anti-Xa Concentrations Research Articles

Gender-Associated Variation in DOAC Levels.

Direct oral anticoagulants (DOAC) such as Xa inhibitors rivaroxaban (riva) and apixaban (apix) are increasingly replacing Vitamin K antagonists in prophylaxis and treatment of venous thromboembolism (VTE). Measurements of DOAC plasma levels may be necessary in certain clinical conditions to determine the further dosage. Making decisions is made more difficult by the fact that the peak and trough plasma levels are subject to strong inter-individual fluctuations with overlapping reference ranges. We wanted to find out whether the peak and trough levels can be narrowed if they are determined based on age and gender. Therefore, we collected data on peak and trough anti-Xa concentrations in patients treated with either rivaroxaban (n = 93) or apixaban (n = 51) in one center. After exclusion of blood samples of uncertain oral intake, 83 samples for rivaroxaban and 49 samples for apixaban remained for further analysis. Differences between male (riva n = 42, apix n = 28) and female (riva n = 41 and apix n = 21) as well as young (≤ 60 years, riva n = 44, apix n = 23) and elder (> 60 years) patients (riva n = 39 and apix n = 26) were analyzed by Student`s t-test and retrospective regression. We found no differences in age and gender for the apix peak levels. But women had significantly higher riva peak concentrations than men (308.8 ± 178.1 ng/mL versus 206.4 ± 80 ng/mL, p = 0.013). Patients older than 60 years had significantly higher riva peak levels than those younger than 60 (293.7 ± 126.7 ng/mL versus 211.7 ± 158.4 ng/mL, p = 1.29 x 10-8). In search of narrowing standard peak and trough levels in patients' sera we found significant differ-ences between patients below and above sixty years of age. Gender-associated differences were found in rivaroxa-ban levels possibly explaining DOAC associated hypermenorrhea. In conclusion, gender and age should be included in the determination of peak blood concentration references.

Apixaban and Rivaroxaban Anti-Xa Concentration Utilization in Clinical Practice

Drug-specific anti-Xa concentrations can be used to assess the presence of drug effects; however, there is inadequate guidance for clinicians on the interpretation and clinical application of these results. The purpose of this study is to review patients' first apixaban and rivaroxaban anti-Xa concentrations to identify indications for monitoring and common therapeutic interventions made based on the results. In addition, we compared bleeding and thrombotic outcomes between the obesity group body mass index ≥40 kg/m 2 and the standard group body mass index 25-39.9 kg/m 2 . A retrospective analysis was conducted at a large academic medical center from January 1, 2020, to December 31, 2020. Primary outcomes were indications for anti-Xa concentrations and interventions on results. A total of 180 patients were included in the analysis, with 119 patients (66%) in the apixaban group and 61 patients (34%) in the rivaroxaban group. The most common indications for anti-Xa concentrations were extreme body weight (23%) and concern for bleeding (22%). About half of the anti-Xa concentrations resulted in therapy changes including holding for procedure, switching to heparin or enoxaparin, holding for an elevated anti-Xa concentration or concern for bleeding, adjusting direct-acting oral anticoagulant dose, or switching to an alternative oral anticoagulant. There were no differences in bleeding complications (5% [2] vs. 16% [14], P = 0.11) or thrombotic complications (8% [3] vs. 9% [8], P = 0.85) between the obesity group and the standard group. Despite the lack of validation of therapeutic ranges for anti-Xa concentrations, this study showed clinical situations where anti-Xa concentration monitoring can be of value.

Critical appraisal of evidence for anti-Xa monitoring and dosing of low-molecular-weight heparin in renal insufficiency

ABSTRACT Introduction Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments Areas covered We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. Expert opinion The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50–65% and 75–85% of the original dose for patients with a creatinine clearance (CrCL) of <30 ml/min and 30–60 ml/min, respectively. Tinzaparin should be adjusted to around 50% of the original dose for patients with a CrCL of <30 ml/min. In case anti-Xa monitoring is applied, trough concentration anti-Xa monitoring is preferred over peak monitoring, aiming at a maximum concentration of 0.4 IU/mL for once-daily dosed tinzaparin and 0.5 IU/mL for twice-daily dosed enoxaparin and nadroparin.

Direct oral to parenteral anticoagulant transitions: Role of factor Xa inhibitor-specific anti-Xa concentrations.

The increasing use of oral factor Xa inhibitors (FXaI) has led to a growing interest in the clinical utility of laboratory monitoring to enhance safety and effectiveness. Particularly, the use of FXaI-specific anti-Xa concentrations has gained traction and been advocated for several indications, but limited studies have explored the role of anti-Xa concentrations in guiding inpatient transitions from oral to parenteral anticoagulants. Therefore, additional data on such approaches are warranted to help balance bleeding and thrombotic risks in the higher acuity inpatient setting. This study sought to compare two strategies for oral-to-parenteral anticoagulant transitions: FXaI anti-Xa concentration-guided versus standard of care (i.e., per-package insert). This was an observational, single-center, retrospective cohort study conducted from May 2016 to May 2021. Hospitalized patients converted from an oral FXaI (apixaban or rivaroxaban) to therapeutic parenteral anticoagulation with or without FXaI anti-Xa concentration guidance were reviewed. The primary outcome of major bleeding, according to the International Society on Thrombosis and Hemostasis criteria, was compared between groups. Cox proportional hazard modeling was used to evaluate patient characteristics associated with major bleeding events. A total of 845 patients (388 in the concentration-guided group and 457 in the non-concentration-guided group) met the inclusion criteria. Major bleeding was significantly lower in the concentration-guided versus the non-concentration-guided group (2.2% vs. 11.3%; p < 0.001, respectively). There were no differences between the groups in thromboembolic complications (1.8% concentration guided vs. 1.5% non-concentration guided; p=0.72) despite a significantly longer time from last oral FXaI dose to parenteral anticoagulant initiation in the concentration-guided group (27.9 h vs. 15.1 h; p < 0.01). The concentration-guided group had an 80% lower risk of major bleeding compared with the non-concentration-guided group (adjusted hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.10-0.39; p < 0.01). This analysis suggests using FXaI anti-Xa concentrations to guide the transition from oral to parenteral anticoagulants may be beneficial in reducing major bleeds in select patient populations.

Anti-factor X activity levels with continuous intravenous infusion and subcutaneous administration of enoxaparin after coronary artery bypass grafting: A randomized clinical trial.

Low-molecular-weight heparin enoxaparin is widely used in pharmacological thromboprophylaxis after coronary artery bypass grafting (CABG). The aim of this study was to compare anti-factor X activity (anti-Xa) levels when the thromboprophylactic dose of enoxaparin was provided after CABG, with two different administration routes: continuous intravenous infusion (CIV) and subcutaneous bolus (SCB) injection. We hypothesized that the current standard method of SCB administration might lead to lower anti-Xa levels than recommended in other patient groups, due to reduced bioavailability. In this prospective, randomized, controlled clinical trial, 40 patients scheduled for elective CABG were randomized to receive 40 mg of enoxaparin per day either as CIV or SCB for 72 h. Enoxaparin was initiated 6-10h after CABG. Anti-Xa levels were measured 12-14 times during the study period. The primary outcome, that is, the maximum anti-Xa concentration over 0-24 h (Cmax0-24h ), was calculated from these measured values. Secondary outcomes were Cmax25-72h and the trough concentration of anti-Xa after 72 h of enoxaparin initiation (C72h ). Twenty patients were randomized to the CIV-group and 19 to the SCB-group. The median anti-Xa Cmax0-24h was significantly lower in the CIV-group than in the SCB-group: 0.15 [interquartile range (IQR) 0.13-0.19] IU/ml versus 0.25 (IQR 0.18-0.32) IU/ml, p < .005. The median anti-Xa Cmax25-72h was 0.12 (IQR, 0.1-0.17) IU/ml versus 0.23 (IQR 0.19-0.31) IU/ml, respectively, p < .005. At 72 h, there was no difference between the groups in their anti-Xa levels. In this low-risk CABG patient population, SCB administration of a thromboprophylactic dose of enoxaparin provided anti-Xa levels that are considered sufficient for thromboprophylaxis in other patient groups. CIV administration resulted in lower anti-Xa levels compared to the SCB route.

Use of Real-World Data and Physiologically-Based Pharmacokinetic Modeling to Characterize Enoxaparin Disposition in Children With Obesity.

Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low‐molecular‐weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. To address this clinical question, 2,825 anti–activated factor X (anti‐Xa) surrogate concentrations were collected from the electronic health records of 596 children, including those with obesity. Using linear mixed‐effects regression models, we observed that 4‐hour anti‐Xa concentrations were statistically significantly different in children with and without obesity, even for children with the same absolute dose (P = 0.004). To further mechanistically explore obesity‐associated differences in anti‐Xa concentration, a pediatric physiologically‐based pharmacokinetic (PBPK) model was developed in adults, and then scaled to children with and without obesity. This PBPK model incorporated binding of enoxaparin to antithrombin to form anti‐Xa and elimination via heparinase‐mediated metabolism and glomerular filtration. Following scaling, the PBPK model predicted real‐world pediatric concentrations well, with an average fold error (standard deviation of the fold error) of 0.82 (0.23) and 0.87 (0.26) in children with and without obesity, respectively. PBPK model simulations revealed that children with obesity have at most 20% higher 4‐hour anti‐Xa concentrations under recommended, total body weight–based dosing compared to children without obesity owing to reduced weight‐normalized clearance. Enoxaparin exposure was better matched across age groups and obesity status using fat‐free mass weight‐based dosing.

Evaluation of anti-factor Xa concentrations using a body mass index-based enoxaparin dosing protocol for venous thromboembolism prophylaxis in trauma patients.

The aim of this study was to evaluate the effectiveness of a body mass index (BMI)-based enoxaparin prophylaxis dosing protocol at achieving target anti-factor Xa (anti-Xa) concentrations in the trauma population. This retrospective chart review evaluated anti-Xa concentrations in adult trauma patients who received prophylactic enoxaparin over a three-month period. The primary outcome was the percentage of patients that achieved target anti-Xa concentrations after ≥3 doses of enoxaparin. Secondary outcomes included correlations of anti-Xa concentrations with enoxaparin dose per BMI, total body weight (TBW), and estimated blood volume (EBV). The prevalence of clinically relevant bleeding and venous thromboembolism was also recorded. Multivariable logistic regression was used to identify associated variables for target anti-Xa concentration attainment. Ninety-nine consecutive patients were included in the study. Included patients were predominately male (69.7%) and Black (50.5%) with a mean age of 44.1years. Target anti-Xa concentrations were achieved in 62.6% of patients. Anti-Xa concentrations were moderately correlated with enoxaparin dose per EBV (ρ=0.57), followed by dose per TBW (ρ=0.46), and dose per BMI (ρ=0.20). Multivariable logistic regression demonstrated that categorization of enoxaparin dose per EBV and per TBW were the only statistically significant predictors of reaching target anti-Xa concentrations (p=<0.001). In adult trauma patients, the rate of achieving target anti-Xa concentrations remains suboptimal and provides room for further improvement. Enoxaparin dose per EBV was more closely correlated with anti-Xa concentrations when compared to TBW and BMI. Dosing per EBV and TBW was the only variables associated with reaching target anti-Xa concentrations within the study. Further investigation is warranted to elucidate optimal EBV- and TBW-based dosing regimens.

Therapeutic versus Prophylactic Anticoagulation for Patients Admitted to Hospital with COVID-19 and Elevated D-dimer Concentration (ACTION): An Open-Label, Multicentre, Randomised, Controlled Trial

Background. COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. Methods. We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio &gt;1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. Findings. From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28.899 (34.8%) wins in the therapeutic group and 34.288 (41.3%) in the prophylactic group (win ratio 0.86 [95% CI 0.59–1.22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3.64 [95% CI 1.61–8.27], p=0.0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. Interpretation. In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

BackgroundCOVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population.MethodsWe did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed.FindingsFrom June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59–1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61–8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group.InterpretationIn patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.FundingCoalition COVID-19 Brazil, Bayer SA.

Impact of antithrombin III and enoxaparin dosage adjustment on prophylactic anti-Xa concentrations in trauma patients at high risk for venous thromboembolism: a randomized pilot trial.

The impact of antithrombin III activity (AT-III) on prophylactic enoxaparin anti-factor Xa concentration (anti-Xa) is unknown in high-risk trauma patients. So too is the optimal anti-Xa-adjusted enoxaparin dosage. This prospective, randomized, pilot study sought to explore the association between AT-III and anti-Xa goal attainment and to preliminarily evaluate two enoxaparin dosage adjustment strategies in patients with subprophylactic anti-Xa. Adult trauma patients with Risk Assessment Profile (RAP) ≥ 5 prescribed enoxaparin 30mg subcutaneously every 12h were eligible. AT-III and anti-Xa were drawn 8h after the third enoxaparin dose and compared between patients with anti-Xa ≥ 0.1IU/mL (goal; control group) or anti-Xa < 0.1IU/mL (subprophylactic; intervention group). The primary outcome was difference in baseline AT-III. Subsequently, intervention group patients underwent 1:1 randomization to either enoxaparin 40mg every 12h (up to 50mg every 12h if repeat anti-Xa < 0.1IU/mL) (enox12) or enoxaparin 30mg every 8h (enox8) with repeat anti-Xa assessments. The proportion of patients achieving goal anti-Xa after dosage adjustment were compared. A total of 103 patients were included. Anti-Xa was subprophylactic in 50.5%. Baseline AT-III (median [IQR]) was 87% [80-98%] in control patients versus 82% [71-96%] in intervention patients (p = 0.092). Goal trough anti-Xa was achieved on first assessment in 38.1% enox12 versus 50% enox8 patients (p = 0.67), 84.6% versus 53.3% on second assessment (p = 0.11), and 100% vs. 54.5% on third trough assessment (p = 0.045). AT-III activity did not differ between high-risk trauma patients with goal and subprophylactic enoxaparin anti-Xa concentrations, although future investigation is warranted. Enoxaparin dose adjustment rather than frequency adjustment may be associated with a higher proportion of patients achieving goal anti-Xa over time.

Impact of Weight on Anti-Xa Attainment in High-Risk Trauma Patients on Enoxaparin Chemoprophylaxis

BackgroundSerum anti-factor Xa (anti-Xa) concentration may guide low molecular weight heparin chemoprophylaxis in trauma patients. Higher total body weight (TBW) is a risk factor for subprophylactic anti-Xa and venous thromboembolism (VTE). The purpose of this study was to evaluate TBW differences in patients with subprophylactic versus prophylactic trough anti-Xa. MethodsThis retrospective study included adults admitted to the trauma service who received enoxaparin chemoprophylaxis, trough anti-Xa assessment, and screening duplex ultrasound. Initial enoxaparin dose was determined per trauma team weight-tiered protocol with subsequent 10 mg increase if anti-Xa was subprophylactic. Patients were stratified into subprophylactic (anti-Xa <0.1 IU/ml) and prophylactic (anti-Xa ≥0.1 IU/mL) groups. The primary outcome was difference in TBW. Secondary outcomes were weight-adjusted enoxaparin dose (mg/kg), VTE, red blood cell (pRBC) transfusions. ResultsA total of 887 patients were included with 681 (76.8%) having subprophylactic anti-Xa. The subprophylactic group had significantly younger age, higher proportion male sex, higher Injury Severity Score (ISS), higher BMI, and longer length of hospital stay. The subprophylactic group had higher TBW (median [IQR], 87.8 [74-102] kg vs. 78.9 [68-91.8] kg; P < 0.001) which equated to a lower weight-adjusted dose (0.34 [0.3-0.41] mg/kg vs. 0.38 (0.33-0.44) mg/kg; P < 0.001). There were no differences in VTE (10.4% vs. 9.2%; P = 0.71) or pRBC administration (17.0% vs. 16.0%; P = 0.81). ConclusionsTBW is higher and weight-adjusted enoxaparin dose is lower in high-risk trauma patients with subprophylactic anti-Xa concentrations. These data suggest TBW should be considered when determining the optimal prophylactic enoxaparin dose in high-risk trauma patients.

Effect of short-term low molecular weight heparin on patency following successful salvage of arteriovenous access with recurrent thrombosis.

This study aims to investigate the effect of low molecular weight heparin (LMWH) in maintaining the patency of arteriovenous (AV) access with recurrent thrombosis. Following successful thrombectomy, 66 patients with recurrent thrombosis were included in the study. The primary, assisted primary and secondary patency rates of patients who received LMWH (n = 24) were compared with those who did not receive anticoagulant (n = 42) using Kaplan-Meier analysis. Cox-regression analysis was performed to investigate potential predictors of patency rates. The mean dose of enoxaparin used was 40 ± 13.1 mg or 0.74 ± 0.2 mg/kg daily for a median duration of 14 (IQR 7,28) days. The mean trough anti-Xa concentrations measured after two doses of LMWH was 0.17 ± 0.13 IU/mL. Kaplan-Meier analyses for mean primary, assisted primary and secondary patency rates of LMWH vs no anticoagulation groups were 149 (95% CI: 91 - 207) vs 87 (95% CI: 42-132) days (P < .006), 230 (95% CI: 142-320) vs 107 (95% CI: 62-150) days (P = .01) and 438 (299-579) vs 294 (95% CI: 197-392) days (P = .08) respectively. LMWH remained a significant protective predictor of primary (HR: 0.49; 95% CI: 0.25-0.86; P = .02) and assisted primary patency rates (HR: 0.51; 95% CI: 0.27-0.98; P = .04) after adjusting for patient age, access age, type of AV access, presence of peripheral vascular disease and haemoglobin levels. LMWH may improve short and mid-term patency rates for AV accesses with recurrent thrombosis.

Evaluation of a Pediatric Enoxaparin Dosing Protocol and the Impact on Clinical Outcomes.

Enoxaparin has been studied for prophylaxis and treatment of thromboembolism in the pediatric population. Dose-finding studies have suggested higher mean maintenance dose requirements in younger children; however, the current recommended dosing schema endorsed by the American College of Chest Physicians remains conservative, likely secondary to limited data on the safety and efficacy of escalated starting doses. Primary objectives of this study included the identification of patient characteristics and risk factors with associations to anti-factor Xa (anti-Xa) values. The secondary objective was to determine an association between the initial anti-Xa value and thrombus resolution. Safety outcomes related to bleeding were also assessed. This retrospective cohort study reviewed records of all pediatric patients ≤18 years of age who were initiated on therapeutic subcutaneous enoxaparin between October 1, 2008, and October 1, 2018, at Children's Hospitals and Clinics of Minnesota for an indication of incident thrombus (N = 283). Successful resolution of thrombus was directly associated with attaining a therapeutic anti-Xa concentration upon first laboratory evaluation. Other characteristics with associations to initial anti-Xa values included age, body mass index, and certain diagnoses. The rate of composite bleeding was consistent across concentrations of anti-Xa (p = 0.4944). Despite adherence to protocol, the current enoxaparin dosing nomogram is only successful at achieving a therapeutic anti-Xa concentration (0.5-1.0 unit/mL) 55.8% of the time. A more aggressive enoxaparin dosing nomogram is warranted, as delaying time to therapeutic anti-Xa values impacts clinical outcomes, specifically thrombus resolution. Further investigation into characteristics with association to anti-Xa concentrations is needed.

A Systemwide Approach for Navigating the Dilemma of Oral Factor Xa Inhibitor Interference With Unfractionated Heparin Anti-Factor Xa Concentrations.

Oral factor Xa inhibitors are known to significantly increase heparin anti-Xa concentrations, which leads to inaccuracies when monitoring intravenous unfractionated heparin (IV UFH). Guidance for managing this laboratory interference is lacking, creating substantial uncertainty in clinical practice. To describe a strategy used by a large academic institution for managing the controversy of laboratory interference in the setting of oral factor Xa inhibitor use and provide effectiveness and safety data for this approach. In December 2016, a new Heparin IV Direct Oral Anticoagulant (DOAC) Interference PowerPlan (a comprehensive order set) was made available in the electronic health record (Cerner, North Kansas City, MO) throughout the health system. We retrospectively examined 169 patients with events reported in the error reporting system, RISKMASTER, and evaluated reports with and without the use of the PowerPlan. Effectiveness was determined through evaluation of thrombosis. The Naranjo criteria for causality were applied to assess thrombotic events. Of 56 events that were reported with apixaban when the PowerPlan was not ordered, 4 (7%) thrombotic events occurred within 7 days of UFH initiation. One out of the 4 events (25%) that occurred when the PowerPlan was not appropriately initiated was considered probable using the Naranjo Scale. Three additional events (75%) were possible using the Naranjo Scale. The Heparin IV DOAC Interference PowerPlan appears to be conducive to positive patient outcomes when evaluating voluntary reported events and may assist clinicians with managing the therapeutic dilemma of this laboratory interference.

Admission thrombelastography does not guide dose adjustment of enoxaparin in trauma patients

BackgroundEnoxaparin is used as chemoprophylaxis to reduce incidence of venous thromboembolism and its complications following trauma. Serum anti-Xa monitoring is used to assess efficacy but requires several doses to be administered. Thrombelastography assesses hypercoagulability and may have utility identifying high-risk patients for venous thromboembolism. The objective was to evaluate whether thrombelastography parameters could identify trauma patients requiring enoxaparin dose adjustment earlier than serum anti-Xa concentrations. MethodsA single-center, retrospective medical record review evaluated patients admitted to a regional level I trauma center that received an admission thrombelastography and a dose of enoxaparin with a serum trough anti-Xa concentration drawn. Patients were divided into standard-dose or dose-adjusted enoxaparin. Venous thromboembolism incidence between groups and risk factors for enoxaparin dose adjustment and venous thromboembolism development were evaluated. ResultsA total of 204 patients were included. Differences observed between groups included age (standard-dose enoxaparin, 48.5 [29.3–72] vs dose-adjusted enoxaparin, 38.5 [25–55.7] years; P = .005), admission creatinine clearance (standard-dose enoxaparin, 92.9 [67.4–113.4] vs dose-adjusted enoxaparin, 102.1 [83.8–129.2] mL/min; P = .017), and time to venous thromboembolism prophylaxis initiation (standard-dose enoxaparin, 23.8 [11.2–36.4] vs dose-adjusted enoxaparin, 34.5 [18.3–52.7] hours; P = .004). No differences in thrombelastography parameters or venous thromboembolism incidence were observed. No independent risk factors for enoxaparin dose adjustment were identified; however, risk assessment profile score > 10 was an independent risk factor for venous thromboembolism development. ConclusionNo relationship between admission thrombelastography and need for enoxaparin dose adjustment in trauma patients was observed. As thrombelastography continues growing in clinical use, it is prudent to investigate other potential applications. Currently, thrombelastography should not be used to guide enoxaparin dosing.

Venous thromboembolism chemoprophylaxis regimens in trauma and surgery patients with obesity: A systematic review.

Venous thromboembolism (VTE) continues to be a devastating source of morbidity and mortality in obese patients who suffer traumatic injuries or obese surgery patients. High incidence rates in VTE despite adherence to prevention protocols have stirred interest in new dosing regimens. The purpose of this study was to systematically review the literature and present the existing VTE chemoprophylaxis regimens for obese trauma and surgical patients in terms of efficacy and safety as measured by the incidence of VTE, anti-factor Xa levels, and the occurrence of bleeding events. An online search of seven literature databases including PubMed, Excerpta Medica Database, GoogleScholar, JAMA Network, CINAHL, Cochrane, and SAGE Journals was performed for original studies evaluating the safety and efficacy of VTE chemoprophylaxis dosing regimens according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The risk of bias was assessed using the Cochrane Risk of Bias Tool and the quality of evidence was determined using the GRADE Working Group criteria. Of the 5,083 citations identified, 45 studies with 27,717 patients met inclusion criteria. In this group, six studies evaluated weight-based dosing regimens, four used a weight-stratified or weight-tiered strategy, five used a body mass index-stratified approach, 29 assessed fixed-dose regimens, and two used continuous infusions. The majority of the studies evaluated anti-factor Xa levels as their primary outcome rather than reduction in VTE. Weight-based and high fixed-dose chemoprophylaxis regimens achieved target anti-Xa concentrations more frequently than standard fixed-dose regimens but were not associated with a reduction in VTE. Additionally, high fixed-dose approaches are associated with increased bleeding complications. Further evaluation with large randomized trials is warranted in trauma and surgery patients with obesity. Systematic review, level III.

Determination of Optimal Weight-Based Enoxaparin Dosing and Associated Clinical Factors for Achieving Therapeutic Anti-Xa Assays for Deep Venous Thrombosis Prophylaxis

Previous studies have evaluated dose-to-weight ratios to define best practices for obtaining therapeutic anti-Xa assays for enoxaparin venous thromboembolism (VTE) prophylaxis. These studies have not examined relationships among dosing, patient characteristics, and therapeutic assays. This study examines factors associated with therapeutic assays and enoxaparin prophylaxis. This is a retrospective review of patients admitted to a Level 1 trauma center between March 2016 and June 2018. Prophylaxis was managed according to the trauma service's enoxaparin VTE prophylaxis protocol, which targets anti-Xa concentrations of 0.2 to 0.5 IU/mL. Assays were divided into sub-therapeutic, therapeutic, and super-therapeutic groups to determine factors associated with therapeutic concentrations. Overall, 623 patients (634 total anti-Xa assays) were identified during the study period. Patients with sub-therapeutic (n= 35) and therapeutic (n= 536) assays did not differ. Significant differences were identified between patients with therapeutic and super-therapeutic assays (n= 63). Receiver operating characteristic curve analysis was used to determine that the optimal cutoff for the dose-to-weight ratio was 0.4 mg/kg/dose (area under the curve 0.78; 95% CI 0.73 to 0.84; p < 0.001) differentiating therapeutic and super-therapeutic assays. Logistic regression revealed male sex, doses of 0.31 to 0.4 mg/kg, and creatinine clearance > 90 mL/min were independently associated with therapeutic assays. The combined effect of these 3 variables showed that therapeutic assays were 13.76 times more likely to occur (OR 13.76; 95% CI 3.43 to 56.96; p < 0.001). These data demonstrate that a dose of 0.4 mg/kg predicts a therapeutic anti-Xa level. When regimens of 0.31 to 0.4 mg/kg/dose are administered in males with a creatinine clearance >90 mL/min therapeutic results are 13.76 times more likely, suggesting that monitoring with anti-Xa assays might be unnecessary in this subgroup. Additional prospective study of these findings is warranted.

Unfractionated heparin dosing requirements in the presence of inflammation during the first six months of life

BackgroundCritically ill neonates with inflammation secondary to SIRS or sepsis often develop an acquired pro-thrombotic state. Unfractionated heparin (UFH) is commonly prescribed in this population, but these subjects often remain sub-therapeutic or require very high doses of UFH to achieve and sustain therapeutic anti-Xa activity. This is due, in part, to the unique pharmacokinetics/dynamics of this population but may also be influenced by the degree of inflammation. ObjectiveTo evaluate UFH dosing requirements in neonates and infants <6 months of age with variable degrees of systemic inflammation. Clinical outcomes of bleeding and clotting will also be examined. Subjects/methodsA retrospective chart review was performed in infants <6 months of age treated with intravenous UFH for at least 24 h with intent to reach a goal anti-Xa of 0.3–0.7 U/mL at Children's Hospital Colorado between October 2008 and August 2014. Subjects were divided into two groups, based on their ability to achieve and maintain anti-Xa concentrations between 0.3 and 0.7 U/mL. The relationship between UFH dose (U/kg/h) and inflammatory status (using pediatric age-specific definitions for SIRS, sepsis, severe sepsis, or septic shock) was examined. ResultsSeventy-three subjects were included in the analysis. Twenty-three subjects (mean age = 41.2 days ± standard deviation [SD] 52.3) achieved therapeutic anti-Xa concentrations while fifty subjects (mean age = 43.4 days ± SD 53) did not. The median UFH dose needed in subjects who achieved goal anti-Xa concentrations in the absence of SIRS or sepsis criteria was 24.5 U/kg/h (interquartile range [IQR] = 23.6–25.9) while the median dose of UFH in subjects who achieved goal anti-Xa level in the setting of infection, SIRS, or sepsis of any type was 36.1 U/kg/h (IQR = 34–43.5) (p < 0.0001). In subjects who maintained therapeutic anticoagulation, there was a direct relationship between UFH dose and the severity of inflammation as determined by pediatric SIRS/sepsis criteria. ConclusionsMaintenance of therapeutic UFH levels remains a challenge in infants, especially in those with concomitant inflammatory processes. Infection, SIRS, and sepsis of any type were collectively associated with a 32% increase in unfractionated heparin dose required to achieve and maintain therapeutic anti-Xa serum concentrations.

Therapeutic drug monitoring: using Bayesian methods to evaluate hospital practice

AbstractBackgroundTherapeutic drug monitoring (TDM) is used to improve effectiveness and reduce toxicity of various high‐risk medications. It is guided by drug specific protocols and/or TDM management software.AimThe aim of this study was to evaluate the therapeutic drug monitoring (TDM) of high‐risk drugs, using Bayesian simulation.MethodsPatients prescribed vancomycin, enoxaparin or warfarin and who had plasma concentrations measured for the purposes of TDM were recruited to the study. A Bayesian software package was used to simulate individual patient concentration time curves incorporating patient demographics, dosing data from their course of therapy and all plasma concentrations. The proportion of therapeutic concentrations was determined using the simulated data for each patient and drug. Combined analysis of all patients allowed identification of gaps in TDM at a hospital level. The appropriateness of sampling time and dose adjustments were also investigated.ResultsIn all, 78 patients were recruited who had 279 observed concentrations to allow simulation. Of the 100 observed vancomycin troughs, 66% were sampled incorrectly, as were 34% of 32 observed peak anti‐Xa concentrations (measurement of activity for enoxaparin); all international normalised ratios (INRs) were taken appropriately. Approximately 50% of simulated concentrations were not therapeutic. Most patients administered vancomycin had subtherapeutic concentrations for the first 24–48 h of therapy and most patients treated with enoxaparin had toxic anti‐Xa concentrations within the first 96 h of therapy. INRs were therapeutic only 68% of the time.ConclusionBayesian simulation allowed the identification of gaps in the TDM service and future dose recommendations, including the use of loading doses for vancomycin and dose reductions in extended courses of enoxaparin. TDM practices can now be optimised with the aim of incorporating Bayesian software into clinical practice.