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Zhang Y, Qian W, Fei W, Zheng Y, Yao Y, Kong M, Zhu X, Peng Y, He D, Zheng C. Revolutionizing anticoagulation: Nanoengineered therapies and precision medicine approaches. Int J Pharm 2025; 676:125596. [PMID: 40239875 DOI: 10.1016/j.ijpharm.2025.125596] [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: 02/19/2025] [Revised: 03/29/2025] [Accepted: 04/12/2025] [Indexed: 04/18/2025]
Abstract
With the advancement of therapeutic concepts, early intervention with antithrombotic therapy for patients at potential thrombotic risk is becoming more proactive. Anticoagulant therapy, a critical component of antithrombotic treatment, thus plays a key role in the prevention and treatment of cardiovascular diseases. Unfortunately, existing anticoagulation treatments still face many challenges, including abnormal bleeding, allergic reactions, and drug resistance. To identify novel technologies for addressing these issues and explore the latest research developments in the field of anticoagulation, this paper reviewed the advances of anticoagulant factor-loaded nanoplatforms firstly. These systems can precisely deliver anticoagulant drugs to specific targets, improving drug bioavailability and reducing unnecessary systemic side effects. Subsequently, the paper delved into the development of anticoagulant technologies, including the advancements in biocompatible anticoagulant nanomaterials, the application of DNA origami technology, and the progress in external energy-mediated anticoagulation strategies. A common feature of these engineered anticoagulation systems is their ability to modulate the dynamic balance of anticoagulant factors in the body without relying on traditional drugs, enabling more personalized and efficient anticoagulation effects. Finally, the paper examined novel precision anticoagulation strategies that combine biomedical engineering technologies with precision anticoagulation therapy. These strategies can tailor anticoagulation treatments to the specific pathological conditions of individual patients, such as thrombin activity, thereby reducing the risk of excessive anticoagulation. In conclusion, the engineered anticoagulation therapy strategies proposed in this paper represent cutting-edge advancements in anticoagulation medicine, providing more precise and safer solutions for the treatment of thrombotic diseases, and offering important theoretical and practical guidance for future personalized medicine and precision therapies.
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Affiliation(s)
- Ying Zhang
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenqiang Qian
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Weidong Fei
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yongquan Zheng
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yao Yao
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Maiqi Kong
- School of Medicine & Nursing, Huzhou University, Huzhou 313000, China
| | - Xiaojun Zhu
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yujie Peng
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Dan He
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Caihong Zheng
- Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
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Sinha T, Mayow AH, Abedin TT, Phoo CN, Shawl SH, Muhammad A, Kholoki S, Hirani S. Comparison of Effectiveness and Safety of Direct-Acting Oral Anticoagulants and Vitamin K Agonists in Patients With Atrial Fibrillation and End-Stage Kidney Disease: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e57447. [PMID: 38699102 PMCID: PMC11063964 DOI: 10.7759/cureus.57447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2024] [Indexed: 05/05/2024] Open
Abstract
The objective of the study is mentioned, but it could be further clarified by explicitly stating the aim to compare the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) specifically in patients with atrial fibrillation (AF) and end-stage renal disease (ESRD). We conducted a thorough electronic search of the literature, encompassing databases such as PubMed, EMBASE, Cochrane Library, and Web of Science from their inception up to March 5, 2024. Furthermore, we meticulously examined the bibliographies of included studies to identify additional relevant literature. The reporting of this meta-analysis adhered to the guidelines outlined in the Preferred Reporting of Systematic Review and Meta-analysis guidelines. The endpoints evaluated in this meta-analysis included all-cause mortality, stroke or systemic embolism, and major bleeding. Data analysis was carried out utilizing RevMan Version 5.4 (Cochrane, London, United Kingdom). Dichotomous outcomes, including all-cause mortality, stroke or systemic embolism, and major bleeding, were presented as risk ratios (RRs) with corresponding 95% confidence intervals (CI). A total of 11 studies were incorporated in this meta-analysis, comprising a pooled sample size of 44,863 participants with AF. The pooled analysis revealed no significant disparity between DOACs and VKAs concerning stroke or systemic embolism (RR: 0.93, 95% CI: 0.77 to 1.14) and all-cause mortality (RR: 0.86, 95% CI: 0.74 to 1.00). However, there was a noteworthy reduction in the risk of major bleeding events associated with DOACs compared to VKAs (RR: 0.84, 95% CI: 0.73 to 0.96). Consequently, DOACs may be considered a viable alternative to warfarin in patients with ESRD. However, we need further larger clinical trials to validate these findings.
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Affiliation(s)
- Tanya Sinha
- Medicine, Tribhuvan University, Kathmandu, NPL
| | - Abshiro H Mayow
- Medicine, St. Georges University School of Medicine, Chicago, USA
| | | | - Chaw N Phoo
- Internal Medicine, University of Medicine, Mandalay, Mandalay, MMR
| | - Saima H Shawl
- Internal Medicine/Sleep Medicine, Midwest Sleep and Wellness Clinic, Chicago, USA
- Medicine, Chattogram Medical College Hospital, Chittagong, BGD
| | - Ali Muhammad
- Neurology, King Edward Medical Univeristy, Lahore, Lahore, PAK
- Medicine, King Edward Medical Univeristy, Lahore, Lahore, PAK
| | - Samer Kholoki
- Internal Medicine, La Grange Memorial Hospital, Chicago, USA
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Heuts S, Ceulemans A, Kuiper GJAJM, Schreiber JU, van Varik BJ, Olie RH, Ten Cate H, Maessen JG, Milojevic M, Maesen B. Optimal management of cardiac surgery patients using direct oral anticoagulants: recommendations for clinical practice. Eur J Cardiothorac Surg 2023; 64:ezad340. [PMID: 37812245 PMCID: PMC10585358 DOI: 10.1093/ejcts/ezad340] [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: 07/26/2023] [Revised: 09/26/2023] [Accepted: 10/06/2023] [Indexed: 10/10/2023] Open
Abstract
OBJECTIVES Literature is scarce on the management of patients using direct oral anticoagulants (DOACs) undergoing elective, urgent and emergency surgery. Therefore, we summarize the current evidence and provide literature-based recommendations for the management of patients on DOACs in the perioperative phase. METHODS A general literature review was conducted on the pharmacology of DOACs and for recommendations on the management of cardiac surgical patients on DOACs. Additionally, we performed a systematic review for studies on the use of direct DOAC reversal agents in the emergency cardiac surgical setting. RESULTS When surgery is elective, the DOAC cessation strategy is relatively straightforward and should be adapted to the renal function. The same approach applies to urgent cases, but additional DOAC activity drug level monitoring tests may be useful. In emergency cases, idarucizumab can be safely administered to patients on dabigatran in any of the perioperative phases. However, andexanet alfa, which is not registered for perioperative use, should not be administered in the preoperative phase to reverse the effect of factor Xa inhibitors, as it may induce temporary heparin resistance. Finally, the administration of (activated) prothrombin complex concentrate may be considered in all patients on DOACs, and such concentrates are generally readily available. CONCLUSIONS DOACs offer several advantages over vitamin K antagonists, but care must be taken in patients undergoing cardiac surgery. Although elective and urgent cases can be managed relatively straightforwardly, the management of emergency cases requires particular attention.
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Affiliation(s)
- Samuel Heuts
- Department of Cardiothoracic Surgery, Maastricht University Medical Centre+, Maastricht, Netherlands
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
| | - Angelique Ceulemans
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
- Department of Neurology, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Gerhardus J A J M Kuiper
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
- Department of Anaesthesiology and Pain Treatment, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Jan U Schreiber
- Department of Anaesthesiology and Pain Treatment, Maastricht University Medical Centre+, Maastricht, Netherlands
| | | | - Renske H Olie
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
- Thrombosis Expertise Centre, Maastricht University Medical Centre+, Maastricht, Netherlands
- Department of Internal Medicine, Section Vascular Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Hugo Ten Cate
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
- Thrombosis Expertise Centre, Maastricht University Medical Centre+, Maastricht, Netherlands
- Department of Internal Medicine, Section Vascular Medicine, Maastricht University Medical Centre+, Maastricht, Netherlands
| | - Jos G Maessen
- Department of Cardiothoracic Surgery, Maastricht University Medical Centre+, Maastricht, Netherlands
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
| | - Milan Milojevic
- Department of Cardiac Surgery and Cardiovascular Research, Dedinje Cardiovascular Institute, Belgrade, Serbia
| | - Bart Maesen
- Department of Cardiothoracic Surgery, Maastricht University Medical Centre+, Maastricht, Netherlands
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands
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Pacchiarini MC, Regolisti G, Greco P, Di Motta T, Benigno GD, Delsante M, Fiaccadori E, Di Mario F. Treatment of dabigatran intoxication in critically ill patients with Acute Kidney Injury: The role of Sustained Low-Efficiency Dialysis. Int J Artif Organs 2023; 46:574-580. [PMID: 37853619 DOI: 10.1177/03913988231204516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
The use of dabigatran in patients with non-valvular atrial fibrillation (AF) has widely increased in the last decades, due to its positive effects in terms of safety/efficacy. However, because of the risk of major bleeding, a great degree of attention has been suggested in elderly patients with multiple comorbidities. Notably, dabigatran mainly undergoes renal elimination and dose adjustment is recommended in patients with Chronic Kidney Disease (CKD). In this regard, the onset of an abrupt decrease of kidney function may further affect dabigatran pharmacokinetic profile, increasing the risk of acute intoxication. Idarucizumab is the approved antagonist in the case of dabigatran-associated major bleeding or concomitant need of urgent surgery, but its clinical use is limited by the lack of data in patients with Acute Kidney Injury (AKI). Thus, the early start of Extracorporeal Kidney Replacement Therapy (EKRT) could be indicated to remove the drug and to reverse the associated excess anticoagulation. Sustained Low-Efficiency Dialysis (SLED) could represent an effective therapeutic option to reduce the dabigatran plasma levels rapidly while avoiding post-treatment rebound. We present here a case series of three AKI patients with acute dabigatran intoxication, effectively and safely resolved with a single SLED session.
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Affiliation(s)
- Maria Chiara Pacchiarini
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
| | - Giuseppe Regolisti
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
- UO Clinica e Immunologia Medica, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - Paolo Greco
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
| | - Tommaso Di Motta
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
| | - Giuseppe Daniele Benigno
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
| | - Marco Delsante
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
| | - Enrico Fiaccadori
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
| | - Francesca Di Mario
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
- Scuola di Specializzazione in Nefrologia, Università di Parma, Parma, Italy
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Lahham E, Abu Ta’a M, Hayek A, Lahham C. Dental Implant Surgery for Patients Receiving Non-vitamin K Antagonist Oral Anticoagulants (NOACs); Clinical Considerations and Management: A Mini-review. Open Dent J 2023; 17. [DOI: 10.2174/18742106-v17-e230202-2022-130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/09/2022] [Accepted: 01/11/2023] [Indexed: 02/05/2023] Open
Abstract
Background:
Dental implants are one of the most prevalent operations in dental clinics, as they are the ideal solution to replace teeth. However, many patients who need this treatment are older and suffering from heart diseases, especially atrial fibrillation, which requires anticoagulants. Non-vitamin K antagonist oral anticoagulants (NOACs) are considered modern anticoagulants, and they include four common medications: dabigatran, rivaroxaban, apixaban, and edoxaban.
Materials and Methods:
In this study, we review the literature regarding the proper management of patients receiving NOACs in dental implant clinics based on papers published in the last decade (2010-2022). A comprehensive search on the PubMed, Scopus, and Web of Science databases was conducted to identify articles evaluating the relationship between Non-vitamin K dependent oral anticoagulants and dental implant surgery.
Results:
Despite the limitations of this study, it has been found that dental implants require discontinuation of NOACs for 24 hours or more prior to implant surgery. This depends on the type of anticoagulant and the creatinine clearance (CrCl).
Conclusion:
Implant surgery requires interruption of NOACs ≥24 hours preoperatively. However, there is a need for further clinical studies in order to establish more evidence-based guidelines.
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Lasica R, Asanin M, Djukanovic L, Radovanovic N, Savic L, Polovina M, Stankovic S, Ristic A, Zdravkovic M, Lasica A, Kravic J, Perunicic J. Dilemmas in the Choice of Adequate Therapeutic Treatment in Patients with Acute Pulmonary Embolism—From Modern Recommendations to Clinical Application. Pharmaceuticals (Basel) 2022; 15:ph15091146. [PMID: 36145366 PMCID: PMC9501350 DOI: 10.3390/ph15091146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/03/2022] [Accepted: 09/06/2022] [Indexed: 11/24/2022] Open
Abstract
Pulmonary thromboembolism is a very common cardiovascular disease, with a high mortality rate. Despite the clear guidelines, this disease still represents a great challenge both in diagnosis and treatment. The heterogeneous clinical picture, often without pathognomonic signs and symptoms, represents a huge differential diagnostic problem even for experienced doctors. The decisions surrounding this therapeutic regimen also represent a major dilemma in the group of patients who are hemodynamically stable at initial presentation and have signs of right ventricular (RV) dysfunction proven by echocardiography and positive biomarker values (pulmonary embolism of intermediate–high risk). Studies have shown conflicting results about the benefit of using fibrinolytic therapy in this group of patients until hemodynamic decompensation, due to the risk of major bleeding. The latest recommendations give preference to new oral anticoagulants (NOACs) compared to vitamin K antagonists (VKA), except for certain categories of patients (patients with antiphospholipid syndrome, mechanical valves, pregnancy). When using oral anticoagulant therapy, special attention should be paid to drug–drug interactions, which can lead to many complications, even to the death of the patient. Special population groups such as pregnant women, obese patients, patients with antiphospholipid syndrome and the incidence of cancer represent a great therapeutic challenge in the application of anticoagulant therapy. In these patients, not only must the effectiveness of the drugs be taken into account, but great attention must be paid to their safety and possible side effects, which is why a multidisciplinary approach is emphasized in order to provide the best therapeutic option.
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Affiliation(s)
- Ratko Lasica
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
- Correspondence:
| | - Milika Asanin
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Lazar Djukanovic
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Nebojsa Radovanovic
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Lidija Savic
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Marija Polovina
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Sanja Stankovic
- Center for Medical Biochemistry, University Clinical Center of Serbia, 11000 Belgrade, Serbia
- Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Arsen Ristic
- Department of Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | | | | | - Jelena Kravic
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Jovan Perunicic
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia
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Elfar S, Elzeiny SM, Ismail H, Makkeyah Y, Ibrahim M. Direct Oral Anticoagulants vs. Warfarin in Hemodialysis Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis. Front Cardiovasc Med 2022; 9:847286. [PMID: 35757350 PMCID: PMC9218480 DOI: 10.3389/fcvm.2022.847286] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 05/20/2022] [Indexed: 11/22/2022] Open
Abstract
Background The use of Direct Oral Anticoagulants (DOACs) in patients who have both atrial fibrillation (AF) and end-stage renal disease (ESRD) requiring hemodialysis remains controversial, with warfarin remaining the mainstay of the treatment. As hemodialysis patients were excluded from most clinical DOACs trials, the evidence of their efficacy and safety is lacking in this cohort of patients. Aim To review the current evidence investigating safety profile and the efficacy of DOACs in comparison with warfarin in patients with AF and end-stage renal disease (ESRD) requiring hemodialysis. Methods and Results We included five studies with a total of 34,516 patients in our meta-analysis. The outcomes were major bleeding, ischemic stroke, systemic embolization, hemorrhagic stroke, gastrointestinal bleeding, minor bleeding, and death. Of these patients, 31,472 (92.14%) received warfarin and 3,044 patients received DOACs (8.91%). No significant differences in the incidence of hemorrhagic stroke, major bleeding, hemodialysis access site bleeding, ischemic stroke, and GI bleeding were found between DOACs and warfarin. However, there were higher rates of systemic embolization, minor bleeding, and death events in patients who received DOACs than in the warfarin group (3.39% vs. 1.97%, P-value = 0.02), (6.78% vs. 2.2%, P-value 0.02), and (11.38% vs. 5.12%, P-value < 0.006) respectively. Conclusion In patients on dialysis who require anticoagulation for AF, warfarin could be associated with a significant reduction in minor bleeding, systemic embolization, and death compared to DOACs. These findings need to be validated by further prospective studies to address the best strategy to deal with the increased thrombotic and bleeding risks in such patients.
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Affiliation(s)
- Sohil Elfar
- Cardiology Department, Faculty of Medicine, Portsaid University, PortSaid, Egypt
- *Correspondence: Sohil Elfar
| | - Sara Mohamed Elzeiny
- Cardiology Department, Nasser Institute for Research and Treatment, Cairo, Egypt
| | - Hesham Ismail
- Adult Intensive Care Unit, Royal Brompton and Harefield Hospitals, London, United Kingdom
| | - Yahya Makkeyah
- Neprology Department, North West Anglia National Health Services (NHS) Foundation Trust, Huntingdon, United Kingdom
| | - Mokhtar Ibrahim
- Cardiology Department, University Hospitals of Leicester, Leicester, United Kingdom
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Jackson R, Trus RM, El-Diasty M. Hemadsorption for removal of ticagrelor and direct oral anticoagulants in cardiac surgery. Expert Rev Cardiovasc Ther 2022; 20:141-150. [PMID: 35179425 DOI: 10.1080/14779072.2022.2044306] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Cardiac patients on antiplatelets or oral anticoagulation undergoing emergent cardiac surgery without appropriate washout periods are at increased risk for developing perioperative bleeding. CytoSorb is a commercially available hemadsorption filter that can simultaneously remove a wide range of substances including ticagrelor, and direct oral anticoagulants (DOACs). Areas covered: Although CytoSorb has been used to remove various protein-bound substances, this review will specifically evaluate and review current evidence for applying CytoSorb in removing ticagrelor and DOACs using 4 in vivo studies, 3 case reports, one retrospective clinical study and 2 cost analysis studies. Based on limited evidence, CytoSorb may be effective in reducing perioperative bleeding as demonstrated by reducing chest tube output, blood product transfusions, and re-thoracotomy rates. CytoSorb can also reduce length of intensive care unit (ICU) and hospital stay. Although, CytoSorb has an initial upfront cost, it was proven to be cost effective due to potential health resource savings on both short- and long-term projections.Expert Commentary: CytoSorb provides a novel strategy to remove ticagrelor and DOACs in patients requiring emergency cardiac surgery. Although promising results, more solid evidence is required to establish its clinical effectiveness in reducing perioperative bleeding, bleeding-related complications, mortality, and finally, its overall safety.
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Affiliation(s)
- Robyn Jackson
- Department of Cardiology, Queen's University, Ontario, Canada
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9
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Systemic Anticoagulation and Reversal. Surg Clin North Am 2021; 102:53-63. [PMID: 34800389 DOI: 10.1016/j.suc.2021.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
An increasing number of patients are on anticoagulation for a variety of indications. Patients on anticoagulation who present to the hospital with life-threatening hemorrhage, whether trauma related or not, must be assessed for the reversal of anticoagulation. Identification of the type of anticoagulation, the timing of the most recent usage of anticoagulation, and the efficacy of the anticoagulation all have an impact on whether reversal agents should be used. There are a variety of reversal agents, both nonspecific and specific, that could be used for reversal; however, not all reversal agents work for all anticoagulation medication. As more anticoagulation medications are used and indications expand, providers must be aware of the reversal agents available and the efficacy and indications for these reversal agents.
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10
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Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis. Clin Pharmacokinet 2021; 59:809-825. [PMID: 32020532 PMCID: PMC7292816 DOI: 10.1007/s40262-019-00857-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background Application of idarucizumab and hemodialysis are options to reverse the action of the oral anticoagulant dabigatran in emergency situations. Objectives The objectives of this study were to build and evaluate a mechanistic, whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of idarucizumab, including its effects on dabigatran plasma concentrations and blood coagulation, in healthy and renally impaired individuals, and to include the effect of hemodialysis on dabigatran exposure. Methods The idarucizumab model was built with the software packages PK-Sim® and MoBi® and evaluated using the full range of available clinical data. The default kidney structure in MoBi® was extended to mechanistically describe the renal reabsorption of idarucizumab and to correctly reproduce the reported fractions excreted into urine. To model the PD effects of idarucizumab on dabigatran plasma concentrations, and consequently also on blood coagulation, idarucizumab-dabigatran binding was implemented and a previously established PBPK model of dabigatran was expanded to a PBPK/PD model. The effect of hemodialysis on dabigatran was implemented by the addition of an extracorporeal dialyzer compartment with a clearance process governed by dialysate and blood flow rates. Results The established idarucizumab-dabigatran-hemodialysis PBPK/PD model shows a good descriptive and predictive performance. To capture the clinical data of patients with renal impairment, both glomerular filtration and tubular reabsorption were modeled as functions of the individual creatinine clearance. Conclusions A comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy. Electronic supplementary material The online version of this article (10.1007/s40262-019-00857-y) contains supplementary material, which is available to authorized users.
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11
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Radaelli F, Fuccio L, Paggi S, Bono CD, Dumonceau JM, Dentali F. What gastroenterologists should know about direct oral anticoagulants. Dig Liver Dis 2020; 52:1115-1125. [PMID: 32532603 DOI: 10.1016/j.dld.2020.04.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/24/2020] [Accepted: 04/26/2020] [Indexed: 12/11/2022]
Abstract
Direct oral anticoagulants are being increasingly used in patients with non-valvular atrial fibrillation and venous thromboembolism, due to their improved efficacy/ safety ratio, a predictable anticoagulant effect without need for routine coagulation monitoring, and fewer food and drug interactions compared with vitamin K antagonists. Gastrointestinal bleeding remains a serious complication, whose management is challenging for gastroenterologists due to the lack of a standardized clinical approach. Clinical experience on periendoscopic management of these drugs is still limited and there is a paucity of clinical data supporting guidelines recommendations', and this ultimately turns out in different, unsubstantiated and potentially harmful practices of patient management. Present study will provide a thorough revision on the risk of GI bleeding for DOAC therapy and the identification of patient risk factors to individualize treatment. Moreover, the approach to management of DOACs in case of bleeding complications is discussed, and an algorithm of different strategies in presence or not of plasma level measurement is proposed. Finally the periendoscopic management for elective procedures will be reviewed, at the light of the guideline recommendations and new evidences from observational studies.
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Affiliation(s)
- F Radaelli
- Gastroenterology Department, Valduce Hospital, Como, Italy.
| | - L Fuccio
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - S Paggi
- Gastroenterology Department, Valduce Hospital, Como, Italy
| | - C Del Bono
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - J M Dumonceau
- Gastroenterology Service, Hôpital Civil Marie Curie, Charleroi, Belgium
| | - F Dentali
- Department of Medicine and Surgery, Insubria University, Varese, Italy
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An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants. Adv Hematol 2020; 2020:7636104. [PMID: 32231703 PMCID: PMC7097770 DOI: 10.1155/2020/7636104] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 08/26/2019] [Accepted: 09/25/2019] [Indexed: 12/19/2022] Open
Abstract
Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.
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13
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Abstract
PURPOSE OF REVIEW Anticoagulants in general, but especially the relatively new direct oral anticoagulants and platelet inhibitors, pose a great challenge for physicians in the hemorrhaging patient. The aim of the present review is to provide an overview on recent studies dealing with the reversal of anticoagulation in the hemorrhaging patient and to describe our therapeutic emergency strategy for those patients. RECENT FINDINGS A specific antidote for dabigatran is already on the market and antidotes for the direct and indirect factor Xa inhibitors are in development. Moreover, bleeding under platelet inhibitors remains critical with very little evidence on effective reversal strategies. SUMMARY To reverse anticoagulation in the hemorrhaging patient, specific antidotes should be the first option if available, followed by four-factor prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor seven as the emergency strategy. Fibrinogen concentrate, antifibrinolytics and oral charcoal, respectively, can be considered as an additional measure. Massive blood loss and thrombocytopenia should be treated independently according to the respective, local guidelines for (massive) transfusion of blood and blood products.
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Billoir P, Girault C, Barbay V, Boyer D, Grangé S, Fresel M, Chrétien MH, Le Cam Duchez V. Management of dabigatran after overdosage: two case reports and suggestions for monitoring. Blood Coagul Fibrinolysis 2019; 29:653-655. [PMID: 30045050 DOI: 10.1097/mbc.0000000000000763] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
: Bleeding is the main complication of anticoagulant treatments as dabigatran etexilate. In patients with atrial fibrillation, dabigatran, at certain doses, has been associated with similar rates of stroke and embolism, and a lower rate of major hemorrhage compared to warfarin. Before the recent possibility of reversing the anticoagulant effect of dabigatran with idarucizumab, prothrombin complex concentrate (PCC) was the main available treatment in cases of severe bleeding or emergency surgery . We describe two different cases with very high overdosage in which PCC or idarucizumab was used to reverse the effect of dabigatran etexilate.
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Affiliation(s)
- Paul Billoir
- Normandie Univ, UNIROUEN, INSERM U1096, Rouen University Hospital, Vascular Hemostasis Unit
| | - Christophe Girault
- Normandie Univ, UPRES EA 3830-IRIB, Rouen University Hospital.,Rouen University Hospital, Medical Intensive Care Department
| | - Virginie Barbay
- Rouen University Hospital, Vascular Hemostasis Unit, F 76000 Rouen, France
| | - Deborah Boyer
- Rouen University Hospital, Medical Intensive Care Department
| | - Steven Grangé
- Rouen University Hospital, Medical Intensive Care Department
| | - Marielle Fresel
- Rouen University Hospital, Vascular Hemostasis Unit, F 76000 Rouen, France
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Sheikh-Taha M. Reversal of dabigatran requiring hemodialysis, fresh frozen plasma, and 2 doses of idarucizumab in a patient with acute kidney injury. Am J Health Syst Pharm 2019; 76:9-12. [PMID: 31381100 DOI: 10.1093/ajhp/zxy008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE A case report of dabigatran-associated coagulopathy that lasted for about 1 week after drug discontinuation despite use of several treatment measures is presented. SUMMARY Life-threatening hemorrhage can occur in patients receiving dabigatran, a direct-acting oral anticoagulant. Idarucizumab is a newly approved dabigatran antidote that neutralizes the drug's anticoagulant activity. An 80-year-old Caucasian man with a medical history of hypertension, coronary artery disease, congestive heart failure, gout, and atrial fibrillation was hospitalized with acute kidney injury (AKI) caused by bilateral hydronephrosis secondary to distal urethral stricture. The patient had prolonged coagulation parameters and major bleeding. Initial laboratory values revealed anemia, with a hemoglobin concentration of 8.9 g/dL; a serum creatinine concentration of 3.9 mg/dL; a prothrombin time of 15 seconds; an International Normalized Ratio of 1.1; and a platelet count of 142,000 platelets/mm3. Three hemodialysis sessions and administration of fresh frozen plasma (FFP), packed red blood cells, and 2 doses of idarucizumab were required in order to achieve hemostasis 8 days after dabigatran was discontinued. CONCLUSION A patient with AKI who had been taking dabigatran and developed major bleeding needed 2 doses of idarucizumab in addition to FFP and 3 sessions of hemodialysis in order for hemostasis to be restored. This case suggests that idarucizumab might not produce hemostasis in a timely manner in patients with poor renal function.
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Affiliation(s)
- Marwan Sheikh-Taha
- Department of Pharmacy Practice, Lebanese American University, Byblos, Lebanon
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16
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17
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Dager WE, Roberts AJ, Nishijima DK. Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. Thromb Res 2018; 173:71-76. [PMID: 30476716 DOI: 10.1016/j.thromres.2018.11.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 10/05/2018] [Accepted: 11/08/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event. DESIGN Retrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event. SETTING Academic medical center PATIENTS: Consecutive patients between May 2011 and April 2017 receiving FEIBA for a DOAC-related bleed INTERVENTIONS: None MEASUREMENTS & MAIN RESULTS: Of the 64 patients included in this analysis, 38 patients received low dose FEIBA (mean 10.0 ± 3.6 units/kg) and 26 received moderate dose (mean 24.3 ± 2.1 units/kg) FEIBA; an additional dose was requested in 6 patients. Six dabigatran patients received idarucizumab. 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired. Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions. CONCLUSIONS Low (<20 units/kg) to moderate (20-30 units/kg) doses of FEIBA, with the option for a repeat dose, may be an effective management strategy for obtaining hemostasis in DOAC-related major bleeding events.
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Affiliation(s)
- W E Dager
- Department of Pharmacy, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, United States of America.
| | - A J Roberts
- Department of Pharmacy, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, United States of America
| | - D K Nishijima
- Department of Emergency Medicine, University of California Davis Medical Center, 2315 Stockton Blvd, Sacramento, CA 95817, United States of America
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18
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Mahmood M, Lip GY. Anticoagulantes orales no dependientes de la vitamina K para pacientes con fibrilación auricular e insuficiencia renal grave. Rev Esp Cardiol 2018. [DOI: 10.1016/j.recesp.2018.03.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Nonvitamin K Oral Anticoagulants in Patients With Atrial Fibrillation and Severe Renal Dysfunction. ACTA ACUST UNITED AC 2018; 71:847-855. [PMID: 29958809 DOI: 10.1016/j.rec.2018.05.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 03/12/2018] [Indexed: 12/17/2022]
Abstract
Both atrial fibrillation (AF) and chronic kidney disease (CKD) are highly prevalent, especially with increasing age and associated comorbidities, such as hypertension, diabetes, heart failure, and vascular disease. The relationship between both AF and CKD seems to be bidirectional: CKD predisposes to AF while onset of AF seems to lead to progression of CKD. Stroke prevention is the cornerstone of AF management, and AF patients with CKD are at higher risk of stroke, mortality, cardiac events, and bleeding. Stroke prevention requires use of oral anticoagulants, which are either vitamin K antagonists (eg, warfarin), or the nonvitamin K antagonist oral anticoagulants (NOACs). While NOACs have been shown to be effective in mild-to-moderate renal dysfunction, there are a paucity of data regarding NOACs in severe and end-stage renal dysfunction. This review first discusses the evidence for NOACs in CKD. Second, we summarize the current knowledge regarding the efficacy and safety of NOACs to prevent AF-related stroke and systemic embolism in severe and end-stage renal disease.
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Andresen K, Atar D, Gjertsen E, Ghanima W, Roseth S, Johansen OE. Mechanisms of action and clinical use of specific reversal agents for non-vitamin K antagonist oral anticoagulants. SCAND CARDIOVASC J 2018; 52:156-162. [DOI: 10.1080/14017431.2018.1453613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
| | - Dan Atar
- Dept. of Cardiology B, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Erik Gjertsen
- Dept. of Cardiology, Vestre Viken HF, Drammen Hospital, Drammen, Norway
| | - Waleed Ghanima
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Dept of Medicine, Østfold Hospital, Kalnes, Norway
| | - Svein Roseth
- Medical Dept, Boehringer Ingelheim Norway, Asker, Norway
| | - Odd Erik Johansen
- Therapeutic Area Cardiometabolism, Boehringer Ingelheim Norway, Asker, Norway
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21
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Mourafetis J, Doctor N, Leung S. Treatment of gastrointestinal bleeding with idarucizumab in a patient receiving dabigatran. Am J Health Syst Pharm 2018; 75:177-182. [PMID: 29343478 DOI: 10.2146/ajhp160980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
PURPOSE A case report describing use of idarucizumab for dabigatran reversal without the use of hemostatic agents in a patient who developed acute upper gastrointestinal (GI) bleeding while receiving triple antithrombotic therapy is presented. SUMMARY A 77-year-old man with a complex cardiac history presented to the emergency room with chief complaints of black tarry stools and low blood pressures for 4 days. His past medical history included recent percutaneous coronary intervention (PCI) and drug-eluting stent (DES) placement, atrial fibrillation, hypertension, hyperlipidemia, coronary artery disease, coronary artery bypass graft surgery, stage 3 chronic kidney disease, and cholecystectomy. His triple antithrombotic therapy consisted of aspirin, clopidogrel, and dabigatran. The patient stated that his last dose of dabigatran was taken the night before. Serum dabigatran levels were not measured. Due to suspicion of acute upper GI bleeding, all antithrombotic agents were withheld. Treatment with idarucizumab, i.v. pantoprazole, and blood transfusion was ordered. An upper endoscopy was safely performed 24 hours later and revealed a minor Mallory-Weiss tear. The patient was discharged 48 hours later with prescriptions for acid suppressant and triple antithrombotic therapy; his melena had resolved before discharge. At 14-week follow-up, the patient reported that his cardiologist had deleted aspirin from his antithrombotic regimen. CONCLUSION A patient who had recently undergone PCI and DES placement and was receiving aspirin, clopidogrel, and dabigatran for atrial fibrillation was successfully treated for acute GI bleeding with idarucizumab without the use of a hemostatic agent.
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22
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Novak JE, Alamiri K, Yee J. Dabigatran Reversal in a Patient With End-Stage Liver Disease and Acute Kidney Injury. Am J Kidney Dis 2018; 71:137-141. [DOI: 10.1053/j.ajkd.2017.03.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 03/27/2017] [Indexed: 11/11/2022]
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23
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Edwards G, Roman C, Jithoo R, Mitra B. Use of Idarucizumab for dabigatran reversal: Emergency department experience in two cases with subdural haematoma. Trauma Case Rep 2017; 13:46-49. [PMID: 29644298 PMCID: PMC5887121 DOI: 10.1016/j.tcr.2017.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/26/2017] [Indexed: 11/28/2022] Open
Abstract
Introduction Idarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran, a Direct Oral Anticoagulant. Despite recent trials demonstrating reversal of clinically relevant bleeding, there is a paucity of data on use outside the trial setting. This manuscript describes the use of Idarucizumab to reverse dabigatran in two patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH). Methods Patients were identified through retrospective review of medication dispensing systems and electronic medical records. Results Two cases of Idarucizumab use were identified. Case 1 was of a 63-year-old male who presented following a motorcycle crash. Case 2 was of a 77-year-old male who presented with a 3-week history of ataxia and recurrent falls. Both patients were taking dabigatran for atrial fibrillation (AF). CT Brain revealed acute SDH with clinical indications for urgent surgical evacuation. Serum dabigatran levels were obtained on arrival in the emergency department with levels of 155 ng/ml and 110 ng/ml (reference range 117–275 ng/ml). Idarucizumab for dabigatran reversal was commenced; Case 1 received 5 g Idarucizumab as an intravenous bolus dose, while Case 2 received 5 g Idarucizumab as two 2.5 g intravenous infusions. Serum dabigatran levels for Cases 1 and 2 were 0 ng/ml at 75 min and 340 min post Idarucizumab administration respectively. Both patients proceeded to craniotomy with evacuation of the SDH. There was no extension of the SDH in either case. Anticoagulation was withheld until outpatient clinic review, and both patients transferred for rehabilitation prior to discharge home. Conclusion Idarucizumab was clinically effective for reversing dabigatran, resulting in undetectable serum levels, and should be considered in patients presenting to hospital with clinically significant bleeding associated with dabigatran therapy.
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Affiliation(s)
- Gail Edwards
- Pharmacy Department, The Alfred Hospital, Melbourne, Australia
| | - Cristina Roman
- Pharmacy Department, The Alfred Hospital, Melbourne, Australia.,Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia
| | - Rondhir Jithoo
- Department of Neurosurgery, The Alfred Hospital, Melbourne, Australia
| | - Biswadev Mitra
- Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia.,Department of Epidemiology & Preventative Medicine, Monash University, Melbourne, Australia.,National Trauma Research Institute, Melbourne, Australia
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25
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Ebinger J, Granger CB, Zhu A, Chang A, Henry TD. Idarucizumab since FDA approval: Use in the real-world. Am Heart J 2017; 193:93-94. [PMID: 29129261 DOI: 10.1016/j.ahj.2017.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 08/11/2017] [Indexed: 12/17/2022]
Affiliation(s)
| | | | - Alexander Zhu
- University of Iowa Carver School of Medicine, Iowa City, IA
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Abstract
The use of anticoagulation in the prevention of strokes due to atrial fibrillation or the treatment of venous thromboembolic disease has been on the rise. With the advent and proliferation of direct oral anticoagulation medications, the management of anticoagulation reversal has become increasingly complex, especially when urgent or emergent reversal is required. This review details the commonly used parenteral and oral anticoagulants, the treatment strategies necessary for their reversal, and therapies still in development.
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Affiliation(s)
- Jeremy L Holzmacher
- Center for Trauma and Critical Care, Department of Surgery, George Washington University Medical Center, 2150 Pennsylvania Avenue Northwest, Suite 6B, Washington, DC 20037, USA
| | - Babak Sarani
- Center for Trauma and Critical Care, Department of Surgery, George Washington University Medical Center, 2150 Pennsylvania Avenue Northwest, Suite 6B, Washington, DC 20037, USA.
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27
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Simon A, Domanovits H, Ay C, Sengoelge G, Levy JH, Spiel AO. The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran. J Thromb Haemost 2017; 15:1317-1321. [PMID: 28426914 DOI: 10.1111/jth.13706] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Indexed: 08/31/2023]
Abstract
Essentials Reversal of anticoagulant effects of dabigatran may occur despite application of idarucizumab. Monitoring of dabigatran level after antidote application is crucial to detect rebound. Repeated doses of idarucizumab may be necessary in cases of massive dabigatran accumulation. Combination of antidote application and renal replacement therapy may offer additional benefit. SUMMARY Idarucizumab is a monoclonal antibody fragment designed for reversing the anticoagulant effects of dabigatran. Administration is recommended as two intravenous boluses of 2.5 g within 15 min of each other or as a single 5 g bolus. However, in certain situations a second dose of the drug could be necessary. We report the case of a 77-year-old man, treated with dabigatran for paroxysmal atrial fibrillation. He presented at our department with acute renal failure, concomitant massive dabigatran accumulation and subsequent acute gastrointestinal bleeding. Fifty minutes after the administration of idarucizumab, the dabigatran plasma concentration decreased from a peak of 1630 ng ml-1 to a level below the detection limit of 30 ng ml-1 and bleeding stopped. Eight hours after administration, the dabigatran plasma level started to increase up to 1560 ng ml-1 (96% of the maximum value obtained), accompanied by a further drop in hemoglobin. Concomitant hemodialysis and hemofiltration led to a continuous decrease in dabigatran plasma levels. However, sepsis and multiorgan failure ensued, which led to death. With this case report we raise the question of whether massive dabigatran accumulation requires repeated doses of idarucizumab, or alternatively, if the combination of antidote with hemodialysis/renal replacement therapy is advisable in order to remove circulating levels of dabigatran.
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Affiliation(s)
- A Simon
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - H Domanovits
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - C Ay
- Medical University of Vienna, Clinical Division of Hematology and Hemostaseology, Vienna, Austria
| | - G Sengoelge
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - J H Levy
- Department of Anesthesiology, Duke University, Durham, NC, USA
| | - A O Spiel
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
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28
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Park I. Neurocritical Care for Patients with Kidney Dysfunction. JOURNAL OF NEUROCRITICAL CARE 2017. [DOI: 10.18700/jnc.170008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Abstract
The incidence of patients with trauma on novel oral anticoagulants (NOACs) for the treatment of thromboembolic disorders is increasing. In severe bleeding or hemorrhage into critical spaces, urgent reversal of this underlying pharmacologic coagulopathy becomes paramount. Optimal reversal strategy for commonly used NOACs is still evolving. Basic tenets of evaluation of patients with trauma and resuscitation remain the same. Clinical outcomes data in bleeding human patients with trauma are lacking, but are needed to establish efficacy and safety in these treatments. This article summarizes the available evidence and provides the optimal reversal strategy for bleeding patients with trauma on NOACs.
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Affiliation(s)
- Jason Weinberger
- Department of Surgical Critical Care, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, 22 South Greene Street, T1R53, Baltimore, MD 21201, USA
| | - Mark Cipolle
- Department of Surgery, Christiana Care Health System, Sidney Kimmel School of Medicine, Thomas Jefferson University, 4755 Ogletown-Stanton Road, Suite 1320, Wilmington, DE 19718, USA.
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Abstract
The standard of care for oral anticoagulation therapy has primarily been warfarin, which is limited by its indirect mechanism-of-action, variable kinetics, tolerability, and routine monitoring concerns. The direct-acting oral anticoagulants (DOACs) have predictable pharmacokinetics and pharmacodynamics, and improved safety and efficacy compared to warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation and prevention or management of venous thromboembolism. Consequential bleeding is a concern with all anticoagulants. Vitamin K is not a rapid reversal agent for warfarin; rather it facilitates synthesis of new vitamin K-dependent clotting factors, which can take longer than 24 h. Other nonspecific agents, including recombinant activated factor VII, three- and four-factor prothrombin complex concentrates (PCC), and activated PCC or Factor Eight Inhibitor Bypassing Activity (FEIBA®), are options based on clinical need. Specific agents to quickly reverse the effects of DOACs have been under development, and idarucizumab, a monoclonal antibody fragment that rapidly binds dabigatran, has been approved for clinical use in cases of dabigatran-related life-threatening bleeding, or if a dabigatran-treated patient needs emergency surgery or an invasive procedure. Idarucizumab specifically and rapidly reverses dabigatran-induced anticoagulation as measured by established coagulation assays. However, this does not guarantee complete hemostasis, especially if a patient has underlying comorbidities such as renal or liver disease, or has experienced recent trauma that requires urgent surgery. In these cases, concomitant supportive therapy and/or administration of concentrated clotting factors may be considered. Emerging data from ongoing trials and clinical experience will further inform providers regarding optimal approaches for anticoagulation reversal.
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Affiliation(s)
- William E Dager
- a Department of Pharmaceutical Services , University of California, Davis Medical Center , Sacramento , CA , US
| | - Linda Banares
- b Department of Clinical Sciences , Touro University California, College of Pharmacy , Vallejo , CA , US
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Abstract
PURPOSE OF REVIEW To review the current understanding of hemodialysis-mediated clearance of commonly used cardiovascular medications. RECENT FINDINGS Although cardiovascular drug dialyzability is poorly understood, many drug classes appear to include agents with substantially different degrees of dialyzability. Recent data suggest that more readily dialyzable beta-blockers associate with higher short-term mortality in patients initiating these drugs when on hemodialysis. Although this relationship was not observed in a later study with angiotensin-converting enzyme inhibitors of varying dialyzability, studies of this kind are currently limited by pharmacokinetic data that are either incomplete or no longer applicable to modern hemodialysis procedures. SUMMARY There are substantial deficits in our understanding of cardiovascular medication dialyzability, which relates in large part to advances in the process of hemodialysis that have rendered older studies of dialyzability irrelevant. The importance of cardiovascular disease in patients receiving hemodialysis demands a better understanding of the effect hemodialysis exerts on cardiovascular drug pharmacokinetics.
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Raval AN, Cigarroa JE, Chung MK, Diaz-Sandoval LJ, Diercks D, Piccini JP, Jung HS, Washam JB, Welch BG, Zazulia AR, Collins SP. Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association. Circulation 2017; 135:e604-e633. [PMID: 28167634 DOI: 10.1161/cir.0000000000000477] [Citation(s) in RCA: 163] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Non-vitamin K oral anticoagulants (NOACs) are now widely used as alternatives to warfarin for stroke prevention in atrial fibrillation and management of venous thromboembolism. In clinical practice, there is still widespread uncertainty on how to manage patients on NOACs who bleed or who are at risk for bleeding. Clinical trial data related to NOAC reversal for bleeding and perioperative management are sparse, and recommendations are largely derived from expert opinion. Knowledge of time of last ingestion of the NOAC and renal function is critical to managing these patients given that laboratory measurement is challenging because of the lack of commercially available assays in the United States. Idarucizumab is available as an antidote to rapidly reverse the effects of dabigatran. At present, there is no specific antidote available in the United States for the oral factor Xa inhibitors. Prothrombin concentrate may be considered in life-threatening bleeding. Healthcare institutions should adopt a NOAC reversal and perioperative management protocol developed with multidisciplinary input.
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Dager W, Hellwig T. Current knowledge on assessing the effects of and managing bleeding and urgent procedures with direct oral anticoagulants. Am J Health Syst Pharm 2017; 73:S14-26. [PMID: 27147455 DOI: 10.2146/ajhp150960] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE Current knowledge on managing major bleeding events with available hemostatic agents, including their combined use with potential reversal agents, in patients taking direct oral anticoagulant (DOACs) is reviewed. SUMMARY Over the past five years, a new generation of oral agents, the DOACs, has emerged as commonly used anticoagulants for stroke prevention in non-valvular atrial fibrillation, and treatment or secondary prevention of venous thromboembolism. Management of a bleeding event in the setting of DOAC therapy should take into account the relative risks of bleeding and thrombosis, which will determine the degree of anticoagulant reversal required. In the setting of a major (critical) bleeding event associated with notable blood loss, management may include transfusions of blood products to sustain the function of organ systems, and the availability of specific reversal agents will provide additional options for bleeding management. Beyond withholding the DOAC and providing supportive management that addresses any factors contributing to the bleeding event, clinicians may desire to expedite the removal of any anticoagulation effects. In general, this is accomplished by either removing or neutralizing the anticoagulant or by independently establishing hemostasis. CONCLUSION With or without reversal agents, patients may require supportive management such as mechanical pressure, volume support, transfusions of blood products, and, depending on the situation, surgery to repair the bleeding source. Specific reversal agents are currently under development or have recently been approved for the urgent management of bleeding events or the facilitation of invasive procedures in patients receiving DOACs.
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Affiliation(s)
- William Dager
- University of California Davis Medical Center, Sacramento, CA.
| | - Thaddaus Hellwig
- South Dakota State University College of Pharmacy, Sioux Falls, SDSanford USD Medical Center, Sioux Falls, SD
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Porru M, Mameli A, Cianchetti ME, Musu M, Schirru P, Ruberto MF, Barcellona D, Marongiu F. Dabigatran overdose: a case report of acute hepatitis. Extracorporeal treatment. Int J Hematol 2016; 105:532-535. [PMID: 27910004 DOI: 10.1007/s12185-016-2158-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/22/2016] [Accepted: 11/24/2016] [Indexed: 12/01/2022]
Abstract
Dabigatran is an oral, direct thrombin inhibitor approved by international regulatory agencies for stroke prevention in patients with paroxysmal or persistent non-rheumatic atrial fibrillation (AF). The benefits of dabigatran are widely described, but its use in the geriatric population is not without risk. Chronic kidney disease is a common comorbidity with AF, and thus frequent checks of renal function in elderly patients are recommended. We report a case of dabigatran intoxication in an elderly man affected by heart failure and worsening renal function, who developed acute hepatitis and coma, which was successfully treated with continuous veno-venous hemodiafiltration. Although extracorporeal therapy has been suggested as a strategy for clearing dabigatran during acute bleeding, this approach may be useful in other dabigatran-related, life-threatening conditions, such as that described in this report.
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Affiliation(s)
- Mariagrazia Porru
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - Antonella Mameli
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy.
| | - Maria E Cianchetti
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - Mario Musu
- Intensive Care Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, Monserrato, Cagliari, Italy
| | - Paola Schirru
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - Maria F Ruberto
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - Doris Barcellona
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
| | - Francesco Marongiu
- Internal Medicine and Haemocoagulopathies Unit, Azienda Ospedaliero Universitaria (A.O.U.), Presidio "Duilio Casula", University of Cagliari, SS 554, Bivio per Sestu, 09042, Monserrato, Cagliari, Italy
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Abstract
The prevalence and embolic risk of atrial fibrillation (AF) increase with age. Vitamin K antagonists (VKAs) or direct-acting oral anticoagulants (DOACs) reduce the risk of stroke or embolism. The aim of this review was to summarize the paucity of information regarding the safety and efficacy of DOACs in AF patients aged 90 years or older. The maximum age of included patients is not listed in any of the available DOAC investigating trials and registries, thus it is unclear if nonagenarians were included. Additionally, we could not find any subgroup analysis addressing this issue. There is an urgent need to collect more information on the safety and efficacy of oral anticoagulants in nonagenarians, especially regarding the role of DOACs, which are increasingly prescribed to this group of patients despite the lack of data. The best solution to this problem would be a prospective, randomized trial in this group of patients, however that would require a large investment of time, effort, and funds. In the meantime, we suggest subgroup analyses addressing the effects and safety of VKAs versus DOACs in nonagenarians, in case they have been included in previously completed or ongoing trials or registries. This could be feasible and would be desirable in view of the large amount of data already accumulated. Irrespective of age, anemia in patients receiving DOACs should be carefully investigated to rule out occult blood loss. With their known interaction profile and the possibility of monitoring these drugs, VKAs should be favored over DOACs in nonagenarians until more data are available regarding the safety of DOACs.
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Keeling D, Tait RC, Watson H. Peri-operative management of anticoagulation and antiplatelet therapy. Br J Haematol 2016; 175:602-613. [DOI: 10.1111/bjh.14344] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/26/2016] [Accepted: 07/31/2016] [Indexed: 12/14/2022]
Affiliation(s)
- David Keeling
- Oxford University Hospitals NHS Foundation Trust; Oxford UK
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Marino KK, Santiago RA, Dew RB, Berliner N, Connors JM, Connell NT, Tucker JK. Management of Dabigatran-Associated Bleeding with Two Doses of Idarucizumab Plus Hemodialysis. Pharmacotherapy 2016; 36:e160-e165. [DOI: 10.1002/phar.1830] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Kaylee K. Marino
- Department of Pharmacy; Brigham and Women's Faulkner Hospital; Jamaica Plain Massachusetts
| | - Raul A. Santiago
- Department of Pharmacy; Brigham and Women's Faulkner Hospital; Jamaica Plain Massachusetts
| | - Richard B. Dew
- Department of Pharmacy; Brigham and Women's Faulkner Hospital; Jamaica Plain Massachusetts
| | - Nancy Berliner
- Department of Medicine; Division of Hematology; Brigham and Women's Hospital; Boston Massachusetts
| | - Jean M. Connors
- Department of Medicine; Division of Hematology; Brigham and Women's Hospital; Boston Massachusetts
| | - Nathan T. Connell
- Department of Medicine; Division of Hematology; Brigham and Women's Hospital; Boston Massachusetts
| | - John Kevin Tucker
- Department of Medicine; Division of Nephrology; Brigham and Women's Faulkner Hospital; Jamaica Plain Massachusetts
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Management Overview: Taking a Patient with Intracranial Hemorrhage Related to Direct Oral Anticoagulants to the Operating Room. World Neurosurg 2016; 90:262-267. [DOI: 10.1016/j.wneu.2016.02.070] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/13/2016] [Accepted: 02/15/2016] [Indexed: 11/23/2022]
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Use of Continuous Renal Replacement Therapy for Removal of Dabigatran in a Patient in Need of Emergent Surgery. Case Rep Crit Care 2016; 2016:9692568. [PMID: 27313909 PMCID: PMC4899578 DOI: 10.1155/2016/9692568] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Revised: 04/22/2016] [Accepted: 04/28/2016] [Indexed: 01/07/2023] Open
Abstract
Purpose. To report the ability to remove serum dabigatran using continuous renal replacement therapy (CRRT) in a patient with life-threatening bleeding. Summary. A 77-year-old female with history of atrial fibrillation who takes dabigatran for stroke prevention presented with abdominal pain. Patient was found to have bleeding and possible mesenteric ischemia and was taken to the operating room and had continued bleeding postoperatively. CRRT was initiated for the removal of any remaining dabigatran, with serum dabigatran levels collected to evaluate removal of dabigatran with CRRT. This patient had an increased dabigatran level prior to intervention, which decreased to an undetectable level after use of CRRT. Greater than 80% of the drug was removed due to 4 hours of CRRT and residual kidney function. Reversal of dabigatran is an area of current research with recent FDA approval of idarucizumab for use. Conclusion. Bleeding may occur as a result of the use of dabigatran and change in patient's clinical condition. Use of CRRT may be an option in removing serum dabigatran in the case of a life-threatening bleed.
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Summers RL, Sterling SA. Emergent Bleeding in Patients Receiving Direct Oral Anticoagulants. Air Med J 2016; 35:148-155. [PMID: 27255877 DOI: 10.1016/j.amj.2016.01.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 01/13/2016] [Indexed: 06/05/2023]
Abstract
Direct oral anticoagulants (DOACs) offer clinical advantages over warfarin, such as minimal medication and food interactions and fixed dosing without the need for routine monitoring of coagulation status. As with all anticoagulants, bleeding, either spontaneous or provoked, is the most common complication. The long-term use of these drugs is increasing, and there is a crucial need for emergency medicine service professionals to understand the optimal management of associated bleeding. This review aims to describe the indications and pharmacokinetics of available DOACs; to discuss the risk of bleeding; to provide a treatment algorithm to manage DOAC-associated emergency bleeding; and to discuss future directions in bleeding management, including the role of specific reversal agents, such as the recently approved idarucizumab for reversal of the direct thrombin inhibitor dabigatran. Because air medical personnel are increasingly likely to encounter patients receiving DOACs, it is important that they have an understanding of how to manage patients with emergent bleeding.
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Affiliation(s)
- Richard L Summers
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
| | - Sarah A Sterling
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, USA
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Gosselin RC, Adcock DM. The laboratory's 2015 perspective on direct oral anticoagulant testing. J Thromb Haemost 2016; 14:886-93. [PMID: 26791879 DOI: 10.1111/jth.13266] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 01/12/2016] [Indexed: 01/28/2023]
Abstract
The introduction of direct oral anticoagulant (DOAC) therapy into clinical use in the past 5 years has had significant impact on the clinical laboratory. Clinicians' desire to determine plasma drug presence or measure drug concentration, and more recent observations regarding the limitations and utility of coagulation testing in the setting of DOAC treatment, suggest that early published recommendations regarding laboratory testing should be reassessed. These initial recommendations, furthermore, were often based on drug-spiked plasma studies, rather than samples from patients receiving DOAC therapy. We have demonstrated that reagent sensitivity varies significantly whether drug-spiked samples or samples from DOAC-treated patients are tested. Data from drug-enriched samples must therefore be interpreted with caution or be used as a guide only. We present laboratory assays that can be used to determine drug presence and to measure drug concentration, and provide recommended testing algorithms. As DOAC therapy may significantly impact on specialty coagulation assays, we review those tests with the potential to give false-positive and false-negative results.
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Affiliation(s)
- R C Gosselin
- University of California, Davis Health System, Sacramento, CO, USA
| | - D M Adcock
- Laboratory Corporation of America® Holdings, Colorado Coagulation, Englewood, CO, USA
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Use of Extracorporeal Techniques in the Removal of Dabigatran. Am J Ther 2016; 23:e485-8. [PMID: 24987943 DOI: 10.1097/mjt.0000000000000082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Dabigatran is a novel direct thrombin inhibitor that has proven effective in the prevention of vascular events in patients with nonvalvular atrial fibrillation. Not much is known about the clearance capability with extracorporeal techniques of dabigatran. This review showcases the pharmacokinetics and a perusal of the current literature regarding cases that involved the clearance of the drug in patients with normal renal function and end-stage renal disease. Renal replacement therapy represents a therapeutic option to eliminate dabigatran and decreased the risk of bleeding in patients undergoing emergent surgical procedures on dabigatran.
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Wang K, Ehlers JP. Bilateral Spontaneous Hyphema, Vitreous Hemorrhage, and Choroidal Detachment With Concurrent Dabigatran Etexilate Therapy. Ophthalmic Surg Lasers Imaging Retina 2016; 47:78-80. [PMID: 26731215 DOI: 10.3928/23258160-20151214-13] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 10/08/2015] [Indexed: 11/20/2022]
Abstract
A 79-year-old woman was referred for rapid onset of painless bilateral vision loss. Anterior segment exams revealed bilateral spontaneous hyphema and fibrin accumulation. Observation of the posterior chamber by B-scan ultrasound showed vitreous hemorrhage and choroidal detachment bilaterally. No evidence of additional intraocular inflammation was present. Laboratory work-up for hematologic abnormalities was unremarkable. These hemorrhagic events were suspected to be a complication from taking the novel anticoagulant, dabigatran etexilate (Pradaxa; Boehringer, Ingelheim, Germany). She initially underwent non-surgical therapy, which included immediate cessation of dabigatran, and administration of topical and systemic steroids. The lack of response to medical therapy in the left eye led to surgical treatment of vitreous and persistent subcapsular hemorrhage via pars planar vitrectomy with capsulectomy.
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Vlad I, Armstrong J, Ridgley J, Pascu O. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila) 2016; 54:286-9. [PMID: 26735702 DOI: 10.3109/15563650.2015.1126287] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CONTEXT Dabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications - however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function. CASE DETAILS Two patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10 × 150 mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100 × 110 mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half-life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels. CONCLUSION There is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding.
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Affiliation(s)
- Ioana Vlad
- a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia
| | - Jason Armstrong
- a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia
| | - James Ridgley
- b Intensive Care Unit, Joondalup Hospital , Perth , Australia
| | - Ovidiu Pascu
- a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia
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Awad NI, Brunetti L, Juurlink DN. Enhanced elimination of dabigatran through extracorporeal methods. J Med Toxicol 2015; 11:85-95. [PMID: 25448250 DOI: 10.1007/s13181-014-0448-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Several pharmacokinetic studies have suggested that dabigatran possesses a number of ideal properties for expedited removal via extracorporeal methods. However, this practice has not been prospectively evaluated in patients with life-threatening bleeding or requiring emergency surgery secondary to dabigatran-associated coagulopathy. The purpose of this literature review is to evaluate the published evidence surrounding extracorporeal removal of dabigatran in the setting of emergency surgery or life-threatening bleeding. A query of MEDLINE, Web of Science, International Pharmaceutical Abstracts, and Google Scholar using the terms dabigatran, dabigatran etexilate, hemodialysis, renal replacement therapy, hemorrhage, and atrial fibrillation was used to retrieve relevant literature. Furthermore, a manual search of the references of the identified literature was performed to capture additional data. Current evidence suggests that extracorporeal removal of dabigatran may play a role in the setting of life-threatening bleeding and emergent surgery. Conflicting evidence exists with regard to the potential for redistribution based on serum dabigatran concentrations. In addition, a number of practicalities must be considered before incorporating this technique in the clinical setting. Extracorporeal removal of dabigatran may be a treatment modality in selected patients who require emergency reversal.
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Affiliation(s)
- Nadia I Awad
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Room 423, Piscataway, NJ, USA,
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Palareti G, Poli D. The challenges and limitations of widespread direct oral anticoagulant treatment: practical suggestions for their best use. Expert Rev Cardiovasc Ther 2015; 14:163-76. [DOI: 10.1586/14779072.2016.1115344] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Dabigatran overdose: case report of laboratory coagulation parameters and hemodialysis of an 85-year-old man. Blood Coagul Fibrinolysis 2015; 26:225-9. [PMID: 25629417 DOI: 10.1097/mbc.0000000000000221] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Dabigatran is an oral direct inhibitor indicated for stroke prevention in patients with atrial fibrillation. Unlike warfarin, dabigatran's observed therapeutic window and minimal drug-to-drug interaction suggest that laboratory test and dose adjustments are not necessary; nevertheless, circumstances of excessive anticoagulation, decreased kidney function, and instances of significant bleeding and thrombosis require laboratory assessment. In order to gather experience in the management of global [activated partial thromboplastin time (APTT) and thrombin time (TT) with extended endpoint] and specific [ecarin chromogenic assay (ECA) and diluted thrombin time (dTT)] laboratory coagulation tests in patients receiving dabigatran with untoward effects, we describe a case in which hemodialysis was used in attempt to remove dabigatran in a patient with excessive anticoagulation, rectal bleeding, and severe anemia. Our experience confirmed that APTT is an unreliable method for the assessment of dabigatran in patients with acute complications because it was often normal in spite of the therapeutic drug plasma levels. Both ECA and dTT showed a linear correlation with dabigatran levels over a broad range, and identified therapeutic and supratherapeutic levels. TT assay, which is highly sensitive to dabigatran, correlated well and linearly not only with low drug levels, but also, because of the introduction of the extended endpoint (400 s), with high concentrations of the drug, and demonstrated to be a simple and reliable alternative to ECA and dTT to assess dabigatran in patients with acute complications.
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King AE, Szarlej DK, Rincon F. Dabigatran-Associated Intracranial Hemorrhage: Literature Review and Institutional Experience. Neurohospitalist 2015; 5:234-44. [PMID: 26425251 PMCID: PMC4572378 DOI: 10.1177/1941874415569069] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Dabigatran etexilate is an oral direct thrombin inhibitor approved for prevention of stroke and systemic embolization in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. Although dabigatran has a favorable safety profile, predictable pharmacokinetics, fewer drug interactions than warfarin, and does not require monitoring, clinical data regarding dabigatran reversal are limited. In addition, currently available laboratory assays allow measurement of the presence, but not extent, of dabigatran-associated anticoagulation. Patient age, renal function, weight, concurrent drug therapy, adherence, and concomitant disease states can affect dabigatran's efficacy and safety. Management of dabigatran-related intracranial hemorrhage must be approached on a case-by-case basis and include assessment of degree of anticoagulation, severity of hemorrhage, renal function, timing of last dabigatran dose, and risk of thromboembolic events. Initial management includes dabigatran discontinuation and general supportive measures. Oral activated charcoal should be administered in those who ingested dabigatran within 2 hours. Four-factor prothrombin complex concentrates (4PCCs), activated PCC, or recombinant activated factor VII use may be reasonable but is not evidence based. Reserve fresh frozen plasma for patients with dilutional coagulopathy. If readily available, hemodialysis should be considered, particularly in patients with advanced kidney injury or excessive risk of thromboembolic events. More clinical studies are needed to determine a standardized approach to treating dabigatran-associated intracranial hemorrhage. Institutional protocol development will facilitate safe, efficacious, and timely use of the limited management options.
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Affiliation(s)
- Amber E. King
- Department of Pharmacy Practice, Thomas Jefferson University, Jefferson School of Pharmacy, Philadelphia, PA, USA
| | - Dorota K. Szarlej
- Department of Pharmacy, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA
| | - Fred Rincon
- Department of Neurological Surgery, Thomas Jefferson University and Jefferson College of Medicine, Philadelphia, PA, USA
- Division of Critical Care and Neurotrauma, Jefferson Hospital for Neuroscience, Philadelphia, PA, USA
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