, Volume 63, Issue 21, pp 2357–2377


A Review of its Use in the Prevention of Venous Thromboembolism and Treatment of Deep Vein Thrombosis
Adis Drug Evaluation



Bemiparin (bemiparin sodium; Hibor®, Ivor®, Zibor®, Badyket®) is a low molecular weight heparin (LMWH) with a lower mean molecular weight (3600D) and a higher anti-Xa/IIa ratio (8:1) than other LMWHs.

Bemiparin was effective as thromboprophylaxis in surgical patients in well controlled clinical trials. No cases of venous thromboembolism (VTE) were reported in low- to moderate-risk patients receiving prophylaxis with bemiparin 2500 anti-Xa IU/day for 7 days or unfractionated heparin (UFH) 5000 anti-XaIU twice daily for 7 days. In high-risk patients, bemiparin 3500 anti-Xa IU/day for ≥8 days was more effective than UFH 5000 anti-XaIU twice daily for ≥8 days in the prevention of VTE in patients undergoing total hip replacement. Postoperative bemiparin 3500 anti-Xa IU/day for 10 days was as effective as enoxaparin 4000 anti-Xa IU/day for 10 days commenced 12 hours before surgery in high-risk patients undergoing total knee replacement.

As a short-term treatment for acute established deep vein thrombosis (DVT), bemiparin 5000–10 000 anti-Xa IU/day (dependent on bodyweight) for 7 or 10 days was more effective than intravenous UFH (5000 anti-XaIU bolus followed by 30 000 or 40 000 anti-Xa IU/day for 7 days) in reducing thrombus size from baseline. Bemiparin 3500 anti-Xa IU/day was also as effective as oral warfarin (10 mg/day for the first 3 days, then adjusted to achieve an international normalised ratio between 2 and 3) for the long-term (12 weeks) treatment of DVT, although data are limited.

Subcutaneous bemiparin was generally well tolerated. The most commonly reported adverse events in clinical trials were postoperative bleeding complications (similar incidence to that with UFH or enoxaparin in high-risk patients, lower incidence in low- to moderate-risk patients).

Conclusions: Bemiparin is a new LMWH which has shown efficacy in a small number of well controlled trials in the prevention of postoperative VTE in low- to moderate- and high-risk patients and in the treatment of established DVT. It can be initiated pre- or post-operatively, whereas recommendations for other LMWHs in Europe primarily involve preoperative initiation. Additional comparative studies would be beneficial in determining the overall place of bemiparin, particularly with respect to the relative incidence of bleeding complications. In the meantime, available data suggest that bemiparin is an effective and useful addition to the available range of LMWHs for the prevention of VTE and treatment of DVT.

Pharmacodynamic Properties

Bemiparin is obtained by the chemical depolymerisation (β elimination) and fractionation of porcine mucosal unfractionated heparin (UFH). With a mean molecular weight of 3600D and approximately 85% of its polysaccharide chains under 6000D, bemiparin has been referred to as a ‘second-generation’ low molecular weight heparin (LMWH).

Bemiparin has anti-Xa activity of 80–120 IU/mg and an anti-IIa activity of 5–20 IU/mg. The anti-Xa/IIa ratio of approximately 8: 1 is higher than that of other LMWHs, including enoxaparin (3.8: 1), dalteparin (2.7: 1), reviparin (3.5: 1) and tinzaparin (1.9: 1). It is thought that the high anti-Xa/IIa ratio of bemiparin may lead to greater antithrombotic activity without increasing the risk of bleeding.

In healthy volunteers and patients at risk of venous thromboembolism (VTE), subcutaneous bemiparin significantly increased anti-Xa activity; however, anti-IIa activity and levels of antithrombin were generally not affected. The anti-Xa activity of bemiparin was reduced by protamine sulfate.

In vitro, bemiparin, dalteparin and UFH significantly increased the expression, release and activity of tissue factor pathway inhibitor (TFPI) in static endothelial cells to similar extents. However, in endothelial cells under arterial shear stress in vitro, bemiparin increased the secretion and cell surface activity of TFPI while UFH and dalteparin did not increase the production of TFPI.

Bemiparin, UFH, enoxaparin and nadroparin all reduced mean red cell aggregability to a similar extent.

Bemiparin does not appear to have any clinically significant effect on the activated partial thromboplastin time and the thrombin time. The effects of bemiparin on the production of tissue-plasminogen activator (t-PA) in human umbilical vein endothelial cells (HUVECs) in vitro was similar to that of control cells. In contrast, UFH induced a 3-fold increase in t-PA. Bemiparin and UFH increased levels of the inhibitor of t-PA (plasminogen activator inhibitor-1) in HUVECs in vitro to a similar extent. However, unlike UFH, bemiparin had no effect on the production of tissue factor in HUVECs in vitro.

Bemiparin suppressed markers of hypercoagulability (e.g. D-dimer, thrombin-antithrombin complexes and factor VII:c) and increased levels of protein C in 100 patients with congestive heart failure.

In vitro the binding of bemiparin to dead leucocytes was lower than that of UFH. In addition, heparin binding proteins were less effective at blocking the antithrombin activity of bemiparin than that of UFH.

Pharmacokinetic Profile

After a single subcutaneous administration of bemiparin 2500–12 500 anti-XaIU to healthy volunteers the anti-Xa activity increased in a dose-dependent manner; however, maximum anti-Xa activity (Emax) was reached within 2–6 hours, regardless of dose. Subcutaneous bemiparin had high bioavailability in healthy volunteers and the mean volume of distribution of anti-Xa after intravenous administration of bemiparin 5000 anti-XaIU to healthy volunteers was 5.1L.

Bemiparin undergoes linear elimination via the renal route. A single dose of subcutaneous bemiparin 2500–12 000 has a long elimination half-life (4–5 hours) and MRT (>7 hours). The mean total clearance of anti-Xa activity after intravenous administration of bemiparin to healthy volunteers was 0.90 L/h (15.5 mL/ min).

The pharmacokinetic profile of bemiparin 3500 anti-XaIU was generally similar to that of enoxaparin 4000 anti-XaIU; however, the area under the effect-time curve was significantly greater after administration of bemiparin than enoxaparin (3.78 vs 3.42 IU · h/mL; p < 0.05). Bemiparin 3500 anti-XaIU exerted a significantly more rapid and greater anti-Xa activity than tinzaparin 4500 anti-XaIU (p < 0.005 for all comparisons).

Establishing the pharmacokinetic profile of the TFPI effect is important because potent anticoagulant synergism results in vitro when both the anti-Xa amidolytic and TFPI effects occur simultaneously. The effect of bemiparin on the release of TFPI was not dose dependent. The Emax of the TFPI effect was reached earlier than the Emax of the anti-Xa effect after subcutaneous administration of bemiparin 2500–12 500 anti-XaIU to healthy volunteers. Bemiparin and enoxaparin had a similar effect on the release of TFPI; however, the Emax of the TFPI effect was significantly lower after administration of bemiparin than after tinzaparin in healthy volunteers (94.05 vs 128.92 ng/mL; p < 0.01).

Clinical Efficacy

The efficacy of subcutaneous bemiparin in the prevention of venous thromboembolism (VTE) in low- to moderate-patients after abdominal surgery or high-risk patients after orthopaedic surgery has been established in three randomised, double-blind, multicentre comparative trials with UFH or enoxaparin and three noncomparative trials.

Subcutaneous bemiparin provided effective prophylaxis for the prevention of VTE in both low- to moderate-risk and high-risk patients undergoing surgery. In low- to moderate-risk patients undergoing abdominal surgery, the efficacy of bemiparin 2500 anti-Xa IU/day administered for 7 days with the first dose administered 2 hours prior to surgery was similar to that of subcutaneous UFH 5000 anti-XaIU twice daily also for 7 days. However, in high-risk patients undergoing hip replacement, bemiparin 3500 anti-Xa IU/day for >8 days was more effective than UFH 5000 anti-XaIU twice daily for the same duration in the prevention of VTE, with fewer bemiparin recipients experiencing VTE or deep vein thrombosis (DVT). Furthermore, in an extended follow-up (56 days after surgery) in this trial, only one patient receiving bemiparin experienced a VTE event; in the same period four UFH recipients developed a VTE event.

Bemiparin 3500 anti-XaIU for 10 ± 2 days with the initial dose administered postoperatively (6 hours after surgery) was as effective for the prophylaxis of VTE as enoxaparin 40 mg/day for 10 ± 2 days commenced preoperatively (12 hours prior to surgery) in high-risk patients, 94% of whom underwent neuraxial blockade; however, this trial was not powered to demonstrate statistical superiority of one regimen over another.

The results of noncomparative studies in moderate- or high-risk patients supported data reported in the comparative studies.

In a randomised, nonblind, multicentre trial, bemiparin had better efficacy than UFH in the immediate treatment of acute established DVT. Significantly more patients receiving bemiparin (500 anti-Xa IU/day if bodyweight <50kg, 7500 anti-Xa IU/day if bodyweight 50–70kg and 10 000 anti-Xa IU/day if bodyweight >70kg) for 7 or 10 days experienced venographic reduction in thrombus size between baseline and day 14 than those receiving UFH (a 5000 anti-XaIU bolus followed by a continuous infusion of 40 000 anti-Xa IU/day in patients at low risk of bleeding and 30 000 anti-Xa IU/day in patients at high risk of bleeding) for 7 days (72%, 72% and 52%, respectively; p < 0.005 for both comparisons), as assessed by Marder score. However, there was no significant difference between the treatment groups for the long-term (12 week) treatment of DVT, as assessed by the percentage of patients with partial or complete recanalisation of the involved veins and the incidence of recurrent VTE events.


Clinical trials have shown that subcutaneous bemiparin is well tolerated when used for the prophylaxis of VTE or treatment of DVT. Bleeding complications including blood loss, wound haematomas and haematomas at the injection site were the most common adverse events in clinical trials.

In high-risk patients, bemiparin was associated with a similar incidence of major bleeding complications to that of UFH. Similarly, the incidence of major or minor bleeding complications associated with postoperative bemiparin was similar to that of enoxaparin with the initial dose administered preoperatively. However, the incidence of haematoma and other local reactions at the injection site was significantly lower in patients receiving bemiparin compared with enoxaparin recipients (22.7% vs 32.5%; p = 0.03). Of note, no neuraxial complications were reported for patients receiving postoperative bemiparin and enoxaparin started preoperatively with neuraxial blackade.

In low- to moderate-risk patients, no major bleeding events were reported with bemiparin prophylactic therapy; however, 3.7% of patients receiving UFH experienced required transfusion with more than two units of red blood cells and 2.4% required reoperation because of major bleeding events. The incidence of wound haematoma (6% vs 18%; p = 0.015) and the mean number and size of haematomas at the injection site (data not reported; p = 0.004 and p = 0.017) were significantly lower in patients receiving bemiparin than in UFH recipients.

In patients receiving treatment for established DVT, the incidence of major or minor bleeding complications was similar for patients receiving short-term UFH plus long-term warfarin, short-term bemiparin plus long-term warfarin or long-term bemiparin (time of assessment not reported).

The total incidence of unspecified adverse events was similar for patients receiving bemiparin, UFH or enoxaparin in high-risk patients.

In comparative trials, bemiparin prophylaxis generally did not result in any significant changes to haematological or biochemical parameters. Platelet counts were similar between bemiparin and its comparators. In one trial, a mild and transient decrease in platelet count was reported in 3.2% of high-risk patients receiving bemiparin and 2.6% of enoxaparin recipients. In another trial, 2.0%, 1.9% and 3.2% of patients receiving UFH plus long-term warfarin, short-term bemiparin plus long-term warfarin and long-term bemiparin as treatment for established DVT experienced heparin-induced thrombocytopenia. However, none of these patients developed further thrombotic or bleeding complications.

Pharmacoeconomic Considerations

Data from a cost-analysis and cost-minimisation evaluation of a small prospective, nonrandomised pharmacoeconomic study from a Spanish institutional perspective suggest that although bemiparin has a lower acquisition cost than that of other LMWHs (enoxaparin or dalteparin) [4589 vs 10 174 pesetas; p < 0.0001, 1 peseta ≈ 0.006 Euro] there were no significant differences between treatment groups for total costs, hospitalisation costs, costs of other treatments or outpatient prophylaxis (currency year not reported).

Results of a cost-minimisation analysis showed that treatment with bemiparin resulted in a mean saving of 2146–5585 pesetas per patient when only drug costs were considered (significance not reported) and a mean cost saving of 13 601–33 471 pesetas per patient when total costs were considered; however, this was not significant.

Dosage and Administration

Bemiparin is approved in a number of European countries for the prevention of VTE in patients undergoing general surgery (moderate-risk patients) or orthopaedic surgery (high-risk patients) and for the treatment of established DVT. It is recommended that bemiparin be administered by subcutaneous injection via the abdomen. Bemiparin should not be administered intramuscularly.

Patients at moderate risk of postsurgical VTE should receive subcutaneous bemiparin 2500 anti-Xa IU/day and patients at high risk should receive 3500 anti-Xa IU/day until they are completely mobile. The first dose should be administered 2 hours before surgery or within 6 hours after surgery.

The dosage of bemiparin for the treatment of acute established DVT is dependent on the patient’s bodyweight (5000 anti-Xa IU/day if body weight <50kg; 7500 anti-Xa IU/day if bodyweight 50–70kg; 10 000 anti-Xa IU/day if bodyweight >70kg).

Caution should be exercised when bemiparin is to be administered to patients with uncontrolled hypertension, increased risk of bleeding, ulceration of the stomach or intestine, acute bacterial endocarditis, cerebral vascular accident or renal or hepatic impairment. There have been no clinical studies on bemiparin in pregnant or lactating women.


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© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 1311New Zealand

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