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Clinical Pharmacokinetics Jul 2024Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve...
BACKGROUND AND OBJECTIVE
Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct. METHODS: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0-18 years, TBW) or fat-free mass (2-18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity.
RESULTS
A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied.
CONCLUSION
Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.
PubMed: 38955947
DOI: 10.1007/s40262-024-01388-x -
Neurocritical Care Jul 2024Viscoelastic hemostatic assays (VHAs) provide more comprehensive assessments of coagulation compared with conventional coagulation assays. Although VHAs have enabled...
BACKGROUND
Viscoelastic hemostatic assays (VHAs) provide more comprehensive assessments of coagulation compared with conventional coagulation assays. Although VHAs have enabled guided hemorrhage control therapies, improving clinical outcomes in life-threatening hemorrhage, the role of VHAs in intracerebral hemorrhage (ICH) is unclear. If VHAs can identify coagulation abnormalities relevant for ICH outcomes, this would support the need to investigate the role of VHAs in ICH treatment paradigms. Thus, we investigated whether VHA assessments of coagulation relate to long-term ICH outcomes.
METHODS
Patients with spontaneous ICH enrolled into a single-center cohort study receiving admission Rotational Thromboelastometry (ROTEM) VHA testing between 2013 and 2020 were assessed. Patients with previous anticoagulant use or coagulopathy on conventional coagulation assays were excluded. Primary ROTEM exposure variables were coagulation kinetics and clot strength assessments. Poor long-term outcome was defined as modified Rankin Scale ≥ 4 at 6 months. Logistic regression analyses assessed associations of ROTEM parameters with clinical outcomes after adjusting for ICH severity and hemoglobin concentration.
RESULTS
Of 44 patients analyzed, the mean age was 64 years, 57% were female, and the median ICH volume was 23 mL. Poor 6-month outcome was seen in 64% of patients. In our multivariable regression models, slower, prolonged coagulation kinetics (adjusted odds ratio for every second increase in clot formation time 1.04, 95% confidence interval 1.00-1.09, p = 0.04) and weaker clot strength (adjusted odds ratio for every millimeter increase of maximum clot firmness 0.84, 95% confidence interval 0.71-0.99, p = 0.03) were separately associated with poor long-term outcomes.
CONCLUSIONS
Slower, prolonged coagulation kinetics and weaker clot strength on admission VHA ROTEM testing, not attributable to anticoagulant use, were associated with poor long-term outcomes after ICH. Further work is needed to clarify the generalizability and the underlying mechanisms of these VHA findings to assess whether VHA-guided treatments should be incorporated into ICH care.
PubMed: 38955933
DOI: 10.1007/s12028-024-02051-w -
Injury Jun 2024Surgical stabilization of rib fractures (SSRF) is increasingly performed, however the outcome of patients undergoing SSRF while on pre-injury antithrombotic therapy...
BACKGROUND
Surgical stabilization of rib fractures (SSRF) is increasingly performed, however the outcome of patients undergoing SSRF while on pre-injury antithrombotic therapy remains unknown. We compared surgical variables and outcomes of patients who were and were not on antithrombotic therapy. We hypothesize pre-injury anticoagulation is associated with delay in SSRF and worse outcomes.
METHODS
For this retrospective cohort study, we queried the Chest Injury International Database, for patients undergoing SSRF between 08/2018 and 03/2022. Antithrombotic therapy was categorized into antiplatelet and anticoagulant use. Primary outcome was time from admission to SSRF. Secondary outcomes included SSRF duration and complications. Numerical data were presented as median (IQR), categorical data as number (%). Inverse probability weighting was used to control for confounding.
RESULTS
Two hundred and eighteen SSRF patients were included, 25 (11 %) were on antithrombotic therapy. These patients were older (72 years, (65-80) versus 57 years, (43-66); p < 0.001) with lower ISS (14, (10-20) versus 21, (14-30); p = 0.002). Time from admission to SSRF was comparable (2 days, (1-4) versus 2 days, (1-4); p = 0.37) as was operative time (154 mins, (120.0-212.0) versus 177 mins, (143.0-210.0); p = 0.34). Patients using antithrombotics had fewer ICU-free days (24 (22-26) versus 28 (23-28); p = 0.003) but more ventilator free days (28, (28-28) versus 27 (27-28); p < 0.008). After adjusting for confounding, pre-injury anticoagulation was not significantly associated with delayed SSRF (Relative Risk, RR=1.37, 95 % CI 0.30-6.24), operative time (RR=1.07, 95 % CI0.88-1.31), IFD <=28 (RR=2.05, 95 %CI:0.33-12.67), VFD<=27 (RR=0.71, 95 %CI:0.15-3.48) or complications (RR=0.55, 95 % CI0.06-5.01).
CONCLUSION
Pre-injury antithrombotic drug use neither delayed SSRF nor impacted operative time in patients requiring SSRF and was not associated with increased risk of complications. Our data suggest SSRF can be safely performed without delay in patients who use anticoagulation pre-injury.
LEVEL OF EVIDENCE
IV.
STUDY TYPE
Therapeutic/care management.
PubMed: 38955570
DOI: 10.1016/j.injury.2024.111708 -
Open Heart Jul 2024The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once...
BACKGROUND
The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry.
METHODS
Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA.
RESULTS
Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs.
CONCLUSION
Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.
Topics: Humans; Atrial Fibrillation; Factor Xa Inhibitors; Patient Selection; Stroke; Pyrazoles; Pyridones; Rivaroxaban; Male; Female; Aged; Treatment Outcome; Registries; Administration, Oral; Risk Factors; Randomized Controlled Trials as Topic; Risk Assessment; Anticoagulants; Vitamin K
PubMed: 38955399
DOI: 10.1136/openhrt-2024-002708 -
Migration of sclerosant material to the left renal vein following coil embolisation of a varicocele.BMJ Case Reports Jul 2024Percutaneous testicular varicocele embolisation for symptomatic and subfertile males is often preferred over surgical ligation of the gonadal vein due to its minimally...
Percutaneous testicular varicocele embolisation for symptomatic and subfertile males is often preferred over surgical ligation of the gonadal vein due to its minimally invasive approach and reduced complication rate. Glues, coils, vascular plugs, balloons and sclerosants are used in various combinations to achieve sufficient venous occlusion. Here, we report on the first known case of sclerosant material migration beyond the placement of an embolisation coil for treatment of a varicocele, resulting in a left renal vein thrombus. A man in his 20s presented to the emergency department 2 days following uncomplicated left varicocele embolisation with acute left-sided abdominal pain, found to have sclerosant material causing an ipsilateral non-occlusive left renal vein thrombus with extension towards his inferior vena cava on CT. He was treated with 3 months of anticoagulation and follow-up imaging at 3 months showed resolution of this thrombus without renal impairment.
Topics: Humans; Male; Varicocele; Embolization, Therapeutic; Renal Veins; Foreign-Body Migration; Sclerosing Solutions; Adult; Young Adult; Tomography, X-Ray Computed
PubMed: 38955381
DOI: 10.1136/bcr-2023-259262 -
ACS Applied Bio Materials Jul 2024In the realm of clinical applications, the concern surrounding biomedical device-related infections (BDI) is paramount. To mitigate the risk associated with BDI,...
In the realm of clinical applications, the concern surrounding biomedical device-related infections (BDI) is paramount. To mitigate the risk associated with BDI, enhancing surface characteristics such as lubrication and antibacterial efficacy is considered as a strategic approach. This study delineated the synthesis of a multifunctional copolymer, embodying self-adhesive, lubricating, and antibacterial properties, achieved through free radical polymerization and a carbodiimide coupling reaction. The copolymer was adeptly modified on the surface of stainless steel 316L (SS316L) substrates by employing a facile dip-coating technique. Comprehensive characterizations were performed by using an array of analytical techniques including Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, optical interferometry, scanning electron microscopy, and atomic force microscopy. Nanoscale tribological assessments revealed a notable reduction in the value of the friction coefficient of the copolymer-coated SS316L substrates compared to bare SS316L samples. The coating demonstrated exceptional resistance to protein adsorption, as evidenced in protein contamination models employing bovine serum albumin and fibrinogen. The bactericidal efficacy of the copolymer-modified surfaces was significantly improved against pathogenic strains such as and . Additionally, evaluations of blood compatibility and cellular compatibility underscored the remarkable anticoagulant performance and biocompatibility. Collectively, these findings indicated that the developed copolymer coating represented a promising candidate, with its facile modification approach, for augmenting lubrication and antifouling properties in the field of biomedical implant applications.
PubMed: 38954747
DOI: 10.1021/acsabm.4c00144 -
European Heart Journal Jul 2024
PubMed: 38953790
DOI: 10.1093/eurheartj/ehae388 -
European Heart Journal Jul 2024
PubMed: 38953778
DOI: 10.1093/eurheartj/ehae389 -
European Heart Journal Jul 2024Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is not a dichotomous disease trait. Technological innovations enable long-term rhythm monitoring...
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is not a dichotomous disease trait. Technological innovations enable long-term rhythm monitoring in many patients and can estimate AF burden. These technologies are already used to detect and monitor AF. This review describes the relation between AF burden and outcomes and potential effects of AF burden reduction. A lower AF burden is associated with a lower risk of stroke and heart failure in patients with AF: stroke risk without anticoagulation is lower in patients with device-detected AF and a low AF burden (stroke rate 1%/year) than in patients with persistent and permanent AF (stroke rate 3%/year). Paroxysmal AF shows intermediate stroke rates (2%/year). Atrial fibrillation burden-reducing interventions can reduce cardiovascular outcomes in patients with AF: early rhythm control reduces cardiovascular events including stroke and heart failure in patients with recently diagnosed AF and cardiovascular conditions. In patients with heart failure and AF, early rhythm control and AF ablation, interventions that reduce AF burden, reduce mortality and heart failure events. Recent technological innovations allow to estimate AF burden in clinical care, creating opportunities and challenges. While evidence remains limited, the existing data already suggest that AF burden reduction could be a therapeutic goal. In addition to anticoagulation and treatment of cardiovascular conditions, AF burden reduction emerges as a therapeutic goal. Future research will define the AF burden that constitutes a relevant risk of stroke and heart failure. Technologies quantifying AF burden need careful validation to advance the field.
PubMed: 38953776
DOI: 10.1093/eurheartj/ehae373 -
Scandinavian Journal of Clinical and... Jul 2024There are important pharmacological differences between direct oral anticoagulants (DOAC) and a deeper knowledge of how they influence different aspects of hemostasis in...
INTRODUCTION
There are important pharmacological differences between direct oral anticoagulants (DOAC) and a deeper knowledge of how they influence different aspects of hemostasis in patients on treatment is desirable.
MATERIALS AND METHODS
Blood samples from patients on dabigatran ( = 23), rivaroxaban ( = 26), or apixaban ( = 20) were analyzed with a fibrin network permeability assay, a turbidimetric clotting and lysis assay, the calibrated automated thrombogram (CAT), plasma levels of thrombin-antithrombin complex (TAT) and D-dimer, as well as DOAC concentrations, PT-INR and aPTT. As a comparison, we also analyzed samples from 27 patients on treatment with warfarin.
RESULTS
Patients on dabigatran had a more permeable fibrin network, longer lag time (CAT and turbidimetric assay), and lower levels of D-dimer in plasma, compared with patients on rivaroxaban- and apixaban treatment, and a more permeable fibrin network than patients on warfarin. Clot lysis time was slightly longer in patients on dabigatran than in patients on rivaroxaban. Warfarin patients formed a more permeable fibrin network than patients on apixaban, had longer lag time than patients on rivaroxaban (CAT assay), and lower peak thrombin and ETP compared to patients on treatment with both FXa-inhibitors.
CONCLUSIONS
Results from this study indicate dabigatran treatment is a more potent anticoagulant than apixaban and rivaroxaban. However, as these results are not supported by clinical data, they are probably more related to the assays used and highlight the difficulty of measuring and comparing the effect of anticoagulants.
PubMed: 38953609
DOI: 10.1080/00365513.2024.2369993