Original ResearchPharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity
Introduction
During the past 30 years, there has been a rapid increase in the prevalence of both atrial fibrillation (AF) and obesity among the world's adult population.1,2 Obesity affects the pharmacokinetic properties of drugs, including the Vd, in particular for the lipophilic drugs, as well as CL/F. Indeed, the renal blood flow and the creatinine clearance are increased in obesity and could favor the elimination of the oral anticoagulants.3 Patients with obesity who are receiving treatment with vitamin K antagonists (VKAs) require larger doses and longer lead-in periods for achieving therapeutic international normalized ratio values.4 Direct oral anticoagulants (DOACs) are recommended over VKAs for stroke prevention in patients with AF eligible for oral anticoagulation therapy5; however, data and clinical experiences supporting the use DOACs in morbid obesity (patients with a body mass index [BMI] ≥40 kg/m2 or weight >120 kg) remain limited.6, 7, 8 The current guidelines of the International Society of Thrombosis and Haemostasis recommend the use of VKAs in patients with morbid obesity and suggest checking a drug-specific peak and trough level (anti-FXa for apixaban, edoxaban, and rivaroxaban, ecarin time or dilute thrombin time with appropriate calibrators for dabigatran, or mass spectrometry drug level for any of the DOACs), when DOACs are administrated in these patients. The switch to VKA is recommended if any drug level is found below the expected range (Table I).9 This approach is also suggested by the latest European Heart Rhythm Association practical guide on the use of DOACs in patients with AF.10 The aim of our study was to evaluate the DOAC plasma levels among a cohort of patients with extreme obesity (BMI ≥40 kg/m2) and obesity in a real-world setting.
Section snippets
Study Population
We enrolled all consecutive patients with extreme obesity and AF receiving DOAC treatment who were followed up at Monaldi Hospital, Naples, Italy, from September 2019 to December 2020. Extreme obesity was defined as a BMI of ≥40 kg/m2. The temporary discontinuation of DOAC treatment or the lack of adherence verified through medical history were considered as an exclusion criterion. Patient demographic characteristics, clinical characteristics, and laboratory data were collected; moreover, the
Results
A total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] BMI, 44.43 [3.54] kg/m2) and AF who were receiving DOAC treatment were included in the present study. A total of 24 patients (41.4%) were taking apixaban, 12 (20.7%) were taking dabigatran, 9 (15.5%) were taking rivaroxaban, and 13 (22.4%) were taking edoxaban. The DOAC dose was appropriate in 51 patients (87.9%); in contrast, 7 patients (12.1%) were taking DOACs not in compliance with the
Discussion
The main findings of this study can be summarized as follow: 15.5% of patients with extreme obesity and AF treated with DOACs had DOAC plasma concentration out of the expected range; in particular, the trough plasma concentrations were below the lower reference limit; the inappropriate low DOAC dosing seems to be the only independent clinical predictor of DOAC plasma concentration out of the expected range.
Few data are available on the DOAC plasma concentration among patients with obesity and
Conclusions
The findings of this study suggest that patients with extreme obesity and AF receiving DOAC therapy had a DOAC plasma concentration in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with the drugs’ plasma concentration out of the expected range.
Acknowledgments
Author contributions are as follows: Vincenzo Russo: conceptualization, methodology; Dario Cattaneo: data curation; Laura Giannetti: writing–original draft preparation; Nunzia Laezza: visualization, investigation; Roberta Bottino: supervision; Luigi Atripaldi: validation; Emilio Clementi: writing–reviewing and editing. All authors have approved the final article.
DISCLOSURE
The authors have indicated that they have no conflicts of interest regarding the content of this article.
References (35)
- et al.
Impact of BMI on clinical outcomes of NOAC therapy in daily care: results of the prospective Dresden NOAC Registry (NCT01588119)
Int J Cardiol
(2018) - et al.
Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH
J Thromb Haemost
(2016) - et al.
Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants
J Am Coll Cardiol
(2014) - et al.
The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients
J Am Coll Cardiol
(2014) - et al.
Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study)
Am J Cardiol
(2007) - et al.
Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial
Lancet
(2015) - et al.
Randomized, double-blind comparison of half-dose versus full-dose edoxaban in 14,014 patients with atrial fibrillation
J Am Coll Cardiol
(2021) - et al.
Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: a retrospective study
Res Pract Thromb Haemost
(2018) - et al.
Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study
Circulation
(2014) - Obesity and overweight. Accessed May 15, 2021....
Glomerular hemodynamics in severe obesity
Am J Physiol Renal Physiol
Comparison of initial warfarin response in obese patients versus non-obese patients
J Thromb Thrombolysis
2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS)
Eur Heart J
Comparing the efficacy and safety of direct oral anticoagulants with warfarin in the morbidly obese population with atrial fibrillation
Ann Pharmacother
Clinical performance of nonvitamin K antagonist oral anticoagulants in real-world obese patients with atrial fibrillation
Semin Thromb Hemost
2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation
EP Europace
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2022, Pharmacological ResearchCitation Excerpt :These indications are based on the results of two metanalysis of randomized clinical trials (RCTs) including 71.683 AF patients [3] and 24.455 DVT patients [4], respectively. Moreover, the safety and effectiveness of NOACs have been confirmed among several real-world observational studies, resulting in a rapid increase of their use, over vitamin K antagonists (VKAs) [5], across the following clinical scenarios: obesity [6,7], malignancy [8,9], elderly [10], bioprosthetic valves or prior valves repair [11], AF patients scheduled for electrical cardioversion [12] and hospitalized patients with coronavirus disease 2019 (COVID-19) [13]. NOACs elicit their effects by inhibiting the activated factor X (FXa) or thrombin (FIIa), both involved into the final common pathway of the coagulation cascade [14]; moreover, FXa and FIIa show “pleiotropic” effects on inflammation pathway, through the activation of protease-activated receptors (PARs) family [15,16].
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