Bemiparin: second-generation,low-molecular-weight heparin for treatment and prophylaxis of venous thromboembolism

Low-molecular-weight heparins (LMWHs) form a heterogeneous group of compounds that exhibit an extended range of pharmacodynamic profiles and, potentially, different anti-thrombotic properties. Bemiparin has the lowest MW (3600 Da), the longest half-life (5.3 h) and the highest anti-FXa/anti-FIIa activity ratio (8:1) of any second-generation LMWH. The safety and efficacy of bemiparin has been demonstrated in several studies and it is currently licensed for treatment and prophylaxis of venous thromboembolism (VTE), as well as for the prevention of clotting in the extracorporeal circuit during hemodialysis. In particular, bemiparin is the only LMWH licensed in Europe for starting thromboprophylaxis after either general or orthopedic surgery. Results from multicenter pharmacoeconomic studies in the Spanish Health Care System indicate that bemiparin is more cost effective than enoxaparin for the prevention of VTE in total knee replacement and may be a safe, cost-saving alternative to unfractionated heparin in the short-term treatment of VTE, and a safe cost-neutral alternative to oral anticoagulant therapy in long-term treatment. In the near future, information from ongoing clinical trials could be key to establishing the potential of bemiparin in different clinical settings.     

New challenges for a second-generation low-molecular-weight heparin: focus on bemiparin

Bemiparin is a second-generation low-molecular-weight heparin (LMWH) that has the lowest molecular weight, the longest half-life and the highest anti-Factor Xa/anti-Factor IIa activity ratio. The safety and efficacy of bemiparin has been demonstrated in several studies and currently it is licensed for the treatment and prophylaxis of venous thromboembolism (VTE), as well as for the prevention of clotting in the extracorporeal circuit during hemodialysis. Multicenter pharmacoeconomic studies carried out in the Spanish National Health system indicate that bemiparin is more cost effective than enoxaparin for the prevention of VTE in total knee replacement. Interestingly, recent results suggest that bemiparin could be useful as an adjuvant treatment in the management of lower-extremity diabetic ulcers. Since international guidelines recommend LMWHs for initial and continuous anticoagulant treatment in cancer patients with VTE, as well as for its prevention, results from ongoing trials could be critical to establish the potential of bemiparin in oncological patients. Finally, the pharmacokinetics of two oral bemiparin formulations are currently being analyzed in a Phase I trial.     

Current strategies in prophylaxis and treatment of venous thromboembolism

During the past two decades well designed randomized controlled trials have addressed every important aspect of prophylaxis against venous thromboembolism (VTE) and treatment of established VTE. In addition, systematic reviews and meta-analyses have been performed in most of these areas. The most important advances are the widely accepted and effective VTE prophylaxis in major orthopedic surgery and the shift from in-hospital to outpatient treatment of a majority of patients with established VTE. The major hurdles at this point are efficient selection of the appropriate medically ill patients for prophylaxis and the inconvenience of long-term secondary prophylaxis with vitamin K antagonists. Although new, orally available anticoagulants without need for monitoring or dose adjustments have been in clinical trials for a decade, none is approved yet, and will not be discussed in this review.     

Strategies for venous thromboembolism prophylaxis programs

Prevention of venous thromboembolism (VTE) is often overlooked in clinical practice, despite being a frequent and serious complication of various medical conditions and surgical procedures. The need to reduce hospital-acquired VTE is becoming increasingly recognized in the United States, and various quality-improvement initiatives have been developed. Prevention of VTE through evidence-based, practice-informed pathways includes assessing the patient's risk of VTE and provision of VTE at different stages: at admission, during hospitalization, and after hospital discharge. A multidisciplinary approach, involving physicians working with pharmacists, nurses, and other staff, can ensure that VTE prevention is routinely addressed. Patients admitted to hospitals should undergo VTE risk assessment, and the appropriate dose, type, and duration of medication should be administered with regular monitoring for VTE events and bleeding complications. Venous thromboembolism risk assessment should continue throughout hospitalization with appropriate prophylaxis when necessary. Patients may need to continue anticoagulation into the outpatient setting to achieve adequate prophylaxis duration. Useful approaches to ensure successful transition of care include patient education and support, with the accurate and timely transfer of information from the hospital to the primary care physician. Various strategies and tools are available to help physicians establish good VTE practices at each stage, including risk assessment models, reminders, clinical decision support systems, educational programs, and online resources, such as those from the Society of Hospital Medicine. Effective use of these strategies by physicians, with the engagement and support of nurses and pharmacists, should help to improve current practices and to reduce the considerable burden of VTE.     

Low-molecular-weight heparin, bemiparin, in the outpatient treatment and secondary prophylaxis of venous thromboembolism in standard clinical practice: the ESFERA Study

The objective of this study is to assess the clinical and economic outcomes associated with outpatient treatment and secondary prophylaxis of acute venous thromboembolism (VTE) with a low-molecular-weight heparin, bemiparin. This study was designed as an open-label, multicentre, prospective, cohort study in standard clinical practice. Sixty-three investigators from 54 Spanish centres participated in the study. Five hundred eighty-three patients (434 outpatients and 149 inpatients) with acute VTE were followed up for 98 days (median). Outcome measures were costs and adverse events during initial VTE treatment with bemiparin (outpatient vs. inpatient cohorts) and long-term treatment [bemiparin (BEM) vs. vitamin K antagonists (VKA) cohorts]. Mean total costs per patient were lower in the outpatient cohort as compared with those in the inpatient cohort (1206 vs. 5191 euros; difference = -3985 euros; p < 0.001), with similar rates of adverse events (5.1 outpatient vs. 7.4% inpatient; p = 0.196) over 98 days. Mean total costs per patient were similar in the BEM/BEM and BEM/VKA cohorts (3616 vs. 3831 euros; difference = -215 euros; p = 0.412), but patients on long-term bemiparin treatment had lower rates of major bleeding (0.4 vs. 1.7%; p = 0.047), minor bleeding (1.8 vs. 6%; p = 0.032) and total adverse events (2.9 vs. 9.5%; p = 0.007) than patients in the BEM/VKA cohort. Outpatient management of VTE with bemiparin in selected patients resulted in significant cost-savings compared to inpatient treatment, while maintaining effectiveness and safety. Bemiparin may be a safer and cost-neutral alternative to VKA for long-term treatment of VTE.     

Secondary prophylaxis of venous thromboembolism

Making decisions about any modality of secondary prophylaxis in patients with venous thromobembolism (VTE) has to balance the risk of bleeding induced by anticoagulants against the benefit of reducing the risk of recurrent disease. It has to be kept in mind that the magnitude of risk is not only defined by the number of events per time period but also by the impact of the event on the fate of the patient. With standard intensity vitamin K antagonists (VKA), the risk of bleeding is more closely related to comorbidities than to other factors, eg age. The risk of VTE recurrence differs largely between patient groups. The criterion of presence or absence of a permanent or transient clinical trigger factor for the actual VTE episode has a greater impact than an abnormal result in thrombophilia testing. The standard period of secondary prophylaxis for proximal DVT and for PE is three to six months. The concept of prolonging this period for several months according to the risk of recurrence is seriously challanged by the observation that the prolongation period seems to delay recurrencies rather than truly avoiding them. For this reason, patients who clearly are threatened by recurrent episodes should receive indefinitive secondary prophylaxis. This is the case for cancer patients, patients with the antiphospholipid syndrome, and those who belong to families with severe and symptomatic protein C, protein S, or antithrombin deficiencies. Patients with recurrent VTE, with idiopathic VTE, or with combined thrombophilic conditions may only benefit from indefinitive secondary prophylaxis if the bleeding risk of the anticoagulant regimen under consideration is very low.     

Primary and secondary prophylaxis of venous thromboembolism with low-molecular-weight heparins: prolonged thromboprophylaxis, an alternative to vitamin K antagonists

Low-molecular-weight heparins (LMWHs) are used widely in the treatment and prevention of venous thromboembolism (VTE). The LMWHs dalteparin and enoxaparin reduce the rate of VTE by at least 50% if administered for 4-5 weeks following major orthopedic surgery, compared with in-hospital prophylaxis for 7-15 days. Meta-analyses have confirmed that the size of the reduction is similar for both clinical and asymptomatic VTE. Vitamin K antagonists (VKAs) have been shown to be associated with significantly higher bleeding rates compared with LMWH when used as prolonged prophylaxis against VTE following major orthopedic surgery. Patients with cancer are a recognized group at high risk of VTE, and those undergoing major surgery for their malignancy are at particular risk. Evidence from clinical trials is amassing to show that prolonged prophylaxis with LMWH (dalteparin, enoxaparin) in these patients can significantly reduce the rate of postoperative VTE. In cancer patients with acute VTE, the traditional approach is to initiate acute treatment with unfractionated heparin or LMWH followed by long-term treatment with VKA to prevent recurrence. However, clinical trial data have confirmed that the LMWH dalteparin, when administered for 6 months, is significantly more effective than VKA in preventing recurrence, cutting the rate of VTE by 52% without increasing the risk of bleeding. A new and intriguing area of interest is whether LMWH can enhance survival in patients with cancer. Preliminary data suggest that a biological effect of LMWH may act to prolong survival in patients with cancer.     

Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study.

INTRODUCTION: Secondary prevention of venous thromboembolism (VTE) with vitamin K antagonists is often problematic in patients with cancer. We prospectively evaluated the effectiveness and safety of long-term subcutaneous dalteparin in a series of consecutive patients with symptomatic VTE and metastatic cancer. PATIENTS AND METHODS : The study included 203 patients, aged 36-96 years. The initial treatment consisted of a 7-day course of subcutaneous dalteparin according to body weight. Then, patients received a fixed dose of 10 000 IU dalteparin once daily for at least 3 months. In patients developing transient thrombocytopenia the dose was reduced to 5000 IU daily while the platelet count remained <50,000; and to 2500 IU daily while it remained <10 000. Patients undergoing any surgical intervention during the study were put on 5000 IU daily during the first 4 days, switching thereafter to 10,000 IU. Patients undergoing any other invasive procedure (i.e. biopsies, punctures) received a 5000 IU dose the same day, instead of 10 000 IU. RESULTS: Eleven patients (5.4%) developed major bleeding complications (6 fatal) during the 3-month study period, and 18 patients (8.9%) developed VTE recurrences (2 patients died). There were no higher complication rates in patients with either liver or brain metastases, nor during thrombocytopenia, surgery or invasive procedures. CONCLUSIONS: Fixed dose 10,000 IU subcutaneous dalteparin once daily for 3 months was not associated with more complications in patients with liver or brain metastases. The dose adjustment for patients with thrombocytopenia, surgery or invasive procedures was safe too.     

Efficacy of unfractionated heparin for thromboembolism prophylaxis in medical patients

A common mode of deep vein thrombosis prophylaxis in medical inpatients is unfractionated heparin 5000 U subcutaneously (s.q.) twice daily. We examined the evidence in favor of using this dose of heparin in this group of patients. MEDLINE was searched for studies using the words deep vein thrombosis prophylaxis and heparin. All randomized controlled trials comparing heparin and placebo or heparin and a low molecular weight heparin were used. Relative risk was 0.4 (95% confidence interval 0.22-0.73) in studies comparing heparin 5000 U s.q. b.i.d. with placebo. Relative risk was 0.28 (95% confidence interval 0.21-0.38) in studies comparing heparin 5000 units s.q. t.i.d. versus placebo. In studies comparing unfractionated heparin with enoxaparin relative risk was 1.42 (95% confidence interval 0.99-2.05). Heparin 5000 U s.q. b.i.d. is less efficacious than low molecular weight heparins and unfractionated heparin 5000 U s.q. t.i.d.     

An overview of venous thromboembolism: impact, risks, and issues in prophylaxis

Venous thromboembolism (VTE) is a major cause of cardiovascular death, and its close association with increased age portends an increasing clinical and economic impact for VTE as the US population ages. Studies show that rates of VTE prophylaxis remain inadequate both in the hospital and at the time of discharge. Health care accreditation and quality organizations are taking interest in VTE risk assessment and prophylaxis as a measure for hospital performance ratings and even reimbursement. To set the stage for the rest of this supplement, this article reviews the rationale for VTE prophylaxis, surveys current prophylaxis rates and strategies to increase those rates, and provides an overview of risk factors for VTE and therapeutic options for VTE prophylaxis.     

Utilization of low-molecular-weight heparin prophylaxis in pediatric and adolescent trauma patients

The objective of this study was to use trauma registry data to describe the number and characteristics of patients 21 years or younger receiving thromboprophylaxis with low-molecular-weight heparin at 2 pediatric and 2 adult level 1 trauma centers. Among 706 patients, the average age was 18.5 years, and 94.6% were hospitalized at adult centers. The most common injuries were lower extremity fractures (35.6%) and head injuries (20.4%). Major bleeding was reported in 3 patients (0.4%), and thrombotic events were reported in 15 patients (2.1%). Despite a lack of scientific evidence, low-molecular-weight heparin prophylaxis is being used in young trauma patients (primarily those 14 years or older). Prospective multicenter studies are needed to accurately describe the risks and benefits of low-molecular-weight heparin prophylaxis in young trauma patients, thereby identifying those who truly benefit from this intervention.     

Ximelagatran for treatment of venous thromboembolism

Acute venous thromboembolism including asymptomatic and symptomatic pulmonary embolism without respiratory or cardiac failure is currently treated for 6 months, initially with subcutaneous low-molecular-weight heparin followed by oral anticoagulation. The main drawback of oral anticoagulation is caused by severe bleeding complications. Oral Ximelagatran has shown to be as effective and safe for the initial treatment of acute deep venous thrombosis compared to subcutaneous low-molecular-weight heparin followed by oral warfarin over a period of 4 weeks. Currently, oral ximelagatran is investigated versus subcutaneous low-molecular-weight heparin and oral warfarin over 6 months to demonstrate an almost equal efficacy and safety. The study is performed on a double blind and double dummy basis. Six months after oral anticoagulation of patients with acute deep venous thrombosis, recurrent venous thromboembolism may occur in up to 25% within 2 years. Ximelagatran is currently investigated versus placebo to demonstrate a reduced recurrence rate of venous thromboembolism over a period of 18 months.     

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer

Summary. Background: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. Objectives: To establish a common international consensus addressing practical, clinically relevant questions in this setting. Methods: An international consensus working group of experts was set up to develop guidelines according to an evidence‐based medicine approach, using the GRADE system. Results: For the initial treatment of established VTE: low‐molecular‐weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case‐by‐case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long‐term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3–6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit‐risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12–2 h preoperatively and continued for at least 7–10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l ‐asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low‐dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl < 30 mL min^?1), thrombocytopenia and pregnancy. Guidances are provided in these contexts. Conclusions: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.