A pharmacologic overview of current and emerging anticoagulants

For over 50 years, anticoagulant options for the treatment and prevention of thrombosis have been limited mainly to traditional agents such as unfractionated heparin and oral vitamin K antagonists such as warfarin. These traditional agents are fraught with limitations that complicate their clinical use. A variety of novel anticoagulants with improved pharmacologic and clinical profiles have recently been introduced or are in development, offering benefits over traditional therapies. Specifically, progress has been made in the development of low-molecular-weight heparins, factor Xa inhibitors, and direct thrombin inhibitors. Because of their convenience and ease of use, some of these novel compounds are competing with the traditional anticoagulants and are needed additions to the antithrombotic arsenal.     

Low-molecular-weight heparin in outpatient treatment of DVT

Patients with a diagnosis of acute deep venous thrombosis have traditionally been hospitalized and treated with unfractionated heparin followed by oral anticoagulation therapy. Several clinical trials have shown that low-molecular-weight heparin is at least as safe and effective as unfractionated heparin in the treatment of uncomplicated deep venous thrombosis. The use of low-molecular-weight heparin in an outpatient program for the management of deep venous thrombosis provides a treatment alternative to hospitalization in selected patients. Use of low-molecular-weight heparin on an outpatient basis requires coordination of care, laboratory monitoring, and patient education and participation in treatment. Overlapping the initiation of warfarin permits long-term anticoagulation. Advantages include a decreased incidence of heparin-induced thrombocytopenia and fewer episodes of bleeding complications. Future clinical trials evaluating the safety and efficacy of low-molecular-weight heparin in the treatment of complicated deep venous thrombosis will further define appropriate indications for use and strategies for outpatient management.     

Recent advances in search of oral heparin therapeutics

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are first choices of clinicians among available anticoagulants. Currently, these agents are administered either parenterally or subcutaneously, which reduces patient compliance and acceptability. Oral heparin may serve as an alternative to both parenteral heparin as well as presently available oral anticoagulants such as warfarin. This review focuses mainly upon recent perspectives in the development of heparin as an oral anticoagulant. The possibility of its success with special emphasis to nanotechnological approaches has been elaborated. Important strategies such as the use of penetration enhancers, the development of lipid conjugates of heparin, and the incorporation of heparin in polymeric matrix systems have been discussed. Additionally, introductory information on biological activities, physiochemical aspects, and pharmacokinetic and pharmacodynamic parameters of heparin is summarized. A brief comparison of UFH and LMWH is also included for reader's benefit. Informative discussion on clinical trials with the successes and limitations of oral heparin formulations is also presented. Overall, the present review provides complete insight to the research that has been carried out for the development of heparin as oral anticoagulant.     

Venous thromboembolism prevention with LMWHs in medical and orthopedic surgery patients

OBJECTIVE: To discuss the role of low-molecular-weight heparins (LMWHs) in the prevention of venous thromboembolism (VTE) in medical and orthopedic surgery patients. VTE prophylaxis trials in these practice settings establishing the current use of LMWHs marketed in the US are included. An overview is also provided of VTE incidence, risk factors, and prophylaxis consensus guidelines. DATA SOURCES AND STUDY SELECTION: Clinical trials, review articles, and meta-analyses for Food and Drug Administration-approved LMWHs were identified from a MEDLINE search (1980-March 2002). Search terms included dalteparin, enoxaparin, internal medicine, low-molecular-weight heparin, orthopedic surgery, risk factors, tinzaparin, and venous thromboembolism. DATA SYNTHESIS: Consensus guidelines are useful as an initial guide to appropriate VTE prophylaxis; however, a review of the primary literature is needed to identify optimal agents, regimens, or interventions. LMWHs have demonstrated sound efficacy in VTE prevention; however, the quantity and quality of literature are not always comparable for the available agents. CONCLUSIONS: Enoxaparin has demonstrated efficacy and safety in VTE prevention in medical patients, whereas information is limited or lacking for dalteparin and tinzaparin. Total hip replacement (THR) trials have been conducted with all US-marketed LMWHs and have demonstrated the efficacy and safety of each agent. Trials specifically establishing the efficacy of an LMWH in total knee replacement surgery (TKR) have been published for enoxaparin. One combination THR and TKR trial has been published for tinzaparin. These trial outcomes have positioned the LMWHs as key alternatives to adjusted-dose warfarin for VTE prophylaxis in orthopedic surgery. Inherent differences between LMWHs prevent the extrapolation of clinical outcomes from 1 trial to another.     

New blood thinner offers first potential alternative in 50 years: ximelagatran

Traditional anticoagulants employed in the treatment of thrombosis include the injectable heparins and oral warfarin. Though effective, these traditional agents are fraught with limitations in their ease of use in the clinical setting. Warfarin, for example, has many pharmacokinetic properties and food-and-drug interactions that result in unpredictable patient response and the need for expensive and time-consuming monitoring of coagulation status. Ximelagatran is a novel, promising, orally active, direct thrombin inhibitor currently in development that, for the first time in 50 years, offers a potential alternative to the mainstay oral agent "warfarin." Advantages of ximelagatran over warfarin include predictable pharmacokinetics and pharmacodynamics, a broad therapeutic window, no routine anticoagulant monitoring, no clinically significant drug interactions, and fixed-dose administration. Ximelagatran has been evaluated for thromboprophylaxis following orthopedic surgery, acute treatment and secondary prevention of venous thrombosis, stroke prevention in atrial fibrillation, and acute coronary syndromes. Results of clinical trials suggest that ximelagatran is equally or more efficacious than warfarin and/or low-molecular-weight heparin therapy without increasing rates of minor or major bleeding. Although postmarketing surveillance will provide the final test of this drug, the future looks promising for addition of a new anticoagulant with the potential to provide excellent efficacy, predictable response, and reduced adverse effects. Pending regulatory approval, ximelagatran may help overcome barriers to appropriate anticoagulant therapy, thereby decreasing morbidity and mortality associated with thrombotic diseases.     

Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism

Background

The prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available.

Methods

MEDLINE and EMBASE databases were searched to identify relevant original articles.

Results

Low-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding.

Conclusions

Parenteral anticoagulants should be prescribed in accordance with recommended dose regimens for each clinical indication, based on the available clinical evidence for each agent to assure optimal safety and efficacy.     

Successful anticoagulation with dalteparin in a patient with mechanical heart valves

BACKGROUND: Standard thromboprophylaxis of patients with mechanical heart valves is achieved using warfarin. In certain patients this may be very difficult; thus, alternative pharmacotherapy must be used. OBJECTIVE: To report a case of a patient who successfully used dalteparin, a low-molecular-weight heparin, for anticoagulation. CASE SUMMARY: A 58-year-old white woman with mechanical aortic and mitral heart valves initially received warfarin for anticoagulation. Thromboprophylaxis was very challenging. Her international normalized ratios (INRs) were erratic and occasionally responded paradoxically to changes in dose. Finally, she experienced a left hemispheric stroke when her INR was extremely subtherapeutic. Subsequently, despite best efforts, her INR again was subtherapeutic; warfarin was discontinued and dalteparin was initiated with daily self-administered subcutaneous injections of 16 000 units. No complications have arisen since initiation of the new pharmacotherapy approximately 18 months ago. DISCUSSION: The use of low-molecular-weight heparin for the treatment and prevention of venous thromboembolism is well described. There are few reports of its use for thromboprophylaxis of patients with mechanical heart valves. Our patient has been managed successfully with dalteparin. CONCLUSIONS: Dalteparin was effectively and safely used for the thromboprophylaxis of a patient with mechanical heart valves whose anticoagulation was previously difficult to manage with warfarin. Dalteparin deserves further study in patients who are unable to tolerate warfarin.     

Extended duration of thromboprophylaxis in acutely ill medical patients: optimizing therapy?

Summary. Patients who are hospitalized for an acute medical illness are at risk of venous thromboembolism (VTE). Current evidence-based guidelines recommend prophylaxis with unfractionated heparin or low-molecular-weight heparin in acutely ill medical patients who are admitted to hospital with congestive heart failure, severe respiratory disease, or who are bedridden with an additional VTE risk factor. The need for thromboprophylaxis is therefore clear in this patient population; however, the optimal duration of prophylaxis in these patients is less clear. In patients undergoing orthopedic or cancer surgery, extended-duration prophylaxis has been shown to be superior to placebo. To date, however, no large-scale clinical trials have assessed the benefits of extended-duration prophylaxis in acutely ill medical patients. This review therefore focuses on the VTE risk profile of acutely ill medical patients, examines the currently available literature for evidence of a potential benefit of extended-duration prophylaxis in these patients, and provides a rationale for the testing of such a hypothesis in a randomized clinical trial.     

LMWH for perioperative anticoagulation in patients on chronic warfarin therapy

OBJECTIVE: To review current data regarding low-molecular-weight heparin (LMWH) use for perioperative anticoagulation in patients receiving chronic warfarin therapy. DATA SOURCES: Data were obtained from the Sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy guidelines and a MEDLINE search (1996-January 2003). Search terms included heparin, low-molecular-weight heparin, warfarin, perioperative care, and anticoagulants. DATA SYNTHESIS: Heparin is the most common agent used as bridge therapy for perioperative anticoagulation in patients on chronic warfarin therapy; LMWHs are also used. Studies that evaluated enoxaparin and/or dalteparin were reviewed. CONCLUSIONS: Although published studies demonstrate efficacy and safety of LMWHs, more data are needed to support their use as bridge therapy.     

抗Ⅹa活性检测在抗凝治疗中的临床应用现状与前景

随着检测技术的进步,临床中各种疾病伴随血栓的检出率越来越高.普通肝素和低分子量肝素是目前临床应用较多的注射用抗凝剂,其中普通肝素的半衰期短、无肾毒性、有拮抗剂;低分子量肝素半衰期较长,需在一些特殊人群如儿童、孕妇、老人中进行监测.口服抗凝剂中,除华法林等传统药物外,靶向活化凝血因子Ⅹa的抗凝药物如利伐沙班亦越来越多地应...     

Anticoagulation management in the ambulatory surgical setting

Many people receiving maintenance anticoagulation therapy require surgery each year in ambulatory surgery centers. National safety organizations focus attention toward improving anticoagulation management, and the American College of Chest Physicians has established guidelines for appropriate anticoagulation management to balance the risk of thromboembolism when warfarin is discontinued with the risk of bleeding when anticoagulation therapy is maintained. The guidelines recommend that patients at high or moderate risk for thromboembolism should be bridged with subcutaneous low-molecular-weight heparin or IV unfractionated heparin with the interruption of warfarin, and low-risk patients may require subcutaneous low-molecular-weight heparin or no bridging with the interruption of warfarin. The guidelines recommend the continuation of warfarin for patients who are undergoing minor dermatologic or dental procedures or cataract removal. The literature reveals, however, that there is not adequate adherence to these recommendations and guidelines. Management of anticoagulation therapy by a nurse practitioner may improve compliance and safety in ambulatory surgery centers.     

Pharmacologic treatment of migraine

Nonsteroidal anti-inflammatory drugs are the mainstay of migraine treatment for children and adolescents by most primary care physicians. Not all patients respond to these readily available agents. Triptans have been studied in children and adolescents, and there is reasonable evidence to support the use of these agents in these populations. Other agents, such as combination preparations and ergot compounds, are also used in clinical practice, although there has been little scientific study. Prophylactic agents have been less well studied in those under 18 years of age. Agents such as antidepressants, anticonvulsants, and antihypertensives are commonly used in clinical practice. Safety issues are fairly well understood because of historical use and use for other conditions. Efficacy and optimal dosing have yet to be established for the treatment of migraine in children and adolescents in double-blind, randomized, placebo-controlled trials.     

Low-molecular-weight Heparins for the Treatment of Venous Thromboembolism

Recent studies have indicated that certain low-molecular-weight heparins given subcutaneously may replace continuous intravenous unfractionated heparin for the treatment of venous thromboembolism. Low-molecular-weight heparins have a predictably high absorption rate when given subcutaneously and they do not require laboratory monitoring. These characteristics of low-molecular-weight heparin therapy raise the possibility of treating uncomplicated patients with deep venous thrombosis or pulmonary embolism in the outpatient setting. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient lowmolecular-weight heparin will likely prove to be highly cost-effective. At the present time, the findings associated with an individual low-molecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight heparins and each must be evaluated in separate clinical trials. Recent randomized clinical trials indicate that low-molecular-weight heparin may be safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. A decreased mortality rate, which was particularly striking in patients with metastatic carcinoma, was unexpected and requires confirmation in further prospective randomized trials.     

Antithrombotics in thrombosis and cancer

Many cancer patients reportedly are in a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) interfere with various processes involved in tumor growth and metastasis. These include fibrin formation, binding of heparin to angiogenic growth factors such as basic fibroblast growth factor and vascular endothelial growth factor, modulation of tissue factor and, perhaps, other more important modulatory mechanisms such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of LMWH, compared with UFH on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from our laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa and LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH, warfarin, anti-VIIa or TFPI might be a useful therapeutic option for the inhibition of angiogenesis associated with human tumor growth and metastasis.     

Antithrombotics in thrombosis and cancer

Many cancer patients reportedly are in a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) interfere with various processes involved in tumor growth and metastasis. These include fibrin formation, binding of heparin to angiogenic growth factors such as basic fibroblast growth factor and vascular endothelial growth factor, modulation of tissue factor and, perhaps, other more important modulatory mechanisms such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of LMWH, compared with UFH on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from our laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa and LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH, warfarin, anti-VIIa or TFPI might be a useful therapeutic option for the inhibition of angiogenesis associated with human tumor growth and metastasis.     

Old and new anticoagulant drugs: a minireview

Abstract The limits of traditional anticoagulants, such as heparin and warfarin, have prompted the search for new agents for prophylaxis and treatment of arterial and venous thromboembolism, including factor Xa and thrombin inhibitors. These agents can be given orally, and their most significant advantage is that no laboratory monitoring is needed. The anti-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran etexilate are licensed for prophylaxis of venous thromboembolism (VTE) in high-risk orthopedic surgery. They are at least as safe and effective as heparins but much more expensive. Dabigatran, rivaroxaban, and other agents currently in the pipeline of clinical development have the potential to replace warfarin in the two most frequent indications for anticoagulation, i.e. secondary prophylaxis of VTE and atrial fibrillation. Prevention and treatment of coronary artery thrombosis in patients with ischemic heart disease is another area of investigation for the role of new anticoagulants. These drugs have the potential to meet some currently unmet needs of traditional anticoagulants, but available clinical data warrant confirmation and expansion. Lack of specific antidotes for anticoagulation reversal and the high cost are important limitations of their use.     

Clinical applications of bivalirudin in the cardiac catheterization laboratory

Heparin has been used in the catheterization laboratory to prevent ischemic complications of percutaneous coronary intervention (PCI). Bivalirudin, a direct thrombin inhibitor, is an anticoagulant that has several pharmacologic advantages over heparin, and it has been proposed that bivalirudin is superior to heparin in its ability to prevent bleeding complications of PCI. As such, there have been a variety of large prospective clinical trials comparing bivalirudin and heparin over the past 13 years. The results of these trials have prompted the general acceptance of bivalirudin as a safe alternative to heparin use during PCI, and bivalirudin has been given a class 1 recommendation by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for a variety of clinical indications. This article will review the data supporting the use of bivalirudin in the cardiac catheterization laboratory and describe several advantages of bivalirudin over traditional heparin use. We also include a discussion of the use of bivalirudin in conjunction with other medications that are frequently used in the catheterization laboratory. We end with an analysis of the economic differences between bivalirudin and heparin and the impact that financial factors may have on the choice of anticoagulant.     

A review of the practical advantages of low molecular weight heparin in the treatment of cancer-related venous thromboembolism

Patients with cancer, particularly those with metastatic cancer, are at high risk of venous thromboembolism (VTE), which places a huge burden on healthcare resources and can adversely affect patients' prognosis. In addition, VTE can have a negative impact on quality of life and increase the management challenges faced by physicians and nurses. Conventional long-term treatment using vitamin K antagonists, such as warfarin, presents many practical problems for cancer patients including frequent monitoring and dose adjustment, drug interactions, and disruption of anticoagulation for invasive procedures. The aim of this article is to review the potential advantages of using low molecular weight heparin (LMWH) in the treatment of cancer-related VTE in comparison to conventional therapy with warfarin or standard heparin. The potential advantages were determined via a literature review. LMWH is at least as effective as standard heparin or warfarin, and has been shown to have several benefits over warfarin in cancer patients. The simplicity of this therapy enables patients to be treated at home, and has been shown to have a positive impact on overall quality of life. The use of LMWH provides a treatment alternative to patients with cancer offering them hope and optimism regarding their care.     

Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents

Summary.  Heparin, low molecular weight heparin (LMWH) and coumarins are familiar to most clinicians, inexpensive, highly effective when correctly used and widely available. However, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and can cause thrombosis in some settings (e.g. hereditary protein C deficiency, heparin induced thrombocytopenia, warfarin loading). Additionally, warfarin and heparin require monitoring of their therapeutic effect. These real and perceived limitations have led to the development of 'novel' anticoagulants. However, these new agents have one general limitation – a lack of a widely available antidote. We focus on the management of bleeding in anticoagulated patients, with particular regard to novel anticoagulants.     

Multi-focal motor neuropathy: one treatment works but many uncertainties remain

The activity of a set of peptidases (proteases) involved in cancer progression is collectively known as the cancer ‘degradome’. Invasion and metastasis were initially considered as late events in cancer development and the processes in which proteases were involved. However, recent studies indicate that invasion and metastasis are not late events, but can occur during early stages as well. Moreover, other processes occurring in various stages of cancer progression are also protease-dependent, such as (upregulation of) cell proliferation, (downregulation of) apoptosis, involvement of white blood cells, angiogenesis and induction of multi-drug resistance. Proteolytic activity in tumours is regulated in a complex manner, as both genetically unstable cancer cells and stable stromal cells, such as fibroblasts, endothelial cells and inflammatory cells, are involved. In vitro studies and studies using animal models have clearly shown protease dependency of many processes in carcinogenesis. However, clinical trials using protease inhibitors have thus far been unsuccessful except for a few applications of matrix metalloprotease (MMP) inhibitors when used in combination with cytostatic anticancer agents and/or in the early stages of cancer. Antithrombotics, such as low-molecular-weight heparin and warfarin, were also successful in clinical trials, probably by interfering with proteases of the coagulation cascade. The two-way association between cancer and thrombosis has long been recognised in the clinic. The poor outcome of other clinical trials of protease inhibitors is probably due to the late stages of cancer of the patient populations included, and the limited understanding of the complex regulation and effects of the activity of the various proteases in tumours depending on, among others, tumour type and stage, interactions between the cancer cells, other cells and the extracellular matrix in tumours. Therefore, a better fundamental understanding of the proteolytic complexity in tumours is essential before clinical trials can be rationally designed. At present, antithrombotics, the urokinase-type plasminogen activator system, the membrane-bound membrane-type 1-MMP, cathepsin L and the proteasome seem the most promising candidates as targets for anticancer strategies in early stages of cancer in combination with cytotoxic drugs. Moreover, metronomic therapy is an attractive approach using low doses of inhibitors for prolonged periods of time without interruption to specifically target endothelial cells that are involved in angiogenesis.