|
1
|
Rossi JM, Panckeri KA, Ghosh S, Grosser T, Cuker A, Diamond SL. Rapid Determination of Xa Inhibitor Activity in Blood Using a Microfluidic Device that Measures Platelet Deposition and Fibrin Generation Under Flow. TH OPEN 2025; 9:a25475710. [PMID: 40182435 PMCID: PMC11967380 DOI: 10.1055/a-2547-5710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Abstract
Background Patients taking direct oral anticoagulants (DOACs) often present complicated scenarios following major bleeding, stroke, or emergency surgery. Rapid whole blood assays of DOAC levels would aid clinical decisions such as the need for DOAC reversal. Methods We developed a single-use, storage-stable, eight-channel microfluidic device to estimate factor Xa (FXa) inhibitor (apixaban or rivaroxaban) levels in venous thromboembolism or atrial fibrillation patients. The assay simultaneously measured whole blood clotting dynamics on collagen/tissue factor (TF; wall shear rate, 200 -1 ) under four ex vivo conditions: no-treatment control, high dose Factor Xa inhibition, low dose or high dose FXa reversal agent (andexanet alfa). Fibrin and platelet deposition dynamics were monitored via two-color epifluorescence microscopy. Plasma samples were also evaluated by LC-MS/MS for DOAC concentrations. Results Experiments with healthy volunteer blood spiked with DOAC verified device performance (DOAC IC 50 ∼120 nM) and confirmed that andexanet alfa added to healthy donor blood had no off-target effect on platelet or fibrin signal. Patient whole blood monitored for 15 to 25 minutes (17 minutes mean runtime) allowed calculation of functional DOAC concentrations ranging from 2 to 500 nM that correlated well with LC-MS/MS determination of apixaban or rivaroxaban (R 2 = 0.7 or 0.9, respectively). Platelet dysfunction was not observed in any patient on DOAC. For a threshold of 100 nM DOAC, the area under the curve (AUC) was found to be 0.881 for apixaban and 0.933 for rivaroxaban. Conclusion Microfluidic testing of whole blood can provide a rapid estimate of DOAC levels over the on-therapy range.
Collapse
Affiliation(s)
- Jason M. Rossi
- Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- FloBio LLC, Philadelphia, Pennsylvania, United States
| | - Karen A. Panckeri
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Soumita Ghosh
- Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Tilo Grosser
- Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Translational Pharmacology, Bielefeld University, Bielefeld, Germany
| | - Adam Cuker
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Scott L. Diamond
- Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia, Pennsylvania, United States
| |
Collapse
|
|
2
|
Brand L, Mitrov-Winkelmolen L, Kuijper TM, Bosch TM, Krens LL. Evaluation and validation of a clinical decision support system for dose optimisation in hospitalized patients with (morbid) obesity - a retrospective, observational study. BMC Med Inform Decis Mak 2025; 25:140. [PMID: 40108614 PMCID: PMC11921672 DOI: 10.1186/s12911-025-02963-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Obesity changes a patient's pharmacokinetics and pharmacotherapeutic advices should be personalized to ensure proper treatment. Currently, implementations of advices regarding the obese population are lacking and weight and body mass index (BMI) are rarely monitored. The Maasstad Hospital built a clinical decision support system (CDSS) for pharmacists, based on current Dutch guidelines, to supply therapeutic advices for (morbidly) obese patients based on patient characteristics. In this study we evaluated whether patients receiving inadequate pharmacotherapy are indeed identified via this CDSS and to which extent irrelevant alerts are generated. Moreover, it is investigated to which extent pharmacists carry on the generated advices and to which extent physicians act upon these. METHODS The research concerned a retrospective observational study performed at the Maasstad Hospital in Rotterdam, the Netherlands between January 2021 and august 2021. The drugs included were dalteparin, apixaban, dabigatran, edoxaban, rivaroxaban, vancomycin and ciprofloxacin. Dispensing data, patient characteristics and CDSS processing were collected. Dispensing data was included when the patient's weight or BMI could potentially lead to dose adjustments via the CDSS. The CDSS was evaluated for sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Additionally, excess alerts, defined as irrelevant alerts on the moment of assessment, of the CDSS and adherence to the CDSS were investigated. RESULTS 1218 alerts over 3735 drug dispenses were generated. 568 alerts (46.6%) resulted in a pharmacotherapeutic advice by the pharmacist to the physician. In most cases, the sensitivity, specificity, PPV and NPV were 100.0% with varying 95% CIs. For some drugs technical adjustments were needed, including the initially incorrect BMI setting of vancomycin within the CDSS, resulting in a high excess alerts of 56.9%. Dabigatran had a NPV of 22.2% 95% CI [6.3-54.7] and a sensitivity of 56.3% 95% CI [33.2-76.9]. Overall excess alerts varied from 22.2% to 56.9%. Depending on the drug, the advices resulted in 6.9-100.0% real pharmacotherapy adjustments in practise. CONCLUSION The (morbid) obesity CDSS functions as expected and identifies the (morbidly) obese patients with inadequate pharmacotherapy. The adherence of physicians and the follow-up in practise varies widely and requires further investigation. TRIAL REGISTRATION Non-WMO research W21.218.
Collapse
Affiliation(s)
- Lianne Brand
- Department of Clinical Pharmacology and Toxicology, Maasstad Hospital, MaasstadLab, Rotterdam, The Netherlands.
- Hospital Pharmacy, Maasstad Hospital, Rotterdam, The Netherlands.
| | | | - T M Kuijper
- Science Bureau, Maasstad Hospital, Rotterdam, The Netherlands
| | - T M Bosch
- Department of Clinical Pharmacology and Toxicology, Maasstad Hospital, MaasstadLab, Rotterdam, The Netherlands
- Hospital Pharmacy, Maasstad Hospital, Rotterdam, The Netherlands
| | - L L Krens
- Hospital Pharmacy, Maasstad Hospital, Rotterdam, The Netherlands.
| |
Collapse
|
|
3
|
Wu H, Yu Q, Jin P, Huo L, An J. Association of rivaroxaban plasma trough concentrations with clinical characteristics and outcomes. Front Pharmacol 2025; 16:1563745. [PMID: 40170732 PMCID: PMC11958709 DOI: 10.3389/fphar.2025.1563745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 02/24/2025] [Indexed: 04/03/2025] Open
Abstract
Background Rivaroxaban use has increased significantly among older adults; however, no definitive plasma concentration thresholds for bleeding or thrombosis have been established. However, dose adjustments for this population remain controversial. Methods Between January 2022 and August 2023, we analyzed trough plasma samples from hospitalized patients treated with rivaroxaban for at least three consecutive days. Clinical data, including demographics, comorbidities, and adverse events, were extracted from electronic medical records. The plasma concentrations of rivaroxaban were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Statistical analyses were performed to identify factors influencing rivaroxaban exposure and clinical outcomes. Results Among 360 plasma samples analyzed (55% male; median age: 72 years), age (P = 0.042) and renal function (P = 0.002) were significant predictors of rivaroxaban concentration-to-dose ratio. Bleeding events were associated with higher trough concentrations (median: 81.85 ng/mL in the bleeding group vs. 26.80 ng/mL in others; P < 0.001) and were more common in patients with malignancies or prior bleeding history. Thrombotic events occurred predominantly in older patients with a history of stroke (P < 0.05). Patients who died were older and had higher CHA2DS2-VASc scores (P < 0.05), prolonged prothrombin times (P < 0.001), and multiple comorbidities. Conclusion Routine monitoring of rivaroxaban plasma concentrations may improve safety in older adults with multiple comorbidities or impaired hepatic, renal, or coagulation functions. Further research is required to establish specific therapeutic thresholds for bleeding and thrombosis.
Collapse
Affiliation(s)
- Huizhen Wu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
| | - Qiaoling Yu
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
- Graduate School, Hebei Medical University, Shijiazhuang, China
| | - Panpan Jin
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
- Graduate School, Hebei Medical University, Shijiazhuang, China
| | - Lijing Huo
- Department of Laboratory, Hebei General Hospital, Shijiazhuang, China
| | - Jing An
- Department of Pharmacy, Hebei Key Laboratory of Clinical Pharmacy, Hebei General Hospital, Shijiazhuang, China
| |
Collapse
|
|
4
|
Menichelli D, Pannunzio A, Baldacci E, Cammisotto V, Castellani V, Mormile R, Palumbo IM, Chistolini A, Violi F, Harenberg J, Pastori D, Pignatelli P. Plasma Concentrations of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation and Different Degrees of Obesity. Clin Pharmacokinet 2025; 64:453-462. [PMID: 39937335 PMCID: PMC11954712 DOI: 10.1007/s40262-025-01474-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2024] [Indexed: 02/13/2025]
Abstract
BACKGROUND Atrial fibrillation (AF) has multiple cardio-metabolic comorbidities, including obesity. The use of direct oral anticoagulants (DOACs) in patients with AF and obesity is still uncertain owing to the concern of possible ineffective DOAC plasma concentration. We evaluated the peak and trough plasma concentrations of DOACs in AF patients with different degrees of obesity. METHODS Observational single-center study including patients with obesity and AF, between April 2022 and April 2024. Obesity was defined as body mass index (BMI) ≥ 30.0 kg/m2. The 2-hour peak and trough DOAC plasma concentrations were assessed. Intake of DOAC was verified on site. Multivariable logistic regression analysis was used to assess the odds ratio (OR) and 95% confidence interval (95% CI) of factors associated with below-range trough concentration (BRTC) and below-range peak concentration (BRPC). RESULTS In total, 160 patients (33.8% women) with a mean age of 73.2 ± 9.1 years were included. The median BMI was 32.3 kg/m2. DOACs prescribed were apixaban (46.8%), rivaroxaban (21.8%), dabigatran (16.4%), and edoxaban (15.0%); 18.1% and 14.4% had BRTC and BRPC concentrations, respectively. Patients with BRTC were more frequently treated with edoxaban and dabigatran and had a higher BMI. On multivariable logistic regression analysis, dabigatran [hazard ratio (HR) 3.039, 95% CI 1.155-7.999, p = 0.024) and BMI ≥ II class (OR 2.625, 95% CI 1.087-6.335, p = 0.032] were associated with BRTC. Dabigatran (OR 4.296, 95% CI 1.523-12.120, p = 0.006) and apixaban (OR 0.277, 95% CI 0.096-0.802, p = 0.018) were directly and inversely associated with BRPC, respectively. CONCLUSIONS A nonnegligible proportion of patients with obesity and AF have below-range plasma concentrations of DOACs. Assessment of DOAC plasma concentration in obesity class ≥ II may be useful in these patients.
Collapse
Affiliation(s)
- Danilo Menichelli
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Arianna Pannunzio
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Erminia Baldacci
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Valentina Castellani
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy
| | - Rosaria Mormile
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Ilaria Maria Palumbo
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy
| | - Antonio Chistolini
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesco Violi
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy
| | - Job Harenberg
- Ruprecht Karls University of Heidelberg, Heidelberg, Germany
| | - Daniele Pastori
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy.
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, Italy.
| | - Pasquale Pignatelli
- Department of General Surgery, Surgical Specialties and Organ Transplantation "Paride Stefanini", Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
5
|
Ezaldin S, Abdelsalam M, Annie F, Chumbe JT, Gharib E. "Evaluating the efficacy and safety of direct oral anticoagulants compared to warfarin in very morbidly obese patients with non-valvular atrial fibrillation: A retrospective cohort study". Heliyon 2025; 11:e41596. [PMID: 39866424 PMCID: PMC11758958 DOI: 10.1016/j.heliyon.2024.e41596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/28/2025] Open
Abstract
•DOACs are effective and safe in very morbidly obese AF patients (BMI ≥50 kg/m2).•DOACs show similar stroke and bleeding risks as warfarin in this population.•Findings support DOACs in anticoagulation guidelines for very morbidly obese patients.
Collapse
Affiliation(s)
- Shady Ezaldin
- Cardiovascular Department, Charleston Area Medical Center, Charleston, WV, USA
| | - Mahmoud Abdelsalam
- Cardiovascular Department, Charleston Area Medical Center, Charleston, WV, USA
| | - Frank Annie
- Cardiovascular Department, Charleston Area Medical Center, Charleston, WV, USA
| | | | - Elie Gharib
- Cardiovascular Department, Charleston Area Medical Center, Charleston, WV, USA
| |
Collapse
|
|
6
|
Hilu M, Issawy M, Colodner R, Eitam H, Avraham GR, Ram KC, Elias M, Shimoni O, Schwartzberg E, Goldstein LH. The Influence of High Body Mass Index (BMI > 35 kg/m 2) on Apixaban Plasma Concentration in Patients with Atrial Fibrillation. Am J Cardiovasc Drugs 2025; 25:113-123. [PMID: 39424747 PMCID: PMC11775066 DOI: 10.1007/s40256-024-00678-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/22/2024] [Indexed: 10/21/2024]
Abstract
PURPOSE Apixaban, a direct oral anticoagulant is administered for stroke prevention in atrial fibrillation patients. Dosing adjustment is guided by renal function, age, and body weight. However, no data exist on its pharmacokinetics in patients with a body mass index (BMI) ≥ 35 kg/m2. The aim was to investigate the effects of BMI ≥ 35 kg/m2 on trough plasma concentrations of apixaban in patients with atrial fibrillation. METHODS This prospective study compared steady-state trough concentrations of apixaban in patients with a BMI ≥ 35 kg/m2 and patients with a BMI < 35 kg/m2. RESULTS Sixty patients were included. In patients receiving 5 mg apixaban twice daily, the median trough plasma concentration was 29% lower in patients with a BMI ≥ 35 kg/m2 than in those with a BMI < 35 kg/m2 (148.9 ng/ml, interquartile range [IQR] 94.5-205.6, compared to 209.1 ng/ml, IQR 167-266.8 ng/ml, respectively; P = 0.044). However, median trough concentrations fell within the manufacturer's predicted range for effective steady-state apixaban exposure. A similar trend was observed with 2.5 mg apixaban twice daily, although statistical significance was not reached. Multivariate analysis revealed no correlation between BMI values and trough concentrations. CONCLUSION BMI ≥ 35 kg/m2 patients exhibited lower apixaban trough concentrations, while remaining within the manufacturer's established range for effective steady-state apixaban, suggesting that dose adjustment is unnecessary for this specific patient group.
Collapse
Affiliation(s)
- May Hilu
- Pharmacy Department, Clalit Healthcare, North District, Nof Hagalil, Israel
- School of Pharmacy, Ben Gurion University of the Negev, Beersheba, Israel
| | - Mariana Issawy
- Technion Israel Institute of Technology, Rappaport Faculty of Medicine, Haifa, 3109601, Israel
| | - Raul Colodner
- Central Laboratory, HaEmek Medical Center, Afula, Israel
| | - Harel Eitam
- Central Laboratory, HaEmek Medical Center, Afula, Israel
| | - Gilat Ron Avraham
- Technion Israel Institute of Technology, Rappaport Faculty of Medicine, Haifa, 3109601, Israel
| | - Kerstin Carlin Ram
- Technion Israel Institute of Technology, Rappaport Faculty of Medicine, Haifa, 3109601, Israel
| | - Mazen Elias
- Technion Israel Institute of Technology, Rappaport Faculty of Medicine, Haifa, 3109601, Israel
| | - Orli Shimoni
- School of Pharmacy, Ben Gurion University of the Negev, Beersheba, Israel
| | - Eyal Schwartzberg
- School of Pharmacy, Ben Gurion University of the Negev, Beersheba, Israel
| | - Lee Hilary Goldstein
- Technion Israel Institute of Technology, Rappaport Faculty of Medicine, Haifa, 3109601, Israel.
- HaEmek Medical Center, Internal Department C, Afula, Israel.
| |
Collapse
|
|
7
|
Wei M, Wu X, Wang L, Gu Z, Tu Y, Zhang L, Zhang J, Xie H, Zhou Q, Chu Y, Cheng Z, Zhou G, Song Q. Rivaroxaban for Thromboembolism Prophylaxis in Patients with Nephrotic Syndrome: A Single-Arm, Prospective Study. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:346-358. [PMID: 39430289 PMCID: PMC11488834 DOI: 10.1159/000540107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/24/2024] [Indexed: 10/22/2024]
Abstract
Introduction Thromboembolism is a recognized complication of nephrotic syndrome (NS). Evidence supporting the use of rivaroxaban to prevent NS-related thrombosis is limited and controversial. This study aimed to explore the impact of NS on rivaroxaban pharmacokinetics and to collect observational data on the efficacy and safety of rivaroxaban as primary thromboprophylaxis in patients with NS. Methods This prospective study analyzed 141 patients with NS who received rivaroxaban (10 mg/day) for thromboprophylaxis. High-performance liquid chromatography-tandem mass spectrometry was used to measure the trough and peak plasma concentrations (Ctrough and Cmax) of rivaroxaban. The influence of clinical and genetic factors on these concentrations was examined using multivariate logistic regression. Results The median Cmax and Ctrough were 68.5 ng/mL (interquartile range [IQR], 31.7-105.5 ng/mL) and 4.4 ng/mL (IQR, 1.2-11.9 ng/mL), respectively. The incidence of thromboembolic events (TEs) was 12.8%, while that of bleeding events was 14.2%, although all were classified as minor. Albumin level was the most significant factor affecting Cmax (ρ = 0.55; p < 0.001) and was also significantly associated with TEs (0.81; 0.71-0.91 per 1.0 g/dL increase; p = 0.001) and bleeding risks (1.11; 1.03-1.19 per 1.0 g/dL increase; p = 0.008). Single nucleotide polymorphisms in the ABCB1 gene significantly influenced Ctrough but were not associated with clinical outcomes. Conclusion Hypoalbuminemia significantly affects the pharmacokinetics of rivaroxaban in NS patients. A dose-adjustment strategy based on rivaroxaban concentrations, accounting for variable albumin levels, may improve the safety and efficacy of thromboprophylaxis in this population.
Collapse
Affiliation(s)
- Meng Wei
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Clinical Pharmacy, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xue Wu
- Department of Clinical Pharmacy, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Liteng Wang
- Department of Clinical Pharmacy, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Zhichun Gu
- Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanmao Tu
- National Clinical Research Center of Kidney Disease, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lihua Zhang
- National Clinical Research Center of Kidney Disease, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jiong Zhang
- National Clinical Research Center of Kidney Disease, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Honglang Xie
- National Clinical Research Center of Kidney Disease, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qing Zhou
- Department of Clinical Pharmacy, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yanan Chu
- Department of Clinical Pharmacy, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhen Cheng
- National Clinical Research Center of Kidney Disease, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Guohua Zhou
- Department of Clinical Pharmacy, Jinling Hospital Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qinxin Song
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
8
|
Al-Aieshy F, Skeppholm M, Fyrestam J, Johansson F, Pohanka A, Malmström RE. Apixaban plasma concentrations in patients with obesity. Eur J Clin Pharmacol 2024; 80:1343-1354. [PMID: 38822847 PMCID: PMC11303434 DOI: 10.1007/s00228-024-03696-4] [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: 02/08/2024] [Accepted: 04/27/2024] [Indexed: 06/03/2024]
Abstract
PURPOSE Routine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients. METHODS Forty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LC‒MS/MS methodology. RESULTS The median trough concentrations in patients with obesity (58.7, range 10.7-200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0-150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0-277.5) and 113.5 ng/ml (range 75.5-334.6) in patients with obesity and normal weight, respectively. CONCLUSION Apixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach.
Collapse
Affiliation(s)
- Fadiea Al-Aieshy
- Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital Solna, 17176, Stockholm, Sweden.
| | - Mika Skeppholm
- Department of Clinical Sciences, Karolinska Institutet & Division of Cardiovascular Medicine, Danderyd Hospital, Stockholm, Sweden
| | - Jonas Fyrestam
- Department of Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Johansson
- Department of Clinical Sciences, Karolinska Institutet & Medical library, Danderyd Hospital, Stockholm, Sweden
| | - Anton Pohanka
- Department of Laboratory Medicine (LABMED), Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden
| | - Rickard E Malmström
- Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital Solna, 17176, Stockholm, Sweden
| |
Collapse
|
|
9
|
Karakasis P, Ktenopoulos N, Pamporis K, Sagris M, Soulaidopoulos S, Gerogianni M, Leontsinis I, Giannakoulas G, Tousoulis D, Fragakis N, Tsioufis K. Efficacy and Safety of Direct Oral Anticoagulants versus Warfarin in Obese Patients (BMI ≥ 30 kg/m 2) with Atrial Fibrillation or Venous Thromboembolism: An Updated Systematic Review and Meta-Analysis. J Clin Med 2024; 13:3784. [PMID: 38999350 PMCID: PMC11242099 DOI: 10.3390/jcm13133784] [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: 05/30/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/14/2024] Open
Abstract
Background: Real-world data show limited utilization of direct oral anticoagulants (DOACs) in obese patients (body mass index [BMI] ≥ 30 kg/m2) due to concerns regarding their efficacy and safety in this demographic. Aim: This review aimed to consolidate current evidence on the efficacy and safety of DOACs versus warfarin in obese patients with non-valvular atrial fibrillation (AF) or venous thromboembolism (VTE). The primary efficacy outcome assessed a composite of all-cause mortality, stroke, systemic embolism (SE), and myocardial infarction (MI). Methods: A systematic search was conducted in MEDLINE, SCOPUS, and Cochrane databases from inception to December 28, 2023. Data were synthesized using random-effects meta-analysis. Results: A total of 35 studies involving 434,320 participants were analyzed. DOAC use was associated with a significant reduction in the risk of the composite outcome (RR = 0.80, 95% CI [0.65, 0.98], I2 = 95%), hemorrhagic stroke (RR = 0.58, 95% CI [0.38, 0.88], I2 = 92%), major bleeding (RR = 0.76, 95% CI [0.63, 0.92], I2 = 94%), gastrointestinal bleeding (RR = 0.59, 95% CI [0.49, 0.72], I2 = 88%), and intracranial bleeding (RR = 0.45, 95% CI [0.34, 0.60], I2 = 44%) compared to warfarin. A non-significant benefit of DOACs was observed for all-cause mortality, MI, the composite of stroke or SE, ischemic stroke, SE, VTE, and minor bleeding compared to warfarin. Subgroup analysis indicated no significant effect modification based on the indication for anticoagulation or study design. Conclusions: DOACs demonstrated a favorable efficacy and safety profile in obese individuals compared to warfarin.
Collapse
Affiliation(s)
- Paschalis Karakasis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (P.K.); (I.L.); (N.F.)
| | - Nikolaos Ktenopoulos
- School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (K.P.); (S.S.); (D.T.); (K.T.)
| | - Konstantinos Pamporis
- School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (K.P.); (S.S.); (D.T.); (K.T.)
- Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Marios Sagris
- School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (K.P.); (S.S.); (D.T.); (K.T.)
| | - Stergios Soulaidopoulos
- School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (K.P.); (S.S.); (D.T.); (K.T.)
| | - Maria Gerogianni
- Endocrine Unit, 2nd Propaedeutic Department of Internal Medicine, School of Medicine, Research Institute and Diabetes Center, Attikon University Hospital, National and Kapodistrian University of Athens, 12641 Athens, Greece;
| | - Ioannis Leontsinis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (P.K.); (I.L.); (N.F.)
| | - George Giannakoulas
- First Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Dimitris Tousoulis
- School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (K.P.); (S.S.); (D.T.); (K.T.)
| | - Nikolaos Fragakis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (P.K.); (I.L.); (N.F.)
| | - Konstantinos Tsioufis
- School of Medicine, Hippokration General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (N.K.); (K.P.); (S.S.); (D.T.); (K.T.)
| |
Collapse
|
|
10
|
Alalawneh M, Awaisu A, Abdallah I, Elewa H, Danjuma M, Matar KM, ElKashlan AM, Elshayep Y, Ibrahim F, Rachid O. Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK). Clin Transl Sci 2024; 17:e13853. [PMID: 38847347 PMCID: PMC11157419 DOI: 10.1111/cts.13853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 06/10/2024] Open
Abstract
The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m2) or non-obese (body mass index 18.5-24.9 kg/m2). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration-time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.
Collapse
Affiliation(s)
| | - Ahmed Awaisu
- College of Pharmacy, Health SectorQatar UniversityDohaQatar
| | - Ibtihal Abdallah
- Internal Medicine, Hamad General HospitalHamad Medical CorporationDohaQatar
| | - Hazem Elewa
- College of Pharmacy, Health SectorQatar UniversityDohaQatar
| | - Mohammed Danjuma
- Internal Medicine, Hamad General HospitalHamad Medical CorporationDohaQatar
- College of Medicine, Health SectorQatar UniversityDohaQatar
| | - Kamal M. Matar
- Department of Pharmacology & Therapeutics, Faculty of PharmacyKuwait UniversityKuwait CityKuwait
| | - Akram M. ElKashlan
- Department of Biochemistry, Faculty of PharmacyUniversity of Sadat CitySadat CityEgypt
- International Center for Bioavailability, Pharmaceutical, and Clinical ResearchCairoEgypt
| | - Yasser Elshayep
- International Center for Bioavailability, Pharmaceutical, and Clinical ResearchCairoEgypt
| | - Fathy Ibrahim
- International Center for Bioavailability, Pharmaceutical, and Clinical ResearchCairoEgypt
- Faculty of PharmacyAl‐Azhar UniversityCairoEgypt
| | - Ousama Rachid
- College of Pharmacy, Health SectorQatar UniversityDohaQatar
| |
Collapse
|
|
11
|
Laporte S, Benhamou Y, Bertoletti L, Frère C, Hanon O, Couturaud F, Moustafa F, Mismetti P, Sanchez O, Mahé I. [Translation into French and republication of: "Management of cancer-associated thromboembolism in vulnerable population"]. Rev Med Interne 2024; 45:366-381. [PMID: 38789323 DOI: 10.1016/j.revmed.2024.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 11/17/2023] [Indexed: 05/26/2024]
Abstract
Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with TAC on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR less than 30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (less than 50,000platelets/μL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.
Collapse
Affiliation(s)
- S Laporte
- Unité de recherche clinique, innovation et pharmacologie, hôpital Nord, CHU de Saint-Étienne, Sainbiose Inserm, université Jean-Monnet, 42000 Saint-Étienne, France; F-CRIN INNOVTE network, Saint-Étienne, France.
| | - Y Benhamou
- F-CRIN INNOVTE network, Saint-Étienne, France; Service de médecine interne, CHU Charles-Nicolle, université de Rouen Normandie, Inserm U1096, Normandie université, Rouen, France
| | - L Bertoletti
- F-CRIN INNOVTE network, Saint-Étienne, France; Service de médecine vasculaire et thérapeutique, équipe dysfonction vasculaire et hémostase, CHU de Saint-Étienne, Inserm UMR1059, université Jean-Monnet, Inserm CIC-1408, Saint-Étienne, France
| | - C Frère
- Inserm UMRS 1166, GRC 27 Greco, DMU BioGeMH, hôpital de la Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Sorbonne université, Paris, France
| | - O Hanon
- Service de gérontologie, hôpital Broca, AP-HP, EA 4468, université de Paris Cité, Paris, France
| | - F Couturaud
- F-CRIN INNOVTE network, Saint-Étienne, France; Département de médecine interne, médecine vasculaire et pneumologie, CHU de Brest, Inserm U1304-Getbo, université de Brest, Brest, France
| | - F Moustafa
- F-CRIN INNOVTE network, Saint-Étienne, France; Département urgence, Inrae, UNH, hôpital de Clermont-Ferrand, université Clermont-Auvergne, Clermont-Ferrand, France
| | - P Mismetti
- F-CRIN INNOVTE network, Saint-Étienne, France; Service de médecine vasculaire et thérapeutique, hôpital Nord, CHU de Saint-Étienne, Saint-Étienne, France
| | - O Sanchez
- F-CRIN INNOVTE network, Saint-Étienne, France; Innovations thérapeutiques en hémostase, université Paris Cité, Inserm UMR S1140, Paris, France; Service de pneumologie et de soins intensifs, hôpital européen Georges-Pompidou, AP-HP, Paris, France
| | - I Mahé
- F-CRIN INNOVTE network, Saint-Étienne, France; Innovations thérapeutiques en hémostase, université Paris Cité, Inserm UMR S1140, Paris, France; Service de médecine interne, hôpital Louis-Mourier, AP-HP, Colombes, France
| |
Collapse
|
|
12
|
Ioannou M, Leonidou E, Chaziri I, Mouzarou A. Direct Oral Anticoagulants: Navigating Through Clinical Challenges. Cardiovasc Drugs Ther 2024; 38:637-650. [PMID: 37552381 DOI: 10.1007/s10557-023-07499-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/28/2023] [Indexed: 08/09/2023]
Abstract
PURPOSE Direct oral anticoagulants (DOACs) have been approved, for over a decade, by both European and American medicine agencies, for treatment and prevention of several cardiovascular conditions. Since then, an increasing amount of data has been added to the medical literature day by day, resulting in a dichotomy in selection of the appropriate agent, dosage, and duration of treatment for special populations with multiple comorbidities. Considering these issues, we have prepared a comprehensive review for the clinical practitioner, to optimize the DOAC utilization in clinical practice. METHODS A thorough literature search and review was conducted, concerning mainly the last decade. Our review focused on the current guidelines and the most recently published studies in PubMed, Science Direct Scopus, and Google Scholar to date. CONCLUSION The purpose of this study is to provide guidance for healthcare professionals for making proper decisions when confronted with clinical challenges. Nevertheless, further research is required to establish DOAC superiority in complicated cases, where there is clinical uncertainty.
Collapse
Affiliation(s)
- Maria Ioannou
- Department of Cardiology, General Hospital Limassol, State Health Organization Services, 4131, Limassol, Cyprus.
| | - Elena Leonidou
- Department of Cardiology, General Hospital Limassol, State Health Organization Services, 4131, Limassol, Cyprus
| | - Ioanna Chaziri
- Department of Pneumonology, Northern Älvborg County Hospital, Trollhättan, Sweden
| | - Angeliki Mouzarou
- Department of Cardiology, General Hospital Paphos, State Health Organization Services, Paphos, Cyprus
| |
Collapse
|
|
13
|
Fadraersada J, Alva-Gallegos R, Skořepa P, Musil F, Javorská L, Matoušová K, Krčmová LK, Paclíková M, Carazo A, Blaha V, Mladěnka P. Head-to-head ex vivo comparison of clinically used direct anticoagulant drugs. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4461-4470. [PMID: 38112731 DOI: 10.1007/s00210-023-02891-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 12/04/2023] [Indexed: 12/21/2023]
Abstract
An imbalance in coagulation is associated with cardiovascular events. For prevention and treatment, anticoagulants, currently mainly xabans and gatrans, are used. The purpose of the present study was to provide a head-to-head comparison since there are no studies directly evaluating these novel anticoagulants. An additional aim was to find whether selected anthropological and biochemical factors can affect their anticoagulant properties as they are used in fixed doses. In this cross-sectional study, blood from 50 generally healthy donors was collected, and coagulation responses to dabigatran, argatroban, rivaroxaban, and apixaban, at a concentration of 1 μM, were analyzed. Heparin was used as a positive control. Prothrombin time (PT) expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were measured and compared. Rivaroxaban was the most active according to PT/INR while argatroban according to aPTT. The ex vivo anticoagulant effect measured by INR correlated inversely with body mass index (BMI) in all four anticoagulants tested. Shortening of aPTT was associated with higher cholesterol and triglyceride levels. No sex-related differences were observed in response to the anticoagulant treatments. As this was an ex vivo study and pharmacokinetic factors were not included, the influence of BMI is of high therapeutic importance.
Collapse
Affiliation(s)
- Jaka Fadraersada
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Raúl Alva-Gallegos
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Pavel Skořepa
- 3rd Department of Internal Medicine-Metabolic Care and Gerontology, University Hospital and Faculty of Medicine in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic
- Department of Military Internal Medicine and Military Hygiene, Faculty of Military Health Sciences, University of Defence, Hradec Králové, Czech Republic
| | - František Musil
- Department of Occupational Medicine, University Hospital and Faculty of Medicine in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic
| | - Lenka Javorská
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Kateřina Matoušová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - Lenka Kujovská Krčmová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Hradec Králové, Czech Republic
- Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Markéta Paclíková
- 3rd Department of Internal Medicine-Metabolic Care and Gerontology, University Hospital and Faculty of Medicine in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic
| | - Alejandro Carazo
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic
| | - Vladimír Blaha
- 3rd Department of Internal Medicine-Metabolic Care and Gerontology, University Hospital and Faculty of Medicine in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
| |
Collapse
|
|
14
|
Sulaiman KA, Aljuhani O, Alkofide H, Aljohani MA, Badreldin HA, Al Harbi M, Aquil G, Alhajaji R, Alqahtani RA, Babonji A, Altuwayr M, Alshehri AA, Alfaifi M, Alharthi AF, Alzahrani M, Al Sulaiman T, Alqahtani N, Alshahrani WA, Al Katheri A, Albekairy AM. Evaluation of Apixaban standard dosing in underweight patients with non-valvular atrial fibrillation: a retrospective cohort study. Thromb J 2024; 22:43. [PMID: 38778323 PMCID: PMC11110266 DOI: 10.1186/s12959-024-00613-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Recent guidelines recommend using direct oral anticoagulants (DOACs) as first-line agents in patients with non-valvular atrial fibrillation (NVAF). Research is currently investigating the use of Apixaban in underweight patients, with some results suggesting altered pharmacokinetics, decreased drug absorption, and potential overdosing in this population. This study examined the effectiveness and safety of standard Apixaban dosing in adult patients with atrial NVAF weighing less than 50 kg. METHODS This is a retrospective cohort study conducted at King Abdulaziz Medical City (KAMC); adult patients with a body mass index (BMI) below 25 who received a standard dose of Apixaban (5 mg twice daily) were categorized into two sub-cohorts based on their weight at the time of Apixaban initiation. Underweight was defined as patients weighing ≤ 50 kg, while the control group (Normal weight) comprised patients weighing > 50 kg. We followed the patients for at least one year after Apixaban initiation. The study's primary outcome was the incidence of stroke events, while secondary outcomes included bleeding (major or minor), thrombosis, and venous thromboembolism (VTE). Propensity score (PS) matching with a 1:1 ratio was used based on predefined criteria and regression model was utilized as appropriate. RESULTS A total of 1,433 patients were screened; of those, 277 were included according to the eligibility criteria. The incidence of stroke events was lower in the underweight than in the normal weight group at crude analysis (0% vs. 9.1%) p-value = 0.06), as well in regression analysis (OR (95%CI): 0.08 (0.001, 0.76), p-value = 0.002). On the other hand, there were no statistically significant differences between the two groups in the odds of major and minor bleeding (OR (95%CI): 0.39 (0.07, 2.03), p-value = 0.26 and OR (95%CI): 1.27 (0.56, 2.84), p-value = 0.40, respectively). CONCLUSION This exploratory study revealed that underweight patients with NVAF who received standard doses of Apixaban had fewer stroke events compared to normal-weight patients, without statistically significant differences in bleeding events. To confirm these findings, further randomized controlled trials with larger sample sizes and longer observation durations are required.
Collapse
Affiliation(s)
- Khalid Al Sulaiman
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
- College of Pharmacy, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh, 11426, Saudi Arabia.
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
- Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia.
- Saudi Society for Multidisciplinary Research Development and Education (SCAPE Society), Riyadh, Saudi Arabia.
| | - Ohoud Aljuhani
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hadeel Alkofide
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Drug Regulation Research Unit, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Manal A Aljohani
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Hisham A Badreldin
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Pharmacy, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh, 11426, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Mahasen Al Harbi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Ghalia Aquil
- Pharmaceutical Care Department, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Raghad Alhajaji
- Public Health Department, Makkah Health Affairs, Makkah, Saudi Arabia
- Primary Health Department, Makkah Health Cluster, Makkah, Saudi Arabia
| | - Rahaf A Alqahtani
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Alaa Babonji
- Pharmaceutical Care Department, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | | | - Asma A Alshehri
- Pharmaceutical care departments, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Mashael Alfaifi
- Pharmaceutical Services Administration, King Saud Medical City, Riyadh, Saudi Arabia
| | | | - Mohammed Alzahrani
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Pharmacy, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh, 11426, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Tareq Al Sulaiman
- Department of Orthopedic Surgery, Imam Abdulrahman Al Faisal Hospital, Riyadh, Saudi Arabia
| | | | - Walaa A Alshahrani
- College of Pharmacy, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh, 11426, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
| | - Abdulmalik Al Katheri
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Pharmacy, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh, 11426, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Abdulkareem M Albekairy
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Pharmacy, Ministry of National Guard Health Affairs (MNGHA), King Saud bin Abdulaziz University for Health Sciences, PO Box 22490, Riyadh, 11426, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| |
Collapse
|
|
15
|
Shaikh F, Wynne R, L. Castelino R, Inglis SC, Davidson PM, Ferguson C. Direct oral anticoagulant use in hospitalized patients with atrial fibrillation across body mass index categories: design and rationale for a retrospective cohort study. Ther Adv Drug Saf 2024; 15:20420986241227014. [PMID: 38300763 PMCID: PMC10823844 DOI: 10.1177/20420986241227014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
Background Atrial fibrillation (AF) and obesity are common conditions globally; yet, there remains suboptimal pharmacological management contributing to high rates of hospitalization in patients with AF. The altered pathophysiology of both obese and underweight individuals may influence the pharmacology of medications, including those used to manage AF. This, in turn, increases the risk of adverse events and impacts patient risk for stroke and rehospitalization. Despite the well-established complications of obesity, research investigating the relationship between obesity and AF is scant. Objectives The primary aim of this study is to describe cardiovascular-related hospitalization in AF patients according to BMI categories. A secondary aim is to describe anticoagulant and antiarrhythmic prescribing practice patterns in patients with AF, according to the BMI category. Design A retrospective, exploratory descriptive observational cohort study, using routinely collected electronic medical record data from five public hospitals within a single health district, with a population dominantly that is culturally and linguistically diverse, and has a low socioeconomic status. Methods and analysis Data extraction will include a 24-month period (January 2017 to December 2018) with a 12-month follow-up. All adult (⩾18 years) patients at discharge diagnosed with AF, prescribed any oral anticoagulant and/or oral rate/rhythm control agent, will be eligible for inclusion. Ethics and dissemination Ethics approval from the health district and the University of Wollongong has been granted. Findings will seek to demonstrate associations between management strategies and patient outcomes, as well as describe patterns of acute care management from prescribers. These data will be used to inform and generate hypotheses for large-scale studies examining the impact of body weight on anticoagulation prescribing at national and global scales.
Collapse
Affiliation(s)
- Fahad Shaikh
- School of Nursing, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
| | - Rochelle Wynne
- School of Nursing, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
- The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Ronald L. Castelino
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Pharmacy Department, Blacktown Hospital, Western Sydney Local Health District, Blacktown, NSW, Australia
| | - Sally C. Inglis
- Improving Palliative, Aged and Chronic Care through Clinical Research and Translation (IMPACCT), University of Technology Sydney, Sydney, NSW, Australia
| | | | - Caleb Ferguson
- Centre for Chronic & Complex Care Research, Blacktown Hospital, Western Sydney Local Health District, Blacktown, NSW, Australia
- School of Nursing, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia
| |
Collapse
|
|
16
|
Yu M, Li X, Zong L, Wang Z, Lv Q. A Novel Body Mass Index-Based Thromboembolic Risk Score for Overweight Patients with Nonvalvular Atrial Fibrillation. Anatol J Cardiol 2024; 28:35-43. [PMID: 37961898 PMCID: PMC10796238 DOI: 10.14744/anatoljcardiol.2023.3373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 09/15/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND A novel risk prediction model appears to be urgently required to improve the assessment of thrombotic risk in overweight patients with nonvalvular atrial fibrillation (NVAF). We developed a novel body mass index (BMI)-based thromboembolic risk score (namely AB2S score) for these patients. METHODS A total of 952 overweight patients with NVAF were retrospectively enrolled in this study with a 12-month follow-up. The primary endpoint was 1-year systemic thromboembolism and the time to thrombosis (TTT). The candidate risk variables identified by logistic regression analysis were included in the final nomogram model to construct AB2S score. The measures of model fit were evaluated using area under the curve (AUC), C-statistic, and calibration curve. The performance comparison of the AB2S score to the CHADS2 and CHA2DS2-VASc score was performed in terms of the AUC and decision analysis curve (DAC). RESULTS The AB2S score was constructed using 7 candidate risk variables, including a 3-category BMI (25 to 30, 30 to 34, or ≥35 kg/m2). It yielded a c-index of 0.885 (95% CI, 0.814-0.954) and an AUC of 0.885 (95% CI, 0.815-0.955) for predicting 1-year systemic thromboembolism in patients with NVAF. Compared to the CHADS2 score and CHA2DS2-VASc score, the AB2S score had greater AUC and DAC values in predicting the thromboembolic risk and better risk stratification in TTT (P <.0001, P =.082, respectively). CONCLUSION Our results highlighted the importance of a BMI-based AB2S score in determining systemic thromboembolism risk in overweight patients with NVAF, which may aid in decision-making for these patients to balance the effectiveness of anticoagulation from the underlying thrombotic risk.
Collapse
Affiliation(s)
- Meixiang Yu
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoye Li
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liuliu Zong
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zi Wang
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qianzhou Lv
- Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
17
|
Laporte S, Benhamou Y, Bertoletti L, Frère C, Hanon O, Couturaud F, Moustafa F, Mismetti P, Sanchez O, Mahé I. Management of cancer-associated thromboembolism in vulnerable population. Arch Cardiovasc Dis 2024; 117:45-59. [PMID: 38065754 DOI: 10.1016/j.acvd.2023.11.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 11/17/2023] [Indexed: 12/27/2023]
Abstract
Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data, on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with CAT on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR<30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (<50,000 platelets/μL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.
Collapse
Affiliation(s)
- Silvy Laporte
- SAINBIOSE Inserm, unité de recherche clinique, innovation et pharmacologie, hôpital Nord, université Jean-Monnet, CHU de Saint-Étienne, Saint-Étienne, France; F-CRIN INNOVTE network, Saint-Étienne, France.
| | - Ygal Benhamou
- UNI Rouen U1096, service de médecine interne, Normandie université, CHU Charles-Nicolle, Rouen, France; F-CRIN INNOVTE network, Saint-Étienne, France
| | - Laurent Bertoletti
- Service de médecine vasculaire et thérapeutique, CHU de Saint-Étienne, INSERM, UMR1059, Equipe Dysfonction Vasculaire et Hémostase, Université Jean-Monnet, INSERM, CIC-1408, CHU Saint-Étienne, Saint-Étienne, France; F-CRIN INNOVTE network, Saint-Étienne, France
| | - Corinne Frère
- Inserm UMRS 1166, GRC 27 GRECO, DMU BioGeMH, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, Paris, France
| | - Olivier Hanon
- Service de Gérontologie, hôpital Broca, AP-HP, EA 4468, Université de Paris Cité, Paris, France
| | - Francis Couturaud
- Inserm U1304 - GETBO, département de médecine interne, médecine vasculaire et pneumologie, université de Brest, CHU de Brest, Brest, France; F-CRIN INNOVTE network, Saint-Étienne, France
| | - Farès Moustafa
- Inrae, UNH, département urgence, hôpital de Clermont-Ferrand, université Clermont Auvergne, Clermont-Ferrand, France; F-CRIN INNOVTE network, Saint-Étienne, France
| | - Patrick Mismetti
- Service de Médecine Vasculaire et Thérapeutique, CHU Saint-Etienne, Hôpital Nord, Saint-Étienne, France; F-CRIN INNOVTE network, Saint-Étienne, France
| | - Olivier Sanchez
- Université Paris Cité, Inserm UMR S1140, innovations thérapeutiques en hémostase, Paris, France; Service de pneumologie et de soins intensifs, hôpital européen Georges-Pompidou, AP-HP, Paris, France; F-CRIN INNOVTE network, Saint-Étienne, France
| | - Isabelle Mahé
- Université Paris Cité, Inserm UMR S1140, innovations thérapeutiques en hémostase, Paris, France; Service de médecine interne, hôpital Louis-Mourier, AP-HP, Colombes, France; F-CRIN INNOVTE network, Saint-Étienne, France
| |
Collapse
|
|
18
|
Hindley B, Lip GYH, McCloskey AP, Penson PE. Pharmacokinetics and pharmacodynamics of direct oral anticoagulants. Expert Opin Drug Metab Toxicol 2023; 19:911-923. [PMID: 37991392 DOI: 10.1080/17425255.2023.2287472] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 11/21/2023] [Indexed: 11/23/2023]
Abstract
INTRODUCTION Direct oral anticoagulants (DOACs) have overtaken vitamin K antagonists to become the most widely used method of anticoagulation for most indications. Their stable and predictable pharmacokinetics combined with relatively simple dosing, and the absence of routine monitoring has made them an attractive proposition for healthcare providers. Despite the benefits of DOACs as a class, important differences exist between individual DOAC drugs in respect of their pharmacokinetic and pharmacodynamic profiles with implications for dosing and reversal in cases of major bleeding. AREAS COVERED This review summarizes the state of knowledge relating to the pharmacokinetics of dabigatran (factor IIa/thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (factor Xa) inhibitors. We focus on pharmacokinetic differences between the drugs which may have clinically significant implications. EXPERT OPINION Patient-centered care necessitates a careful consideration of the pharmacokinetic and pharmacodynamic differences between DOACs, and how these relate to individual patient circumstances. Prescribers should be aware of the potential for pharmacokinetic drug interactions with DOACs which may influence prescribing decisions in patients with multiple comorbidities. In order to give an appropriate dose of DOAC drugs, accurate estimation of renal function using the Cockcroft-Gault formula using actual body weight is necessary. An increasing body of evidence supports the use of DOACs in patients who are obese, and this is becoming more routine in clinical practice.
Collapse
Affiliation(s)
- B Hindley
- Pharmacy Department, Aintree University Hospital, Liverpool, UK
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - G Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
- Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - A P McCloskey
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
| | - P E Penson
- Clinical Pharmacy and Therapeutics Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
| |
Collapse
|
|
19
|
Alalawneh M, Rachid O, Abdallah I, Mahfouz A, Elewa H, Danjuma MIM, Mohamed AE, Awaisu A. Trends in prescribing and outcomes in obese versus non-obese patients receiving rivaroxaban therapy: an observational study using real-world data. Eur J Clin Pharmacol 2023; 79:1675-1685. [PMID: 37816816 PMCID: PMC10663176 DOI: 10.1007/s00228-023-03572-7] [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: 06/17/2023] [Accepted: 09/17/2023] [Indexed: 10/12/2023]
Abstract
PURPOSE To investigate real-world prescribing trends and clinical outcomes based on body mass index (BMI) categorization in patients who received rivaroxaban therapy. METHODS This was a retrospective cohort study involving all patients who received rivaroxaban therapy across all Hamad Medical Corporation (HMC) hospitals from 2015 to 2020. RESULTS The number of patients initiated on rivaroxaban therapy significantly increased from 152 (3.3%) in 2015 to 1342 (28.9%) in 2020 (p <0.001). Within BMI categories, a similar increasing trend was observed in underweight, normal, and overweight patients, while from 2018 to 2020, there was a decreasing trend in rivaroxaban prescribing in all obese classes. The prevalence rate of all-cause mortality differed significantly between the BMI groups, with the highest mortality being among morbidly obese patients (BMI ≥ 40 kg/m2) (p< 0.001). On the other hand, no significant differences were found between the BMI groups in terms of bleeding, pulmonary embolism, deep vein thrombosis and stroke incidences. Multivariate logistic regression analyses showed that the likelihood of all-cause mortality was significantly higher in overweight and all categories of obese patients compared to underweight patients: overweight (OR: 5.3, 95% CI: 2.3-11.9, p< 0.001); obese class 1 (OR: 5.4, 95% CI: 2.3 - 12.2, p< 0.001); obese class 2 (OR: 6.5, 95% CI: 2.7 - 15.6, p< 0.001); and obese class 3 (OR: 3.7, 95% CI: 1.6 - 8.7, p = 0.003). CONCLUSIONS Rivaroxaban prescribing has significantly increased over the years across general population, with a noticeable decline in obese population during the last few years (from 2018 onwards). Furthermore, an appreciable association was evident between all-cause mortality and BMI of these patients.
Collapse
Affiliation(s)
- Majdoleen Alalawneh
- College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Ousama Rachid
- College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Ibtihal Abdallah
- Clinical Pharmacy Services, Hamad General Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Ahmed Mahfouz
- Pharmacy Department, Heart Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Hazem Elewa
- College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Mohammed Ibn-Mas'ud Danjuma
- Department of Internal Medicine, Hamad General Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Asmaa Ezzeldin Mohamed
- Clinical Pharmacy Services, Hamad General Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Ahmed Awaisu
- College of Pharmacy, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
| |
Collapse
|
|
20
|
Speed V, Czuprynska J, Patel JP, Arya R. Use of direct oral anticoagulants for venous thromboembolism treatment at extremes of body weight, renal and liver function: an illustrated review. Res Pract Thromb Haemost 2023; 7:102240. [PMID: 38193047 PMCID: PMC10772894 DOI: 10.1016/j.rpth.2023.102240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/07/2023] [Accepted: 10/19/2023] [Indexed: 01/10/2024] Open
Abstract
Direct oral anticoagulants (DOACs) have been a welcome addition to clinical practice due to the practical advantages they confer over traditional anticoagulants. In many countries, DOACs are now used as first-line treatment for the management of venous thromboembolism (VTE). Traditional anticoagulants allow for a degree of individualization, either through monitoring the international normalized ratio in the case of vitamin-K antagonists or through dose titration according to bodyweight in the case of low-molecular-weight heparin. However, the use of fixed doses and removal of the need for routine monitoring has created uncertainty in prescribing DOACs for patients at the extremes of bodyweight, renal function, and patients with liver impairment, who were not well represented in the DOAC licensing clinical trials. The discipline of pharmacokinetics is concerned with the movement of drugs through the body. Although the extremes of bodyweight and renal and liver function will influence the pharmacokinetics of DOACs, are these changes significant enough to affect clinical outcomes of bleeding and thrombosis? In other words, can the fixed-dosing strategy of DOACs accommodate these differences in physiology? In this review, we recap key pharmacokinetic principles for drug dosing; review venous thromboembolism trial and real-world data on patients prescribed DOACs at the extremes of bodyweight, renal function, and liver function; relate this to the pharmacokinetic properties of DOACs; and summarize the state of the field and current unknowns.
Collapse
Affiliation(s)
- Victoria Speed
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
- Bennett Institute for Applied Data Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Julia Czuprynska
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
| | - Jignesh P. Patel
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
- Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Roopen Arya
- King’s Thrombosis Centre, Department of Haematological Medicine, King’s College Hospital Foundation NHS Trust, London, United Kingdom
| |
Collapse
|
|
21
|
Park DY, An S, Arif AW, Sana MK, Vij A. Factor Xa inhibitors versus vitamin K antagonist in morbidly obese patients with venous thromboembolism: a systematic review and meta-analysis. BMC Cardiovasc Disord 2023; 23:100. [PMID: 36814196 PMCID: PMC9945392 DOI: 10.1186/s12872-023-03067-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 01/13/2023] [Indexed: 02/24/2023] Open
Abstract
INTRODUCTION Guidelines have endorsed non-vitamin K antagonist oral anticoagulants (NOACs), consisting of factor Xa inhibitors (xabans) and direct thrombin inhibitors, as the first line of treatment in venous thromboembolism (VTE) and atrial fibrillation. However, morbidly obese patients were under-represented in landmark trials of NOACs. Therefore, this study aimed to systematically review and perform a meta-analysis of studies on xabans versus vitamin K antagonist (VKA) in this high-risk population with VTE. METHODS PubMed, Embase, Medline, Cochrane library, and Google Scholar databases were searched to identify studies that compared xabans and VKA in treating morbidly obese patients with VTE. Morbid obesity was defined as body weight ≥ 120 kg or BMI ≥ 40 kg/m2. Outcomes of interest included recurrent VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB). RESULTS Eight studies comprising 30,895 patients were included. A total of 12,755 patients received xabans while 18,140 received VKAs. No significant difference in the odds of recurrent VTE (OR 0.75, 95% CI 0.55-1.01) and CRNMB (OR 0.69, 95% CI 0.44-1.09) was observed between the xabans group and the VKA group. However, the xabans group was associated with lower odds of major bleeding (OR 0.70, 95% CI 0.59-0.83). CONCLUSION Xabans have lower odds of major bleeding but similar odds of recurrent VTE when compared with VKAs in treating VTE in morbidly obese patients. Large registry analyses or future randomized controlled trials will be helpful in confirming these findings.
Collapse
Affiliation(s)
- Dae Yong Park
- Department of Medicine, John H. Stroger Jr Hospital of Cook County, Chicago, IL, USA
| | - Seokyung An
- Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
| | - Abdul Wahab Arif
- Department of Medicine, John H. Stroger Jr Hospital of Cook County, Chicago, IL, USA
| | - Muhammad Khawar Sana
- Department of Medicine, John H. Stroger Jr Hospital of Cook County, Chicago, IL, USA
| | - Aviral Vij
- Division of Cardiology, Cook County Health, Chicago, IL, USA. .,Division of Cardiology, Rush Medical College, Chicago, IL, USA.
| |
Collapse
|
|
22
|
Zhao Y, Guo M, Li D, Xu W, Pan C, He C, Cui X. Pharmacokinetics and Dosing Regimens of Direct Oral Anticoagulants in Morbidly Obese Patients: An Updated Literature Review. Clin Appl Thromb Hemost 2023; 29:10760296231153638. [PMID: 36760080 PMCID: PMC9943962 DOI: 10.1177/10760296231153638] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Data on the impact of morbid obesity (body mass index [BMI] ≥ 40 kg/m2) on the pharmacokinetics (PK), pharmacodynamics (PD) of direct oral anticoagulants (DOACs) are relatively limited, making it difficult to design optimal dosing regimens in morbidly obese patients.To review literature on PK/PD profile, efficacy, and safety of DOACs in venous thromboembolism (VTE) and nonvalvular atrial fibrillation (AF) patients with morbid obesity and make recommendations regarding optimal dosing regimens in these patient populations.A detailed literature search was conducted (from inception to June 22, 2022) for relevant articles involving PK/PD and clinical data on DOACs use in morbidly obese patients with VTE or AF, or healthy volunteers.A total of 28 studies were identified. DOAC-specific PK variations and clinical outcomes have been observed. Obesity may have a modest effect on PK/PD of dabigatran, apixaban, or rivaroxaban. Dabigatran was effective in AF patients with morbid obesity but might increase the risk of gastrointestinal bleeding. Standard dosing of apixaban or rivaroxaban is effective and safe for VTE and AF patients with morbid obesity. Trough edoxaban concentration and anti-Xa activity were similar in different BMI groups (18.5 to >40 kg/m2), and standard dosing of edoxaban may be effective and safe for AF patients.Current evidence suggests dabigatran should be used with caution in patients with AF as it might increase the risk of gastrointestinal bleeding; Standard dosing of apixaban or rivaroxaban can be used in VTE or AF patients; Standard dosing of edoxaban may be considered in AF patients.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Xiangli Cui
- Xiangli Cui, Department of Pharmacy,
Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
23
|
Carbone A, Bottino R, D’Andrea A, Russo V. Direct Oral Anticoagulants for Stroke Prevention in Special Populations: Beyond the Clinical Trials. Biomedicines 2023; 11:131. [PMID: 36672639 PMCID: PMC9856013 DOI: 10.3390/biomedicines11010131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/19/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Currently, direct oral anticoagulants (DOACs) are the first-line anticoagulant strategy in patients with non-valvular atrial fibrillation (NVAF). They are characterized by a more favorable pharmacological profile than warfarin, having demonstrated equal efficacy in stroke prevention and greater safety in terms of intracranial bleeding. The study population in the randomized trials of DOACs was highly selected, so the results of these trials cannot be extended to specific populations such as obese, elderly, frail, and cancer patients, which, on the other hand, are sub-populations widely represented in clinical practice. Furthermore, due to the negative results of DOAC administration in patients with mechanical heart valves, the available evidence in subjects with biological heart valves is still few and often controversial. We sought to review the available literature on the efficacy and safety of DOACs in elderly, obese, underweight, frail, cancer patients, and in patients with bioprosthetic heart valves with NVAF to clarify the best anticoagulant strategy in these special and poorly studied subpopulations.
Collapse
Affiliation(s)
- Andreina Carbone
- Department of Cardiology, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy
| | - Roberta Bottino
- Department of Cardiology, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy
| | - Antonello D’Andrea
- Unit of Cardiology and Intensive Coronary Care, “Umberto I” Hospital, 84014 Nocera Inferiore, Italy
| | - Vincenzo Russo
- Department of Cardiology, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy
- Monaldi Hospital, P.zzale Ettore Ruggeri, 80131 Naples, Italy
| |
Collapse
|
|
24
|
Wang TF. The 5 most frequently asked questions about factor Xa inhibitors. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2022; 2022:515-521. [PMID: 36485108 PMCID: PMC9821165 DOI: 10.1182/hematology.2022000385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Direct oral anticoagulants (DOACs) are commonly used oral factor Xa inhibitors in recent years. However, in some special clinical situations, the appropriate use of these anticoagulants may be of concern. In this article, we address the 5 commonly asked questions regarding their use for the treatment of venous thromboembolism, including in the setting of obesity, renal impairment, gastrointestinal (GI) malignancy, catheter-related thrombosis, and drug-drug interactions. Data on the use of DOACs in the presence of significant obesity or renal failure are mainly observational. Some DOACs are shown to have an increased risk of bleeding in patients with unresected luminal GI malignancy but not others, so selection of appropriate patients is the key. Furthermore, literature on the use of DOACs for catheter-related thrombosis or when drug-drug interactions are of concern is limited, and more research is welcome.
Collapse
Affiliation(s)
- Tzu-Fei Wang
- Correspondence Tzu-Fei Wang, The Ottawa Hospital, General Campus, 501 Smyth Road, Box 201A, Ottawa, ON K1H 8L6, Canada; e-mail:
| |
Collapse
|
|
25
|
Samoš M, Bolek T, Stančiaková L, Péč MJ, Brisudová K, Škorňová I, Staško J, Mokáň M, Kubisz P. Tailored Direct Oral Anticoagulation in Patients with Atrial Fibrillation: The Future of Oral Anticoagulation? J Clin Med 2022; 11:jcm11216369. [PMID: 36362597 PMCID: PMC9655219 DOI: 10.3390/jcm11216369] [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: 09/14/2022] [Revised: 10/17/2022] [Accepted: 10/26/2022] [Indexed: 11/24/2022] Open
Abstract
Direct oral anticoagulants (DOAC) are currently the drug of choice for drug prevention of stroke or systemic embolism in patients with atrial fibrillation (AF). However, repeated ischemic stroke or systemic embolism and bleeding while on DOAC is still a challenging clinical phenomenon in the management of future long-term anticoagulation. It is not known whether tailoring the DOAC therapy to achieve optimal therapeutic drug levels could improve the clinical course of DOAC therapy. To be able to tailor the therapy, it is necessary to have a valid laboratory method for DOAC level assessment, to be aware of factors influencing DOAC levels and to have clinical options to tailor the treatment. Furthermore, the data regarding clinical efficacy/safety of tailored DOAC regimes are still lacking. This article reviews the current data on tailored direct oral anticoagulation in patients with AF.
Collapse
Affiliation(s)
- Matej Samoš
- Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03659 Martin, Slovakia
- Correspondence: ; Tel.: +421-907-612-943 or +421-43-4203-820
| | - Tomáš Bolek
- Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03659 Martin, Slovakia
| | - Lucia Stančiaková
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Blood, Transfusion, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Martin Jozef Péč
- Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03659 Martin, Slovakia
| | - Kristína Brisudová
- Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03659 Martin, Slovakia
| | - Ingrid Škorňová
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Blood, Transfusion, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Ján Staško
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Blood, Transfusion, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Marián Mokáň
- Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03659 Martin, Slovakia
| | - Peter Kubisz
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Blood, Transfusion, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia
| |
Collapse
|
|
26
|
Erstad BL, Barletta JF. Dilemmas Related to Direct-Acting Oral Anticoagulant Administration in Patients With Extreme Obesity. Ann Pharmacother 2022; 57:727-737. [PMID: 36258660 DOI: 10.1177/10600280221130456] [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: 11/16/2022] Open
Abstract
OBJECTIVE The objective of the study was to discuss the controversies surrounding the use and dosing of direct-acting oral anticoagulants (DOACs) in obese patients recognizing the limitations of the existing evidence base that preclude strong recommendations. DATA SOURCES A literature search of MEDLINE was performed (2020 to end August 2022) subsequent to recent guidelines using the following search terms: direct acting anticoagulants, obesity, rivaroxaban, apixaban, edoxaban, dabigatran, dabigatran etexilate, and clinical practice guidelines. STUDY SELECTION AND DATA ABSTRACTION English-language studies and those conducted in adults were selected. DATA SYNTHESIS The available randomized studies evaluating DOACs had relatively small numbers of patients with more extreme forms of obesity (body mass index [BMI] > 40 kg/m2) and none of the larger studies had a specific focus on dosing DOACs in obese patients. Recent guidelines by the International Society on Thrombosis and Haemostasis (ISTH) have specific recommendations for dosing DOACs in obesity. There are pharmacokinetic/pharmacodynamic and observational studies published before and after the ISTH guidelines with a focus on DOAC dosing in obese patients that generally support the recommendations in the guidelines, but most involved small numbers of patients usually with BMIs <45 kg/m2. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE This review discusses DOAC dosing in obesity with important considerations for clinicians related to DOAC choice and dosing. CONCLUSIONS Dosing alterations of DOACs do not appear to be necessary when used for either prophylaxis or treatment in patients with BMIs up to approximately 45 to 50 kg/m2, but research is needed for BMIs >50 kg/m2.
Collapse
Affiliation(s)
- Brian L Erstad
- Department of Pharmacy Practice and Science, The University of Arizona, Tucson, AZ, USA
| | - Jeffrey F Barletta
- Department of Pharmacy Practice, College of Pharmacy-Glendale Campus, Midwestern University, Glendale, AZ, USA
| |
Collapse
|
|
27
|
Mausteller KG, Eisele CD, Julian K, Patel P, Bansal A, Jain R, Jain R. Anticoagulation and BMI: effect of high body weight on the safety and efficacy of direct oral anticoagulants. Future Cardiol 2022; 18:829-837. [PMID: 36052844 DOI: 10.2217/fca-2021-0146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Obesity is an epidemic with rising prevalence, and obese patients are predisposed to comorbid conditions that increase risk for thromboembolic events. It is critical to identify safe and effective anticoagulation therapy for use in this population. Direct oral anticoagulants (DOACs) are a preferred option for anticoagulation in patients of normal weight due to many benefits and equivalent safety and efficacy to their vitamin K antagonist counterparts. However, the safety and efficacy of DOACs in obese patients is not well understood. This review describes recent studies on the pharmacokinetics, safety and efficacy, and clinical outcomes of the DOACs apixaban, rivaroxaban, edoxaban and dabigatran in obese patient populations. DOACs may be a beneficial alternative to vitamin K antagonist therapy in obese patient populations.
Collapse
Affiliation(s)
| | | | | | - Puja Patel
- Department of Internal Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA 17033, USA
| | - Amit Bansal
- UHS Wilson Medical Center, Johnson City, NY 13790, USA
| | - Rahul Jain
- Division of Cardiology, University of Missouri Columbia Healthcare, Columbia, MO 65212, USA
| | - Rohit Jain
- Department of Internal Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA 17033, USA
| |
Collapse
|
|
28
|
Ishii M, Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, Tsujita K, AFIRE Investigators. Rivaroxaban Monotherapy in Atrial Fibrillation and Stable Coronary Artery Disease Across Body Mass Index Categories. JACC. ASIA 2022; 2:882-893. [PMID: 36713761 PMCID: PMC9876995 DOI: 10.1016/j.jacasi.2022.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/05/2022] [Accepted: 08/18/2022] [Indexed: 02/01/2023]
Abstract
Background The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial showed both noninferiority for efficacy and superiority for safety endpoints of rivaroxaban monotherapy compared with those of rivaroxaban plus antiplatelet therapy (combination therapy) in patients with atrial fibrillation and stable coronary artery disease. Objectives This study sought to evaluate outcomes of rivaroxaban monotherapy in those patients across body mass index (BMI) categories. Methods Patients were categorized into 4 groups: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 to <25 kg/m2), overweight (BMI 25 to <30 kg/m2), and obesity (BMI ≥30 kg/m2). Efficacy (a composite of all-cause death, myocardial infarction, unstable angina requiring revascularization, stroke, or systemic embolism) and safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria) were compared between rivaroxaban monotherapy and combination therapy across BMI categories. Results This study analyzed 2,054 patients with a median age of 75.0 years and CHA2DS2-VASc score of 4. A significant interaction was not observed between BMI categories and effect of monotherapy for efficacy (P = 0.83) and safety (P = 0.07), although monotherapy was superior to combination therapy for efficacy in normal weight (HR: 0.64; 95% CI: 0.44-0.95) and safety in overweight (HR: 0.25; 95% CI: 0.10-0.62), whereas a significant difference in the endpoints was not observed in the other BMI categories. Conclusions Rivaroxaban monotherapy had a similar effect on prognosis across all BMI categories in patients with atrial fibrillation and stable coronary artery disease. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease [AFIRE]; UMIN000016612, NCT02642419).
Collapse
Affiliation(s)
- Masanobu Ishii
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
| | - Koichi Kaikita
- Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan
- Address for correspondence: Dr Koichi Kaikita, Division of Cardiovascular Medicine and Nephrology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
| | - Satoshi Yasuda
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masaharu Akao
- Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Kyoto, Japan
| | - Junya Ako
- Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Tetsuya Matoba
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
| | - Masato Nakamura
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan
| | - Katsumi Miyauchi
- Department of Cardiovascular Medicine, Juntendo Tokyo Koto Geriatric Medical Center, Koto-ku, Tokyo, Japan
| | - Nobuhisa Hagiwara
- Department of Cardiology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
| | - Kazuo Kimura
- Cardiovascular Center, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
| | - Atsushi Hirayama
- Department of Cardiology, Osaka Police Hospital, Osaka, Osaka, Japan
| | - Kunihiko Matsui
- Department of General Medicine and Primary Care, Kumamoto University Hospital, Kumamoto, Kumamoto, Japan
| | - Hisao Ogawa
- Kumamoto University, Kumamoto, Kumamoto, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
| | | |
Collapse
|
|
29
|
Novak AR, Shakowski C, Trujillo TC, Wright GC, Mueller SW, Kiser TH. Evaluation of safety and efficacy outcomes of direct oral anticoagulants versus warfarin in normal and extreme body weights for the treatment of atrial fibrillation or venous thromboembolism. J Thromb Thrombolysis 2022; 54:276-286. [PMID: 35689140 DOI: 10.1007/s11239-022-02668-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/18/2022] [Indexed: 10/18/2022]
Abstract
Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to measure the impact of DOACs compared to warfarin on safety and efficacy outcomes in extreme body weight patients. This multi-center, health system, retrospective study examined the outcomes of patients with all body weights and extreme body weights prescribed a DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) or warfarin for atrial fibrillation or venous thromboembolism over a 9-year period. The primary outcome was a composite of thromboembolism, symptomatic recurrent VTE, or severe bleeding; analyzed by pre-determined BMI cutoffs. A total of 19,697 patients were included in the study: 11,604 in the DOAC group and in the 8093 in the warfarin group. 295 patients were underweight and 9108 patients were pre-obese to obese class 3. After adjusting for potential confounders, warfarin patients had higher odds of experiencing the composite outcome compared to DOAC patients (OR 1.337, 95% CI 1.212-1.475). Additionally, obese patients were 24.6% more likely to experience the outcome compared to normal BMI patients. Adjusted modeling showed that warfarin patients experienced higher bleed rates compared to DOAC patients (OR 1.432, 95% CI 1.266-1.620). Obese patients were less likely to be diagnosed with a bleed (OR 0.749, 95% CI 0.658-0.854), and underweight patients were more likely to be diagnosed with a bleed (OR 1.522, 95% CI 1.095-2.115) compared to normal BMI patients. In conclusion, DOACs for atrial fibrillation or VTE in patients with extreme body weights appear safe and effective when compared to warfarin.
Collapse
Affiliation(s)
- Alison R Novak
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, C238, Aurora, CO, 80045, USA
- Department of Pharmacy, University of Colorado Hospital, UCHealth, Aurora, CO, USA
| | - Courtney Shakowski
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, C238, Aurora, CO, 80045, USA
- Department of Pharmacy, University of Colorado Hospital, UCHealth, Aurora, CO, USA
| | - Toby C Trujillo
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, C238, Aurora, CO, 80045, USA
| | - Garth C Wright
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, C238, Aurora, CO, 80045, USA
| | - Scott W Mueller
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, C238, Aurora, CO, 80045, USA
- Department of Pharmacy, University of Colorado Hospital, UCHealth, Aurora, CO, USA
| | - Tyree H Kiser
- Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E Montview Blvd, C238, Aurora, CO, 80045, USA.
- Department of Pharmacy, University of Colorado Hospital, UCHealth, Aurora, CO, USA.
| |
Collapse
|
|
30
|
Camm CF, Virdone S, Goto S, Bassand JP, van Eickels M, Haas S, Gersh BJ, Pieper K, Fox KAA, Misselwitz F, Turpie AGG, Goldhaber SZ, Verheugt F, Camm J, Kayani G, Panchenko E, Oh S, Luciardi HL, Sawhney JPS, Connolly SJ, Angchaisuksiri P, ten Cate H, Eikelboom JW, Kakkar AK. Association of body mass index with outcomes in patients with newly diagnosed atrial fibrillation: GARFIELD-AF. Open Heart 2022. [PMCID: PMC9362832 DOI: 10.1136/openhrt-2022-002038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Objective While greater body mass index (BMI) is associated with increased risk of developing atrial fibrillation (AF), the impact of BMI on outcomes in newly diagnosed AF is unclear. We examine the influence of BMI on outcomes and whether this is modified by sex and evaluate the effect of non-vitamin K oral anticoagulants (NOACs) in patients with high BMI. Methods GARFIELD-AF is a prospective registry of 52 057 newly diagnosed AF patients. The study population comprised 40 482 participants: 703 underweight (BMI <18.5 kg/m2), 13 095 normal (BMI=18.5–24.9 kg/m2), 15 043 overweight (BMI=25.0–29.9 kg/m2), 7560 obese (BMI=30.0–34.9 kg/m2) and 4081 extremely obese (BMI ≥35.0 kg/m2). Restricted cubic splines quantified the association of BMI with outcomes. Comparative effectiveness of NOACs and vitamin K antagonists (VKAs) by BMI was performed using propensity score overlap-weighted Cox models. Results The median age of participants was 71.0 years (Q1; Q3 62.0; 78.0), and 55.6% were male. Those with high BMI were younger, more often had vascular disease, hypertension and diabetes. Within 2-year follow-up, a U-shaped relationship between BMI and all-cause mortality was observed, with BMI of ~30 kg/m2 associated with the lowest risk. The association with new/worsening heart failure was similar. Only low BMI was associated with major bleeding and no association emerged for non-haemorrhagic stroke. BMI was similarly associated with outcomes in men and women. BMI did not impact the lower rate of all-cause mortality of NOACs compared with VKAs. Conclusions In the GARFIELD-AF registry, underweight and extremely obese AF patients have increased risk of mortality and new/worsening heart failure compared with normal or obese patients.
Collapse
|
|
31
|
A retrospective cohort study of the effectiveness and safety of dabigatran versus rivaroxaban in overweight patients with nonvalvular atrial fibrillation. Int J Clin Pharm 2022; 44:1149-1157. [DOI: 10.1007/s11096-022-01443-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/09/2022] [Indexed: 11/27/2022]
|
|
32
|
Adeyeye E, Maniero C, Magavern EF, Ferner RE, McGettigan P. Prescribing direct-acting oral anticoagulants - mind the evidence gap. Br J Clin Pharmacol 2022; 88:4724-4731. [PMID: 35771028 DOI: 10.1111/bcp.15450] [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: 03/28/2022] [Revised: 06/16/2022] [Accepted: 06/20/2022] [Indexed: 11/30/2022] Open
Abstract
Direct-acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non-valvular atrial fibrillation amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using 4 clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non-Europid ethnic backgrounds.
Collapse
Affiliation(s)
- Elizabeth Adeyeye
- Department of Clinical Pharmacology, Cardiovascular Medicine, Barts Health NHS Trust, London, UK
| | - Carmela Maniero
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, UK
| | - Emma F Magavern
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, UK
| | - Robin E Ferner
- West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham, UK.,School of Clinical and Experimental Medicine, University of Birmingham, UK
| | - Patricia McGettigan
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, UK
| |
Collapse
|
|
33
|
Anusim N, Ghimire B, Smalley M, Jaiyesimi I, Gaikazian S. Safety and efficacy of Apixaban and Rivaroxaban in obese patients with acute thrombosis/embolism. Eur J Haematol 2022; 109:409-412. [PMID: 35739626 DOI: 10.1111/ejh.13817] [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: 05/22/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Direct oral anticoagulants (DOACs) have significant advantages over vitamin K antagonists in the treatment of venous thromboembolism and as prophylaxis against recurrence. However, there is inadequate data to support the safety and efficacy of DOACs in the morbidly obese, and warfarin treatment is currently recommended by the International Society of Hemostasis and Thrombosis for this population. MATERIALS AND METHODS We performed a retrospective review of outcomes in 499 patients with BMI ≥ 40 kg/m2 admitted from January 2013 to January 2020 with acute venous thromboembolism (VTE) and treated with either rivaroxaban (n=296) or apixaban (n=203). RESULTS There were 38 (7.6%) bleeding and clotting events within 60 days of the initiation of DOACs, of which 35 (7.0%) were bleeding events and 3 (0.6%) were clotting events. Patients treated with rivaroxaban had more bleeding episodes (23, 7.8% vs. 12, 5.9%) and higher mortality (21, 7.1% vs. 13, 6.4%) compared with those treated with apixaban; however, these differences were not statistically significant (p=.427 and p=.764, respectively). Most of the bleeding occurred in the genitourinary and gastrointestinal tracts. CONCLUSIONS Our study indicates that apixaban and rivaroxaban are not associated with an increase in VTE recurrence in the morbidly obese; however, bleeding rates were slightly higher in the rivaroxaban group compared to the apixaban group.
Collapse
Affiliation(s)
- Nwabundo Anusim
- Department of Hematology and Oncology, Beaumont Health, Royal Oak, Michigan, USA
| | - Bipin Ghimire
- Department of Hematology and Oncology, Beaumont Health, Royal Oak, Michigan, USA
| | - Melanie Smalley
- Department of Hematology and Oncology, Beaumont Health, Royal Oak, Michigan, USA
| | - Ishmael Jaiyesimi
- Department of Hematology and Oncology, Beaumont Health, Royal Oak, Michigan, USA
| | - Susanna Gaikazian
- Department of Hematology and Oncology, Beaumont Health, Royal Oak, Michigan, USA
| |
Collapse
|
|
34
|
Humphrey TJ, O'Brien TD, Melnic CM, Verrier KI, Bedair HS, Ahmed KF. Morbidly Obese Patients Undergoing Primary Total Joint Arthroplasty May Experience Higher Rates of Venous Thromboembolism When Prescribed Direct Oral Anticoagulants vs Aspirin. J Arthroplasty 2022; 37:1189-1197. [PMID: 35131389 DOI: 10.1016/j.arth.2022.01.089] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/26/2022] [Accepted: 01/30/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Morbidly obese (body mass index [BMI] >40 kg/m2) patients undergoing total joint arthroplasty (TJA) are at high risk for postoperative venous thromboembolism (VTE); however, there is debate surrounding the optimal pharmacologic agent for prevention of VTE after TJA in this patient subset. Current guidelines recommend against direct-acting oral anticoagulants (DOACs) in patients of BMI >40 kg/m2 due to low quality evidence justifying their use. We evaluated whether patients of BMI >40 kg/m2 undergoing primary unilateral TJA would have increased risk of postoperative VTE if prescribed DOACs compared to non-DOAC agents such as aspirin. METHODS This retrospective study analyzed 897 patients of BMI >40 kg/m2 undergoing primary unilateral TJA. Demographic and comorbidity-related variables were collected. The association between postoperative VTE and prophylactic pharmacologic agent prescribed was evaluated by multivariate logistic regression. RESULTS After controlling for comorbidities, we found that the sole use of DOACs, specifically apixaban, for VTE prophylaxis was associated with an increased risk of developing VTE compared to prophylaxis with aspirin alone in patients of BMI >40 kg/m2 (odds ratio 2.962, P = .016). Regardless of VTE prophylactic agent, patients with BMI >40 kg/m2 undergoing TKA had at least 4.5-fold increased odds of developing VTE compared to patients undergoing THA (OR 4.830, P = .019). CONCLUSION In our retrospective study of a large sample size of patients with BMI >40 kg/m2, we found that the use of DOACs, specifically apixaban, for VTE prophylaxis following TJA was associated with increased odds of a VTE complication compared to the use of aspirin alone.
Collapse
Affiliation(s)
- Tyler J Humphrey
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA; Kaplan Joint Center, Newton-Wellesley Hospital, Newton, MA
| | - Todd D O'Brien
- Department of Orthopaedic Surgery, North Shore Medical Center, Danvers, MA
| | - Christopher M Melnic
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA; Kaplan Joint Center, Newton-Wellesley Hospital, Newton, MA
| | - Kimberly I Verrier
- Department of Orthopaedic Surgery, North Shore Medical Center, Danvers, MA
| | -
- Department of Orthopaedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Quality and Patient Experience, Mass General Brigham, Somerville, MA
| | - Hany S Bedair
- Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA; Kaplan Joint Center, Newton-Wellesley Hospital, Newton, MA
| | | |
Collapse
|
|
35
|
Candeloro M, Eikelboom JW, Chan N, Bhagirath V, Douketis JD, Schulman S. Carbamazepine, phenytoin, and oral anticoagulants: Drug-drug interaction and clinical events in a retrospective cohort. Res Pract Thromb Haemost 2022; 6:e12650. [PMID: 35224414 PMCID: PMC8851583 DOI: 10.1002/rth2.12650] [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: 10/21/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Carbamazepine and phenytoin are potent inducers of enzymes that metabolize oral anticoagulants. OBJECTIVES To determine the clinical impact of drug-drug interactions between these anticonvulsants and oral anticoagulants, and whether they affect the treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). MATERIAL AND METHODS Data on patients cotreated with carbamazepine or phenytoin and an oral anticoagulant were retrospectively retrieved from medical records from 2011 to 2020. Outcomes were time in therapeutic range (TTR), DOAC levels, thromboembolic events, major bleeding, and all-cause mortality. RESULTS Among 85 patients (37% female, median age 68 years) treated with carbamazepine (n = 43 [51%]) or phenytoin (n = 42 [49%]), 53 (62%) were initially treated with VKAs and 32 (38%) with DOACs. TTR in VKA patients was 63%, which improved in year 2. Four of seven trough and five of 12 peak DOAC plasma levels were lower than expected. The incidence rate (95% confidence interval) per 100 person-years for thromboembolism was 3.6 (3.1-4.2) for VKA patients and 4.4 (3.5-5.6) for DOAC patients; for major bleeding 1.8 (1.5-2.1) and 1.5 (1.2-1.9), and for all-cause mortality 3.6 (3.1-4.2) and 1.5 (1.2-1.9), respectively. Incidence rates between VKAs and DOACs and between carbamazepine and phenytoin were similar. CONCLUSION There was a high incidence of thromboembolism in patients cotreated with anticoagulants and carbamazepine or phenytoin. The incidence rates of thrombotic and bleeding events were similar between VKA and DOAC patients. DOAC levels were lower than expected in 47% of cases tested, without correlation with clinical outcomes.
Collapse
Affiliation(s)
- Matteo Candeloro
- Department of Innovative Technologies in Medicine and Dentistry“G. D'Annunzio” UniversityChietiItaly
- Department of Medicine, Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonOntarioCanada
| | - John W. Eikelboom
- Department of Medicine, Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonOntarioCanada
- Population Health Research InstituteMcMaster UniversityHamiltonOntarioCanada
| | - Noel Chan
- Department of Medicine, Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonOntarioCanada
- Population Health Research InstituteMcMaster UniversityHamiltonOntarioCanada
| | - Vinai Bhagirath
- Department of Medicine, Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonOntarioCanada
- Population Health Research InstituteMcMaster UniversityHamiltonOntarioCanada
| | - James D. Douketis
- Department of Medicine, Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonOntarioCanada
| | - Sam Schulman
- Department of Medicine, Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonOntarioCanada
- Department of Obstetrics and GynecologyI.M. Sechenov First Moscow State Medical UniversityMoscowRussia
| |
Collapse
|
|
36
|
Alalawneh M, Awaisu A, Rachid O. Rivaroxaban Pharmacokinetics in Obese Subjects: A Systematic Review. Clin Pharmacokinet 2022; 61:1677-1695. [PMID: 36201149 PMCID: PMC9734246 DOI: 10.1007/s40262-022-01160-z] [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] [Accepted: 07/20/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Venous thromboembolism (VTE) is a leading cause of morbidity and mortality globally. The direct oral anticoagulants, including rivaroxaban, are relatively novel therapeutic options in the treatment and prevention of VTE. There is a conflicting and inconclusive evidence surrounding the pharmacokinetics (PK) of rivaroxaban in patients with VTE who are obese. OBJECTIVES We conducted a systematic review to provide an overview, and to synthesize the available evidence in the current literature pertaining to rivaroxaban PK in obese subjects who are healthy or diseased. METHODS The PubMed, Embase, ScienceDirect, Rayyan, and Cochrane Library databases were systematically searched from 1 May 2021 through 28 February 2022. Studies investigating rivaroxaban PK in adult obese subjects were included in the review. Pertinent data, including anthropometric parameters, rivaroxaban dosage regimen, PK parameters, PK model, and outcome measures were extracted. Reference values of rivaroxaban PK parameters in the general population were used for comparison purposes. The review protocol was registered in the PROSPERO database (CRD42020177770). RESULTS In the 11 studies included in this systematic review, over 7140 healthy or diseased subjects received rivaroxaban therapy, with varying clinical indications in the diseased population. The reported PK parameters of rivaroxaban in obese subjects compared with reference values in the general population were variable. The reported values of the volume of distribution (Vd) among obese subjects (73.4-82.8 L) fell within the range of values reported/calculated for the general population (59.4-104 L), assuming complete bioavailability. However, some of the reported values of clearance (CL) in obese subjects (7.86-16.8 L.h-1) do not fall within the range of values reported/calculated for the general population (5.57-11.3 L.h-1). The reported maximum plasma concentrations in obese subjects versus the general population following a 10 mg dose were 149 vs. 143-180 µg.L-1, and following a 20 mg dose were 214-305 vs. 299-360 µg.L-1, respectively. The area under the plasma concentration versus time curves (AUC) over different intervals in obese subjects versus the general population following a 10 mg dose were 1155 (AUC from time zero to infinity [AUC∞]) vs. 1029 (AUC∞) µg.h.L-1; and 1204-2800 (AUC from time zero to 24 h [AUC24]) vs. 3200 (AUC24) µg.h.L-1, respectively, following a 20 mg dose. The reported values of half-life and time to reach the maximum plasma concentration in obese subjects versus the general population were not consistent across studies. CONCLUSION Variable changes and inconsistencies in different rivaroxaban PK parameters were reported in obese subjects. Further well-designed studies are warranted to better characterize the PK and clinical outcomes of rivaroxaban in subjects with obesity.
Collapse
Affiliation(s)
| | - Ahmed Awaisu
- College of Pharmacy, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| | - Ousama Rachid
- College of Pharmacy, QU Health, Qatar University, PO Box 2713, Doha, Qatar
| |
Collapse
|
|
37
|
Javed A, Ajmal M, Wolfson A. Dabigatran in cardiovascular disease management: A comprehensive review. World J Cardiol 2021; 13:710-719. [PMID: 35070113 PMCID: PMC8716972 DOI: 10.4330/wjc.v13.i12.710] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 09/27/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Dabigatran, a direct thrombin inhibitor, has robust data for the treatment of deep venous thrombosis and pulmonary embolism, stroke prevention in non-valvular atrial fibrillation, and the prophylaxis of venous thromboembolism (VTE) after knee and hip replacement. Recent studies have evaluated dabigatran to determine its safety and efficacy in such conditions as VTE in malignancy, coronary artery disease, mechanical and bioprosthetic valves, and antiphospholipid syndrome. This article provides a comprehensive review on the role of dabigatran in various cardiovascular diseases.
Collapse
Affiliation(s)
- Ayesha Javed
- Department of Internal Medicine, University of Arizona, Tucson, AZ 85719, United States
| | - Muhammad Ajmal
- Department of Cardiology, University of Arizona, Tucson, AZ 85719, United States.
| | - Aaron Wolfson
- Department of Cardiology, University of Southern California, Los Angeles, CA 90007, United States
| |
Collapse
|
|
38
|
Navarro-Almenzar B, Cerezo-Manchado JJ, García-Candel F. Real life behaviour of direct oral anticoagulants in patients with nonvalvular atrial fibrillation and morbid obesity. IJC HEART & VASCULATURE 2021; 37:100913. [PMID: 34825048 PMCID: PMC8603013 DOI: 10.1016/j.ijcha.2021.100913] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 10/17/2021] [Accepted: 10/30/2021] [Indexed: 01/13/2023]
Abstract
Atrial fibrillation (AF) is the most prevalent arrhythmia worldwide and the main cause of anticoagulation, being direct oral anticoagulants (DOAC) increasingly used in this context. On the other hand, obesity is a known risk thromboembolic factor. In the clinical trials that led to the approval of DOAC for ischemic stroke prevention, patients with morbid obesity were underrepresented. The International Society of Thrombosis and Haemostasis suggests not using these drugs in morbid obese patients. Thus, the primary objectives of this study were to analyse the rates of mortality, thrombotic and haemorrhagic events in patients with morbid obesity. As secondary objectives, factors statistically associated with these events were analysed. Methods: multicentre retrospective study that included patients diagnosed with AF on treatment with DOAC from January 2013 to December 2016. The subgroup of patients with morbid obesity (BMI > 40 and / or weight > 120 kg) was analysed. Mean follow-up was 1.7 years. Results: Amongst 2,492 patients included in the study, 135 patients had morbid obesity (mean age was 71 ± 11 years). The mean scores of the CHA2DS2-VASc and HAS-BLED risk scales were 3.7 ± 1.6 and 2.2 ± 0.9, respectively. Neither differences were found regarding mortality (5.2 vs 6/100 patient-years, p = 0.662), ischemic stroke (0.8 vs 1.9/100 patient-years, p = 0.261) and major bleeding rates (3 vs 3.1/100 patient-years, p = 0.983) between morbidly obese population and general population. Nor was there an association found between the degree of obesity and any of the events studied. Conclusion: DOAC are safe and effective in morbidly obese patients.
Collapse
|
|
39
|
Nasser MF, Jabri A, Gandhi S, Rader F. Oral Anticoagulant Use in Morbid Obesity and Post Bariatric Surgery: A Review. Am J Med 2021; 134:1465-1475. [PMID: 34403701 DOI: 10.1016/j.amjmed.2021.07.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 01/06/2023]
Abstract
Bariatric surgery has emerged as a therapy for obesity and the associated comorbidities. Obesity has been shown to be a risk factor for atrial fibrillation as well as venous thromboembolism, both of which are conditions that warrant anticoagulation. There is significant underrepresentation of the morbidly obese population in prospective trials that evaluated direct oral anticoagulants and vitamin K antagonists in atrial fibrillation and venous thromboembolism. We aim to review all the available data that assessed these oral anticoagulants in the morbidly obese population (body mass index >40 kg/m2 and weight >120 kg) and in the post-bariatric surgery population. Our findings suggest that direct oral anticoagulants may be safe and effective for anticoagulation in morbidly obese patients for both atrial fibrillation and venous thromboembolism. However, warfarin is the preferred agent in the post-bariatric surgery population, given the limited number of studies on direct oral anticoagulants in this population. Further adequately powered randomized control trials are needed to confirm the safety and efficacy of these oral anticoagulants in the morbidly obese and post-bariatric surgery population.
Collapse
Affiliation(s)
- Mohamed Farhan Nasser
- Heart and Vascular Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio
| | - Ahmad Jabri
- Heart and Vascular Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio
| | - Sanjay Gandhi
- Heart and Vascular Center, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio.
| | - Florian Rader
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, Calif
| |
Collapse
|
|
40
|
O'Kane CP, Avalon JCO, Lacoste JL, Fang W, Bianco CM, Davisson L, Piechowski KL. Apixaban and rivaroxaban use for atrial fibrillation in patients with obesity and BMI ≥50 kg/m 2. Pharmacotherapy 2021; 42:112-118. [PMID: 34820876 DOI: 10.1002/phar.2651] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/11/2021] [Accepted: 11/23/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Apixaban and rivaroxaban are increasingly used for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation (NVAF) and commonly in patients with obesity and body mass index (BMI) ≥50 kg/m2 despite the limited data. OBJECTIVES This study aimed to establish the effectiveness and safety of apixaban and rivaroxaban in patients with NVAF and BMI ≥50 kg/m2 . METHODS A single health-system, retrospective cohort study evaluated the effectiveness and safety of apixaban and rivaroxaban initiated in adult patients (≥18 years of age) with BMI ≥50 kg/m2 and NVAF. Outcomes of ischemic stroke, systemic embolic events, and bleeding were compared to a cohort of patients with BMI 18 to 30 kg/m2 . RESULTS After 1619 patient-years worth of follow-up in 595 patients, the primary endpoint of incidence of ischemic stroke was numerically similar in both groups, 1.3 per 100 patient-years in the BMI ≥50 kg/m2 group, compared to 2.0 per 100 patient-years in the BMI <30 kg/m2 group (RR 0.65, 95% CI 0.38-1.82, p = 0.544). Incidence of major bleeding and clinically relevant non-major bleeding was also numerically similar between the two groups. CONCLUSIONS This study demonstrated that apixaban and rivaroxaban in patients with a BMI ≥50 kg/m2 for treatment of NVAF may be safe and effective at preventing thromboembolic events and had no increased risk of bleeding. Although, findings should be interpreted with caution and confirmed with additional studies. This study contributes to the growing body of evidence that direct oral anticoagulants (DOACs) may be effective and safe to use for the treatment of NVAF in patients with BMI ≥50 kg/m2 .
Collapse
Affiliation(s)
- Cavan P O'Kane
- Department of Pharmacy, WVU Medicine, Morgantown, West Virginia, USA
| | - Juan Carlo O Avalon
- Department of Internal Medicine, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Jordan L Lacoste
- Department of Pharmacy, WVU Medicine, Morgantown, West Virginia, USA
| | - Wei Fang
- West Virginia Clinical and Translational Science Institute, Morgantown, West Virginia, USA
| | - Christopher M Bianco
- Department of Cardiovascular and Thoracic Surgery, WVU Medicine, Morgantown, West Virginia, USA
| | - Laura Davisson
- Department of Internal Medicine, West Virginia University School of Medicine, Morgantown, West Virginia, USA.,WVU Medicine Medical and Surgical Weight Loss Center's Medical Weight Management Program, Morgantown, West Virginia, USA
| | - Kara L Piechowski
- Department of Pharmacy, WVU Medicine, Morgantown, West Virginia, USA
| |
Collapse
|
|
41
|
Clinical outcomes of dabigatran use in patients with non-valvular atrial fibrillation and weight >120 kg. Thromb Res 2021; 208:176-180. [PMID: 34808409 DOI: 10.1016/j.thromres.2021.11.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/03/2021] [Accepted: 11/11/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Patients with obesity were underrepresented in studies evaluating the safety and effectiveness of direct oral anticoagulants (DOAC) in patients with non-valvular atrial fibrillation (NVAF). This study compared clinical outcomes in patients with NVAF and weighing >120 kg and ≤120 kg who were receiving dabigatran. MATERIALS AND METHODS This retrospective, matched, longitudinal cohort study included patients from three integrated healthcare delivery systems. Patients ≥18 years of age with NVAF were included if between September 1, 2016 and June 30, 2019 they received dabigatran. Patients >120 kg and ≤120 kg were matched up to 1:6 on age, sex, and CHA2DS2-VASc score. Data were extracted from administrative databases. The primary outcome was a composite of ischemic stroke, clinically-relevant bleeding, systemic embolism, and all-cause mortality. Multivariable regression analyses were performed. RESULTS 777 and 3522 patients >120 kg and ≤120 kg, respectively, were matched. The >120 kg group tended to be younger with a higher burden of chronic disease. There was no difference between groups in the composite outcome (adjusted hazard ratio [AHR] 1.10, 95% confidence interval 0.89-1.37) or individual components of the composite. A subanalysis of clinically-relevant bleeding identified that patients >120 kg were at a greater risk of gastrointestinal bleeding (AHR 1.44, 95% CI 1.01-2.05). CONCLUSIONS In patients with NVAF and >120 kg, dabigatran use was associated with a small increased risk of gastrointestinal bleeding but no differences in stroke, mortality or clinically-relevant bleeding. These findings suggest that dabigatran use is reasonable in patients with NVAF and weight >120 kg.
Collapse
|
|
42
|
Ballerie A, Nguyen Van R, Lacut K, Galinat H, Rousseau C, Pontis A, Nédelec-Gac F, Lescoat A, Belhomme N, Guéret P, Mahé G, Couturaud F, Jégo P, Gouin-Thibault I. Apixaban and rivaroxaban in obese patients treated for venous thromboembolism: Drug levels and clinical outcomes. Thromb Res 2021; 208:39-44. [PMID: 34689080 DOI: 10.1016/j.thromres.2021.10.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/24/2021] [Accepted: 10/12/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Direct oral anticoagulants (DOAC) use remains challenging in obese patients treated for Venous-Thrombo-Embolism (VTE) due to the paucity of prospective and dedicated studies. OBJECTIVE To assess rivaroxaban and apixaban concentrations at different time-points after intake, in obese patients followed at a thrombosis center and treated for VTE; to define factors associated with DOAC levels outside the on-therapy ranges; and to evaluate bleeding and thrombosis rates during follow-up. METHODS Observational prospective study in two French University hospitals. Apixaban or rivaroxaban concentrations were measured after the first visit, regardless of last intake in obese patients receiving DOAC for VTE. Concentrations were compared to published reference values for non-obese patients. Demographic, clinical, biological and therapeutic data were collected. Univariate and multivariate analyses were performed to identify factors associated to DOAC concentrations outside the on-therapy ranges. RESULTS Out of the 146 patients included, 22 (15%) had DOAC concentrations outside the on-therapy ranges, mainly in the rivaroxaban group (n = 17). Age ≤ 63 years, use of rivaroxaban and time since last intake ≤8 h were associated with DOAC concentrations outside the on-therapy ranges, in multivariable analysis. During the median follow-up of 16 months, two (1%) patients receiving apixaban had recurrent VTE. No patient had major bleeding, 11 (8%) patients had minor bleeding. CONCLUSION In this specific prospective bi-centric study dedicated to VTE obese patients, use of DOACs at fixed doses led to concentrations similar to those of non-obese patients in a high proportion of patients, without any effect of the BMI, and with risk-benefit profile comparable to non-obese patients.
Collapse
Affiliation(s)
- Alice Ballerie
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France; Univ Rennes, Rennes University Hospital, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France
| | - Rémi Nguyen Van
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France
| | - Karine Lacut
- Department of Internal Medecine and Chest Diseases, Brest University Hospital, Bretagne Occidentale University, EA 3878, CIC INSERM 1412, Brest, FCRIN INNOVTE, France
| | - Hubert Galinat
- Hematology Laboratory, Brest University Hospital, Bretagne Occidentale University, EA 3878, Brest, France
| | - Chloé Rousseau
- Clinical Investigation Center INSERM 1414, Department of Clinical Pharmacology, Rennes University Hospital, F-35033, France
| | - Adeline Pontis
- Hematology Laboratory, Rennes University Hospital, Rennes, France
| | | | - Alain Lescoat
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France; Univ Rennes, Rennes University Hospital, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France
| | - Nicolas Belhomme
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France
| | - Pierre Guéret
- Hematology Laboratory, Rennes University Hospital, Rennes, France
| | - Guillaume Mahé
- Vascular Medicine Unit, Rennes University Hospital, INSERM CIC 1414, Clinical Investigation Center, Univ Rennes, M2S - EA 7470, F-35033 Rennes, France
| | - Francis Couturaud
- Department of Internal Medecine and Chest Diseases, Brest University Hospital, Bretagne Occidentale University, EA 3878, CIC INSERM 1412, Brest, FCRIN INNOVTE, France
| | - Patrick Jégo
- Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France; Univ Rennes, Rennes University Hospital, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France
| | - Isabelle Gouin-Thibault
- Univ Rennes, Rennes University Hospital, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France; Hematology Laboratory, Rennes University Hospital, Rennes, France.
| |
Collapse
|
|
43
|
Kampouraki E, Avery P, Biss T, Wynne H, Kamali F. Assessment of exposure to direct oral anticoagulants in elderly hospitalised patients. Br J Haematol 2021; 195:790-801. [PMID: 34658009 DOI: 10.1111/bjh.17899] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 09/30/2021] [Accepted: 09/30/2021] [Indexed: 11/30/2022]
Abstract
It is unclear whether elderly patients established on direct oral anticoagulants (DOACs) have greater exposure to these drugs, which could subsequently increase their risk of bleeding. We assessed DOAC exposure and factors affecting it in a real-world elderly cohort of patients. For this, 151 medically stable hospital inpatients (76 established on apixaban, 61 on rivaroxaban, 14 on dabigatran) with a median [interquartile range (IQR)] age of 84 (78-89) years were recruited. Patients provided blood samples for measurement of peak and trough plasma DOAC concentrations. There was up to 48-fold and 13-fold variation in trough and peak plasma drug concentrations respectively. A significantly greater proportion of patients on apixaban had peak plasma drug concentrations within the reported ranges compared to those on either rivaroxaban or dabigatran (82·9% vs. 44·3% vs. 64·3% respectively; P < 0·001). A third of the variability in DOAC plasma concentrations was attributed to the influences of DOAC dosage, renal function and gender. To what extent the observed increases in DOAC exposure in the older patients is the cause of their increased risk of bleeding, which could potentially be ameliorated by dosing titration, requires further investigation.
Collapse
Affiliation(s)
- Emmanouela Kampouraki
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Peter Avery
- School of Mathematics, Statistics & Physics, Newcastle University, Newcastle upon Tyne, UK
| | - Tina Biss
- Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Hilary Wynne
- Older People's Medicine, Freeman Hospital, Newcastle upon Tyne, UK
| | - Farhad Kamali
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| |
Collapse
|
|
44
|
Mocini D, Di Fusco SA, Mocini E, Donini LM, Lavalle C, Di Lenarda A, Riccio C, Caldarola P, De Luca L, Gulizia MM, Oliva F, Gabrielli D, Colivicchi F. Direct Oral Anticoagulants in Patients with Obesity and Atrial Fibrillation: Position Paper of Italian National Association of Hospital Cardiologists (ANMCO). J Clin Med 2021; 10:4185. [PMID: 34575306 PMCID: PMC8468506 DOI: 10.3390/jcm10184185] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/11/2021] [Accepted: 09/13/2021] [Indexed: 11/17/2022] Open
Abstract
The use of the direct oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban (DOACs) offers some major advantages over warfarin and other vitamin K antagonists (VKAs). One advantage is the possibility to use a fixed dose in normal-weight patients, overweight patients and patients with obesity. However, the "one size fits all" strategy raised a concern regarding the possibility to undertreat patients with a high body mass index. No randomized controlled trials (RCTs) have ever compared VKAs and DOACs in this population. We analyzed data from the literature on DOAC pharmacokinetics and pharmacodynamics, results from the four pivotal phase III trials on non-valvular atrial fibrillation, retrospective observational studies and metanalyses. While we are aware of the limitation imposed by the absence of specific RCTs, we propose the position of the Italian Association of Hospital Cardiologists (ANMCO) on the use of DOACs in patients with obesity based on the existing evidence.
Collapse
Affiliation(s)
- David Mocini
- U.O.C. Cardiologia Clinica e Riabilitativa, Presidio Ospedaliero San Filippo Neri, ASL Roma 1, 00135 Roma, Italy; (S.A.D.F.); (F.C.)
| | - Stefania Angela Di Fusco
- U.O.C. Cardiologia Clinica e Riabilitativa, Presidio Ospedaliero San Filippo Neri, ASL Roma 1, 00135 Roma, Italy; (S.A.D.F.); (F.C.)
| | - Edoardo Mocini
- Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy; (E.M.); (L.M.D.)
| | - Lorenzo Maria Donini
- Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy; (E.M.); (L.M.D.)
| | - Carlo Lavalle
- Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological and Geriatric Sciences, “Sapienza” University of Rome, Policlinico Umberto I, 00161 Rome, Italy;
| | - Andrea Di Lenarda
- S.C. Cardiovascolare e Medicina dello Sport, Azienda Sanitaria Universitaria Giuliano Isontina-ASUGI, 34128 Trieste, Italy;
| | - Carmine Riccio
- UOSD “Follow up del paziente post acuto”, Dipartimento Cardiovascolare, Azienda Ospedaliera Sant’Anna e San Sebastiano, 81100 Caserta, Italy;
| | | | - Leonardo De Luca
- U.O.C. di Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, 00152 Roma, Italy; (L.D.L.); (D.G.)
| | - Michele Massimo Gulizia
- U.O.C. Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione “Garibaldi”, 95126 Catania, Italy;
- Fondazione per il Tuo cuore—Heart Care Foundation, 50121 Firenze, Italy
| | - Fabrizio Oliva
- 1-Emodinamica, Unità di Cure Intensive Cardiologiche, Dipartimento Cardiotoracovascolare “A. De Gasperis”, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milano, Italy;
| | - Domenico Gabrielli
- U.O.C. di Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, 00152 Roma, Italy; (L.D.L.); (D.G.)
| | - Furio Colivicchi
- U.O.C. Cardiologia Clinica e Riabilitativa, Presidio Ospedaliero San Filippo Neri, ASL Roma 1, 00135 Roma, Italy; (S.A.D.F.); (F.C.)
| |
Collapse
|
|
45
|
Russo V, Cattaneo D, Giannetti L, Bottino R, Laezza N, Atripaldi U, Clementi E. Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity. Clin Ther 2021; 43:e255-e263. [PMID: 34366151 DOI: 10.1016/j.clinthera.2021.07.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/10/2021] [Accepted: 07/05/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Direct oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity. METHODS We enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs' peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs' plasma concentration out of the expected range. FINDINGS A total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m2) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges. IMPLICATIONS Patients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.
Collapse
Affiliation(s)
- Vincenzo Russo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli" - Monaldi Hospital, Via Leonardo Bianchi, Naples, Italy.
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, Fatebenefratelli-Sacco University Hospital, Milano, Italy
| | - Laura Giannetti
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli" - Monaldi Hospital, Via Leonardo Bianchi, Naples, Italy
| | - Roberta Bottino
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli" - Monaldi Hospital, Via Leonardo Bianchi, Naples, Italy
| | - Nunzia Laezza
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli" - Monaldi Hospital, Via Leonardo Bianchi, Naples, Italy
| | - Umberto Atripaldi
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli" - Monaldi Hospital, Via Leonardo Bianchi, Naples, Italy
| | - Emilio Clementi
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Fatebenefratelli-Sacco University Hospital, Università di Milano, Milano, Italy; Scientific Institute IRCCS Eugenio Medea, Lecco, Italy
| |
Collapse
|
|
46
|
Wiethorn EE, Bell CM, Wiggins BS. Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation and Weighing ≥ 120 Kilograms versus 60-120 Kilograms. Am J Cardiovasc Drugs 2021; 21:545-551. [PMID: 33782909 DOI: 10.1007/s40256-021-00470-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/19/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Direct oral anticoagulants (DOACs) have become favorable choices for anticoagulation due to their fixed-dose schedule, limited need for monitoring, and non-inferiority or superiority to warfarin. DOACs are currently not recommended in patients with a body weight ≥ 120 kg or body mass index ≥ 40 kg/m2 due to limited data regarding safety and efficacy. OBJECTIVE The aim of this study was to compare the safety and efficacy of DOACs in patients with nonvalvular atrial fibrillation (NVAF) and weighing ≥ 120 kg with those weighing < 120 kg. METHODS A single-center, retrospective study was conducted in patients weighing ≥ 120 kg who received either apixaban, dabigatran, or rivaroxaban for stroke risk reduction in NVAF, and matched to patients who weighed < 120 kg. The primary outcome was the incidence of stroke, deep vein thrombosis, pulmonary embolism, or myocardial infarction, while the safety outcome was the incidence of major or clinically relevant non-major bleeding based on the International Society on Thrombosis and Haemostasis (ISTH) definitions. RESULTS A total of 318 patients weighing ≥ 120 kg with NVAF and meeting the inclusion criteria were evaluated and matched with 318 patients weighing < 120 kg. The primary outcome occurred in 2.5% of patients in the ≥ 120 kg group and in 3.1% of patients in the < 120 kg group (p = 0.632). The safety outcome occurred in 5.3% and 6.6% of patients in these respective groups (p = 0.503). CONCLUSION Apixaban, dabigatran, or rivaroxaban may be well-tolerated and effective anticoagulant options in patients with NVAF weighing ≥ 120 kg.
Collapse
Affiliation(s)
- Eryne E Wiethorn
- Department of Pharmacy Services, Medical University of South Carolina, 150 Ashley Avenue, MSC 584, Charleston, SC, 29425, USA.
| | - Carolyn Magee Bell
- Department of Pharmacy Services, Medical University of South Carolina, 150 Ashley Avenue, MSC 584, Charleston, SC, 29425, USA
| | - Barbara S Wiggins
- Department of Pharmacy Services, Medical University of South Carolina, 150 Ashley Avenue, MSC 584, Charleston, SC, 29425, USA
| |
Collapse
|
|
47
|
Beyer-Westendorf J, Fay M, Amara W. The Importance of Appropriate Dosing of Nonvitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation. TH OPEN 2021; 5:e353-e362. [PMID: 34435170 PMCID: PMC8382498 DOI: 10.1055/s-0041-1731777] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/22/2021] [Indexed: 12/18/2022] Open
Abstract
Preventing thromboembolic events, while minimizing bleeding risks, remains challenging when managing patients with atrial fibrillation (AF). Several factors contribute to current dosing patterns of nonvitamin K antagonist oral anticoagulants (NOACs), including patient characteristics, comorbidities, and physician judgment. Application of NOAC doses inconsistent with the drug labels may cause patients to receive either subtherapeutic (increasing stroke risk) or supratherapeutic (increasing bleeding risk) anticoagulant levels. In clinical practice, under- or over-dosing of NOACs in patients with AF is not uncommon. This analysis of prospective and retrospective registry and database studies on NOAC use in patients with AF (with at least 250 patients in each treatment arm) showed that under-dosing may be associated with reduced effectiveness for stroke prevention, with similar or even increased bleeding than with the standard dose. This may reflect underlying conditions and patient factors that increase bleeding despite NOAC dose reduction. Such factors could drive the observed overuse of reduced NOAC dosages, often making the prescription of reduced-dose NOAC an intentional label deviation. In contrast, over-dosing more likely occurs accidentally; instead of providing benefits, it may be associated with worse safety outcomes than the standard dose, including increased bleeding risk and higher all-cause mortality rates. This review summarizes the main findings on NOAC doses usually prescribed to patients with AF in clinical practice.
Collapse
Affiliation(s)
- Jan Beyer-Westendorf
- Thrombosis Research Unit, Division Hematology, Department of Medicine I, University Hospital "Carl Gustav Carus" Dresden, Dresden, Germany.,Department of Haematology, Kings Thrombosis Service, Kings College London, United Kingdom
| | - Matthew Fay
- Westcliffe Medical Practice, Westcliffe Road, Shipley, United Kingdom
| | - Walid Amara
- Groupe Hospitalier Intercommunal Le Raincy-Montfermeil, Montfermeil, France
| |
Collapse
|
|
48
|
Wang TF, Carrier M, Fournier K, Siegal DM, Le Gal G, Delluc A. Oral anticoagulant use in patients with morbid obesity: A systematic review and meta-analysis. Thromb Haemost 2021; 122:830-841. [PMID: 34399433 DOI: 10.1055/a-1588-9155] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Obesity is associated with increased risks of atrial fibrillation (AF) and venous thromboembolism (VTE) for which anticoagulation is commonly used. However, data on the efficacy and safety of oral anticoagulants in patients with morbid obesity are limited. METHODS We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) for AF or VTE in patients with morbid obesity. RESULTS We included 3 randomized controlled trials (5 studies) and 18 observational studies in adult patients with a body weight ≥ 120 kg, body mass index (BMI) ≥ 40 kg/m2 or classified as morbid obesity who received DOACs or VKAs for AF or VTE (N=77,687). The primary efficacy outcome was stroke/systemic embolism or recurrent VTE, and the primary safety outcome was major bleeding. DOACs were associated with a pooled incidence rate of stroke/systemic embolism of 1.16 per 100 person-years, compared to 1.18 with VKAs. The incidence of recurrent VTE on DOACs was 3.83 per 100 person-years, compared to 6.81 on VKAs. In both VTE and AF populations, DOACs were associated with lower risks of major bleeding compared to VKAs. However, all observational studies had moderate to serious risks of bias. CONCLUSIONS Patients with morbid obesity on DOACs had similar risks of stroke/systemic embolism, lower rates of recurrent VTE and major bleeding events compared to those on VKAs. However, the certainty of evidence was low given that studies were mostly observational with high risk of confounding.
Collapse
Affiliation(s)
- Tzu-Fei Wang
- Department of Medicine, Division of Hematology, University of Ottawa, Ottawa, Canada
| | - Marc Carrier
- Department of Medicine. University of Ottawa, Ottawa Hospital Research Institute, Ottawa, Canada
| | | | - Deborah M Siegal
- Department of Medicine, Division of Hematology, University of Ottawa, Ottawa, Canada
| | - Grégoire Le Gal
- Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada.,Clinical Epidemiology Unit, Ottawa Health Research Institute, Ottawa, Canada.,Université de Bretagne Occidentale, Brest, France.,INNOVTE (INvestigation Network On Venous ThromboEmbolism) F-CRIN (French Clinical Research Infrastructure) Network, Saint Etienne, France
| | | |
Collapse
|
|
49
|
Martin KA, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost 2021; 19:1874-1882. [PMID: 34259389 DOI: 10.1111/jth.15358] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 12/27/2022]
Abstract
Although direct-acting oral anticoagulants (DOACs) have widespread first-line use for treatment and prevention of venous thromboembolism (VTE), uncertainty remains regarding their efficacy and safety in patients with obesity. We reviewed available data for use of DOACs for VTE treatment and prevention in patients with obesity, including phase 3, phase 4, meta-analyses, and pharmacokinetic and pharmacodynamics studies. In addition, we reviewed available data regarding DOACs in bariatric surgery. We provide updated guidance recommendations on using DOACs in patients with obesity for treatment and prevention of VTE, as well as following bariatric surgery.
Collapse
Affiliation(s)
- Karlyn A Martin
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jan Beyer-Westendorf
- Thrombosis Research Unit, Division Hematology and Hemostasis, Department of Medicine 1, University Hospital, Technische University Dresden, Dresden, Germany
| | - Bruce L Davidson
- Pulmonary and Critical Care Medicine, Washington State University Elson S Floyd College of Medicine and Providence Health System, Seattle, WA, USA
| | - Menno V Huisman
- Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
| | - Per Morten Sandset
- Department of Hematology, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Stephan Moll
- Division of Hematology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| |
Collapse
|
|
50
|
Boriani G, De Caterina R, Manu MC, Souza J, Pecen L, Kirchhof P. Impact of Weight on Clinical Outcomes of Edoxaban Therapy in Atrial Fibrillation Patients Included in the ETNA-AF-Europe Registry. J Clin Med 2021; 10:2879. [PMID: 34209595 PMCID: PMC8269173 DOI: 10.3390/jcm10132879] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/11/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Extremes of body weight may alter exposure to non-vitamin K antagonist oral anticoagulants and thereby impact clinical outcomes. This ETNA-AF-Europe sub-analysis assessed 1-year outcomes in routine care patients with atrial fibrillation across a range of body weight groups treated with edoxaban. METHODS ETNA-AF-Europe is a multinational, multicentre, observational study conducted in 825 sites in 10 European countries. Overall, 1310, 5565, 4346 and 1446 enrolled patients were categorised into ≤60 kg, >60-≤80 kg (reference weight group), >80-≤100 kg and >100 kg groups. RESULTS Patients weighing ≤60 kg were older, more frail and had a higher CHA2DS2-VASc score vs. the other weight groups. The rates of stroke/systemic embolism, major bleeding and ICH were low at 1 year (0.82, 1.05 and 0.24%/year), with no significant differences among weight groups. The annualised event rates of all-cause death were 3.50%/year in the overall population. After adjustment for eGFR and CHA2DS2-VASc score, the risk of all-cause death was significantly higher in extreme weight groups vs. the reference group. CONCLUSIONS Low rates of stroke and bleeding were reported with edoxaban, independent of weight. The risk of all-cause death was higher in extremes of weight vs. the reference group after adjustment for important risk modifiers, thus no obesity paradox was observed.
Collapse
Affiliation(s)
- Giuseppe Boriani
- Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, 41100 Modena, Italy
| | - Raffaele De Caterina
- Chair of Cardiology, Cardiology Division, Pisa University Hospital, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy;
- Fondazione Villa Serena per la Ricerca, Città Sant’Angelo, 65013 Pescara, Italy
| | | | - José Souza
- Daiichi Sankyo Europe GmbH, Zielstattstraße 48, 81379 Munich, Germany; (M.C.M.); (J.S.)
| | - Ladislav Pecen
- Institute of Computer Science of the Czech Academy of Sciences, 18207 Prague, Czech Republic;
| | - Paulus Kirchhof
- Department of Cardiology, University Heart and Vascular Centre UKE Hamburg, 20246 Hamburg, Germany;
- Institute of Cardiovascular Sciences, University of Birmingham, SWBH and UHB NHS Trusts, Birmingham B152TT, UK
- The Atrial Fibrillation NETwork (AFNET), 48149 Münster, Germany
| |
Collapse
|