Direct Oral Anticoagulant Concentrations in Obese and High Body Weight Patients: A Cohort Study

2020 ◽  
Author(s):  
Anne Céline Martin ◽  
William Thomas ◽  
Zahra Mahir ◽  
Maeve P. Crowley ◽  
Terry Dowling ◽  
...  
Keyword(s):  
Body Weight ◽  
Creatinine Clearance ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
High Body Weight ◽  
High Body ◽  
Trough Concentrations ◽  
Fxa Inhibitor ◽  
Age Range

Abstract Background Direct oral anticoagulants (DOACs) are prescribed for atrial fibrillation (AF) and venous thromboembolism (VTE) and both occur more frequently in obese patients. Outcomes from DOAC trials included few individuals ≥ 120 kg leading to uncertainty whether high body weight (BW) reduces DOAC concentrations. Objectives This article investigates the relationship between factor Xa (FXa) inhibitor concentrations, BW, and renal function, and compares them in high BW patients with unselected populations. Methods Consecutive patients in two United Kingdom centers, weighing ≥ 120 kg receiving 5 mg twice daily apixaban or 20 mg once daily rivaroxaban for AF or VTE were prospectively included. Peak or trough concentrations were measured using specific chromogenic assays, expressed in mean or median (5th–95th percentiles). On-therapy range was the interval from the 5th percentile trough concentration to the 95th percentile peak concentration. Results One hundred patients were included; age range: 23 to 78 years, 31% were women, 58% had AF, creatinine clearance range: 67 to 474 mL/min. Median BW was 139 kg, and 84% had body mass index (BMI) ≥ 40 kg/m2. DOAC peak and trough concentrations varied from 44 to 727 and 14 to 299 ng/mL, respectively. There was no linear relationship between FXa inhibitor concentrations at peak or trough and BW or BMI, and creatinine clearance. Apixaban troughs in AF and rivaroxaban peaks in VTE were lower than in unselected populations. However, only two trough concentrations were below the expected range, and 109/116 were within the on-therapy range. Conclusion These data indicated that obese or high BW patients generally achieve therapeutic FXa inhibitor concentrations. However, further investigations assessing clinical outcomes are required.

Direct-acting oral anticoagulant use at extremes of body weight: Literature review and recommendations

2020 ◽  
Vol 77 (11) ◽  
pp. 865-876
Author(s):  
Kelly Covert ◽  
Donald L Branam
Keyword(s):  
Body Weight ◽  
Oral Anticoagulants ◽  
Careful Consideration ◽  
Cardioembolic Stroke ◽  
Safety And Efficacy ◽  
High Body Weight ◽  
High Body ◽  
Published Evidence ◽  
Agent Selection ◽  
Direct Acting

Abstract Purpose To review the literature on treatment of venous thromboembolism (VTE) and prevention of cardioembolic stroke with direct-acting oral anticoagulants (DOACs) in low- and high-body-weight patients and to make recommendations regarding agent selection and dosing in these patient populations. Summary The selection and optimal dosing of DOACs in low- and high-body-weight patients has not yet been fully elucidated by clinical trials; however, evidence suggests that issues of both safety and efficacy in patients at the extremes of body weight may warrant careful consideration when selecting a DOAC for such patients. This review provides a thorough discussion of the use of DOACs in the treatment of VTE and prevention of cardioembolic stroke in patients at the extremes of body weight and provides guidance regarding agent selection. Conclusion While the published evidence on use of DOACs in patients at extremes of body weight is sparse, apixaban and rivaroxaban appear to have the most favorable safety and efficacy profiles. Edoxaban and dabigatran should be avoided.

Direct Oral Anticoagulants in Obesity: An Updated Literature Review

2020 ◽  
Vol 54 (11) ◽  
pp. 1144-1158 ◽  
Author(s):  
Jamielynn Sebaaly ◽  
Denise Kelley
Keyword(s):  
Body Weight ◽  
Patient Population ◽  
Data Extraction ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
High Body Mass Index ◽  
Review Literature ◽  
Quality Data ◽  
Nonvalvular Atrial Fibrillation ◽  
High Body

Objective: To review literature on the use of direct-acting oral anticoagulants (DOACs) in patients with high body weight (BW) and/or high body mass index (BMI) and to make recommendations regarding use in this patient population. Data Sources: A search using PubMed was conducted (inception to April 13, 2020) using the term DOAC AND the terms obesity OR body weight. A separate search was also conducted with individual DOACs (dabigatran, apixaban, rivaroxaban, edoxaban) and the aforementioned terms. Study Selection and Data Extraction: Studies included examined the effect of BW and/or BMI on DOAC pharmacokinetics, efficacy, or safety. Included studies had DOAC indications of prevention of stroke in nonvalvular atrial fibrillation, or treatment or long-term prevention of venous thromboembolism. Data Synthesis: The efficacy and safety of DOACs in patients with high BW/BMI has not yet been elucidated by randomized trials; however, 2016 international guidelines suggest avoiding their use in patients with a BW >120 kg or BMI >40 kg/m2. Since 2016, several studies have been published examining use of DOACs in this patient population. Relevance to Patient Care and Clinical Practice: This review thoroughly discusses the literature on DOACs in patients with a BW >120 kg or BMI >40 kg/m2 pre-2016 and post-2016 guidelines. Conclusions: Evidence indicates that each DOAC may have differences in outcomes when used in patients with a high BW/BMI. Currently, low-quality data are available that support avoiding dabigatran and considering apixaban or rivaroxaban; lack of sufficient data preclude a recommendation for edoxaban use in this patient population.

460Edoxaban versus warfarin in atrial fibrillation patients with low, mid and high body weight: analysis of outcomes in the engage AF TIMI 48 trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G Boriani ◽  
C T Ruff ◽  
J F Kuder ◽  
M Shi ◽  
H Lanz ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Body Weight ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Clinical Status ◽  
Similar Efficacy ◽  
Relative Reduction ◽  
High Body Weight ◽  
High Body ◽  
The Impact

Abstract Background The impact on outcomes of oral anticoagulants in pts at extremes of body weight have not been well-characterized. Aim To analyse the outcomes of pts with atrial fibrillation (AF) enrolled in ENGAGE AF-TMI 48 randomized to warfarin (W) targeting INR 2.0–3.0, higher (HDE) or lower dose regimens of edoxaban (LDE), focusing on subgroups of patients at the extremes of weight. Methods and results Among 21105 pts enrolled in the trial we identified 3 subgroups: 1082 with low body weight (LBW) (<5th percentile, <55kg), 2153 with mid body weight (MBW) (45–55th percentile, 80–84 kg), and 1093 patients with high body weight (HBE) (>95th percentile, >120 kg). Baseline characteristics differed markedly (LWB pts were older and more likely Asian, women, with prior TIA/stroke, renal dysfunction) resulting in a trend towards higher rates of stroke/systemic embolism (SSE: 6.5% vs 4.7% in MBW vs 1.6% in HBW) and major bleeding (MB: 9.3% vs 7.7% in MBW vs 6.5% in HBW) in the warfarin arm. The risks of SSE (Pint = 0.52) were similar between W and HDE regardless of body weight, while the relative reduction in MB was greatest in LBW patients (HR reduction45%, 23%, 1% across weight groups; Pint = 0.35) (Figure). Net clinical outcomes (SEE/major bleeding/death) tended to be most favourable for LBW pts (HR 0.67 [0.50–0.90]; Pint 0.084) (Figure). Main outcomes during follow up Conclusions In ENGAGE AF-TIMI 48 the profile of AF pts with LBW markedly differed suggesting a more fragile clinical status. Use of dose-adjusted edoxaban, as compared to W, was associated with similar efficacy regardless of weight, while bleeding and net outcomes were most favourable in LBW pts.

scholarly journals Heparin is more effective than apixaban in inhibiting in vitro contact activated coagulation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.M Engelen ◽  
C Van Laer ◽  
M Jacquemin ◽  
C Vandenbriele ◽  
K Peerlinck ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Heart Valves ◽  
Thrombus Formation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Mechanical Heart Valves ◽  
Contact Activation

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

Influence of Direct Oral Anticoagulants on Anti–Factor Xa Measurements Utilized for Monitoring Heparin

2017 ◽  
Vol 52 (2) ◽  
pp. 154-159 ◽  
Author(s):  
Kelly A. Macedo ◽  
Peter Tatarian ◽  
Kenneth R. Eugenio
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa

scholarly journals Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Alok Dabi ◽  
Aristides P. Koutrouvelis
Keyword(s):  
Side Effects ◽  
Intracranial Hemorrhage ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Reversal Agents ◽  
United States Food ◽  
Life Threatening

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients

2018 ◽  
Vol 35 (9) ◽  
pp. 903-908 ◽  
Author(s):  
Teresa A. Allison ◽  
Pei Jen Lin ◽  
Jennifer A. Gass ◽  
Kenneth Chong ◽  
Samuel J. Prater ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Prothrombin Complex Concentrate ◽  
Low Dose ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Final Analysis ◽  
Factor Xa Inhibitor ◽  
Direct Factor

Objective: This study investigated the percentage of patients who achieved hemostasis with 4-factor prothrombin complex concentrate (4-factor PCC) 35 U/kg. The primary end point was to determine the effect of 4-factor PCC 35 U/kg on bleeding progression, assessed using computed tomography. Methods: This was a retrospective, observational, single-center study conducted in patients with a major bleed admitted to a level 1 trauma center from May 1, 2013, to June 15, 2015, who received 4-factor PCC 35 U/kg for reversal of a direct factor Xa inhibitor taken prior to admission. Results: Thirty-three patients were included in the study, with 31 patients in the final analysis. The mean (standard deviation) age was 73 (14.8) years; 54.5% of patients were female. Of the 33 patients, 13 presented with a traumatic brain injury, 9 with an aneurysmal subarachnoid hemorrhage, 8 with an intracerebral hemorrhage, 1 with a gastrointestinal bleed, 1 with a hematoma with active extravasation, and 1 with an intra-abdominal bleed. The most frequently used direct factor Xa inhibitor was rivaroxaban (81.8%). Overall, 83.8% of patients achieved hemostasis with 4-factor PCC 35 U/kg. Progression of hemorrhage was observed in 4 patients on repeat computed tomography scan and 1 patient had continued surgical bleeding. No thromboembolic events were reported. Conclusions: Low-dose, 4-factor PCC 35 U/kg appeared to produce hemostasis in a majority of the patients. This may be an effective dosing regimen for anticoagulant reversal of factor Xa inhibitors in clinically bleeding patients.

scholarly journals The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Kyle M. Ware ◽  
Douglas L. Feinstein ◽  
Israel Rubinstein ◽  
Prudhvi Battula ◽  
Jose Otero ◽  
...  
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Hemoglobin Concentration ◽  
Thrombin Inhibitor ◽  
Free Hemoglobin ◽  
Intracranial Hemorrhages ◽  
The Brain

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

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