3-day period.
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Affiliation(s)
- Yu-Bin Liu
- Beijing Institute of Radiation Medicine, Beijing, China
- Institute of Zhejiang University, Quzhou, Zhejiang, China
| | - Yan Liang
- Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui-Chen Liu
- Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Guang-Xun Feng
- Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xing-Chen Zhou
- Beijing Institute of Radiation Medicine, Beijing, China
- Institute of Zhejiang University, Quzhou, Zhejiang, China
| | - Lin Zhang
- Beijing Institute of Radiation Medicine, Beijing, China
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Zhejiang, China
| | | | - Qiang Li
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Bo-Yuan Ren
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Xia Xia
- Beijing SH Biotechnology Co., Ltd., Beijing, China
| | - Jun Zhu
- Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Chu-Tse Wu
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Ji-de Jin
- Beijing Institute of Radiation Medicine, Beijing, China
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Zhang M, Zhang S, Wang L, Zhang Z, Hu Q, Liu D. Key Factors for Improving Predictive Accuracy and Avoiding Overparameterization of the PBPK Absorption Model in Food Effect Studies of Weakly Basic Water-Insoluble Compounds in Immediate Release Formulations. Pharmaceutics 2024; 16:1324. [PMID: 39458653 PMCID: PMC11511194 DOI: 10.3390/pharmaceutics16101324] [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: 08/08/2024] [Revised: 09/16/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Physiologically based pharmacokinetic (PBPK) absorption models are instrumental for assessing drug absorption prior to clinical food effect studies, though discrepancies in predictive and actual outcomes are observed. This study focused on immediate release formulations of weakly basic water-insoluble compounds, namely rivaroxaban, ticagrelor, and PB-201, to investigate factors that could improve the predictive accuracy of PBPK models regarding food effects. Methods: Comprehensive in vitro experimental results provided the basis for the development of mechanistic absorption models, which were then combined with mechanistic disposition models to predict the systemic exposure of the model drugs in both fasted and fed states. Results: The developed PBPK models showed moderate to high predictive accuracy for food effects in Caucasian populations. For the Chinese population, the ticagrelor model's initial overestimation of fed-state absorption was addressed by updating the permeability parameters from Caco-2 cell assays to those derived from parallel artificial membrane permeability assays in FaSSIF and FeSSIF media. This refinement was also applied to the rivaroxaban and ticagrelor models, leading to a more accurate representation of absorption in Caucasians. Conclusions: This study highlights the importance of apparent permeability in enhancing the predictive accuracy of PBPK absorption models for weakly basic water-insoluble compounds. Furthermore, the precipitation of PB-201 in the two-stage transfer experiments suggests that precipitation may not be a universal phenomenon for such compounds in vivo. Consequently, the precipitation rate constant, a theoretically essential parameter, should be determined based on experimental evidence to avoid overparameterization and ensure robust predictive accuracy of PBPK models.
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Affiliation(s)
- Miao Zhang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China;
- Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, MA 02115, USA
| | - Shudong Zhang
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Lin Wang
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Zhe Zhang
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Qin Hu
- NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Institute for Drug Control, Beijing 102206, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China;
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7
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Kocjan M, Kosowski M, Mazurkiewicz M, Muzyk P, Nowakowski K, Kawecki J, Morawiec B, Kawecki D. Bleeding Complications of Anticoagulation Therapy in Clinical Practice-Epidemiology and Management: Review of the Literature. Biomedicines 2024; 12:2242. [PMID: 39457555 PMCID: PMC11505300 DOI: 10.3390/biomedicines12102242] [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: 08/21/2024] [Revised: 09/14/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024] Open
Abstract
Due to their very wide range of indications, anticoagulants are one of the most commonly used drug groups. Although these drugs are characterized by different mechanisms of action, the most common complication of their use is still bleeding episodes, the frequency of which depends largely on the clinical condition of the patient using such therapy. For this reason, to this day, the best method of preventing bleeding complications remains the assessment of bleeding risk using scales such as HAS-BLED. There are many reports in the literature assessing the occurrence of this type of complication after the use of drugs affecting the coagulation process, as well as many reports comparing individual groups of drugs with different mechanisms of action. However, there are still no clear guidelines that would indicate which group of anticoagulants should be preferred in particular groups of patients. The aim of our article is to summarize the data collected so far regarding the safety of using specific groups of anticoagulants and the frequency of bleeding complications after their use.
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Affiliation(s)
- Maciej Kocjan
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (M.K.); (M.M.); (P.M.); (J.K.); (D.K.)
| | - Michał Kosowski
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland;
| | - Michalina Mazurkiewicz
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (M.K.); (M.M.); (P.M.); (J.K.); (D.K.)
| | - Piotr Muzyk
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (M.K.); (M.M.); (P.M.); (J.K.); (D.K.)
| | - Krzysztof Nowakowski
- Department of Urology and Urological Oncology in Rybnik, Faculty of Medical Sciences in Zabrze, Academy of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Jakub Kawecki
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (M.K.); (M.M.); (P.M.); (J.K.); (D.K.)
| | - Beata Morawiec
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (M.K.); (M.M.); (P.M.); (J.K.); (D.K.)
| | - Damian Kawecki
- 2nd Department of Cardiology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, 40-055 Katowice, Poland; (M.K.); (M.M.); (P.M.); (J.K.); (D.K.)
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Carlin S, Cuker A, Gatt A, Gendron N, Hernández-Gea V, Meijer K, Siegal DM, Stanworth S, Lisman T, Roberts LN. Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH. J Thromb Haemost 2024; 22:2653-2669. [PMID: 38823454 DOI: 10.1016/j.jtha.2024.05.023] [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: 02/15/2024] [Revised: 05/14/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024]
Abstract
While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.
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Affiliation(s)
- Stephanie Carlin
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
| | - Adam Cuker
- Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alexander Gatt
- Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
| | - Nicolas Gendron
- University Paris Cité, Innovative Therapies in Haemostasis, National Institute for Health and Medical Research (INSERM), Paris, France; Hematology Department, Assistance Publique Hôpitaux de Paris, Centre-Université de Paris (APHP, CUP), Paris, France
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, Barcelona, Spain; Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain
| | - Karina Meijer
- Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
| | - Deborah M Siegal
- Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Simon Stanworth
- Transfusion Medicine, National Health Service Blood and Transplant, Oxford, United Kingdom; Department of Haematology, Oxford University Hospitals, National Health Service Foundation Trust, Oxford, United Kingdom; Radcliffe Department of Medicine, University of Oxford and National Institute for Health and Care Research Oxford Biomedical Research Centre (Haematology), Oxford, United Kingdom
| | - Ton Lisman
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lara N Roberts
- King's Thrombosis Centre, Department of Haematological Medicine, King's College Hospital, London, United Kingdom
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9
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Jannati S, Patnaik R, Banerjee Y. Beyond Anticoagulation: A Comprehensive Review of Non-Vitamin K Oral Anticoagulants (NOACs) in Inflammation and Protease-Activated Receptor Signaling. Int J Mol Sci 2024; 25:8727. [PMID: 39201414 PMCID: PMC11355043 DOI: 10.3390/ijms25168727] [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: 06/16/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 09/02/2024] Open
Abstract
Non-vitamin K oral anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs-apixaban, rivaroxaban, edoxaban, and dabigatran-not only as anticoagulants, but also as modulators of inflammation via protease-activated receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as factor Xa (FXa) and thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles, but also paves the way for future research and clinical applications in inflammation and cardiovascular health.
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Affiliation(s)
- Shirin Jannati
- Yajnavalkaa Banerrji Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health, Dubai P.O. Box 505055, United Arab Emirates; (S.J.); (R.P.)
| | - Rajashree Patnaik
- Yajnavalkaa Banerrji Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health, Dubai P.O. Box 505055, United Arab Emirates; (S.J.); (R.P.)
| | - Yajnavalka Banerjee
- Yajnavalkaa Banerrji Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health, Dubai P.O. Box 505055, United Arab Emirates; (S.J.); (R.P.)
- Centre for Medical Education, University of Dundee, Dundee DD1 4HN, UK
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10
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Pereira Portela C, Gautier LA, Zermatten MG, Fraga M, Moradpour D, Bertaggia Calderara D, Aliotta A, Veuthey L, De Gottardi A, Stirnimann G, Alberio L. Direct oral anticoagulants in cirrhosis: Rationale and current evidence. JHEP Rep 2024; 6:101116. [PMID: 39100819 PMCID: PMC11296254 DOI: 10.1016/j.jhepr.2024.101116] [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: 10/04/2023] [Revised: 04/19/2024] [Accepted: 04/30/2024] [Indexed: 08/06/2024] Open
Abstract
Cirrhosis is a major health concern worldwide with a complex pathophysiology affecting various biological systems, including all aspects of haemostasis. Bleeding risk is mainly driven by portal hypertension, but in end-stage liver disease it is further increased by alterations in haemostatic components, including platelet function, coagulation, and fibrinolysis. Concurrently, patients with cirrhosis are prone to venous thromboembolic events (VTE) because of the altered haemostatic balance, in particular an increase in thrombin generation. In patients with cirrhosis, vitamin K antagonists (VKA) and low molecular weight heparins (LMWH) are currently the standard of care for VTE prevention, with VKA also being standard of care for stroke prevention in those with atrial fibrillation. However, direct oral anticoagulants (DOAC) could have specific advantages in this patient population. Clinical experience suggests that DOAC are a safe and possibly more effective alternative to traditional anticoagulants for the treatment of VTE in patients with compensated cirrhosis. In addition, emerging data suggest that primary prophylactic treatment with anticoagulants may improve clinical outcomes in patients with cirrhosis by reducing the risk of hepatic decompensation. The selection of the most appropriate DOAC remains to be clarified. This review focuses on the rationale for the use of DOAC in patients with cirrhosis, the specific effects of the different DOAC (as assessed by in vitro and in vivo pharmacokinetic and pharmacodynamic studies), as well as clinical outcomes in patients with cirrhosis on DOAC.
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Affiliation(s)
- Cindy Pereira Portela
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Lucas A. Gautier
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Maxime G. Zermatten
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Debora Bertaggia Calderara
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Alessandro Aliotta
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Lucas Veuthey
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
| | - Andrea De Gottardi
- Luzerner Kantonsspital, Lucerne, Switzerland
- Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland
| | - Lorenzo Alberio
- Hemostasis and Platelet Research Laboratory, Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), CH-1010 Lausanne, Switzerland
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11
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Ma C, Wu S, Liu S, Han Y. Chinese guidelines for the diagnosis and management of atrial fibrillation. Pacing Clin Electrophysiol 2024; 47:714-770. [PMID: 38687179 DOI: 10.1111/pace.14920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 05/02/2024]
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients' quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past two decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of the guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice timely and fully, the Chinese Society of Cardiology of Chinese Medical Association and the Heart Rhythm Committee of Chinese Society of Biomedical Engineering jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. The guidelines comprehensively elaborated on various aspects of AF management and proposed the CHA2DS2‑VASc‑60 stroke risk score based on the characteristics of the Asian AF population. The guidelines also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control.
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Affiliation(s)
- Changsheng Ma
- Chinese Society of Cardiology, Chinese Medical Association, Heart Rhythm Committee of Chinese Society of Biomedical Engineering, Beijing, China
| | - Shulin Wu
- Chinese Society of Cardiology, Chinese Medical Association, Heart Rhythm Committee of Chinese Society of Biomedical Engineering, Beijing, China
| | - Shaowen Liu
- Chinese Society of Cardiology, Chinese Medical Association, Heart Rhythm Committee of Chinese Society of Biomedical Engineering, Beijing, China
| | - Yaling Han
- Chinese Society of Cardiology, Chinese Medical Association, Heart Rhythm Committee of Chinese Society of Biomedical Engineering, Beijing, China
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12
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Diesveld MME, Pijnenburg DWMJ, Weersink RA, Barzel I, Drenth JPH, Lisman T, Metselaar HJ, Monster-Simons MH, Mulder MB, Okel E, Taxis K, Borgsteede SD. Recommendations for the safe use of direct oral anticoagulants in patients with cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data. Eur J Clin Pharmacol 2024; 80:797-812. [PMID: 38430266 DOI: 10.1007/s00228-024-03648-y] [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: 12/22/2023] [Accepted: 02/03/2024] [Indexed: 03/03/2024]
Abstract
PURPOSE The popularity of direct oral anticoagulants (DOACs) is increasing among patients with cirrhosis. Cirrhosis has a major impact on the pharmacokinetics of drugs, potentially increasing adverse events. Safe use of drugs in cirrhosis requires a diligent risk-benefit analysis. The aim of this study is to develop practice recommendations for safe use of DOACs in cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data. METHODS We conducted a systematic literature search to identify studies on pharmacokinetics, pharmacodynamics and safety of DOACs in cirrhosis. Data were collected and presented in summary tables by severity of cirrhosis using the Child-Turcotte-Pugh (CTP) classification. A multidisciplinary expert panel evaluated the results and classified the DOACs according to safety. RESULTS Fifty four studies were included. All DOACs were classified as 'no additional risks known' for CTP A. For CTP B, apixaban, dabigatran and edoxaban were classified as 'no additional risks known'. Apixaban and edoxaban showed fewer adverse events in patients with cirrhosis, while dabigatran may be less impacted by severity of cirrhosis based on its pharmacokinetic profile. Rivaroxaban was classified as 'unsafe' in CTP B and C based on significant pharmacokinetic alterations. Due to lack of data, apixaban, dabigatran and edoxaban were classified as 'unknown' for CTP C. CONCLUSION DOACs can be used in patients with CTP A cirrhosis, and apixaban, dabigatran and edoxaban can also be used in CTP B. It is recommended to avoid rivaroxaban in CTP B and C. There is insufficient evidence to support safe use of other DOACs in CTP C cirrhosis.
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Affiliation(s)
| | | | - Rianne A Weersink
- Deventer Hospital, Department of Clinical Pharmacy, Deventer, The Netherlands
- Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands
| | - Ina Barzel
- Erasmus University Medical Center, Department of Hospital Pharmacy, Rotterdam, The Netherlands
| | - Joost P H Drenth
- Radboud University Medical Center, Department of Gastroenterology, Nijmegen, The Netherlands
| | - Ton Lisman
- University of Groningen, University Medical Center Groningen, Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Groningen, The Netherlands
| | - Herold J Metselaar
- Erasmus University Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, The Netherlands
| | - Margje H Monster-Simons
- Dutch Medicines Evaluation Board, Utrecht, The Netherlands
- University of Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
| | - Midas B Mulder
- Erasmus University Medical Center, Department of Hospital Pharmacy, Rotterdam, The Netherlands
| | - Eline Okel
- Pharmacy Zorgapotheken Flevoland, Almere, The Netherlands
| | - Katja Taxis
- University of Groningen, Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, -Epidemiology & -Economics, Groningen, The Netherlands
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13
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Tadokoro T, Tani J, Manabe T, Takuma K, Nakahara M, Oura K, Mimura S, Fujita K, Nomura T, Morishita A, Kobara H, Himoto T, Ono M, Masaki T. Effectiveness of edoxaban in portal vein thrombosis associated with liver cirrhosis. Sci Rep 2024; 14:10784. [PMID: 38734732 PMCID: PMC11088711 DOI: 10.1038/s41598-024-60235-y] [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: 09/11/2023] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child-Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.
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Affiliation(s)
- Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
| | - Takushi Manabe
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
- Gastroenterology and Hepatology, HITO Medical Center, 788-1 Kamibun-cho, Shikokutyuou, Ehime, 799-0121, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Takashi Himoto
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1, Hara, Mure-Cho, Takamatsu, Kagawa, 761-0123, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
- Division of Innovative Medicine for Hepatobiliary and Pancreatology, Faculty of Medicine, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
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14
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Douros A, Cui Y, Platt RW, Filion KB, Sebastiani G, Renoux C. Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study. Thromb Res 2024; 237:71-78. [PMID: 38552497 DOI: 10.1016/j.thromres.2024.03.024] [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: 11/02/2023] [Revised: 03/19/2024] [Accepted: 03/22/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND AND AIMS The effects of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) and liver disease remain poorly understood. Our multinational cohort study assessed the effectiveness and safety of DOACs in this high-risk population. METHODS We assembled two population-based cohorts in United Kingdom and in Québec of NVAF patients with liver disease initiating DOACs or vitamin K antagonists (VKAs) between 2011 and 2020. Using an as-treated exposure definition, we compared DOACs to VKAs and apixaban to rivaroxaban. After inverse probability of treatment weighting, Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95 % confidence intervals (CIs) of ischemic stroke and major bleeding. Site-specific estimates were pooled using random-effects models. Analyses were repeated among NVAF patients with cirrhosis. RESULTS There were 11,881 NVAF patients with liver disease (2683 with cirrhosis). Among those, 8815 initiated DOACs (4414 apixaban, 2497 rivaroxaban) and 3696 VKAs. The HRs (95 % CIs) for DOACs compared to VKAs were 1.01 (0.76-1.34) for ischemic stroke and 0.87 (0.77-0.99) for major bleeding. Results were consistent among patients with cirrhosis. The HRs (95 % CIs) for apixaban compared to rivaroxaban were 0.85 (0.60-1.20) for ischemic stroke and 0.80 (0.68-0.95) for major bleeding. This decreased bleeding risk was not observed among patients with cirrhosis (HR, 1.01; 95 % CI 0.72-1.43). CONCLUSIONS Among NVAF patients with liver disease, DOACs were as effective and slightly safer than VKAs, and apixaban was as effective but safer than rivaroxaban. The safety benefit with apixaban was not present among patients with cirrhosis.
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Affiliation(s)
- Antonios Douros
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Québec, Canada; Department of Medicine, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
| | - Ying Cui
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada
| | - Robert W Platt
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Department of Pediatrics, McGill University, Montreal, Québec, Canada
| | - Kristian B Filion
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Québec, Canada; Department of Medicine, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada
| | - Giada Sebastiani
- Department of Medicine, McGill University, Montreal, Québec, Canada; Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Québec, Canada
| | - Christel Renoux
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Québec, Canada; Department of Medicine, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada
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15
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Ayoub M, Faris C, Chumbe JT, Daglilar E, Anwar N, Naravadi V. Safety of DOACs in patients with Child-Pugh Class C cirrhosis and atrial fibrillation. JGH Open 2024; 8:e13074. [PMID: 38699468 PMCID: PMC11063728 DOI: 10.1002/jgh3.13074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 03/20/2024] [Accepted: 04/12/2024] [Indexed: 05/05/2024]
Abstract
Background Anticoagulation (AC) is used for stroke prevention in atrial fibrillation (AF). Direct Oral Anticoagulants (DOACs) are safe in patients with AF without cirrhosis, they are hardly studied in patients with advanced cirrhosis. Our study evaluates the safety and outcomes of DOACs in patients with Child-Pugh class C cirrhosis (CPC). Methods We queried TriNetX Database. Patients with CPC and AF were divided into three cohorts: patients on DOACs, no AC, and warfarin. Three study arms were created using a 1:1 propensity score matching system (PSM). Results Totally 16 029 patients met the inclusion criteria. Of those, 20.2% (n = 3235) were on DOACs, 47.1% (n = 7552) were not on AC, and 32.7% (n = 5242) were on warfarin. First arm comparing AC versus no AC, a statistically significant benefit was identified in 3-year mortality risk (47% vs 71%, P < 0.0001) and transplant status (17% vs 5%, p < 0.0001) with AC. However, no significant difference was identified regarding intracranial hemorrhage and GI bleeding risk. Second arm comparing patients on DOACs versus no AC, we identified mortality benefit (40% vs 72%, P < 0.0001) and a higher transplant rate (9% vs 3.2%, P < 0.0001) with DOACs. Intracranial hemorrhage rates (6% vs 4%, P = 0.03) were higher in patients on DOACs. Third arm comparing patients on DOACs versus Warfarin, a statistically significant lower risk of intracranial hemorrhage (6.6% vs 8.7%, P = 0.004) and GI bleed (2% vs 2.4%, P < 0.0001) were identified in patients on DOACs. Conclusion Anticoagulation is safe in patients with CPC with AF and may provide a mortality benefit. DOACs are a safer alternative to warfarin.
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Affiliation(s)
- Mark Ayoub
- West Virginia University Charleston Division, Internal Medicine DepartmentCharleston Area Medical CenterCharlestonWest VirginiaUSA
| | - Carol Faris
- Marshall University School of MedicineSurgery DepartmentHuntingtonWest VirginiaUSA
| | - Julton Tomanguillo Chumbe
- West Virginia University Charleston Division, Internal Medicine DepartmentCharleston Area Medical CenterCharlestonWest VirginiaUSA
| | - Ebubekir Daglilar
- Department of Gastroenterology, Charleston DivisionWest Virginia University School of Medicine, Charleston Area Medical CenterCharlestonWest VirginiaUSA
| | - Nadeem Anwar
- Department of Gastroenterology, Charleston DivisionWest Virginia University School of Medicine, Charleston Area Medical CenterCharlestonWest VirginiaUSA
| | - Vishnu Naravadi
- Department of Gastroenterology, Charleston DivisionWest Virginia University School of Medicine, Charleston Area Medical CenterCharlestonWest VirginiaUSA
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16
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MA CS, WU SL, LIU SW, HAN YL. Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. J Geriatr Cardiol 2024; 21:251-314. [PMID: 38665287 PMCID: PMC11040055 DOI: 10.26599/1671-5411.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024] Open
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients' quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past two decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice in a timely and comprehensive manner, the Chinese Society of Cardiology of the Chinese Medical Association and the Heart Rhythm Committee of the Chinese Society of Biomedical Engineering have jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. The guidelines have comprehensively elaborated on various aspects of AF management and proposed the CHA2DS2-VASc-60 stroke risk score based on the characteristics of AF in the Asian population. The guidelines have also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control.
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17
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Cross B, Turner RM, Zhang JE, Pirmohamed M. Being precise with anticoagulation to reduce adverse drug reactions: are we there yet? THE PHARMACOGENOMICS JOURNAL 2024; 24:7. [PMID: 38443337 PMCID: PMC10914631 DOI: 10.1038/s41397-024-00329-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 02/11/2024] [Accepted: 02/15/2024] [Indexed: 03/07/2024]
Abstract
Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.
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Affiliation(s)
- Benjamin Cross
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
| | - Richard M Turner
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
- GSK, Stevenage, Hertfordshire, SG1 2NY, UK
| | - J Eunice Zhang
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK
| | - Munir Pirmohamed
- Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, 1-5 Brownlow Street, Liverpool, L69 3GL, UK.
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18
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Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, Deswal A, Eckhardt LL, Goldberger ZD, Gopinathannair R, Gorenek B, Hess PL, Hlatky M, Hogan G, Ibeh C, Indik JH, Kido K, Kusumoto F, Link MS, Linta KT, Marcus GM, McCarthy PM, Patel N, Patton KK, Perez MV, Piccini JP, Russo AM, Sanders P, Streur MM, Thomas KL, Times S, Tisdale JE, Valente AM, Van Wagoner DR. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2024; 149:e1-e156. [PMID: 38033089 PMCID: PMC11095842 DOI: 10.1161/cir.0000000000001193] [Citation(s) in RCA: 807] [Impact Index Per Article: 807.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
AIM The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.
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Affiliation(s)
| | | | | | | | | | | | - Anita Deswal
- ACC/AHA Joint Committee on Clinical Practice Guidelines liaison
| | | | | | | | | | - Paul L Hess
- ACC/AHA Joint Committee on Performance Measures liaison
| | | | | | | | | | - Kazuhiko Kido
- American College of Clinical Pharmacy representative
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19
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Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, Deswal A, Eckhardt LL, Goldberger ZD, Gopinathannair R, Gorenek B, Hess PL, Hlatky M, Hogan G, Ibeh C, Indik JH, Kido K, Kusumoto F, Link MS, Linta KT, Marcus GM, McCarthy PM, Patel N, Patton KK, Perez MV, Piccini JP, Russo AM, Sanders P, Streur MM, Thomas KL, Times S, Tisdale JE, Valente AM, Van Wagoner DR. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2024; 83:109-279. [PMID: 38043043 PMCID: PMC11104284 DOI: 10.1016/j.jacc.2023.08.017] [Citation(s) in RCA: 260] [Impact Index Per Article: 260.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2023]
Abstract
AIM The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.
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20
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Song JJ, Jackson NJ, Shang H, Honda HM, Boulier K. Assessing Safety of Anticoagulation for Atrial Fibrillation in Patients with Cirrhosis: A Real-World Outcomes Study. J Cardiovasc Pharmacol Ther 2024; 29:10742484241256271. [PMID: 39053441 PMCID: PMC11981305 DOI: 10.1177/10742484241256271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
AIMS In patients with atrial fibrillation (AF) and stroke risk factors, randomized trials have demonstrated that anticoagulation decreases the risk of ischemic stroke. However, all trials to date have excluded patients with significant liver disease, leaving guidelines to extrapolate recommendations. We aim to evaluate the impact of anticoagulation on safety events in patients with AF and cirrhosis. METHODS AND RESULTS In this retrospective cohort study, we obtained de-identified health record data to extract anticoagulation strategy, comorbidities, prescriptions, lab values, and procedures for a cohort of patients with cirrhosis who develop AF. After selecting a propensity matched population to match patients with various anticoagulation strategies, we tracked data on outcomes for death, transfusion requirements, hospital and ICU admissions. After propensity score weighting and multivariable adjustment, anticoagulation strategy was associated with increased hospital admission count (OR = 1.74 per admission, P < .001), binary risk of hospital admission (OR = 1.54, P = .010) and risk of ICU admission (OR = 1.41, P = .047). We detected no significant differences in mortality, transfusion of blood products, or average length of stay. Direct oral anticoagulant (DOAC) prescriptions were associated with increased binary risk of hospital admission compared to warfarin prescriptions. In a third comparison, DOAC strategy alone was associated with increased hospital admission count (OR = 1.41 per admission, P < .001) and binary risk of hospital admission (OR = 1.52, P = .038) compared to no anticoagulation strategy. CONCLUSION Anticoagulation strategy in patients with cirrhosis and AF was associated with increased rate of hospital admission and ICU admission but not associated with increased risk of mortality or transfusion requirement.
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Affiliation(s)
- Justin J. Song
- Department of Medicine, UCLA Medical Center, Los Angeles, USA
| | | | - Helen Shang
- Department of Medicine, UCLA Medical Center, Los Angeles, USA
| | - Henry M. Honda
- Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, USA
| | - Kristin Boulier
- Division of Cardiology, Department of Medicine, UCLA Medical Center, Los Angeles, USA
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21
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Cheng C, Hua J, Xiong L. Comparison of the Efficacy and Safety of Direct Oral Anticoagulants and Warfarin in Cirrhotic Patients: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost 2024; 30:10760296241301402. [PMID: 39552309 PMCID: PMC11571256 DOI: 10.1177/10760296241301402] [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: 08/15/2024] [Revised: 10/20/2024] [Accepted: 11/01/2024] [Indexed: 11/19/2024] Open
Abstract
OBJECTIVE Currently, there is limited evidence regarding the use of direct oral anticoagulants (DOACs) for patients with liver cirrhosis (LC). We performed a meta-analysis to compare the efficacy and safety of DOACs versus warfarin in this population. METHODS We searched PubMed, Cochrane Library, Web of Science, Embase and Scopus databases from inception to August 2024. Clinical studies comparing the use of DOACs with warfarin in cirrhotic patients were included. Hazard ratios (HRs) with 95% CIs were estimated by either fixed or random effects models. Primary efficacy outcomes were ischemic stroke/thromboembolism (IS/TE) and all-cause death, the primary safety outcomes were the bleeding risks. RESULTS Sixteen studies were included (16 829 individuals). DOACs had similar benefits in preventing IS/TE (HR = 0.87, 95% CI: 0.69-1.10), but DOACs were significantly associated with reduced risk of all-cause death (HR = 0.87, 95% CI: 0.79-0.97). On the other hand, we observed significantly reduced risks of any bleeding (HR = 0.60; 95%CI: 0.37-0.95), major bleeding (HR = 0.72; 95%CI: 0.63-0.82), intracranial hemorrhage (ICH) (HR = 0.47; 95%CI: 0.30-0.73), and gastrointestinal bleeding (GIB) (HR = 0.72, 95% CI: 0.60-0.87) in patients receiving DOACs. Results were consistent in cirrhotic patients with AF. Furthermore, DOACs reduced the incidence of major bleeding (HR = 0.65, 95%CI: 0.55-0.78) and ICH (HR = 0.17, 95%CI: 0.04-0.76) in patients with moderate to severe cirrhosis. CONCLUSION Our study demonstrates that DOACs, compared with warfarin, exerted comparable efficacy and better safety and may represent a safer alternative to warfarin in cirrhotic patients.
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Affiliation(s)
- Chunwei Cheng
- School of Medicine, Jiangxi University of Technology, Nanchang, China
| | - Juan Hua
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Liang Xiong
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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22
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Afzal A. Direct oral anticoagulants to treat deep venous thrombosis and pulmonary embolism in patients with cirrhosis: are we there yet? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2023; 2023:289-293. [PMID: 38066879 PMCID: PMC10727053 DOI: 10.1182/hematology.2023000514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
A 59-year-old female with Child-Pugh class B cirrhosis attributed to nonalcoholic steatohepatitis complicated by hepatic encephalopathy, portal hypertension with esophageal varices, and thrombocytopenia is seen for management of an acute segmental right lower lobe pulmonary embolism in a clinic. She is hemodynamically stable. Complete blood count is notable for hemoglobin 11.6 g/dL and platelets 80 K/μL. Prothrombin time is 12.6 seconds; partial thromboplastin time, 33.7 seconds; and fibrinogen, 221 mg/dL. She was referred to discuss if a direct oral anticoagulant (DOAC) can be used for anticoagulation. What would you suggest?
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Affiliation(s)
- Amber Afzal
- Division of Hematology, Department of Medicine, Washington University, St Louis, MO
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23
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Hindley B, Lip GYH, McCloskey AP, Penson PE. Pharmacokinetics and pharmacodynamics of direct oral anticoagulants. Expert Opin Drug Metab Toxicol 2023; 19:911-923. [PMID: 37991392 DOI: 10.1080/17425255.2023.2287472] [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: 06/07/2023] [Accepted: 11/21/2023] [Indexed: 11/23/2023]
Abstract
INTRODUCTION Direct oral anticoagulants (DOACs) have overtaken vitamin K antagonists to become the most widely used method of anticoagulation for most indications. Their stable and predictable pharmacokinetics combined with relatively simple dosing, and the absence of routine monitoring has made them an attractive proposition for healthcare providers. Despite the benefits of DOACs as a class, important differences exist between individual DOAC drugs in respect of their pharmacokinetic and pharmacodynamic profiles with implications for dosing and reversal in cases of major bleeding. AREAS COVERED This review summarizes the state of knowledge relating to the pharmacokinetics of dabigatran (factor IIa/thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (factor Xa) inhibitors. We focus on pharmacokinetic differences between the drugs which may have clinically significant implications. EXPERT OPINION Patient-centered care necessitates a careful consideration of the pharmacokinetic and pharmacodynamic differences between DOACs, and how these relate to individual patient circumstances. Prescribers should be aware of the potential for pharmacokinetic drug interactions with DOACs which may influence prescribing decisions in patients with multiple comorbidities. In order to give an appropriate dose of DOAC drugs, accurate estimation of renal function using the Cockcroft-Gault formula using actual body weight is necessary. An increasing body of evidence supports the use of DOACs in patients who are obese, and this is becoming more routine in clinical practice.
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Affiliation(s)
- B Hindley
- Pharmacy Department, Aintree University Hospital, Liverpool, UK
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - G Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - A P McCloskey
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
| | - P E Penson
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
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24
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Hu T, Li YH, Han WQ, Maduray K, Chen TS, Hao L, Zhong JQ. Direct Oral Anticoagulants versus Vitamin K Antagonists in Cirrhotic Patients with Atrial Fibrillation: Update of Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs 2023; 23:683-694. [PMID: 37639201 DOI: 10.1007/s40256-023-00598-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/17/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Prevention of ischemic stroke is an essential part of managing atrial fibrillation (AF). In recent years, direct oral anticoagulants (DOACs) have emerged as an alternative to vitamin K antagonists (VKAs). Little is understood regarding the efficacy and safety of DOACs in AF patients with liver cirrhosis (LC). OBJECTIVE This meta-analysis is designed to evaluate the benefits and risks of DOACs compared to VKAs in AF patients with concomitant LC. METHODS A thorough search was conducted in PubMed, Cochrane Library, Web of Science, Embase, Scopus, and CNKI databases up to February 2023. A total of seven clinical studies including 7551 patients were analyzed in this meta-analysis. All data analyses were performed using Review Manager software version 5.3. RESULTS Regarding efficacy outcomes, DOACs had comparable clinical benefit in reducing ischemic stroke/systemic thromboembolism (HR=0.79, 95% CI [0.59, 1.06], p = 0.12) to VKAs. The incidence of all-cause death was similar between the DOACs and VKAs group (HR 0.94, 95% CI [0.69, 1.28], p = 0.69). Regarding safety outcomes, DOACs were associated with a significantly lower risk of major bleeding (HR 0.61, 95% CI [0.50, 0.75], p < 0.00001), intracranial hemorrhage (HR 0.55, 95% CI [0.31, 0.98], p = 0.04) and major gastrointestinal bleeding (HR 0.66, 95% CI [0.51, 0.85], p = 0.001) than VKAs. Additional subgroup analysis of advanced cirrhosis revealed that DOACs were associated with a significantly lower risk of major bleeding (HR 0.59, 95% CI [0.39, 0.89], p = 0.01) than VKAs. There were no significant differences between the DOACs and VKAs group concerning the incidence of ischemic stroke/systemic thromboembolism (HR 1.38, 95% CI [0.75, 2.55], p = 0.31) and major gastrointestinal bleeding (HR 0.65, 95% CI [0.41, 1.04], p = 0.08). CONCLUSION DOACs are associated with more favorable safety outcomes and may be a feasible option of oral anticoagulant for individuals with atrial fibrillation and cirrhosis. Pending validation by randomized prospective studies, the findings of this study should be interpreted with caution.
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Affiliation(s)
- Tong Hu
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yi-Han Li
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Wen-Qiang Han
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Kellina Maduray
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Tong-Shuai Chen
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Li Hao
- Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Jing-Quan Zhong
- National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
- Department of Cardiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
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25
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Speed V, Czuprynska J, Patel JP, Arya R. Use of direct oral anticoagulants for venous thromboembolism treatment at extremes of body weight, renal and liver function: an illustrated review. Res Pract Thromb Haemost 2023; 7:102240. [PMID: 38193047 PMCID: PMC10772894 DOI: 10.1016/j.rpth.2023.102240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/07/2023] [Accepted: 10/19/2023] [Indexed: 01/10/2024] Open
Abstract
Direct oral anticoagulants (DOACs) have been a welcome addition to clinical practice due to the practical advantages they confer over traditional anticoagulants. In many countries, DOACs are now used as first-line treatment for the management of venous thromboembolism (VTE). Traditional anticoagulants allow for a degree of individualization, either through monitoring the international normalized ratio in the case of vitamin-K antagonists or through dose titration according to bodyweight in the case of low-molecular-weight heparin. However, the use of fixed doses and removal of the need for routine monitoring has created uncertainty in prescribing DOACs for patients at the extremes of bodyweight, renal function, and patients with liver impairment, who were not well represented in the DOAC licensing clinical trials. The discipline of pharmacokinetics is concerned with the movement of drugs through the body. Although the extremes of bodyweight and renal and liver function will influence the pharmacokinetics of DOACs, are these changes significant enough to affect clinical outcomes of bleeding and thrombosis? In other words, can the fixed-dosing strategy of DOACs accommodate these differences in physiology? In this review, we recap key pharmacokinetic principles for drug dosing; review venous thromboembolism trial and real-world data on patients prescribed DOACs at the extremes of bodyweight, renal function, and liver function; relate this to the pharmacokinetic properties of DOACs; and summarize the state of the field and current unknowns.
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Affiliation(s)
- Victoria Speed
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
- Bennett Institute for Applied Data Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Julia Czuprynska
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
| | - Jignesh P. Patel
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
- Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Roopen Arya
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
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26
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Monaco G, Bucherini L, Stefanini B, Piscaglia F, Foschi FG, Ielasi L. Direct oral anticoagulants for the treatment of splanchnic vein thrombosis: A state of art. World J Gastroenterol 2023; 29:4962-4974. [PMID: 37731994 PMCID: PMC10507502 DOI: 10.3748/wjg.v29.i33.4962] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/07/2023] [Accepted: 08/17/2023] [Indexed: 09/01/2023] Open
Abstract
Splanchnic vein thrombosis (SVT) is a manifestation of venous thromboembolism in an unusual site. Portal, mesenteric, and splenic veins are the most common vessels involved in SVT which occurs mainly in patients with liver cirrhosis, although non-cirrhotic patients could be affected as well. Thrombosis of hepatic veins, also known as Budd-Chiari syndrome, is another manifestation of SVT. Prompt diagnosis and intervention are mandatory in order to increase the recalization rate and reduce the risk of thrombus progression and hypertensive complications. Traditional anticoagulation with heparin and vitamin-K antagonists is the treatment of choice in these cases. However, recent studies have shown promising results on the efficacy and safety of direct oral anticoagulants (DOACs) in this setting. Available results are mainly based on retrospective studies with small sample size, but first clinical trials have been published in the last years. This manuscript aims to provide an updated overview of the current evidence regarding the role of DOACs for SVT in both cirrhotic and non-cirrhotic patients.
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Affiliation(s)
- Giovanni Monaco
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Luca Bucherini
- Department of Internal Medicine, Ospedale degli Infermi di Faenza, Faenza 48018, Italy
| | - Bernardo Stefanini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | | | - Luca Ielasi
- Department of Internal Medicine, Ospedale degli Infermi di Faenza, Faenza 48018, Italy
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Zhang C, Shen Z, Li J, Wu Y, Xu Z, Gu W, Jian J, Wu Z, Liu W, Yang H, Su J. Pharmacokinetics, Bioequivalence, and Safety Evaluation of 2 Formulations of 10-mg Rivaroxaban Tablets: A 4-Period Crossover Trial. Clin Pharmacol Drug Dev 2023; 12:920-926. [PMID: 37210712 DOI: 10.1002/cpdd.1261] [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: 01/09/2023] [Accepted: 04/02/2023] [Indexed: 05/23/2023]
Abstract
This study compared the safety, bioequivalence, and pharmacokinetic properties of 2 formulations of 10-mg rivaroxaban tablets in healthy Chinese participants in fasting and fed arms. The trial was an open, randomized, 4-period, replicated crossover scheme, and 36 volunteers were recruited separately for the fasting and fed arms. Volunteers were randomly administered a single dose of the test or reference formulation (10 mg) orally, followed by a 5-day washout period. Rivaroxaban concentrations in the plasma were determined using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were obtained from the concentration-time profiles. The mean values of the test and the reference product for the area under the plasma concentration-time curve from time 0 to the last measurable concentration, area under the plasma concentration-time curve from time 0 to infinity, and maximum plasma concentration were 996 and 1014 ng • h/mL, 1024 and 1055 ng • h/mL, and 150 and 152 ng/mL in the fasting arm, respectively; the values were 1155 and 1167 ng • h/mL, 1160 and 1172 ng • h/mL, and 202 and 193 ng/mL in the fed arm, respectively. All the parameters were within acceptable limits in terms of bioequivalence. No serious adverse events were observed. This study demonstrated that the 2 rivaroxaban tablets were bioequivalent in healthy Chinese participants under fasting and fed conditions.
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Affiliation(s)
- Canhua Zhang
- Guangzhou Panyu Central Hospital, Guangzhou, China
- School of Pharmacy, Guangdong Medical University, Dongguan, China
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Zihan Shen
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jianhao Li
- Guangzhou Panyu Central Hospital, Guangzhou, China
- Cardiovascular Institute of Panyu, Guangzhou, China
| | - Yaofen Wu
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Zuoheng Xu
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Wenzhao Gu
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | | | - Zixing Wu
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Weixiong Liu
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Hui Yang
- Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Jianfen Su
- Guangzhou Panyu Central Hospital, Guangzhou, China
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Luo X, Saleem A, Shafique U, Sarwar S, Ullah K, Imran M, Zeb A, Din FU. Rivaroxaban-loaded SLNs with treatment potential of deep vein thrombosis: in-vitro, in-vivo, and toxicity evaluation. Pharm Dev Technol 2023; 28:625-637. [PMID: 37366661 DOI: 10.1080/10837450.2023.2231069] [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: 03/29/2023] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 06/28/2023]
Abstract
OBJECTIVES Rivaroxaban (RXB), a novel Xa inhibitor having groundbreaking therapeutic potential. However, this drug is associated with few limitations, including its pharmacokinetics related toxicities. Here, we developed RXB-loaded SLNs (RXB-SLNs) to improve its biopharmaceutical profile. Methods: High pressure homogenizer was used to prepare RXB-SLNs, followed by their particle characterization, Transmission electron microscopy (TEM), Dynamic light scattering (DSC), and Powder X-ray diffraction (PXRD) analysis. Beside this, in-vitro, ex-vivo, and in-vivo evaluation, prothrombin time assessment and toxicity was investigated. RESULTS RXB-SLNs had their particle size in nano range (99.1 ± 5.50 nm) with excellent morphology and low polydispersity index (0.402 ± 0.02) and suitable zeta potential (-25.9 ± 1.4 mV). The incorporation efficiency was observed around 95.9 ± 3.9%. In-vitro release profiles of the RXB-SLNs exhibited enhanced dissolution (89 ± 9.91%) as compared to pure drug (11 ± 1.43%) after 24 h of the study. PK study demonstrated a seven times enhanced bioavailability of RXB-SLNs when compared with pure drug. Furthermore, RXB-SLNs exhibited an expressive anti-coagulant behavior in human and rat blood plasma. Also, the final formulation exhibited no toxicity after oral administration of the SLNs. CONCLUSIONS All together, these studies revealed the capability of the SLNs for carrying the RXB with enhanced therapeutic efficacy and no toxicity, most importantly for the treatment of deep vein thrombosis.
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Affiliation(s)
- Xuemei Luo
- Department of General Surgery, Mianzhu Peoples Hospital of Sichuan, Mianzhu, Sichuan, China
| | - Aiman Saleem
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Uswa Shafique
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sadia Sarwar
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Kalim Ullah
- Department of Zoology, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Imran
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Alam Zeb
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Fakhar Ud Din
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
- Nanomedicine Research Group, Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
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29
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Muller M, Godet J, Delabranche X, Sattler L, Millard D, Marzak H, Mertes PM, Steib A, Grunebaum L, Jesel L, Tacquard CA. Study of Modifications Induced by Continued Direct Oral Anticoagulant Therapy during Atrial Fibrillation Ablation Procedures on Standard Hemostasis Parameters. J Clin Med 2023; 12:jcm12062236. [PMID: 36983237 PMCID: PMC10054854 DOI: 10.3390/jcm12062236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/05/2023] [Accepted: 03/11/2023] [Indexed: 03/15/2023] Open
Abstract
Background: Unfractionated heparin (UFH) is used as an anticoagulant during the atrial fibrillation (AF) ablation procedure to prevent the occurrence of thromboembolic events. Guidelines recommend an activated clotting time (ACT) greater than 300 s (s) based on studies of patients treated with vitamin K antagonist (VKA) for their AF. However, direct oral anticoagulants (DOACs) have supplanted VKAs in AF and are now used as first-line therapy. It is recommended not to interrupt them during the procedure, which could interfere with the ACT measures. Objective: To assess the real-life relationship between ACT, DOAC concentrations, and UFH anti-Xa activity in patients treated by uninterrupted DOAC therapy. Methods: We conducted a single-center retrospective study. We analyzed consecutive patients with AF who underwent catheter ablation under DOAC therapy. Results: In total, 40 patients were included, including 15 (37.5%), 20 (50.0%), and 5 (12.5%) on rivaroxaban, apixaban, and dabigatran, respectively. Baseline ACT was significantly lower in the apixaban group. ACT was linearly correlated with the residual concentration of apixaban and dabigatran but not with rivaroxaban. After UFH injection, ACT was linearly correlated with the anti-Xa activity, regardless of DOAC. Patients in the apixaban group received a higher total dose of UFH during the procedure to achieve a target ACT > 300 s, which resulted in significantly higher anti-Xa activity during the procedure. Conclusion: Our results raise the question of optimal management of intra-procedural heparin therapy and highlight the limitations of the ACT test, particularly in patients on apixaban.
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Affiliation(s)
- Marie Muller
- Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Julien Godet
- Groupe Méthodes en Recherche Clinique (GMRC), Hôpitaux Universitaires de Strasbourg, Hôpital Civil, 67000 Strasbourg, France
| | - Xavier Delabranche
- Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Laurent Sattler
- Laboratoire d’Hématologie, Unité Hémostase, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - David Millard
- Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Halim Marzak
- Service de Cardiologie, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Paul Michel Mertes
- Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Annick Steib
- Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Lelia Grunebaum
- Laboratoire d’Hématologie, Unité Hémostase, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Laurence Jesel
- Service de Cardiologie, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- UMR 1260 INSERM Nanomedecine Regenerative, CRBS, Strasbourg University, 67200 Strasbourg, France
| | - Charles Ambroise Tacquard
- Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Correspondence:
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30
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Hydes TJ, Lip GYH, Lane DA. Use of Direct-Acting Oral Anticoagulants in Patients With Atrial Fibrillation and Chronic Liver Disease. Circulation 2023; 147:795-797. [PMID: 36877772 DOI: 10.1161/circulationaha.122.063195] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Affiliation(s)
- Theresa J Hydes
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, UK (T.J.H., G.Y.H.L., D.A.L.).,Liverpool University Hospitals National Health Service Foundation Trust, Aintree University Hospital, Lower Lane, UK (T.J.H.)
| | - Gregory Y H Lip
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, UK (T.J.H., G.Y.H.L., D.A.L.).,Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, UK (G.Y.H.L., D.A.L.).,Department of Clinical Medicine, Aalborg University, Denmark (G.Y.H.L., D.A.L.)
| | - Deirdre A Lane
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, UK (T.J.H., G.Y.H.L., D.A.L.).,Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, UK (G.Y.H.L., D.A.L.).,Department of Clinical Medicine, Aalborg University, Denmark (G.Y.H.L., D.A.L.)
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31
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Ma J, Chalasani NP, Schwantes-An L, Björnsson ES. Review article: the safety of anticoagulants and antiplatelet agents in patients with cirrhosis. Aliment Pharmacol Ther 2023; 57:52-71. [PMID: 36373544 DOI: 10.1111/apt.17297] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/26/2022] [Accepted: 10/27/2022] [Indexed: 11/16/2022]
Abstract
Patients with cirrhosis were long thought to be coagulopathic. However, this paradigm has changed in recent years and currently, cirrhosis is recognised as a prothrombotic state. Due to the increasing incidence of cirrhosis from nonalcoholic steatohepatitis which is closely associated with cardiac disease, patients with cirrhosis increasingly require therapy with anticoagulants and antiplatelet agents. However, their potential for causing catastrophic and life-threatening bleeding in patients with cirrhosis leads to hesitancy about their use in patients with cirrhosis. Overall, traditional anticoagulation is safe for all Child-Pugh classes while newer direct oral anticoagulants (DOACs) are mostly safe in Child-Pugh class A/B and contraindicated in severe hepatic impairment. For different indications, published data to date suggest that anticoagulation is overall safe for patients with cirrhosis who have venous thromboembolism, atrial fibrillation and portal vein thrombosis, and does not increase the risk of variceal bleeding. Moreover, DOACs appear to have similar safety profiles as traditional anticoagulants. Finally, most studies suggest that antiplatelet agents are also safe to use in patients with cirrhosis although they are mostly contraindicated in severe hepatic impairment. For both anticoagulants and antiplatelet agents, severe thrombocytopaenia presents a relative contraindication to their use. More prospective trials and large cohort studies are needed to advance our understanding of the safety and nuances of DOACs and antiplatelet agents in patients with advanced cirrhosis.
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Affiliation(s)
- Jiayi Ma
- Indiana University School of Medicine and Indiana University Health, Indianapolis, Indiana, USA
| | - Naga P Chalasani
- Indiana University School of Medicine and Indiana University Health, Indianapolis, Indiana, USA
| | - Linus Schwantes-An
- Indiana University School of Medicine, Medical & Molecular Genetics, Indianapolis, Indiana, USA
| | - Einar Stefán Björnsson
- Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland.,Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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32
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Trough Concentration Deficiency of Rivaroxaban in Patients With Nonvalvular Atrial Fibrillation Leading to Thromboembolism Events. J Cardiovasc Pharmacol 2022; 80:869-876. [PMID: 36027599 DOI: 10.1097/fjc.0000000000001360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 08/14/2022] [Indexed: 12/13/2022]
Abstract
ABSTRACT This retrospective study investigated factors influencing the steady-state trough concentrations (C trough ) of rivaroxaban in patients with nonvalvular atrial fibrillation (NVAF). We retrieved data from patients with NAVF who first started rivaroxaban anticoagulation at the Fujian Provincial Hospital from October 2017 to October 2020 through the electronic medical record system. Patients were followed for 1 year after the first dose of rivaroxaban, and the primary efficacy and safety end points were recorded. All follow-up visits were completed by October 2021. A C trough of <12 ng/mL was defined as C trough deficiency. Factors that influenced rivaroxaban C trough deficiency were investigated using multivariate binary logistic regression analysis. Kaplan-Meier survival curve analysis was used to determine differences between C trough deficiency and event-free survival. A total of 167 patients with NVAF were enrolled in the study, including 113 men and 54 women, with an average (± SD) age of 70.40 ± 12.46 years. High albumin levels were an independent protective factor against C trough deficiency (odds ratio, 0.932; P = 0.031). C trough deficiency was associated with the probability of freedom from thrombotic events ( P = 0.004); however, there were no significant differences in the probability of freedom from bleeding events ( P > 0.05). In conclusion, among the variables studied, a low albumin level was the main contributor to C trough deficiency. Rivaroxaban C trough deficiency also increased thrombotic events, but this was not associated with hemorrhagic events in Chinese patients with NVAF.
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33
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Liu XQ, Zhang YF, Ding HY, Yan MM, Jiao Z, Zhong MK, Ma CL. Population pharmacokinetic and pharmacodynamic analysis of rivaroxaban in Chinese patients with non-valvular atrial fibrillation. Acta Pharmacol Sin 2022; 43:2723-2734. [PMID: 35354961 PMCID: PMC9525623 DOI: 10.1038/s41401-022-00892-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/20/2022] [Indexed: 12/12/2022]
Abstract
Rivaroxaban, a direct factor Xa inhibitor, is widely used for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to conduct a population pharmacokinetic-pharmacodynamic (PK-PD) analysis of rivaroxaban in Chinese patients with NVAF to assess ethnic differences and provide model-based precision dosing. A total of 256 rivaroxaban plasma concentrations and 244 prothrombin time (PT) measurements were obtained from 195 Chinese NVAF patients from a prospective clinical trial. The population PK-PD model was developed using nonlinear mixed effects modeling (NONMEM) software. The PK of rivaroxaban was adequately described using a one-compartment model with first-order adsorption and elimination. Estimated glomerular filtration rate (eGFR) was identified as a major covariate for apparent clearance. No single nucleotide polymorphism was identified as a significant covariate. PT exhibited a linear relationship with rivaroxaban concentration. Total bilirubin (TBIL) and eGFR were identified as significant covariates for baseline PT. According to the Monte Carlo simulation, 15 mg for Chinese patients with eGFR ≥50 mL/min and normal liver function yielded an exposure comparable to 20 mg for Caucasian patients. Patients with moderately impaired renal function may require a lower dose of rivaroxaban to avoid overexposure. Moreover, there was an approximate 26% increase in PT levels in patients with TBIL of 34 μmol/L and eGFR of 30 mL/min, which could increase the risk of major bleeding. The established population PK-PD model could inform individualized dosing for Chinese NVAF patients who are administered rivaroxaban.
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Affiliation(s)
- Xiao-Qin Liu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yu-Fei Zhang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Hong-Yan Ding
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Ming-Ming Yan
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Zheng Jiao
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Ming-Kang Zhong
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Chun-Lai Ma
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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34
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Belialov F. Drug classification for patients with comorbidities. J Pharm Policy Pract 2022; 15:56. [PMID: 36138411 PMCID: PMC9494913 DOI: 10.1186/s40545-022-00453-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/17/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Farid Belialov
- Department of Gerontology, Geriatrics, and Clinical Pharmacology, Russian Medical Academy of Continuous Professional Education, Yubileiny 100/4, Irkutsk, 664079, Russia.
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35
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Chiang CE, Chao TF, Choi EK, Lim TW, Krittayaphong R, Li M, Chen M, Guo Y, Okumura K, Lip GY. Stroke Prevention in Atrial Fibrillation: A Scientific Statement of JACC: Asia (Part 2). JACC. ASIA 2022; 2:519-537. [PMID: 36624790 PMCID: PMC9823285 DOI: 10.1016/j.jacasi.2022.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/29/2022] [Accepted: 06/22/2022] [Indexed: 01/12/2023]
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with substantial increases in the risk for stroke and systemic thromboembolism. With the successful introduction of the first non-vitamin K antagonistdirect oral anticoagulant agent (NOAC) in 2009, the role of vitamin K antagonists has been replaced in most clinical settings except in a few conditions for which NOACs are contraindicated. Data for the use of NOACs in different clinical scenarios have been accumulating in the past decade, and a more sophisticated strategy for patients with AF is now warranted. JACC: Asia recently appointed a working group to summarize the most updated information regarding stroke prevention in AF. The aim of this statement is to provide possible treatment options in daily practice. Local availability, cost, and patient comorbidities should also be considered. Final decisions may still need to be individualized and based on clinicians' discretion. This is part 2 of the statement.
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Affiliation(s)
- Chern-En Chiang
- General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan,Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Address for correspondence: Dr Chern-En Chiang, General Clinical Research Center and Division of Cardiology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. @en_chern
| | - Tze-Fan Chao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Eue-Keun Choi
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Toon Wei Lim
- National University Heart Centre, National University Hospital, Singapore, Singapore
| | - Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Mingfang Li
- Division of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Minglong Chen
- Division of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yutao Guo
- Department of Pulmonary Vessel and Thrombotic Disease, Sixth Medical Centre, Chinese PLA General Hospital, Beijing, China,Liverpool Centre for Cardiovascular Science, University of Liverpool & Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
| | - Ken Okumura
- Division of Cardiology, Saiseikai Kumamoto Hospital, Kumamoto, Japan
| | - Gregory Y.H. Lip
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea,Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand,Division of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China,Liverpool Centre for Cardiovascular Science, University of Liverpool & Liverpool Heart and Chest Hospital, Liverpool, United Kingdom,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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36
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Singkham N, Phrommintikul A, Pacharasupa P, Norasetthada L, Gunaparn S, Prasertwitayakij N, Wongcharoen W, Punyawudho B. Population Pharmacokinetics and Dose Optimization Based on Renal Function of Rivaroxaban in Thai Patients with Non-Valvular Atrial Fibrillation. Pharmaceutics 2022; 14:pharmaceutics14081744. [PMID: 36015370 PMCID: PMC9414338 DOI: 10.3390/pharmaceutics14081744] [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: 07/09/2022] [Revised: 08/15/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl < 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study’s findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication’s dose in accordance with renal function.
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Affiliation(s)
- Noppaket Singkham
- Division of Clinical Pharmacy, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Arintaya Phrommintikul
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Phongsathon Pacharasupa
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Lalita Norasetthada
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Siriluck Gunaparn
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Narawudt Prasertwitayakij
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Wanwarang Wongcharoen
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
- Correspondence: (W.W.); (B.P.)
| | - Baralee Punyawudho
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
- Correspondence: (W.W.); (B.P.)
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Sychev D, Ostroumova O, Cherniaeva M, Shakhgildian N, Mirzaev K, Abdullaev S, Denisenko N, Sozaeva Z, Kachanova A, Gorbatenkova S, Shastina V. The Influence of ABCB1 (rs1045642 and rs4148738) Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Aged 80 Years and Older with Nonvalvular Atrial Fibrillation. High Blood Press Cardiovasc Prev 2022; 29:469-480. [PMID: 35960493 DOI: 10.1007/s40292-022-00536-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/18/2022] [Indexed: 01/01/2023] Open
Abstract
INTRODUCTION ABCB1 gene polymorphisms are associated with rivaroxaban distribution changes and adverse reactions but the data are controversial. AIM To evaluate the influence of ABCB1 (rs1045642 and rs4148738) gene polymorphisms on rivaroxaban pharmacokinetics in patients aged 80 years and older with nonvalvular atrial fibrillation (NAF). METHODS 128 patients aged 80 years and older (median [Me] age 87.5 [83.0-90.0] years) with NAF were included. We performed ABCB1 (rs1045642 and rs4148738) genotyping, measured the trough steady-state plasma concentration (Cmin,ss) of rivaroxaban and prothrombin time (PT) and analyzed prior medical records for clinically relevant non-major bleeding (CRNMB). RESULTS CC genotype carriers had no differences in Cmin,ss (p > 0.05) compared with the CT and TT rs1045642 and rs4148738 genotypes carriers. CC genotype carriers had no differences in PT (p > 0.05) compared with the CT rs1045642 and rs4148738 and TT rs4148738 genotypes carriers. In the TT genotype PT levels were higher than in the CC rs1045642 genotype: Me 14.2 [13.0-16.1] sec vs 13.3 [12.4-14.5] sec (p = 0.049). Incidence of CRNMB was higher in patients with the TT genotype compared with the CC rs1045642 (29.3% vs 4.5%, p = 0.021) and rs4148738 (39.3% vs 8.1%, p = 0.008) and the CT genotype rs4148738 (39.3% vs 14.3%, p = 0.002). CONCLUSION ABCB1 (rs1045642 and rs4148738) polymorphisms didn't influence rivaroxaban pharmacokinetics in patients aged 80 years and older with NAF. TT carriers developed CRNMB more frequently compared with the CC rs1045642 and the CC and CT rs4148738 genotypes. The haplotype TT-TT haplotype was associated with a higher frequency of CRNMB.
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Affiliation(s)
- Dmitry Sychev
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation
| | - Olga Ostroumova
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation.,Department of Therapy and Polymorbid Pathology, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation
| | - Marina Cherniaeva
- Department of Internal and Preventive Medicine, Central State Medical Academy of the Presidential Administration of the Russian Federation, Marshal Timoshenko Street, 19, Building 1A, Moscow, 121359, Russian Federation. .,State Budgetary Institution of Health "Hospital for War Veterans No. 2" of the Department of Health of Moscow, Volgogradskiy Prospekt, 168, Moscow, 109472, Russian Federation.
| | - Nataliia Shakhgildian
- Lomonosov Moscow State University Medical Research and Educational Center, 27\10, Lomonosovskiy Prospekt, Moscow, 119991, Russian Federation
| | - Karin Mirzaev
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation.,Research Center for Medical Genetics, 1 Moskvorechye st., Moscow, 115522, Russian Federation.,Department of Personalized Medicine, Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 7/2 2nd Bokinskiy Drive, Moscow, 125284, Russian Federation
| | - Sherzod Abdullaev
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation.,Department of Molecular Medicine, Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 7/2 2nd Bokinskiy Drive, Moscow, 125284, Russian Federation
| | - Natalia Denisenko
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation.,Department of Personalized Medicine, Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 7/2 2nd Bokinskiy Drive, Moscow, 125284, Russian Federation
| | - Zhannet Sozaeva
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation.,Department of Personalized Medicine, Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 7/2 2nd Bokinskiy Drive, Moscow, 125284, Russian Federation
| | - Anastasia Kachanova
- Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, 2/1 Barrikadnaya St., Moscow, 123242, Russian Federation.,Department of Molecular Medicine, Research Institute of Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, 7/2 2nd Bokinskiy Drive, Moscow, 125284, Russian Federation
| | - Svetlana Gorbatenkova
- State Budgetary Institution of Health "Hospital for War Veterans No. 2" of the Department of Health of Moscow, Volgogradskiy Prospekt, 168, Moscow, 109472, Russian Federation
| | - Vera Shastina
- State Budgetary Institution of Health "Hospital for War Veterans No. 2" of the Department of Health of Moscow, Volgogradskiy Prospekt, 168, Moscow, 109472, Russian Federation
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38
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Willmann S, Ince I, Ahsman M, Coboeken K, Zhang Y, Thelen K, Kubitza D, Zannikos P, Zhou W, Pina LM, Post T, Lippert J. Model‐informed bridging of rivaroxaban doses for thromboprophylaxis in pediatric patients aged 9 years and older with congenital heart disease. CPT Pharmacometrics Syst Pharmacol 2022; 11:1111-1121. [PMID: 35665486 PMCID: PMC9381895 DOI: 10.1002/psp4.12830] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/09/2022] [Accepted: 05/23/2022] [Indexed: 12/04/2022] Open
Abstract
Rivaroxaban is approved in various regions for the treatment of acute venous thromboembolism (VTE) in children aged between 0 and 18 years and was recently investigated for thromboprophylaxis in children aged between 2 and 8 years (with body weights <30 kg) with congenital heart disease who had undergone the Fontan procedure. In the absence of clinical data, rivaroxaban doses for thromboprophylaxis in post‐Fontan children aged 9 years and older or ≥30 kg were derived by a bridging approach that used physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) models based on pharmacokinetic (PK) data from 588 pediatric patients and from adult patients who received 10 mg once daily for thromboprophylaxis after major orthopedic surgeries as a reference. Both models showed a tendency toward underestimating rivaroxaban exposure in post‐Fontan patients aged between 2 and 5 years but accurately described rivaroxaban PK in post‐Fontan patients aged between 5 and 8 years. Under the assumption that hepatic function is not impaired in post‐Fontan patients, PBPK and popPK simulations indicated that half of the rivaroxaban doses for the same body weight given to pediatric patients treated for acute VTE would yield in pediatric post‐Fontan patients exposures similar to the exposure observed in adult patients receiving 10 mg rivaroxaban once daily for thromboprophylaxis. Simulation‐derived doses (7.5 mg rivaroxaban once daily for body weights 30–<50 kg and 10 mg once daily for body weights ≥50 kg) were therefore included in the recent US label of rivaroxaban for thromboprophylaxis in children aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.
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Affiliation(s)
- Stefan Willmann
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
| | - Ibrahim Ince
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
| | - Maurice Ahsman
- Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics Leiden The Netherlands
| | - Katrin Coboeken
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
| | - Yang Zhang
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
| | - Kirstin Thelen
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
| | - Dagmar Kubitza
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
| | - Peter Zannikos
- Janssen Research & Development, LLC Raritan New Jersey USA
| | - Wangda Zhou
- Janssen Research & Development, LLC Raritan New Jersey USA
| | | | - Teun Post
- Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics Leiden The Netherlands
| | - Jörg Lippert
- Bayer AG, Research & Development, Pharmaceuticals Wuppertal/Leverkusen Germany
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Esmaeili T, Rezaee M, Abdar Esfahani M, Davoudian A, Omidfar D, Rezaee S. Rivaroxaban population pharmacokinetic and pharmacodynamic modeling in Iranian patients. J Clin Pharm Ther 2022; 47:1284-1292. [PMID: 35504629 DOI: 10.1111/jcpt.13673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/30/2022] [Accepted: 04/05/2022] [Indexed: 12/22/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Although predictable pharmacokinetic and pharmacodynamic of rivaroxaban allow fixed dosing regimens without routine coagulation monitoring, there is still the necessity to monitor and predict the effects of rivaroxaban in specific conditions and different populations. The current study was designed and conducted to analyze the rivaroxaban population pharmacokinetics in Iranian patients and establish a pharmacokinetic/pharmacodynamic model to predict the relationship between rivaroxaban concentration and its anticoagulant activity. METHODS A sequential nonlinear mixed effect pharmacokinetic/pharmacodynamic modeling method was used to establish the relation between rivaroxaban concentration and anti-factor Xa activity, prothrombin time, and activated partial thromboplastin time (aPTT) as pharmacodynamic biomarkers in a population of sixty-nine Iranian patients under treatment with oral rivaroxaban. Rivaroxaban plasma concentration was quantified by a validated high-performance liquid chromatography-tandem mass spectrometry. RESULTS AND DISCUSSION The typical population values (inter-individual variability%) of the oral volume of distribution and clearance for a one-compartment model were 61.2 L (21%) and 3.68 L·h-1 (61%), respectively. Creatinine clearance and Child-Turcotte-Pugh score were found to affect the clearance. A direct link linear structural model best fitted the data for both prothrombin time and aPTT. The baseline estimates of aPTT and prothrombin time in the population were 35.0 (15%) and 12.6 (2%) seconds, respectively. The slope of the relationship between apTT, prothrombin time, and rivaroxaban concentration was 0.033 (28%) and 0.018 (54%) s·ml·ng-1 , respectively. The selected model for anti-factor Xa activity consisted of a direct link inhibitory Emax model with Hill coefficient. The maximum level of inhibition (Emax ) was 4 IU·ml-1 . The concentration of rivaroxaban producing 50% of the maximum inhibitory effect (EC50 ) was 180 (24%) ng·ml-1 , and Hill coefficient (γ) was 1.44 (108%). No covariates showed a statistically significant effect on PT and activated partial thromboplastin time prolonging properties and anti-factor Xa activity. WHAT IS NEW AND CONCLUSION Our results confirmed that pharmacokinetic/pharmacodynamic models similar to those of the other studies describe the relationship between the rivaroxaban concentration and its anticoagulant effect in Iranian patients. However, considerable differences were observed in the parameters of the pharmacodynamics-pharmacokinetic models with the results of other reports that can explain the unpredictable effects of rivaroxaban in some patients.
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Affiliation(s)
- Tayebeh Esmaeili
- Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mahmood Rezaee
- Department of Cardiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morteza Abdar Esfahani
- Department of Cardiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Azadeh Davoudian
- Department of Cardiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Saeed Rezaee
- Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
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Villa E, Bianchini M, Blasi A, Denys A, Giannini EG, de Gottardi A, Lisman T, de Raucourt E, Ripoll C, Rautou PE. EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis. J Hepatol 2022; 76:1151-1184. [PMID: 35300861 DOI: 10.1016/j.jhep.2021.09.003] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022]
Abstract
The prevention and management of bleeding and thrombosis in patients with cirrhosis poses several difficult clinical questions. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics, including current views on haemostasis in liver disease, controversy regarding the need to correct thrombocytopenia and abnormalities in the coagulation system in patients undergoing invasive procedures, and the need for thromboprophylaxis in hospitalised patients with haemostatic abnormalities. Multiple recommendations in this document are based on interventions that the panel feels are not useful, even though widely applied in clinical practice.
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Biolato M, Paratore M, Di Gialleonardo L, Marrone G, Grieco A. Direct oral anticoagulant administration in cirrhotic patients with portal vein thrombosis: What is the evidence? World J Hepatol 2022; 14:682-695. [PMID: 35646264 PMCID: PMC9099104 DOI: 10.4254/wjh.v14.i4.682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 09/22/2021] [Accepted: 04/03/2022] [Indexed: 02/06/2023] Open
Abstract
In recent years, the traditional concept that cirrhosis-related coagulopathy is an acquired bleeding disorder has evolved. Currently, it is known that in cirrhotic patients, the hemostatic system is rebalanced, which involves coagulation factors, fibrinolysis and platelets. These alterations disrupt homeostasis, skewing it toward a procoagulant state, which can lead to thromboembolic manifestations, especially when hemodynamic and endothelial factors co-occur, such as in the portal vein system in cirrhosis. Portal vein thrombosis is a common complication of advanced liver cirrhosis that negatively affects the course of liver disease, prognosis of cirrhotic patients and success of liver transplantation. It is still debated whether portal vein thrombosis is the cause or the consequence of worsening liver function. Anticoagulant therapy is the mainstay treatment for acute symptomatic portal vein thrombosis. In chronic portal vein thrombosis, the role of anticoagulant therapy is still unclear. Traditional anticoagulants, vitamin K antagonists and low-molecular-weight heparin are standard-of-care treatments for portal vein thrombosis. In the last ten years, direct oral anticoagulants have been approved for the prophylaxis and treatment of many thromboembolic-related diseases, but evidence on their use in cirrhotic patients is very limited. The aim of this review was to summarize the evidence about the safety and effectiveness of direct oral anticoagulants for treating portal vein thrombosis in cirrhotic patients.
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Affiliation(s)
- Marco Biolato
- Internal and Liver Transplant Medicine Unit, CEMAD, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
- Institute of Internal Medicine, Catholic University of Sacred Heart, Rome 00168, Italy.
| | - Mattia Paratore
- Institute of Internal Medicine, Catholic University of Sacred Heart, Rome 00168, Italy
| | - Luca Di Gialleonardo
- Institute of Internal Medicine, Catholic University of Sacred Heart, Rome 00168, Italy
| | - Giuseppe Marrone
- Internal and Liver Transplant Medicine Unit, CEMAD, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
- Institute of Internal Medicine, Catholic University of Sacred Heart, Rome 00168, Italy
| | - Antonio Grieco
- Internal and Liver Transplant Medicine Unit, CEMAD, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
- Institute of Internal Medicine, Catholic University of Sacred Heart, Rome 00168, Italy
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Zhang F, Chen X, Wu T, Huang N, Li L, Yuan D, Xiang J, Wang N, Chen W, Zhang J. Population Pharmacokinetics of Rivaroxaban in Chinese Patients with Non-Valvular Atrial Fibrillation: A Prospective Multicenter Study. Clin Pharmacokinet 2022; 61:881-893. [PMID: 35316848 DOI: 10.1007/s40262-022-01108-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND AND OBJECTIVE Rivaroxaban is a novel oral anticoagulant widely used for thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF). The present study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban in Chinese patients with NVAF. METHODS We performed a prospective multicenter study. The plasma concentration of rivaroxaban was directly detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and indirectly by rivaroxaban-calibrated chromogenic anti-Xa assay (STA®). Gene polymorphisms were detected by MassARRAY single nucleotide polymorphism genotyping technology. Nonlinear mixed-effects modeling was used to develop the PPK model for rivaroxaban in patients with NVAF, and we simulated the steady-state rivaroxaban exposures under different dosing strategies in different covariate levels. RESULTS A total of 150 patients from five centers were recruited, including 263 plasma concentrations detected by HPLC-MS/MS, 2626 gene polymorphisms, and 131 plasma concentrations detected by anti-Xa assay. In our study, an oral one-compartment model was used to describe the pharmacokinetics of rivaroxaban in patients with NVAF. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 5.79 L/h (relative standard error [RSE] 4.4%) and 51.5 L (RSE 5.0%), respectively. Covariates in the final model included creatinine clearance, total bilirubin, rs4728709, and body weight. The simulation results showed that in the 15 mg once-daily dosing regimen, in most instances the maximum plasma concentration at steady state (Cmax,ss) and trough plasma concentration at steady state (Cmin,ss) were in the target range for different covariate levels. When patients were administered rivaroxaban 15 or 20 mg once daily, the Cmax,ss and Cmin,ss in the different bodyweight levels were also in the target range. For patients with the ABCB1 rs4728709 mutation, the Cmin,ss in the 10, 15, and 20 mg once-daily dosing regimens were lower than the target range. The anti-Xa assay was highly linearly correlated with the HPLC-MS/MS method [y = 1.014x - 2.4648 (R2 = 0.97)]. CONCLUSIONS Our study was the first multicenter PPK model for rivaroxaban in Chinese patients with NVAF (Alfalfa-RIVAAF-PPK). The study found that 15 mg once daily may be suitable as the principal rivaroxaban dose for Chinese patients with NVAF. For patients with the rs4728709 mutation, it may be necessary to examine insufficient anticoagulation. We found that the rivaroxaban-calibrated chromogenic anti-Xa assay and HPLC-MS/MS method were highly linearly correlated. Prospective studies with larger sample sizes and real-world studies are needed for further verification.
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Affiliation(s)
- Feilong Zhang
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xuehai Chen
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Tingting Wu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Nianxu Huang
- Department of Pharmacy, Taikang Tongji (Wuhan) Hospital, Wuhan, China
| | - Li Li
- Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, China
| | - Dongdong Yuan
- Department of Pharmacy, The Seventh People's Hospital of Zhengzhou, Zhengzhou, China
| | - Jing Xiang
- Department of Pharmacy, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Na Wang
- Department of Pharmacy, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenjun Chen
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jinhua Zhang
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, China.
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Lee ZY, Suah BH, Teo YH, Teo YN, Syn NLX, Yeo TC, Wong RCC, Chai P, Wong YJ, Ho JSY, Leow AST, Yeo LLL, Tan BYQ, Sia CH. Comparison of the Efficacy and Safety of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Atrial Fibrillation and Concomitant Liver Cirrhosis: A Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs 2022; 22:157-165. [PMID: 34008145 DOI: 10.1007/s40256-021-00482-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with atrial fibrillation (AF) have a higher risk of developing thromboembolic events. Current guidelines recommend the use of oral anticoagulants for stroke prevention in these patients. Several clinical trials demonstrated that direct oral anticoagulants (DOACs) have similar efficacy and are safer alternatives to traditional oral anticoagulants. However, patients with concomitant liver cirrhosis were excluded from these trials. OBJECTIVE We aimed to systematically identify and review published clinical studies on the use of DOACs in patients with AF and liver cirrhosis and assess the efficacy and safety of DOACs in these patients. METHODS A systematic review of clinical trials and retrospective studies was conducted by searching the PubMed, Cochrane Library, Embase, SCOPUS, and Web of Science databases up to September 2020. RESULTS Three retrospective studies were included, involving 4011 patients with AF and liver cirrhosis. The use of DOACs was associated with a significant reduction in ischemic stroke (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.42-0.90; p = 0.01), major bleeding events (HR 0.64; 95% CI 0.57-0.72; p < 0.001), and intracranial hemorrhage (HR 0.49; 95% CI 0.40-0.59; p < 0.001). CONCLUSIONS Compared with warfarin in patients with AF and liver cirrhosis, DOACs appear to be associated with improved efficacy and safety outcomes. Randomized controlled trials are warranted to confirm these findings.
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Affiliation(s)
- Zhi-Yan Lee
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Boon-Hao Suah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yao Hao Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yao Neng Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas L X Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tiong-Cheng Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - Raymond C C Wong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - Ping Chai
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - Yu Jun Wong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore
| | - Jamie S Y Ho
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | | | - Leonard L L Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Neurology, University Medicine Cluster, National University Health System, Singapore, Singapore
| | - Benjamin Y Q Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Neurology, University Medicine Cluster, National University Health System, Singapore, Singapore
| | - Ching-Hui Sia
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore.
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Liao JN, Kuo L, Liu CM, Chen SA, Chao TF. Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients with advanced chronic kidney and liver diseases. Eur Heart J Suppl 2022; 24:A11-A18. [PMID: 35185405 PMCID: PMC8850708 DOI: 10.1093/eurheartj/suab154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Advanced chronic kidney disease (CKD) or chronic liver disease (CLD) is frequent in patients with atrial fibrillation (AF) because of their common risk factors. Chronic kidney disease and CLD superimposed on AF are associated with increased risks of thrombosis and bleeding, which further complicates the use of oral anticoagulants (OACs). Because currently approved non-vitamin K antagonist oral anticoagulants (NOACs) undergo certain degrees of metabolism and clearance in the liver and kidney, increased exposure to medications and risk of bleeding are major concerns with the use of NOACs in patients with advanced CKD and CLD. Besides, these patients were mostly excluded from landmark trials of NOACs and related cohort studies are also limited. Therefore, the optimal strategy for the use of NOACs in this population remains unclear. This review would go through current evidence regarding the safety and efficacy of NOACs in AF patients with advanced CKD and CLD and provide a comprehensive discussion for clinical practices.
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Affiliation(s)
- Jo-Nan Liao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
- Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ling Kuo
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
- Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Min Liu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
- Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shih-Ann Chen
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
- Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Tze-Fan Chao
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
- Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Su F, Northup PG. Anticoagulants and Antiplatelet Agents in Cirrhosis. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:23-48. [DOI: 10.1007/978-981-19-2615-0_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chao T, Joung B, Takahashi Y, Lim TW, Choi E, Chan Y, Guo Y, Sriratanasathavorn C, Oh S, Okumura K, Lip GYH. 2021 Focused update of the 2017 consensus guidelines of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation. J Arrhythm 2021; 37:1389-1426. [PMID: 34887945 PMCID: PMC8637102 DOI: 10.1002/joa3.12652] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/22/2021] [Indexed: 12/19/2022] Open
Abstract
The consensus of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation (AF) has been published in 2017 which provided useful clinical guidance for cardiologists, neurologists, geriatricians, and general practitioners in Asia-Pacific region. In these years, many important new data regarding stroke prevention in AF were reported. The Practice Guidelines subcommittee members comprehensively reviewed updated information on stroke prevention in AF, and summarized them in this 2021 focused update of the 2017 consensus guidelines of the APHRS on stroke prevention in AF. We highlighted and focused on several issues, including the importance of AF Better Care (ABC) pathway, the advantages of non-vitamin K antagonist oral anticoagulants (NOACs) for Asians, the considerations of use of NOACs for Asian patients with AF with single 1 stroke risk factor beyond gender, the role of lifestyle factors on stroke risk, the use of oral anticoagulants during the "coronavirus disease 2019" (COVID-19) pandemic, etc. We fully realize that there are gaps, unaddressed questions, and many areas of uncertainty and debate in the current knowledge of AF, and the physician's decision remains the most important factor in the management of AF.
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Affiliation(s)
- Tze‐Fan Chao
- Division of CardiologyDepartment of MedicineTaipei Veterans General HospitalTaipeiTaiwan
- Institute of Clinical Medicine, and Cardiovascular Research CenterNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Boyoung Joung
- Division of CardiologyDepartment of Internal MedicineYonsei University College of MedicineSeoulRepublic of Korea
| | - Yoshihide Takahashi
- The Department of Advanced Arrhythmia ResearchTokyo Medical and Dental UniversityTokyoJapan
| | - Toon Wei Lim
- National University Heart CentreNational University HospitalSingaporeSingapore
| | - Eue‐Keun Choi
- Department of Internal MedicineSeoul National University HospitalSeoulRepublic of Korea
| | - Yi‐Hsin Chan
- Microscopy Core LaboratoryChang Gung Memorial HospitalLinkouTaoyuanTaiwan
- College of MedicineChang Gung UniversityTaoyuanTaiwan
- Microscopy Core LaboratoryChang Gung Memorial HospitalLinkouTaoyuanTaiwan
| | - Yutao Guo
- Pulmonary Vessel and Thrombotic DiseaseChinese PLA General HospitalBeijingChina
| | | | - Seil Oh
- Department of Internal MedicineSeoul National University HospitalSeoulRepublic of Korea
| | - Ken Okumura
- Division of CardiologySaiseikai Kumamoto HospitalKumamotoJapan
| | - Gregory Y. H. Lip
- Liverpool Centre for Cardiovascular ScienceUniversity of Liverpool & Liverpool Heart and Chest HospitalLiverpoolUK
- Aalborg Thrombosis Research UnitDepartment of Clinical MedicineAalborg UniversityAalborgDenmark
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Chang WH, Mueller SH, Tan YY, Lai AG. Antithrombotic therapy in patients with liver disease: population-based insights on variations in prescribing trends, adherence, persistence and impact on stroke and bleeding. THE LANCET REGIONAL HEALTH. EUROPE 2021; 10:100222. [PMID: 34806071 PMCID: PMC8589727 DOI: 10.1016/j.lanepe.2021.100222] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
BACKGROUND Patients with liver disease have complex haemostasis and due to such contraindications, landmark randomised controlled trials investigating antithrombotic medicines have often excluded these patients. As a result, there has been limited consensus on the safety, efficacy and monitoring practices of anticoagulant and antiplatelet therapy in patients with liver disease. This study aims to investigate prescribing prevalence, adherence, persistence and impact of adherence on bleeding and stroke risk in people with and without liver disease taking anticoagulants and antiplatelets. METHODS We employed a population-based cohort consisting of person-level linked records from primary care, secondary care and the death registry. The cohort consisted of 3,929,596 adults aged ≥ 30 years during the study period of 1998 to 2020 and registered with an NHS general practitioner in England. The primary outcome was prescribing prevalence, adherence to and persistence with anticoagulant and antiplatelet therapy comparing patients with and without liver disease. Risk factors for non-adherence and non-persistence were analysed using multivariable logistic regression and Cox regression. Impact of adherence on bleeding and ischaemic stroke was assessed. FINDINGS Among patients with any of the six liver diseases (ALD, autoimmune liver disease, cirrhosis, HBV, HCV and NAFLD), we identified 4,237 individuals with incident atrial fibrillation (indication for anticoagulants) and 4,929 individuals with incident myocardial infarction, transient ischaemic attack, unstable angina or peripheral arterial disease (indication for antiplatelets). Among patients without liver disease, 321,510 and 386,643 individuals were identified as having indications for anticoagulant and antiplatelet therapy, respectively. Among drug-naïve individuals, prescribing prevalence was lower in patients with liver disease compared with individuals without liver disease: anticoagulants (20.6% [806/3,921] vs. 33.5% [103,222/307,877]) and antiplatelets (56.2% [2,207/3,927] vs. 71.1% [249,258/350,803]). Primary non-adherence rates (stopping after one prescription) were higher in patients with liver disease, compared with those without liver disease: anticoagulants (7.9% [64/806] vs. 4.7% [4,841/103,222]) and antiplatelets (6.2% [137/2,207] vs. 4.4% [10,993/249,258]). Among individuals who were not primary non-adherent and had at least 12 months of follow-up, patients with liver disease however had a higher one-year adherence rate: anticoagulants (33.1% [208/628] vs. 29.4% [26,615/90,569]) and antiplatelets (40.9% [743/1,818] vs. 34.4% [76,834/223,154]). Likelihood of non-adherence was lower in apixaban and rivaroxaban (relative to warfarin) and lower in clopidogrel (relative to aspirin). Increased comorbidity burden (by CHA2DS2VASc score) was associated with decreased risk of non-adherence and non-persistence with anticoagulants. Overall rates of 'non-adherent, non-persistent' were highest in warfarin (compared with apixaban and rivaroxaban) and aspirin (compared with clopidogrel or dipyridamole) in patients with and without liver disease. Among patients without liver disease, not taking antithrombotic medications for >3 months was associated with a higher risk of stroke, however, adherence to these medications was also associated with a small increase in risk of bleeding. Patients with liver disease (when compared with those without liver disease) had higher risks of stroke, especially when they stopped taking antiplatelets for >3 months. Patients with liver disease who were adherent to antiplatelets, however, had a higher risk of bleeding compared with patients without liver disease. INTERPRETATION Use of antithrombotic medicines in patients with and without liver disease is suboptimal with heterogeneity across medicines. As patients with liver disease are excluded from major randomised trials for these drugs, our results provide real-world evidence that may inform medicine optimisation strategies. We outline challenges and opportunities for tackling non-adherence, which begins with understanding patients' views of medicines to help them make informed decisions about appropriate use. FUNDING AGL is supported by funding from the Wellcome Trust (204841/Z/16/Z), National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre (BRC714/HI/RW/101440), NIHR Great Ormond Street Hospital Biomedical Research Centre (19RX02), the Health Data Research UK Better Care Catalyst Award (CFC0125) and the Academy of Medical Sciences (SBF006\1084). The funders have no role in the writing of the manuscript or the decision to submit it for publication.
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Affiliation(s)
- Wai Hoong Chang
- Institute of Health Informatics, University College London, London, UK
| | | | - Yen Yi Tan
- Institute of Health Informatics, University College London, London, UK
| | - Alvina G. Lai
- Institute of Health Informatics, University College London, London, UK
- Corresponding author.
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Han AN, Han BR, Zhang T, Heimbach T. Hepatic Impairment Physiologically Based Pharmacokinetic Model Development: Current Challenges. CURRENT PHARMACOLOGY REPORTS 2021; 7:213-226. [DOI: 10.1007/s40495-021-00266-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/09/2021] [Indexed: 01/03/2025]
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Semmler G, Pomej K, Bauer DJM, Balcar L, Simbrunner B, Binter T, Hartl L, Becker J, Pinter M, Quehenberger P, Trauner M, Mandorfer M, Lisman T, Reiberger T, Scheiner B. Safety of direct oral anticoagulants in patients with advanced liver disease. Liver Int 2021; 41:2159-2170. [PMID: 34152697 PMCID: PMC8456813 DOI: 10.1111/liv.14992] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/28/2021] [Accepted: 06/18/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited. METHODS Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low-molecular-weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti-Xa peak levels and thrombomodulin-modified thrombin generation assays (TM-TGAs) were measured in a subgroup of 35/28 DOAC patients. RESULTS Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child-Pugh-stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure-related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow-up of 10.5 (IQR: 4.0-27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS-B/C (at 12 months: 36.9% vs CPS-A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59-6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82-9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti-Xa peak levels were higher in patients with CPS-B/C (345 [95% CI: 169-395] vs CPS-A: 137 [95% CI: 96-248] ng/mL, P = .048) and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients. CONCLUSIONS Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.
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Affiliation(s)
- Georg Semmler
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Katharina Pomej
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - David J. M. Bauer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Lorenz Balcar
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Teresa Binter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Lukas Hartl
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Jeannette Becker
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Matthias Pinter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Peter Quehenberger
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
| | - Ton Lisman
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Bernhard Scheiner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria
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Douros A, Cui Y, Platt RW, Filion KB, Sebastiani G, Renoux C. Utilization and long-term persistence of direct oral anticoagulants among patients with nonvalvular atrial fibrillation and liver disease. Br J Clin Pharmacol 2021; 88:994-1009. [PMID: 34409636 DOI: 10.1111/bcp.15046] [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: 11/19/2020] [Revised: 07/25/2021] [Accepted: 08/07/2021] [Indexed: 11/28/2022] Open
Abstract
AIMS We characterized the utilization and long-term treatment persistence of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF) and liver disease. METHOD Using the UK Clinical Practice Research Datalink, we assembled a population-based cohort of NVAF patients with liver disease initiating oral anticoagulants between 2011 and 2020. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of the association between patient characteristics and initiation of DOACs vs vitamin K antagonists (VKAs). Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of the association between patient characteristics and the switch from VKAs to DOACs vs remaining on VKAs. We also assessed the 5-year treatment persistence with DOACs vs VKAs, and whether ischemic stroke or bleeding preceded treatment discontinuation. RESULTS Our cohort included 3167 NVAF patients with liver disease initiating DOACs (n = 2247, 71%) or VKAs (n = 920, 29%). Initiators of DOACs were more likely to have prior ischemic stroke (OR 1.44, 95% CI 1.12-1.85) than VKA initiators but less likely to have used antiplatelet agents (OR 0.66, 95% CI 0.53-0.82). Patients switching to DOACs were more likely to have used selective serotonin reuptake inhibitors (HR 1.64, 95% CI 1.13-2.37) than those remaining on VKAs. At 5 years, 31% of DOAC initiators and 9% of VKA initiators remained persistent. Only few patients were diagnosed with ischemic stroke or bleeding prior to treatment discontinuation. CONCLUSION Most NVAF patients with liver disease initiated treatment with DOACs. Long-term persistence with DOACs was higher than with VKAs but remained relatively low.
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Affiliation(s)
- Antonios Douros
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada.,Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada.,Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Ying Cui
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada
| | - Robert W Platt
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.,Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Kristian B Filion
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada.,Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada
| | - Giada Sebastiani
- Department of Medicine, McGill University, Montreal, Quebec, Canada.,Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Christel Renoux
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.,Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
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