Elsevier

Clinical Therapeutics

Volume 43, Issue 9, September 2021, Pages e255-e263
Clinical Therapeutics

Original Research
Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity

https://doi.org/10.1016/j.clinthera.2021.07.003Get rights and content

Highlights

  • Data supporting the use of DOACs in patients with extreme obesity are lacking

  • Current guidelines suggest measurements of DOACs levels in morbidly obese patients

  • Patients with extreme obesity and atrial fibrillation on DOACs therapy show DOAC's plasma concentration in the expected range.

  • There is no correlation between plasma concentration in extreme obese patients and the hyperfiltrating patients (clearance of creatinine>95 ml/min).

  • DOACs inappropriate underdosing is the only predictor of DOACs plasma concentration out of the expected range.

Abstract

Purpose

Direct oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity.

Methods

We enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found ​​below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range.

Findings

A total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m2) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges.

Implications

Patients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.

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.

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