Peak anti-Xa Levels Research Articles

#2147 Enoxaparin dosing in advanced chronic kidney disease: importance of monitoring with anti-Xa levels

Abstract Background and Aims Enoxaparin is a low-molecular-weight heparin (LMWH) that is commonly used in the prevention of deep venous thrombosis (DVT) and the treatment of acute thomboembolic diseases. Current literature indicates that in advanced chronic kidney disease (CKD), there is a reduced clearance and increased half-life of LMWH and therefore, a dose adjustment is recommended. The prescription label recommends a dose adjustment of enoxaparin to 0.5 mg/kg/day for prophylaxis of DVT and 1 mg/kg/day for therapeutic anticoagulation when eGFR <30 ml/min. The aim of this study was to examine the accuracy of this dosing strategy to achieve the desired target of anticoagulation in advanced CKD. Method We conducted a prospective study in patients admitted from May 2019 to April 2023 in the Nephrology ward at our centre, who started anticoagulant treatment with enoxaparin during their in-hospital stay for prophylactic or therapeutic indications. We excluded patients with eGFR >30 ml/min at the onset of anticoagulation with enoxaparin. The dosing strategy was 0.5 mg/kg/day for prophylaxis of DVT and 1 mg/kg/day for therapeutic anticoagulation in all patients. Blood samples were drawn 4 hours after the third dose of enoxaparin to monitor anti-Xa levels in all cases. Results The study included 153 patients; 70 patients with stage 4-5 CKD and 83 patients on renal replacement therapy. 132 patients (86.3%) received enoxaparin for a therapeutic indication, while 21 patients (13.7%) received it as prophylaxis of DVT. In patients receiving enoxaparin for a therapeutic indication, 73 patients (55.3%) reached the therapeutic target anti-Xa levels (0.6-1), while 32.6% of patients had peak anti-Xa levels below the therapeutic target (<0.6) and 12.1% were over-anticoagulated (>1). There was an inverse relationship between the proportion of patients who were adequately anticoagulated and CKD stage; 66.7%, 58.6% and 48.6% of patients reached the target peak anti-Xa levels in CKD stage 4, 5 and 5D respectively. There was no significant association between anti-Xa levels and obesity or liver disease. In patients receiving enoxaparin for prophylaxis of DVT, 42.9% reached the target anti-Xa levels for prophylaxis (0.3-0.6), while 38.1% had anti-Xa levels below this range and 19% were over-anticoagulated. Conclusion The enoxaparin dosing recommendations indicated by its label entails a high proportion of patients with advanced CKD who do not achieve the target therapeutic levels of antiXa, especially in patients on renal replacement therapy. To ensure adequate anticoagulation in these patients, we recommend using individualized dosing adjustments based on monitoring of anti-Xa levels for the prevention of thromboembolic events and reducing the risk of hemorrhagic events.

114 Burn Specific VTE Prophylaxis: Higher Enoxaparin Dose and Anti-Xa Adjustments Is Safe and Potentially Beneficial

Abstract Introduction Burn and trauma patients are at high risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolus (PE). VTE prophylaxis guidelines for trauma patients recommends a higher standard dose of enoxaparin and anti-Xa level adjustments in select patients; however, no guidelines specific to burn patients exist. We hypothesize that higher standard doses of enoxaparin and anti-Xa level adjustments will be safe and effective at reducing VTE complications in burn patients. Methods This retrospective review included patients admitted to a regional burn center six months prior to and after the initiation of a VTE prophylaxis quality improvement protocol. The protocol doubled the standard dose of enoxaparin, 40 mg daily to 40 mg twice a day, for all burn patients who were > 50 kg and had creatinine clearance > 60mg/dl. Peak anti-Xa level monitoring was indicated if a high-risk factor (TBSA ≥20%, inhalation injury, burn shock, BMI ≥40) was present. Patients on therapeutic anticoagulation or anti-platelet therapy, had a history of chronic kidney disease, decompensated cirrhosis, coagulation disorder, heparin induced thrombocytopenia (HIT), or were admitted for polytrauma were excluded. Efficacy was evaluated by rates of VTE within 31 days of discharge. Safety was evaluated by bleeding complications, including estimated blood loss (EBL), number of transfusions and gastrointestinal (GI) bleeding events. Differences between groups were compared using a two-sample t-test or Wilcoxon rank-sum test. A p-value of < 0.05 signified statistical significance. Results The pre-protocol group included 217 patients and the post-protocol group included 207 patients. There were no significant differences in age (45 vs 44 years), BMI (27 vs 26.4 kg/m2), TBSA (5.9 vs 5.3%), IHI (4.6 vs 7%), number of procedures (3 vs 3), mortality (4.1 vs 3%), or ICU length of stay (1.9 vs 1.6 days) between groups. No significant difference in EBL (50 vs 25 cc), number of transfusions (3.3 vs 2.4 units), or GI bleeding events (1 vs 1) was noted between groups, and no patient developed thrombocytopenia or HIT. There were 5 patients (2.3%) with a VTE within 31 days of discharge in the pre-protocol group compared to 1 patient (0.4%) in the post-protocol group (p=0.19). There was not enough power to determine statistically significant VTE prevention. Conclusions A lack of VTE prophylaxis recommendations for burn patients leads to variability in protocols among burn centers. These protocols are infrequently studied. This protocol, which doubled the standard dose of enoxaparin and adjusted based on anti-Xa levels for high-risk patients, was safe. Efficacy and applicability to other centers needs further elucidation. Applicability of Research to Practice Enoxaparin 40mg twice a day with anti-Xa level adjustments is safe and a promising strategy to reduce the rates of VTE in the burn population without increasing bleeding complications.

Prophylactic Enoxaparin Dosing Using Anti-Factor Xa Levels in Hepatic Surgery Patients: A Pilot Study.

This study examines the safety and efficacy of using peak anti-Xa levels to achieve prophylactic enoxaparin (Lovenox, Sanofi-Aventis) levels in patients who underwent hepatic surgery. Prospectively enrolled patients undergoing major and minor hepatic procedures received postoperative enoxaparin dosing. The enoxaparin dose was adjusted to attain a peak anti-Xa level ≥ 0.20U/ml. This group was compared to a historical cohort of patients who underwent similar procedures and received standard postoperative VTE chemoprophylaxis dosing. Inpatient postoperative VTE rates were higher in the control group when compared to the experimental group (0 patients [0.00%] vs 4 patients [8.16%]; P = .035). There was no statistically significant difference in number of postoperative blood transfusions, discharge hemoglobin, or in-hospital bleeding events. Adjusting enoxaparin dosing to achieve prophylactic peak anti-Xa levels of ≥0.20IU/ml was associated with a reduced incidence of symptomatic inpatient postoperative VTE in patients who underwent hepatic surgery without increasing postoperative bleeding events.

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.

Anti-Xa Monitoring of Apixaban (ZyQuis) in Venous Thrombo-Embolism and Atrial Fibrillation.

Apixaban is a direct oral Xa inhibitor and is indicated for the treatment of venous thrombo-embolism (VTE) and prevention of stroke in atrial fibrillation (AF). Recently, a generic (ZyQuis, Zydus Lifesciences Limited, India) has received Food and Drug Administration approval. While bioequivalence has been demonstrated with Eliquis (Bristol-Myers Squibb/Pfizer, UK), it is necessary to monitor its effectiveness prior to acceptance in medical practice. This prospective study independently evaluated Apixaban (ZyQuis) at two accredited laboratories. Participants were converted from Warfarin or Rivaroxaban to Apixaban 5 mg bd for a duration of one month. Peak anti-Xa levels were measured 3-4 h post the morning dose. The samples were processed on the Atellica COAG 360 (Siemens Healthineers, Marburg, Germany) analyzers with a chromogenic anti-Xa assay (Innovance, reference interval 69-321 ng/mL). There were 26 participants; 5 men, 21 women; mean ± standard deviation age of 46 ± 12 years. Indications for anticoagulation included: VTE (88.5%) and AF (11.5%). 69.2% of the participants had at least one comorbidity. 96.2% of the anti-Xa levels were within the laboratory's 95% reference interval. Mean anti-Xa activity was 191 ± 69 ng/mL and 186 ± 68 ng/mL measured at respective laboratories. Mean differences in anti-Xa measurements represented by Bland-Altman statistics were small (bias of -2.6%, 95% confidence interval -1.11 to -4.09) and a strong correlation was observed on Deming regression analysis (0.995). Apixaban (ZyQuis) was effective for the management of VTE and AF as evidenced by anti-Xa activity.

Risk Stratification for Supratherapeutic Peak Anti-Xa Levels in Adult Patients on Therapeutic Enoxaparin.

The American Society of Hematology Guidelines for the management of venous thromboembolism recommend against the use of anti-Xa monitoring for assessing enoxaparin dosing based on a low level of evidence associating supratherapeutic levels with an increased risk of bleeding. However, institutions still utilize anti-Xa levels in select patient populations with altered volume of distribution and/or excretion to monitor and adjust therapy. The primary objective of this study was to identify risk factors associated with supratherapeutic peak anti-Xa levels (≥1.10 IU/mL) for patients receiving therapeutic enoxaparin. This was a retrospective single-center study performed at an academic tertiary care hospital. Patients who received enoxaparin at 1 mg/kg twice daily and peak anti-Xa monitoring were separated into supratherapeutic and therapeutic/subtherapeutic cohorts. A total of 436 patients were screened, and 215 were included, with a mean age of 62 years. There were 108 in the therapeutic/subtherapeutic cohort and 107 in the supratherapeutic cohort. Acute kidney injury (AKI), body mass index (BMI), weight, female sex, intensive care unit (ICU) service, Sequential Organ Failure Assessment (SOFA) score ≥4, and creatinine clearance at the time of peak anti-Xa level collection were associated with supratherapeutic anti-Xa levels in univariate models. Adjusted logistic regression models were created and identified BMI in the 30 to 34.9 kg/m2 (odds ratio [OR] 4.35; 95% confidence interval [CI] 1.70-11.13, P < 0.005) and ≥35 kg/m2 (OR 6.75; 95% CI 3.05-14.94, P < 0.005) and AKI (OR 2.62; 95% CI 1.04-6.62, P = 0.042) as significant risk factors for supratherapeutic anti-Xa levels. Our study identified BMI ≥ 30 kg/m2, AKI, female sex, ICU service, SOFA score ≥4, and creatinine clearance as risk factors for supratherapeutic anti-Xa levels in patients receiving 1 mg/kg twice daily dosing of enoxaparin. Further research should be done to provide evidence for the association between anti-Xa levels and bleeding risk.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

British Society for Haematology guideline for anticoagulantmanagement of pregnant individuals with mechanical heart valves.

Monitoring anti-Xa Levels to Optimize Low-Molecular-Weight-Heparin Thromboprophylaxis in High-Risk Hospitalized Patients: A Stratified Meta-Analysis.

It is uncertain whether monitoring or targeting anti-Xa levels is necessary when using low-molecular-weight-heparin (LMWH) to prevent venous thromboembolism (VTE). This stratified meta-analysis assessed whether monitoring trough or peak anti-Xa levels with LMWH dosing would reduce risk of VTE. Twelve non-randomized studies involving 3604 hospitalized patients met the inclusion criteria and were subject to meta-analysis. Eight studies assessed the association between VTE and peak anti-Xa levels (between .2 and .5 IU/ml) and four studies assessed the benefits of targeting the trough anti-Xa levels (>.1 IU/ml). Achieving an adequate peak or trough anti-Xa level was associated with a reduced risk of VTE (random-effects model odds ratio [OR] .52, 95% confidence interval [CI] .34-.77; P = .001, I2 = 30% and P-value for heterogeneity = .171) compared with using a fixed standard dose of LMWH. Targeting the trough level (OR .40, 95%CI 0.22-.75, P = .004) appeared to be more effective than targeting the peak level (OR .62, 95%CI 0.37-1.03, P = .066), although a formal interaction analysis did not confirm they were statistically different (ratio of ORs = 1.52, 95%CI 0.68-3.40; z score = 1.03, P = .306). Targeting a higher anti-Xa level did not appear to increase the risk of bleeding or transfusion (OR 1.20, 95%CI 0.46-3.17, P = .707).

Anticoagulation for mechanical heart valves during pregnancy: A case report and a literature review

Most previous treatment guidelines for pregnant women with mechanical heart valves recommend that low molecular weight heparin (LMWH) should be applied once every 12 hours and only as required to reach peak anti-Xa levels of approximately 1.0 to 1.2 IU/mL, but it is commonly associated with subtherapeutic trough levels, consequently with an inadequate level of anticoagulation. Our case report here together with a literature review suggests that dose-adjusted (Target trough anti-Xa levels of 0.6 to 0.7 IU/mL and with peak anti-Xa levels of around 1.0 to 1.2 IU/mL or < 1.5 IU/mL) LMWH should be given thrice daily throughout pregnancy. In addition, the findings of this rare case indicate that a combination of LMWH and warfarin is effective in the treatment of small thromboses in pregnancy. In the 1st trimester of pregnancy, a 28-year old pregnant female with a mechanical valve had a significant increase in the aortic valve flow rate and suspected mechanical valve thrombosis. The peak velocity of the pregnant female aortic mechanical valve increased, and mechanical valve thrombosis was suspected. We adjusted the enoxaparin sodium dose every 12 hours to 1 injection every 8 hours, with a total daily dose of 160 mL. Based on the original application of LMWH, warfarin (3 mg/day) was recommended. The pregnant woman delivered a live baby by cesarean section, and the peak flow velocity of the mechanical valve in the aortic position was reduced to nearly equivalent to the patient's pre-pregnancy status. The mother and the baby were in good health at the time of discharge. LMWH is administered twice daily, and anti-Xa trough levels are mostly in a subtherapeutic state, which may lead to insufficient anticoagulation and thrombosis. Dose-adjusted LMWH thrice daily throughout pregnancy is the recommended treatment for pregnant women with mechanical heart valves. The combination of LMWH and warfarin exhibited good efficacy for the treatment of small thromboses.

Optimising the Nadroparin Dose for Thromboprophylaxis During Hemodialysis by Developing a Population Pharmacodynamic Model Using Anti-Xa Levels.

The optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥0.4 IU/mL and <2.0 IU/mL are suggested to prevent thrombus formation within the extracorporeal circuit whilst minimizing bleeding risk. We aimed to characterize the variability in the association between dose and anti-Xa levels, identify patient and dialysis characteristics that explained this variability, and optimize nadroparin dosing based on the identified characteristics. Anti-Xa samples were collected in patients who received intravenous nadroparin as thromboprophylaxis during routine dialysis sessions. A population pharmacodynamic model was developed using non-linear mixed-effects modelling. The percentage of patients ≥0.4 IU/mL (efficacy) and <2.0 IU/mL (safety) was simulated for different doses, patient and dialysis characteristics. Patients (n =137) were predominantly receiving standard hemodialysis (84.7% vs. hemodiafiltration 15.3%) and had a mean bodyweight of 76.3 kg (±16.9). Lean body mass (LBM), mode of dialysis, and dialyzer partially explained between-subject variability in anti-Xa levels. Patients on hemodiafiltration and those receiving hemodialysis with a high LBM (≥80 kg) had a low probability (<29%) of anti-Xa levels ≥0.4 IU/mL during the entire dialysis session. All patients, except hemodialysis patients with a low LBM (<50 kg), had a high probability (>70%) of peak anti-Xa levels <2.0 IU/mL. Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels <2.0 IU/mL.

One size does not fit all: Sex bias in pharmacologic venous thromboembolism prophylaxis.

The optimal enoxaparin dosing strategy to achieve venous thromboembolism (VTE) prophylaxis in trauma patients remains unclear. Current dosing guidelines often include weight, age, and renal function but still fail to achieve appropriate prophylactic anti-Xa levels in many patients. We hypothesized that additional patient factors influence anti-Xa response to enoxaparin in trauma patients. This is a retrospective review of patients admitted to a Level 1 trauma center for ≥4 days from July 2015 to September 2020, who received enoxaparin VTE prophylaxis per protocol (50-59 kg, 30 mg/dose; 60-99 kg, 40 mg/dose; ≥100 kg, 50 mg/dose; all doses every 12 hours) and had an appropriately timed peak anti-Xa level. Multivariate regression was performed to identify independent predictors of prophylactic anti-Xa levels (0.2-0.4 IU/mL) upon first measurement. The cohort (N = 1,435) was 76.4% male, with a mean ± SD age of 49.9 ± 20.0 years and a mean ± SD weight of 82.5 ± 20.2 kg (males, 85.2 kg; females, 73.7 kg; p <0.001). Overall, 68.6% of patients (n = 984) had a prophylactic anti-Xa level on first assessment (69.6% of males, 65.1% of females). Males were more likely to have a subprophylactic level than females (22.1% vs. 8.0%, p <0.001), whereas females were more likely to have supraprophylactic levels than males (26.9% vs. 8.3%, p < 0.001). When controlling for creatinine clearance, anti-Xa level was independently associated with dose-to-weight ratio (odds ratio, 0.191 for 0.5 mg/kg; p < 0.001; confidence interval, 0.151-0.230) and female sex (odds ratio, 0.060; p < 0.001; confidence interval, 0.047-0.072). Weight and age were not significant when controlling for the other factors. Male patients have a decreased anti-Xa response to enoxaparin when compared with female patients, leading to a greater incidence of subprophylactic anti-Xa levels in male patients at all dose-to-weight ratios. To improve the accuracy of VTE chemoprophylaxis, sex should be considered as a variable in enoxaparin dosing models. Therapeutic/Care Management; Level III.

Observed Apixaban Anti-Xa Levels in Obese Patients.

Recent guidelines suggest that, for venous thromboembolism (VTE), standard doses of apixaban are appropriate in patients with body mass index (BMI) >40 kg/m2 or >120 kg. Atrial fibrillation (AF) is excluded from this recommendation. The goals of our study were to measure and describe anti-Xa levels of patients with a BMI ≥40 kg/m2 and/or a weight ≥120 kg with a clinical indication of AF or VTE who were treated with apixaban, and to determine whether BMI or weight are associated with anti-Xa levels in this population. We conducted an observational cohort study at a single health care system in Oregon, USA. Patients meeting enrollment criteria were recruited and had peak and trough apixaban anti-Xa levels drawn. Of 55 patients enrolled, 5 (9%) had peak anti-Xa levels below the reference range and 3 (6%) had trough anti-Xa levels below the reference range. BMI did not significantly correlate with peak or trough anti-Xa levels (r = -0.10, p = 0.45 and r = -0.14, p = 0.31). Weight had a moderate, negative correlation with peak anti-Xa levels (r = -0.42, p = 0.002) and a weak, negative correlation with trough anti-Xa levels (r = -0.32, p = 0.02). This study provides evidence that anti-Xa levels among obese patients are not substantially different from patients with nomral BMI and weight. This supports recent ISTH guidance for standard dosing of apixaban for VTE patients with BMI >40 kg/m2 or weight >120 kg and provides additional evidence that the standard dosing may also be appropriate in patients with AF.

Effect of low-molecular-weight heparins on anti-Xa peak levels and adverse reactions in Chinese patients with recurrent spontaneous abortion: a single-center, observational study

ObjectiveTo compare three commonly used low-molecular-weight heparins (LWMHs) in the treatment of recurrent spontaneous abortion (RSA) by evaluating the anti-Xa peak levels and adverse reactions.MethodsIn this single-center, observational study, we enrolled 310 patients with RSA in whom anti-Xa levels were measured during pregnancy. Patients were divided into three groups according to the LMWH they used: the nadroparin group, enoxaparin group and dalteparin group. We compared the peak anti-Xa levels and the coagulation status of each group, and analyzed the incidence of adverse reactions, including local allergy, liver and renal dysfunction, and the impact on platelet.ResultsPatients in the enoxaparin group had a higher anti-Xa peak level than those in the nadroparin group (0.80 ± 0.22 IU/ml vs. 0.61 ± 0.24 IU/ml; P < 0.0001), although most patients in the three groups reached the target concentration of anti-Xa. Furthermore, patients in the enoxaparin group had a more stable anti-Xa levels during pregnancy. In addition, patients in the nadroparin group had a higher rate of local allergy than those in the enoxaparin group (60.5% vs. 42.5%; P = 0.004) and those in the dalteparin group (60.5% vs. 33.3%; P = 0.002). Further examination by the type of local allergy indicated a dramatic difference in pruritus and induration between the nadroparin group and the other two groups. No difference was found in the incidence of liver and renal dysfunction and thrombocytopenia.ConclusionCompared with nadroparin and daltepatin, enoxaparin showed a better performance regarding anti-Xa levels and the incidence of adverse reactions in the treatment of RSA.

Extended thromboprophylaxis post gynaecological cancer surgery; the effect of weight adjusted and fixed dose LMWH (Tinzaparin)

ObjectiveGynaecological cancer surgery is associated with high rates of venous thromboembolism (VTE) despite recommended prophylaxis. We sought to investigate the impact of extended prophylaxis with fixed dose and weight based LMWH in patients undergoing gynaecological cancer surgery. MethodsVTE rates were recorded in patients who received LMWH prophylaxis (4500 IU Tinzaparin once daily) for the duration of hospital stay (2006–2012) (n = 610) and were compared with VTE rates in patients who underwent surgery after the introduction of extended prophylaxis (3500/4500 IU Tinzaparin for patients with BMI < 40kg/m2 and 75 IU/kg for BMI > 40 kg/m2) (2012–2017) (n = 651). Peak (4 h) anti-Xa levels in a subset of patients were also evaluated. Results73 (5.7%) cases of VTE were recorded during 1 year of follow-up. 20 cases occurred during hospital stay. There was no significant difference in the rate of VTE between the extended prophylaxis cohort and the standard prophylaxis cohort. 23/24 patients who developed VTE in the extended prophylaxis cohort received a fixed (4500 units) dose of Tinzaparin. 63% of patients who received a fixed LMWH dose had peak anti-Xa levels below the target range (0.2–0.4 IU/ml). Peak anti-Xa was lower in patients who subsequently developed VTE compared with those who received either fixed dose (P = 0.041) and weight adjusted Tinzaparin (P = 0.0006). ConclusionsExtended prophylaxis with Tinzaparin does not significantly reduce VTE rates in gynaecological cancer patients post surgery. Peak anti-Xa levels may be suboptimal in many patients receiving a fixed LMWH dose. Further studies are required to determine whether weight adjusted doses of Tinzaparin may provide more effective prophylaxis following gynaecological cancer surgery.

Safety and Efficacy of Prophylactic Enoxaparin Adjusted by Anti-Factor Xa Peak Levels in Pancreatic Surgery.

Recommended prophylactic doses of enoxaparin (Lovenox) are associated with subprophylactic anti-Factor Xa (anti-Xa) levels. This study examines the safety and efficacy of anti-Xa-guided dosing of enoxaparin in pancreatic surgery. Prospectively enrolled patients undergoing pancreatic surgery received enoxaparin dosing adjusted based on peak anti-Xa levels and were compared to a historical cohort of patients. Baseline characteristics were similar between the intervention and control groups. In the intervention group, 73.9% initially had subprophylactic peak anti-Xa levels. There were no differences in the venous thromboembolism (VTE) rates between the intervention and control groups (0% vs. 7.69%; P = .084), major bleeding events (4.35% vs. 2.56%; P = .627), RBC transfusion (15.2% vs. 25.6%; P = .257), or Hgb on discharge (9.82 vs. 9.44g/dL; P = .244). Subtherapeutic anti-Xa levels were correlated with a higher BMI (P = .033), longer OR time (P = .011), and length of stay (P = .018). Enoxaparin 40mg once daily is associated with subprophylactic peak anti-Xa levels. Dose adjustment based on anti-Xa levels trended toward a lower rate of in-hospital VTE without an increase in bleeding or transfusion requirement.

Fixed-dose enoxaparin provides efficient DVT prophylaxis in mixed ICU patients despite low anti-Xa levels: A prospective observational cohort study.

Deep vein thrombosis (DVT) is a serious but preventable complication of critical illness with a reported incidence from 4 to 17%. Anti-Xa activity in critically ill patients achieved with standard dosing of low-molecular-weight heparins (LMWH) is often below the target of 0.2-0.5 IU/mL. However, the clinical significance of this finding is unclear. The quality of thromboprophylaxis also strongly impacts the incidence of DVT. We performed a prospective observational study to evaluate the incidence of DVT in a mixed medical-surgical-trauma intensive care unit (ICU) using a thromboprophylaxis protocol with a fixed dose of enoxaparin. We also explored the relation between DVT incidence and anti-Xa activity. All consecutive patients with expected ICU stay ≥72 hours and without evidence of DVT upon admission were included. They underwent ultrasound screening for DVT twice a week until ICU discharge, death, DVT or pulmonary embolism. Peak anti-Xa activity was measured twice a week. Patients received 40 mg of enoxaparin subcutaneously (60 mg in obese, 20 mg in case of renal failure). Graduated compression stockings were used in case of LMWH or another anticoagulant contraindication. A total of 219 patients were enrolled. We observed six cases of DVT (incidence of 2.7%). The agreement between expected and delivered DVT prophylaxis was 94%. Mean peak anti-Xa activity level was 0.24 (SD, 0.13) IU/mL. There was no significant difference in anti-Xa activity in DVT and non-DVT group. A low incidence of DVT was achieved with meticulous adherence to the standard prophylactic protocol. The low incidence of DVT was observed despite low levels of anti-Xa activity. Our findings suggest that enoxaparin dose adjustment based on regular monitoring of anti-Xa activity is unlikely to result in further reduction of DVT incidence in a mixed ICU population. ClinicalTrials.gov, NCT03286985.

A Weight- and Anti-Xa-Guided Enoxaparin Dosing Protocol for venous thromboembolism Prophylaxis in intensive care unit Trauma Patients

Trauma patients are high risk for venous thromboembolism (VTE) and the optimal dosing strategy for prophylactic enoxaparin remains unknown. The purpose of this quality improvement project was to evaluate a weight-based and anti-Xa-guided enoxaparin dosing protocol in intensive care unit (ICU) trauma patients and to determine if the protocol led to reduced clinical VTE rates. Adult trauma patients admitted for ≥ 48 hours to our surgical or neurosurgical ICUs who received ≥ 3 consecutive weight-based enoxaparin doses were eligible for inclusion into this pre-post implementation cohort study. Enoxaparin 30 mg every 12 hours was used for weight 50 to 100 kg and body mass index (BMI) < 40 kg/m2 and enoxaparin 40 mg every 12 hours for weight ≥ 100 kg or BMI ≥ 40 kg/m2. PRE cohort patients did not routinely receive anti-Xa level monitoring, while in the POST cohort, dosing was subsequently titrated to peak anti-Xa levels of 0.2 to 0.4 IU/mL. A total of 110 and 113 patients were included in the PRE and POST cohorts, respectively. Clinical VTE rates were similar between groups. In the POST cohort, 75% of patients achieved goal anti-Xa levels without dose titrations, while 12% of higher weight patients and 9.1% of lower weight patients required adjustment. When comparing weight quartiles, patients > 100 kg were more likely to have sub-prophylactic anti-Xa levels than those ≤ 69 kg. Our enoxaparin dosing protocol was safe and frequently achieved initial anti-Xa levels within goal, indicating that weight-based dosing alone may be sufficient. However, patients > 100 kg may benefit from anti-Xa monitoring as they are highest risk for sub-prophylactic levels despite higher initial enoxaparin dosing.

A fixed dose approach to thrombosis chemoprophylaxis may be inadequate in heavier critically ill patients

Objectives: Overweight patients are at greater risk of venous thromboembolism. We aimed to describe prescribing patterns of thrombosis chemoprophylaxis in critically ill patients weighing ≥ 100 kg and quantify the effectiveness of these regimens using the surrogate biomarker of plasma anti-Xa level. Design, setting and patients: A prospective single-centre cohort study was conducted over a 6-month period. Patients weighing ≥ 100 kg who were prescribed enoxaparin for chemoprophylaxis and expected to remain in the intensive care unit for > 48 hours were eligible. Anti-Xa levels were measured once a patient had received at least three consecutive doses of enoxaparin. Peak levels were measured 4-6 hours after the third dose and trough levels were measured before the fourth dose. Anti-Xa levels were compared with established target ranges for peak and trough anti-Xa levels (0.2-0.5 IU/mL and > 0.1 IU/mL, respectively). Results: Eighty-eight patients met the eligibility criteria, and anti-Xa levels for 42 patients were obtained. Fixed dose chemoprophylaxis approaches varied considerably, with 40 mg once daily (54/88 [61%]) and 40 mg twice daily (20/88 [23%]) being the most frequently prescribed regimens. No patient had a peak anti-Xa level > 0.5 IU/mL. When comparing 40 mg once daily versus twice daily, the once daily regimen had lower median trough levels (0.01 IU/mL [interquartile range (IQR), 0.00-0.04] v 0.09 IU/mL [IQR, 0.05-0.13]; P < 0.001) and greater proportions of patients with levels below the established range (< 0.1 IU/mL) (15/16 [95%] v 7/14 [50%]; P = 0.002) and levels that were undetectable (0.00 IU/mL) (8/16 [50%] v 1/14 [7%]; P = 0.01). Conclusions: At a single centre, thrombosis chemoprophylaxis prescribing patterns for heavier critically ill patients varied considerably. Current fixed dose approaches may be inadequate in this cohort.

Australian and New Zealand Registry of Anticoagulation in the Obese: Prescribing Patterns, Drug Levels and Patient Outcomes

Background: There is limited data to guide prescribing of all available anticoagulants in obese patients, in particular those weighing &amp;gt; 150kg or with a BMI &amp;gt; 40kg/m2. We aimed to examine anticoagulant prescribing patterns in obese patients in Australia and New Zealand including choice of agent and dosing, determine whether patients with obesity achieve appropriate direct oral anticoagulant (DOAC) levels and evaluate the efficacy and safety of anticoagulation in obese patients. Methods: Patients with a BMI &amp;gt; 35kg/m2 or weight &amp;gt; 120kg receiving anticoagulant therapy are prospectively identified at 7 sites in Australia and New Zealand. Demographic data, indication for anticoagulation and choice of anticoagulant are collected at baseline. At follow-up visits, drug specific levels, dose adjustments and clinical progress (symptoms, imaging, recurrent thrombosis and adverse events) are recorded. Results: 155 patients have been recruited across seven sites (recruitment ongoing). The median age of patients was 53 (range 22-85) and 49% of patients were male. 77 (50%) of patients were anticoagulated for pulmonary embolus (PE) while 40% were anticoagulated for deep vein thrombosis (DVT) without PE. Initial anticoagulant prescribed was apixaban in 37 patients, dabigatran in 4 patients, rivaroxaban in 57 patients, low molecular weight heparin (LMWH) in 29 patients and warfarin in 28 patients (Table 1). A subset of patients initially received LMWH for 5-14 days prior to transition to a DOAC (rivaroxaban in 7, dabigatran in 6). There was cross-over between agents during the study period. Table 2 demonstrates median peak and trough DOAC levels. All peak apixaban levels and 25 of 37 (68%) peak rivaroxaban levels were within the therapeutic ranges published by the International Council for Standardization in Haematology (Gosselin, Thromb Haemost. 2018). Assessment of appropriate trough levels was limited by the limit of detection at different laboratories. 27 patients receiving enoxaparin had at least one peak Anti-Xa level (target peak 0.5-1.2U/ml). The median enoxaparin dose to achieve therapeutic peak Anti-Xa was 0.9mg/kg (range 0.52-1.3). 15 patients weighing &amp;gt; 150kg had a recorded peak Anti-Xa, 10 of these patients were prescribed a capped dose of 150mg BD (weight range 155-290kg) and nine had a therapeutic Anti-Xa and one had a supratherapeutic Anti-Xa measurement. One patient had a PE on apixaban 5mg twice daily (in the setting of suspected non-compliance), one patient had a new confirmed PE after 4 days of non-compliance with rivaroxaban 20mg daily and another patient had a confirmed recurrence on therapeutic warfarin. 1 patient had a PE when warfarin was withheld for emergency surgery. An equivocal recurrence occurred on enoxaparin with a supratherapeutic Anti-Xa (1.76 U.ml) and 1 DVT occurred on dabigatran for a cardiac indication (no drug level available). One patient had recurrent superficial thrombophlebitis on rivaroxaban 20mg daily (peak 301ng/L and trough &amp;lt;30ng/L). There was one episode of life-threatening gastrointestinal bleeding on dabigatran. Conclusion: There is limited data to guide prescribing of all anticoagulants in obese patients, in particular in patients weighing &amp;gt; 150kg or BMI &amp;gt; 40kg/m2. There is increasing use of DOACs in Australia and New Zealand in patients with obesity given the ease of administration and lack of monitoring required. Despite the recommendation to perform DOAC levels in this group of patients, interpretation of levels is difficult due to a lack of well validated therapeutic ranges with clinical correlation. Further data regarding the clinical utility of DOAC levels, appropriate dosing strategy for enoxaparin, and clinical outcomes in this population is required. Our registry provides data regarding drug levels in this population, prescribing characteristics and clinical outcome data. Disclosures No relevant conflicts of interest to declare.

Weight-Based Enoxaparin Achieves Adequate Anti-Xa Levels More Often in Trauma Patients: A Prospective Study.

Previous research demonstrates that twice-daily enoxaparin is inadequate for venous thromboembolic (VTE) prophylaxis in critically ill trauma patients prompting dose adjustment based on anti-Xa levels. Most studies evaluate peak anti-Xa levels; however, data suggest that trough levels are associated with decreased VTE. We evaluated trough anti-Xa levels in noncritically ill trauma patients receiving fixed or weight-based enoxaparin. Peak and trough anti-Xa levels were prospectively collected from patients receiving at least 3 consecutive doses of enoxaparin (PRE). A performance improvement project prompted a change to weight-based dosing. Peak and trough levels were subsequently prospectively collected from the weight-based group (POST). Adequate peak was defined as ≥0.2 IU/mL and adequate trough as ≥0.1 IU/mL. PRE and POST groups were compared. 200 patients were evaluated (100 PRE, 100 POST). In the PRE group, only 34% of trough and 61% of peak anti-Xa levels were adequate compared with 82% and 97%, respectively, in the POST group (P < .01). Median trough improved from 0.07 IU/mL to 0.2 IU/mL (P < .01). Median peak improved from 0.22 IU/mL to 0.47 IU/mL (P < .01). More patients achieved adequate peak and trough levels in the POST group (79% vs 31%, P < .01). 95% of patients with adequate troughs also had adequate peaks, whereas 75% with adequate peaks had adequate troughs. Traditional enoxaparin dosing in noncritically ill trauma patients results in suboptimal anti-Xa levels. Weight-based enoxaparin improves both trough and peak anti-Xa levels obviating dose adjustment. Furthermore, troughs better predict adequate anti-Xa levels.