679 Pharmacokinetics of direct oral anticoagulants in patient with atrial fibrillation and extreme obesity

Abstract Aims 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 and results 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 two groups. Univariate and multivariate logistic regression analyses were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range. 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 was included in the present study. In nine 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. Conclusions 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.

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Switching to Another Oral Anticoagulant and Drug Discontinuation Among Elderly Patients With Nonvalvular Atrial Fibrillation Treated With Different Direct Oral Anticoagulants

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029619870249 ◽

2019 ◽

Vol 25 ◽

pp. 107602961987024 ◽

Cited By ~ 2

Author(s):

Christine L. Baker ◽

Amol D. Dhamane ◽

Jigar Rajpura ◽

Jack Mardekian ◽

Oluwaseyi Dina ◽

...

Keyword(s):

Atrial Fibrillation ◽

Elderly Patients ◽

Oral Anticoagulant ◽

Cox Regression ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Drug Discontinuation ◽

Research Database ◽

Nonvalvular Atrial Fibrillation ◽

Study Population

We compared the risks of switching to another oral anticoagulant (OAC) and discontinuation of direct oral anticoagulants (DOACs) among elderly patients with nonvalvular atrial fibrillation (NVAF) who were prescribed rivaroxaban or dabigatran versus apixaban. Patients (≥65 years of age) with NVAF prescribed DOACs (January 1, 2013 to September 30, 2017) were identified from the Humana research database and grouped into DOAC cohorts. Cox regression analyses were used to evaluate whether the risk for switching to another OAC or discontinuing index DOACs differed among cohorts. Of the study population (N = 38 250), 55.9% were prescribed apixaban (mean age: 78.6 years; 49.8% female), 37.3% rivaroxaban (mean age: 77.4 years; 46.7% female), and 6.8% dabigatran (mean age: 77.0 years; 44.0% female). Compared to patients prescribed apixaban, patients prescribed rivaroxaban (hazard ratio [HR]: 2.08; 95% confidence interval [CI], 1.92-2.25; P < .001) or dabigatran (HR: 3.74; 95% CI, 3.35-4.18, P < .001) had a significantly higher risk of switching to another OAC during the follow-up; compared to patients prescribed apixaban, the risks of discontinuation were also higher for patients treated with rivaroxaban (HR: 1.10; 95% CI, 1.07-1.13, P < .001) or dabigatran (HR: 1.29; 95% CI, 1.23-1.35, P < .001).

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Management of Severe Bleeding in Patients Treated with Direct Oral Anticoagulants

Anesthesiology ◽

10.1097/aln.0000000000001631 ◽

2017 ◽

Vol 127 (1) ◽

pp. 111-120 ◽

Cited By ~ 28

Author(s):

Keyword(s):

Plasma Concentration ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Management Strategies ◽

Plasma Concentrations ◽

Severe Bleeding ◽

Direct Oral Anticoagulant ◽

Prothrombin Complex Concentrates ◽

Bleeding Events

Abstract Background The use of prothrombin complex concentrates and the role of plasma concentration of anticoagulants in the management of bleeding in patients treated with direct oral anticoagulants are still debated. Our aim was to describe management strategies and outcomes of severe bleeding events in patients treated with direct oral anticoagulants. Methods We performed a prospective cohort study of 732 patients treated with dabigatran, rivaroxaban, or apixaban hospitalized for severe bleeding, included prospectively in the registry from June 2013 to November 2015. Results Bleeding was gastrointestinal or intracranial in 37% (212 of 732) and 24% (141 of 732) of the cases, respectively. Creatinine clearance was lower than 60 ml/min in 61% (449 of 732) of the cases. The plasma concentration of direct oral anticoagulants was determined in 62% (452 of 732) of the cases and was lower than 50 ng/ml or higher than 400 ng/ml in 9.2% (41 of 452) and in 6.6% (30 of 452) of the cases, respectively. Activated or nonactivated prothrombin complex concentrates were administered in 38% of the cases (281 of 732). Mortality by day 30 was 14% (95% CI, 11 to 16). Conclusions Management of severe bleeding in patients treated with direct oral anticoagulants appears to be complex. The use of prothrombin complex concentrates differs depending on bleeding sites and direct oral anticoagulant plasma concentrations. Mortality differs according to bleeding sites and was similar to previous estimates.

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Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: Results observed in four anticoagulation clinics

Thrombosis Research ◽

10.1016/j.thromres.2015.12.001 ◽

2016 ◽

Vol 137 ◽

pp. 178-183 ◽

Cited By ~ 74

Author(s):

Sophie Testa ◽

Armando Tripodi ◽

Cristina Legnani ◽

Vittorio Pengo ◽

Rosanna Abbate ◽

...

Keyword(s):

Atrial Fibrillation ◽

Plasma Levels ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Real Life ◽

Anticoagulation Clinics

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Outcomes of Direct Oral Anticoagulants in Atrial Fibrillation Patients Across Different Body Mass Index Categories

JACC: Clinical Electrophysiology ◽

10.1016/j.jacep.2021.02.002 ◽

2021 ◽

Author(s):

Amr F. Barakat ◽

Sandeep Jain ◽

Ahmad Masri ◽

Laith Alkukhun ◽

Mourad Senussi ◽

...

Keyword(s):

Atrial Fibrillation ◽

Body Mass Index ◽

Body Mass ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants

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Safety and efficacy of dronedarone from clinical trials to real-world evidence: implications for its use in atrial fibrillation

EP Europace ◽

10.1093/europace/euz193 ◽

2019 ◽

Cited By ~ 2

Author(s):

Giuseppe Boriani ◽

Carina Blomström-Lundqvist ◽

Stefan H Hohnloser ◽

Lennart Bergfeldt ◽

Giovanni L Botto ◽

...

Keyword(s):

Atrial Fibrillation ◽

Real World ◽

Liver Toxicity ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Plasma Concentrations ◽

Low Risk ◽

Safety Concerns ◽

Real World Evidence ◽

Liver Safety

Abstract Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone–digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban–dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban–dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

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Laboratory Assessment of the Anticoagulant Activity of Apixaban in Patients With Nonvalvular Atrial Fibrillation

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029618802364 ◽

2018 ◽

Vol 24 (9_suppl) ◽

pp. 194S-201S ◽

Cited By ~ 3

Author(s):

Elias Kyriakou ◽

Konstantinos Katogiannis ◽

Ignatios Ikonomidis ◽

George Giallouros ◽

Georgios K. Nikolopoulos ◽

...

Keyword(s):

Atrial Fibrillation ◽

Thrombin Generation ◽

Anticoagulant Activity ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Plasma Concentrations ◽

Nonvalvular Atrial Fibrillation ◽

Laboratory Assessment ◽

Thrombin Generation Assay ◽

Significant Difference

Our aim is to determine the most appropriate laboratory tests, besides anti-factor Xa (anti-FXa) chromogenic assays, to estimate the degree of anticoagulation with apixaban and compare it with that of rivaroxaban in real-world patients. Twenty patients with nonvalvular atrial fibrillation treated with apixaban 5 mg twice daily and 20 patients on rivaroxaban 20 mg once daily were studied. Conventional coagulation tests, thrombin generation assay (TGA), and thromboelastometry (nonactivated TEM [NATEM] assay) were performed in the 40 patients and 20 controls. The anti-FXa chromogenic assays were used to measure apixaban and rivaroxaban plasma levels. The NATEM measurements showed no significant difference between the 2 groups of patients. Concerning TGA, endogenous thrombin potential (ETP) was significantly decreased in patients on rivaroxaban as compared to those treated with apixaban ( P < .003). A statistically significant, strong inverse correlation between apixaban plasma concentrations and ETP ( P < .001) was observed. Apixaban significantly reduces ETP compared to controls, but to a lesser extent than rivaroxaban. Thrombin generation assay might provide additional information on apixaban exposure, which is required in order to individualize treatment especially for patients with a high bleeding risk. Our findings have to be further investigated in studies with larger sample sizes, in the entire range of apixaban exposure, with other direct oral anticoagulants, and in relation to clinical outcomes.

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

Clinical Therapeutics ◽

10.1016/j.clinthera.2021.07.003 ◽

2021 ◽

Author(s):

Vincenzo Russo ◽

Dario Cattaneo ◽

Laura Giannetti ◽

Roberta Bottino ◽

Nunzia Laezza ◽

...

Keyword(s):

Atrial Fibrillation ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Extreme Obesity

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Comprehensive Intraprocedural Unfractionated Heparin Protocol During Catheter Ablation of Atrial Fibrillation in the Presence of Direct Oral Anticoagulants and Wide Spectrum of Body Mass Index

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248421998492 ◽

2021 ◽

pp. 107424842199849

Author(s):

Michael Safani ◽

Serge Tobias ◽

Adrian H. Shandling ◽

Kathryn Redmond ◽

Mark Young Lee

Keyword(s):

Atrial Fibrillation ◽

Body Mass Index ◽

Catheter Ablation ◽

Unfractionated Heparin ◽

Body Mass ◽

Wide Spectrum ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Optimal Dosing ◽

The Mean

Introduction: Data on optimal dosing of unfractionated heparin (UFH) in the presence of a direct oral anticoagulant (DOAC) to achieve and maintain an activated clotting time (ACT) of ≥300 seconds during catheter ablation of atrial fibrillation (CA-AF) are limited and prevalence of obesity adds to the unpredictable response to UFH. Methods and Results: One hundred seventeen consecutive patients undergoing CA-AF were prospectively administered weight-adjusted, weight-based UFH using a pre-specified detailed protocol and retrospectively analyzed. Due to lack of distribution of UFH into muscle or adipose tissue and lower degree of vascularity in the latter compartment, each patient’s ideal and actual weights were used to determine the adjusted-weight for use in all UFH doses. A UFH bolus of 200 units/kg was administered intravenously followed by an infusion of 35 units/kg/hour. The mean age was 65 years, and 85 patients (72.6%) were male. The average body mass index (BMI) was 30 (range 18-50) kg/m2. After the initial UFH bolus dose, 99 patients (84.6%) achieved ACT ≥300 sec with a mean (± SD) of 380 ± 79 sec. The mean time to reach an ACT ≥300 in all patients was 14.6 ± 12.4 minutes. Among all measured ACT values, 423 (90.8%) were ≥300 seconds. These results were consistent within all BMI categories. There were no intraprocedural thrombotic or hemorrhagic complications. Two patients (1.7%) sustained groin vascular access site hematoma without subsequent intervention and 7 patients (6%) experienced minor oozing post-procedurally. Conclusions: Our comprehensive weight-adjusted, weight-based UFH protocol, during CA-AF in presence of a DOAC, rapidly achieved and maintained an effective ACT irrespective of BMI.

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Abstract P003: Effectiveness And Safety Of Direct Oral Anticoagulants Compared With Warfarin In Patients With Atrial Fibrillation Across Body Mass Index Categories

Circulation ◽

10.1161/circ.143.suppl_1.p003 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Yoshihiro Tanaka ◽

Sadiya Khan ◽

Rachel Kaplan ◽

Philip Greenland ◽

Rod S Passman ◽

...

Keyword(s):

Atrial Fibrillation ◽

Body Mass Index ◽

Body Mass ◽

Intracranial Hemorrhage ◽

Propensity Scores ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Safety Outcome ◽

One Year

Background: Although direct oral anticoagulants (DOACs) are preferred for most patients needing anticoagulation for atrial fibrillation (AF), uncertainty remains in the effectiveness and safety of DOACs compared with warfarin in patients with obesity. Available data from large real-word cohorts are lacking. Purpose: To examine the effectiveness and safety of DOACs compared with warfarin in patients with obesity and AF. Methods: We conducted a retrospective cohort study at an integrated, multi-site healthcare system. We included patients with AF prescribed either a DOAC or warfarin with ≥ one year of follow-up between 2010-2017. The primary effectiveness outcome was ischemic stroke or systemic embolism (S/SE) and the primary safety outcome was incident intracranial hemorrhage (ICH). Using logistic regression, we calculated propensity scores (PS) of prescription for DOAC in each body mass index (BMI) category (<25 kg/m2, 25.0-29.9 kg/m2, 30.0 to 34.9 kg/m2, and BMI≥35.0 kg/m2) using the following covariates: age, sex, race, ethnicity, BMI, systolic blood pressure, and CHA 2 DS 2 -VASc score. We used inverse probability weighting (IPW) based on the PS and IPW-weighted hazard ratios with 95% confidence intervals were calculated by Cox proportional hazard model. Results: Of a total of 17,905 patients included, mean (standard deviation [SD]) age was 70 ± 12 years and mean (SD) BMI was 29.9 ± 6.7 kg/m 2 ; nearly half received a prescription for DOAC (42.7%) and 57.3% for warfarin. During median follow-up of 3.8 years (interquartile range: 2.2-6.0), a total of 159 stroke and 376 intracranial hemorrhage events were observed. Patients on DOACs had a similar or lower HRs for both S/SE and ICH events compared with warfarin across each BMI category (Figure). Conclusion: In this retrospective study, DOACs were as safe and effective compared with warfarin across BMI categories in patients with AF.

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