|
1
|
Abbasalizadeh A, Afshar Mogaddam MR, Farajzadeh MA, Nemati M, Sorouraddin SM. Dispersive solid phase extraction of apixaban from human plasma samples prior to capillary electrophoresis determination using zirconium-based metal organic frameworks prepared by different modulator and solvent. J Chromatogr B Analyt Technol Biomed Life Sci 2025; 1251:124417. [PMID: 39705892 DOI: 10.1016/j.jchromb.2024.124417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 11/14/2024] [Accepted: 11/29/2024] [Indexed: 12/23/2024]
Abstract
Here, a zirconium-based metal organic framework-dispersive solid phase extraction method was established as an efficient, robust, and accurate approach for quantifying apixabanin human plasma samples prior to capillary electrophoresis with diode array detection. Various types of metal organic frameworks based on UiO-66-NH2 were synthesized by altering modulators and solvents and applied as sorbents in the extraction procedure. Among the tested sorbents, UiO-66-NH2 prepared in dimethylformamide in the presence of acetic acid was found to be the best sorbent in this method for the extraction of apixaban with high extraction efficiency comparable to other types of UiO-66-NH2 metal organic frameworks. The extraction and preconcentration of apixaban were carried out by adding 5 mg of synthesized sorbent to a 5 mL sample solution, followed by vortexing for 3 min. After discarding the supernatant, the adsorbed analyte was eluted from the sorbent surface using 60 µL acetonitrile under vortexing for 2 min. The effective parameters of the offered method were optimized and validated using a one-parameter-at-a- time strategy. The detection and quantification limits of the method were 9.9 and 32 ng mL-1 in plasma and 1.5 and 4.9 ng mL-1 in deionized water, respectively. The method was linear ranging from 4.9 to 1000 ng mL-1 in deionized water and from 32 to 500 ng mL-1 in plasma, respectively. The enrichment factor and extraction recovery values were 44 % and 53 %, respectively. The relative standard deviations were ≤6.2 % for intra- and inter-day precisions. Finally, the proposed method was successfully employed to quantify apixaban in human plasma samples.
Collapse
Affiliation(s)
- Aysa Abbasalizadeh
- Department of Analytical Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran; Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Afshar Mogaddam
- Food and Drug Safety Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Chemistry and Chemical Engineering Department, Khazar University, 41 Mehseti Street, Baku AZ1096, Azerbaijan.
| | - Mir Ali Farajzadeh
- Department of Analytical Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran; Engineering Faculty, Near East University, 99138 Nicosia, North Cyprus, Mersin 10, Turkey
| | - Mahboob Nemati
- Food and Drug Safety Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | |
Collapse
|
|
2
|
Jaradat A, Alomari EA, Bayan MF, Naser AY. Knowledge, attitudes and practices regarding medication splitting and crushing among the general public in Jordan: a cross-sectional study. BMJ Open 2024; 14:e087109. [PMID: 39542471 PMCID: PMC11575342 DOI: 10.1136/bmjopen-2024-087109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Splitting or crushing medications are used for dosage administration when a certain dose is not easily accessible. Understanding the splitting or crushing of medications is essential to guarantee safe medication administration since inappropriate handling might impact therapeutic efficacy, safety and patient outcomes. OBJECTIVES This study intends to examine the practices, attitudes and knowledge of the Jordanian population regarding the splitting/crushing of medications. STUDY DESIGN AND SETTING This is a cross-sectional survey study conducted in Jordan between November 2022 and March 2023. The questionnaire tool was adapted from previous literature, and binary logistic regression analysis was used, to identify the predictors of participants' knowledge concerning medication splitting/crushing. PARTICIPANTS A total of 1259 participants from the general public were involved, without restrictions on gender or age. RESULTS Around 22.2% of participants confirmed that tablet splitting/crushing is a useful way to reduce medication costs. 67.0% reported that they are not sure whether tablets are suitable for splitting/crushing/crushing. 75.8% reported that they refer to package leaflet information to check whether tablets are suitable for splitting/crushing. 84.8% correctly believed that scored tablets can be split, while unscored tablets cannot. 72.0% identified correctly that not all types of tablets and capsules can be split/crushed or dissolved. The mean knowledge score of study participants was 2.7 (SD: 1.5) out of 6, which is equal to 45% of the maximum attainable score and reflects a weak level of knowledge about tablet crushing. Those who hold a bachelor's degree and have an income level of JD500-JD1000 (which is equal to US$715-US$1428) were more likely to have knowledge about tablet crushing. Around 39.2% of the participants reported that they had split or crushed tablets to reach their desired dose, of which the vast majority (82.9%) were using scored tablets. CONCLUSION Understanding of tablet-splitting and crushing techniques ought to be enhanced while encouraging prescribing practices that stress safety and well-informed decision-making. Patients should actively seek reliable sources of information, have an awareness of which tablets can be safely divided and actively engage with healthcare experts to receive appropriate guidance.
Collapse
Affiliation(s)
- Abdolelah Jaradat
- Department of Applied Pharmceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman, Jordan
| | - Esra'a Ali Alomari
- Department of Applied Pharmceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman, Jordan
| | | | - Abdallah Y Naser
- Department of Applied Pharmceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University, Amman, Jordan
| |
Collapse
|
|
3
|
Hemdan M, Ali MA, Doghish AS, Mageed SSA, Elazab IM, Khalil MM, Mabrouk M, Das DB, Amin AS. Innovations in Biosensor Technologies for Healthcare Diagnostics and Therapeutic Drug Monitoring: Applications, Recent Progress, and Future Research Challenges. SENSORS (BASEL, SWITZERLAND) 2024; 24:5143. [PMID: 39204840 PMCID: PMC11360123 DOI: 10.3390/s24165143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/01/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024]
Abstract
This comprehensive review delves into the forefront of biosensor technologies and their critical roles in disease biomarker detection and therapeutic drug monitoring. It provides an in-depth analysis of various biosensor types and applications, including enzymatic sensors, immunosensors, and DNA sensors, elucidating their mechanisms and specific healthcare applications. The review highlights recent innovations such as integrating nanotechnology, developing wearable devices, and trends in miniaturisation, showcasing their transformative potential in healthcare. In addition, it addresses significant sensitivity, specificity, reproducibility, and data security challenges, proposing strategic solutions to overcome these obstacles. It is envisaged that it will inform strategic decision-making, drive technological innovation, and enhance global healthcare outcomes by synthesising multidisciplinary insights.
Collapse
Affiliation(s)
- Mohamed Hemdan
- School of Biotechnology, Badr University in Cairo (BUC), Badr City 11829, Egypt; (M.H.); (M.A.A.)
| | - Mohamed A. Ali
- School of Biotechnology, Badr University in Cairo (BUC), Badr City 11829, Egypt; (M.H.); (M.A.A.)
| | - Ahmed S. Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Egypt;
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Egypt
| | - Sherif S. Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City 11829, Egypt;
| | - Ibrahim M. Elazab
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt;
| | - Magdy M. Khalil
- Medical Biophysics, Department of Physics, Faculty of Science, Helwan University, Cairo 11795, Egypt;
- School of Applied Health Sciences, Badr University in Cairo (BUC), Badr City 11829, Egypt
| | - Mostafa Mabrouk
- Refractories, Ceramics and Building Materials Department, National Research Centre, 33 El Bohouth St., Giza 12622, Egypt;
| | - Diganta B. Das
- Department of Chemical Engineering, Loughborough University, Loughborough LE11 3TU, UK
| | - Alaa S. Amin
- Chemistry Department, Faculty of Science, Benha University, Benha 13511, Egypt;
| |
Collapse
|
|
4
|
Choi H, Kang HJ, Ahn I, Gwon H, Kim Y, Seo H, Cho HN, Han J, Kim M, Kee G, Park S, Kwon O, Roh JH, Kim AR, Kim JH, Jun TJ, Kim YH. Machine learning models to predict the warfarin discharge dosage using clinical information of inpatients from South Korea. Sci Rep 2023; 13:22461. [PMID: 38105280 PMCID: PMC10725866 DOI: 10.1038/s41598-023-49831-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 12/12/2023] [Indexed: 12/19/2023] Open
Abstract
As warfarin has a narrow therapeutic window and obvious response variability among individuals, it is difficult to rapidly determine personalized warfarin dosage. Adverse drug events(ADE) resulting from warfarin overdose can be critical, so that typically physicians adjust the warfarin dosage through the INR monitoring twice a week when starting warfarin. Our study aimed to develop machine learning (ML) models that predicts the discharge dosage of warfarin as the initial warfarin dosage using clinical data derived from electronic medical records within 2 days of hospitalization. During this retrospective study, adult patients who were prescribed warfarin at Asan Medical Center (AMC) between January 1, 2018, and October 31, 2020, were recruited as a model development cohort (n = 3168). Additionally, we created an external validation dataset (n = 891) from a Medical Information Mart for Intensive Care III (MIMIC-III). Variables for a model prediction were selected based on the clinical rationale that turned out to be associated with warfarin dosage, such as bleeding. The discharge dosage of warfarin was used the study outcome, because we assumed that patients achieved target INR at discharge. In this study, four ML models that predicted the warfarin discharge dosage were developed. We evaluated the model performance using the mean absolute error (MAE) and prediction accuracy. Finally, we compared the accuracy of the predictions of our models and the predictions of physicians for 40 data point to verify a clinical relevance of the models. The MAEs obtained using the internal validation set were as follows: XGBoost, 0.9; artificial neural network, 0.9; random forest, 1.0; linear regression, 1.0; and physicians, 1.3. As a result, our models had better prediction accuracy than the physicians, who have difficulty determining the warfarin discharge dosage using clinical information obtained within 2 days of hospitalization. We not only conducted the internal validation but also external validation. In conclusion, our ML model could help physicians predict the warfarin discharge dosage as the initial warfarin dosage from Korean population. However, conducting a successfully external validation in a further work is required for the application of the models.
Collapse
Affiliation(s)
- Heejung Choi
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43 gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Hee Jun Kang
- Division of Cardiology, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Imjin Ahn
- Department of Information Medicine, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Hansle Gwon
- Department of Information Medicine, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Yunha Kim
- Department of Information Medicine, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Hyeram Seo
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43 gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Ha Na Cho
- Department of Information Medicine, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - JiYe Han
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43 gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Minkyoung Kim
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43 gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Gaeun Kee
- Department of Information Medicine, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Seohyun Park
- Department of Information Medicine, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Osung Kwon
- Division of Cardiology Department of Internal Medicine, Eunpyeong St Mary's Hospital, Catholic University of Korea, Seoul, Republic of Korea
| | - Jae-Hyung Roh
- Department of Internal Medicine, Chungnam National University College of Medicine, Chungnam National University Sejong Hospital, 20, Bodeum 7-ro, Sejong-si, 30099, Sejong, Republic of Korea
| | - Ah-Ram Kim
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyeon Kim
- Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea
| | - Tae Joon Jun
- Big Data Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea
| | - Young-Hak Kim
- Division of Cardiology, Department of Information Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympicro 43gil, Songpagu, Seoul, 05505, Republic of Korea.
| |
Collapse
|
|
5
|
Steiner HE, Carrion KC, Giles JB, Lima AR, Yee K, Sun X, Cavallari LH, Perera MA, Duconge J, Karnes JH. Local Ancestry-Informed Candidate Pathway Analysis of Warfarin Stable Dose in Latino Populations. Clin Pharmacol Ther 2023; 113:680-691. [PMID: 36321873 PMCID: PMC9957812 DOI: 10.1002/cpt.2787] [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: 07/25/2022] [Accepted: 10/16/2022] [Indexed: 11/06/2022]
Abstract
Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of five variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (P < 0.0125) in standard models. Local ancestry-adjusted analysis unveiled 35 associated variants with absolute effects ranging from β = 9.04 ( ±2.23) to 39.18 ( ±10.89) per ancestral allele in the discovery cohort and β = 6.47 (± 2.02) to 17.82 (± 6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.
Collapse
Affiliation(s)
- Heidi E Steiner
- Data Science Institute, University of Arizona, Tucson, Arizona, USA
- Department of Pharmacy Practice and Science, University of Arizona R. Ken Coit College of Pharmacy, Tucson, Arizona, USA
| | - Kelvin Carrasquillo Carrion
- Research Centers in Minority Institutions (RCMI) Program, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Jason B Giles
- Department of Pharmacy Practice and Science, University of Arizona R. Ken Coit College of Pharmacy, Tucson, Arizona, USA
| | - Abiel Roche Lima
- Research Centers in Minority Institutions (RCMI) Program, Center for Collaborative Research in Health Disparities (CCRHD), Academic Affairs Deanship, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Kevin Yee
- Banner University Medical Center-Tucson, Tucson, Arizona, USA
| | - Xiaoxiao Sun
- Department of Biostatistics, University of Arizona Mel and Enid Zuckerman College of Public Health, Tucson, Arizona, USA
| | - Larisa H Cavallari
- Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA
| | - Minoli A Perera
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jorge Duconge
- Department of Pharmaceutical Sciences, University of Puerto Rico School of Pharmacy, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Jason H Karnes
- Department of Pharmacy Practice and Science, University of Arizona R. Ken Coit College of Pharmacy, Tucson, Arizona, USA
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| |
Collapse
|
|
6
|
Higher OAK (Oral Anticoagulation Knowledge) score at baseline associated with better TTR (Time in Therapeutic Range) in patients taking warfarin. J Thromb Thrombolysis 2023; 55:141-148. [PMID: 36326967 DOI: 10.1007/s11239-022-02718-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/12/2022] [Indexed: 11/06/2022]
Abstract
A lack in patient knowledge of warfarin therapy is associated with poor adherence. This knowledge gap may result in a lower INR Time in Therapeutic Range (TTR). To investigate association between patient anticoagulation knowledge and warfarin control. Michigan Anticoagulation Quality Improvement Initiative (MAQI2) is a Blue Cross Blue Shield of Michigan sponsored consortium of six anticoagulation management services. Patients prescribed warfarin at two MAQI2 sites completed a voluntary Oral Anticoagulation Knowledge (OAK) questionnaire at warfarin initiation and 6-month follow-up. The results of 20 OAK questions and TTRs (excluding 1st month post-initiation) were compared using chi-square tests, t-tests and multivariate analysis adjusting for SAMe-TT2R2 and days on warfarin. Of 1836 surveys distributed at warfarin initiation, 481 (26.2%) patients completed the baseline questionnaire (within 1 month post-initiation): mean OAK score: 14.6 ± 3.4. Of those, 147 (30.6%) completed 6-month follow-up surveys (OAK: 12.7 ± 5.8). Patients with TTR ≥ 70% at baseline scored higher on OAK tests than patients with TTR < 70% in unadjusted analyses (15.1 ± 3.2 v. 14.2 ± 3.5, p = 0.003) and adjusted analysis (p = 0.020). There was no unadjusted or adjusted difference in OAK scores at 6-month follow-up between patients with TTR ≥ 70% and TTR < 70%. For patients who completed baseline and follow-up surveys, there was a decrease of 2.4 points in OAK score between baseline and 6-month follow up (p < 0.001). Higher baseline, but not follow-up, OAK score is associated with better warfarin control and average OAK scores decreased between baseline and follow-up. Further studies are needed to determine what type of patient education may improve patient knowledge retention and warfarin control.
Collapse
|
|
7
|
Souza-Silva MVR, Domingues MLDP, Chagas VS, Pereira DN, de Sá LC, Almeida MSS, Sales TLS, Raposo MC, Guimarães NS, Oliveira JADQ, Ribeiro ALP, Cardoso CS, Martins MAP, Enes TB, Soares TBDC, Baldoni AO, Marcolino MS. Implementation of a text messaging intervention to patients on warfarin therapy in Brazilian primary care units: a quasi-experimental study. BMC PRIMARY CARE 2022; 23:54. [PMID: 35321654 PMCID: PMC8942053 DOI: 10.1186/s12875-022-01647-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/23/2022] [Indexed: 11/10/2022]
Abstract
Background Warfarin remains the most affordable oral anticoagulant in many countries. However, it may have serious side effects, and the success of the therapy depends on the patient’s understanding of the medication and their adherence to treatment. The use of short messages services (SMS) is a strategy that can be used to educate patients, but there are no studies evaluating this intervention in patients taking warfarin. Therefore, we aimed to develop, implement, and assess the feasibility of an intervention using SMS to primary care patients taking warfarin in a medium-sized Brazilian city. Methods A bank of 79 SMS was drafted and validated by an expert panel. During 6 months, three times a week, patients received messages about anticoagulation with warfarin. At baseline and after 3 months, we assessed their knowledge and adherence with validated instruments. At the end of the follow-up, participants answered a satisfaction questionnaire. Subsequently, a scale-up phase was conducted, with another round of the intervention including 82 participants (29 from the first phase and 53 newly recruited). Seven months after the end of the scale-up, we asked the patients for their insights about the long-term effects of this program. All patients signed informed consent. The study was approved by the Research and Ethics committee of the Universidade Federal de Minas Gerais. Results In the pilot, 33 (89.2%) patients completed the follow-up. Among the participants who answered the satisfaction questionnaire (n = 29), 86.2% considered that the intervention motivated a healthy lifestyle and improved their understanding of warfarin therapy. All patients were willing to continue receiving the messages. Adherence measured by the Measure of Adherence to Treatment (MAT) test was high in the pre-intervention assessment and remained high (96.7% vs. 93.3%; p = 1.0000). The proportion of patients who achieved > 75% correct answers on the Oral Anticoagulation Knowledge (OAK) test increased from 6.5% to 25.6, p = 0.0703. In the scale-up, 23 patients answered the long-term assessment questionnaire. The main long-term knowledge reported was dietary information. Nine patients received the messages but did not remember their content. Conclusion The intervention was well-accepted and had a positive impact on patient’s knowledge about oral anticoagulation therapy. The scale-up assessment reinforced the need to constantly monitor digital interventions. Supplementary Information The online version contains supplementary material available at 10.1186/s12875-022-01647-5.
Collapse
|
|
8
|
Bontempi M. Semi-empirical anticoagulation model (SAM): INR monitoring during Warfarin therapy. J Pharmacokinet Pharmacodyn 2021; 49:271-282. [PMID: 34652608 DOI: 10.1007/s10928-021-09783-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/15/2021] [Indexed: 12/01/2022]
Abstract
The International Normalized Ratio (INR) monitoring is an essential component to manage thrombotic disease therapy. This study presents a semi-empirical model of INR as a function of time and assigned therapy (Warfarin, k-vitamin). With respect to other methodologies, this model is able to describe the INR using a limited number of parameters and is able to describe the time variation of INR described in the literature. The presented methodology showed great accuracy in model calibration [(trueness (precision)]: 0.2% (0.1%) to 1.2% (0.3%) for coagulation factors, from 5% (9%) to 9.7% (12%) for Warfarin-related parameters and 38% (40%) for K-vitamin-related parameters. The latter value was considered acceptable given the assumptions made in the model. It has two other important results: the first is that it was able to correctly estimate INR with respect to daily therapy doses taken from the literature. The second is that it introduces a single numeric semi-empirical parameter that is able to correlate INR/dose response to physiological and environmental condition of patients.
Collapse
Affiliation(s)
- Marco Bontempi
- Struttura Complessa Scienze e Tecnologie Chirurgiche, IRCCS Istituto Ortopedico Rizzoli, via di Barbiano 1/10, I-40136, Bologna, BO, Italy.
| |
Collapse
|
|
9
|
Wen X, Wang S, Taveira TH, Akhlaghi F. Required warfarin dose and time in therapeutic range in patients with diagnosed Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH). PLoS One 2021; 16:e0251665. [PMID: 34525124 PMCID: PMC8443040 DOI: 10.1371/journal.pone.0251665] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/29/2021] [Indexed: 12/29/2022] Open
Abstract
Warfarin has been widely used to treat thromboembolism. The effect of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), on warfarin dosing remains unknown. This study aims to examine the effects of NAFLD/NASH on the average daily dose (ADD) of warfarin and the time in therapeutic range (TTR). This is a retrospective study utilizing an administrative data. We included patients with at least 2 months of warfarin dispensing and two subsequent consecutive INR measures. The ADD of warfarin to achieve therapeutic range INR levels, and TTR were compared between patients with and without NAFLD/NASH in four subgroups of patients accounting for the presence of obesity and diabetes. Generalized linear models (GLM) with Propensity score (PS) fine stratification were applied to evaluate the relative differences (RD) of warfarin ADD and TTR (>60%) in four subgroups. A total of 430 NAFLD/NASH patients and 38,887 patients without NAFLD/NASH were included. The ADD and TTR, were not significant in the overall cohort between those with and without NAFLD/NASH. However, GLM results in patients without diabetes or obesity (N = 26,685) showed a significantly lower warfarin ADD (RD: -0.38; 95%CI: -0.74–-0.02) and shorter TTR (OR: 0.71; 95%CI: 0.52–0.97) in patients diagnosed with NAFLD/NASH. The effects of NAFLD/NASH on warfarin dose or TTR were observed in patients without obesity and diabetes. Obesity and diabetes appear to be significant modifiers for the effects of NAFLD/NASH on warfarin dose and TTR.
Collapse
Affiliation(s)
- Xuerong Wen
- Health Outcomes, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America
| | - Shuang Wang
- Health Outcomes, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America
| | - Tracey H Taveira
- Health Outcomes, Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America.,Cardiovascular Department, Providence Veterans Affairs Medical Center, Providence, RI, United States of America.,Warren Alpert School of Medicine, Brown University, Providence, RI, United States of America
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Science, College of Pharmacy, University of Rhode Island, Kingston, RI, United States of America
| |
Collapse
|
|
10
|
Hu C, Chen X, Zhao Z, Gao D, Gong S, Zhang L, Xu Y, Li L, Zhang L. A Two-Sequence, Four-Period, Crossover, Replicate Study to Demonstrate Bioequivalence of Warfarin Sodium Tablet in Healthy Chinese Subjects Under Fasting and Fed Conditions. Clin Pharmacol Drug Dev 2020; 9:527-536. [PMID: 32052925 DOI: 10.1002/cpdd.783] [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: 07/03/2019] [Accepted: 01/07/2020] [Indexed: 11/06/2022]
Abstract
Warfarin is a narrow therapeutic index anticoagulant drug, and several generic formulations have been approved worldwide. However, there has been no report evaluating the bioequivalence of warfarin sodium according to US Food and Drug Administration draft guidance. We designed a 2-sequence and 4-period crossover study to compare the pharmacokinetic profile and assess bioequivalence between the test warfarin sodium tablet and reference product Coumadin (2.5 mg) in 56 healthy Chinese subjects under fasting and fed conditions. The plasma concentration of warfarin was analyzed by a validated liquid chromatography-tandem mass spectrometry assay, and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters. The results showed that the point estimate of geometric mean ratios of Cmax and AUC0-t for warfarin were 103.21% and 99.31%, respectively, in the fasting condition and 100.62% and 98.98%, respectively, in the fed condition, and the 90% confidence intervals were all within the range of 90.00%-111.11%. The upper limit of the 90% confidence interval of estimated within-subject variation ratios of the test and reference products was 1.33 for Cmax and 2.22 for AUC0-t under the fasting condition and 1.68 for Cmax and 2.15 for AUC0-t under the fed condition. Overall, bioequivalence of the 2 warfarin sodium products was demonstrated.
Collapse
Affiliation(s)
- Chaoying Hu
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Xiaoping Chen
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Zirun Zhao
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Dan Gao
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Shili Gong
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| | | | | | - Lin Li
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Lan Zhang
- Department of Pharmacy, Phase I Clinical Trial Unit, Xuanwu Hospital Capital Medical University, Beijing, China
| |
Collapse
|
|
11
|
Jeong HC, Kim TE, Shin KH. Quantification of apixaban in human plasma using ultra performance liquid chromatography coupled with tandem mass spectrometry. Transl Clin Pharmacol 2019; 27:33-41. [PMID: 32055579 PMCID: PMC6989270 DOI: 10.12793/tcp.2019.27.1.33] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/11/2019] [Accepted: 03/11/2019] [Indexed: 11/19/2022] Open
Abstract
Apixaban, an inhibitor of direct factor Xa, is used for the treatment of venous thromboembolic events or prevention of stroke. Unlike many other anticoagulant agents, it does not need periodic monitoring. However, monitoring is still required to determine the risk of bleeding due to overdose or surgery. Usually, apixaban concentrations are indirectly quantified using an anti-factor Xa assay. However, this method has a relatively narrow analytical concentration range, poor selectivity, and requires an external calibrator. Therefore, the goal of current study was to establish an analytical method for determining plasma levels of apixaban using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). To this end, apixaban was separated using 2.5 mM ammonium formate (pH 3.0) (A) and 100% methanol containing 0.1% formic acid (B) using the gradient method with a Thermo hypersil GOLD column. The mass detector condition was optimized using the electrospray ionization (ESI) positive mode for apixaban quantification. The developed method showed sufficient linearity (coefficient of determination [r2 ≥ 0.997]) at calibration curve ranges. The percentage (%) changes in accuracy, precision, and all stability tests were within 15% of the nominal concentration. Apixaban concentration in plasma from healthy volunteers was quantified using the developed method. The mean maximum plasma concentration (Cmax) was 371.57 ng/mL, and the median time to achieve the Cmax (Tmax) was 4 h after administration of 10 mg apixaban alone. Although the results showed low extraction efficiency (~16%), the reproducibility (% change was within 15% of nominal concentration) was reliable. Therefore, the developed method could be used for clinical pharmacokinetic studies.
Collapse
Affiliation(s)
- Hyeon-Cheol Jeong
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
| | - Tae-Eun Kim
- Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul 05030, Republic of Korea
| | - Kwang-Hee Shin
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
| |
Collapse
|
|
12
|
Lindström J, Henriksson AE. The agreement between capillary and venous sampling for plasma PT/INR results. Scandinavian Journal of Clinical and Laboratory Investigation 2018; 78:524-526. [DOI: 10.1080/00365513.2018.1488178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Joakim Lindström
- Department of Laboratory Medicine, Sundsvall County Hospital, Sundsvall, Sweden
| | - Anders E. Henriksson
- Department of Laboratory Medicine, Sundsvall County Hospital, Sundsvall, Sweden
- Department of Natural Sciences, Mid Sweden University, Sundsvall, Sweden
| |
Collapse
|
|
13
|
Takeda K, Ikenaka Y, Tanaka KD, Nakayama SMM, Tanikawa T, Mizukawa H, Ishizuka M. Investigation of hepatic warfarin metabolism activity in rodenticide-resistant black rats (Rattus rattus) in Tokyo by in situ liver perfusion. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2018; 148:42-49. [PMID: 29891376 DOI: 10.1016/j.pestbp.2018.03.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 02/26/2018] [Accepted: 03/25/2018] [Indexed: 06/08/2023]
Abstract
Anti-blood coagulation rodenticides, such as warfarin, have been used all over the world. They inhibit vitamin K epoxide reductase (VKOR), which is necessary for producing several blood clotting factors. This inhibition by rodenticides results in lethal hemorrhage in rodents. However, heavy usage of these agents has led to the appearance of rodenticide-resistant rats. There are two major mechanisms underlying this resistance, i.e., mutation of the target enzyme of warfarin, VKOR, and enhanced metabolism of warfarin. However, there have been few studies regarding the hepatic metabolism of warfarin, which should be related to resistance. To investigate warfarin metabolism in resistant rats, in situ liver perfusion of warfarin was performed with resistant black rats (Rattus rattus) from Tokyo, Japan. Liver perfusion is an in situ methodology that can reveal hepatic function specifically with natural composition of the liver. The results indicated enhanced hepatic warfarin hydroxylation activity compared with sensitive black rats. On the other hand, in an in vitro microsomal warfarin metabolism assay to investigate kinetic parameters of cytochrome P450, which plays a major role in warfarin hydroxylation, the Vmax of resistant rats was slightly but significantly higher compared to the results obtained in the in situ study. These results indicated that another factor like electron donators may also contribute to the enhanced metabolism in addition to high expression of cytochrome P450.
Collapse
Affiliation(s)
- Kazuki Takeda
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan
| | - Yoshinori Ikenaka
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan; Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa
| | - Kazuyuki D Tanaka
- Technical Research Laboratory, IKARI SHODOKU CO. LTD., 1-12-3 Akanehama, Narashino, Chiba 275-0024, Japan
| | - Shouta M M Nakayama
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan
| | - Tsutomu Tanikawa
- Technical Research Laboratory, IKARI SHODOKU CO. LTD., 1-12-3 Akanehama, Narashino, Chiba 275-0024, Japan
| | - Hazuki Mizukawa
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan
| | - Mayumi Ishizuka
- Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18 Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
| |
Collapse
|
|
14
|
Abstract
This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.
Collapse
|
|
15
|
Freeman JV, Hutton DW, Barnes GD, Zhu RP, Owens DK, Garber AM, Go AS, Hlatky MA, Heidenreich PA, Wang PJ, Al-Ahmad A, Turakhia MP. Cost-Effectiveness of Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation Based on Results From PROTECT AF Versus PREVAIL. Circ Arrhythm Electrophysiol 2017; 9:CIRCEP.115.003407. [PMID: 27307517 DOI: 10.1161/circep.115.003407] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 03/31/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown varying results, and its cost effectiveness compared with anticoagulation has not been evaluated using all available contemporary trial data. METHODS AND RESULTS We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation (PROTECT AF) and Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation (PREVAIL) randomized trials. Using data from PROTECT AF, the incremental cost-effectiveness ratios compared with warfarin and dabigatran were $20 486 and $23 422 per quality-adjusted life year, respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (8.44, 8.54, and 8.59 quality-adjusted life years, respectively) and more costly. At a willingness-to-pay threshold of $50 000 per quality-adjusted life year, LAA closure was cost effective 90% and 9% of the time under PROTECT AF and PREVAIL assumptions, respectively. These results were sensitive to the rates of ischemic stroke and intracranial hemorrhage for LAA closure and medical anticoagulation. CONCLUSIONS Using data from the PROTECT AF trial, LAA closure with the Watchman device was cost effective; using PREVAIL trial data, Watchman was more costly and less effective than warfarin and dabigatran. PROTECT AF enrolled more patients and has substantially longer follow-up time, allowing greater statistical certainty with the cost-effectiveness results. However, longer-term trial results and postmarketing surveillance of major adverse events will be vital to determining the value of the Watchman in clinical practice.
Collapse
Affiliation(s)
- James V Freeman
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.).
| | - David W Hutton
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Geoffrey D Barnes
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Ruo P Zhu
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Douglas K Owens
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Alan M Garber
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Alan S Go
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Mark A Hlatky
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Paul A Heidenreich
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Paul J Wang
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Amin Al-Ahmad
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| | - Mintu P Turakhia
- From the Yale University School of Medicine, New Haven, CT (J.V.F.); University of Michigan, Ann Arbor (D.W.H., G.D.B., R.P.Z.); VA Palo Alto Health Care System, CA (D.K.O., P.A.H., M.P.T.); Stanford University School of Medicine, CA (D.K.O., A.S.G., M.A.H., P.A.H., P.J.W., M.P.T.); Harvard University, Cambridge, MA (A.M.G.); Kaiser Permanente Northern California Division of Research, Oakland (A.S.G.); University of California, San Francisco (A.S.G.); and Texas Cardiac Arrhythmia Institute, Austin (A.A.-A.)
| |
Collapse
|
|
16
|
Jacobs A, Bassa F, Decloedt EH. A preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa. Cardiovasc J Afr 2017; 28:346-349. [PMID: 28656193 PMCID: PMC5885058 DOI: 10.5830/cvja-2017-029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 05/16/2017] [Indexed: 11/06/2022] Open
Abstract
AIM Warfarin is a widely used anticoagulant for the prevention and treatment of thromboembolism. We conducted a retrospective review to determine the causes and management of warfarin toxicity of patients admitted to Tygerberg hospital between June 2014 and June 2015. RESULTS We identified and evaluated 126 patients who met the inclusion criteria. The cause of warfarin toxicity was identified and addressed in only 14.3% (18/126) of patients. Where the cause was identified, 56% (10/18) was due to dosing errors and 17% (3/18) drug-drug interaction (DDI). However, 77% (97/126) of patients were retrospectively identified as receiving concomitant medicines known to interact with warfarin at the time of admission. Twenty-eight percent (35/126) of patients presented with major bleeding, which included seven cases of intracranial haemorrhage. Patients were admitted for a median of eight days at an average treatment cost of R10 578. CONCLUSION We found that warfarin toxicity carries significant mortality and cost, but little attention is paid to the causes of toxicity.
Collapse
Affiliation(s)
- Annemarie Jacobs
- Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.
| | - Fatima Bassa
- Division of Haematology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa
| | - Eric H Decloedt
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa
| |
Collapse
|
|
17
|
Li W, Bu F, Li R, Wang B, Shaikh AS, Zhang Y, Guo R, Zhang R. Bioequivalence Study of Warfarin in Healthy Chinese Volunteers With a Validated High-Performance Liquid Chromatography-Mass Spectrometry Method. Clin Pharmacol Drug Dev 2017; 7:256-262. [PMID: 28371488 DOI: 10.1002/cpdd.348] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 02/16/2017] [Indexed: 11/09/2022]
Affiliation(s)
- Wenlong Li
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Fanlong Bu
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Rong Li
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Benjie Wang
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Abdul Sami Shaikh
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Yunyun Zhang
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Ruichen Guo
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| | - Rui Zhang
- Institute of Clinical Pharmacology, Qilu Hospital of Shandong University; Jinan Shandong Province China 250012
| |
Collapse
|
|
18
|
Xu C, Wu G, Liu X, He Y, Hou X, Li H, Chen C, Yang P, Lin C. Preclinical Study of Anticoagulation Regimens in Sheep After Implantation of CH-VAD Blood Pump. Artif Organs 2016; 42:891-898. [PMID: 27925225 DOI: 10.1111/aor.12595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Effective anticoagulation regimens are needed to reduce risks of thrombosis and bleeding in animal models of ventricular assist device to verify its hemocompatibility, biologic safety and reliability. This study is to develop a validated anticoagulation procedure for a sheep model to test the newly developed CH-VAD. CH-VAD models were established in six healthy sheep by constructing blood bypass of left ventricle → ventricular assist device → descending aorta. Heparin infusion was used during operation and in the prior 4 days to maintain activated clotting time 1.5-2.0 times the baseline. From the third day, proper dosage of warfarin was used orally to maintain international normalized ratio values within the range of 1.2-2.0. After termination, we examined whether there was thrombosis in the blood pump, grafts, and anastomotic stoma. Macroscopic and histopathologic examinations were performed in major organs to check for congestion and infarction. Bleeding complications were not found in any animals throughout the experiments. Activated clotting time values were 326 ± 33 s intraoperatively and 157 ± 28 s in the prior 4 days postoperatively. Activated partial thromboplastin time values increased slowly and reached the lower limit of the target range on the fourth day. Only in one of six cases was thrombus or fibrosis tissue found in the blood flow channel of the pump. Pathologic analysis showed no thrombosis, necrosis and microembolus in end-stage organs. Under the anticoagulation regimens, coagulation system could be well controlled to avoid thrombosis and bleeding complications in sheep models for CH-VAD.
Collapse
Affiliation(s)
- Chuangye Xu
- Department of Biomedical Engineering, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Biomedical Engineering, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China
| | - Guanghui Wu
- Department of Biomedical Engineering, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Biomedical Engineering, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China
| | - Xiujian Liu
- Department of Biomedical Engineering, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Biomedical Engineering, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China
| | - Yuna He
- Department of Biomedical Engineering, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Biomedical Engineering, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China
| | - Xiaotong Hou
- Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Haiyang Li
- Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Chen Chen
- Head Office, ChinaHeart Biomedical Inc., Suzhou, China
| | - Peng Yang
- Head Office, ChinaHeart Biomedical Inc., Suzhou, China
| | - Changyan Lin
- Department of Biomedical Engineering, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Department of Biomedical Engineering, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing, China
| |
Collapse
|
|
19
|
DeCarolis DD, Westanmo AD, Chen YC, Boese AL, Walquist MA, Rector TS. Evaluation of a Potential Interaction Between New Regimens to Treat Hepatitis C and Warfarin. Ann Pharmacother 2016; 50:909-917. [PMID: 27465881 DOI: 10.1177/1060028016660325] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE New regimens to treat hepatitis C virus infection have expanded the eligible patient population to include more patients receiving concurrent warfarin. The primary objective of this study was to assess whether a drug interaction occurs when these regimens are added to warfarin therapy. METHODS This was a retrospective cohort design using a nationwide database of the Veterans Affairs Health System. Patients on warfarin therapy treated with sofosbuvir or ombitasvir, paritaprevir-ritonavir, and dasabuvir (OBV-PTV/r-DSV) from March 2014 through October 2015 were identified. The warfarin dose response was calculated using a warfarin sensitivity index (WSI) defined as the steady-state INR divided by the mean daily warfarin dose. The primary outcome was the change in WSI from hepatitis C treatment initiation to completion. RESULTS The final sample consisted of 271 patients. The WSI decreased 23% from a mean baseline value of 0.53 to 0.39 (decrease of 0.14; 95% CI = 0.11 to 0.16; P < 0.001). OBV-PTV/r-DSV produced a significantly greater decrease than any sofosbuvir regimen. Concurrent ribavirin accounted for an additional decrease in warfarin sensitivity of -0.09 (95% CI = -0.06 to -0.12; P < 0.001). The percentage of subtherapeutic INR results increased from 26% prior to hepatitis C treatment to 58% during treatment. CONCLUSIONS Results indicate a clinically significant reduction in warfarin dose-response when hepatitis C treatment regimens were added to warfarin. They were most profound with OBV-PTV/r-DSV. Ribavirin was associated with an additive effect. Clinicians should be aware of this potential drug interaction to closely monitor and minimize subtherapeutic levels of anticoagulation.
Collapse
Affiliation(s)
| | | | | | - Amanda L Boese
- 1 Minneapolis VA Health Care System, Minneapolis, MN, USA
| | | | | |
Collapse
|
|
20
|
Daba FB, Tadesse F, Engidawork E. Drug-related problems and potential contributing factors in the management of deep vein thrombosis. BMC HEMATOLOGY 2016; 16:2. [PMID: 26855783 PMCID: PMC4743403 DOI: 10.1186/s12878-016-0043-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 01/22/2016] [Indexed: 02/02/2023]
Abstract
Background Patients receiving anticoagulant drugs must be carefully screened for drug-related problems, as such medications, including warfarin have narrow therapeutic ranges and a high potential for complications. Thus, this study was designed to assess drug-related problems in the management of patients with deep vein thrombosis at Tikur Anbessa Specialized Hospital. Methods A cross-sectional descriptive study involving retrospective chart review of adult patients with deep vein thrombosis was conducted from patients who visited the hospital from July 2012 to June 2013, using structured data collection format and this was complemented by key informant interview. Results The study included 91 patients with venous thromboembolism. Fifty three (58.2 %) were females. Mean age was 38.6 (±13.76) years and more than 2/3 were below the age of 44 years. About 54 % of them presented with concurrent medical conditions and most commonly with cancer. Adjustment of warfarin dose up or down was done in increments of 16 to 100 % for recent subtherapeutic International Normalized Ratios, 16 to 50 % for therapeutic and 11 to 66 % for overtherapeutic International Normalized Ratios, with the mean of 36.5 (±18.03) based on the cumulative weekly dose of warfarin. There was significant linear relationship between percentage of dose change and consequent International Normalized Ratio values (R2 = 0.419; p = 0.000). Accordingly, more than 51 % of them presented with nontherapeutic International Normalized Ratio ranges following dose adjustment. Conclusions The most prevalent anticoagulation drug-related problems were subtherapeutic doses, overtherapeutic doses and potential drug interactions. Institutional validated decision support tools for dosing decisions during maintenance anticoagulation therapy should be developed and used accordingly in order to prevent recurrent and hemorrhagic complications and to improve clinical outcomes.
Collapse
Affiliation(s)
- Fekede Bekele Daba
- Department of Pharmacy, College of Health Sciences, Jimma University, P.O. Box 378, Jimma, Ethiopia
| | - Fisihatsion Tadesse
- Department of Internal Medicine, Tikur Anbessa specialized hospital, Addis Ababa University, Addis Ababa, Ethiopia
| | - Ephrem Engidawork
- Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O. Box 1176, Addis Ababa, Ethiopia
| |
Collapse
|
|
21
|
Predictive factors for bleeding during treatment with rivaroxaban and warfarin in Japanese patients with atrial fibrillation - Subgroup analysis of J-ROCKET AF. J Cardiol 2016; 68:523-528. [PMID: 26796348 DOI: 10.1016/j.jjcc.2015.12.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 11/30/2015] [Accepted: 12/15/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. METHODS The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. RESULTS The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. CONCLUSIONS Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively.
Collapse
|
|
22
|
Zhao Y, Liu N, Wang Y, Hickey KT. A rolling-horizon pharmacokinetic pharmacodynamic model for warfarin inpatients in transient clinical states. Per Med 2016; 13:21-32. [DOI: 10.2217/pme.15.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To design a pharmacokinetic pharmacodynamic model to make individualized and adaptive international normalized ratio (INR) predictions for warfarin inpatients in changing clinical status. Methods: We tested a new model on 60 inpatients at Columbia University. The model personalizes four submodels and minimizes the number of parameters to be estimated. Prediction accuracy was assessed by prediction error, absolute prediction error and percentage absolute prediction error. Results: The INRs were accurately predicted 5 days into the future. Median prediction error: 0.01–0.12; median absolute prediction error: 0.17–0.5 and median percentage absolute prediction error: 9.85–26.06%. Conclusion: Patients exhibit interindividual and intertemporal variability. The model captures the variability and provides accurate and personalized INR predictions.
Collapse
Affiliation(s)
- Yao Zhao
- Department of Supply Chain Management, Rutgers Business School, Rutgers – the State University of New Jersey, Newark, NJ, USA
| | - Nan Liu
- Department of Health Policy & Management, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Yijun Wang
- Department of Supply Chain Management, Rutgers Business School, Rutgers – the State University of New Jersey, Newark, NJ, USA
| | - Kathleen T Hickey
- Columbia University School of Nursing, Columbia University Medical Center, NY, USA
| |
Collapse
|
|
23
|
Watanabe KP, Kawata M, Ikenaka Y, Nakayama SMM, Ishii C, Darwish WS, Saengtienchai A, Mizukawa H, Ishizuka M. Cytochrome P450-mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species: In vitro assays in several birds and in vivo assays in chicken. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2015; 34:2328-2334. [PMID: 25959534 DOI: 10.1002/etc.3062] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 01/05/2015] [Accepted: 05/04/2015] [Indexed: 06/04/2023]
Abstract
Coumarin-derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin, a classic coumarin derivative, chickens have a high median lethal dose (LD50), whereas mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to warfarin are to be expected. The authors previously reported substantial differences in warfarin metabolism among avian species; however, the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, the authors sought to provide an in-depth characterization of warfarin metabolism in birds using in vivo and in vitro approaches. A kinetic analysis of warfarin metabolism was performed using liver microsomes of 4 avian species, and the metabolic abilities of the chicken and crow were much higher in comparison with those of the mallard and ostrich. Analysis of in vivo metabolites from chickens showed that excretions predominantly consisted of 4'-hydroxywarfarin, which was consistent with the in vitro results. Pharmacokinetic analysis suggested that chickens have an unexpectedly long half-life despite showing high metabolic ability in vitro. The results suggest that the half-life of warfarin in other bird species could be longer than that in the chicken and that warfarin metabolism may not be a critical determinant of species differences with respect to warfarin sensitivity.
Collapse
Affiliation(s)
- Kensuke P Watanabe
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Minami Kawata
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Yoshinori Ikenaka
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa
| | - Shouta M M Nakayama
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Chihiro Ishii
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Wageh Sobhi Darwish
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Food Control Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Aksorn Saengtienchai
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Department of Pharmacology, Faculty of Veterinary Medicine, Kasetsart University, Lat Yao Chatuchak, Bangkok, Thailand
| | - Hazuki Mizukawa
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Mayumi Ishizuka
- Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| |
Collapse
|
|
24
|
Mensch A, Stock S, Stollenwerk B, Müller D. Cost effectiveness of rivaroxaban for stroke prevention in German patients with atrial fibrillation. PHARMACOECONOMICS 2015; 33:271-283. [PMID: 25404426 DOI: 10.1007/s40273-014-0236-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
OBJECTIVE The aim of this study was to assess the cost effectiveness of the novel fixed-dose anticoagulant rivaroxaban compared with the current standard of care, warfarin, for the prevention of stroke in patients with atrial fibrillation (AF). METHODS A Markov model was constructed to model the costs and health outcomes of both treatments, potential adverse events, and resulting health states over 35 years. Analyses were based on a hypothetical cohort of 65-year-old patients with non-valvular AF at moderate to high risk of stroke. The main outcome measure was cost per quality-adjusted life-year (QALY) gained over the lifetime, and was assessed from the German Statutory Health Insurance (SHI) perspective. Costs and utility data were drawn from public data and the literature, while event probabilities were derived from both the literature and rivaroxaban's pivotal ROCKET AF trial. RESULTS Stroke prophylaxis with rivaroxaban offers health improvements over warfarin treatment at additional cost. From the SHI perspective, at baseline the incremental cost-effectiveness ratio of rivaroxaban was <euro>15,207 per QALY gained in 2014. The results were robust to changes in the majority of variables; however, they were sensitive to the price of rivaroxaban, the hazard ratios for stroke and intracranial hemorrhage, the time horizon, and the discount rate. CONCLUSIONS Our results showed that the substantially higher medication costs of rivaroxaban were offset by mitigating the shortcomings of warfarin, most notably frequent dose regulation and bleeding risk. Future health economic studies on novel oral anticoagulants should evaluate the cost effectiveness for secondary stroke prevention and, as clinical data from direct head-to-head comparisons become available, new anticoagulation therapies should be compared against each other.
Collapse
Affiliation(s)
- Alexander Mensch
- Cologne Institute for Health Economics and Clinical Epidemiology, University of Cologne, Gleueler Straße 176-178, 50935, Cologne, Germany,
| | | | | | | |
Collapse
|
|
25
|
Pirmohamed M, Kamali F, Daly AK, Wadelius M. Oral anticoagulation: a critique of recent advances and controversies. Trends Pharmacol Sci 2015; 36:153-63. [PMID: 25698605 DOI: 10.1016/j.tips.2015.01.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Revised: 01/18/2015] [Accepted: 01/20/2015] [Indexed: 12/17/2022]
Abstract
There have recently been significant advances in the field of oral anticoagulation, but these have also led to many controversies. Warfarin is still the commonest drug used for clotting disorders but its use is complicated owing to wide inter-individual variability in dose requirement and its narrow therapeutic index. Warfarin dose requirement can be influenced by both genetic and environmental factors. Two recent randomized controlled trials (RCTs) came to different conclusion regarding the utility of genotype-guided dosing; we critically explore the reasons for the differences. The new generation of oral anticoagulants have been demonstrated to be as efficacious as warfarin, but further work is needed to evaluate their safety in real clinical settings.
Collapse
Affiliation(s)
- Munir Pirmohamed
- The University of Liverpool, Liverpool L69 3BX, UK; Royal Liverpool and Broadgreen University Hospital National Health Service (NHS) Trust, Prescot Street, Liverpool L7 8XP, UK.
| | - Farhad Kamali
- Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Ann K Daly
- Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | | |
Collapse
|
|
26
|
Lomonaco T, Ghimenti S, Piga I, Biagini D, Onor M, Fuoco R, Di Francesco F. Influence of sampling on the determination of warfarin and warfarin alcohols in oral fluid. PLoS One 2014; 9:e114430. [PMID: 25478864 PMCID: PMC4257678 DOI: 10.1371/journal.pone.0114430] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 11/10/2014] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND OBJECTIVE The determination of warfarin, RS/SR- and RR/SS-warfarin alcohols in oral fluid may offer additional information to the INR assay. This study aimed to establish an optimized sampling technique providing the best correlation between the oral fluid and the unbound plasma concentrations of these compounds. MATERIALS AND METHODS Samples of non-stimulated and stimulated oral fluid, and blood were collected from 14 patients undergoing warfarin therapy. After acidification, analytes were extracted with a dichloromethane/hexane mixture and determined by HPLC with fluorescence detection. Plasma samples were also ultrafiltered for the determination of the unbound fraction. The chromatographic separation was carried out in isocratic conditions with a phosphate buffer/methanol mobile phase on a C-18 reversed-phase column. The absence of interfering compounds was verified by HPLC-ESI-Q-TOF. RESULTS Stimulation generally increased the oral fluid pH to values close to blood pH in about 6 minutes. The concentration of warfarin and RS/SR-warfarin alcohols in oral fluid followed the same trend, whereas the concentration of RR/SS-warfarin alcohols was not affected. Six minute stimulation with chewing gum followed by collection with a polyester swab was the best sampling procedure, with a good repeatability (RSD < 10%) and relatively low inter-subject variability (RSD = 30%) of the oral fluid to plasma ratio. This procedure provided strong correlations between the measured oral fluid and unbound plasma concentration of warfarin (r = 0.92, p < 0.001) and RS/SR-warfarin alcohols (r = 0.84, p < 0.001), as well as between stimulated oral fluid and total plasma concentration of warfarin (r = 0.78, p < 0.001) and RS/SR-warfarin alcohols (r = 0.81, p < 0.001). CONCLUSION The very good correlation between oral fluid and unbound plasma concentration of warfarin and RS/SR-warfarin alcohols suggests that oral fluid analysis could provide clinically useful information for the monitoring of anticoagulant therapy, complementary to the INR assay.
Collapse
Affiliation(s)
- Tommaso Lomonaco
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Silvia Ghimenti
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Isabella Piga
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Denise Biagini
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Massimo Onor
- Institute of Chemistry of Organometallic Compounds, CNR, Pisa, Italy
| | - Roger Fuoco
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
| | - Fabio Di Francesco
- Department of Chemistry and Industrial Chemistry, University of Pisa, Pisa, Italy
- Institute of Clinical Physiology, CNR, Pisa, Italy
| |
Collapse
|
|
27
|
Pakraftar S, Atencio D, English J, Corcos A, Altschuler EM, Stahlfeld K. Dabigatran etixilate and traumatic brain injury: Evolving anticoagulants require evolving care plans. World J Clin Cases 2014; 2:362-366. [PMID: 25133148 PMCID: PMC4133427 DOI: 10.12998/wjcc.v2.i8.362] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 05/30/2014] [Accepted: 07/14/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate the outcomes of trauma patients with traumatic brain injury (TBI) on Dabigatran Etexilate (DE).
METHODS: Following IRB approval, all patients taking DE who were admitted to our level 1 trauma service were enrolled in the study. Injury complexity, length of stay (LOS), intensive care length of stay, operative intervention, therapeutic interventions and outcomes were analyzed retrospectively.
RESULTS: Twenty-eight of 4310 admissions were taking DE. Eleven patients were excluded on concurrent antiplatelet therapy. Average age was 77.14 years (64-94 years), and average LOS was 4.7 d (1-35 d). Thirty-two percent were admitted with intracranial hemorrhage. Eighteen percent received factor VII, and 22% received dialysis in attempts to correct coagulopathy. Mortality was 21%.
CONCLUSION: The low incidence, absence of reversal agents, and lack of practice guidelines makes managing patients with TBI taking DE frustrating and provider specific. Local practice guidelines may be helpful in managing such patients.
Collapse
|
|
28
|
Duraes AR, Roriz PD, Bulhoes FV, Nunes BDA, Muniz JQ, Neto IN, Fernandes AM, Reis FJ, Camara EJ, Junior ED, Segundo DT, Silva FPEA, Aras R. Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: protocol. JMIR Res Protoc 2014; 3:e21. [PMID: 24691436 PMCID: PMC4004148 DOI: 10.2196/resprot.3014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 03/09/2014] [Accepted: 03/13/2014] [Indexed: 01/21/2023] Open
Abstract
Background Warfarin and similar vitamin K antagonists have been the standard therapy for patients with mechanical or biological valve prosthesis and atrial fibrillation (AF). Even with the appropriate use of therapy, some studies have reported that there is a high incidence of thromboembolic events, 1%-4% per year. Furthermore, a bleeding risk is significant, ranging from 2% to 9% per year, according to some studies. Objective The objective of our study was to examine the effect of dabigatran etexilate versus dose-adjusted warfarin for the prevention of intracardiac thrombus in persistent or permanent AF at least 3 months after aortic and/or mitral bioprosthesis replacement. Methods Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively (DAWA) is a phase 2, prospective, open label, randomized exploratory pilot study. The main variable to be observed in this study is intracardiac thrombus. From August 2013 to April 2015, 100 patients, at least 3 months after aortic and/or mitral bioprosthesis replacement and permanent or persistent AF postoperatively, who match eligibility criteria will be selected from Ana Nery Hospital in Salvador-Bahia with a follow-up of three months. Patients were randomly assigned in a 1:1 ratio to receive either dabigatran etexilate or warfarin. Results Although the present study has no statistic power to proof non-inferiority, it is expected that the dabigatran etexilate group will be protected as well as the warfarin group from intracardiac thrombus, without increasing the bleeding rates, since we are using safer doses (110 mg bid). The lack of necessity of monitoring INR is also another factor that contributes to a better adherence to the new drug and it can make all the difference in the manner of doing anticoagulation for patients with similar clinical characteristics. Conclusions The study is in the recruitment phase. It is possible that dabigatran etexilate is as effective as warfarin in preventing the emergence of intracardiac thrombus in patients with AF and mitral and/or aortic bioprosthesis. Trial Registration Clinicaltrials.gov NCT01868243; http://clinicaltrials.gov/ct2/show/NCT01868243 (Archived by WebCite at http://www.webcitation/6OABiuasd).
Collapse
Affiliation(s)
- Andre Rodrigues Duraes
- Hospital Ana Nery, Serviço de Cardiologia, Universidade do Estado da Bahia, Salvador, Brazil.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Mueller JA, Patel T, Halawa A, Dumitrascu A, Dawson NL. Warfarin Dosing and Body Mass Index. Ann Pharmacother 2014; 48:584-8. [DOI: 10.1177/1060028013517541] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Warfarin is still the most commonly used anticoagulant for the treatment of venous thromboembolism and other hypercoagulable states. Warfarin metabolism is affected by multiple factors, including diet, medications, and individual patient characteristics. As both underdosing and overdosing can increase risks to patients, several studies have attempted to develop dosing protocols. However, few have investigated how patient weight and body mass index (BMI) affect warfarin dosing. Objective: The objective of this study was to determine the association between BMI and the total weekly dose (TWD) of warfarin. Methods: In this retrospective study, we identified patients taking warfarin who had an international normalized ratio (INR) within the therapeutic range to assess if there was a significant correlation between TWD, that is, maintenance warfarin dosing, and BMI in obese and nonobese patients. Results: A total of 831 patients were studied, with a BMI range between 13.4 and 63.1 kg/m2. We found that BMI is positively correlated with the total weekly warfarin dose. Our study showed that for each 1-point increase in BMI, the weekly warfarin dose increased by 0.69 mg. We found that the average warfarin weekly dose in this population can be estimated using the formula: 12.34 + 0.69 × BMI. Conclusion: There is an association between BMI and the TWD of warfarin. This could have dosing implications for both patients and prescribers, as patients with a high BMI will be expected to require higher doses of warfarin to maintain a therapeutic INR.
Collapse
|
|
30
|
Eymin G, Jaffer AK. Evidence behind quality of care measures for venous thromboembolism and atrial fibrillation. J Thromb Thrombolysis 2013; 37:87-96. [DOI: 10.1007/s11239-013-0874-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
31
|
Crone E, Saliba N, George S, Hume E, Newall F, Jones S. Commencement of warfarin therapy in children following the Fontan procedure. Thromb Res 2013; 131:304-7. [DOI: 10.1016/j.thromres.2013.01.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 12/18/2012] [Accepted: 01/14/2013] [Indexed: 01/21/2023]
|
|
32
|
Galanis T, Merli GJ. Direct thrombin and factor Xa inhibition for stroke prevention in patients with atrial fibrillation. Hosp Pract (1995) 2013; 41:26-36. [PMID: 23466965 DOI: 10.3810/hp.2013.02.1010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Nonvalvular atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia occurring in patients in the United States. The primary clinical consequence of AF is an increase in the risk and severity of strokes. Treatment guidelines recommend anticoagulation therapy for most patients with AF. One risk-stratification scheme, the CHADS2 index, is simple and widely used to determine the management of patients with AF in regard to stroke prevention. However, new schemes, such as CHA2DS2-VASc, further refine risk stratification to identify patients who would obtain a net clinical benefit from a particular management strategy, thus improving the quality of management. For patients with AF for whom oral anticoagulation (OAC) is advisable, vitamin K antagonist (VKA) therapy is well established and effective. However, OAC with VKAs presents challenges to prescribers and patients in maintaining therapeutic efficacy. Novel OACs may offer alternatives to VKAs. Dabigatran etexilate, a direct thrombin inhibitor, was approved by the US Food and Drug Administration (FDA) in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF. The activated factor X (factor Xa) inhibitor rivaroxaban was recently approved by the FDA both for prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip arthroplasty, and for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF. Apixaban, another factor Xa inhibitor, was recently shown to be effective for stroke prevention in patients with nonvalvular AF. This article reviews clinical considerations regarding new agents that may offer alternatives to VKA therapy for the prevention of stroke in patients with AF.
Collapse
Affiliation(s)
- Taki Galanis
- Thomas Jefferson University Hospitals, Philadelphia, PA, USA
| | | |
Collapse
|
|
33
|
Carvalho ARDS, Ciol MA, Tiu F, Rossi LA, Dantas RAS. Oral Anticoagulation: the impact of the therapy in health-related quality of life at six-month follow-up. Rev Lat Am Enfermagem 2013; 21 Spec No:105-12. [DOI: 10.1590/s0104-11692013000700014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 10/23/2012] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE: to study the changes in health-related quality of life from beginning of anticoagulation therapy to six-month follow-up, and to study associations of sociodemographic and clinical characteristics with measures of quality of life and general health status at six-month follow-up, in individuals using oral anticoagulation due to various medical indications for the therapy. METHOD: prospective study performed at a city in the state of Paraná, Brazil, composed of 78 patients. Measures included the Duke Anticoagulation Satisfaction Scale and the Medical Outcomes Survey Short Form SF-36. RESULTS: mean age was 57 years (S.D.= 16) and 54% were women. Compared to the beginning of therapy, there was a statistically significant improvement in health-related quality of life at six-month follow-up. Linear regression analyses explained 32% and 30%, respectively, of the variance of the Duke Anticoagulation Satisfaction Scale and of the general health status. There was improvement in all components of the SF-36, except Mental Health. CONCLUSION: The use of oral anticoagulation therapy was associated with improvement in health-related quality of life in the first six months of therapy. This study is longitudinal and therefore, has fewer limitations than cross-sectional studies published to date in the Nursing literature in Brazil.
Collapse
|
|
34
|
Amin A. Oral anticoagulation to reduce risk of stroke in patients with atrial fibrillation: current and future therapies. Clin Interv Aging 2013; 8:75-84. [PMID: 23378750 PMCID: PMC3556861 DOI: 10.2147/cia.s37818] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Atrial fibrillation (AF) is associated with an increased incidence and severity of strokes. The burden of AF-related stroke is expected to increase in parallel with the aging of the population. Oral anticoagulation with warfarin has been the pharmacologic standard for stroke risk reduction in patients with AF. When used with close attention to dosing and monitoring, warfarin is effective prophylactic therapy against thromboembolic stroke. However, it is underused by physicians, in part because of the known risks of adverse events with warfarin. Consequently, many patients with AF live with an avoidably elevated risk of stroke. New options, ie, oral anticoagulants with novel mechanisms of action, have recently been approved to reduce the risk of stroke in AF, and others are in development. These newer agents may address some of the complexities of warfarin use while providing similar or better efficacy and safety.
Collapse
Affiliation(s)
- Alpesh Amin
- Hospitalist Program, University of California, Irvine, Orange, CA 92868, USA.
| |
Collapse
|
|
35
|
Interpretation and management of INR results: A case history based survey in 13 countries. Thromb Res 2012; 130:309-15. [DOI: 10.1016/j.thromres.2012.02.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 02/14/2012] [Accepted: 02/21/2012] [Indexed: 01/07/2023]
|
|
36
|
Bauman ME, Mack G, Bruce AK, Bauman ML, Nolan K, Massicotte MP. Natural Health Product Utilization in Warfarinized Children; Prevalence and Knowledge. J Pharm Technol 2012. [DOI: 10.1177/875512251202800303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background:The need for long-term thromboprophylaxis in children using warfarin therapy is increasing. Natural health products (NHPs) are administered to children by parents who perceive them to be useful and acceptable adjuncts or alternatives to conventional therapies. Interactions of NHPs with prescribed therapies may result in serious adverse events. NHP usage is underevaluated in children and there are no studies evaluating NHP usage in warfarinized children.Objectives:To explore NHP use in warfarinized children and their siblings to determine the prevalence, varieties, and reasons for NHP usage, as well as the potential effect on warfarinization (eg, time in therapeutic range [TTR]).Methods:This is a 3-phase cross-sectional cohort study that includes the (1) prevalence (2) NHP education and knowledge assessment, and (3) the follow-up NHP utilization phase.Results:Forty-six percent of warfarinized children consumed NHPs, with time in therapeutic range of 74%. The mean score for baseline knowledge of NHPs and warfarin following the education phase was 67%. Follow-up NHP use was 30%, and increased consistency of utilization with TTR was 83% (p < 0.05), consistent with education provided.Conclusions:The consistent prevalence rates over time of NHP usage in warfarinized children indicate the need for future studies. Education remains vital to combat the potential risks of NHP-warfarin interaction, encouraging patient disclosure and consistency.
Collapse
Affiliation(s)
- Mary E Bauman
- MARY E BAUMAN MN NP, Nurse Practitioner, Pediatric Cardiology, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada
| | - Gordon Mack
- GORDON MACK MD, Fellow, Stollery Children's Hospital
| | - Aisha K Bruce
- AISHA K BRUCE MD FRCPC, Staff Physician, Stollery Children's Hospital
| | - Michelle L Bauman
- MICHELLE L BAUMAN BScN, Research Student, Stollery Children's Hospital
| | - Kyle Nolan
- KYLE NOLAN BA, Research Student, Stollery Children's Hospital
| | | |
Collapse
|
|
37
|
Bejarano-Achache I, Levy L, Mlynarsky L, Bialer M, Muszkat M, Caraco Y. Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study. Clin Ther 2012; 34:811-23. [PMID: 22417713 DOI: 10.1016/j.clinthera.2012.02.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2012] [Indexed: 11/16/2022]
Abstract
BACKGROUND The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K(1) in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K(1) metabolism and the need for a higher maintenance dosage in patients receiving warfarin. OBJECTIVE The purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase. METHODS Warfarin-naive white patients in whom warfarin was scheduled to be initiated with a target INR of 2 to 3 were enrolled into the study. On enrollment, a single blood sample for the genotyping of CYP4F2, CYP2C9, and VKORC1 was drawn. The international normalized ratio (INR) was followed daily during induction and twice weekly until stable anticoagulation was reached. The relationships between several markers of warfarin response during induction and CYP4F2 polymorphism were determined. RESULTS The cohort consisted of 241 patients (115 men; mean [SD] age, 55.2 [19.4] years; weight, 79.5 [18.3] kg). Most of the patients were carriers of the CYP4F2 CC genotype (112 patients) or the CT genotype (104 patients). In carriers of the TT genotype (25 patients), INR >3 was >4-fold lower compared with that in carriers of the CC or CT genotype, suggesting that patients with the TT genotype were less sensitive to warfarin during induction. Also in TT carriers, the extent of excessive anticoagulation was >10-fold lower than in the other carriers. Both of these findings had a nominal P value of <0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of <0.05. Among CC carriers, the concurrent use of a statin was associated with a 1-mg/d reduction in warfarin maintenance dosage. No similar effect was noted in the CT or TT carriers, suggesting a possible genetic influence on warfarin-statin interaction. CONCLUSIONS These preliminary findings suggest that among white patients treated with warfarin, CYP4F2 polymorphism had a measurable effect on warfarin responsiveness during induction; however, the observed differences failed to reach the level of statistical significance. The possibility that the effect of statins on warfarin anticoagulation varies among carriers of different CYP4F2 genotypes could not be excluded and should be evaluated further in a larger patient sample.
Collapse
Affiliation(s)
- Idit Bejarano-Achache
- Clinical Pharmacology Unit, Division of Medicine, Hadassah University Hospital, Jerusalem, Israel
| | | | | | | | | | | |
Collapse
|
|
38
|
Factors affecting medication adherence and anticoagulation control in Korean patients taking warfarin. J Cardiovasc Nurs 2012; 26:466-74. [PMID: 21912274 DOI: 10.1097/jcn.0b013e31820914e7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND RESEARCH OBJECTIVE Poor adherence in patients taking warfarin may be one of the most common barriers to obtain favorable anticoagulation outcomes. This study was conducted to identify factors affecting medication adherence and their relationships with anticoagulation control in Korean patients taking warfarin. SUBJECTS AND METHODS In a cross-sectional survey, 204 patients taking warfarin who had visited an outpatient clinic of a cardiovascular center located in Seoul, Korea, were included as research subjects. Medication adherence, knowledge about warfarin, self-efficacy, and patient understanding of the international normalized ratio (INR) were investigated. Participants' medical records were also reviewed to identify clinical characteristics including comorbid conditions, warfarin regimen, and INR. RESULTS AND CONCLUSIONS When medication adherence was defined as taking warfarin according to medical advice (frequency, dosage, time, and precautions), 56 (27.5%) of 204 respondents were adherent. The adherent group had a greater understanding about warfarin than the nonadherent group as measured by 10 survey items (7.20 ± 1.70 vs 6.56 ± 1.84; P < .05) and had significantly higher self-efficacy (P < .000). However, medication adherence was not associated with good anticoagulation level as measured by INR. The results show that knowledge about warfarin and self-efficacy exert significant influence on medication adherence, and yet medication adherence did not predict therapeutic anticoagulation control. Further studies are needed to identify factors predicting favorable anticoagulation control in patients taking warfarin.
Collapse
|
|
39
|
Abstract
Atrial fibrillation is the most common cardiac arrhythmia that increases in prevalence with age. As the general population grows older, general practitioners will more frequently see this disease in their clinic population. In order to most effectively treat these patients, physicians need to understand key issues, including the use of rhythm control versus ventricular rate control and how to reduce the risk of ischemic stroke. This article will review recent advancements in the understanding of the pathophysiology, management, stroke risk stratification and prevention of thromboembolic complications in atrial fibrillation.
Collapse
Affiliation(s)
- Anne B Riley
- Beth Israel Deaconess Medical Center, Department of Cardiology, Boston, MA, USA
| | | |
Collapse
|
|
40
|
Fustinoni O. The case for an elderly targeted stroke management. Front Neurol 2012; 2:89. [PMID: 22232616 PMCID: PMC3248648 DOI: 10.3389/fneur.2011.00089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 12/13/2011] [Indexed: 01/20/2023] Open
Abstract
Stroke is a leading cause of death and disability worldwide. The elderly, in whom atrial fibrillation (AF) is most prevalent, carry the greatest risk, undergoing more recurrent, deadlier strokes, with bigger deficits, slower recoveries, and more comorbidities. Evidence-based data on advanced age stroke management are scarce. Age-related cerebral changes might undermine the benefit of established stroke treatments. Nevertheless, the elderly should probably also undergo thrombolysis for ischemic stroke: they do not bleed more, and die not because of hemorrhage but of concomitant illnesses. Beyond natural bleeding risks, AF in advanced age has a high embolic potential if not anticoagulated. Standard or lower intensity warfarin anticoagulation prevents embolic stroke in the elderly with a hemorrhage risk even lower than aspirin. In fact, adverse effects seem to occur more often with aspirin. Excess anticoagulation hazards are prevented with lower starting doses, stricter corrections, more frequent International Normalized Ratio monitoring, and longer adjustment intervals. Validated prognostic scores such as CHADS2 help minimize bleeds. Direct inhibitors have recently shown a benefit similar to warfarin with fewer hemorrhages. Carefully tailoring antithrombotics to this age group is therefore useful. Antihypertensives probably help 80-plus stroke patients as well, but the risk/benefit of lowering blood pressure in secondary stroke prevention at that age is uncertain. Evidence-based data on diabetes management and use of lipid-lowering drugs are still lacking in this age group. In summary, emerging data suggest that stroke management should be specifically targeted to the elderly to better prevent its devastating consequences in the population at the highest risk.
Collapse
Affiliation(s)
- Osvaldo Fustinoni
- Department of Neurology, INEBA-Instituto de Neurociencias Buenos Aires, Facultad de Medicina, Universidad de Buenos Aires Buenos Aires, Argentina
| |
Collapse
|
|
41
|
Verstuyft C, Delavenne X, Rousseau A, Robert A, Tod M, Diquet B, Lebot M, Jaillon P, Becquemont L. A Pharmacokinetic–Pharmacodynamic Model for Predicting the Impact of CYP2C9 and VKORC1 Polymorphisms on Fluindione and Acenocoumarol During Induction Therapy. Clin Pharmacokinet 2012; 51:41-53. [DOI: 10.2165/11595560-000000000-00000] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
|
|
42
|
Ghimenti S, Lomonaco T, Onor M, Murgia L, Paolicchi A, Fuoco R, Ruocco L, Pellegrini G, Trivella MG, Di Francesco F. Measurement of warfarin in the oral fluid of patients undergoing anticoagulant oral therapy. PLoS One 2011; 6:e28182. [PMID: 22164240 PMCID: PMC3229510 DOI: 10.1371/journal.pone.0028182] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 11/02/2011] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Patients on warfarin therapy undergo invasive and expensive checks for the coagulability of their blood. No information on coagulation levels is currently available between two controls. METHODOLOGY A method was developed to determine warfarin in oral fluid by HPLC and fluorimetric detection. The chromatographic separation was performed at room temperature on a C-18 reversed-phase column, 65% PBS and 35% methanol mobile phase, flow rate 0.7 mL/min, injection volume 25 µL, excitation wavelength 310 nm, emission wavelength 400 nm. FINDINGS The method was free from interference and matrix effect, linear in the range 0.2-100 ng/mL, with a detection limit of 0.2 ng/mL. Its coefficient of variation was <3% for intra-day measurements and <5% for inter-day measurements. The average concentration of warfarin in the oral fluid of 50 patients was 2.5±1.6 ng/mL (range 0.8-7.6 ng/mL). Dosage was not correlated to INR (r = -0.03, p = 0.85) but positively correlated to warfarin concentration in the oral fluid (r = 0.39, p = 0.006). The correlation between warfarin concentration and pH in the oral fluid (r = 0.37, p = 0.009) confirmed the importance of pH in regulating the drug transfer from blood. A correlation between warfarin concentration in the oral fluid and INR was only found in samples with pH values ≥7.2 (r = 0.84, p = 0.004). CONCLUSIONS Warfarin diffuses from blood to oral fluid. The method allows to measure its concentration in this matrix and to analyze correlations with INR and other parameters.
Collapse
Affiliation(s)
- Silvia Ghimenti
- Dipartimento di Chimica e Chimica Industriale – Università di Pisa, Pisa, Italy
| | - Tommaso Lomonaco
- Dipartimento di Chimica e Chimica Industriale – Università di Pisa, Pisa, Italy
| | - Massimo Onor
- Istituto di Chimica dei Composti Organometallici – CNR, Pisa, Italy
| | - Laura Murgia
- Dipartimento di Chimica e Chimica Industriale – Università di Pisa, Pisa, Italy
| | - Aldo Paolicchi
- Dipartimento di Patologia Sperimentale BMIE, sez. Patologia Generale e Clinica – Università di Pisa, Pisa, Italy
| | - Roger Fuoco
- Dipartimento di Chimica e Chimica Industriale – Università di Pisa, Pisa, Italy
| | - Lucia Ruocco
- Laboratorio di Analisi Chimico – Cliniche - Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Giovanni Pellegrini
- Laboratorio di Analisi Chimico – Cliniche - Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | | | - Fabio Di Francesco
- Dipartimento di Chimica e Chimica Industriale – Università di Pisa, Pisa, Italy
| |
Collapse
|
|
43
|
Lao W, Gan J. Enantioselective degradation of warfarin in soils. Chirality 2011; 24:54-9. [DOI: 10.1002/chir.21023] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 08/10/2011] [Indexed: 11/09/2022]
|
|
44
|
Donati G, Colì L, Cianciolo G, La Manna G, Cuna V, Montanari M, Gozzetti F, Stefoni S. Thrombosis of Tunneled-Cuffed Hemodialysis Catheters: Treatment With High-Dose Urokinase Lock Therapy. Artif Organs 2011; 36:21-8. [DOI: 10.1111/j.1525-1594.2011.01290.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
45
|
The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin Pharmacol Ther 2011; 89:408-15. [PMID: 21270790 DOI: 10.1038/clpt.2010.322] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
It is well recognized that the genetic variants VKORC1-1639, CYP2C9*2, and CYP2C9*3 contribute to warfarin dose response. This has led to warfarin dosing algorithms that include these polymorphisms and explains between 47% and 56% of variability in dose in Caucasians. However, these polymorphisms explain significantly less of the variance in dose among African Americans. In order to identify novel variations that affect warfarin dose in African Americans, we used a targeted resequencing strategy that examined evolutionarily conserved sequences and regions of putative transcriptional binding. Through ethnicity-specific warfarin dose model building in 330 African Americans, we identified two novel genetic associations with higher warfarin dose, namely, VKORC1-8191 (rs61162043, P = 0.0041) and 18786 in CYP2C9 (rs7089580, P = 0.035). These novel finds are independent of the previous associations with these genes. Our regression model, encompassing both genetic and clinical variables, explained 40% of the variability in warfarin dose in African-American subjects, significantly more than any model thus far.
Collapse
|
|
46
|
Wittkowsky AK, Spinler SA, Dager W, Gulseth MP, Nutescu EA. Dosing guidelines, not protocols, for managing warfarin therapy. Am J Health Syst Pharm 2010; 67:1554-6. [PMID: 20811035 DOI: 10.2146/ajhp100064] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Ann K Wittkowsky
- School of Pharmacy, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
| | | | | | | | | |
Collapse
|
|
47
|
Ernst ME, Shaw RF, Ernst EJ, Alexander B, Kaboli PJ. Atmospheric pressure changes and unexplained variability in INR measurements. Blood Coagul Fibrinolysis 2009; 20:263-70. [PMID: 19300239 DOI: 10.1097/mbc.0b013e3283257ffc] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Changes in atmospheric pressure may influence hepatic blood flow and drug metabolism. Anecdotal experience suggests international normalized ratio (INR) variability may be temporally related to significant atmospheric pressure changes. We investigated this potential association in a large sample of patients with multiple INRs. This is a retrospective review of outpatient anticoagulation records from the Iowa City Veteran's Affairs Medical Center and affiliated outpatient clinics from October 1999 to July 2007. All patients, receiving at least one prescription for warfarin and INR at least 30 days or more from the date of the first warfarin prescription, were identified. INRs during periods of hospitalization and vitamin K use were excluded. Proximity analysis using geocoding of ZIP codes of identified patients to the nearest National Oceanic and Atmospheric Administration station was performed to assign atmospheric pressure with INR. Spearman's Rho and Pearson's correlation were used to evaluate atmospheric pressure and INR. Unique patients (1441) with 45 187 INRs were analyzed. When limited to nontherapeutic INRs following a previously therapeutic INR (1121 unique patients/5256 INRs), a small but clinically insignificant association between delta INR and delta atmospheric pressure was observed (r = -0.025; P = 0.038), but not for actual INR and atmospheric pressure (P = 0.06). Delta atmospheric pressure demonstrated greater variation during fall/winter months compared with spring/summer (0.23 vs. 0.15 inHg; P < 0.001); however, variability in INRs for the corresponding seasons was not significant (P = 0.136). No significant difference was detected in the proportions of nontherapeutic INRs among the different seasons (P = 0.371). No correlation was observed between atmospheric pressure changes and INR variability. These findings refute the anecdotal experience seen in our anticoagulation clinic.
Collapse
Affiliation(s)
- Michael E Ernst
- Division of Clinical and Administrative Pharmacy, College of Pharmacy, Department of Family Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
| | | | | | | | | |
Collapse
|
|
48
|
Kilic S, Yuksel B, Doganay M, Bardakci H, Akinsu F, Uzunlar O, Mollamahutoglu L. The effect of levonorgestrel-releasing intrauterine device on menorrhagia in women taking anticoagulant medication after cardiac valve replacement. Contraception 2009; 80:152-7. [DOI: 10.1016/j.contraception.2009.02.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Revised: 02/06/2009] [Accepted: 02/09/2009] [Indexed: 11/16/2022]
|
|
49
|
Schulman S, Melinyshyn A, Ennis D, Rudd-Scott L. Single-dose adjustment versus no adjustment of warfarin in stably anticoagulated patients with an occasional international normalized ratio (INR) out of range. Thromb Res 2009; 125:393-7. [PMID: 19640572 DOI: 10.1016/j.thromres.2009.07.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 07/01/2009] [Accepted: 07/07/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND Well-controlled patients on warfarin may still have occasional International Normalized Ratios (INRs) outside the therapeutic range. It is unclear whether there is any benefit of a single-dose correction in this situation. AIM To evaluate whether patients with very stable INR results should continue with the maintenance dose of warfarin without a single-dose correction, even when the result unexpectedly is moderately below or above the therapeutic range. METHODS A) We reviewed retrospectively 364 patients with unchanged maintenance dose for at least 6 months and an occasional INR outside the therapeutic range regarding decision on dosing and the effect on the next INR. B) We randomized 160 patients with at least 3 months of unchanged maintenance dose, an occasional INR deviating to a minimum of 1.5 or a maximum of 4.4 and unexplained or temporary, removable cause to a single-dose Change or No change. Follow-up INRs and telephone interviews were obtained after 2 weeks. RESULTS A) Retrospectively, the proportion of follow-up INRs outside the therapeutic range was 29.9% after No change, 27.1% after Increased dose and 25.7% after Skipped/reduced dose. However, the decision on No change was mainly taken in case of minimal INR deviations. B) Forty-eight (60%) of the patients randomized to Change were within the therapeutic range at follow-up versus 45 (56%) of those with No change, odds ratio 1.17 (95% confidence interval 0.59-2.30). For baseline INRs deviating down to 1.6 or up to 3.6 (therapeutic range, INR 2.0-3.0) the 2-week INRs did not differ between the groups. CONCLUSION Our results suggest only a small or no difference between the two managements of an occasional INR out of range in terms of the 2-week follow-up INR. In stable patients on warfarin with an occasional INR outside the therapeutic range it seems reasonable to continue with the same dose without a single-dose change and perform a repeat test in about 2 weeks. (ClinicalTrials.gov number, NCT00814177.).
Collapse
Affiliation(s)
- S Schulman
- Department of Medicine, McMaster University, Hamilton, ON, Canada.
| | | | | | | |
Collapse
|
|
50
|
Patrick AR, Avorn J, Choudhry NK. Cost-effectiveness of genotype-guided warfarin dosing for patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2009; 2:429-36. [PMID: 20031873 DOI: 10.1161/circoutcomes.108.808592] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND CYP2C9 and VKORC1 genotyping has been advocated as a means of improving the accuracy of warfarin dosing. However, the effectiveness of genotyping in improving anticoagulation control and reducing major bleeding has not yet been compellingly demonstrated. Genotyping currently costs $400 to $550. METHODS AND RESULTS We constructed a Markov model to evaluate whether and under what circumstances genetically-guided warfarin dosing could be cost-effective for newly diagnosed atrial fibrillation patients. Estimates of clinical event rates, treatment and adverse event costs, and utilities for health states were derived from the published literature. The cost-effectiveness of genetically-guided dosing was highly dependent on the assumed effectiveness of genotyping in increasing the amount of time patients spend appropriately anticoagulated. If genotyping increases the time spent in the target international normalized ratio range by <5 percentage points, its incremental cost-effectiveness ratio would be greater than $100,000 per quality-adjusted life year. The incremental cost-effectiveness ratio falls below $50,000 per quality-adjusted life year if genotyping increases the time spent in range by 9 percentage points. The results were also sensitive to assumptions about the rate of major bleeding events during treatment initiation and the cost of the test. CONCLUSIONS Our results suggest that genotyping before warfarin initiation will be cost-effective for patients with atrial fibrillation only if it reduces out-of-range international normalized ratio values by more than 5 to 9 percentage points compared with usual care. Given the current uncertainty surrounding genotyping efficacy, caution should be taken in advocating the widespread adoption of this strategy.
Collapse
Affiliation(s)
- Amanda R Patrick
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02120, USA.
| | | | | |
Collapse
|