Therapeutic anti-Xa Levels Research Articles

Pharmacokinetic model-guided enoxaparin dosing in the Neonatal ICU: Retrospective cohort study to plan for prospective feasibility trial.

Traditional milligram per kilogram (mg/kg) dosing of enoxaparin in neonates frequently fails to achieve target anti-Xa levels promptly, necessitating repeated laboratory monitoring and dose adjustments. This study investigated whether a personalized dosing strategy based on predicted individual clearance and volume of distribution could improve outcomes, comparing standard-of-care (SOC) mg/kg dosing to pharmacokinetic (PK) model-informed precision dosing (MIPD). A retrospective analysis was conducted on hospitalized neonates treated with enoxaparin at less than 44 weeks postmenstrual age from 2019 to 2022. Data on demographics, drug dosing, PK model covariates, and clinical outcomes were extracted from electronic health records and analyzed using the Pumas-AI Lyv dosing tool. The primary focus was on comparing the initial SOC dose to the MIPD-recommended dose. The secondary outcome measured was the time required to achieve therapeutic anti-Xa levels. The study included 168 neonates with a median postnatal age of 15 days (range 1-149) and a median dosing weight of 3.1 kg (range: 0.82-5.2). MIPD-recommended initial doses were 20%-60% higher than SOC doses in 32% of the cases and over 60% higher in 11% of cases. Neonates who received SOC doses that were much lower than the MIPD recommendation showed the longest delays in reaching therapeutic anti-Xa levels. The results indicate that PK model-informed of enoxaparin dosing leads to higher initial dosages than SOC in neonates, potentially reducing the time to therapeutic anti-Xa levels. These findings are being utilized to define dosing limits for a prospective trial of MIPD in neonatal intensive care settings.

Retrospective study evaluating safety, clinical effect, and dosing of dalteparin for the treatment of venous thromboembolism in term neonates.

There is an increased risk of venous thromboembolism (VTE) among neonates due to their unique hemostatic system. However, there is lack of approved treatment options for VTE in neonatal population. Importantly, dalteparin, a low molecular weight heparin approved for pediatric VTE in children ≥1month of age, has also been used for the treatment of neonatal VTE. Based on the request from the Food and Drug Administration, this retrospective study aimed to characterize the safety, clinical effects, and dosing of dalteparin for treatment of VTE among neonates. Data from electronic medical records for neonates (born ≥35weeks of gestation) treated with dalteparin for VTE between January 2010 and December 2021 were collected. The data assessed included bleeding and deterioration in hematological biomarkers among other adverse events, changes in relevant factor antifactor Xa (anti-Xa) levels and VTE status, and dosing of dalteparin and corresponding anti-Xa assay levels. Sixteen neonates from five participating sites in the United Kingdom were included. There were no bleeding events or deaths. Only one serious adverse event of hypoglycemic brain injury (unrelated to dalteparin) was documented in a patient with a history of hyperinsulinism. Median (range) daily dose of dalteparin at initiation was 309 (297-314)IU/kg. Eight of 16 neonates achieved therapeutic anti-Xa level, including two patients who did so after the first dose. Dalteparin treatment in neonates raised no major safety concerns. Larger cohort studies may help provide further insights on clinical effects of dalteparin for neonatal VTE.

Enoxaparin treatment dosing for venous thromboembolism in pediatric patients with obesity.

The optimal enoxaparin dosing for treatment of venous thromboembolism (VTE) in pediatric patients with obesity remains uncertain. We described the mean enoxaparin dose required to attain anti-factor Xa (anti-Xa) levels of 0.5-1unit/mL in pediatric patients with obesity. Pediatric patients with obesity (body mass index [BMI]≥95th percentile) who received treatment dose of enoxaparin from 2013 to 2022 and had at least one appropriately timed anti-Xa level were retrospectively evaluated. Daily enoxaparin dose required to achieve an anti-Xa level of 0.5-1unit/mL was reviewed and compared by the severity of obesity. The correlation coefficients between enoxaparin dose requirement and BMI, BMI percentile, and weight were measured by Spearman's rank correlation coefficient. Pediatric patients with obesity (n=89) required a mean enoxaparin dose of 0.8±0.18mg/kg twice daily to attain a therapeutic anti-Xa level. Children with BMI 95th-99th percentile and weight ≤100kg achieved the target level on a significantly higher weight-based enoxaparin dose compared to BMI greater than 99th percentile (0.95±0.15 vs. 0.75±0.15mg/kg twice daily; p<.001) and weight greater than 100kg (0.95±0.14 vs. 0.7±0.12mg/kg twice daily; p<.001). BMI, BMI percentile, and weight showed a moderate to strong negative correlation with enoxaparin dose requirement. Pediatric patients with obesity required a lower weight-based dose of enoxaparin to achieve a therapeutic anti-Xa than the recommended starting dose of 1mg/kg twice daily for treatment of VTE. Among obesity indices, weight showed the strongest negative correlation with total daily enoxaparin requirement.

INFLUENCE OF VARIOUS FACTORS ON ANTI-XA LEVELS IN HOSPITALIZED MEDICAL PATIENTS RECEIVING PARENTERAL THROMBOPROPHYLAXIS

Objective: Venous thromboembolism (VTE) stands as a prevalent vascular disease, intimately linked to increased risk for morbidity and mortality. The aim of this study was to investigate the influence of various factors on anti-Xa levels in hospitalized medical patients receiving parenteral thromboprophylaxis. Design and method: This is a single-center cohort study encompassing patients admitted to the Internal Medicine Department of the University Hospital of Heraklion, from March to August 2023. These patients were placed on thromboprophylaxis due to a heightened risk of developing VTE. Data regarding demographics, past medical history, somatometric and laboratory findings as well as the type and dose of parenteral anticoagulant were recorded. The measurement of anti-Xa levels were conducted 4 hours subsequent to the third subcutaneous administration of anticoagulant. Results: In this study, we enrolled 150 individuals [91 women (60.7%)], with an average age of 80 years. Sixty-two (41.4%) patients exhibited non-therapeutic anti-Xa levels. The levels were subtherapeutic (&lt;0.2units/mL) in 36 patients and supratherapeutic (&gt;0.5units/mL) in 26 patients. Non-therapeutic anti-Xa levels were observed in all underweight patients and in 12 out of 13 obese class II and III patients. It's noteworthy that therapeutic anti-Xa levels were observed in more than half of healthy-weight and overweight patients. A univariate logistic regression analyses was conducted to explore factors (age, sex, past medical history, somatometric and laboratory findings) that had impact on anti-Xa levels. Among these, only body weight emerged as independent factor influencing anti-Xa levels. Conclusions: In our study, we demonstrated that 41.3% of medical patients who were administered parenteral thromboprophylaxis exhibited non-therapeutic anti-Xa levels. This was more profound for underweight or obese class II and III patients. Body weight was emerged as independent factor influencing anti-Xa levels. Further studies on weight-based LMWH thromboprophylaxis dosing in this population are likely to yield new insights improving decisions in daily clinical practice.

Smaller nadroparin dose reductions required for patients with renal impairment: A multicenter cohort study

BackgroundGuidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15–29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment. AimsTo determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment. MethodsA retrospective cohort study was conducted in five hospitals. Patients ≥18 years of age, with an eGFR ≥ 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after ≥ third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression. Results770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65–359 and 68-168 IU/kg in eGFR 15–29, 30–60 and > 60 ml/min/1.73m2, respectively. In eGFR 15–29 and 30-60 ml/min/1.73m2, doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min. ConclusionWe advise against anti-Xa based dose-adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m2, which are achieved by smaller dose reductions.

How enoxaparin underdosing and sex contribute to achieving therapeutic anti-Xa levels.

Anti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels. This multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike's information criterion as metric was applied to refine the logistic regression model. A total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40-30.05, p < 0.001). Despite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies.

Anti-factor Xa as the preferred assay to monitor heparin for the treatment of pulmonary embolism.

The mainstay of acute pulmonary embolism (PE) treatment is anticoagulation. Timely anticoagulation correlates with decreased PE-associated mortality, but the ability to achieve a therapeutic activated partial thromboplastin time (aPTT) with unfractionated heparin (UFH) remains limited. Although some institutions have switched to a more accurate and reproducible test to assess for heparin's effectiveness, the anti-factor Xa (antiXa) assay, data correlating a timely therapeutic antiXa to PE-associated clinical outcomes remains scarce. We evaluated time to a therapeutic antiXa using intravenous heparin after PE response team (PERT) activation and assessed clinical outcomes including bleeding and recurrent thromboembolic events. This was a retrospective cohort study at NYU Langone Health. All adult patients ≥18 years with a confirmed PE started on IV UFH with >2 antiXa levels were included. Patients were excluded if they received thrombolysis or alternative anticoagulation. The primary endpoint was the time to a therapeutic antiXa level of 0.3-0.7 units/mL. Secondary outcomes included recurrent thromboembolism, bleeding and PE-associated mortality within 3 months. A total of 330 patients with a PERT consult were identified with 192 patients included. The majority of PEs were classified as sub massive (64.6%) with 87% of patients receiving a bolus of 80 units/kg of UFH prior to starting an infusion at 18 units/kg/hour. The median time to the first therapeutic antiXa was 9.13 hours with 93% of the cohort sustaining therapeutic anticoagulation at 48 hours. Recurrent thromboembolism, bleeding and mortality occurred in 1%, 5% and 6.2%, respectively. Upon univariate analysis, a first antiXa <0.3 units/ml was associated with an increased risk of mortality [27.78% (5/18) vs 8.05% (14/174), p = 0.021]. We observed a low incidence of recurrent thromboembolism or PE-associated mortality utilizing an antiXa titrated UFH protocol. The use of an antiXa based heparin assay to guide heparin dosing and monitoring allows for timely and sustained therapeutic anticoagulation for treatment of PE.

An Evaluation of the Appropriateness of Initial Enoxaparin Dosing Among Pediatric Patients.

Background Enoxaparin is a low molecular weight heparin that irreversibly inactivates factor Xa leading to the inhibition of clot formation. Despite the non-FDA approval in pediatrics, enoxaparin is recommended with an initial dose of 1.5mg/kg/q12hrs for patients aged ≤ 2 months and 1mg/kg/q12hrs for patients > 2 months, targeting therapeutic anti-Xa with a range of 0.5 to 1 units/mL. Due to more rapid clearance in pediatrics, our study aims to assess the need for initial higher doses than recommended by the guideline to reach the target anti-Xa level. Methods A retrospective chart review of all pediatric patients under all specialties who were treated with enoxaparin either in inpatient or outpatient settings between February 2021 and June 2022 at children's specialized hospital and meet the inclusion criteria, including age ≤ 15 years old and treated with enoxaparin with initial dose according to the American College of Chest Physicians (CHEST) guideline, while patients who received prophylaxis dosesdid not have anti-Xa levels or creatinine clearance < 30 mL/min/1.73m2 were excluded. Demographic data, laboratory data, and enoxaparin dosing were all collected to assess whether the initial enoxaparin dose will result in a therapeutic level as a primary endpoint and secondary endpoints including the average enoxaparin dose required to achieve the therapeutic level and to report any side effects. All data were entered and analyzed using the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 25, Armonk, NY), and all categorical variables were reported as frequency and percentage while continuous variables expressed as mean ± SD and the study was approved by our research center institutional review board (IRB). Results Thirty patients were included in the study (17 males), 10 patients were aged ≤ 2 months, four were between 3 and 12 months and 16 were > 12 months, most of the patients received enoxaparin for deep vein thrombosis. In the majority of patients (76.7%), the initial dose failed to achieve the target anti-Xa while a mean dose of 2 mg/kg/q12hrs in patients ≤ 2 months, 1.7mg/kg/q12hrs in patients 3-12 months and 1.3 mg/kg/q12hrs in patients > 12 months was sufficient to reach the target level. After achieving a therapeutic anti-Xa level, only one patient experienced major bleeding while four patients experienced minor bleeding, no edema or thrombocytopenia were reported. Conclusion In conclusion, initiating enoxaparin according to the recommended dose by the guideline failed to achieve target anti-Xa in the majority of patients which necessitates starting enoxaparin with initial higher doses according to the patient's age to provide more prompt achievement of target anti-Xa.

Abstract 14891: Time to Therapeutic Range for Patients With Acute Pulmonary Embolism Undergoing Mechanical Thrombectomy

Introduction: Anticoagulation therapy is the mainstay for the management of patients with acute pulmonary embolism (PE) and achieving a timely time to therapeutic range (TTR) is important. We sought to determine the TTR in patients with acute PE referred for mechanical thrombectomy (MT) and the proportion of patients with therapeutic activated clotting time (ACT) at the time of MT. Methods: This single center retrospective study included all patients who underwent percutaneous MT at a large academic public hospital from January 2020 through April 2023. Therapeutic anticoagulation was defined as an ACT &gt;200 seconds or if the patient received enoxaparin within 6 hours prior to MT. Results: A total of 63 patients (average age 58 years, 43% female) with intermediate or high-risk PE were included in the analysis. The median time from the diagnosis of PE or clot-in-transit (CIT) to MT was 15 (IQR 6.1-23.2) hours. Fifteen patients (23.8%) were initiated on enoxaparin at the diagnosis of acute PE or CIT. Among these patients, 5 (7.9%) were on enoxaparin only and 10 (15.9%) patients were initiated on enoxaparin and then transitioned to a heparin infusion prior to MT. One patient was initiated on argatroban, while the remaining 47 patients were initiated on a heparin infusion at time of diagnosis (77.6% received heparin bolus). In patients who received a heparin infusion, the median ACT in the cath lab was 134 (IQR 118-159) seconds. Only a total of 9/63 (14.3%) were therapeutic by ACT at the time of MT or received therapeutic enoxaparin within 6 hours of MT. Excluding patients who received enoxaparin initially, 34/48 (70.8%) patients reached a therapeutic anti-Xa or partial thromboplastin time (PTT) levels. The median time to reach a therapeutic anti-Xa or aPTT was 5.6 (IQR 3.3-8.2) hours (Figure). Conclusion: In patients with acute PE referred for MT, only a minority of patients had therapeutic ACT prior to mechanical thrombectomy.

Evaluation of anti-Xa levels in patients with venous thromboembolism within the first 48 h of anticoagulation with unfractionated heparin.

Background: A 2019 study by Prucnal and colleagues found that the majority of patients treated with unfractionated heparin for pulmonary embolism did not maintain therapeutic activated partial thromboplastin time levels during the first 48 h of therapy. Objective: The purpose of this study was to evaluate the ability of an institution's unfractionated heparin dosing protocol to achieve and maintain therapeutic anti-Xa levels within the first 48 h of therapy in patients with venous thromboembolism. Methods: This retrospective study included 205 patients from May 2016 through September 2020. Patients were divided into two cohorts: bolus plus infusion (N = 89) and infusion only (N = 116). The primary objective was to determine the number of patients who achieved at least one therapeutic level. Results: Overall, 200 patients (97.6%) had at least one therapeutic level with no statistically significant difference between cohorts (p = 0.65). No more than 60% of patients achieved a therapeutic level at any of the 6-h intervals throughout the timeframe. The median time to the first therapeutic level in the overall group was 12.8 h with no statistically significant difference between the bolus plus infusion and infusion-only cohorts (13.3 h versus 12.7 h, respectively, p = 0.48). Conclusions: Most patients were able to achieve at least one therapeutic level within the first 48 h, but fewer were able to maintain therapeutic levels. Further studies are warranted to determine whether alternative dosing strategies would yield consistent achievement of therapeutic levels and affect patient-oriented outcomes.

Achieving Therapeutic Anti-Xa Levels Using Rivaroxaban for Venous Thromboembolism in a Morbidly Obese Patient with a BMI >70

Background: Anticoagulation (AC) is the cornerstone of treatment for venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) have become the standard of care during the acute and extended phases of therapy for VTE, mostly due to their ease of use, efficacy, and safety profiles. There is a 9.2% prevalence of severe obesity (BMI>40) in Americans as of 2017-2020 with a 6.2-fold increased risk of VTE in obese individuals. The 2021 International Society on Thrombosis and Haemostasis (ISTH) guidelines recommend using standard dosages of DOACs in patients with a BMI >40 kg/m2 or weight >120 kg. Despite these recommendations, their use in severely obese individuals at extremes of weight like our patient with a BMI > 70 kg/m2 remains uncertain. Case Presentation Herein, we present a 38-year-old morbidly obese female with no significant past medical history who presented with an acute worsening of dyspnea on exertion saturating 60% on room air. The diagnosis of intermediate-high risk pulmonary embolism (PE) was made based on computed tomographic angiography (CTA) with right ventricular strain and elevated cardiac biomarkers. A concomitant proximal DVT from the left common femoral to the distal peroneal vein was also noted. The patient's weight was 243kg with a calculated BMI of 72.3 kg/m2. After the patient had received parenteral anticoagulation with heparin for 4 days, it was decided to switch to Rivaroxaban 15mg BID for 21 days followed by 20 mg daily. With a history of irregular menses, the patient developed heavy menstrual bleeding (HMB) following the initiation of rivaroxaban. Her hemoglobin remained stable with no blood transfusion requirements. However, this led to the decision to switch to rivaroxaban 20 mg PO daily earlier than planned due to a lack of improvement in menstrual bleeding which was considered to be clinically relevant non-major bleeding (CRNMB). Despite this switch, there was no effect on efficacy and the patient did not develop any signs or symptoms of VTE recurrence during her prolonged hospital stay with a significant improvement in her oxygenation levels and VTE symptomatology. In our patient, we demonstrated the use of rivaroxaban in a morbidly obese individual with a BMI>70 by achieving therapeutic anti-Xa levels. Figure 1 shows the therapeutic peak and trough anti-Xa levels throughout the patient's hospitalization. The highest Anti Xa level of 314 mcg/mL was reported on day 19 correlating with the patient's menorrhagia, which self-limited with the transition from rivaroxaban 15 mg twice daily to 20 mg daily. Discussion: Two pivotal clinical trials, the EINSTEIN-DVT/PE trials, where 14% of patients in both arms weighed >100 kg, showed that patients on rivaroxaban (15 mg BID for 3 weeks, followed by 20 mg once daily) vs those on enoxaparin followed by a vitamin K antagonist, had no significant difference in recurrence rates of VTE and bleeding rates [Moore KT, et Al. Influences of Obesity, Am J Med 2017]. A recent post-hoc analysis of the EINSTEIN DVT/PE trials also portrayed no correlation between weight/BMI and risk of recurrent VTE or bleeding in those who received rivaroxaban. Our case illustrates the attainment of therapeutic anti-Xa levels with no recurrent VTE in our morbidly obese patient. Despite her heavy menstrual bleeding, the bleeding was controlled once the switch to rivaroxaban 20mg daily was completed. Another study in which its heaviest participant at 172 kg, showed compelling evidence that morbid obesity has minimal influence on the safety and efficacy of rivaroxaban [Speed V, et al. Fixed dose rivaroxaban. JTH 2020]. This remains true for our patient at 243 kg. Conclusion: Our case demonstrates that standard doses of rivaroxaban for the treatment of DVT/PE in individuals with morbid obesity with BMI>70 kg/m2 can be effective, and safer for the initial phase of treatment for VTE and in prevention of VTE recurrence. It also portrays that increased dosages attempting to account for high bodyweight/fat can potentially result in major bleeding events. Despite the 2021 ISTH guidelines, further prospective studies and randomized controlled trials are warranted, to assess the safety and efficacy of DOACs in VTE, particularly in such challenging clinical scenarios like morbid obesity. Alongside clinical assessment, additional studies will be essential to evaluate the need for universal and external validation of anti-Xa levels in patients taking DOACs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Increased Enoxaparin Dosing on Anti-Xa Levels for Venous Thromboembolism Prophylaxis in Trauma Patients.

Venous thromboembolism (VTE) contributes to significant morbidity in trauma patients while increasing hospital costs and length of stay. Standard trauma prophylaxis dosing with enoxaparin 30mg twice daily may be inadequate to prevent VTEs. The objective of this study was to compare standard dosing of enoxaparin to an increased dose of enoxaparin 40mg twice daily for trauma patients. We hypothesized that increasing thromboprophylaxis dosing leads to an increase in therapeutic anti-Xa levels and reduced VTE rates. A retrospective study was performed from January 2020 to June 2021 at a Level I trauma center, following implementation of an increased enoxaparin dosing strategy. Patients with increased enoxaparin dosing were compared with those who received standard dosing. The primary outcome evaluated was the incidence of subtherapeutic anti-Xa levels. Secondary outcomes evaluated VTE rates and clinically significant bleed. A total of 204 trauma patients were identified. Ninety-one patients received an increased enoxaparin dose compared to 113 who received standard dosing. The baseline demographics of both groups were similar (P > .05). Subtherapeutic levels were higher with standard dosing compared to the increased dose (50 vs 22%, P = .003). Higher VTE rates were observed with standard dosing compared to higher dosing (6.2 vs 3.3%) but with a lower incidence of major bleed (1.8 vs 4.4%). Overall annual VTE rates decreased from 1.6 to 1.3% after implementation of the increased dosing regimen. This study demonstrated that an increased dosing strategy decreased rates of subtherapeutic anti-Xa levels and trended toward lower overall VTE rates in trauma.

Heparin Resistance in SARS-CoV-2 Infected Patients with Venous Thromboembolism.

Introduction: Heparin resistance has been reported in coronavirus disease 2019 (COVID-19) patients receiving intravenous unfractionated heparin (IV UFH). Anti-Xa monitoring of IV UFH has been suggested over activated partial thromboplastin times due to laboratory interference from elevated factor VIII and fibrinogen levels in COVID-19 patients. Information on heparin resistance with anti-Xa monitoring in COVID-19 patients with confirmed venous thromboembolism (VTE) is lacking. Methods: In this retrospective cohort study of patients with radiographically confirmed VTE, IV UFH dosage requirements in COVID-19 positive patients were compared with COVID-19 negative patients. The primary endpoint was the IV UFH dose needed to achieve a therapeutic anti-Xa level. Secondary endpoints included time to therapeutic anti-Xa, number of dose adjustments to achieve therapeutic anti-Xa, and bleeding. Results: Sixty-four patients with confirmed VTE were included (20 patients COVID-19 positive, 44 patients COVID-19 negative). Eighty-five percent (17 of 20) of COVID-19 positive patients achieved anti-Xa ≥ 0.3 units/mL with the first anti-Xa level drawn post-IV UFH infusion initiation. The median UFH dose needed to achieve first therapeutic anti-Xa was similar between COVID-19 positive and COVID-19 negative patients (median [IQR]: 18 units/kg/hour [18-18] vs 18 units/kg/hour [18-18], P = .423). The median number of dose adjustments and time to achieve therapeutic anti-Xa were also similar between the 2 groups. The frequency of patients receiving IV UFH of more 35 000 units/day did not differ between the 2 groups. Two cases of clinically significant heparin resistance in the COVID-19 positive group were identified. Conclusions: During the first wave of COVID-19, heparin dose and time to therapeutic anticoagulation appeared to be similar between COVID-19 positive and COVID-19 negative patients monitored by anti-Xa at our institution. More studies are required to evaluate clinically significant heparin resistance in the context of the wide range of viral variants which developed, and beyond the population observed in this single center retrospective study.

Emergency Department Management of Acute Venous Thromboembolism in Patients With Obesity With Intravenous Unfractionated Heparin and Anti-Xa Monitoring

Background: Unfractionated heparin (UFH) remains a frequently utilized agent in the emergency department (ED) for management of acute venous thromboembolism (VTE). While various protocols of UFH dosing have been proposed for patients with obesity, the optimal dosing and monitoring strategy is unclear. Objective: This study aims to compare the time to the first therapeutic anti-Xa level in obese acute VTE patients following the use of either total body weight (TBW) or adjusted body weight-based (AdjBW) dosing of UFH in the ED, and to analyze the impact of different dosing strategies on patient outcomes. Methods: Inclusion criteria included adult patients with a BMI > 30 kg/m2, and suspected VTE managed with UFH per institutional protocol utilizing a bolus dose followed by maintenance infusion and anti-Xa monitoring. The primary outcome was time to the first therapeutic anti-Xa level in the group dosed per TBW compared with the group dosed per AdjBW. Safety outcomes included incidence of bleeding events, protamine administration, and mortality. Results: There were 32 patients included in the study. Patients dosed per TBW achieved a median time to first therapeutic anti-Xa level of 14.5 hours compared with 15 hours in the AdjBW group (P = .613). The median therapeutic UFH infusion rate was 16 units/kg/hr in the TBW group compared with 13.5 units/kg/hr in the AdjBW group (P < .001). Safety outcomes were not significantly different between groups. Conclusion: Patients presenting to the ED with acute VTE may be managed with UFH using either a TBW or AdjBW dosing strategy.

Antithrombin III Supplementation in a Premature Infant: Is There a Target Antithrombin Level?

The optimal antithrombin (AT) activity for low-molecular-weight heparin efficacy and the benefits of antithrombin III (ATIII) supplementation in premature infants diagnosed with venous thromboembolism are unknown. Currently, there are no neonatal-specific guidelines directing the appropriate target AT activity during supplementation. This case report describes a critically ill premature infant with a progressive, occlusive inferior vena cava thrombus who received supplemental ATIII during enoxaparin treatment. The patient did not achieve therapeutic anti-Xa levels despite increasing enoxaparin dosing to 3 mg/kg every 12 hours. ATIII supplementation sufficient to attain an AT activity of >40%, in combination with an enoxaparin dosing of >2 mg/kg every 12 hours, was needed to achieve therapeutic anti-Xa levels. Future large studies are needed to determine if there is an optimal target AT activity for critically ill premature infants.

Enoxaparin Reduces Catheter-associated Venous Thrombosis After Infant Cardiac Surgery

BackgroundCentral venous catheter (CVC) related venous thrombosis (VT) after pediatric cardiac surgery increases morbidity and mortality. Although VT prevention using low-dose anticoagulation therapy has proven ineffective, anticoagulation therapy using high-dose enoxaparin to achieve a therapeutic anti-Xa level has not been studied. We hypothesized that high-dose enoxaparin would reduce VT after pediatric cardiac surgery. MethodsEnoxaparin was administered to infants aged less than 150 days when postoperative CVC duration was anticipated to extend beyond 5 days. The primary outcome was the rate of VT, reexploration for bleeding, and postoperative red blood cell transfusions per 1000 CVC days. ResultsFrom 2012 to 2019, 157 infants were treated with enoxaparin. Infants were divided into two groups: (1) subtherapeutic (n = 51), in which therapeutic anti-Xa level (0.5 to 1.0 IU/mL) was not achieved; and (2) therapeutic (n = 106), in which therapeutic anti-Xa level was achieved. Baseline demographics demonstrated a lower age at operation in the therapeutic group. The subtherapeutic group had a higher VT rate per 1000 CVC days (8.2) compared with the therapeutic group (2.6; P = .005). Reexploration for bleeding was similar between groups. The number of postoperative red blood cell transfusions per 1000 CVC days was significantly greater in the subtherapeutic group (109.4 vs 81.6; P = .008). Multivariate analysis demonstrated that higher median anti-Xa levels reduced the risk of VT (odds ratio 0.02; 95% confidence interval, 0.001 to 0.63; P = .02). ConclusionsThese data suggest that enoxaparin treatment resulting in a therapeutic anti-Xa level reduces postoperative CVC-associated VT without increasing bleeding complications.

MO732HD-PATIENTS WITH ATRIAL FIBRILLATION TREATED ADEQUATELY AND SAFE WITH DOAC BY INDIVIDUAL DOSING USING ROUTINE ANTI-XA DRUG-EFFECT MONITORING: LONG-TERM CLINICAL PRACTICE DATA

Abstract Background and Aims Hemodialysis (HD) patients (Pts) with nonvalvular atrial fibrillation (AF) on anti-vitamin-K oral anticoagulation (VK-OAC) are at high risk for cardio-vascular events, major bleeding and rapid vascular/valvular calcification. Thus, current VK-OAC is debated since prospective studies are missing, but all direct oral anticoagulation drugs (DOACs) are not labeled for ESRD. We studied the clinical feasibility of long-term DOAC treatment in HD-pts using individual dosing by regular anticoagulant drug-effect monitoring. Method We analysed 9 HD-patients with AF (median age 77 yrs; range=R: 59-86; 7 Male) on DOAC therapy for at least 6 months (n=1 rivaroxaban=Riva, n=8 apixaban=Apix) initiated by cardiologist with patients informed consent with lower dose as in CKD-4 under regular (weekly) anti-Xa drug-effect monitoring (prior HD) using available routine laboratory test validated for low-molecular heparin: Target trough range (12-24h after drug) was 0.1-1.0 U/ml (=prophylactic to therapeutic anti-Xa levels; test range &amp;lt;0.1, &amp;gt;1.6 U/ml). Bleeding caused drug stop/reduction until anti-Xa control. Results Median study time was 14 months (R: 6-24). We analysed 310 anti-Xa levels on Apix and 83 levels on Riva. After dose adjustment finally 2 Apix-Pts (22%) received full CKD-4 dose (35 mg/week=wk) and 7 patients (78%) had median dose of 10 mg/wk (10-27 mg; 6x Apix) or 40 mg/wk Riva, i.e. 29% and 38% of usual CKD-4 dose. Two Pts with higher dose had clinical reasons: short-bowl-syndrome (less resorption) or high grade (3-4) left atrial sludge (therapeutic goal). Overall, median anti-Xa level was 0.47 U/ml (R: &amp;lt;0.1-&amp;gt;1.6) and 80% were in center-accepted targets: 0.1-1.2 U/ml. Lower dose Pts had higher in-target-rate (83%) than the 2 high dose Pts (70%) by more exceeding the upper limit. During our study we saw no cerebral/systemic thrombo-embolic event or major bleeding, but 2 pts had epistaxis (need out-patient intervention), 1x persistent macrohematuria (need catheterization) and 3 pts. had multiple subcutaneous hematoma, none needed event-related transfusion. We saw two non-cardiovascular deaths (22%; 2/9): 1x pneumonic sepsis, 1x advanced cancer. Conclusion We provide new clinical feasibility data on long-term DOACs therapy in HD-patients. Since DOACs are not labelled for ESRD we recommend strict indication plus regular anti-Xa drug-effect monitoring for adequate individual dosing. Our data support initial doses as for CKD-4 but applied only on HD-free days (4x/wk; =57% of usual) and adjustment in steady-state (1-2 wks): final individual doses were increased up to 100% in some patients, but mostly were reduced to 30-40% of usual CKD-4 doses. Overall, this individual dosing approach for DOACs provided adequate anti-Xa levels to prevent thrombo-embolic as well as major bleeding events. This initial data need to be confirmed in larger studies to improve evidence-based management of HD-patients with nonvalvular AF.

Risk factors for postdischarge venous thromboembolism among bariatric surgery patients and the evolving approach to extended thromboprophylaxis with enoxaparin.

Venous thromboembolism (VTE) is one of the most common causes of postoperative mortality following bariatric surgery. The majority of VTE events occur after discharge from the hospital. Little consensus exists regarding who should receive extended enoxaparin thromboprophylaxis or how they should be dosed, namely whether to use weight-based or BMI-stratified dosing strategies. Provide an overview of the risk factors associated with VTE in procedures among bariatric patients including the use of predictive tools to stratify risk and the various approaches to enoxaparin chemoprophylaxis in obesity. Multiple centers. A review of the literature identified studies evaluating risk factors for VTE including demographic characteristics, co-morbidities, and operative factors. The use of calculators to stratifypatients by risk and approaches to extended thromboprophylaxis in obesity were evaluated as well. VTE was associated with increased age, weight, male sex, and prior history of VTE, all frequently included in risk calculators. Outside of those major risk factors, there is little consensus about the importance of patient diagnoses. Weight-based dosing was often superior to standardized dosing in studies across disciplines in generating target anti-Xa levels however there is no consistent association of reduced risk of VTE with therapeutic anti-Xa levels. Risk calculators may be a valuable tool for identifying patients at high-risk for VTE, but their efficacy depends on the rating algorithm and inclusion of various risk factors and is methodologically limited by prophylactic interventions. Future work should consider if biochemical factors should be included in patient stratification approaches in particular when defining the ideal chemoprophylaxis approach. Transparency and consistency in data collection and reporting is needed to better assess and inform the ideal dosing strategy to prevent VTE following bariatric surgery.

Utilization practices of low molecular weight heparin in pediatric patients with acquired and congenital heart disease

BackgroundEnoxaparin is a commonly used anticoagulant for treatment of thrombosis in pediatric patients. Its use in pediatric cardiac patients has not been well described. We sought to examine the utilization trends, dosing, and safety of enoxaparin in pediatric cardiac patients. MethodsRetrospective study of pediatric cardiac patients treated with enoxaparin from 2011 to 2018. Starting and final doses of enoxaparin, number of dose adjustments, and time to therapeutic anti-factor Xa level were compared between age groups utilizing the Kruskal Wallis test with the Dunn test for pairwise comparisons. ResultsSeventy-one patients were treated with 77 courses of enoxaparin. Most enoxaparin courses were started on patients aged >12 months (40%) and for arterial thrombosis (22 patients, 29%). The most common cardiac diagnosis was hypoplastic left heart syndrome (12 patients, 17%). The mean final dose of enoxaparin was significantly different when comparing patients 0–3-month, 3–12 month, and >12 months (2.1 ± 0.5 mg/kg vs. 1.5 ± 0.4 mg/kg vs. 1.2 ± 1.4 mg/kg, respectively; p < 0.02). Patients 0–3 months and 3–12 months had significantly higher final to initial enoxaparin dose differences than the >12-month age group (0.4 ± 0.4 mg/kg vs. 0.4 ± 0.4 mg/kg vs. 0.1 ± 0.3 mg/kg, respectively; p < 0.01). All age groups needed 2–2.5 days to reach therapeutic anti-Xa levels. Patients aged 0–3 months had significantly more dose changes compared to those >12 months (2.2 ± 1.6 vs. 1.4 ± 1.4, p = 0.02). Antiplatelet therapy was used in 74% of courses. Adverse events were rare and had no relationship to antiplatelet use. ConclusionsEnoxaparin is an effective and safe anticoagulant in pediatric cardiac patients. Initial enoxaparin dosing should be increased from current recommended doses in patients between 3 and 12 months of age to achieve more timely therapeutic anticoagulation.

Enoxaparin Utilization Evaluation and Its Clinical and Laboratory Outcomes in Pediatric Patients in a Children’s Teaching Hospital

Backgrounds: In recent years, low molecular weight heparin use has increased in children. Dose of enoxaparin to achieve target anti-Xa and time to achieve anti-Xa are evolving and efficacy outcome data in terms of laboratory and clinical response rate in children still remains to be elucidated. Thus, in this drug utilization and evaluation study, we assessed patterns of enoxaparin use, its concordance with guidelines and laboratory and clinical outcomes in pediatric patients in a Children’s teaching hospital. Methods: In a prospective observational study, all pediatric patients with a thrombotic event who underwent treatment with enoxaparin were included. Demographic data, clinical outcome data based on follow-up sonography results, laboratory response based on anti-Xa and concordance with guidelines in terms of initial daily dose, duration of treatment, performing sonography to evaluate response, anti Xa check and time of anti-Xa check were evaluated. Results: During a 9-month period, 41 pediatric patients suffered a thrombotic event and received enoxaparin. Median age of participants was 18.5 months. The anti-Xa level became therapeutic on mean day 4.7 with a mean enoxaparin dose of 1.24 mg/kg. Among participants 42% achieved therapeutic anti-Xa with initial empirical dosing. Less than 25 % of participants had a follow-up sonography and among them, 77% demonstrated complete thrombosis resolution after 4-6 weeks of enoxaparin therapy. We observed one major bleeding event. Concordance with guidelines was low in the aspects of duration of treatment, performing sonography to evaluate response and anti-Xa check. Conclusion: With initial empiric dosing, it may take several days before anti-Xa become therapeutic. Among half of the children, a higher than recommended 1 mg/kg dose was required to achieve therapeutic anti-Xa level. Educational processes are mandatory regarding enoxaparin use and monitoring among clinicians to improve concordance with guidelines.