Plasma anti-Xa Research Articles

E0415 The contrast research in safety and efficacy between nadroparin and dalteparin before elective percutaneous coronary intervention

BackgroundTo evaluate the contrast research in safety and effective time between nadroparin and dalteparin before elective percutaneous coronary intervention (PCI) in Chinese population. Investigating the relationship among anti-Xa activities APTT...

Routine Plasma Anti-Xa Monitoring is Required for Low-Molecular-Weight Heparins

Low-molecular-weight heparins are anticoagulants used in the treatment of thrombosis. They have effectiveness and safety profiles similar to those of unfractionated heparin but are considered an attractive alternative because of their predictable pharmacokinetic characteristics. In this article, we demonstrate the need for therapeutic monitoring of low-molecular-weight heparins by addressing evidence arising from the literature and from modelling and simulation. First, treatment targets for unfractionated heparin and enoxaparin sodium were identified. Then, 10 000 virtual patients were simulated and the rate of treatment success was calculated. Treatment success was found to be similar between the two drugs (48% with unfractionated heparin and 54% with enoxaparin sodium). These results are consistent with empirical evidence from the literature and reflect the inadequacy of current dosing strategies in achieving desired biomarker targets. These results, along with recent advances in Bayesian forecasting techniques, support the need for routine monitoring and dose individualization of enoxaparin sodium in order to improve treatment success.

Antithrombotic Effect of Enoxaparin in Clinically Healthy Cats: A Venous Stasis Model

Systemic arterial thromboembolic events are a serious complication of cardiac disease in cats. To determine if enoxaparin induces an antithrombotic effect in cats at a dosage of 1 mg/kg SC q12h and if this antithrombotic effect is predicted by anti-Xa activity. Fourteen clinically healthy cats were divided into 3 groups: control (4 cats), treated and assessed at 4 hours (5 cats), and treated and assessed at 12 hours (5 cats). A venous stasis model was used and the extent of thrombus formation estimated by measuring thrombus weight and accretion of 125I-fibrinogen. Plasma anti-Xa activity was measured in treated cats. There was a significant reduction in thrombus formation in the 4 h group compared with control (median weight, 0.000 versus 0.565mg/mm, P < .01; median % 125I-fibrinogen accretion, 0.0 versus 42.0%, P < .01). There was a reduction in thrombus formation in the 12 h group (median weight, 0.006 mg/mm, P = .09; median % 125I-fibrinogen accretion, 3.83%, P = .09) but this reduction was not significant. The median percent thrombus inhibition for treated cats was 100.0% at 4 hours and 91.4% at 12 hours. Plasma anti-Xa activity was not significantly correlated with thrombus formation. This pilot study demonstrates that enoxaparin, when administered at a dosage of 1 mg/kg SC q12h, produces an antithrombotic effect in a venous statsis model in clinically healthy cats. Furthermore, this study demonstrates that anti-Xa activity is a poor predictor of enoxaparin's antithrombotic effect.

No Accumulation of Peak Anti-Xa Activity of Tinzaparin in Elderly Patients with Moderate to Severe Renal Impairment: A Substudy of IRIS Clinical Trial.

Abstract 172The “Innohep® in Renal Insufficiency Study” (IRIS) was an international, multicentre, open, randomized, parallel group clinical trial with a primary objective to compare the safety of tinzaparin and unfractionated heparin in terms of clinically relevant bleeding (CRB) in elderly patients with impaired renal function for initial treatment of acute deep vein thrombosis. In the elderly, concerns have been raised about the risk of an accumulation effect and/or overdose due to the renal elimination of low molecular weight heparins (LMWH). In a subset of centres participating in the IRIS study, we conducted a substudy in order to assess whether there was an accumulation of anti-Xa activity and whether there was any relationship between anti-Xa activity and age, weight, creatinine clearance or clinical outcomes in patients treated with tinzaparin (175 IU/kg/24h) for venous thromboembolism. Plasma anti-Xa activity was to be analysed at peak level (4–6 hours after injection) on Day 2 or Day 3 and on Day 5 or at visit S (VS: day of visit at end of SC treatment) using a chromogenic assay (Rotachrom® heparin, Diagnostica Stago®). Of the complete IRIS study population who received tinzaparin (n=268), data from 87 patients (32%) were analysed. The patient characteristics (mean age 83±5 years [75–99 years], mean creatinine clearance (Cockcroft-Gault) 40.8 mL/min (SD 11.7, range 14–59) were consistent with those of the overall population of IRIS study. Of note, 24.1% had severe renal impairment (creatinine clearance < 30 mL/min). The mean peak anti-Xa activities, which were 0.86 (SD 0.34) and 0.87 (SD 0.31) IU/mL on Day2/3 and Day5/VS, respectively, were found close to the mean 0.85 IU/mL reported in the literature in patients receiving tinzaparin at therapeutic dose. There was no correlation between the anti-Xa activity and age, weight, or creatinine clearance. There was no significant difference in the anti-Xa levels between patients with, versus those without, severe renal impairment. The mean accumulation ratio (defined as anti-Xa activity on Day5/VS divided by the anti-Xa activity on Day2/3) was 1.06 (SD 0.30, 90% CI:1.01–1.11): as the 90% CI of the accumulation did not exceed the pre-defined upper limit of 1.25, no significant accumulation was detected. The mean anti-Xa activity did not differ significantly between the 8 patients experiencing a CRB during tinzaparin treatment and the 79 who did not experience a CRB during tinzaparin treatment. Among the 8 patients who had a CRB, one had an anti-Xa activity > 2.0 IU/mL (considered above therapeutic level) whereas the seven others had anti-Xa < 1.5 IU/mL. Interestingly, we found that the mean anti-Xa activities were significantly lower in the 12 patients with infectious disease at baseline compared to the patients without infectious disease: 0.66 (SD 0.18) vs 0.8 (SD 0.35) IU/mL on Day2/3, p=0.007; 0.62 (SD 0.23) vs 0.91 (SD 0.30) IU/mL on Day5/VS, p=0.002). These numbers are small but may require further investigation. There was no statistically significant difference in anti-Xa levels when comparing patients with versus those without ongoing malignancy. In conclusion, an IRIS substudy demonstrated no accumulation of anti-Xa activity in elderly patients with moderate to severe renal impairment receiving unadjusted recommended full dose of tinzaparin and confirms previous pharmacokinetic studies in similar populations. The high proportion of higher molecular weight moieties in tinzaparin may account for reduced dependence on renal elimination of the anti-Xa activity seen in elderly patients with renal impairment. Disclosures:Siguret:Leo-Pharma: this work was supported by a grant from Leo-Pharma. Leizorovicz:GSK: Consultancy. Gouin-Thibault:Leo-Pharma: this work was supported by a grant from Leo-Pharma.

A 2007 Survey of Extracorporeal Life Support Members: Personnel and Equipment

Extracorporeal membrane oxygenation (ECMO) is used to support patients with cardiopulmonary failure in the intensive care unit. The purpose of this study is to determine what professional qualifications, equipment, and tests are used by established ECMO programs registered with the Extracorporeal Life Support Organization (ELSO). A survey link (Survey-Monkey) was e-mailed to the 110 registered ELSO program coordinators. Forty-nine responses were received. A test of binomial portions showed that nurses were more likely to be ECMO providers than respiratory therapists or perfusionists (p&lt; .05). A χ2test identified a difference in the type of pump (roller or centrifugal) based on patient age (p&lt; .005). The most common monitoring/safety devices were battery back-up (84%), pre- and post-oxygenator pressure (82%), mixed venous oxygen saturation (80%), venous line pressure (76%), blood flowmeter (63%), bubble detector (61%), point-of-care blood gases (59%), and in-line blood gas monitoring (47%). Laboratory tests available included d-dimer (65%), plasma-free hemoglobin (63%), anti-Xa plasma heparin concentration (43%), thromboelastograph (37%), and heparin concentration using protamine titration (35%). This survey of ELSO-registered centers represents an overview of current ECMO practices.

A Comparison of the Biological Activity of 2 Formulations of Enoxaparin in 12 Healthy Volunteers

India is one of the few countries where biosimilar enoxaparin is available for clinical use. Despite availability since past 4 to 5 years, there is a paucity of published literature regarding their biological activity. The aim of the current study is to compare the biological activity of an endogenously developed formulation of enoxaparin with the branded formulation. Twelve healthy male volunteers received 1 subcutaneous injection of 2 different formulations of enoxaparin in a randomized, open-label, balanced, 2-treatment, 2-period, 2-sequence, cross-over study. The test formulation was Injection Troynoxa (enoxaparin sodium 40 mg/0.4 mL, Troikaa Pharmaceuticals Ltd., India) and reference formulation was Injection Clexane (enoxaparin sodium 40 mg/ 0.4 mL, Sanofi-Aventis, UK). The plasma anti-Xa activity and activated partial thromboplastin time (aPTT) were estimated on fully automated coagulometer predose and at 2, 4, 6, 8, and 10 hours following dosing with 40 mg/0.4 mL of enoxaparin. The results of mixed model analysis of repeated measures analysis of variance (ANOVA) for estimating difference between least square means of test and reference formulations, at all time points, showed no significant differences in anti-Xa activity and plasma aPTT levels. Both formulations were well tolerated and there were no bleeding episodes. After a single-dose injection in healthy participants, anti-Xa activities of 2 formulations of LMWH enoxaparin were comparable. No significant difference was observed in the mean plasma aPTT. It remains to be seen whether the 2 formulations would show comparable clinical efficacy.

Granules in the improvement of oral heparin bioavailability

Low molecular weight heparins (LMWHs), mainly used for the prevention of deep vein thrombosis, are so far only administered by parenteral route. Presumably, due to their large size and negative charge, LMWHs are not absorbed efficiently across the mucus of the gastrointestinal tract. Since parenteral administration requires medical assistance and is not the most convenient route of application, the development of an oral dosage form of heparin would improve patients’ comfort and replace vitamin K antagonists. Thus, we developed granules of two LMWHs, enoxaparin and bemiparin, based on primary granules of microcrystalline cellulose and loaded with ethylcellulose (Aquacoat ®ECD) or a polycationic polymer (Eudragit ®RS30D (ERS)) or their mixtures. The highest maximal plasma anti-Xa activities and the highest bioavailabilities for enoxaparin granules (0.45 ± 0.12 IU/mL; 19.00 ± 0.30%, respectively) and for bemiparin granules (0.54 ± 0.08 IU/mL; 29.02 ± 4.12%, respectively) were found after oral administration of granules loaded with ERS alone at a dose of 600 IU anti-Xa/kg to rabbits. These results confirm the oral absorption of LMWH from granules loaded with polycationic polymer and open up this technology for peptides and proteins that are very sensitive to organic solvents and have poor drug absorption from the gastrointestinal tract.

Comparison of activated clotting times obtained using Hemochron and Medtronic analysers in patients receiving anti-thrombin therapy during cardiac catheterisation

Accurate monitoring of anti-thrombin therapy with activated clotting time (ACT) is important to prevent thrombotic and haemorrhagic complications during cardiac catheterisation. Significant variability in ACT tests exists when different analysers are used. Our objective was to compare ACT results obtained using Hemochron and Medtronic ACT PLUS devices and antiXa activity in patients undergoing cardiac catheterisation. Thirty-two patients who received unfractionated heparin or argatroban therapy during cardiac catheterisation were enrolled. Blood sampling was performed to determine ACT values using Hemochron and Medtronic (with high-range cartridges) devices in all patients (n = 130 pairs), and anti-Xa activity following heparin administration. In the heparin group, ACT tests (n = 95 pairs) showed very good correlation (r = 0.84, y = 1.31x-0.81; p<0.001). However, Hemochron values were consistently higher and the difference more pronounced with increasing ACT (for ACT>150 sec, mean difference 65 +/- 48 sec; p<0.001). Both Hemochron and Medtronic ACT tests correlated well with plasma anti-Xa levels (r = 0.85, r = 0.81, respectively; p<0.001); Hemochron ACT>300 sec corresponded to anti-Xa>1.48 IU/ml. With concomitant eptifibatide therapy, the divergence in ACT was greater compared to heparin alone. In the argatroban group, ACT tests (n = 35 pairs) demonstrated excellent correlation (r = 0.94, y = 0.61x+79.9; p<0.001). In contrast to the heparin group, ACT values were higher with Medtronic compared to Hemochron. Therefore, despite good correlation between Hemochron and Medtronic ACT results, and strong association with anti-Xa activity, Medtronic ACT values were consistently lower compared to Hemochron following heparin anticoagulation. Paradoxically, Medtronic ACT results were higher after argatroban therapy. Understanding this discrepancy is crucial when using ACT to guide invasive cardiac procedures.

Treatment of deep venous thrombosis in pregnant women

The recommended dosage of tinzaparin in the treatment of thromboembolism during pregnancy is 175 IU/kg/day, as for non-pregnant subjects. In clinical practice, we have experienced a need for a higher dosage, especially in the initial phase of the treatment of deep vein thrombosis, based on four-hour post-dose measurements of anti-Xa activity. Twenty-two pregnant patients with a confirmed deep venous thrombosis were treated with tinzaparin either in a once- or twice-daily regimen. Four-hour post-dosage plasma anti-Xa activity was measured in 357 sequential blood samples during treatment. An higher dosage than recommended, was required to maintain anti-Xa activity in the target range. We suggest that the starting dosage should be 250 IU/kg/day in a twice-daily regimen, and that the dose in the initial phase be adjusted by daily monitoring of anti-Xa.

Management of refractory venous thrombosis associated with malignancy using a supra-therapeutic enoxaparin regimen

For many years, it has been recognised that venous thrombo-embolism (VTE) represents a common complication of malignancy. Moreover, VTE in the form of pulmonary embolism (PE) is life-threatening, and constitutes the second leading cause of death in patients with cancer. Consequently, overall survival is significantly reduced in cancer patients who develop thrombosis. In addition, treatment of VTE with anticoagulation is often difficult to manage in the context of cancer. Studies have shown that the risk of recurrent VTE, and the risk of major bleeding are both increased significantly in cancer patients on therapeutic anticoagulant therapy. In this case report, we describe a patient with metastatic carcinoma of the cervix, who developed recurrent thrombotic complications despite being maintained on standard therapeutic doses of both warfarin, and subsequently low molecular weight heparin. However, her refractory VTE was successfully managed using a supra-therapeutic dose low-molecular-weight-heparin (LMWH) regimen, together with close monitoring of plasma anti-Xa levels.

The Feasibility and Safety of Anticoagulation during Chemotherapy Associated Thrombocytopenia for Thrombotic Complications of Malignancy.

The optimal management of patients with hematological malignancies who require therapeutic anticoagulation for thromboembolic disease or prosthetic cardiac valves while receiving myelosuppressive chemotherapy has not been established. In particular, the role of anticoagulation during chemotherapy-induced thombocytopenia, with its attendant increased risk of bleeding, is undefined. We describe the feasibility and safety of a dynamic dosing strategy for continuous anticoagulation during chemotherapy-induced thrombocytopenia. Sixty patients with haematological malignancies who required anti-coagulation for venous thromboembolism or prosthetic cardiac valves while receiving chemotherapy were assessed. All were receiving myelosuppressive chemotherapy for a haematological malignancy (27 Acute myeloid or promyelocytic leukaemia; 18 non-Hodgkin lymphoma; 9 plasma cell myeloma; 6 Acute lymphoblastic leukaemia), and required anticoagulation for either proven deep venous thrombosis (catheter-related thrombosis in 32 patients; non-catheter associated deep venous thrombosis in 18) or pulmonary embolus (9) or prosthetic cardiac valves (1). Three patients underwent allogeneic stem cell transplantation and 7 autologous stem cell transplantation. Median time from diagnosis of the thromboembolic disease to commencement chemotherapy was 10 days (range 0–40). Patients were anticoagulated with subcutaneous enoxaparin 1mg/kg body weight twice daily while the platelet count was ≥50×109/L and 0.5mg/kg once daily to maximum of 40mg while it was <50×109/L; platelets were transfused to maintain a count ≥20×109/L. Patients were clinically assessed daily for clinical evidence of bleeding or thrombosis, and underwent regular radiological screening for thrombotic complications. Plasma anti-Xa levels were assayed regularly only in patients with elevated serum creatinine (4 patients) or body mass index (1 patient). Median number of days of chemotherapy-induced thrombocytopenia <150×109/L was 20 (range 1--84); <50×109/L 12 (0–41), and <20×109/L was 2 (0–30). Enoxaparin was delivered at full dose on 31% of thrombocytopenic days (median per patient 12 days, range 5–23), at reduced dose on 63% of days (median per patient 20 days, range 0–68), and withheld on 6% of days (median per patient 1 day, range 0–8). Of days where enoxaparin was withheld, 45% were for procedures; 20% bleeding; and 35% other reasons, including refractory thrombocytopenia <20×109/L. Serious bleeding complications during anticoagulation were uncommon. Three patients (5%) experienced major bleeding episodes: two developed gastrointestinal bleeding requiring endoscopic intervention and transfusion while receiving reduced dose anticoagulation with platelet counts of 20–50 ×109/L; one developed bleeding requiring surgical intervention at an existing wound site when the platelet count was 19 ×109/L, but had not received enoxaprin that day. Minor bleeding, including bruising at the sites of injections and menorrhagia was common. No further thromboembolic complications were identified in any patient. This study suggests that dynamically dosed anticoagulation is safe and feasible during thrombocytopenia following chemotherapy, including conditioning for stem cell transplantation, in patients who are carefully selected and closely monitored. This strategy was not associated with excessive bleeding and appeared effective in preventing further thromboembolic complications.

Evaluation of self-dissolving needles containing low molecular weight heparin (LMWH) in rats

Feasibility study of self-dissolving needles containing polysaccharide was performed. Low molecular weight heparin (LMWH) was used as a representative polysaccharide. Using chondroitin, dextran and dextrin as the base, self-dissolving needles (SDN) were prepared. The obtained SDNs were evaluated in rat absorption experiment, where pharmacological availability (PA) was calculated by comparing the plasma anti-Xa activity vs. time curves between SDNs and i.v. solution. After the insertion of SDNs to rats skin where the doses of LMWH were 25, 50 and 100 IU/kg, plasma samples were collected for 6 h and anti-Xa activity was measured as the pharmacological index of LMWH. The anti-Xa level was maintained above 0.2 IU/ml, the therapeutic level, for about 2 h at a dose of 100 IU/kg. Almost the same PAs of LMWH were obtained with dextran and dextrin SDNs, 97.7% and 102.3%, though lower PA was obtained with chondroitin SDN, 81.5%. In vitro dissolution experiment showed that LMWH was released from dextran, dextrin and chondroitin SDNs within 10 min. The T 50%s were 0.84 ± 0.06 min for dextran SDN, 1.07 ± 0.12 min for chondroitin SDN and 2.11 ± 0.31 min for dextrin SDN, respectively. Plasma anti-Xa activity vs. time profiles showed good dose-dependency in the 25–100 IU/kg range and high PAs were obtained, 90.0% for 25 IU/kg, 95.4% for 50 IU/kg and 97.7% for 100 IU/kg from dextran SDNs. Stability experiment was performed with dextran SDNs for 3 months. Above 97% of LMWH were remained in SDNs under three different conditions, −80, 4 and 40 °C. These results suggest the usefulness of SDN to polysaccharide drug.

Heparin Monitoring During Cardiopulmonary Bypass Surgery Using the One-Step Point-of-Care Whole Blood Anti-Factor-Xa Clotting Assay Heptest-POC-Hi

The activated clotting time (ACT) generally used for monitoring heparinization during cardiopulmonary bypass (CPB) surgery does not specifically measure heparin anticoagulant activities. This may result in heparin over- or under-dose and subsequent severe adverse events. A new point-of-care whole blood clotting assay (Heptest POC-Hi [HPOCH]) for quantifying heparin anticoagulant activity specifically was compared with ACT and anti-factor Xa (anti-Xa) heparin plasma levels (Coatest heparin) in 125 patients undergoing CPB surgery. The analytical reliability of the HPOCH and the influence of preanalytical variables on assay results were also examined. The ACT and HPOCH clotting times determined throughout the entire observation period correlated closely (n= 683;r= 0.80;p&lt; .0001). Similarly, there was a significant linear correlation between HPOCH and Coatest anti-Xa levels (n= 352;r= 0.87;p&lt; .0001). Pre- and post-CBP values of HPOCH, ACT, and anti-Xa plasma levels correlated closely with each other (correlation coefficients betweenr= 0.90 andr= 0.99;p&lt; .0001). During CPB, there was no significant relationship between ACT and whole blood or plasma heparin levels determined by HPOCH (n= 157;r= 0.19) and the chromogenic anti-Xa assay (n= 157;r= 0.04), respectively. In contrast, HPOCH and anti-Xa plasma levels correlated strongly during CPB (n= 157;r= 0.57;p&lt; .0001). However, bias analysis showed that the HPOCH and Coatest heparin could not be used interchangeably. The HPOCH was well reproducible and not influenced by aprotinin, hemodilution, or other factors affecting ACT. The HPOCH seems to be a promising new tool for specific on-site measurement of heparin activities in whole blood during CPB.

Papain: An Effective Permeation Enhancer for Orally Administered Low Molecular Weight Heparin

The purpose of this study was to evaluate an effect of the proteolytic enzyme papain on permeation of low molecular weight heparin (LMWH) in vitro and in vivo. In vitro permeation studies were performed using rat small intestine as permeation barrier. In order to determine the ratio of papain to heparin resulting in the highest heparin permeation rate, molar ratios 1:1, 1:2 and 2:1 of papain to heparin were tested. Interactions of heparin with papain were investigated spectro-photometrically. For in vivo studies, 15 mg tablets containing heparin (13%), papain (64%) and hydroxyethylcellulose (22%) were orally administered to rats. Since molar ratio papain to heparin 1:1 resulted in the highest permeation rate, it was used for in vivo studies. The results of binding studies of papain with heparin indicated a strong interaction between papain and heparin. Oral administration of tablets containing LMWH/papain/HEC resulted in sevenfold improvement of plasma anti-Xa activity in comparison to control. For tablets based on heparin/papain/HEC, a relative bioavailability of 9.1% vs. subcutaneous injection was obtained, whereas the relative bioavailability of control was 2.4%. The co-administration of papain with heparin represents a new approach in improvement of absorption and bioavailability of orally administered heparin.

A novel enoxaparin regime for ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: A WEST sub‐study

To evaluate the anticoagulation effect of subcutaneous (SQ) and intravenous (IV) enoxaparin through systematic anti-Xa sampling during primary PCI for acute STEMI. Although appropriate anticoagulation is essential to maximize the efficacy and safety of primary PCI, the optimal dosing of enoxaparin in this setting is unclear. STEMI patients randomized to primary PCI received ASA, clopidogrel 300 mg and enoxaparin 1 mg/kg SQ at earliest point of care, including prehospital. Plasma anti-Xa determination occurred just prior to and after primary PCI. Supplemental IV enoxaparin (0.3-0.5 mg/kg) and abciximab was encouraged prior to PCI. The 1st anti-Xa level 56 min (median, IQR 47-77) post SQ enoxaparin was 0.28 U/ml (0.23-0.41); 85% of patients (28/33) were <0.5 U/ml (the recommended therapeutic level). Following PCI, 126 min (118-185) after SQ enoxaparin in those without IV dosing (8/33) the 2nd anti-Xa level was 0.44 U/ml (0.29-0.53); 6 of 8 patients remained <0.5 U/ml. With IV enoxaparin (25/33) the 2nd anti-Xa was 0.96 U/ml (0.82-1.16) 97 min (82-109) after SQ enoxaparin: all were >or=0.5 U/ml and 2 had levels 1.5 U/ml. A single SQ enoxaparin dose fails to achieve anti-Xa levels >or=0.5 U/ml in the majority of STEMI patients. When combined with a strategy of supplemental IV enoxaparin, adequate anti-Xa levels were achieved in all patients with few having levels >1.5 U/ml. This regime of SQ injection with additional IV enoxaparin provides an attractive strategy enhancing effective early anti-thrombotic therapy at first medical contact prior to primary PCI.

Thrombelastography monitoring of resistance to enoxaparin anticoagulation in thrombophilic pregnancy patients

The anticoagulant effect of enoxaparin is readily observed by Thrombelastography (TEG®), particularly on the reaction time ( R) to form a clot, and is completely reversed by heparinase. In this study, recalcified citrated whole blood with heparinase (CNHR) and without (CNR), along with TEG R time, was used to derive a delta R (CNR − CNHR). This delta R (Δ R) was then used to measure enoxaparin anticoagulation, which was correlated by linear regression ( r 2 = 0.806) with plasma anti-Xa in 48 thrombophilic pregnancy patients. In a follow up study whole blood from 15 thrombophilic and 15 normal pregnancy subjects was titrated ex vivo with enoxaparin and TEG Δ R determined. Linear dose responses (all r 2 > 0.9) of Δ R versus plasma enoxaparin concentration were obtained for each subject. A large variation in slope was observed for both thrombophilic (> 7 fold, 217 to 1588 s Δ R/unit anti-Xa) and normal (> 3 fold, 788 to 2758) pregnancy subjects. The average slope for the thrombophilic group (710 s Δ R/unit anti-Xa) was significantly ( P = 0.002) lower than the normal pregnancy group (1354 s), indicating resistance to enoxaparin anticoagulation in the thrombophilic group. This technique may help gauge the appropriate dose of enoxaparin for each individual, check for residual anticoagulation before invasive procedures, and perhaps help screen for thrombophilic subjects.

Evaluation of the pharmacokinetics of dalteparin in patients with renal insufficiency

The pharmacokinetics of the low-molecular weight heparin (LMWH), dalteparin, was evaluated after a single intravenous bolus injection of 50 IU anti-Xa/kg in 8 healthy volunteers, 8 patients with moderate/severe renal failure (Cl(crea) 13.1-56.5 ml/min) and 8 hemodialysis patients. Venous blood samples were taken over a 1-day period to determine anti-Xa activity, anti-IIa activity and plasma levels of free tissue factor pathway inhibitor (free TFPI). Plasma anti-Xa and anti-IIa activities were measured using chromogenic assays and free TFPI levels using an ELISA technique. The anti-Xa clearance was significantly decreased (p < 0.05) in both groups with renal insufficiency when compared with healthy volunteers. There was a positive correlation between creatinine clearance and anti-Xa clearance in the healthy volunteers and patients with moderate/severe renal failure. The anti-Ila activity was characterized by 3- to 4-fold lower plasma concentrations and faster elimination compared with the anti-Xa activity. In patients with moderate/severe renal failure the elimination of anti-lla was only slightly decreased, whereas in hemodialysis patients anti-Ila clearance was significantly decreased (p < 0.01). There was no correlation between creatinine clearance and anti-IIa clearance. The baseline mean free TFPI plasma levels in the two groups with renal insufficiency were significantly higher (p < 0.01) than in healthy volunteers. Dalteparin administration induced a transient, 6.0- to 8.1-fold increase in the free TFPI values in the three study groups. Dalteparin induced an increase in C(max) and AUC(0 - infinity) values of free TFPI in the two groups with renal insufficiency that was higher than in healthy volunteers. No bleeding complications occurred during the study. In conclusion, this is the first report showing retarded elimination of dalteparin and enhanced free TFPI plasma levels induced by a LMWH in patients with renal insufficiency.

Epidural Blood Patch in a Patient Receiving Large Dose Enoxaparin (Lovenox)

To the Editor: There is very little information concerning the performance of epidural blood patches on patients receiving enoxaparin (Lovenox™; Aventis Pharmaceuticals, Somerville, NJ) with regard to the safety of the intervention as well as the effectiveness of the blood patch. We present a case in which a successful epidural blood patch was performed in a female patient taking 1.3 mg/kg of enoxaparin twice daily, 30 h after the last dose was given. A 39-yr-old female taking enoxaparin, 100 mg orally twice a day, underwent an uneventful lumbar puncture by her neurologist to exclude pseudotumor cerebri. Soon afterwards the patient developed a debilitating headache in the occipital region that became excruciating in the upright position. Her history was significant for deep venous thrombosis (DVT). The patient was treated with IV hydration and IV caffeine for 24 h without relief. Thirty hours after the last dose of enoxaparin, an epidural blood patch was performed with 20 mL of autologous blood with complete resolution of her postural headache. Low molecular weight heparinoids (LMWH) are increasingly prescribed for systemic anticoagulation therapy and DVT treatment and prophylaxis (1–3). Gaiser et al. (4) reported a partially successful epidural blood patch in a female patient 24 h after 190 mg of LMWH administered subcutaneously. There appears to be a predictable and reproducible dose response to enoxaparin when dosed on a weight-adjusted basis in small doses for thromboprophylaxis (5). With the lack of predictability at larger doses pharmacokinetic simulation is extremely difficult. The terminal half-life of plasma anti-Xa activity of enoxaparin is between 3–4 h. Therefore, we elected to wait for more than 7 half-lives to perform an epidural blood patch. To our knowledge, a successful epidural blood patch on a patient receiving enoxaparin more than 1.5 mg/kg/day has not been reported. Nalini Vadivelu, MD Craig Freiberg, MD James Kim, MD Mathew Wallace, MD Raymond Sinatra, MD, PhD Department of Anesthesiology Yale University School of Medicine New Haven, CT [email protected]

Preparation and evaluation of oral solid heparin using emulsifier and adsorbent for in vitro and in vivo studies

Oral anticoagulant therapy with heparin has been challenged by formulating heparin in oral solid preparation. As heparin, low molecular weight heparin (LMWH) was used. LMWH was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with three kinds of adsorbents, microporous calcium silicate (Florite™ RE), magnesium alminometa silicate (Neusilin™ US 2) and silicon dioxide (Sylysia™ 320). The in vitro release study showed that the T50%s were 3.2 ± 0.1 min for Sylysia 320, 4.6 ± 0.2 min for Florite RE, 13.7 ± 0.1 min for Neusilin US 2. The in vivo rat absorption study showed that Florite RE system had the highest C max, 0.42 ± 0.01 IU/mL and AUC, 0.59 ± 0.06 IU h/mL, where plasma LMWH levels were measured as anti-Xa activity. Other preparations had the C max and AUC, 0.12 ± 0.01 IU/mL and 0.15 ± 0.02 IU h/mL for Neusilin US 2 and 0.25 ± 0.02 IU/mL and 0.40 ± 0.03 IU h/mL for Sylysia 320, respectively. The bioavailability (BA) of LMWH from the microporous calcium silicate preparation, Florite RE, was 18.8% in rats by comparing the AUC obtained after i.v. injection of LMWH, 40 IU/kg to another group of rats. Florite RE system was evaluated in dogs after oral administration in an enteric capsule made of Eudragit S100 at the LMWH dose of 200 IU/kg. High plasma anti-Xa activity levels were obtained, i.e., the C max was 0.48 ± 0.11 IU/mL and AUC was 1.64 ± 0.32 IU h/mL. These results suggest that adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as LMWH.

A randomized comparative study of using enoxaparin instead of unfractionated heparin in the intervention treatment of coronary heart disease

Low molecular weight heparin (LMWH) was more effective than unfractionated heparin (UFH) in treating acute coronary syndrome (ACS). However, it remains uncertain whether LMWH can be used in patients undergoing percutaneous coronary intervention (PCI) instead of UFH. This study aimed to evaluate the efficacy and safety of using enoxaparin instead of UFH in the intervention treatment of patients with coronary heart disease (CHD). From October 2003 to Febuary 2005, 966 patients with CHD were enrolled into this study. Among 966 patients, 455 patients received the PCI, including 283 patients with Non-ST segment elevation ACS (NSTEACS), 511 patients did not received PCI due to mild, moderate lesions or were suitable for coronary artery bypass graft (CABG). The 966 patients were randomized to enoxaparin group (484 patients) and UFH group (482 patients). Patients in the enoxaparin group were given enoxaparin at least twice subcutaneously (1 mg/kg, q12 h) before catheterization. Plasma anti-Xa activity was determined 1 - 8 hours after the last dose of enoxaparin was determined. The catheterization was performed within 8 hours after the last dose of enoxaparin. The sheath was removed immediately after the procedure. Patients in the UFH group were given UFH 25 mg intravenously before coronary angiography. Additional 65 mg was given intravenously if PCI was to be performed. The sheath was removed 4 hours after the procedure. A total of 227 patients in the enoxaparin group and 228 patients in the UFH group received PCI. In the enoxaparin group, one patient developed acute thrombosis during PCI and resulted in acute myocardial infarction (AMI), no acute or subacute thrombosis was found during hospitalization. In the UFH group, no acute or subacute thrombosis occurred during PCI procedure and hospitalization. Therefore, the incidence of major adverse cardiovascular events (MACEs) during the hospitalization was 0.44% in the enoxaparin group and 0 in the UFH group. In the enoxaparin group, the sheath was removed immediately after the procedure and 8 patients had hematoma on the puncture site. In the UFH group, the sheath was removed 4 hours after the procedure and 20 cases had hematoma on the puncture site. The incidence of hematoma on the puncture site was significantly higher in the UFH group than that in the enoxaparin group (P < 0.05). Anti-Xa activity was determined in 174 patients in LMWH group. The mean anti-Xa activity was (0.87 +/- 0.23) U/ml, and 94.8% of them had anti-Xa activity >0.5 U/ml and 6.9% of the patient >1.2 U/ml. There was no death and AMI occurred in enoxaparin group, but one patient had AMI caused by subacute thrombosis in UFH group during 30-day follow-up. MACE rate at 30-day follow-up was 0 in enoxaparin group and 0.43% in UFH group. The results of the study suggest that it is safe and efficient to give enoxaparin at least twice before the PCI procedure, and the sheath can be removed immediately after PCI. For NSTEACS patient who has received enoxaparin more than twice during the hospitalization can undergo PCI directly and no UFH is necessary before or during PCI.