Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity |
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| Affiliation: | 1. Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli” – Monaldi Hospital, Via Leonardo Bianchi, Naples, Italy;2. Unit of Clinical Pharmacology, Fatebenefratelli-Sacco University Hospital, Milano, Italy;3. Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, Fatebenefratelli-Sacco University Hospital, Università di Milano, Milano, Italy;4. Scientific Institute IRCCS Eugenio Medea, Lecco, Italy;1. Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children''s Hospital of Chicago;2. Northwestern University Feinberg School of Medicine, Chicago, Illinois;1. Medical Genetics, Dept. of Clinical and Experimental Medicine, University of Foggia, Italy;2. Atherosclerosis and Thrombosis Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo, Italy;3. Cardiology, Dept of Medical and Surgical Sciences, University of Foggia, Italy;4. Haemostasis and Thrombosis Center, Department of Laboratory Medicine, AO Istituti Ospitalieri, Cremona, Italy;1. Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom;2. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;3. Hospital Universitario La Paz, Universidad Europea, Madrid, Spain;4. Department of Hypertension, Medical University of Lodz, Lodz, Poland;5. Amsterdam UMC, University of Amsterdam, Heart Center, Department of Cardiology, Amsterdam, The Netherlands;6. Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany;7. Dell''Angelo Hospital, Venice-Mestre, Italy;8. Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy;9. Daiichi Sankyo, Inc., Basking Ridge, New Jersy;10. St. Vincenz-Hospital, Paderborn, Germany;11. Working Group: Molecular Electrophysiology, University Hospital Magdeburg, Magdeburg, Germany;1. Pharmacy Services, Alberta Health Services, Edmonton, Alberta, Canada;2. Division of Hematology, University of Alberta, Edmonton, Alberta, Canada;3. Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada |
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| Abstract: | PurposeDirect oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity.MethodsWe enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range.FindingsA total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m2) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges.ImplicationsPatients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range. |
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