Low molecular weight heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers

The pharmacokinetics of a low molecular weight heparin (LMWH) with a mean mw of 4000-6000 D (KABI 2165, Fragmin) was studied in 6 healthy volunteers after intravenous (iv) and subcutaneous (sc) administration of 120 U (anti FXa)/kg. The half-life in plasma of the anti FXa activity after iv injection was 119 +/- 17 min, the volume of distribution (Vd) 3.4 +/- 0.5 1 and the total clearence 20.5 +/- 2.5 ml/min. The maximal anti FXa activity determined 3 min after iv bolus injection amounted to 2.2 +/- 0.3 U (anti FXa)/ml with a corresponding increase of the APTT from 31 +/- 7 sec to 113 +/- 35 sec. The elimination of the anti FXa activity was a monoexponential first order process. After sc administration the plasma half-life of the anti FXa activity was longer than after iv injection, 228 +/- 40 min, corresponding to the absorption rate thus found to be the rate limiting step. After sc administration the peak was reached after 4 hours (0.6 +/- 0.1 U (anti FXa)/ml; APTT increase 5 sec). The bioavailability after sc injection was calculated to be 87 +/- 6%. As a consequence of the high bioavailability and long T1/2 of the anti FXa activity, Fragmin administered sc seems to induce adequate levels of heparin-like activity making this regimen worth further investigation as an alternative for the treatment of deep venous thrombosis.     

Effects of standard heparin and a low molecular weight heparin (Kabi 2165) on fibrinolysis

Previous and recent reports have suggested a fibrinolysis-enhancing property of standard heparin and low molecular weight heparins, but these observations have never been confirmed in a study fulfilling appropriate methodological criteria. The aim of this study was to evaluate the effect of standard heparin and a low molecular weight heparin (Kabi 2165) on fibrinolysis in a randomized cross-over double blind placebo controlled study. Six healthy volunteers received intravenously a bolus dose of the following treatments: placebo; standard heparin, 5,000 I.U.; Kabi 2165, 5,000 anti-Xa U; Kabi 2165, 10,000 anti-Xa U. Before the injection and at established times thereafter, blood samples were collected for the following assays in plasma: t-PA activity, PA inhibitor activity, fibrin plate lysis area (FPLA), plasminogen, alpha 2-antiplasmin, fibrinogen and anti-Xa activity. Placebo and Kabi 2165, 5,000 anti-Xa U, had no effect on t-PA plasma level. Standard heparin and Kabi 2165, 10,000 anti-Xa U, produced a statistically significant increase in t-PA level at 1 hour after the infusion. This increase lasted for at least 1 hour after the infusion. No effect of any treatment on PA inhibitor, plasminogen, FLPA, alpha 2-antiplasmin and fibrinogen was observed. We conclude that an intravenous bolus dose of both standard heparin, 5,000 I.U. and Kabi 2165, 10,000 anti-Xa U produces a delayed and sustained increase in plasma t-PA.     

A randomized double-blind study between a low molecular weight heparin Kabi 2165 and standard heparin in the prevention of deep vein thrombosis in general surgery. A French multicenter trial

The safety and efficacy of a low molecular weight heparin fragment Kabi 2165, given in the dose 2,500 anti-Xa units once daily, in preventing postoperative venous thromboembolism, was assessed against calcium heparin in the dose 5,000 IU twice daily, in a multicenter double blind randomized study. On an intention to treat basis 385 patients scheduled for major surgery were included in this study. Six patients (3.1%) out of 195 developed isotopic DVT in the Kabi 2165 group. Corresponding figures for calcium heparin was 7 patients (3.7%). There was no statistically significant difference between the two groups with respect to the bleeding variables; blood loss during operation, postoperative drainage, blood transfusion, haemoglobin and haematocrit levels; wound haematoma and haematoma at the injection sites. No patient had to undergo evacuation of wound haematoma or reoperation due to bleeding. It is concluded that one single daily injection of Kabi 2165 provides a convenient safe and effective prophylaxis against thromboembolism in general surgery.     

Low molecular weight heparin (KABI 2165) as thromboprophylaxis in elective visceral surgery. A randomized, double-blind study versus unfractionated heparin

In two randomized double-blind studies perioperative bleeding complications and thromboembolic events were assessed in 189 patients (pts) undergoing elective visceral surgery after subcutaneous administration of a low molecular weight (LMW) heparin fragment (KABI fragment 2165) or unfractionated (UF) heparin. The first study comparing 1 X 7'500 anti-factor Xa IU LMW heparin daily with 2 X 5'000 IU UF heparin was interrupted because of excessive bleeding complications (LMW heparin: 11/23 pts, UF heparin: 2/20 pts, p less than 0.01). In the second study (146 pts) the dose of LMW heparin was reduced to 1 X 2'500 anti-factor Xa IU. Bleeding complications (LMW heparin: 14.9%, UF heparin: 15.3%) and thromboembolic events (LMW heparin: 2.86%, UF heparin: 2.94%) were equal among the two groups. 2'500 anti-factor Xa IU/day of this LMW heparin fragment, corresponding to 15 mg/day, is the lowest dose of a LMW heparin used in a randomized clinical trial and was found to be a safe and efficient regimen in perioperative thrombosis prophylaxis. An advantage of LMW heparin over UF heparin is its once daily administration.     

Subcutaneous treatment of deep venous thrombosis with low molecular weight heparin. A dose finding study with LMWH-Novo

Treatment of deep venous thrombosis with low molecular weight heparin (LMWH-Novo, Logiparin) was carried out with two different doses of Logiparin, 75 XaI U/kg b.w. twice daily and 150 XaI U/kg b.w. once daily subcutaneously for 5 days. Simultaneously warfarin was given from the first day of heparin treatment. Mean age of the twenty patients was 65 years and one third was females. No serious side effects, hematomas, pulmonary emboli or signs of recurrent thrombosis occurred during treatment with either dose regime. Venografic assessment with Marder scoring one week after initiation of Logiparin treatment showed a slight not significant improvement apparent in 40 % of the patients. The activities of F-IIaI and F-XaI in the blood plasma were found to increase after injection of Logiparin. These two parameters seem to be the most suitable for monitoring the effect during treatment. For future studies on the therapeutic effect of Logiparin in deep venous thrombosis a single dose of 150 to 200 F-XaI activity per 24 hours seems to be most suitable.     

Fixed-dose,body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis

Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up. In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH. The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50, 50-80 and >80 kg as followed: 0, 3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and 4.2% for UFH. Overall mortality was 1.9% in the Certoparin group and 2.7% in the UFH group. Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.     

Two daily subcutaneous injections of fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT)

In a prospective, randomized, open study 119 consecutive patients with phlebographically verified deep venous thrombosis (DVT) of the leg (36% distal and 64% proximal) were treated either with a low molecular weight heparin (Fragmin, Kabi-Vitrum) subcutaneously (120 anti-FXa U/kg) twice daily or standard heparin (SH) as continuous intravenous infusion (480 IU kg-1 day-1). The Fragmin doses were adjusted to achieve an anti-FXa activity of 0.2-0.4 U/ml before injection and not greater than 1.5 U/ml 4 h after the morning injection. The SH dose was modified to prolong the APTT 2-3 times. Repeat phlebography after 5-7 days showed improvement in 34/45 patients (76%) in the Fragmin group and in 30/49 patients (61%) in the SH group and progress in 2/45 (4%) and 3/49 (6%), respectively. The mean Marder scores decreased from 18.7 +/- 12.1 to 15.7 +/- 12.7 in the Fragmin group and from 16.9 +/- 12.0 to 14.4 +/- 11.8 in the SH group (ns). Two patients in the SH group and none in the Fragmin group had major bleedings. After 22 +/- 7 months follow up 6 rethromboses had occurred in the SH group and 4 in the Fragmin group. Postthrombotic signs and symptoms were similar in both groups. We conclude that two daily sc Fragmin doses seem as effective and safe as continuous SH in the treatment of DVT of the leg.     

Outpatient use of low molecular weight heparin (Dalteparin) for the treatment of deep vein thrombosis of the upper extremity.

Upper extremity deep vein thrombosis (DVT) is now recognized as a major cause of morbidity and mortality. There is little information regarding the most effective treatment of this condition. We report a prospective cohort study of the use of low molecular weight heparin (LMWH) in the outpatient management of upper extremity DVT. Forty-six patients were managed as outpatients for objectively documented upper extremity DVT with dalteparin (200 aXa u/kg), for a minimum of five days. Warfarin was usually initiated on the first day with a target INR of 2.0-3.0. Most patients had an underlying malignancy or a history of a central line. All patients were followed for 12 weeks from diagnosis. Only one patient had a major bleed. No patients developed pulmonary emboli. One patient had a recurrence of DVT during the treatment with LMWH with extension of the existing thrombus. Seven patients died, all due to their underlying disease. This study supports the safety and effectiveness of dalteparin in the treatment of upper extremity DVT. Given that these patients were treated as outpatients, there is a potential for huge cost savings.     

髋关节置换后利伐沙班与低分子肝素预防下肢深静脉血栓的比较

背景：低分子肝素可显著降低髋关节置换后下肢深静脉血栓的发生率,但其因需皮下注射而存在局限性。 目的：比较全髋关节置换后应用利伐沙班与低分子肝素预防下肢深静脉血栓疗效和安全性的差异。 方法：58例全髋关节置换患者按随机数字表法分为2组,利伐沙班组28例,低分子肝素组(达肝素)30例。置换后行双下肢彩色多普勒检查评估DVT形成情况,并观察治疗期间出血情况。 结果与结论：利伐沙班组与达肝素组患者在预防下肢深静脉血栓疗效上差异无显著性意义(P > 0.05)。两组在治疗期间均无严重出血,置换后非严重出血差异也无显著性意义(P > 0.05)。提示利伐沙班在预防全髋置换后下肢深静脉血栓的疗效与安全性上与低分子肝素作用相当。     

Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.

In a prospective multicenter trial, 149 consecutive patients with phlebographically proven proximal and/or distal deep vein thrombosis of the leg were randomly allocated to receive subcutaneously for 10 days either low molecular weight heparin CY 216 (Fraxiparine) in a fixed dose or unfractionated heparin (UFH) in doses adjusted according to the activated partial thromboplastin time. Pre- and post-treatment phlebograms were assessed blindly using the Arnesen's score system in 134 patients available for analysis of the treatment efficacy. The mean phlebographic score after 10 days of treatment was significantly decreased in both groups (p less than 0.001) in comparison with the baseline score but the difference in score changes between the two groups was not statistically significant. There was an improvement in 45/68 patients (66%) in the Fraxiparine group and in 32/66 patients (48%) in the UFH group, and an increase in the thrombus size in 10/68 (15%) and 12/66 (18%), respectively. One symptomatic non-fatal pulmonary embolism and one major bleeding episode were observed in the UFH group. During a follow-up period of 3 months, two rethromboses had occurred in the UFH group and none in the Fraxiparine group. It is concluded that subcutaneous fixed dose Fraxiparine is safe and at least as effective as subcutaneous adjusted UFH in the treatment of deep vein thrombosis.     

Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial

This study aims to establish the relative effectiveness and safety of low molecular weight heparin in elderly patients with venous thrombosis in order to find an alternative to oral anticoagulant therapy with less bleeding complications in the long-term treatment of deep venous thrombosis (DVT). One hundred consecutive elderly patients (>75 years old) with venographically demonstrated proximal DVT were included in a randomized trial. All patients were treated for ten days with adjusted doses of intravenous heparin. Informed consent was obtained and on the eight day, patients were randomly allocated to receive acenocoumarol (INR 2.0-3.0) or subcutaneous enoxaparin (4000 anti-Xa units once a day) for three months. All patients were followed-up clinically and venographically for a one year period. The results were analyzed with Fisher's exact test or chi-square test as appropriate. During the treatment and surveillance period, 6 of the 50 patients (12%) who received acenocoumarol and 8 of the 50 patients (16%) who received enoxaparin had new episodes of venous thromboembolism confirmed by objective testing (p = 0.6; 95% CI for the difference: -19.5 to 11.5). Hemorrhagic complications occurred in six of the 50 patients (12%) who received acenocoumarol and in one (2%) of those on enoxaparin (p = 0.1; 95% CI for the difference: -1.8 to 21.8). Vertebral fractures developed in 2 patients (4%) in the enoxaparin group (p = 0.5; 95% CI for the difference: -11.4 to 3.4). These results show that fixed dose enoxaparin seems to be effective and safe in the long-term treatment of proximal DVT in the elderly. In comparison with oral anticoagulants, the findings are inconclusive due to the wide confidence intervals for differences between outcomes, however they suggest that the former may have less bleeding complications with similar efficacy.     

A comparison of the antithrombotic and haemorrhagic effects of a low molecular weight heparin (LHN-1) and conventional heparin

The antithrombotic effects after intravenous administration of a low molecular weight heparin (LHN-1) and conventional heparin were compared in a rabbit model of experimental thrombosis, where thrombus formation was induced by a combination of endothelial damage and stasis. Both compounds were able to prevent thrombosis completely. However, LHN-1 was significantly less potent than conventional heparin, the ratio between doses with the same antithrombotic effect being 2.4:1 on a weight basis. Bleeding times after administration of LHN-1 and conventional heparin were determined by tail transsection in anaesthetized rats and by template bleeding in the ear of conscious pigs. Given intravenously at a dose ratio of 2.4:1 (w/w), LHN-1 affected APTT less than conventional heparin, whereas the effects on haemostasis were not significantly different. In conclusion, it was found that after intravenous administration LHN-1 prevented experimental thrombosis as effectively as conventional heparin. However, the correlation between antithrombotic and haemorrhagic effects of LHN-1 was the same as that of conventional heparin. The corresponding relation in man remains to be determined.     

Low molecular weight heparin for deep vein thrombosis in glioma patients

The treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism, a common complication in patients with malignant glioma, has remained controversial. We treated 11 patients with malignant glioma and DVT prospectively with low molecular weight heparin (LMWH) at 175 IU/kg for 10 days and then for 3 months at 100 IU/kg. No patient developed bleeding complications or any other severe side effects of LMWH treatment. Two patients had a dose reduction of LMWH to 75 IU/kg because of chemotherapy-induced thrombocytopenia. One patient developed progressive DVT and nonlethal pulmonary embolism on day 14 of LMWH 100 IU/kg. After increasing the dose to 175 IU/kg he had no further recurrence. One patient had recurrence of DVT after a fracture of the leg affected by DVT at 8 months after the diagnosis of DVT and 5 months after the end of LMWH therapy. LMWH therapy may be safe and effective in the treatment and secondary prophylaxis of DVT in patients with malignant glioma. Received: 4 January 2002, Received in revised form: 18 April 2002, Accepted: 23 April 2002 Correspondence to Dr. F. Schmidt     

The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits

In previous studies, we have reported that standard heparin (SH) was cleared by two mechanisms, a saturable mechanism which predominated at low doses (<100 anti-factor Xa U/kg) and a non-saturable mechanism which predominated at higher doses, when the first mechanism became saturated. In this study, we examined the importance of these two mechanisms in the disappearance of a low molecular weight heparin fraction (LMWH) (CY 216), by comparing the pharmacokinetics and the pharmacodyna-mics of a wide range of doses of SH and CY 216 (1.5 to 500 anti-factor Xa U/kg) Pharmacokinetics was measured as the disappearance of ¹²⁵I-radiolabelled SH or CY 216. Pharmacodynamics was measured as the disappearance of the anti-factor Xa activity of SH and CY 216. We found that the saturable mechanism contributed little to the disappearance of CY 216 and that it was cleared predominantly by the non-saturable mechanism at all doses tested. Thus, at low doses (<100 anti-factor Xa U/kg), SH was cleared more rapidly than CY 216, whereas at higher doses, CY 216 was cleared more rapidly than SH. We conclude that the mechanism of disappearance of LMWH's differ significantly from those of SH, and that this difference may explain the apparent prolonged anticoagulant activity of LMWH's within the therapeutic range doses.     

Monitoring of heparin and low molecular weight heparin with capillary and venous whole blood

A method for determination of antifactor Xa-like activity in capillary whole blood obtained from the fingertip is described, which employs the Heptest coagulation assay. Values obtained with capillary whole blood are compared to values of corresponding plasma and venous whole blood samples. Normal values in plasma, venous whole blood, and capillary blood from the fingertip were 17.1 +/- 2.1, 10.0 +/- 1.3 and 10.4 +/- 1.3 sec, respectively. The intraindividual coefficients of variations range from 0.4 to 1.8% in all assays. The day to day coefficient of variation of normal values ranged between 0.8 and 2.0% for all assays. The within assay coefficients of variation ranged from 3.0 to 7.7% for whole blood samples and from 1.5 to 2.2% for plasma samples after addition of no, 0.2 or 1.0 units of normal or LMW heparin to the samples. After administration of heparin or LMW heparin in healthy persons the coagulation values of the different coagulation assay systems displayed coefficients of correlation between r = 0.87 and r = 0.95. Correlation coefficients between the coagulation tests and the S 2222 chromogenic substrate method ranged from r = 0.77 to r = 0.92. In patients, who received LMW heparin for prophylaxis of thromboembolism the coagulation assay correlated between r = 0.78 and 0.92. The coagulation assays and the S 2222 method displayed coefficients of correlation between r = 0.74 and r = 0.83. The data indicate that Heptest sensitively measures antifactor Xa-like activity in capillary whole blood as well as venous whole blood samples containing low quantities of heparin or LMW heparin.     

Laboratory monitoring of thromboprophylaxis with low molecular weight and standard heparin

This study was made to evaluate assays for monitoring of low dose heparin thromboprophylaxis and to evaluate its efficacy in reduction of hypercoagulation. Patients with medical diseases scheduled for routine thromboprophylaxis were subcutaneously treated with either 5.000 anti XaU low molecular weight (LMW) heparin once daily (n=20) or 5.000 IU standard (ST) heparin 3 times daily (n= 19). On days 1,2,3, before, 1 and 4 hours after heparin injection APTT, TCT, anti Xa, Heptest, thrombin-antithrombin complexes (TAT), and D-Dimer levels were measured. In the LMW heparin group, median values of APTT and TCT slightly increased after heparin and the ranges of pre- and postinjection values showed extensive overlap. However, values of anti Xa and Heptest markedly increased, showing complete separation of ranges. In the ST heparin group neither APTT, TCT, anti Xa, nor Heptest were significantly different comparing pre- and postheparin values. Half of the patients in both groups had subclinical hypercoagulation at baseline (TAT>5ng/ml, D-Dimer>200ng/ml). On day 3 of prophylaxis this percentage was not significantly decreased. Moreover, several patients in both groups increased in TAT and D-Dimer. In the LMWheparin group, negative correlations between body weight and 4 h postinjection heparin levels were found (anti Xa R=−0.50, Heptest R=−0.31) and between 1 h postinjection heparin and TAT and D-Dimer levels 3 h later (TAT-anti Xa R=−0.58, TAT-Heptest R=−0.64, D-Dimer-anti Xa R=−0.32, D-Dimer-Heptest R=−0.33). These results show that low dose LMW but not ST heparin therapy can be monitored by the anti Xa test or the Heptest.