Peak anti-Xa Levels Research Articles

PKP-006 Evaluation of the predictive ability of different formulas to estimate renal function when enoxaparin is used

BackgroundExposure to enoxaparin is significantly increased in patients with severe renal impairment (creatinine clearance ClCr <30 mL/min). Thus, a dose adjustment is recommended for both the therapeutic and prophylactic dose...

Heparin thromboprophylaxis in critically ill patients: Is it really changing outcome?

Heparin thromboprophylaxis in critically ill patients: Is it really changing outcome?

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Introduction: Obesity is an independent risk factor for venous thromboembolism (VTE) and a major cause of morbidity and mortality. The optimal enoxaparin dosing for VTE prophylaxis in obese patients based on Anti-Xa levels and correlation of Anti-Xa levels with clinical outcomes remains controversial. Methods: Data were collected retrospectively on 139 adult obese patients (BMI ≥ 30 kg/m2) who received enoxaparin for VTE prophylaxis with at least one appropriately timed Anti-Xa level (drawn 3-5 hours after the third dose) from February 1, 2011 through August 31, 2012. Data were analyzed using appropriate descriptive statistics. Results: The mean BMI and weight were 38.3 kg/m2 (range 30.1 - 66.4) and 116.1 kg (range 70 - 208.7), respectively. The initial mean Anti-Xa level was 0.13 IU/mL (range 0 - 0.47) and 21.6% of patients initially achieved the target peak Anti-Xa level between 0.2 and 0.5 IU/mL. The initial mean enoxaparin dose was 0.56 mg/kg/day (range 0.19 - 0.96). The overall rate of bleeding was 23.7%, but only two patients discontinued enoxaparin due to concern for bleeding. Two VTE events were detected. Conclusions: Standard dosing of enoxaparin for VTE prophylaxis in obese patients is inadequate to achieve target peak Anti-Xa levels. Although a relatively low incidence of bleeding and VTE was observed, the correlation between Anti-Xa levels and clinical outcomes remains unclear. Further studies are needed to elucidate this relationship and to develop an algorithm for enoxaparin VTE prophylactic dosing in obese patients.

Alternative dosing of prophylactic enoxaparin in the trauma patient: is more the answer?

BackgroundInadequate anti–factor Xa levels and increased venous thromboembolic events occur in trauma patients receiving standard prophylactic enoxaparin dosing. The aim of this study was to test the hypothesis that higher dosing (40 mg twice daily) would improve peak anti-Xa levels and decrease venous thromboembolism. MethodsA retrospective review was performed of trauma patients who received prophylactic enoxaparin and peak anti-Xa levels over 27 months. Patients were divided on the basis of dose: group A received 30 mg twice daily, and group B received 40 mg twice daily. Demographics and rates of venous thromboembolism were compared between dose groups and patients with inadequate or adequate anti-Xa levels. ResultsOne hundred twenty-four patients were included, 90 in group A and 34 in group B. Demographics were similar, except that patients in group B had a higher mean body weight. Despite this, only 9% of group B patients had inadequate anti-Xa levels, compared with 33% of those in group A (P = .01). Imaging studies were available in 69 patients and revealed 8 venous thromboembolic events (P = NS, group A vs group B) with significantly more venous thromboembolic events occurring in patients with low anti-Xa levels (P = .02). ConclusionsAlthough higher dosing of enoxaparin led to improved anti-Xa levels, this did not equate to a statistical decrease in venous thromboembolism.

Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient

BackgroundLimited data exist regarding the efficacy of weight-based dosing of low–molecular weight heparin for venous thromboembolism (VTE) prophylaxis in obese trauma patients. MethodsConsecutive obese trauma patients were placed on a weight-based protocol for VTE prophylaxis (enoxaparin .5 mg/kg subcutaneously every 12 hours). Peak anti-Xa levels were drawn, and bilateral lower extremity duplex ultrasound was performed. The incidence of VTE and bleeding complications were recorded. ResultsEighty-six patients met the study criteria. Seventy-four patients achieved target prophylactic anti-Xa concentrations, with a mean level of .42 ± .01 IU/mL. Eighteen patients were found to have deep vein thrombosis. However, in 16 of these patients, deep vein thrombosis was diagnosed before weight-based low–molecular weight heparin initiation. No bleeding complications occurred, and no symptomatic pulmonary emboli were identified. ConclusionsIn obese trauma patients, weight-based enoxaparin is an efficacious regimen that provides adequate VTE prophylaxis, as measured by anti-Xa levels, and appears to be safe without bleeding complications.

A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial

IntroductionCritically ill patients are predisposed to venous thromboembolism. We hypothesized that higher doses of enoxaparin would improve thromboprophylaxis without increasing the risk of bleeding. Peak anti-factor Xa (anti-Xa) levels of 0.1 to 0.4 IU/ml reflect adequate thromboprophylaxis for general ward patients. Studies conducted in orthopaedic patients demonstrated a statistically significant relationship between anti-Xa levels and wound haematoma and thrombosis. Corresponding levels for critically ill patients may well be higher, but have never been validated in large studies.MethodsEighty critically ill patients weighing 50 to 90 kilograms were randomised in a double-blinded study to receive subcutaneous (sc) enoxaparin: 40 mg once daily (QD), 30 mg twice daily (BID), 40 mg BID, or 1 mg/kg QD, each administered for three days. Anti-Xa activity was measured at baseline, and daily at 4, 12, 16 and 24 hours post administration. Antithrombin, fibrinogen, and platelets were measured at baseline and twice daily thereafter.ResultsTwo patients were transferred prior to participation. On day 1, doses of 40 mg QD (n = 20) and 40 mg BID (n = 19) yielded mean peak anti-Xa of 0.20 IU/ml and 0.17 IU/ml respectively. A dose of 30 mg BID (n = 20) resulted in much lower levels (0.08 IU/ml). Patients receiving 1 mg/kg QD (n = 19) achieved near steady-state mean peak anti-Xa levels from day 1 (0.34 IU/ml). At steady state (day 3), mean peak anti-Xa levels of 0.13 IU/ml and 0.15 IU/ml were achieved with doses of 40 mg QD and 30 mg BID respectively. This increased significantly to 0.33 IU/ml and 0.40 IU/ml for doses of 40 mg BID and 1 mg/kg QD respectively. Thus anti-Xa response profiles differed significantly over the three days between enoxaparin treatment groups (P <0.0001). Doses of 40 mg BID and1 mg/kg QD enoxaparin yielded target anti-Xa levels for over 80% of the study period. There were no adverse effects.ConclusionsDoses of 40 mg QD enoxaparin (Europe) or 30 mg BID (North America) yield levels of anti-Xa which may be inadequate for critically ill patients. A weight-based dose yielded the best anti-Xa levels without bioaccumulation, and allowed the establishment of near steady-state levels from the first day of enoxaparin administration.Trial registrationCurrent Controlled Trials ISRCTN91570009.

Anticoagulant choices in pregnant women with mechanical heart valves: Balancing maternal and fetal risks – the difference the dose makes

Long-term anticoagulation is required in all patients with mechanical prosthetic heart valves to prevent complications with valve thrombosis and valve failure or systemic thromboembolism. The prothrombotic environment of pregnancy further increases the risks of these complications. Anticoagulant choices for pregnant women include oral vitamin K antagonists such as warfarin, or heparin – either unfractionated heparin (UFH) or low molecular weight heparin (LMWH). None of the options is without risk for the mother or her baby. Warfarin crosses the placenta and is associated with warfarin embryopathy and fetopathy but is very effective at preventing thromboembolic complications. The dose of warfarin may play a role in the risk of some, but not all fetal complications. Heparin does not cross the placenta but is less effective at preventing thrombosis and LMWH may be more effective than UFH. The optimal dose and target anti-Xa levels for LMWH have not been established. Measurement of trough anti-Xa levels in addition to peak anti-Xa levels may be important.

Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily

BackgroundThe purpose of this study was to analyze whether 2 standard dosing regimens of enoxaparin (30 mg twice daily vs 40 mg once daily) would result in different deep vein thrombosis (DVT) rates and anti-factor Xa activity (anti-Xa) in surgical patients. MethodsPatients who required enoxaparin for prophylaxis were followed prospectively. Demographics were recorded. Patients underwent standardized duplex screening. Peak anti-Xa levels were drawn on 4 consecutive days. ResultsSixty-three patients were followed up (28 patients on 30 mg twice daily, 35 patients on 40 mg once daily). There was no significant difference in demographics between groups. Twenty-five percent of patients on 30 mg twice daily developed a DVT, whereas 2.9% of patients on 40 mg once daily developed a DVT. Patients on 30 mg twice daily had significantly lower anti-Xa levels. ConclusionsThe incidence of DVT is increased in surgical patients who receive 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Dosing of 40 mg once daily results in significantly higher peak anti-Xa levels compared with 30 mg twice daily.

Thrombin generation post elective caesarean section: Effect of low molecular weight heparin

IntroductionCaesarean section (CS) is a significant risk factor for venous thromboembolism.. Low molecular weight heparin (LMWH) is commonly used for thromboprophylaxis post emergency caesarean delivery. However, no consensus exists regarding LMWH thromboprophylaxis following elective caesarean section. Measures of thrombin formation may indicate the full anticoagulant activity of LMWH in this setting. Materials and methodsAnti-Xa, tissue factor pathway inhibitor (TFPI), thrombin anti-thrombin complex (TAT) and endogenous thrombin potential (ETP) were measured in twenty healthy women who received 4,500IU tinzaparin 6hours post CS (CS1), twenty women who received 4,500IU tinzaparin at 10–12hours post delivery (CS2) and twenty women post spontaneous vaginal delivery (SVD). ResultsPrior to initiation of LMWH, TAT levels at 6hours post delivery were significantly higher in the CS1 and CS2 groups than the SVD group (P<0.002); TAT levels were significantly reduced up to 24hours post LMWH treatment despite declining anti-Xa levels (P<0.001). In CS1, peak thrombin and ETP were significantly reduced following LMWH prophylaxis (P<0.0001; P<0.002) and reverted to pre-delivery levels 10hours post LMWH. TFPI levels mirror anti-Xa levels during the 24hours following LMWH treatment in CS1 group with peak levels coinciding with peak anti-Xa levels 4hours post injection. ConclusionIn women post caesarean section, anti-Xa levels do not reflect the full anticoagulant effects of LMWH. In-vivo thrombin production (TAT) is effectively reduced even when anti-Xa levels are negligible. LMWH thromboprophylaxis in this healthy cohort of patients appears to have a sustained effect in reducing excess thrombin production post elective caesarean section.

Welche niedermolekularen Heparine bei Niereninsuffizienz?

Background: In most clinical settings, low-molecular-weight heparins (LMWH) are preferred over unfractionated heparin (UHF). However, the use of LMHW in patients with renal insufficiency is limited because they tend to accumulate. Methods: The literature is reviewed regarding pharmacologic properties of different LMWHs and their use in patients with renal insufficiency. Results: The risk of accumulation is dependent on the molecular weight: smaller LMHW have a higher risk of accumulation. Therefore, a LMHW with high molecular weight should be chosen. The patient's individual renal function, bleeding risk and the chance of upcoming interventions need to be assessed. When LMWH are used in patients with renal insufficiency, peak Anti-Xa levels must be monitored closely. Conclusions: LMWH can be used in patients with severe renal insufficiency if a close monitoring of the patient and the therapeutic effect is possible.

Warfarin versus low molecular weight heparin: a comparison of adverse outcomes in pregnant women with mechanical heart valves

A consensus is yet to be reached regarding the anticoagulation regimen that is both safe for the fetus and effective for women with mechanical heart valves in pregnancy.We compared the...

A need for evidence-based clinical practice guidelines for the use of heparins in the elderly

Low-molecular-weight heparins (LMWHs) have been widely studied in pivotal clinical trials or in several meta-analyses. However, the safety and optimal use of LMWHs in high-risk patients such as the very elderly remains uncertain since these patients are usually excluded from clinical trials. In terms of LMWHs in the elderly, the main concerns are renal failure and the risk of accumulation. A clinical approach consisting of a LMWH dose reduction in the elderly should be considered with great caution in terms of efficacy, since it has been tested neither in the treatment of VTE nor in VTE prophylaxis. If monitoring is considered in patients receiving therapeutic dose LMWHs, appropriate target ranges for peak anti-Xa activity levels should be used and so far, no anti-Xa activity-based guidelines have been issued. Moreover, no data support any laboratory monitoring in elderly patients treated with prophylactic dose LMWHs.

Topical lidocaine and the effect on enoxaparin absorption in children: A pilot study

Enoxaparin, a low molecular weight heparin (LMWH), is frequently used for the prevention and treatment of thromboembolic complications in infants and children (Sutor et al., 2004 [1]). Injection pain and the fear and anxiety associated with needle phobia in the pediatric population are well documented. Best practice pediatric pain management standards of care recommend mitigating the child's pain experience whenever possible. The use of topical anesthetics such as liposomal-lidocaine 4% results in a rapid onset of anesthesia, minimal blanching, without vasoconstriction (Koh et al., 2004 [2]) or risk of methemoglobinemia. Topical lidocaine has been used to reduce the injection pain of enoxaparin, but there is no data available examining whether it will interfere with the absorption of LMWH. Objective To determine if the topical lidocaine, Maxilene, interferes with enoxaparin absorption as measured by peak anti-Xa levels. Methods Infants and children clinically prescribed enoxaparin were eligible for this study. Children in group 1 were pre-treated with Maxilene prior to enoxaparin injection on day 1 with no Maxilene pre-treatment on day 2. For group 2, the order was reversed. Peak anti-Xa levels were measured following each enoxaparin dose and were compared between the groups. Results 26 children of ages 14d-16 y (median 6.7 months) were enrolled. Anti-Xa levels following topical lidocaine administration were 0.070 U/mL (95%CI 0.025; 0.114) lower than without prior topical lidocaine administration. Anti-Xa levels on the second day were on average 0.013 U/mL (95%CI -0.066; 0.040) higher compared to day one regardless of the order of topical lidocaine administration. There were no reported incidences of local reactions such as redness, hives or blanching. Conclusions Topical lidocaine (Maxilene) administration before enoxaparin injection results in a small, clinically non-significant, reduction in anti-Xa levels.

Pharmacodynamics of low molecular weight heparin in patients undergoing bariatric surgery: A prospective, randomised study comparing two doses of parnaparin (BAFLUX STUDY)

Background The optimal dose of low-molecular-weight-heparin (LMWH) to prevent venous thromboembolism (VTE) after bariatric surgery remains controversial. Aim The aim of this study was to evaluate the pharmacodynamic parameters of two doses of the LMWH parnaparin administered to patients undergoing bariatric surgery. Methods Patients were enrolled in a multicentre, open label, pilot study and were randomised to receive 4250 IU/day [n = 36; 30 females; median age: 38 years (23-56); median BMI: 46.7 Kg/m 2 (36.5-58.8)] or 6400 IU/day [n = 30; 24 females; median age: 42 years (22-63); median BMI: 43.7 Kg/m 2 (36.1-64.1)] of parnaparin s.c. for 7-11 days. The pharmacodynamic effects of parnaparin were analysed by measuring the anti Factor Xa activity on day 0 (12 hours after the first parnaparin injection), day 4 and day 6 after surgery (before and 4 hours after parnaparin administration). Results In 98.3% of patients receiving 4250 IU/day the peak anti-Xa levels were in the range of 0.1-0.4 IU/ml. Higher anti-Xa levels were observed in patients receiving 6400 IU/day: in 62.3% of these patients the peak anti-Xa levels were greater than 0.4 IU/ml. The anti-Xa levels measured 4 hours after injection on days 4 and 6 were not statistically correlated with BMI for either dose of-parnaparin (p = 0.077 and p = 0.401 for 4250 or 6400 IU/day, respectively). Conclusion The dose of 4250 IU/day seems adequate to achieve prophylactic anti-Xa levels in morbid obese patients undergoing bariatric surgery. Conversely, most of the patients receiving 6.400 IU/day show anti-Xa levels higher than the recommended prophylactic values.

Weight-based dosing of enoxaparin for VTE prophylaxis in morbidly obese, medically-Ill patients

Introduction In clinical trials, fixed-dose enoxaparin (40 mg once daily) reduces the risk of venous thromboembolism (VTE) in medically-ill patients. However, morbidly obese patients were under-represented in these trials and using fixed-dose enoxaparin in obese patients may be inadequate. We completed a pharmacokinetic study in morbidly obese, medically-ill patients to determine if weight-based dosing of enoxaparin for VTE prophylaxis was feasible, without excessive levels of anticoagulation, as determined by peak anti-Xa levels. Materials and Methods Twenty eight morbidly obese (BMI ≥ 35 kg/m 2) patients were enrolled and completed the study protocol. Enoxaparin 0.5 mg/kg was administered once daily subcutaneously and peak anti-Xa levels were measured approximately 4-6 hours after the enoxaparin dose. Results and Conclusions Overall, 46% of patients were female, the average age (± SD) was 54 (± 11) years, and the average weight and BMI were 135.6 kg (± 25.3) and 48.1 kg/m 2 (± 11.1), respectively. The average daily dose of enoxaparin was 67 mg (± 12). The average peak anti-Xa level was 0.25 (SD ± 0.11, range 0.08 to 0.59) units/mL. Peak anti-Xa levels did not significantly correlate with weight or BMI. There were no bleeding events, symptomatic VTE, or significant thrombocytopenia. In morbidly obese, medically-ill patients, use of weight-based enoxaparin dosed at 0.5 mg/kg once daily is feasible and results in peak anti-Xa levels within or near recommended range for thromboprophylaxis, without any evidence of excessive anti-Xa activity. These data suggest that this weight-based regimen may be more effective than standard fixed-dose enoxaparin. Clinical outcome studies are warranted to determine the clinical safety and efficacy of this regimen.

Differences among Various Low-Molecular-Weight Heparins in Patients with Severe Renal Insufficiency: An Analysis of Recent Clinical Trials

Background: Primarily eliminated by the kidneys, low-molecular-weight heparins (LMWHs) need to be monitored carefully when used in patients with severe renal insufficiency, because of the concern about bioaccumulation, which can increase the risk of bleeding. Individual LMWHs have not been compared with each other in large clinical trials, and currently there is no standard of practice for the use of LMWH in this patient population.Methods: Computerized queries of PubMed, MEDLINE, and the American Society of Hematology abstract database were performed to identify clinical trials assessing the safety of LMWHs in patients with severe renal failure (creatinine clearance [CrCl] <30 mL/min).Results: A meta-analysis of 15 studies of enoxaparin and 2 studies of tinzaparin (N = 5201) showed that when compared with patients with a CrCl >30 mL/min, those with a CrCl ≤30 mL/min had more than double the risk of major bleeding and higher peak anti-Xa levels (Lim et al, 2006). Much of this effect was confined to patients who received standard therapeutic doses of enoxaparin (Mahe et al, 2007). A study of medical patients with a reduced CrCl treated with tinzaparin or enoxaparin showed significantly increased mean anti-Xa activity in the enoxaparin group but not in the tinzaparin group, indicating a significant accumulation of enoxaparin but not of tinzaparin (Mahe et al, 2007). Recent data suggest that dalteparin, when used at prophylactic doses, does not bioaccumulate and can be used safely in patients with severe renal impairment (Tincani et al, 2006; Douketis et al, 2007).Conclusions: Whereas studies suggest that enoxaparin bioaccumulates in patients with severe renal insufficiency (Mahe et al, 2007), dalteparin and tinzaparin do not appear to bioaccumulate to the same degree (Tincani et al, 2006; Mahe et al, 2007; Douketis et al, 2007). These differences may be explained by the fact that smaller LMWH chains (enoxaparin) are cleared primarily by the kidneys, whereas larger chains (dalteparin, tinzaparin) have greater clearance by nonrenal mechanisms. Thus, dalteparin and tinzaparin may be preferred in patients with renal impairment.Table. Summary of recent trials evaluating dalteparin and tinzaparin in patients with renal impairmentTrialStudy Design/RegimenResultsTincani et al, 2006 N = 115Patients with acute medical illness and elevated serum CrCl Dalteparin 2500 IU (low-risk patients) or 5000 IU (high-risk patients) SC once daily for ≥6 daysNo evidence of dalteparin bioaccumulation (increased anti-Xa levels) on Day 6, irrespective of renal function No correlation between degree of renal impairment and peak anti-Xa level on Day 6 No major bleeding or DVT eventsDIRECT (Douketis et al, 2007) N = 138Critically ill patients with CrCl <30 mL/min Dalteparin, 5000 IU SC once daily for ≤30 daysNo evidence of dalteparin bioaccumulation Median trough anti-Xa level <0.1 IU/mL Major bleeds occurred in 10 patients (7.2%), all with trough anti-Xa <0.12 IU/mL DVT occurred in 7 patients (5.1%)Mahe et al, 2007 N = 55Elderly medical patients with a baseline CrCl between 20 and 50 mL/min Enoxaparin 4000 IU SC or tinzaparin 4500 IU SC once daily for 8 daysThe accumulation factor was not significant for tinzaparin (1.05, P= 0.29), whereas it was significant for enoxaparin (1.22, P<0.0001) by Day 8 No patient in the study had a thromboembolic event 4 patients given enoxaparin had bleeding events (1 major) vs 5 in the tinzaparin group (2 major)CrCl = creatinine clearance; DIRECT = Dalteparin's Influence on Renally Compromised: Anti-Ten-A Study; DVT = deep vein thrombosis; SC = subcutaneous.

Efficacy and safety of once daily low molecular weight heparin (tinzaparin sodium) in high risk pregnancy

Low molecular weight heparin (LMWH) is widely regarded as the anticoagulant treatment of choice for the prevention and treatment of venous thromboembolism during pregnancy. However, previous studies have demonstrated that the pharmacokinetic profiles of LMWH vary significantly with increasing gestation. Consequently, it remains unclear whether LMWH regimens recommended for use in nonpregnant individuals can be safely extrapolated to pregnant women. The aims of this study were to assess the safety and the efficacy of tinzaparin sodium (Innohep) administered only once daily during pregnancy. A systematic retrospective review identified a cohort of 37 high-risk pregnancies which had been managed using tinzaparin 175 IU/kg once daily. In 26 cases, the index pregnancy had been complicated by development of an acute venous thromboembolism (17 deep vein thrombosis and nine pulmonary embolism). For each individual, case notes were examined and data extracted using a predetermined questionnaire. No episodes of recurrent venous thromboembolism were identified amongst this cohort of pregnancies managed using once daily LMWH administration. However, two unusual thrombotic complications were observed, including a parietal infarct in one patient, and a postpartum cerebral venous thrombosis in another. Once daily tinzaparin was well tolerated, with no cases of heparin-induced thrombocytopaenia, symptomatic osteoporosis, or foetal malformations. Tinzaparin dose modification based upon peak anti-Xa levels occurred in 45% of the cases examined. The present study is the largest study to have examined the clinical efficacy of once daily LMWH for use in pregnant women at high risk of venous thromboembolism. Our data support the safety and efficacy of antenatal tinzaparin at a dose of 175 IU/kg. In order to determine whether this once daily regimen provides equivalent (or indeed greater) thromboprophylaxis to twice daily LMWH regimens during pregnancy will require highly powered direct comparative studies.

Prophylaxis Against Deep Vein Thrombosis in Critically Ill Patients With Severe Renal Insufficiency With the Low-Molecular-Weight Heparin Dalteparin&lt;subtitle&gt;An Assessment of Safety and Pharmacodynamics: The DIRECT Study&lt;/subtitle&gt;

Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk. To challenge this premise, we evaluated if deep vein thrombosis (DVT) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency. We conducted a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium, 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167). Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL, measured twice weekly. The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3, 10, and 17. We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4-12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%-3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%-10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%-12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower. In critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin sodium, 5000 IU once daily, is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding. clinicaltrials.gov Identifier: NCT00138099.

Once-Daily Enoxaparin for the Treatment of Pediatric Thromboembolic Disease — A Pilot Study.

Background & Aim: The current recommended starting dose of enoxaparin in children is 1 mg/kg/dose administered twice-daily. Studies in adults, however, have demonstrated similar safety and efficacy between once-daily enoxaparin (1.5 mg/kg/dose) and twice-daily (1 mg/kg/dose) in the initial and long-term treatment of venous thromboembolism. Due to known differences in heparin clearance between adults and young children, recommendations for once-daily enoxaparin dosing should not simply be extrapolated from adult literature. Our objective was to perform a pilot study to describe the pharmacodynamics of once-daily enoxaparin in children, and to gather preliminary data regarding safety and feasibility.Methods: 15 patients, ages 3 months to 16 years, with newly diagnosed thromboembolism were enrolled. All began therapy with 1.5 mg/kg enoxaparin administered once-daily. Initial peak anti-Xa levels were drawn 4–6 hours after the second dose of enoxaparin. Dose adjustments were made according to a study nomogram to achieve peak anti-Xa levels between 1–2 U/ml, as recommended by the American College of Pathologists for once-daily enoxaparin dosing. Once therapeutic levels were achieved, a subgroup of 8 patients underwent 24–hour pharmacodynamic (PD) monitoring, with anti-Xa levels drawn at Hours 0, 2, 4, 8, 12, 18, and 24.Results: 14 patients completed the study. 8 of 14 children required a final dose of >2 mg/kg to achieve target peak anti-Xa levels (Table). Only one participant (age 15 years) achieved target levels with the original dose. In PD studies, 7 of 8 children had subtherapeutic anti-Xa levels by Hour 12, and 4 of 8 had unmeasurable levels by Hour 18 (Figure). These results differ from adult studies in which therapeutic levels (0.5–1.0 U/ml) have been measurable 13–18 hours after administration, and prophylactic levels (0.1–0.3 U/ml) have been measurable at 24 hours. There were no new or recurrent thrombotic events. One patient was removed from the study on Day 2 because anticoagulation was permanently discontinued after a post-surgical bleed (anti-Xa 0.23 at time of event).Conclusion: Our pilot data suggests faster clearance of once-daily enoxaparin in the pediatric population as compared to adults. The appropriate starting dose of once-daily enoxaparin in young pediatric patients is likely higher than 1.5 mg/kg.Dose adjustments needed to achieve target peak anti-Xa activity (1–2 IU/ml)PatientAgeWeight (kg)Indication for enoxaparinDose changesFinal dose (mg/kg)13 months6.5DVT with CVL43.8210 months10DVT with CVL44314 months13DVT with CVL22.342 years14DVT with CVL42.753 years14DVT22.768 years83DVT with CVL11.779 years37Arterial ischemic stroke11.9813 years67DVT with CVL22.1914 years65DVT with CVL22.21014 years68DVT11.81115 years60DVT with CVL11.91215 years60Arterial ischemic stroke11.61315 years77DVT with CVL01.51416 years45DVT32.9DVT, deep venous thrombosis; CVL, central venous line [Display omitted]

Massive Subchorionic Hematoma Associated With Enoxaparin

The use of low-molecular-weight heparins is increasing for the prevention of thromboembolism in pregnancy. Subchorionic hematoma as a complication of anticoagulation therapy is rarely reported. A persistent, massive subchorionic hematoma was diagnosed in a pregnant patient with atrial fibrillation and mitral stenosis. Enoxaparin was administered to maintain her trough anti-Xa level 0.5 units/mL or higher. The patient's peak anti-Xa levels never exceeded 1.05 units/mL. The patient underwent cesarean delivery at 34 6/7 weeks of gestation for preterm premature rupture of membranes. Subchorionic hematoma is a potentially serious complication that can occur in pregnant patients receiving enoxaparin for the prevention of thromboembolism.