Assessment of Anti-Factor Xa Levels of Patients Undergoing Colorectal Surgery Given Once-Daily Enoxaparin Prophylaxis: A Clinical Study Examining Enoxaparin Pharmacokinetics.

Importance: Between 4% and 12% of patients undergoing colorectal surgery and receiving enoxaparin, 40 mg per day, have a postoperative venous thromboembolism (VTE) event. An improved understanding of why "breakthrough" VTE events occur despite guideline-compliant prophylaxis is an important patient safety question. Objective: To determine the proportion of patients undergoing colorectal surgery who received adequate anticoagulation based on peak anti-factor Xa (aFXa) levels while receiving enoxaparin at 40 mg per day. Design, Setting, and Participants: This prospective, nonrandomized clinical trial was conducted between February 2017 and July 2018 with 90-day follow-up at a quaternary academic medical center in the Intermountain West and included patients undergoing colorectal surgery who had surgery after receiving general anesthesia, were admitted for at least 3 days, and received enoxaparin, 40 mg once daily. Interventions: All patients had aFXa levels measured after receiving enoxaparin 40 mg per day. Patients whose aFXa level was out of range entered the trial's interventional arm where real-time enoxaparin dose adjustment and repeated aFXa measurement were performed. Main Outcomes and Measures: Primary outcome: in-range peak aFXa levels (goal range, 0.3-0.5 IU/mL) with enoxaparin, 40 mg per day. Secondary outcomes: (1) in-range trough aFXa levels (goal range, 0.1-0.2 IU/mL) and (2) the proportion of patients with in-range peak aFXa levels from enoxaparin, 40 mg once daily, vs the real-time enoxaparin dose adjustment protocol. Results: Over 16 months, 116 patients undergoing colorectal surgery (65 women [56.0%]; 99 white individuals [85.3%], 13 Hispanic or Latino individuals [11.2%], and 4 Pacific Islander individuals [3.5%]; mean [range] age, 52.1 [18-85] years) were enrolled. Among 106 patients (91.4%) whose peak aFXa level was appropriately drawn, 72 (67.9%) received inadequate anticoagulation (aFXa < 0.3 IU/mL) with enoxaparin, 40 mg per day. Weight and peak aFXa levels were inversely correlated (r2 = 0.38). Forty-seven patients (77%) had a trough aFXa level that was not detectable (ie, most patients had no detectable level of anticoagulation for at least 12 hours per day). Real-time enoxaparin dose adjustment was effective. Patients were significantly more likely to achieve an in-range peak aFXa with real-time dose adjustment as opposed to fixed dosing alone (85.4% vs 29.2%, P < .001). Conclusions and Relevance: This study supports the finding that most patients undergoing colorectal surgery receive inadequate prophylaxis from enoxaparin, 40 mg once daily. These findings may explain the high rate of "breakthrough" VTE observed in many clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT02704052.

Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: in vitro and in vivo assessment.

The objective of present research work was to develop alginate coated chitosan core shell nanoparticles (Alg-CS-NPs) for oral delivery of low molecular weight heparin, enoxaparin. Chitosan nanoparticles (CS-NPs) were synthesized by ionic gelation of chitosan using sodium tripolyphosphate. Core shell nanoparticles were prepared by coating CS-NPs with alginate solution under mild agitation. The Alg-CS-NPs were characterized for surface morphology, surface coating, particle size, polydispersity index, zeta potential, drug loading and entrapment efficiency using SEM, Zeta-sizer, FTIR and DSC techniques. Alginate coating increased the size of optimized chitosan nanoparticles from around 213 nm to about 335 nm as measured by dynamic light scattering in zeta sizer and further confirmed by SEM analysis. The performance of optimized enoxaparin loaded Alg-CS-NPs was evaluated by in vitro drug release studies, in vitro permeation study across intestinal epithelium, in vivo venous thrombosis model, particulate uptake by intestinal epithelium using fluorescence microscopy and pharmacokinetic studies in rats. Coating of alginate over the CS-NPs improved the release profile of enoxaparin from the nanoparticles for successful oral delivery. In vitro permeation studies elucidated that more than 75% enoxaparin permeated across the intestinal epithelium with Alg-CS-NPs. The Alg-CS-NPs significantly increased (p<0.05) the oral bioavailability of enoxaparin in comparison to plain enoxaparin solution as revealed by threefold increase in AUC of plasma drug concentration time curve and around 60% reduction in thrombus formation in rat venous thrombosis model. The core shell Alg-CS-NPs showed promising potential for oral delivery and significantly enhanced the in vivo oral absorption of enoxaparin.

Comparative pharmacodynamic assessment of the antiangiogenesis activity of heparin and low-molecular-weight heparin fractions: structure-function relationship.

Effects of unfractionated heparin and low-molecular-weight heparins (LMWHs) on human microvascular endothelial cell sprouting (tube formation assay) in vitro were determined. Antiangiogenesis efficacy of commercially available LMWHs tinzaparin and enoxaparin in the chick chorioallantoic membrane (CAM) model of growth factor-induced angiogenesis was compared. The LMWH tinzaparin was fractionated into different molecular weight (MW) pools by size exclusion chromatography; they inhibited CAM angiogenesis depending on their MW distribution, with optimal inhibition at 8 to 12 kDa and no inhibition at <2 kDa. Tinzaparin demonstrated greater antiangiogenesis efficacy than enoxaparin (P < .001); these CAM results correlated with the endothelial tube formation assay results (P < .001, tinzaparin vs enoxaparin). These data point to the variable antiangiogenesis efficacy of different LMWHs as a function of MW and perhaps other structural differences. Our hypothesis confirmed a relationship between lower release of tissue factor pathway inhibitor by lower MW fractions of tinzaparin or enoxaparin leading to reduced antiangiogenesis efficacy.

Edoxaban administration following enoxaparin: a pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects.

Edoxaban is an oral direct factor (F)Xa inhibitor in advanced stages of clinical development. The primary objective of the present study was to assess the pharmacodynamics (PD) and safety of enoxaparin 1 mg/kg followed 12 hours (h) post-dose by edoxaban 60 mg, which is the regimen being used in the phase III study of edoxaban for the treatment of venous thromboembolism (Hokusai-VTE). This was a phase I, open-label, randomised, four-period, four-treatment cross-over study. Treatments were edoxaban alone (EDOX), enoxaparin alone (ENOX), edoxaban plus enoxaparin (EDOX+ENOX), and enoxaparin followed by edoxaban 12 h later (ENOX12-EDOX). Serial blood samples were collected for PD (thrombin generation, anti-FXa) and pharmacokinetic (PK) variables (edoxaban and its principal metabolite M4 by LC-MS/MS, and anti-FIIa as a surrogate of enoxaparin). The highest effect on thrombin AUC (endogenous thrombin potential, or ETP), thrombin (peak), thrombin generation lag time, and velocity index was observed for EDOX+ENOX, followed by ENOX, ENOX12-EDOX, and EDOX. The greatest effect on anti-FXa activity was observed for EDOX+ENOX, followed by ENOX12-EDOX. As expected, neither edoxaban nor enoxaparin significantly altered the PK of the other drug. There were no serious adverse events during the study. It is concluded that a 60-mg dose of edoxaban can be safely administered 12 h following enoxaparin 1 mg/kg.

Bioequivalence of generic and branded subcutaneous enoxaparin: a single-dose, randomized-sequence, open-label, two-period crossover study in healthy Chinese male subjects.

BACKGROUND: Enoxaparin is a low-molecular-weight heparin (LMWH) indicated for antithrombosis. A branded formulation of subcutaneously administered enoxaparin has been available in China since 2000, and a generic formulation is being developed. In a literature search of the key term enoxaparin (publication years not restricted), no published data were identified regarding the pharmacokinetic profile of generic enoxaparin in Chinese subjects. OBJECTIVE: The aim of this study was to determine the bioequivalence of generic (test) and branded (reference) formulations of enoxaparin 60 mg (6000 IU anti-Xa) SC in healthy subjects for the purpose of meeting regulatory requirements for marketing the generic formulation in China. METHODS: Healthy Chinese male volunteers were eligible for this single-dose, randomized-sequence, open-label, 2-period crossover study. Participants were randomly assigned to receive the test and reference formulations of enoxaparin 60 mg SC injection (fasting state) in randomized order, with the 2 study periods separated by a 1-week washout period. For the assessment of anti-Xa and anti-IIa activities (surrogates used to describe the pharmacokinetic properties and bioavailability of LMWH), heparin clotting assay, and activated partial thromboplastin time (aPTT), blood samples were obtained before (hour 0; baseline) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours after study drug administration. The 2 formulations were to be considered bioequivalent if the 90% CIs for the logarithm-transformed values of C(max), T(max), AUC(0-t), and AUC(0-infinity) fell within the predetermined range of 80% to 125%. Tolerability was assessed by questioning subjects about symptoms of possible adverse events and using laboratory analysis (hematology, biochemistry, hepatic function tests, and urinalysis). RESULTS: Twenty-two subjects participated in the study (mean [SD] age, 21.10 [1.02] years [range, 19-23 years]; weight, 64.07 [5.93] kg [range, 54-75 kg]; and height, 173 [5] cm [range, 163-187 cm]). For anti-Xa activity, the 90% CIs of C(max), AUC(0-t), and AUC(0-infinity) were 100.4% to 106.7%, 100.7% to 105.8%, and 100.7% to 106.1%, respectively. Corresponding values for anti-IIa activity were 85.0% to 102.4%, 80.4% to 94.8%, and 80.1% to 96.0%. For the hepa-rin clotting assay, the values were 97.4% to 102.4%, 98.2% to 102.4%, and 96.0% to 102.7%; and for aPTT, values were 98.2% to 104.3%, 97.4% to 101.6%, and 93.4% to 117.4%. No adverse events were reported during the study. CONCLUSIONS: Based on the 90% CIs of anti-Xa and anti-IIa activities, heparin clotting assay results, and aPTT in these healthy Chinese male subjects, the test and reference formulations of enoxaparin 60 mg SC met the regulatory requirements for bio-equivalence. Both formulations were well tolerated.

Enoxaparin: a review of its use as thromboprophylaxis in acutely ill, nonsurgical patients.

Enoxaparin (Clexane), Lovenox) is a low molecular weight heparin (LMWH) that has been widely used in the prevention of venous thromboembolism (VTE) in surgical patients. More recently, with the recognition of the high incidence of VTE in acutely ill medical (nonsurgical) patients, enoxaparin has been evaluated for thromboprophylaxis in this patient population. Subcutaneous enoxaparin 40 mg once daily has shown efficacy in the short-term thromboprophylaxis of VTE in nonsurgical patients with severely restricted mobility due to acute illness in well controlled clinical trials. The drug is at least similar in efficacy to unfractionated heparin (UFH) and its pharmacological profile allows once-daily administration, in contrast to the twice- or three-times-daily administration required with UFH. The tolerability profile of enoxaparin is also similar to that of UFH, except that the incidences of local haematomas and increased liver enzymes are lower with enoxaparin. The optimal duration of prophylaxis in nonsurgical patients is currently being evaluated and the results of extended prophylaxis with enoxaparin evaluated in the EXCLAIM (EXtended CLinical prophylaxis in Acutely Ill Medical patients) trial are awaited with interest. Currently, short-term enoxaparin appears to provide a cost-effective treatment alternative to UFH for VTE prophylaxis in nonsurgical patients.

Analysis of population pharmacokinetic data using NONMEM and WinBUGS.

The aim of this report is to describe the use of WinBUGS for two datasets that arise from typical population pharmacokinetic studies. The first dataset relates to gentamicin concentration-time data that arose as part of routine clinical care of 55 neonates. The second dataset incorporated data from 96 patients receiving enoxaparin. Both datasets were originally analyzed by using NONMEM. In the first instance, although NONMEM provided reasonable estimates of the fixed effects parameters it was unable to provide satisfactory estimates of the between-subject variance. In the second instance, the use of NONMEM resulted in the development of a successful model, albeit with limited available information on the between-subject variability of the pharmacokinetic parameters. WinBUGS was used to develop a model for both of these datasets. Model comparison for the enoxaparin dataset was performed by using the posterior distribution of the log-likelihood and a posterior predictive check. The use of WinBUGS supported the same structural models tried in NONMEM. For the gentamicin dataset a one-compartment model with intravenous infusion was developed, and the population parameters including the full between-subject variance-covariance matrix were available. Analysis of the enoxaparin dataset supported a two compartment model as superior to the one-compartment model, based on the posterior predictive check. Again, the full between-subject variance-covariance matrix parameters were available. Fully Bayesian approaches using MCMC methods, via WinBUGS, can offer added value for analysis of population pharmacokinetic data.

Venous thromboembolism prophylaxis conversion in nonsurgical inpatients.

OBJECTIVE: To provide venous thromboembolism (VTE) prophylaxis according to national consensus guidelines while minimizing associated medication costs. METHODS: Patients admitted to our institution who were receiving VTE prophylaxis with the low-molecular-weight heparin (LMWH) enoxaparin were identified and evaluated for potential conversion to low-dose unfractionated heparin (LDUH). Patients admitted for general medical conditions were targeted for a potential conversion. Factors that excluded patients from conversion were any surgical intervention or evidence of bleeding. For all eligible patients, the treating physician was contacted through written recommendations in an effort to achieve conversion to an LDUH regimen. RESULTS: Throughout a 10-month period, 463 patients were identified as receiving enoxaparin for VTE prophylaxis. Of these, 112 (24%) were candidates for an LDUH regimen. A total of 88 pharmacy recommendations were provided, of which 59 (67%) were accepted. This conversion program resulted in the avoidance of 250 days of enoxaparin prophylaxis and 8495 US dollars of associated medication costs. CONCLUSIONS: Clinical pharmacy programs directed at converting patients from a more costly LMWH regimen for VTE prophylaxis to an LDUH regimen can significantly reduce medication costs while adhering to consensus guidelines.

Economic evaluation of enoxaparin as prophylaxis against venous thromboembolism in seriously ill medical patients: a US perspective.

OBJECTIVE: To determine the cost and cost effectiveness of adding venous thromboembolism (VTE) prophylaxis with enoxaparin, a low-molecular-weight heparin, to standard care for acutely ill, hospitalized medical patients. METHODS: A pharmacoeconomic model was developed to simulate the 6- to 14-day course of enoxaparin prophylaxis evaluated in the MEDENOX trial in a US healthcare setting. Clinical results as reported for the trial were applied to resource use and treatment costs in a US healthcare environment. The model projects hospital length of stay and cost for an acute medical admission from a third-party payer perspective, as well as costs for the course of enoxaparin. RESULTS: VTE prophylaxis with enoxaparin would account for 1.2% to 2.4% of the cost of a hospital admission, with an additional $23 +/- $28 to $99 +/- $122 to complete the course of prophylaxis out of hospital. Incremental cost effectiveness of VTE prophylaxis relative to no prophylaxis ranges from $1249 to $3088 per VTE avoided. Venous thromboembolism prophylaxis appears to be a break-even intervention, with the cost recouped through avoided treatment, if the rate of treated VTE without prophylaxis is at least 3-4%. DISCUSSION AND CONCLUSIONS: The MEDENOX trial demonstrated that prophylaxis with enoxaparin substantially decreases the risk of VTE among acutely ill, hospitalized medical patients. Economic analysis indicates that this protection represents a small increase in current treatment costs. Prophylaxis is cost effective in terms of incremental cost per VTE avoided. Furthermore, there is a reasonable likelihood that the cost of prophylaxis will be offset by avoided future VTE treatment.

Review of enoxaparin and its clinical applications in venous and arterial thromboembolism.

Venous and arterial thromboembolic disorders are common medical conditions that are associated with considerable morbidity and mortality. Unfractionated heparin (UFH) and its derivatives, the low molecular weight heparins (LMWHs), are the anticoagulants of choice when a rapid anticoagulant effect is required. LMWHs have several advantages over UFH, including a longer plasma half-life and higher bioavailability; a predictable dose response, which enables once- or twice-daily dosing; and a more convenient route of administration (subcutaneous instead of intravenous), which enables patients to self-inject in an out-patient setting. Enoxaparin is a LMWH prepared by alkaline hydrolysis of the benzylin ester of UFH. The efficacy of enoxaparin in the management of venous and arterial thromboembolism has been shown in a wide range of patient groups using doses ranging from fixed doses of 20 - 60 mg o.d. and 0.75 - 1.5 mg/kg b.i.d. Other doses, such as 80 mg/day for pregnant women with combined thrombophilic defects, have also been studied. The use of subcutaneous enoxaparin as an effective and safe home treatment for patients with acute proximal deep vein thrombosis (DVT) has been demonstrated. The benefits of preventing venous thromboembolic events with enoxaparin include reducing the costs associated with investigating the symptoms of DVT, acute treatment and hospitalisation, and potentially the development of post-thrombotic syndrome, while improving quality of life and so making the treatment cost effective. In contrast to other LMWHs, enoxaparin has been shown to provide better outcomes than UFH in the treatment of unstable angina and non-ST-segment elevation myocardial infarction, without increasing major bleeding. Adverse events with enoxaparin are infrequent; the most common events are minor bleeding complications. It should be noted that different doses or indications are approved in each country.

Comparative effectiveness of low-molecular-weight heparins after therapeutic interchange.

Management Case Studies describe approaches to real-life management problems in health systems. Each installment is a brief description of a problem and how it was dealt with. The cases are intended to help readers deal with similar experiences in their own work sites. Problem solving, not hypothesis testing, is emphasized. Successful resolution of the management issue is not a criterion for publication-important lessons can be learned from failures, too.

Overview of enoxaparin in the treatment of deep vein thrombosis.

Standard medical treatment for patients with acute venous thrombosis is antithrombotic therapy. Following a historical overview of the evolution of heparin therapy to include low-molecular weight heparin (LMWH), the pharmacokinetic properties of enoxaparin are described. Therapeutic advantages of LMWH over unfractionated heparin (UFH) are also discussed, including once- or twice-daily subcutaneous dosing, reduced hospital stays, elimination of therapeutic monitoring for most patients, and possibly less bone density loss. Studies have demonstrated that enoxaparin is at least equivalent to UFH with regard to efficacy and safety. Opportunities for future study include evaluation of enoxaparin's efficacy for the prevention of deep vein thrombosis within high-risk groups and for the treatment of thrombosis in such conditions as pregnancy, cancer, obesity, and renal insufficiency, and in children.

Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.

OBJECTIVE: To compare low-molecular-weight preparations of heparin (LMWH) with standard heparin in children requiring anticoagulant treatment for thromboembolic disease. METHODS: We treated 25 children who required heparin, but were at significant risk of bleeding, with LMWH (enoxaparin, Rhone-Poulenc Rorer). The median age was 4 years (range, newborn to 17 years), with nine infants less than 2 months of age. Fourteen children had a deep vein thrombosis or pulmonary embolism, nine had thrombotic complications in the central nervous system, and two had complex congenital heart disease, for which they received prophylaxis at a lower dosage (0.5 mg/kg given subcutaneously twice a day). The remaining 23 children received an initial dose of 1 mg/kg, every 12 hours subcutaneously, with subsequent doses adjusted to achieve a 4-hour anti-factor Xa level between 0.5 and 1.0 unit/ml. RESULTS: Newborn infants had increased dose requirements; an average of 1.60 units/kg was required to achieve therapeutic heparin levels. For the remaining children, the initial dose of 1.0 mg/kg was sufficient. After the initial dose adjustment, LMWH was administered with twice-weekly monitoring. The median duration of therapy with LMWH was 14 days. Two children with previously documented gastrointestinal ulcers bled and required transfusion therapy. Therapy with LMWH was continued without further events. There were no new thrombotic events during the treatment with LMWH. The cost of administering LMWH compared with heparin was reduced by 30% because of decreased laboratory monitoring, blood sampling times, intravenous starts, and nursing time. Needle punctures were reduced with LMWH therapy by the placement of a subcutaneous catheter. CONCLUSION: These results provide the basis for a randomized, controlled trial comparing LMWH with standard heparin in pediatric patients.