Bemiparin: A Low-Molecular-Weight Heparin Antithrombotic Agent

Introduction

Bemiparin is a low molecular weight heparin (LMWH) that has been used in Europe for 10 years (1). It is prescribed for the treatment of acute deep vein thrombosis (DVT), with or without pulmonary embolism (PE). It is also used for the prevention of venous thromboembolism (VTE) in patients undergoing general or orthopedic surgery and for clot prevention in the extracorporeal system during hemodialysis.

European VTE prevention guidelines indicate that 160 people experience DVT and 60 experience PE per 100,000 population per year (2). VTE is also associated with high mortality (3), making thrombosis prevention particularly important for patients at moderate or high risk of VTE. The benefits of unfractionated heparin (UFH) have been confirmed by studies (4). This article reviews the key aspects of using LMWH for long-term VTE prevention and treatment in the general population and specific patient groups, including elderly patients and patients with renal insufficiency.

Properties of Bemiparin

LMWHs are synthesized from UFH by depolymerization, and newer-generation LMWHs, including bemiparin, belong to this group (6). These compounds are characterized by a longer biological half-life and greater selectivity for clotting factor Xa compared with UFH (1).

The main properties of newer-generation LMWHs are a lower molecular weight compared with other LMWHs and UFH (bemiparin 3.6 kDa vs. 4.5 kDa for enoxaparin and 15 kDa for UFH), a higher anti-Xa/anti-IIa activity ratio (bemiparin 8:1 vs. 3.3–5.3:1 for enoxaparin and 1:1 for UFH), and a longer half-life (bemiparin 5.2–5.4 hours vs. 4–4.4 hours for enoxaparin and 0.5–1 hour for UFH) (7).

A higher anti-Xa/anti-IIa activity ratio is achieved because the bemiparin molecule has fewer pentasaccharide chains responsible for thrombin affinity, while this does not affect clotting factor Xa (6, 8). In a study by Da Pozzo et al. (9), bemiparin was found to inhibit angiogenesis in vitro. It is believed that bemiparin also has antioxidant effects (10). In another study, bemiparin reduced subendothelial matrix platelet coverage during blood flow more than dalteparin and UFH (11, 12).

VTE Prevention and Treatment With Bemiparin

Bemiparin is used for VTE prevention and treatment. Clinical studies have compared bemiparin with UFH for the prevention and treatment of VTE.

VTE Prevention in General Surgery

In a multicenter, randomized, double-blind study, bemiparin 2,500 IU/day and UFH 5,000 IU twice daily were compared in patients undergoing abdominal organ surgery with a low or moderate risk of VTE (12). Anticoagulants were administered for 7 days.

There were no cases of VTE, PE, or death in either group, but blood component transfusions were more frequent in the UFH group. Patients in this group also required reoperations due to bleeding more often and had more wound hematomas.

Injection-site hematomas were more frequent and larger in the UFH group than in the bemiparin group. In the bemiparin group, clinically insignificant moderate thrombocytopenia was recorded in one patient. Based on the results of this study, it can be stated that a dose of bemiparin 2,500 IU/day is as effective as UFH for VTE prevention but causes fewer major and minor bleeding events (12).

VTE Prevention in Orthopedic Surgery

Patients undergoing orthopedic surgery are at increased risk of VTE. Navarro-Quilis et al. (13) found that thrombosis prevention with bemiparin is more cost-effective than with enoxaparin in patients undergoing knee arthroplasty.

In this multicenter, controlled, double-blind, randomized study involving 381 patients, bemiparin (3,500 IU, with the first dose administered 6 hours after surgery) was compared with enoxaparin (40 mg, with the first dose administered 12 hours before surgery). Anticoagulants were administered for 10 ± 2 days.

Both drugs were equally effective in terms of the primary outcomes: symptomatic and/or venographically confirmed DVT 10 ± 2 days after surgery, symptomatic PE, and death from any cause. The frequency of VTE in the bemiparin group was 32.1%, compared with 36.9% in the enoxaparin group.

There were no differences in secondary outcomes, including other distal or proximal DVT or PE, or in bleeding episodes. Major and minor bleeding occurred in 3 patients in the bemiparin group and 4 patients in the enoxaparin group. However, injection-site hematomas were more common in the enoxaparin group (32.5% vs. 22.7% in the bemiparin group, p = 0.03).

It has been demonstrated that administering bemiparin 6 hours after surgery is as effective and safe as administering enoxaparin 12 hours before surgery for thrombosis prevention in patients undergoing orthopedic surgery. Furthermore, postoperative administration of bemiparin may reduce the risk of spinal hematoma.

In another prospective, open-label, multicenter study, 7,959 patients were treated during foot immobilization with a cast or during surgical procedures, including knee joint replacement, hip joint replacement, femoral neck surgery after fracture, other limb surgeries, knee arthroscopy, and spinal surgery (14).

For thrombosis prophylaxis, bemiparin was administered for an average of 28 days: 3,500 IU/day to 84.9% of patients and 2,500 IU/day to 15.1% of patients. Symptomatic VTE (DVT or PE), major bleeding, deaths, thrombocytopenia, and other adverse reactions were recorded.

Researchers found a low frequency of VTE (0.91%), rare non-fatal major bleeding (0.17%), a low mortality rate (0.37%), and rare cases of mild to moderate thrombocytopenia (0.51%). Bemiparin dosage, other medications used, age, and obesity did not influence the development of VTE or the frequency of bleeding.

The results showed that 3–4 weeks of thrombosis prophylaxis with bemiparin during leg immobilization or orthopedic procedures in clinical practice is associated with a low risk of DVT, bleeding, and other adverse events.

Acute VTE Treatment With Bemiparin

In a multicenter, prospective, randomized trial conducted by V. Kakkar, the effectiveness of bemiparin and UFH in the acute and long-term treatment of VTE was compared (5). After 14 days, venography showed that bemiparin significantly reduced thrombus size compared with UFH (5). The FLEBUS study (15) confirmed that treatment with bemiparin resulted in a low frequency of recurrent VTE (0.3%), while bleeding occurred rarely (1 major and 3 minor bleeding events – 1.1%). Finally, in the multicenter, prospective cohort study ESFERA, bemiparin was compared with a vitamin K antagonist (VKA) for long-term, 98-day thrombosis prophylaxis. It was found that bemiparin could be a safer and more cost-effective alternative to VKA for long-term DVT treatment (16).

Long-Term VTE Treatment

LMWH is prescribed for long-term VTE treatment in cases where oral anticoagulants are contraindicated. The effectiveness of LMWH and the frequency of bleeding complications are similar to those observed with warfarin (17). Several studies have compared long-term treatment with bemiparin with long-term treatment with UFH (5, 15, 16). It was found that the frequency of recurrent VTE and bleeding after long-term treatment with bemiparin did not differ significantly from that in the control group (5).

Treatment of Specific Patient Populations With VTE

Specific patient populations include elderly patients and those with kidney failure. These patients are rarely included in clinical trials, so reliable evidence on the suitability of medications is often lacking. Clinical trial data show that anticoagulants are often underdosed in elderly patients because of concerns about their comorbidities and general condition (18). Anticoagulants should not be withheld from elderly patients when indicated; instead, the course of treatment should be monitored more closely.

For patients with kidney failure, LMWH and fondaparinux are more strongly recommended than UFH because they cause fewer cases of thrombocytopenia and bleeding (18). Several studies indicate that there is no need to adjust the prophylactic dose of bemiparin in patients with mild to moderate kidney failure, but there are insufficient data on dose adjustment in this patient group. There are also no data on the use of bemiparin in patients with severe kidney failure (19, 20). UFH can be safely used even when creatinine clearance is

Pharmacoeconomic Benefit of Treatment With Bemiparin

Thrombus regression is more pronounced with bemiparin than with UFH when it is prescribed for the treatment of VTE in the acute stage of the disease. Therefore, using a more effective drug may shorten the hospital stay and reduce costs, as each additional day of hospitalization generates expenses.

Several studies have aimed to determine the cost of VTE prophylaxis with bemiparin in surgical patients. The results of one study showed that administering bemiparin 3,500 IU/day after surgery reduces the frequency of bleeding and VTE, thereby shortening the hospitalization period and reducing treatment costs per patient (22). Bonal and colleagues concluded that, in patients undergoing hip joint replacement surgery, reductions in surgical wound complications (p = 0.003) and drainage bleeding frequency (p = 0.046) with bemiparin also reduce costs associated with hospital bed days and medical staff work (23).

Another study confirmed that 6 weeks of thrombosis prophylaxis with bemiparin after knee joint surgery may be more cost-effective than treatment with enoxaparin (24). These results were confirmed by another study, which found that preoperative bemiparin is as effective and safe as postoperative enoxaparin in protecting patients undergoing knee replacement surgery from venous thromboembolism (13).

Conclusion

Bemiparin is an LMWH with certain characteristics that distinguish it from other LMWHs.

Bemiparin is used for the prevention of dangerous blood clots that form in the deep veins of the legs and/or lungs during orthopedic surgery (hip, knee, or other bone surgery), general surgery, as well as during dialysis procedures. It is also used for the treatment of VTE.

Studies show that bemiparin can be administered to elderly patients and those with mild to moderate renal insufficiency. Due to its pharmacokinetic properties, this anticoagulant is administered once daily.

Prepared by Dr. Rasa Geigalienė

Article from the publication "Internistas"

Sources of literature are in the editorial office

LT/Zib/2014/07