Administration Of Nadroparin Research Articles

Pharmacokinetics of low molecular weight heparins in thrombosis, complicate the treatment of children with cancer

Objective: to evaluate the pharmacokinetics of nadroparin and dalteparin in thrombosis complicating the treatment of children with malignant neoplasms.Materials and methods. The results of 52 pharmacokinetic studies performed in 34 patients with malignant neoplasms, whose treatment was complicated by venous thrombosis, were analyzed. The age of the patients is from 7 to 18 years, he median is 14.5 years. Depending on the value of daily dose and type of heparin administered, the results of pharmacokinetic studies were divided into 6 groups. Dalteparin sodium: during period of chemotherapy induced thrombocytopenia, subcutaneous injection at a dose of 51.0 (40.0-72.0) anti Xa IU/kg every 12 hours - 6 studies; subcutaneous injection every 12 hours at a dose of 100.5 (91.0-141.0) anti Xa IU/kg - 18 observations; long-term continuous administration at a constant rate at a daily dose of 201.0 (180.0-265.0) anti Xa IU/kg - 6 pharmacokinetic observations. Nadroparin calcium: 62.0 (53.0-71.0) anti Xa IU/kg every 12 hours - 6 studies; 93.5 (80.0-117.0) anti Xa IU/kg every 12 hours - 10 observations; subcutaneous injection at a dose of 203.0 (170.0-236.0) anti Xa IU/kg once a day - 6 pharmacokinetic observations.Results. At steady-state, the area under the pharmacokinetic curve (AUC) of dalteparin and nadroparin, regardless of the mode of administration, depended on the maximum specific activity and half-life. No relationship was found for dalteparin between AUC and endogenous creatinine clearance. In contrast to dalteparin, the AUC after administration of na-droparin was closely related to endogenous creatinine clearance. The increase in chronometric indices indirectly reflected the presence of an anticoagulant in the blood, but did not allow an objective assessment of therapeutic effect achievement, recorded by the degree of thrombin generation inhibition.Conclusion. There were no significant advantages of nadroparin compared with dalteparin when using in comparable doses in the case of venous thrombosis, complicated the treatment of children with malignant neoplasms. Subcutaneous administration of 50 % nadroparin calcium daily dose with 12 hours interval is preferred over a single administration of 100 % daily dose every 24 hours. It is mandatory to monitor the administration of low molecular weight heparins in children with oncological diseases in order to make a decision on the adequacy of anticoagulant dose to the therapeutic range.

Arterial Versus Venous Port Site Administration of Nadroparin for Preventing Thrombosis of Extracorporeal Blood Circuits in Patients Receiving Hemodiafiltration Treatment

IntroductionAdministration of low-molecular-weight heparins (LMWHs) is necessary for preventing extracorporeal circuit thrombosis during hemodialysis. A substantial amount of LMWH is removed with online hemodiafiltration (OL-HDF) when administered through the inlet site of the extracorporeal circuit. Consequently, administration of LMWH at the outlet site appears to be more efficient. In this study we aimed to compare the effects of nadroparin calcium (NAD) administered through the outlet versus the inlet port site in postdilution OL-HDF and assess the NAD dose reduction.MethodsForty-nine hemodialysis patients were included in 3 consecutive 6-week studies as follows: phase I, inlet port line; phase II, outlet port line; and phase III, outlet port line with reduced dose. We evaluated clotting in the hemodialyzer and venous bubble trap, the dialysis dose (Kt/V), and substitution volume.ResultsThirty four percent, 63%, and 66% were categorized as “white” during phases I, II, and III, respectively. During phases I, II, and III, 75%, 93%, and 95% of the venous bubble traps were “clean,” and 9%, 0.6%, and 0.4% of the dialyzers clotted, respectively. Average NAD dose was 0.43 ml during phase I and 0.3 ml during phase II. During phase III, the LMWH dose was reduced by 33% to 50% in 15 patients. In phase III, Kt/V improved from 1.64 to 1.75 and substitution volume increased from 20.18 to 21.96 L.ConclusionsWhen using OL-HDF, a single administration of NAD at the outlet port line allows for a significant dose reduction and was associated with improved dialysis performance.

Modulation of angiogenesis by topical application of leptin and high and low molecular heparin using the Japanese quail chorioallantoic membrane model.

Pathological angiogenesis characterized by uncontrollable vessel growth is an accompanying feature of many diseases. The avian embryo chorioallantoic membrane (CAM) is an excellent model for angiogenesis research. In our study we used a less common Japanese quail CAM model for the testing of angiogenic potential of leptin, high-molecular (heparin sodium) andlow-molecular (nadroparin calcium) heparins. Heparins play a significant role in vascular endothelial cell function, and they are able to modulate the activities of angiogenic growth factors. On embryonic day 7 leptin (5 μg per CAM), heparin sodium (75 IU per CAM) and nadroparin calcium (47.5 IU per CAM) in 500 μl PBS were applied on the CAM surface. After 24 h the fractal dimension (Df) of the vasculature was evaluated. Samples from each group were histologically analyzed and VEGF-A and Quek1 expression were detected by qPCR. Df was significantly increased in the leptin group. A moderate stimulatory effect of heparin sodium and an inhibitory effect of nadroparin calcium were observed. Both leptin and heparin sodium caused a noticeable increase in the CAM thickness compared to the control and nadroparin calcium groups. We observed an increased number of blood vessels and accumulation of fibroblasts. There was no significant impact on gene expression of VEGF-A and Quek1 24 h after treatment, however, trends similar to the changes in Df and CAM thickness were present. The resulting effect of nadroparin administration on Quek1 levels was exactly the opposite to that of leptin (p < 0.05).

Pharmacokinetic Comparison of Subcutaneous and Intravenous Nadroparin Administration for Thromboprophylaxis in Critically Ill Patients on Vasopressors

Introduction: Critically ill patients are exposed to a high risk of developing thromboembolism. Moreover, standard prophylaxis with subcutaneous (SC) heparin is less efficient in patients requiring vasopressors. The aim is a comparison of pharmacokinetics between SC and intravenous (IV) applied nadroparin. Methods: Thirty-eight ventilated ICU patients requiring vasopressor support were randomized into a single dose of nadroparin 3,800 IU (0.4 mL) subcutaneously (SC group) or 1,900 IU (0.2 mL) intravenously (IV group). Anti-factor Xa activity (anti-Xa) was observed over 24 h; data are stated as median (IQR). Results: Peak anti-Xa was significantly higher in the IV group 0.42 (0.39–0.43) IU/mL than in the SC group 0.16 (0.09–0.18) IU/mL (p < 0.001). There was a trend towards higher area under the curve (AUC) of anti-Xa in the SC group 1.41 (0.41–1.80) IU/mL × h than in the IV group 1.04 (0.93–1.13) IU/mL × h (p = 0.08). In the SC group, there was a negative correlation between anti-Xa AUC and both capillary refill time Xa (r = –0.86) and norepinephrine dose (r = –0.68). In the IV group, anti-Xa decrease half-life was 1.6 (1.4–2.0) h. Conclusions: IV administration of 1,900 IU of nadroparin led to a predictable effective peak anti-Xa. After SC administration, anti-Xa was heterogeneous and significantly influenced by peripheral perfusion.

The Effect of Obesity on Anti-Xa Concentrations in Bariatric Patients.

Morbidly obese patients are at increased risk to develop venous thromboembolism (VTE), especially after bariatric surgery. Adequate postoperative thrombosis prophylaxis is of utmost importance. It is assumed that morbidly obese patients need higher doses of low molecular weight heparin (LMWH) compared to normal-weight patients; however, current guidelines based on relative efficacy in obese populations are lacking. First, we will evaluate the relationship between body weight descriptors and anti-Xa activity prospectively. Second, we will determine the dose-linearity of LMWH in morbidly obese patients. This study was performed in a general hospital specialized in bariatric surgery. Patients were scheduled for a Roux-en-Y gastric bypass with a total bodyweight (TBW) of ≥ 140kg. Patients (n = 50, 64% female) received a daily postoperative dose of 5700IU of nadroparin for 4weeks. Anti-Xa activity was determined 4h after the last nadroparin administration. To determine the dose linearity, anti-Xa was determined following a preoperative dose of 2850IU nadroparin in another 50 patients (52%). TBW of the complete group was 148.5 ± 12.6kg. Mean anti-Xa activity following 5700IU nadroparin was 0.19 ± 0.07IU/mL. Of all patients, 32% had anti-Xa levels below the prophylactic range. Anti-Xa activity inversely correlated with TBW (correlation coefficient - 0.410) and lean body weight (LBW; correlation coefficient - 0.447); 67% of patients with a LBW ≥ 80kg had insufficient anti-Xa activity concentrations. No VTE events occurred. In morbidly obese patients, a postoperative dose of 5700IU of nadroparin resulted in subprophylactic exposure in a significant proportion of patients. Especially in patients with LBW ≥ 80kg, a higher dose may potentially be required to reach adequate prophylactic anti-Xa levels.

Low-molecular weight heparin infusion as anticoagulation for haemodialysis.

BackgroundLow-molecular weight heparin (LMWH) is commonly used as an anticoagulant for haemodialysis by a single-bolus injection. However, its application in extended haemodialysis has been infrequently studied. In particular, for nocturnal home haemodialysis patients sleeping throughout treatment, the need for additional intradialytic bolus might render the use of LMWH impractical. To overcome this limitation, we changed traditional bolus injections to continuous infusion. We first tested our method among in-centre 4-h haemodialysis patients to establish a feasible and safe infusion regimen before utilizing it in extended dialyses at home.MethodsRecruited patients were given nadroparin (standardized at 65 IU/kg) as an anticoagulant for haemodialysis. They were first randomized to receive nadroparin either by bolus injection or infusion. Afterwards, the patients underwent crossover to receive the alternate method of LMWH anticoagulation. The degrees of anticoagulation and bleeding complications were compared.ResultsSixteen haemodialysis patients were recruited. After nadroparin administration, anti-Xa levels at the first hour were significantly higher by the bolus than the infusion methods (0.68 ± 0.10 versus 0.49 ± 0.10 IU/mL, P < 0.001) and were similar by the second hour (0.56 ± 0.10 versus 0.55 ± 0.11 IU/mL, P = 0.64). At the sixth hour, anti-Xa levels by the infusion method were significantly higher (0.35 ± 0.13 versus 0.25 ± 0.10 IU/mL, P < 0.001), suggesting the infusion approach required a dosage reduction. There were no bleeding events reported in either method.ConclusionsLMWH infusion is feasible and safe. The method avoids early excessive anticoagulation caused by bolus injection and reduces the LMWH dose. Future studies should be conducted to evaluate LMWH infusion in extended haemodialysis treatment.

Low molecular weight heparin improves healing of chronic venous ulcers especially in the elderly

Venous ulcers are common, especially in the elderly, accounting for more than 50% of all lower extremity ulcers with important socioeconomic problems. Improving extracellular matrix functioning, by heparin administration, seems to be a way to support wound healing. A total of 284 patients with venous ulcers were recruited in a 4-year period. All patients were subjected to the most appropriate treatment after considering their preference (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 142 persons in each (group A and group B as cases and controls, respectively). Patients of group A, in addition to the basic treatment as described earlier, received administration of nadroparin 2850 IU/0.3 ml through subcutaneous injection once a day for 12 months, whereas group B patients received basic treatment alone. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a healing rate of 83·80% at 12 months, whereas that of group B was 60·56%. Results by age group surprisingly showed that the group of older patients took the most advantage from long-term treatment with low molecular weight heparin; this group also had lowest recurrence rate.

Evaluation of coagulation and anti-Xa factor when using a heparin-coated AN69ST® dialyser.

Hemodialysis systems are potentially thrombogenic, so it is routinely used anticoagulation. Its prescription is with risks though which the recommendations regarding the scheduled dose are still based on very different criteria. We performed a randomized, crossover pilot study. Six patients underwent six sessions of post-dilution hemodiafiltration with polysulfone HF80® dialyzer and standard anticoagulation with nadroparin, and six sessions with heparin-coated poliacrylonitrile AN69ST® membrane without using systemic anticoagulation. Dialyser and the extracorporeal circuit clotting grade was evaluated through visual scale every hour and coagulation parameters like anti-Xa factor. Our endpoint was to assess anti-Xa activity without differences in the rate of massive clotting between the two groups. No complete or grade 4 dialyzer clotting occurred in any of 36 sessions with each dialyzer. A partial lower 25% (grade 1-2) dialyzer clotting was in 32 (89.7%) AN69ST® sessions and 35 (97.2%) with the usual dialyzer and upper 25% (grade 3-4) in 4 (11.1%) AN69ST® sessions and 1 (2.8%) dialysis session with heparin. Arterial chamber blood coagulation was not greater than 25% (grade 3 and 4) in any of the studied sessions and the venous chamber in only 1 (2.8%) session with the usual dialyzer and 3 (8.4%) with no differences AN69ST® between the two dialyzers. The activated partial thromboplastin time at two hours showed differences between techniques related to administration of low molecular weight heparin (33.3 ± 2.7s with polysulfone and 27.5 ± 2.3s in AN69ST®; P < 0.05) which remained significant at the end of the session (29.8 ± 2.1s with polysulfone and 27.2 ± 1.8s with AN69ST®; P < 0.05). Anti-Xa factor activity was maximal two hours after administration of nadroparin, with differences between the two dialyzers (0.46 ± 0.13 IU / ml in dialysis with polysulfone and 0.04 ± 0.04 IU / ml with AN69ST®p<0.005) and went down after 4 hours (0.17 ± 0.12 IU / ml in dialysis with polysulfone and 0.02 ± 0.03 IU / ml in AN69ST®; p<0.05). One patient in dialysis AN69ST®; had an adverse reaction characterized by generalized pruritus and was excluded from the study, by withdrawing the consent in the first session. We demonstrate the low thrombogenicity of the AN69ST®; dialyzer that allows post-dilution hemodiafiltration sessions without systemic anticoagulation, and without increasing the frequency of severe clotting events compared to HF80®; dialyzer with nadroparin and with less risk of bleeding by not modifying the anti-Xa factor activity.

Correspondence (letter to the editor): Evaluate Thrombophilia First.

In this otherwise excellent CME article, one important fact is missing that would be essential for treating physicians to know. The once-daily dosing of nadroparin as recommended table 1 seems not to be applicable to the thrombophilic patient without serious implications, according to the product’s Summary of Product Characteristics (European Medicines Agency) and „Fachinformation“ (Bundesinstitut fur Arzneimittel und Medizinprodukte). Both agencies are cautioning against once-daily administration in patients with thrombophilia, where a twice daily administration of nadroparin should be considered, instead. It follows, therefore, that single daily dose of nadroparin is an unsuitable means of providing immediate and effective anticoagulation to large percentage of patients with thromboses, because time-consuming screening for thrombophilia would have to be evaluated first if this drug was to be given compliance with the above recommendations. This limitation does not apply to any other low-molecular-weight heparin.

Prevention of catheter-related venous thrombosis with nadroparin in patients receiving chemotherapy for hematologic malignancies: a randomized, placebo-controlled study.

Hemato-oncology patients treated with intensive chemotherapy usually require the placement of a central venous catheter (CVC). CVCs are frequently complicated by catheter-related central venous thrombosis (CVT), which has been associated with an increased risk of pulmonary embolism and catheter-related infection. To determine the efficacy and safety of thromboprophylaxis with s.c. low-molecular-weight heparin (nadroparin) administered once daily in a randomized placebo-controlled, double-blind trial in patients with hematologic malignancies. Consecutive patients with hematologic malignancies requiring intensive chemotherapy including autologous stem cell transplantation were eligible. The patients were randomized to receive nadroparin 2850 antifactor Xa units once daily or placebo s.c. for 3 weeks. Venography was performed on day 21 after CVC insertion. Secondary outcomes were bleeding and catheter-related infection. In total, 113 patients were randomized to nadroparin or placebo, and 87 patients (77%) underwent venography. In total, 11 venographically proven catheter-related CVTs were diagnosed. The frequency of catheter-related CVT was not significantly different between study groups, namely four catheter-related CVTs in the placebo group [9%; 95% CI: 0.002-0.16] vs. seven catheter-related CVTs in the nadroparin group (17%; 95% CI: 0.06-0.28). In addition, no difference in the incidence of catheter-related infection or bleeding was observed between the groups. This study showed that the actual risk for catheter-related CVT in patients with hematologic malignancies is lower than suggested in earlier studies in cancer patients. Although prophylactic administration of nadroparin appeared to be safe in this group of patients with a high risk of bleeding, it cannot be recommended for the prevention of catheter-related CVT or catheter-related infection in patients with hematologic malignancies.

Risk of Postoperative Hemorrhage after Intracranial Surgery after Early Nadroparin Administration: Results of a Prospective Study

Risk of Postoperative Hemorrhage after Intracranial Surgery after Early Nadroparin Administration: Results of a Prospective Study

Postoperative nadroparin administration for prophylaxis of thromboembolic events is not associated with an increased risk of hemorrhage after spinal surgery.

To determine the risk of postoperative hemorrhage during a 3-year period of early postoperative administration of nadroparin (Fraxiparin) plus compression stockings in a large cohort of patients who underwent spinal surgery. A total of 1,954 spinal procedures at different levels (503 cervical, 152 thoracic and 1,299 lumbar), performed between June 1999 and 2002 at the Department of Neurosurgery, Johann-Wolfgang-Goethe University Frankfurt, were included in this study. To prevent venous thromboembolic events (VTE), all patients were routinely treated subcutaneously with 0.3 ml of early (less than 24 h) postoperative nadroparin calcium (Fraxiparin) (2850 IU anti-Xa, Sanofi Winthrop Industrie, France) plus intra- and postoperative compression stockings until discharge. The occurrence of a postoperative hematoma (defined as a hematoma requiring surgical evacuation because of space occupation and/or neurological deterioration) and a deep venous thrombosis (DVT) were recorded in a database and analyzed retrospectively. 13 (0.7%) of the 1,954 spinal operations were complicated by major postoperative hemorrhages. In 5 of the 13 patients (38.5%) the hemorrhage occurred on the day of surgery before the administration of nadroparin. Thus, the hemorrhage rate of patients receiving nadroparin was 0.4% (8/1,949). Ten (77%) of the 13 patients with major postoperative hematoma showed a progressive neurological deficit, which resolved in 6 patients and resulted in a hematoma-related morbidity of 31% (4/13). Only 1 patient (0.05%) in this series developed a clinically evident DVT, and none of the patients suffered from pulmonary embolus during the hospital stay. Although retrospective, this is to date the largest study providing information about the hemorrhage rate associated with early postoperative anticoagulation following spinal surgery. The results confirm that early postoperative pharmacological thromboembolic prophylaxis using nadroparin in patients with spinal surgery is not associated with an increased risk of postoperative hemorrhage.

The risk of postoperative hemorrhage after intracranial surgery following early Nadroparin administration - results of a prospective study

The risk of postoperative hemorrhage after intracranial surgery following early Nadroparin administration - results of a prospective study