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Antoun I, Layton GR, Abdelrazik A, Eldesouky M, Zakkar M, Somani R, Ng A. The Pathophysiology of Sex Differences in Stroke Risk and Prevention in Atrial Fibrillation: A Comprehensive Review. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:649. [PMID: 40282940 PMCID: PMC12028954 DOI: 10.3390/medicina61040649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 03/21/2025] [Accepted: 03/30/2025] [Indexed: 04/29/2025]
Abstract
Atrial fibrillation (AF) is the most common chronic arrhythmia and is a leading cause of stroke, with well-documented differences in pathophysiology, clinical manifestations, and prognosis according to the sex of the patient. This review provides an overview of known or hypothesized sex differences in physiology and stroke risk for patients with AF. Women are reported to have more extensive fibrosis of the left atrium, different functional properties of the atria, and higher sensitivity to prothrombotic stimuli, especially after menopause. Variations in stroke risk with AF are linked to age, hypertension, diabetes, and chronic kidney disease; overall, women have worse outcomes. The widely clinically implemented CHA2DS2-VASc score no longer considers sex as a variable, and its propriety for women is still debated. However, women are usually under prescribed anticoagulation despite having a higher long-term risk of stroke compared to men, suggesting a lack of equity of treatment for certain patient groups. New AI-based risk stratification models and precision medicine approaches are potentially useful in reducing these gaps. Future work should also aim to improve sex-based predictive models, considering different gender categories, and understanding the part played by hormonal alterations, atrial structural alterations, and thromboembolic risk in the treatment of AF.
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Affiliation(s)
- Ibrahim Antoun
- Department of Cardiology, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK; (I.A.); (A.A.); (M.E.); (R.S.)
- Department of Cardiovascular Sciences, Clinical Science Wing, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; (G.R.L.); (M.Z.)
| | - Georgia R. Layton
- Department of Cardiovascular Sciences, Clinical Science Wing, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; (G.R.L.); (M.Z.)
- Department of Cardiac Surgery, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK
- National Institute for Health Research, Leicester Research Biomedical Centre, Leicester LE3 9QP, UK
| | - Ahmed Abdelrazik
- Department of Cardiology, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK; (I.A.); (A.A.); (M.E.); (R.S.)
| | - Mahmoud Eldesouky
- Department of Cardiology, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK; (I.A.); (A.A.); (M.E.); (R.S.)
| | - Mustafa Zakkar
- Department of Cardiovascular Sciences, Clinical Science Wing, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; (G.R.L.); (M.Z.)
- National Institute for Health Research, Leicester Research Biomedical Centre, Leicester LE3 9QP, UK
- Leicester British Heart Foundation Centre of Research Excellence, Glenfield Hospital, Leicester LE3 9QP, UK
| | - Riyaz Somani
- Department of Cardiology, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK; (I.A.); (A.A.); (M.E.); (R.S.)
- Department of Cardiovascular Sciences, Clinical Science Wing, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; (G.R.L.); (M.Z.)
| | - André Ng
- Department of Cardiology, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester LE3 9QP, UK; (I.A.); (A.A.); (M.E.); (R.S.)
- Department of Cardiovascular Sciences, Clinical Science Wing, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; (G.R.L.); (M.Z.)
- National Institute for Health Research, Leicester Research Biomedical Centre, Leicester LE3 9QP, UK
- Leicester British Heart Foundation Centre of Research Excellence, Glenfield Hospital, Leicester LE3 9QP, UK
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Zhang Y, Wang Z, Wang Y, Jin W, Zhang Z, Jin L, Qian J, Zheng L. CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms. PeerJ 2024; 12:e18636. [PMID: 39650550 PMCID: PMC11625447 DOI: 10.7717/peerj.18636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 11/12/2024] [Indexed: 12/11/2024] Open
Abstract
CYP3A, a key member of the cytochrome P450 (CYP450) superfamily, is integral to drug metabolism, processing a substantial portion of medications. Their role in drug metabolism is particularly prominent, as CYP3A4 and CYP3A5 metabolize approximately 30-50% of known drugs. The genetic polymorphism of CYP3A4/5 is significant inter-individual variability in enzymatic activity, which can result in different pharmacokinetic profiles in response to the same drug among individuals. These polymorphisms can lead to either increased drug toxicity or reduced therapeutic effects, requiring dosage adjustments based on genetic profiles. Consequently, the study of the enzymatic activity of CYP3A4/5 gene variants is of great importance for the formulation of personalized treatment regimens. This article first reviews the role of CYP3A4/5 in drug metabolism in the human body, including inhibitors and inducers of CYP3A4/5 and drug-drug interactions. In terms of genetic polymorphism, it discusses the detection methods, enzymatic kinetic characteristics, and clinical guidelines for CYP3A5. Finally, the article summarizes the importance of CYP3A4/5 in clinical applications, including personalized therapy, management of drug-drug interactions, and adjustment of drug doses. This review contributes to the understanding of the functions and genetic characteristics of CYP3A4/5, allowing for more effective clinical outcomes through optimized drug therapy.
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Affiliation(s)
- Yuqing Zhang
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ziying Wang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuchao Wang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weikai Jin
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zheyan Zhang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lehao Jin
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianchang Qian
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Long Zheng
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Maegele M. Management of patients with proximal femur fractures under DOACs. Eur J Trauma Emerg Surg 2024; 50:359-366. [PMID: 38400927 PMCID: PMC11035399 DOI: 10.1007/s00068-024-02472-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/09/2024] [Indexed: 02/26/2024]
Abstract
PURPOSE In the past, preinjury direct oral anticoagulant (DOAC) intake has led to delays in time to surgery (TTS) in patients with proximal femur fractures and delays in surgery have been associated with impaired outcomes. Although healthcare institutions/federal committees have set rules for treatment within 24 h of injury, comprehensive guidelines for the perioperative management of these patients, in particular when on preinjury DOACs, are still lacking. This contribution aims to summarize the current evidence on the safe time window for surgery in patients with proximal femur fractures on preinjury DOACs and to outline therapeutic options if emergency DOAC reversal becomes necessary. METHODS Narrative review based upon selective review of the pertinent literature. RESULTS For the majority of patients with proximal femur fractures and on preinjury DOACs, early surgery appears safe as soon as medical clearance has been obtained. There may be an increase in the need for blood products but with data not yet conclusive. Work-up including assessment of remaining anticoagulant activity and potential reversal should be restricted to patients at risk for bleeding complications, in particular in the presence of renal/hepatic impairment. Methodology for rapid assessment of DOACs including quantitative/qualitative concentration levels is work in progress. In the case of bleeding, rapidly acting reversal agents are available. CONCLUSION Preinjury DOAC use should not routinely delay surgery in patients with proximal femur fractures.
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Affiliation(s)
- Marc Maegele
- Department for Trauma and Orthopedic Surgery, Cologne-Merheim Medical Center (CMMC), Witten/Herdecke University, Campus Cologne-Merheim, Ostmerheimer Str. 200, 51109, Cologne, Germany.
- Institute for Research in Operative Medicine (IFOM), Witten/Herdecke University, Campus Cologne-Merheim, Ostmerheimer Str. 200, 51109, Cologne, Germany.
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Elfar S, Mahmoud SA, Hamdi S, Emad AA, Abd-ElGawad M, Taha NA. The safety and efficacy of nonvitamin K antagonist oral anticoagulants in morbidly obese patients with atrial fibrillation: a meta-analysis. BMC Cardiovasc Disord 2024; 24:74. [PMID: 38279126 PMCID: PMC10811832 DOI: 10.1186/s12872-024-03731-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 01/17/2024] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND AND AIM Atrial fibrillation (AF) is the most frequently observed cardiac arrhythmia in clinical settings. Obesity can influence the efficacy of the treatment administered, which requires a larger dose and more time to accomplish therapeutic targets due to altered pathophysiology. Our study aimed to assess the overall efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) versus warfarin in AF patients with morbid obesity (BMI > 40 kg/m2 and/or weight > 120 kg) to prevent complications. METHODS We conducted a literature search on PubMed, Web of Science, the Cochrane Library, and Scopus till October 2022 for articles addressing the efficacy and safety of NOACs versus warfarin for the treatment of AF in morbidly obese patients. We performed the meta-analysis with RevMan software version 5.4 and Open Meta Analyst. The main outcomes assessed were stroke, major bleeding, and minor bleeding after anticoagulation, as did the history of comorbidities and risk factors in morbidly obese patients. Quality assessment was performed using Cochrane's ROB-2 tool and the Newcastle-Ottawa scale. RESULTS Regarding major bleeding events, pooled data showed that patients taking NOACs had a significantly lower risk than patients taking warfarin (OR = 0.54, 95% CI: [0.41-0.70]; p < 0.00001). However, for minor bleeding, there was a nonsignificant effect of NOACs on reducing the risk of bleeding (OR = 0.72, 95% CI = 0.47-1.09; p = 0.12), which became highly significant in favor of NOACs after sensitivity analysis (OR = 0.55, 95% CI = 0.49-0.61]; p < 0.00001). There was a significant difference in the incidence of stroke between the NOAC group and the warfarin group (OR = 0.69, 95% CI = 0.60-0.80]; p < 0.00001). According to the results of the single-arm study analysis, the overall effect of all the outcomes was associated with a high risk of disease development in patients receiving NOACs. CONCLUSION Our meta-analysis showed a favorable effect of NOACs vs warfarin in morbidly obese patients. Some outcomes were not significantly different, which calls for future research to better assess their safety and efficacy in this particular weight group. TRIAL REGISTRATION The study was registered with PROSPERO under registration number CRD42022362493 on October 2022.
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Affiliation(s)
| | | | - Samar Hamdi
- Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Qiao J, Bailly J, Opie J. Key Issues at the Forefront of Diagnosis and Testing for Antiphospholipid Syndrome. Clin Appl Thromb Hemost 2024; 30:10760296241306751. [PMID: 39692090 DOI: 10.1177/10760296241306751] [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: 12/19/2024] Open
Abstract
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by antiphospholipid antibodies associated with thrombosis and pregnancy complications. Catastrophic APS is a severe form involving multiple organ systems with a high mortality rate. The pathogenesis involves antiphospholipid antibodies which target phospholipid-binding proteins and damage endothelial cells thus activating coagulation, triggering a pro-thrombotic state. Laboratory tests for antiphospholipid antibody detection include lupus anticoagulant testing in the coagulation laboratory and serological detection of anticardiolipin and anti-beta 2 glycoprotein I antibodies. Despite recent updates in the diagnostic criteria for APS the recent decades and our improved knowledge of this disease, there remain several key issues pertaining to diagnosis and testing with potential implications to patient management. Here we briefly review APS pathophysiology, strengths and weaknesses of classification criteria, laboratory challenges leading to test interpretation, and clinical management of this complex condition.
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Affiliation(s)
- Jesse Qiao
- Department of Pathology and Laboratory Medicine, University of California, Irvine, USA
| | - Jenique Bailly
- Division of Haematology, Department of Pathology, University of Cape Town and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa
| | - Jessica Opie
- Division of Haematology, Department of Pathology, University of Cape Town and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa
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Yang S, Xu Y, Zhang Y, Li D, Li X. Effectiveness and Safety of Different Oral Anticoagulants with P-glycoprotein/ CYP3A4 Inhibitors: A Network Meta-analysis. Curr Pharm Des 2024; 30:1167-1177. [PMID: 38523519 DOI: 10.2174/0113816128293940240315073345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Metabolism of oral anticoagulants (OAC) is affected by P-glycoprotein (P-gp)/ CYP3A4 enzyme. However, the P-gp/CYP3A4 inhibitors are unavoidably used with OACs. METHODS Medline, Cochrane, and Embase were systematically searched for randomized controlled trials and cohort studies from inception till 23rd November, 2022 to assess the safety and effectiveness of OACs when concomitantly used with P-gp/CYP3A4 inhibitors. The primary outcomes were major bleeding and gastrointestinal (GI) bleeding. Secondary outcomes were stroke/systemic embolism (SE), all-cause mortality, any bleeding as well as intracranial hemorrhage (ICH). We estimated summary odds ratios (OR) with 95% credible intervals (CI) using pairwise and network meta-analysis with random effects. RESULTS A total of 11 studies involving 37,973 patients were included. When concomitantly used with P-pg/ CYP3A4 inhibitors, network meta-analysis indicated that dabigatran, apixaban, and edoxaban were associated with significantly lower risk of major bleeding compared to rivaroxaban, with ORs of 0.56, 0.51 and 0.48, respectively. Rivaroxaban and dabigatran were associated with a significantly increased risk of GI bleeding than warfarin, apixaban and edoxaban. Dabigatran and apixaban were linked with significantly lower risk of any bleeding compared with warfarin (ORs were 0.75 and 0.68, respectively) or rivaroxaban (ORs were 0.67 and 0.60, respectively). Apixaban (OR 0.32) and edoxaban (OR 0.35) were associated with a lower risk of ICH compared with warfarin. There was no difference between any OACs in terms of stroke/SE or all-cause mortality. CONCLUSION When concomitantly used with P-gp/CYP3A4 inhibitors, apixaban and edoxaban were associated with a lower risk of bleeding, though no significant difference in effectiveness was observed among all OACs.
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Affiliation(s)
- Siyu Yang
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ye Xu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yang Zhang
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dandan Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xingang Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Gallant GG, Matzon JL, Beredjiklian PK, Rivlin M. Perioperative Management of Oral Anticoagulants and Antiplatelet Therapy in Hand and Wrist Surgery. J Am Acad Orthop Surg 2023; 31:820-833. [PMID: 37478048 DOI: 10.5435/jaaos-d-22-00751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 05/05/2023] [Indexed: 07/23/2023] Open
Abstract
There is wide variability in the management of patients on antithrombotic therapy requiring surgery of the hand and wrist. There are no specific guidelines regarding whether to temporarily cease or continue oral anticoagulants and antiplatelet agents. Discontinuation of these medications before surgery can lead to perioperative thromboembolic or ischemic events. On the other hand, continuation can lead to intraoperative or postoperative bleeding complications. This review discusses various anticoagulants and antiplatelet agents with special considerations for their management, analyzes the current literature, summarizes current recommendations, and provides direction for additional research.
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Affiliation(s)
- Gregory G Gallant
- From the Hand Surgeon Rothman Orthopaedics, Thomas Jefferson University Rothman Orthopaedics, Sidney Kimmel Medical College, Philadelphia, PA
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Agarwal AR, Das A, Harris A, Campbell JC, Golladay GJ, Thakkar SC. Trends of Venous Thromboembolism After Total Hip Arthroplasty in the United States: Analysis From 2011 to 2019. J Am Acad Orthop Surg 2023; 31:e376-e384. [PMID: 36727960 DOI: 10.5435/jaaos-d-22-00708] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/24/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND In 2011, the American Academy of Orthopaedic Surgeons released a Clinical Practice Guideline` that recommended routine venous thromboembolism (VTE) prophylaxis after total joint arthroplasty. The purpose of this study was to examine (1) the change in the incidence of 90-day VTE, deep vein thrombosis, and pulmonary embolism, (2) the change in the utilization of antithrombotic agents; and (3) the change in the economic burden associated with VTE after total hip arthroplasty (THA) from 2011 to 2019. METHODS National, administrative claims data from 2011 to 2019 were used to identify patients who underwent primary THA for osteoarthritis. Exclusions entailed liver pathology, coagulopathy, malignancy, or those on prior prescribed blood thinners before THA. Multivariable regression was used, controlling for age and Charlson Comorbidity Index for all years, with 2011 as the reference year. RESULTS From 2011 to 2019, there was a significant reduction in 90-day VTE rates after THA, with a significant reduction in deep vein thrombosis and pulmonary embolism during this time frame as well. Of the antithrombotic agents prescribed after THA, the utilization of prescribed aspirin significantly increased and that of nonaspirin anticoagulants significantly decreased. Among nonaspirin anticoagulants, the utilization of direct factor Xa inhibitors and direct thrombin inhibitors significantly increased. The added reimbursements associated with VTE after THA significantly decreased during this period. CONCLUSION Since 2011, the incidence and economic burden associated with VTE after THA have significantly declined. In addition, there has been an increase in prescription aspirin and direct oral anticoagulants. LEVEL OF EVIDENCE Therapeutic, III.
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Affiliation(s)
- Amil R Agarwal
- From the Department of Orthopaedic Surgery, George Washington University School of Medicine, Washington, DC (Agarwal, Das, and Campbell), Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD (Harris and Thakkar), and Department of Orthopaedic Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA (Golladay)
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Huang Z, Xu X, Xu D, Zhao P, Zou M. Efficacy of 11 anticoagulants for the prevention of venous thromboembolism after total hip or knee arthroplasty: A systematic review and network meta-analysis. Medicine (Baltimore) 2023; 102:e32635. [PMID: 36637921 PMCID: PMC9839234 DOI: 10.1097/md.0000000000032635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND To systematically review the efficacy of 11 anticoagulants in the treatment of venous thromboembolism (VTE) after total hip or knee arthroplasty. METHODS PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang Data, VIP, and China Biology Medicine databases were electronically searched for studies assessing the efficacy of different anticoagulants for the prevention of VTE after total hip or knee arthroplasty from January 1, 2010, to January 27, 2022. Two reviewers independently screened the literature, extracted data, and graded the evidence using Confidence in Network Meta-Analysis. The network meta-analysis was then performed using Stata 16.0 software and R 4.1.0 software. RESULTS A total of 61 articles were included. The results of network meta-analysis showed that apixaban, edoxaban, fondaparinux, rivaroxaban, and darexaban were the most effective anticoagulants for the prevention of deep vein thrombosis in patients undergoing total hip or knee arthroplasty (P < .05), while there was no difference in the efficacy among the anticoagulants for the prevention of pulmonary embolism (P > .05). CONCLUSION Apixaban, edoxaban, fondaparinux, rivaroxaban, and darexaban have the best efficacy for the prevention of VTE after total hip or knee arthroplasty.
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Affiliation(s)
- Zhihao Huang
- School of Big Data and Fundamental Sciences, Shandong Institute of Petroleum and Chemical Technology, Dongying, China
| | - Xinru Xu
- College of Food Science, Northeast Agricultural University, Harbin, China
| | - Dan Xu
- Obstetrical department, Lijin County Central Hospital, Dongying, China
| | - Pengfei Zhao
- Department of Clinical Pharmacy, Weifang People’s Hospital, Weifang, China
| | - Miao Zou
- School of Big Data and Fundamental Sciences, Shandong Institute of Petroleum and Chemical Technology, Dongying, China
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Turcato G, Zaboli A, Bonora A, Ricci G, Zannoni M, Maccagnani A, Zorzi E, Pfeifer N, Brigo F. Analysis of Clinical and Laboratory Risk Factors of Post-Traumatic Intracranial Hemorrhage in Patients on Direct Oral Anticoagulants with Mild Traumatic Brain Injury: An Observational Multicenter Cohort. J Emerg Med 2023; 64:1-13. [PMID: 36658008 DOI: 10.1016/j.jemermed.2022.09.039] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/25/2022] [Accepted: 09/04/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Assessing the risk of intracranial hemorrhage (ICH) in patients with a mild traumatic brain injury (MTBI) who are taking direct oral anticoagulants (DOACs) is challenging. Currently, extensive use of computed tomography (CT) is routine in the emergency department (ED). OBJECTIVE This study aims to investigate whether the clinical and laboratory characteristics presented at the ED evaluation can also estimate the risk of post-traumatic ICH in DOAC-treated patients with MTBI. METHODS A retrospective observational study was conducted in three EDs in Italy from January 1, 2016 to March 15, 2020. All patients treated with DOACs who were evaluated for an MTBI in the ED were enrolled. The primary outcome of the study was the presence of post-traumatic ICH in the head CT performed in the ED. RESULTS Of 930 patients on DOACs with MTBI who were enrolled, 6.8% (63 of 930) had a post-traumatic ICH and 1.5% (14 of 930) were treated with surgery or died as a result of the ICH. None of the laboratory factors were associated with an increased risk of ICH. On multivariate analysis, previous neurosurgical intervention, major trauma dynamic, post-traumatic loss of consciousness, post-traumatic amnesia, Glasgow Coma Scale score of 14, and evidence of trauma above the clavicles were associated with a higher risk of post-traumatic ICH. The net clinical benefit provided by risk factor assessment appears superior to the strategy of performing CT on all DOAC-treated patients. CONCLUSIONS Assessment of the clinical characteristics presented at ED admission can help identify DOAC-treated patients with MTBI who are at risk of ICH.
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Affiliation(s)
- Gianni Turcato
- Emergency Department, Hospital of Merano (SABES-ASDAA), Merano, Italy
| | - Arian Zaboli
- Emergency Department, Hospital of Merano (SABES-ASDAA), Merano, Italy
| | - Antonio Bonora
- Department of Emergency Medicine, Policlinico Univeristario di Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Giorgio Ricci
- Department of Emergency Medicine, Hospital Civile Maggiore, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Massimo Zannoni
- Department of Emergency Medicine, Hospital Civile Maggiore, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Antonio Maccagnani
- Department of Emergency Medicine, Policlinico Univeristario di Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Elisabetta Zorzi
- Department of Cardiology and Intensive Care Cardiology, Girolamo Fracastoro Hospital of San Bonifacio, Azienda Ospedaliera Scaligera, San Bonifacio, Verona, Italy
| | - Norbert Pfeifer
- Emergency Department, Hospital of Merano (SABES-ASDAA), Merano, Italy
| | - Francesco Brigo
- Department of Neurology, Hospital of Merano (SABES-ASDAA), Merano, Italy
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Trough Concentration Deficiency of Rivaroxaban in Patients With Nonvalvular Atrial Fibrillation Leading to Thromboembolism Events. J Cardiovasc Pharmacol 2022; 80:869-876. [PMID: 36027599 DOI: 10.1097/fjc.0000000000001360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 08/14/2022] [Indexed: 12/13/2022]
Abstract
ABSTRACT This retrospective study investigated factors influencing the steady-state trough concentrations (C trough ) of rivaroxaban in patients with nonvalvular atrial fibrillation (NVAF). We retrieved data from patients with NAVF who first started rivaroxaban anticoagulation at the Fujian Provincial Hospital from October 2017 to October 2020 through the electronic medical record system. Patients were followed for 1 year after the first dose of rivaroxaban, and the primary efficacy and safety end points were recorded. All follow-up visits were completed by October 2021. A C trough of <12 ng/mL was defined as C trough deficiency. Factors that influenced rivaroxaban C trough deficiency were investigated using multivariate binary logistic regression analysis. Kaplan-Meier survival curve analysis was used to determine differences between C trough deficiency and event-free survival. A total of 167 patients with NVAF were enrolled in the study, including 113 men and 54 women, with an average (± SD) age of 70.40 ± 12.46 years. High albumin levels were an independent protective factor against C trough deficiency (odds ratio, 0.932; P = 0.031). C trough deficiency was associated with the probability of freedom from thrombotic events ( P = 0.004); however, there were no significant differences in the probability of freedom from bleeding events ( P > 0.05). In conclusion, among the variables studied, a low albumin level was the main contributor to C trough deficiency. Rivaroxaban C trough deficiency also increased thrombotic events, but this was not associated with hemorrhagic events in Chinese patients with NVAF.
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Tarek Mahmoud S, Moffid MA, Sayed RM, Mostafa EA. Core shell stationary phase for a novel separation of some COVID-19 used drugs by UPLC-MS/MS Method: Study of grapefruit consumption impact on their pharmacokinetics in rats. Microchem J 2022; 181:107769. [PMID: 35855210 PMCID: PMC9284531 DOI: 10.1016/j.microc.2022.107769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/11/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022]
Abstract
A sensitive and selective UPLC-MS/MS method was developed for the synchronized determination of four drugs used in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, azithromycin, apixaban, dexamethasone, and favipiravir in rat plasma. using a Poroshell 120 EC-C18 column (50 mm × 4.6 mm, 2.7 m) with a high-resolution ESI tandem mass spectrometer detection with multiple reaction monitoring. We used an Agilent Poroshell column, which is characterized by a stationary phase based on non-porous core particles. With a remarkable improvement in the number of theoretical plates and low column backpressure. In addition, the developed method was employed in studying the potential food-drug interaction of grapefruit juice (GFJ) with the selected drugs which affects their pharmacokinetics in rats. The LC-MS/MS operated in positive and negative ionization mode using two internal standards: moxifloxacin and chlorthalidone, respectively. Liquid- liquid extraction of the cited drugs from rat plasma was accomplished using diethyl ether: dichloromethane (70:30, v/v). The analytes were separated using methanol: 0.1 % formic acid in water (95: 5, v/v) as a mobile phase in isocratic mode of elution pumped at a flow rate of 0.3 mL/min. A detailed validation of the bio-analytical method was performed in accordance with US-FDA and EMA guidelines. Concerning the in vivo pharmacokinetic study, the statistical significance between the results of the test groups receiving GFJ along with the cited drugs and the control group was assessed demonstrating that GFJ increased the plasma concentration of azithromycin, apixaban, and dexamethasone. Accordingly, this food-drug interaction requires cautious ingestion of GFJ in patients using (SARS-CoV-2) medications as it can produce negative effects in the safety of the drug therapy. A potential drug-drug interaction is also suggested between those medications requiring a suitable dose adjustment.
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Affiliation(s)
- Sally Tarek Mahmoud
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt
| | - Marwa A Moffid
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt
| | - Rawda M Sayed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt
| | - Eman A Mostafa
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo 11562, Egypt
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13
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Santagata D, Cammà G, Donadini MP, Squizzato A, Ageno W. Current and emerging drug strategies for the prevention of venous thromboembolism in acutely ill medical inpatients. Expert Opin Pharmacother 2022; 23:1651-1665. [PMID: 36154548 DOI: 10.1080/14656566.2022.2128757] [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: 11/04/2022]
Abstract
INTRODUCTION Venous thromboembolism (VTE) is a common complication in patients hospitalized for acute medical illnesses. Therefore, medical inpatients require a careful VTE and bleeding risk assessment to drive optimal strategies for VTE prevention. Low molecular weight heparin and fondaparinux have long been used for inhospital prophylaxis for patients at increased risk of VTE. The selection of patients who require post-discharge prophylaxis, and the role of direct oral anticoagulants remain debated. New molecules currently under development may contribute to improve the risk benefit of VTE prevention in this setting. AREAS COVERED This text summarizes the evidence on approved treatments and on other drugs for the prevention of VTE in acutely ill medical patients. The main focus is on their pharmacological proprieties, clinical efficacy and safety, and the current license approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency), giving the readers a way to compare available drugs to date. The trials presented consider both inhospital and extended prophylaxis. EXPERT OPINION Thanks to the potentially favorable safety profile, factor XI inhibitors may play a role in the prevention of VTE in this setting. The expert opinion section discusses pharmacological properties, prophylaxis trials, and potential clinical applications of this novel class of drugs.
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Affiliation(s)
- D Santagata
- Department of Medicine and Surgery, Research Center on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Via Gucciardini 9, 21100, Varese and Como, Italy
| | - G Cammà
- Department of Internal Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Curore, Largo Francesco Vito 1, 00139, Rome, Italy
| | - M P Donadini
- Department of Medicine and Surgery, Research Center on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Via Gucciardini 9, 21100, Varese and Como, Italy
| | - A Squizzato
- Department of Medicine and Surgery, Research Center on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Via Ravona 20 San Fermo della Battaglia (Como), 22042 Como, Italy
| | - W Ageno
- Department of Medicine and Surgery, Research Center on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Via Gucciardini 9, 21100, Varese and Como, Italy
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Siahaan AMP, Tandean S, Nainggolan BWM. Spontaneous epidural hematoma induced by rivaroxaban: A case report and review of the literature. Surg Neurol Int 2022; 13:420. [PMID: 36324933 PMCID: PMC9610455 DOI: 10.25259/sni_608_2022] [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: 07/07/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Trauma is the most frequent reason for epidural bleeding. However, numerous investigation had discovered that anticoagulants such as rivaroxaban could cause epidural hematoma. Here, we present a case of epidural hematoma in young man who got rivaroxaban as treatment of deep vein thrombosis. Case Description: A 27-year-old male with a history of deep vein thrombosis and one month of rivaroxaban medication presented with seizure and loss of consciousness following a severe headache. A CT scan of the head revealed epidural bleeding, and emergency blood clot removal was performed. As a reversal, prothrombin complex was utilized. Conclusion: Rivaroxaban has the potential to cause an epidural hemorrhage. Reversal anticoagulant should be administered before doing emergency surgery.
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Affiliation(s)
| | - Steven Tandean
- Department of Neurosurgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
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Wang L, Shang K, Feng T, Dong W, Wang F, Shen X. LC-MS/MS Method Assay for Simultaneous Determination of the Apixaban and Metformin in Rat Plasma: Assessment of Pharmacokinetic Drug-Drug Interaction Study. J Chromatogr Sci 2022:6695460. [PMID: 36097794 DOI: 10.1093/chromsci/bmac076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 07/06/2022] [Accepted: 08/21/2022] [Indexed: 11/13/2022]
Abstract
A simple, sensitive and accurate LC-MS/MS method was developed and validated for the simultaneous quantification of apixaban (APB) and metformin (MET) in rat plasma using rivaroxaban as internal standard (IS). An Inertsil ODS3 C18 column (150 × 4.6 mm, 5 μm) was used for chromatographic separation with isocratic elution. Multiple reaction monitoring (MRM) using positive-ion ESI mode to monitor ion transitions of m/z 459.8 → 442.8 for APB, m/z 130.2 → 71.2 for MET, m/z 436.8 → 144.9 for IS. The procedure of method validation included selectivity, linearity, precision, accuracy, matrix effect, extraction recovery and stability were conducted according to the guidelines of EMA and FDA. The method was validated over the concentration range of 0.5-250 ng/mL for APB and 8-8000 ng/mL for MET. The intra- and inter-day precision and accuracy of the quality control samples exhibited relative standard deviations (RSD) < 12.5% and the accuracy values ranged from -8.6 to 12.4%. Recovery and matrix effect values variations were all less than 15%. After oral administration APB and MET to rats, the comparison of pharmacokinetic parameters of APB in the single and co-administrated groups showed significant difference in AUC(0-t) from 730.71 ± 121.31 to 573.07 ± 90.13 ng/mL·h, t1/2 from 5.86 ± 3.21 to 4.24 ± 1.15 h and Cmax from113.54 ± 24.04 to 159.42 ± 54.6 ng/mL. The comparison of pharmacokinetic parameters of MET in the single and co-administrated groups showed significant difference in t1/2 from 2.83 ± 1.81 to 3.97 ± 0.57 h and Cmax from 4015.76 ± 873.23 to 3153.6 ± 1012.51 ng/mL. The results indicated that drug-drug interactions (DDI) occurred might be owing to APB affect one or all of OCTs, MATE1, MATE2-K.
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Affiliation(s)
- Libin Wang
- School of Medicine, Shaanxi Energy Institute, Xianyang, Shaanxi Province 712000, China
| | - Kun Shang
- College of Medicine, Yan'an University, Yan'an, Shaanxi Province 716000, China
| | - Tian Feng
- Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy, Air Force Military Medical University, Xi'an 710032, China
| | - Wei Dong
- School of Medicine, Shaanxi Energy Institute, Xianyang, Shaanxi Province 712000, China
| | - Fang Wang
- School of Medicine, Shaanxi Energy Institute, Xianyang, Shaanxi Province 712000, China
| | - Xin Shen
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China
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Carballo F, Albillos A, Llamas P, Orive A, Redondo-Cerezo E, Rodríguez de Santiago E, Crespo J. Consensus document of the Spanish Society of Digestives Diseases and the Spanish Society of Thrombosis and Haemostasis on massive nonvariceal gastrointestinal bleeding and direct-acting oral anticoagulants. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:375-389. [PMID: 35686480 DOI: 10.17235/reed.2022.8920/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/13/2025]
Abstract
INTRODUCTION there is limited experience and understanding of massive nonvariceal gastrointestinal bleeding during therapy with direct-acting oral anticoagulants. OBJECTIVES to provide evidenced-based definitions and recommendations. METHODS a consensus document developed by the Spanish Society of Digestives Diseases and the Spanish Society of Thrombosis and Haemostasis using modified Delphi methodology. A panel was set up of 24 gastroenterologists with experience in gastrointestinal bleeding, and consensus building was assessed over three rounds. Final recommendations are based on a systematic review of the literature using the GRADE system. RESULTS panelist agreement was 91.53 % for all 30 items as a group, a percentage that was improved during rounds 2 and 3 for items where clinical experience is lower. Explicit disagreement was only 1.25 %. A definition of massive nonvariceal gastrointestinal bleeding in patients on direct-acting oral anticoagulants was established, and recommendations to optimize this condition's management were developed. CONCLUSION the approach to these critically ill patients must be multidisciplinary and protocolized, optimizing decisions for an early identification of the condition and patient stabilization according to the tenets of damage control resuscitation. Thus, consideration must be given to immediate anticoagulation reversal, preferentially with specific antidotes (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors); hemostatic resuscitation, and bleeding point identification and management.
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Affiliation(s)
- Fernando Carballo
- Medicina de Aparato Digestivo, Hospital Clínico Universitario Virgen de la Arrixaca, España
| | - Agustín Albillos
- Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal
| | - Pilar Llamas
- Hematología, Hospital Universitario Fundación Jiménez Díaz
| | - Aitor Orive
- Aparato Digestivo, Hospital Universitario de Araba
| | | | | | - Javier Crespo
- Aparato Digestivo, Hospital Universitario Marqués de Valdecilla
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Fukamachi D, Okumura Y, Fukuda I, Nakamura M, Yamada N, Takayama M, Maeda H, Yamashita T, Ikeda T, Mo M, Yamazaki T, Hirayama A. Characteristics and clinical outcomes of Japanese patients with venous thromboembolism receiving under-dose rivaroxaban: subanalysis of J'xactly. Curr Med Res Opin 2022; 38:1059-1068. [PMID: 35502571 DOI: 10.1080/03007995.2022.2070379] [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] [Indexed: 11/03/2022]
Abstract
OBJECTIVE Rivaroxaban is commonly prescribed to prevent venous thromboembolism (VTE). Although lower than standard dosages (under-dosing) may be administered in the real-world setting, data on subsequent clinical outcomes in Japanese patients are lacking. METHODS The prospective, multicenter, observational J'xactly study enrolled patients with acute symptomatic/asymptomatic deep vein thromboses (DVT), pulmonary embolism (PE), or both, who were prescribed rivaroxaban. This subanalysis investigated patient characteristics and outcomes associated with rivaroxaban under-dosing. RESULTS Among 1016 evaluable patients, 667 (65.6%) received an initial standard dosage of rivaroxaban (30 mg/day) and 349 (34.4%) received an initial under-dosage (20 mg/day, n = 22; 15 mg/day, n = 282; and 10 mg/day, n = 45). Those receiving an under-dose had significantly lower body weight and slower pulse rate compared with the standard-dose group regardless of DVT or PE status. Under-dosing was common for distal DVTs, but less frequent for massive/submassive PEs. There were no differences between under-dose and standard-dose groups in the incidences of recurring symptomatic VTEs (DVT: 1.77% vs. 3.35% per patient-year, p = .138; PE: 0.84% vs. 2.84% per patient-year, p = .208) or major bleeding (DVT: 3.55% vs. 3.41% per patient-year, p = .960; PE: not observed vs. 2.83% per patient-year, p = .132). CONCLUSIONS In the real-world setting, rivaroxaban under-dosing for patients with VTE occurred in those with lower body weight, slower pulse rate, distal DVT, or non-massive PEs. There were no statistically significant differences in the clinical outcomes for patients received under-dose of rivaroxaban at the discretion of the physicians in the clinical practice compared with those received standard dose of rivaroxaban.
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Affiliation(s)
- Daisuke Fukamachi
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuo Okumura
- Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Ikuo Fukuda
- Department of Cardiovascular Surgery, Suita Tokushukai Hospital, Suita, Japan
| | - Mashio Nakamura
- Department of Internal Medicine, Pediatrics and Cardiology, Nakamura Medical Clinic, Kuwana, Japan
| | - Norikazu Yamada
- Department of Cardiology, Kuwana City Medical Center, Kuwana, Japan
| | | | - Hideaki Maeda
- Division of Cardiovascular Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Takeshi Yamashita
- Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan
| | - Takanori Ikeda
- Department of Cardiovascular Medicine, Toho University Faculty of Medicine, Tokyo, Japan
| | - Makoto Mo
- Department of Cardiovascular Surgery, Yokohama Minami Kyosai Hospital, Yokohama, Japan
| | - Tsutomu Yamazaki
- Innovation and Research Support Center, International University of Health and Welfare, Tokyo, Japan
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Satheesh D, Sreenivasulu B, Reddy BS, Reddy UR, Saladi JSC, Gupta PB, Reddy ASK, Aegurla B, Basavaiah K. Synthesis and Characterisation of Impurities of Apixaban Drug Substance ‐ An Anti‐coagulant. J Heterocycl Chem 2022. [DOI: 10.1002/jhet.4501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Deekonda Satheesh
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
- Department of Inorganic & Analytical chemistry, A.U. College of Science & Technology Andhra University Visakhapatnam Andhra Pradesh India
| | - B. Sreenivasulu
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - Bhavanam Sekhara Reddy
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - U. Rajasekhar Reddy
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - J. S. Chakradhar Saladi
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - P. Badrinath Gupta
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - Aaramadaka Sunil Kumar Reddy
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - Balakrishna Aegurla
- Chemical Research Department, APL Research Centre‐II, Aurobindo Pharma Limited, Indrakaran Village Sangareddy (District) Telangana India
| | - Keloth Basavaiah
- Department of Inorganic & Analytical chemistry, A.U. College of Science & Technology Andhra University Visakhapatnam Andhra Pradesh India
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Abd Allah FI, Ali Almrasy A, Abdelhmaid A, Abd-Elmegid OA, Alkashlan A, El-Attar AAMM. Development and Validation of UPLC-MS/MS Method for Quantifying of Free and Total Dabigatran in Human Plasma: An Application for a Bioequivalence Study. Biomed Chromatogr 2022; 36:e5382. [PMID: 35389511 DOI: 10.1002/bmc.5382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/20/2022] [Accepted: 02/07/2022] [Indexed: 11/11/2022]
Abstract
Dabigatran etexilate mesylate (DABE), a prodrug, quickly changes in our bodies after its oral administration into dabigatran (DAB). Accordingly, detecting DABE in plasma is practically unmanageable. A UPLC-MS/MS technique was developed and validated to compute free DAB in participants. For the first time, the central composite design- a type of response surface methodology- was utilized for optimizing variables affecting the cleavage of glucuronide bond. Additionally, the pharmacokinetic parameters of generic medication (okanadab) were determined, and the obtained outcomes were compared to those of branded drug (pradaxa®). The sample preparation was done using methanol as a protein precipitant and the separation was achieved via ACQUITY UPLC BEH C18 column (2.1x50mm, 1.7μm). The elution was isocratically conducted using 10mM ammonium formate: methanol (72:28, v/v) as a mobile phase (MP) and the flow rate was 0.25mL/min. Multiple reaction monitoring (MRM) and positive electrospray ionization (ESI) were used. The determination was performed within 1min, and the calibration growth curve was established over a range of (1.19 - 475) ng/mL using dabigatran-d3 as a tagged internal standard (IS). Bioequivalence research was validated following FDA guidelines for bio-analytical procedures and acceptable outcomes were achieved. The outcomes for okanadab and pradaxa® did not differ significantly.
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Affiliation(s)
- Fathy Ibrahim Abd Allah
- Department of Pharmaceutics, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.,International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Ahmed Ali Almrasy
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo11751, Egypt
| | - Ahmed Abdelhmaid
- International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Osama A Abd-Elmegid
- International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Akram Alkashlan
- International Center for Bioavailability, Pharmaceutical, and Clinical Research
| | - Abdul-Aziz M M El-Attar
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo11751, Egypt
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Goh EL, Chidambaram S, Rai S, Kannan A, Anand S. Timing of Surgery for Hip Fracture in Patients on Direct Oral Anti-coagulants: A Population-Based Cohort Study. Geriatr Orthop Surg Rehabil 2022; 13:21514593221088405. [PMID: 35356074 PMCID: PMC8958519 DOI: 10.1177/21514593221088405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 03/01/2022] [Indexed: 11/18/2022] Open
Abstract
Background In patients with hip fracture on direct oral anti-coagulants (DOACs), timely surgery is important in optimising outcomes but the safety of early surgery is unclear. This study aims to evaluate the timing of surgery on peri- and post-operative outcomes in patients with hip fracture on DOAC therapy. Methods Single-centre, retrospective, population-based cohort study of patients on DOAC therapy compared to standard care with low-molecular-weight heparin (LMWH) undergoing surgery for hip fracture. Data obtained: patient demographics, fracture classification, American Society of Anaesthesiologists (ASA) classification, time to surgery, procedure performed, type of DOAC, timing of last DOAC dose, use of reversal agents or pro-coagulants and length of stay. Outcomes assessed: pre- and post-operative haemoglobin levels, incidence of blood transfusion, major haemorrhage, venous thromboembolism (VTE) and death within 30 days of surgery. Results A total of 755 patients were included. Compared to standard treatment, DOAC use was associated with a similar change in pre- and post-operative haemoglobin levels (P = .90), risk of blood transfusion (RR: 1.04, 95% CI: .70–1.54, P = .84), haemorrhage (RR: 1.51, 95% CI: .53-4.28, P = .44), VTE (RR: .92, 95% CI: .12–7.20, P = .94) and mortality (RR: 1.85, 95% CI: .89–3.84, P = .10), all of which were independent of the timing of surgery. Conclusion This study builds on growing evidence that surgery for hip fracture in patients on DOAC therapy is not associated with an excessive risk of haemorrhage, irrespective of the timing of surgery. Timely surgical fixation of the hip fracture in this population is indicated in the absence of other risk factors for haemorrhage.
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Affiliation(s)
- En Lin Goh
- Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kadoorie Centre, University of Oxford, Oxford, UK.,Oxford University Clinical Academic Graduate School, Medical Sciences Division, University of Oxford, Oxford, UK.,Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Swathikan Chidambaram
- Oxford University Clinical Academic Graduate School, Medical Sciences Division, University of Oxford, Oxford, UK
| | - Suprabha Rai
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Angela Kannan
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Sambandam Anand
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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High-throughput optical assays for sensing serine hydrolases in living systems and their applications. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2022.116620] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Jia Y, Wang SH, Cui NJ, Liu QX, Wang W, Li X, Gu YM, Zhu Y. Idarucizumab reverses dabigatran-induced anticoagulation in treatment of gastric bleeding: A case report. World J Clin Cases 2022; 10:2537-2542. [PMID: 35434066 PMCID: PMC8968591 DOI: 10.12998/wjcc.v10.i8.2537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/30/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The drug instructions for dabigatran recommend adjusting the dosage to 110 mg twice daily for patients with bleeding risk, and performing at least one renal function test per year for patients with moderate renal impairment. However, owing to chronic insidiously worsening renal insufficiency, dabigatran can still accumulate abnormally, necessitating therapy with idarucizumab to reverse the anticoagulation due to severe erosive gastritis with widespread stomach mucosal bleeding.
CASE SUMMARY A 76-year-old woman with a history of atrial fibrillation who took dabigatran 110 mg twice daily as directed to lessen the chance of stroke, was transported to the hospital with hematemesis and melena. Laboratory findings revealed severe life-threatening, blood-loss-induced anemia with a hemoglobin (Hb) level of 41.0 g/L and marked coagulation abnormalities with thrombin time (TT) > 180 s, most likely caused by dabigatran-induced metabolic disorder. Aggressive acid suppressive, hemostatic, and blood transfusion therapy resulted in the misconception that the bleeding was controlled, with subsequent rebleeding. Idarucizumab was administered in a timely manner to counteract dabigatran's anticoagulant impact, and 12 h later, TT was determined to be 17.4 s, which was within the normal range. Finally, the patient had no active bleeding signs and laboratory findings showed an Hb level of 104 g/L and TT of 17.7 s.
CONCLUSION Renal function, coagulation function, and dabigatran concentration should be regularly monitored in older patients. Proton pump inhibitor and dabigatran coadministration is still controversial in preventing upper gastrointestinal tract bleeding.
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Affiliation(s)
- Yu Jia
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
| | - Shao-Hua Wang
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
| | - Na-Juan Cui
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
| | - Quan-Xi Liu
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
| | - Wei Wang
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
| | - Xue Li
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
| | - Ya-Mei Gu
- Department of General Practice, Tiancun Community Health Service Centre, Beijing 100049, China
| | - Yan Zhu
- Department of Gastroenterology, Hospital of Integrated Traditional Chinese and Western Medicine, Beijing 100039, China
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Abstract
Many clinicians increasingly use dry needling in clinical practice. However, whether patients' intake of antithrombotic drugs should be considered as a contraindication for dry needling has not been investigated to date. As far as we know, there are no publications in analyzing the intake of antiplatelet or anticoagulant agents in the context of dry needling techniques. A thorough analysis of existing medications and how they may impact various needling approaches may contribute to improved evidence-informed clinical practice. The primary purpose of this paper is to review the current knowledge of antithrombotic therapy in the context of dry needling. In addition, reviewing guidelines of other needling approaches, such as electromyography, acupuncture, botulinum toxin infiltration, and neck ultrasound-guided fine-needle aspiration biopsy, may provide specific insights relevant for dry needling. Based on published data, taking antithrombotic medication should not be considered an absolute contraindication for dry needling techniques. As long as specific dry needling and individual risks are properly considered, it does not change the risk and safety profile of dry needling. Under specific circumstances, the use of ultrasound guidance is recommended when available.
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Bodega F, Russi A, Melillo F, Blunda F, Rubino C, Leo G, Cappelletti A, Mazzone P, Mattiello P, Della Bella P, Castiglioni A, Alfieri O, De Bonis M, Montorfano M, Tresoldi M, Filippi M, Salerno A, Cera M, Zangrillo A, Alberto M, Godino C. Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and extreme body weight. Eur J Clin Invest 2022; 52:e13658. [PMID: 34310688 DOI: 10.1111/eci.13658] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Limited clinical data exist describing the use of direct oral anticoagulants (DOACs) in patient with extreme body weight. Thus, the International Society of Thrombosis and Haemostasis (ISTH) recommends avoiding DOACs in patients with weight >120 Kg, and on the contrary, no restrictions exist for underweight patients. OBJECTIVE To evaluate the effects of extreme body weight on DOAC activity and to compare the clinical outcomes of patients with an extreme body weight versus patients with a normal weight (61-119 Kg) treated with DOACs. METHODS Single tertiary care Italian centre multidisciplinary registry including nonvalvular atrial fibrillation (NVAF) patients treated with DOACs. Based on weight, three subcohorts were defined: (i) underweight patients (≤60 Kg); (ii) patients with a normal weight (61-119 Kg, as control group); and (iii) overweight patients (≥120 Kg). Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. RESULTS 812 NVAF patients were included, 108 patients weighed ≤60 Kg (13%, underweight), 688 weighed between 61 and 119 Kg (85%, normal weight), and 16 weighed ≥120 Kg (2%, overweight). In particular, among underweight patients, dabigatran was prescribed in 26% patients, apixaban in 27%, rivaroxaban in 28% and edoxaban in 22% ones. Instead, among overweight patients, 44% were treated with dabigatran, 25% with apixaban, 25% with rivaroxaban and 4% with edoxaban. Underweight patients were older, more frequently women, with lower creatinine clearance and a history of previous strokes, resulting in higher CHA2DS2-VASc score than in both remaining groups. Up to 2 years, no statistically significant difference was observed between the three groups of weight for thromboembolic events (P = .765) and for overall bleeding (P = .125), but a trend towards decreased overall bleeding rates was noticed as weight increased (24.1% vs 16.7% vs 12.5%, respectively). CONCLUSION In this tertiary care centre registry, 15% of patients treated with DOACs presented an extreme weight. Compared to patients with a normal weight, no significant rates of thromboembolic events were observed for underweight or overweight patients. A trend towards decreased overall bleeding frequency as weight increased was highlighted up to 2 years. The present results should be considered as preliminary and hypothesis generating.
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Affiliation(s)
| | - Anita Russi
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Fabiana Blunda
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Claudia Rubino
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Giulio Leo
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Patrizio Mazzone
- Arrhythmia and Electrophysiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Paolo Mattiello
- Information Systems Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Paolo Della Bella
- Arrhythmia and Electrophysiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Ottavio Alfieri
- Cardiac Surgery Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Matteo Montorfano
- Interventional Cardiovascular Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Moreno Tresoldi
- General Medicine and Advanced Care Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Anna Salerno
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Michela Cera
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Alberto Zangrillo
- Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Hospital, Milan, Italy
| | | | - Cosmo Godino
- Cardiology Unit, IRCCS San Raffaele Hospital, Milan, Italy
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Akhrass R, Gillinov M, Bakaeen F, Akras D, Cameron SJ, Bishop J, Kapadia S, Svensson L. Emergency cardiac surgery in patients on oral anticoagulants and antiplatelet medications. J Card Surg 2021; 37:214-222. [PMID: 34779523 DOI: 10.1111/jocs.16027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/06/2021] [Accepted: 09/09/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Emergency surgery, blood transfusion, and reoperation for bleeding have been associated with increased operative morbidity and mortality. The recent increased use of direct oral anticoagulants and antiplatelet medications has made the above more challenging. In addition, cardiopulmonary bypass (CPB), with its associated hemodilution, fibrinolysis, and platelet consumption, may exacerbate the pre-existing coagulopathy and increase the risk of bleeding. AIM The aim of this study was to examine available literature with regard to treating patients who are on the above medications and require emergency cardiac surgery. RESULTS Management decisions are typically made on a case-by-case basis. Surgery is delayed when possible, and less invasive percutaneous options should be considered if feasible. Attention is paid to exercising meticulous techniques, avoiding excessive hypothermia, and treating coexisting issues such as sepsis. Ensuring a dry operative field upon entry by correcting the coagulopathy with reversal agents is offset by the concern of potentially hindering efforts to anticoagulate the patient (heparin resistance) in preparation for CPB, in addition to possibly increasing the risk of thromboembolism. CONCLUSION Proper knowledge of anticoagulants, their reversal agents, and the usefulness of laboratory testing are all essential. Platelet transfusion remains the mainstay for antiplatelet medications. Four-factor prothrombin complex concentrate is considered in patients on oral anticoagulants if CPB needs to be instituted quickly. Specific reversal agents such as idarucizumab and andexanet alfa can be considered if significant tissue dissection is anticipated, such as redo sternotomy, but are costly and may lead to heparin resistance and anticoagulant rebound.
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Affiliation(s)
- Rami Akhrass
- Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Marc Gillinov
- Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Faisal Bakaeen
- Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Deena Akras
- Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Scott J Cameron
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jay Bishop
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Samir Kapadia
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Lars Svensson
- Department of Thoracic and Cardiovascular Surgery, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Hu X, Xu Y, Chen J, Shen Y, Yang D, Hu Y, Jiang B, Lou H, Ruan Z. A validated UPLC-MS/MS method for the determination of CX3002 in human plasma and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1183:122954. [PMID: 34628186 DOI: 10.1016/j.jchromb.2021.122954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 09/20/2021] [Accepted: 09/22/2021] [Indexed: 11/24/2022]
Abstract
A simple, selective, rapid, and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine CX3002 in human plasma using CX3002-d3 as the internal standard (IS). After a rapid protein precipitation with acetonitrile (3:1, v/v), the chromatographic separation of CX3002 and IS was performed on a Thermo Hypersil GOLD C18 column (2.1 mm × 50 mm, 1.9 μm) with gradient elution at a flow rate of 0.4 ml/min. Gradient elution was achieved with mobile phase A consisting of water containing 0.1% formic acid and 5 mmol/L ammonium formate and mobile phase B consisting of methanol containing 0.1% formic acid. The detection was performed on AB SCIEX QTRAP® 5500 tandem mass spectrometry in the positive ion mode. Multiple reactions monitoring (MRM) was used for quantitative analysis at transition of m/z 460.3 → 199.3 for CX3002 and m/z 463.3 → 202.3 m/z for IS. The method was fully validated and displayed good linearity over a concentration range of 0.2-400 ng/mL with the correlation coefficient above 0.997. The intra-run and inter-run precision (coefficient of variation, CV) ranged from 0.60%-16.46% and the accuracy bias ranged from -7.09%-9.75%. The mean IS-normalized extraction recovery ranged from 98.30% to 104.52%. The CV(%) of IS-normalized matrix factors at the low and high QC concentration were 4.09% and 1.68%, respectively. The storage stability under different conditions was in accordance with the bioanalytical guidelines. The method was successfully applied to the pharmacokinetic study of CX3002 (30 mg) in healthy Chinese subjects.
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Affiliation(s)
- Xinhua Hu
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yichao Xu
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jinliang Chen
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuting Shen
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dandan Yang
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yin Hu
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Bo Jiang
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Honggang Lou
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zourong Ruan
- Center of Clinical Pharmacology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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Ng CH, Tan DJH, Nistala KRY, Syn N, Xiao J, Tan EXX, Woo FZ, Chew NWS, Huang DQ, Dan YY, Sanyal AJ, Muthiah MD. A network meta-analysis of direct oral anticoagulants for portal vein thrombosis in cirrhosis. Hepatol Int 2021; 15:1196-1206. [PMID: 34417718 DOI: 10.1007/s12072-021-10247-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/06/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Current guidelines have limited consensus on the approach to portal venous thrombosis (PVT) in cirrhotic patients. While there is rising interest in direct oral anticoagulants (DOACs) use for PVT, current evidence is limited by small sample size and lack of comparisons to traditional anticoagulants. Thus, a network meta-analysis was conducted to compare the use of DOACs with traditional anticoagulants. METHODS Medline and Embase were searched for articles about anticoagulation use in cirrhotic patients with nontumorous PVT for articles on DOACs, warfarin, low-molecular weight heparin (LMWH) or antithrombin III. A network analysis was conducted using risk ratios (RR) with surface under the cumulative ranking curve (SUCRA). A single-arm meta-analysis was used to summarize the outcomes of DOAC treatment. RESULTS A total of 10 articles were included in the study. 79.5% (CI 38.8-95.9) of DOACs patients achieved complete or partial recanalization and 9.80% (CI 4.50-20.0) experienced a bleeding event. DOACs were superior to LMWH (RR 2.299, CI 1.037-5.093, p = 0.040), warfarin (RR 1.762, CI 1.017-3.053, p = 0.043) and no treatment (RR 3.489, CI 1.394-8.733, p = 0.008) in complete recanalization. For partial recanalization, while DOACs were not superior to any treatment, they had the highest probability in achieving partial recanalization in SUCRA analysis. Bleeding risk and mortality were similar compared to other treatments. CONCLUSION The network analysis supports the use of DOACs in cirrhotic patients, with significant rates of complete recanalization compared to other treatments without increasing bleeding risk. DOACs can potentially be considered for nontumorous PVT in cirrhosis.
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Affiliation(s)
- Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | | | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- Biostatistics and Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Jieling Xiao
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
| | - Eunice Xiang Xuan Tan
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore
| | - Felicia Zuying Woo
- Department of Pharmacy, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Nicholas W S Chew
- Division of Cardiology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore
| | - Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Mark D Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore, 117597, Singapore.
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore.
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Tower Block Level 10, 1E Kent Ridge Road, Singapore, 119228, Singapore.
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Montinari MR, Minelli S, De Caterina R. Eighty years of oral anticoagulation: Learning from history. Vascul Pharmacol 2021; 141:106918. [PMID: 34537376 DOI: 10.1016/j.vph.2021.106918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/11/2021] [Accepted: 09/14/2021] [Indexed: 02/05/2023]
Abstract
In the year 2021 we celebrate the 80th anniversary of the first clinical use of vitamin K antagonists (VKAs), the mainstay of prevention and long-term treatment of thromboembolic disease. The discovery and development of oral anticoagulants is one of the most important chapters in the history of medicine, a goal pursued by physicians trying to combat the clinical manifestations of thrombosis since ancient times. Until the last decade, VKAs were the only oral anticoagulants available and used in clinical practice. Today, their clinical use has progressively shrunk, as the non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly replacing VKAs in various conditions after the successful completion of several large randomized controlled trials. Currently, new research is tackling upstream components of the intrinsic pathway - particularly factor XI and factor XII - for the development of new, even safer anticoagulants promising to reduce bleeding without compromising efficacy. This review highlights the evolution of oral anticoagulant therapy tracing the key stages of a long and fascinating history that has unfolded from the first part of the twentieth century until today, indeed an intriguing journey where serendipity is intertwined with the tenacious work of many researchers.
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Affiliation(s)
- Maria Rosa Montinari
- Chair of History of Medicine, Department of Biological and Environmental Science and Technology, University of Salento, Lecce, Italy
| | | | - Raffaele De Caterina
- Chair of Cardiology, University of Pisa, University Cardiology Division, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Fondazione VillaSerena, Città Sant'Angelo, Pescara, Italy.
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Beale D, Dennison J, Boyce M, Mazzo F, Honda N, Smith P, Bruce M. ONO-7684 a novel oral FXIa inhibitor: Safety, tolerability, pharmacokinetics and pharmacodynamics in a first-in-human study. Br J Clin Pharmacol 2021; 87:3177-3189. [PMID: 33450079 PMCID: PMC8359378 DOI: 10.1111/bcp.14732] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/13/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
AIMS The objectives of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of ONO-7684, a novel activated factor XI (FXIa) inhibitor, in healthy subjects. METHODS This was a first-in-human (FIH), randomised, placebo-controlled, double-blind, single and multiple dose study in healthy subjects under fed and fasted conditions. This study consisted of two parts: single ascending dose (Part A; 1, 5, 20, 80, 150 or 300 mg ONO-7684 or placebo) and multiple ascending doses (Part B; 80, 150 or 250 mg ONO-7684 or placebo daily for 14 days). In both parts, subjects were randomised in a 3:1 ratio to receive ONO-7684 or placebo. RESULTS ONO-7684 was well tolerated at all dose levels tested following both single and repeated doses, with a low overall incidence of treatment-emergent adverse events. There was no evidence to suggest a bleeding risk. Dose proportionality in exposure was observed for the range of 1-300 mg ONO-7684 in Part A. In Part A, the half-life of ONO-7684 administered in the fasted state ranged from 16.0 to 19.8 hours. In Part B, the half-life of ONO-7684 administered in the fed state ranged from 22.1 to 27.9 hours, supporting once daily oral dosing. ONO-7684 strongly inhibited factor XI coagulation activity (FXI:C) and increased activated partial thromboplastin time (aPTT), with a mean maximum on treatment percentage inhibition versus baseline of 92% and a mean maximum on treatment ratio-to-baseline of 2.78, respectively, at 250 mg ONO-7684 daily. CONCLUSIONS The data generated in this FIH study demonstrate the promising potential of oral FXIa inhibition and ONO-7684 for indications requiring anticoagulation.
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Jiang H, Jiang Y, Ma H, Zeng H, Lv J. Effects of rivaroxaban and warfarin on the risk of gastrointestinal bleeding and intracranial hemorrhage in patients with atrial fibrillation: Systematic review and meta-analysis. Clin Cardiol 2021; 44:1208-1215. [PMID: 34302375 PMCID: PMC8427974 DOI: 10.1002/clc.23690] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/26/2021] [Accepted: 07/01/2021] [Indexed: 01/29/2023] Open
Abstract
To assess the risk of gastrointestinal bleeding and intracranial hemorrhage in patients with atrial fibrillation (AF) after the use of rivaroxaban or warfarin. To investigate the effects of rivaroxaban and warfarin on gastrointestinal and intracranial hemorrhage in patients with AF, we searched PubMed, Embase, and Medline from the establishment of databases up to 2020. We finally included 38 observational studies involving 1 312 609 patients for the assessment of intracranial hemorrhage, and 33 observational studies involving 1 332 956 patients for the assessment of gastrointestinal bleeding. The rates of intracranial hemorrhage were 0.55% in the rivaroxaban group versus 0.91% in the warfarin group (OR 0.59; 95% CI 0.53-0.66; p < .00001, I2 = 78%). The rates of gastrointestinal bleeding were 2.63% in patients with rivaroxaban versus 2.48% in those with warfarin (OR 1.06; 95% CI 0.96-1.17; p < .00001, I2 = 94%). Rivaroxaban could significantly reduce the risk of intracranial hemorrhage in patients with AF than warfarin, but the risk of gastrointestinal bleeding remained controversy due to no statistical significant difference. Notably, a subgroup analysis demonstrated that patients in rivaroxaban group with severe chronic renal diseases or undergoing hemodialysis exposed to less gastrointestinal hemorrhage risk than the group from warfarin.
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Affiliation(s)
- Hongcheng Jiang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue Jiang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haotian Ma
- The First Clinical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hesong Zeng
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiagao Lv
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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El-Shenawy AA, Mahmoud RA, Mahmoud EA, Mohamed MS. Intranasal In Situ Gel of Apixaban-Loaded Nanoethosomes: Preparation, Optimization, and In Vivo Evaluation. AAPS PharmSciTech 2021; 22:147. [PMID: 33948767 DOI: 10.1208/s12249-021-02020-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/18/2021] [Indexed: 12/14/2022] Open
Abstract
The present study was conducted to formulate ethosomal thermoreversible in situ gel of apixaban, an anticoagulant drug, for nasal delivery. Ethosomes were formed, of lecithin, cholesterol, and ethanol, by using thin-film hydration method. The prepared ethosomes were characterized by Zetasizer, transmission electron microscope, entrapment efficiency, and in vitro study. The selected ethosomal formula (API-ETHO2) was incorporated in gel using P407 and P188 as thermoreversible agents and carbopol 934 as mucoadhesive agent. Box-Behnken design was used to study the effect of independent variables (concentration of P407, P188, and carbopol 934) on gelation temperature, mucoadhesive strength, and in vitro cumulative percent drug released at 12h (response variables). The optimized formulation was subjected to compatibility study, ex vivo permeation, histopathological examination for the nasal mucosa, and in vivo study. API-ETHO2 was spherical with an average size of 145.1±12.3 nm, zeta potential of -20±4 mV, entrapment efficiency of 67.11%±3.26, and in vitro % release of 79.54%±4.1. All gel formulations exhibited an acceptable pH and drug content. The optimum gel offered 32.3°C, 1226.3 dyne/cm2, and 53.50% for gelation temperature, mucoadhesive strength, and in vitro percent released, respectively. Apixaban ethosomal in situ gel evolved higher ex vivo permeation (1.499±0.11 μg/cm2h) through the nasal mucosa than pure apixaban gel. Histopathological study assured that there is no necrosis or tearing of the nasal mucosa happened by ethosomal gel. The pharmacokinetic parameters in rabbit plasma showed that intranasal administration of optimized API-ethosomal in situ gel achieved higher Cmax and AUC0-∞ than unprocessed API nasal gel, nasal suspension, and oral suspension. The ethosomal thermoreversible nasal gel established its potential to improve nasal permeation and prolong anticoagulant effect of apixaban.
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Wang L, Jiang S, Li C, Xu Z, Chen Y. Efficacy of rivaroxaban for the treatment of Chinese patients with acute pulmonary embolism: A retrospective study. Medicine (Baltimore) 2021; 100:e25086. [PMID: 33787591 PMCID: PMC8021341 DOI: 10.1097/md.0000000000025086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/17/2021] [Indexed: 01/04/2023] Open
Abstract
Pulmonary embolism (PE) is a life-threatening disease, which accounts for the major type of venous thromboembolism. Currently, there is limited understanding and management for PE. Rivaroxaban is reported to treat patients with PE. However, there is still insufficient evidence on rivaroxaban for the treatment of Chinese patients with acute PE. Thus, this retrospective study investigated the benefits and safety of rivaroxaban for Chinese patients with acute PE.A total of 72 Chinese patient cases with acute PE were analyzed in this study. Of these, 36 cases who received rivaroxaban mono-therapy were assigned to the treatment group, while the remaining 36 cases who received standard therapy were assigned to the control group. The benefits were assessed by the duration of hospital stay, treatment satisfaction, and safety.After treatment, rivaroxaban mono-therapy showed better benefits in decreasing the duration of hospital stay (P < .01), increasing treatment satisfaction (P < .01), and reducing mild bleeding (P = .02) in Chinese patients with acute PE, than standard therapy.The results of this study indicated that rivaroxaban may provide more benefits than the standard therapy for Chinese patients with acute PE. Future studies are still needed to warrant the current results.
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Affiliation(s)
- Lei Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Jiamusi University
| | - Shuang Jiang
- Department of Intensive Care Unit, Jiamusi Traditional Chinese Medicine Hospital
| | - Chao Li
- Department of Emergency, The Second Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Zhi Xu
- Department of Intensive Care Unit, The First Affiliated Hospital of Jiamusi University
| | - Ying Chen
- Department of Intensive Care Unit, The First Affiliated Hospital of Jiamusi University
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Investigation of the arcane inhibition of human organic anion transporter 3 by benzofuran antiarrhythmic agents. Drug Metab Pharmacokinet 2021; 38:100390. [PMID: 33836300 DOI: 10.1016/j.dmpk.2021.100390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/08/2021] [Accepted: 03/07/2021] [Indexed: 12/16/2022]
Abstract
The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected Ki values of 0.042, 0.019, 0.028 and 0.0046 μM respectively. Protein binding effects and probe substrate dependency were accounted for in our assays. Static modelling predicted 1.29-, 1.01-, 1.29- and 1.16-fold increase in rivaroxaban exposure, culminating in a predicted 1.29-, 1.01-, 1.28- and 1.15-fold increase in major bleeding risk respectively, suggesting potential OAT3-mediated DDI between amiodarone and rivaroxaban. Future work involving physiologically-based pharmacokinetic modelling is crucial in holistically predicting the complex DDIs between the benzofuran antiarrhythmic agents and rivaroxaban.
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Current use of rivaroxaban in elderly patients with venous thromboembolism (VTE). J Thromb Thrombolysis 2021; 52:863-871. [PMID: 33674983 DOI: 10.1007/s11239-021-02415-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
Venous thromboembolism (VTE), which is characterized by pulmonary embolism and deep vein thrombosis, has become a serious public concern. Notably, over half of the patients with VTE are over 70 years of age, but elderly patients are at high risk of anti-coagulation and bleeding, which increase with age. Moreover, risk factors and frailty also show a difference between elderly patients and ordinary patients diagnosed with VTE. Rivaroxaban is a direct inhibitor of activated factor Xa and has the advantage of predictable pharmacodynamics and pharmacokinetics, no coagulation monitoring, and few drug interactions. As a first-line therapy for VTE, this drug is more advantageous than traditional therapy and exhibits good efficacy and safety for ordinary patients. However, the effectiveness and safety of rivaroxaban in elderly patients have not been fully elucidated. This article reviewed the use of rivaroxaban in elderly patients, including drug interactions, monitoring, reversal agents of rivaroxaban, and the use of small dosages of rivaroxaban in elderly patients.
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Sun X, Tang S, Hou B, Duan Z, Liu Z, Li Y, He S, Wang Q, Chang Q. Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension. BMC Gastroenterol 2021; 21:2. [PMID: 33407159 PMCID: PMC7789354 DOI: 10.1186/s12876-020-01532-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 11/09/2020] [Indexed: 02/08/2023] Open
Abstract
Background Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination.
Methods The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. Results Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. Conclusions Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.
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Affiliation(s)
- Xiaoyu Sun
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, 0086-116011, China
| | - Shunxiong Tang
- Department of Invasive Technology, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Binbin Hou
- Department of Dermatology, Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhijun Duan
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, 0086-116011, China.
| | - Zhen Liu
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, 0086-116011, China
| | - Yang Li
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.,Department of Breast Surgery, Hospital of Chinese Medical University, Liaoning Provincial Cancer Institute and Hospital, Shenyang, China
| | - Shoucheng He
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, 0086-116011, China
| | - Qiuming Wang
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian, 0086-116011, China
| | - Qingyong Chang
- Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
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Al-Ansari A. Acquired bleeding disorders through antithrombotic therapy: the implications for dental practitioners. Br Dent J 2020; 229:729-734. [PMID: 33311678 DOI: 10.1038/s41415-020-2399-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/28/2020] [Indexed: 11/09/2022]
Abstract
Antithrombotic medications are one of the most common causes of an acquired bleeding disorder. The majority of these medications are administered orally for a variety of clinical indications. It is important that dental surgeons are aware of these medications, their mechanisms of action and how they can influence the dental management of patients, particularly when undertaking procedures which carry a risk of bleeding.
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Affiliation(s)
- Anmar Al-Ansari
- Dental Core Trainee 1 in Oral and Maxillofacial Surgery, Forth Valley Royal Hospital, Stirling Rd, Larbert, FK5 4WR, UK.
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Sebuhyan M, Crichi B, Abdallah NA, Bonnet C, Deville L, Marjanovic Z, Farge D. Drug-drug interaction (DDI) with direct oral anticoagulant (DOAC) in patients with cancer. JOURNAL DE MEDECINE VASCULAIRE 2020; 45:6S31-6S38. [PMID: 33276942 DOI: 10.1016/s2542-4513(20)30517-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients after tumor progression. The treatment of CAT is challenging because of a high risk of VTE recurrence, a high risk of bleeding, common presence of comorbidities, poly-medication, and potential drug-drug interactions (DDI). Since 2018, direct oral anticoagulants (DOACs) represent a promising therapeutic alternative and have been recently included into the 2019 update of the International Initiative on Thrombosis and Cancer (ITAC-CME) clinical practice guidelines for management of CAT. However, pharmacokinetic studies suggest that concomitant treatment with P-gp or CYP3A4 inhibitors will result in an increased exposure to rivaroxaban and apixaban, but the clinical relevance of these studies is unknown. In addition, there is an important inter-individual variability in drug absorption, distribution, metabolism and elimination, even more in cancer patients. Overall, the risk of pharmacokinetic DDI should be estimated based on several individual (patient age, renal and liver function, number of comedications) and diseases-related factors, including inflammation, sarcopenia, and low body weight. In this context, DDI with clinical implications could be expected with anti-neoplastic agents or supportive care treatments, especially with drugs known to be moderate or strong inhibitors/inducers of CYP3A4 and P-gp. Consequently, in the presence of potential DDIs through CYP3A4, and/or P-gp, LMWHs remain the first-line anticoagulant of choice for the long-term treatment of CAT. Multidisciplinary consultation meetings and therapeutic patient education should be emphasized in the complex management of CAT.
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Affiliation(s)
- M Sebuhyan
- Unité de médecine interne : maladies auto-immunes et pathologie vasculaire (UF04), hôpital Saint-Louis, Assistance publique des Hôpitaux de Paris (APHP), 1 avenue Claude-Vellefaux, 75010 Paris, France.
| | - B Crichi
- Unité de médecine interne : maladies auto-immunes et pathologie vasculaire (UF04), hôpital Saint-Louis, Assistance publique des Hôpitaux de Paris (APHP), 1 avenue Claude-Vellefaux, 75010 Paris, France
| | - N Ait Abdallah
- Unité de médecine interne : maladies auto-immunes et pathologie vasculaire (UF04), hôpital Saint-Louis, Assistance publique des Hôpitaux de Paris (APHP), 1 avenue Claude-Vellefaux, 75010 Paris, France
| | - C Bonnet
- Service d'oncologie médicale, hôpital Saint-Louis, Assistance publique des Hôpitaux de Paris (APHP), 1 avenue Claude-Vellefaux, 75010 Paris, France.
| | - L Deville
- Service de pharmacie, hôpital Saint-Louis, Assistance publique des Hôpitaux de Paris (APHP), 1 avenue Claude-Vellefaux, 75010 Paris, France
| | - Z Marjanovic
- Service d'hématologie clinique et thérapie cellulaire, hôpital Saint-Antoine, Assistance publique des Hôpitaux de Paris (APHP), 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - D Farge
- Unité de médecine interne : maladies auto-immunes et pathologie vasculaire (UF04), hôpital Saint-Louis, Assistance publique des Hôpitaux de Paris (APHP), 1 avenue Claude-Vellefaux, 75010 Paris, France; Université de Paris, IRSL, EA-3518, Recherche clinique appliquée à l'hématologie, F-75010 Paris, France; Department of Medicine, McGill University, Montreal, QC, Canada.
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Comparison of Dabigatran Plus a P2Y 12 Inhibitor With Warfarin-Based Triple Therapy Across Body Mass Index in RE-DUAL PCI. Am J Med 2020; 133:1302-1312. [PMID: 32389658 DOI: 10.1016/j.amjmed.2020.03.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Body mass index (BMI) affects drug levels of nonvitamin K antagonist oral anticoagulants. We sought to assess whether BMI affected outcomes in the RE-DUAL PCI trial. METHODS RE-DUAL PCI (NCT02164864) evaluated the safety and efficacy of a dual-antithrombotic-therapy regimen using dabigatran (110 mg or 150 mg twice daily and a P2Y12 platelet antagonist) in comparison with triple therapy of warfarin, aspirin, and a P2Y12 platelet inhibitor in 2725 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI). We compared the risk of first International Society on Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant nonmajor bleeding events (primary endpoint) and the composite of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization (main efficacy endpoint) in relation to baseline BMI. RESULTS Median (range) BMI was 28.1 (14-66) kg/m2. Dabigatran dual therapy versus warfarin triple therapy had relevantly and similarly lower rates of bleeding at both 110 mg and 150 mg twice-daily doses, irrespective of BMI. Thromboembolic event rates appeared consistent across categories of BMI, including those <25 and ≥35 kg/m2 (P for interaction: 0.806 and 0.279, respectively). CONCLUSIONS The reduction in bleeding with dabigatran dual therapy compared with warfarin triple therapy in patients here evaluated appears consistent across BMI categories.
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Brooker V, Brown R, Thornton L, Wood E. Emergency fasciotomy in an anticoagulated patient with low energy posterior thigh injury. BMJ Case Rep 2020; 13:e232709. [PMID: 32900715 PMCID: PMC7478037 DOI: 10.1136/bcr-2019-232709] [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] [Accepted: 08/17/2020] [Indexed: 11/03/2022] Open
Abstract
We present a case of a 58-year-old patient with a low energy trauma developing compartment syndrome. He required multiple surgeries, including fasciotomy and removal of a large haematoma. He continued to bleed with a vacuum-assisted closure dressing in situ, requiring prothrombin complex Concentrate and blood transfusion. This case highlights the need for an increased awareness of possible development of compartment syndrome following low impact trauma in a patient who is anticoagulated and raises the question of a possible period of observation for those who may be at risk.
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Affiliation(s)
| | - Robert Brown
- General Surgery, Countess of Chester Hospital, Chester, UK
| | | | - Edward Wood
- Orthopaedics, Countess of Chester Hospital, Chester, UK
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40
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Rodriguez BA, Bhan A, Beswick A, Elwood PC, Niiranen TJ, Salomaa V, Trégouët DA, Morange PE, Civelek M, Ben-Shlomo Y, Schlaeger T, Chen MH, Johnson AD, Johnson AD. A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling. Am J Hum Genet 2020; 107:211-221. [PMID: 32649856 DOI: 10.1016/j.ajhg.2020.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 06/03/2020] [Indexed: 12/17/2022] Open
Abstract
Dual antiplatelet therapy reduces ischemic events in cardiovascular disease, but it increases bleeding risk. Thrombin receptors PAR1 and PAR4 are drug targets, but the role of thrombin in platelet aggregation remains largely unexplored in large populations. We performed a genome-wide association study (GWAS) of platelet aggregation in response to full-length thrombin, followed by clinical association analyses, Mendelian randomization, and functional characterization including iPSC-derived megakaryocyte and platelet experiments. We identified a single sentinel variant in the GRK5 locus (rs10886430-G, p = 3.0 × 10-42) associated with increased thrombin-induced platelet aggregation (β = 0.70, SE = 0.05). We show that disruption of platelet GRK5 expression by rs10886430-G is associated with enhanced platelet reactivity. The proposed mechanism of a GATA1-driven megakaryocyte enhancer is confirmed in allele-specific experiments. Utilizing further data, we demonstrate that the allelic effect is highly platelet- and thrombin-specific and not likely due to effects on thrombin levels. The variant is associated with increased risk of cardiovascular disease outcomes in UK BioBank, most strongly with pulmonary embolism. The variant associates with increased risk of stroke in the MEGASTROKE, UK BioBank, and FinnGen studies. Mendelian randomization analyses in independent samples support a causal role for rs10886430-G in increasing risk for stroke, pulmonary embolism, and venous thromboembolism through its effect on thrombin-induced platelet reactivity. We demonstrate that G protein-coupled receptor kinase 5 (GRK5) promotes platelet activation specifically via PAR4 receptor signaling. GRK5 inhibitors in development for the treatment of heart failure and cancer could have platelet off-target deleterious effects. Common variants in GRK5 may modify clinical outcomes with PAR4 inhibitors, and upregulation of GRK5 activity or signaling in platelets may have therapeutic benefits.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Andrew D Johnson
- National Heart, Lung, and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, Framingham, MA 01702, USA.
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Wu H, Cao H, Song Z, Xu X, Tang M, Yang S, Liu Y, Qin L. Rivaroxaban treatment for young patients with pulmonary embolism (Review). Exp Ther Med 2020; 20:694-704. [PMID: 32742315 PMCID: PMC7388139 DOI: 10.3892/etm.2020.8791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 04/17/2020] [Indexed: 12/16/2022] Open
Abstract
Pulmonary embolism (PE) is a serious, life-threatening condition that affects young populations (>18 and <50 years old, according to most literature reviews) with improved recognition of its clinical manifestations and the widespread use of sensitive imaging techniques, PE is increasingly diagnosed in younger patients. At present, there is limited understanding of the clinical features and adequate anticoagulant treatment options for this population. Most studies to date have yet to demonstrate significant differences in PE pathophysiology or symptoms between young and elderly patients. Although the overall incidence of PE is lower in young populations compared with elderly patients, important risk factors also apply for young patients. Hereditary thrombophilia is common and is a major cause of PE in younger patients. Immobilization, trauma, obesity, smoking and infection are also becoming increasingly frequent in young patients with PE. Among female patients, oral contraceptive use, pregnancy and postpartum status are predominant risk factors underlying PE. Rivaroxaban is a direct oral anticoagulant with a rapid onset of action that is associated with less drug-drug interactions compared with other therapies. Because the drug is administered at fixed doses with no requirement for routine coagulation monitoring, it is becoming an attractive option for anticoagulation treatment in young patients with PE. Therefore, the present literature review focuses on the clinical characteristics of PE and rivaroxaban therapy in younger patients.
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Affiliation(s)
- Haidi Wu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Hongyan Cao
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Zikai Song
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Xiaoyan Xu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Minglong Tang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Shuo Yang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yang Liu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Ling Qin
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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Bixby AL, Shaikh SA, Naik AS, Cotiguala L, McMurry K, Samaniego‐Picota MD, Marshall VD, Park JM. Safety and efficacy of direct‐acting oral anticoagulants versus warfarin in kidney transplant recipients: a retrospective single‐center cohort study. Transpl Int 2020; 33:740-751. [DOI: 10.1111/tri.13599] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/24/2019] [Accepted: 02/24/2020] [Indexed: 12/26/2022]
Affiliation(s)
- Alexandra L. Bixby
- Department of Pharmacy Services University Hospitals Cleveland Medical Center Cleveland OH USA
| | - Suhail A Shaikh
- Department of Transplant Surgery Keck Medical Center of USC University of Southern California Los Angeles CA USA
| | - Abhijit S. Naik
- Department of Internal Medicine Michigan Medicine Ann Arbor MI USA
| | - Laura Cotiguala
- Department of Pharmacy Services Michigan Medicine Ann Arbor MI USA
| | - Katie McMurry
- Department of Pharmacy Services Michigan Medicine Ann Arbor MI USA
| | | | - Vincent D. Marshall
- Department of Clinical Pharmacy University of Michigan College of Pharmacy Ann Arbor MI USA
| | - Jeong M. Park
- Department of Clinical Pharmacy University of Michigan College of Pharmacy Ann Arbor MI USA
- Department of Pharmacy Services Michigan Medicine Ann Arbor MI USA
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Song ZK, Cao H, Wu H, Wei Q, Tang M, Yang S, Liu Y, Qin L. Current status of rivaroxaban in elderly patients with pulmonary embolism (Review). Exp Ther Med 2020; 19:2817-2825. [PMID: 32256765 PMCID: PMC7086161 DOI: 10.3892/etm.2020.8559] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 01/22/2020] [Indexed: 01/14/2023] Open
Abstract
Acute pulmonary embolism (PE) occurs with a high incidence rate in elderly patients, demonstrating complex clinical manifestations, as well as a difficult anticoagulant treatment strategy. Currently, there is limited understanding of the selection criteria for anticoagulant treatment in elderly patients with PE. In fact, the vitamin K antagonist warfarin, a commonly prescribed anticoagulant, has multiple disadvantages, including a narrow therapeutic range, unpredictable pharmacokinetics, multiple food and drug interactions and genetic polymorphisms resulting in poor response to this therapy; therefore, routine laboratory monitoring is required. Most elderly patients with PE fail to adhere to the treatment regimen or even discontinue it, and clinicians are equally hesitant to initiate oral anticoagulants in elderly patients with PE. This leads to a dilemma regarding the use of anticoagulation therapies and a worse prognosis for the patients. Rivaroxaban, a direct Xa factor inhibitor, has demonstrated considerable practical and clinical advantages, exhibits fast-start action pharmacokinetic and pharmacodynamic characteristics, and has an enhanced predictable anticoagulant effect with fewer drug-drug interactions. Based on randomized controlled trials and real-world clinical practice, rivaroxaban has also been recognized as a safe and effective anticoagulant, and these advantages have improved the therapeutic compliance of elderly patients with PE. Thus, this review focused on the current status of rivaroxaban treatment for elderly patients with PE, and described its significance in changing the current anticoagulation treatment regimens for patients. It is expected that rivaroxaban will become a good choice for the treatment of PE in elderly patients.
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Affiliation(s)
- Zi-Kai Song
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Hongyan Cao
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Haidi Wu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Qi Wei
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Minglong Tang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Shuo Yang
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yang Liu
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Ling Qin
- Department of Cardiology, The First Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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44
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Lee SR, Choi EK, Park CS, Han KD, Jung JH, Oh S, Lip GYH. Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Low Body Weight. J Am Coll Cardiol 2020; 73:919-931. [PMID: 30819360 DOI: 10.1016/j.jacc.2018.11.051] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 11/20/2018] [Accepted: 11/26/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND It is unclear whether the overall effectiveness and safety of direct oral anticoagulants (DOACs) are consistent in patients with nonvalvular atrial fibrillation (AF) and extremely low body weight (<50 kg). OBJECTIVES This study compared DOACs with warfarin in AF patients with low body weight. METHODS Using data from the Korean National Health Insurance Service database from January 2014 to December 2016, AF patients with body weight ≤60 kg and who were treated with oral anticoagulants (n = 14,013 taking DOACs and n = 7,576 taking warfarin) were included and examined for ischemic stroke, intracranial hemorrhage (ICH), gastrointestinal bleeding, major bleeding, all-cause death, and composite outcome. The propensity score weighting was used to balance the 2 groups. RESULTS Baseline characteristics were well balanced between the 2 groups (mean age 73 years, mean CHA2DS2-VASc score 4, and 28% of patients weighed <50 kg). DOACs were associated with lower risks of ischemic stroke (hazard ratio [HR]: 0.591; 95% confidence interval [CI]: 0.510 to 0.686) and major bleeding (HR: 0.705; 95%: CI 0.601 to 0.825), which were caused by a reduction in ICH (HR: 0.554; 95% CI: 0.429 to 0.713) compared with warfarin. DOAC improved the net clinical benefit compared with warfarin (HR for composite outcome: 0.660; 95% CI: 0.606 to 0.717), and this was consistent in patients who weighed <50 kg (HR for composite outcome: 0.665; 95% CI: 0.581 to 0.762). CONCLUSIONS In this real-world Asian AF population with low body weight, DOACs showed better effectiveness and safety than warfarin. These results were consistent in patients with extremely low body weight. Regular dosages of DOACs showed comparable results as reduced dosages of DOACs in both effectiveness and safety.
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Affiliation(s)
- So-Ryoung Lee
- Division of Cardiology, Department of Internal Medicine, Soon Chun Hyang University Hospital Seoul, Seoul, Republic of Korea
| | - Eue-Keun Choi
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
| | - Chan Soon Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Kyung-Do Han
- Department of Medical Statistics, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Jin-Hyung Jung
- Department of Medical Statistics, College of Medicine, Catholic University of Korea, Seoul, Republic of Korea
| | - Seil Oh
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Chest & Heart Hospital, Liverpool, United Kingdom; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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45
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Goh EL, Gurung PK, Ma S, Pilpel T, Dale JH, Kannan A, Anand S. Direct Oral Anticoagulants in the Prevention of Venous Thromboembolism Following Surgery for Hip Fracture in Older Adults: A Population-Based Cohort Study. Geriatr Orthop Surg Rehabil 2020; 11:2151459319897520. [PMID: 31976153 PMCID: PMC6958652 DOI: 10.1177/2151459319897520] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 11/02/2019] [Accepted: 12/08/2019] [Indexed: 02/05/2023] Open
Abstract
Introduction Direct oral anticoagulants (DOACs) decrease the risk of venous thromboembolism (VTE) without increasing the risk of hemorrhage in elective lower limb orthopedic surgery. However, the role of DOACs in preventing VTE following hip fracture surgery in the older adults remains unclear. This study aims to evaluate the efficacy and safety of DOACs in older adults undergoing surgery for hip fracture. Materials and methods Single-center, retrospective, population-based cohort study of patients receiving either a DOAC or low-molecular-weight heparin (LMWH) for VTE prophylaxis following hip fracture surgery. Data obtained included patient demographics, comorbidities, fracture classification, time to surgery, procedure performed, and length of stay. Main outcomes assessed were incidence of VTE, incidence of major hemorrhage, and death within 30 days of surgery. Results A total of 321 patients were included. Incidence of VTE was 0% in the DOAC group and 3.4% in the LMWH group (risk ratio [RR]:0.26, 95% confidence interval [CI]: 0.02-4.34, P = .35). Hemorrhage occurred in 7.4% and 3.0% of patients in the DOAC and LMWH groups, respectively (RR: 2.47, 95% CI: 0.77-7.91, P = .13). Mortality from VTE was 0% in the DOAC group and 0.7% in the LMWH group (RR: 0.97, 95% CI: 0.05-20.02, P = .99). Mortality from hemorrhage was 1.9% in the DOAC group and 0.7% in the LMWH group (RR: 2.47, 95% CI: 0.23-26.78, P = .46). Discussion The use of DOACs for VTE prophylaxis following surgery in older adults with hip fracture was associated with a similar rate of VTE compared to LMWH. However, there was a worrying trend toward an increased risk of hemorrhage. Conclusion In the present study of a carefully selected cohort of patients, the effect of DOACs in reducing the risk of VTE following surgery for hip fracture in the older adults was comparable to LMWH. However, a trend toward increased risk of hemorrhage was noted. Larger prospective studies will be required to identify patients who will benefit the most from treatment.
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Affiliation(s)
- En Lin Goh
- Oxford University Clinical Academic Graduate School, Medical Sciences Division, University of Oxford, Oxford, United Kingdom.,Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Pratha Kumari Gurung
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Shaocheng Ma
- Biomechanics Research Group, Imperial College London, London, United Kingdom
| | - Timothy Pilpel
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - James Henderson Dale
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Angela Kannan
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Sambandam Anand
- Department of Trauma, Horton General Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
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46
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Spina E, Barbieri MA, Cicala G, Bruno A, de Leon J. Clinically relevant drug interactions between newer antidepressants and oral anticoagulants. Expert Opin Drug Metab Toxicol 2019; 16:31-44. [PMID: 31795773 DOI: 10.1080/17425255.2020.1700952] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Introduction: This is a review of the drug interactions (DIs) between newer antidepressants and oral anticoagulants (OACs): vitamin K antagonists (VKAs) and direct-acting OACs (DOACs).Areas covered: Articles were obtained from PubMed searches performed for each of the newer antidepressants and oral anticoagulants. The basic pharmacokinetic and pharmacodynamic mechanisms for DIs with these drugs were summarized. Some newer antidepressants are inhibitors of a number of cytochrome P450 (CYP) isoforms and many antidepressants appear to have potential to impair serotonin platelet function and increase bleeding risk.Expert opinion: Clinicians should not forget that the DIs between newer antidepressants and VKAs can be potentially lethal. Among SSRIs, fluoxetine and fluvoxamine appear to be associated with the highest DI risk with warfarin, the most commonly prescribed VKA worldwide. Case reports featuring duloxetine, mirtazapine and trazadone suggested potential for interaction with warfarin. As CYP3A4 is an important metabolic pathway for all DOACs except dabigatran, it appears reasonable to recommend avoiding the co-prescription of fluoxetine and fluvoxamine (weak to moderate CYP3A4 inhibitors) and St John's wort (CYP3A4 inducer). Many package inserts for the newer antidepressants include a warning regarding an increased risk of bleeding events with concomitant use of these agents with OACs.
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Affiliation(s)
- Edoardo Spina
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | | | - Giuseppe Cicala
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Antonio Bruno
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Jose de Leon
- University of Kentucky Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA.,Psychiatry and Neurosciences Research Group (CTS-549), Institute of Neurosciences, University of Granada, Granada, Spain.,Biomedical Research Centre in Mental Health Net (CIBERSAM), Santiago Apostol Hospital, University of the Basque Country, Vitoria, Spain
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47
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Cheong EJY, Teo DWX, Chua DXY, Chan ECY. Systematic Development and Verification of a Physiologically Based Pharmacokinetic Model of Rivaroxaban. Drug Metab Dispos 2019; 47:1291-1306. [PMID: 31506301 DOI: 10.1124/dmd.119.086918] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 08/28/2019] [Indexed: 02/13/2025] Open
Abstract
Rivaroxaban is indicated for stroke prevention in nonvalvular atrial fibrillation (AF). Its elimination is mediated by both hepatic metabolism and renal excretion. Consequently, its clearance is susceptible to both intrinsic (pathophysiological) and extrinsic (concomitant drugs) variabilities that in turn implicate bleeding risks. Upon systematic model verification, physiologically based pharmacokinetic (PBPK) models are qualified for the quantitative rationalization of complex drug-drug-disease interactions (DDDIs). Hence, this study aimed to develop and verify a PBPK model of rivaroxaban systematically. Key parameters required to define rivaroxaban's disposition were either obtained from in vivo data or generated via in vitro metabolism and transport kinetic assays. Our developed PBPK model successfully predicted rivaroxaban's clinical pharmacokinetic parameters within predefined success metrics. Consideration of basolateral organic anion transporter 3 (OAT3)-mediated proximal tubular uptake in tandem with apical P-glycoprotein (P-gp)-mediated efflux facilitated mechanistic characterization of the renal elimination of rivaroxaban in both healthy and renal impaired patients. Retrospective drug-drug interaction (DDI) simulations, incorporating in vitro metabolic inhibitory parameters, accurately recapitulated clinically observed attenuation of rivaroxaban's hepatic clearance due to enzyme-mediated DDIs with CYP3A4/2J2 inhibitors (verapamil and ketoconazole). Notably, transporter-mediated DDI simulations between rivaroxaban and the P-gp inhibitor ketoconazole yielded minimal increases in rivaroxaban's systemic exposure when P-gp-mediated efflux was solely inhibited, but were successfully characterized when concomitant basolateral uptake inhibition was incorporated in the simulation. In conclusion, our developed PBPK model of rivaroxaban is systematically verified for prospective interrogation and management of untested yet clinically relevant DDDIs pertinent to AF management using rivaroxaban. SIGNIFICANCE STATEMENT: Rivaroxaban is susceptible to DDDIs comprising renal impairment and P-gp and CYP3A4/2J2 inhibition. Here, systematic construction and verification of a PBPK model of rivaroxaban, with the inclusion of a mechanistic kidney component, provided insight into the previously arcane role of OAT3-mediated basolateral uptake in influencing both clinically observed renal elimination of rivaroxaban and differential extents of transporter-mediated DDIs. The verified model holds potential for investigating clinically relevant DDDIs involving rivaroxaban and designing dosing adjustments to optimize its pharmacotherapy in atrial fibrillation.
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Affiliation(s)
- Eleanor Jing Yi Cheong
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (E.J.Y.C., D.W.X.T., D.X.Y.C., E.C.Y.C.); and National University Cancer Institute, National University Hospital Medical Centre, Singapore, Singapore (E.C.Y.C.)
| | - Denise Wun Xi Teo
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (E.J.Y.C., D.W.X.T., D.X.Y.C., E.C.Y.C.); and National University Cancer Institute, National University Hospital Medical Centre, Singapore, Singapore (E.C.Y.C.)
| | - Denise Xin Yi Chua
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (E.J.Y.C., D.W.X.T., D.X.Y.C., E.C.Y.C.); and National University Cancer Institute, National University Hospital Medical Centre, Singapore, Singapore (E.C.Y.C.)
| | - Eric Chun Yong Chan
- Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (E.J.Y.C., D.W.X.T., D.X.Y.C., E.C.Y.C.); and National University Cancer Institute, National University Hospital Medical Centre, Singapore, Singapore (E.C.Y.C.)
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48
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Methods for detection of direct oral anticoagulants and their role in clinical practice. COR ET VASA 2019. [DOI: 10.33678/cor.2019.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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49
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Lee JH, Lee JH, Jo KW, Huh JW, Oh YM, Lee JS. Comparison of rivaroxaban and dalteparin for the long-term treatment of venous thromboembolism in patients with gynecologic cancers. J Gynecol Oncol 2019; 31:e10. [PMID: 31789000 PMCID: PMC6918888 DOI: 10.3802/jgo.2020.31.e10] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/16/2019] [Accepted: 07/27/2019] [Indexed: 12/14/2022] Open
Abstract
Objectives Two randomized, controlled studies comparing outcomes in patients treated with direct oral anticoagulants or low-molecular weight heparin for cancer-associated venous thromboembolism (VTE) have previously been performed. However, gynecologic cancers accounted for approximately 10% of the study populations. We compared the outcomes of patients with primary gynecological cancers who were treated for cancer-associated VTE with either rivaroxaban or dalteparin. Methods The 162 eligible patients with gynecologic cancers who were treated with either dalteparin (n=60) or rivaroxaban (n=102) were reviewed. The primary outcome was a composite event, which included recurrence or clinically relevant bleeding events during the therapeutic period. Secondary outcomes were recurrence, clinically relevant bleeding events, and mortality. Results During the therapeutic period, there were no significant differences between the groups in the proportion of composite events, recurrence, or clinically relevant bleeding. Multivariate analysis using the Cox proportional hazards model also showed no significant difference in the number of composite events and clinically relevant bleeding between the groups. In the rivaroxaban group, 44.0% of patients experienced gastrointestinal bleeding and 24.0% experienced urinary tract bleeding. In the dalteparin group, bleeding was most common in the urinary tract (44.4%) and at the injection site (22.2%). Conclusion In this study, although there were no significant differences in effectiveness or safety between the rivaroxaban and dalteparin groups, rivaroxaban use was associated with a higher rate of clinically relevant bleeding than dalteparin. Therefore, caution should be taken when prescribing rivaroxaban for gynecologic cancer-associated VTE and bleeding events should be carefully monitored.
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Affiliation(s)
- Jang Ho Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joo Hee Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Wook Jo
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Won Huh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeon Mok Oh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Seung Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Center for Pulmonary Hypertension and Venous Thrombosis, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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50
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Hussein HK, Nicolson P, Fordwor K, Lowe GC. Mild bleeding disorders: what every clinician should know. Br J Hosp Med (Lond) 2019; 78:684-710. [PMID: 29240509 DOI: 10.12968/hmed.2017.78.12.684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Patients with mild bleeding disorders are under-recognized and frequently present to general physicians. The underlying reasons for bleeding are multifactorial. There is little evidence to guide diagnostic and management decision making in patients with mild bleeding disorders. This article outlines different types of mild bleeding disorders, with a particular focus on bleeding associated with low levels of von Willebrand factor and mild platelet defects. It gives practical, evidence-based advice on the investigation and management of patients with a suspected or known mild bleeding disorder, considering the scenarios of an acute bleed, stable outpatient, peri-surgical management and thrombosis. Patients with a mild bleeding disorder have variable bleeding because of the interplay of genetic and environmental factors. The clinical history remains of utmost importance in their general management. Liaison with a specialist centre, multidisciplinary assessment and a careful judgement of the balance of risk in each individual circumstance is required to safely manage these patients.
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Affiliation(s)
- H K Hussein
- Specialty Registrar in Clinical Haematology, Department of Clinical Haematology, Queen Elizabeth Hospital, Birmingham
| | - Plr Nicolson
- Specialty Registrar in Clinical Haematology and BHF Clinical Research Training Fellow, Department of Clinical Haematology, Queen Elizabeth Hospital, Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT
| | - K Fordwor
- Core Medical Trainee, Department of Medicine, Chelsea and Westminster Hospital, London
| | - G C Lowe
- Consultant Haematologist, Department of Clinical Haematology, Queen Elizabeth Hospital, Birmingham
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