The safety of fondaparinux for the prevention and treatment of venous thromboembolism

Fondaparinux is the first synthetic selective Factor Xa inhibitor. Along with its antithrombotic efficacy, the safety of fondaparinux has been documented in several Phase II and III clinical trials, including the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery or high-risk abdominal surgery, or in acutely ill medical patients with restricted mobility, and the treatment of patients with deep-vein thrombosis and pulmonary embolism. In all these indications, the safety of fondaparinux used according to its registered regimen was similar to that of reference comparators. In conclusion, due to its superior efficacy and satisfactory safety, fondaparinux may substantially improve the prevention and treatment of venous thrombosis.     

Fondaparinux: a Factor Xa inhibitor for antithrombotic therapy

Fondaparinux (Arixtra) is the first of a new class of antithrombotic compounds - Factor Xa inhibitors. This synthetic pentasaccharide acts by inhibiting Factor Xa selectively. Its efficacy and safety have been demonstrated in animal models of venous and arterial thromboses and bleeding risk. In humans, its pharmacokinetic profile after subcutaneous injection shows a rapid onset of antithrombotic activity and an elimination half-life that reliably allows once-daily dosing. As the inter-subject variability is limited, no laboratory monitoring of coagulation parameters is needed. The efficacy and safety of fondaparinux have been examined in several Phase II and III clinical trials. So far, the largest programme has involved approximately 9000 patients undergoing major orthopaedic surgery of the lower limbs. In the setting of short-term prophylaxis, the efficacy of fondaparinux for preventing venous thromboembolism was significantly superior to that of the low-molecular-weight heparin, enoxaparin (common reduction in risk: 50.6%; p < 0.001). The benefit of extended thromboprophylaxis with fondaparinux in hip fracture surgery patients was also demonstrated. Fondaparinux also showed benefit in the prevention of venous thromboembolism in other surgical and medical settings and in the treatment of patients with venous thromboembolism. Overall, fondaparinux therapy was as well-tolerated as currently available treatments. In conclusion, selective inhibition of Factor Xa is an effective antithrombotic strategy. Fondaparinux may substantially improve the prevention and treatment of thrombosis. Fondaparinux 2.5 mg once-daily s.c. has been approved for the prevention of venous thromboembolism after major orthopaedic surgery. Fondaparinux use in extended prophylaxis (4 weeks) after hip fracture surgery has also been recently approved.     

Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent

Fondaparinux (Arixtra^®, Sanofi-Synthélabo/Organon) is the first of a new class of antithrombotic agents distinct from low molecular weight heparins (LMWHs) and heparin. It is a chemically synthetic pentasaccharide mimicking the site of heparin that binds to antithrombin III (AT). It exhibits only factor (F) Xa (FXa) inhibitor activity via binding to AT, which in turn inhibits thrombin generation. In contrast to heparin and LMWH, plasma anti-Xa activity corresponds directly to levels of fondaparinux. It does not release tissue factor pathway inhibitor (TFPI). There is nearly complete bioavailability by the sc. route, rapid onset of action, a prolonged half-life in both iv. and sc. (14 - 20 h) dosing regimens and no metabolism preceding renal excretion. Phase IIb clinical studies have identified a dose of 2.5 mg once-daily for prophylaxis of venous thrombosis. Four Phase III studies (n > 7000) have demonstrated a combined 50% relative risk reduction of venous thromboembolic events in orthopaedic surgery patients in comparison to the LMWH, enoxaparin. Haemmorrhagic complications for fondaparinux were either comparable to or higher than those for LMWH. The activated partial thromboplastin time (aPTT) is not affected by fondaparinux. At present, laboratory monitoring is not recommended. Clinical trials for treatment of established thrombosis, coronary syndromes and adjunct to thrombolytic therapy are in progress.     

Fondaparinux:一个新的选择性Ⅹa因子抑制剂

fondaparinux是一个化学合成的全新戊聚糖化合物 ,能够有效地预防大型的下肢骨科手术后常见的静脉血栓栓塞。本文就其药效学、药动学、临床应用及其现状等作一综述。     

Fondaparinux as a treatment option for heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication that can occur after exposure to heparin products. Because patients with HIT are at increased risk for thrombosis, anticoagulation is warranted. The direct thrombin inhibitors lepirudin and argatroban are approved by the United States Food and Drug Administration (FDA) for this indication. Bivalirudin, another direct thrombin inhibitor, is approved for use in patients with HIT who must undergo percutaneous coronary intervention. The synthetic pentasaccharide fondaparinux lacks FDA approval for treating patients with HIT; however, a few published reports describe its use. Furthermore, various small-scale, in vitro studies have demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT.     

Fondaparinux versus enoxaparin for the prevention of venous thromboembolism

Venous thromboembolism is a frequent, life-threatening, postoperative complication of hip-fracture and total-knee-replacement surgery. Fondaparinux is a synthetic polysaccharide that selectively binds to antithrombin, the primary endogenous regulator of blood coagulation. Low molecular weight heparins, such as enoxaparin, are less specific inhibitors of coagulation. In patients undergoing hip-fracture surgery, fondaparinux is more effective than once-daily enoxaparin as prophylaxis for venous thromboembolism. Fondaparinux (25 mg/day s.c.) was also more effective than enoxaparin (30 mg s.c. b.i.d.) as prophylaxis for venous thromboembolism in elective knee surgery. These differences may be explained by the fact that there is less prophylaxis cover with enoxaparin, as it has a much shorter duration of action than fondaparinux. Thus, with the present dosing regimens, fondaparinux is probably preferable to enoxaparin for the prevention of venous thromboembolism.     

Novel factor Xa inhibitors: a patent review

Importance of the field. New oral anticoagulants with favorable safety profiles and fixed doses are required for the management of thromboembolism and stroke prevention in patients with atrial fibrillation. Among them, fXa inhibitors (the so-called xabans) are attractive options that can overcome limitations (e.g., bleeding) of the current oral antithrombotic therapy. The rational design of small-molecule direct fXa inhibitors, whose importance is testified by the growing number of publications and patents recently registered, has been fully supported by the X-ray crystallography of enzyme–ligand complexes.

Areas covered in this review. Pubmed, SciFinder^® Scholar, ISI web of knowledge^SM, http://ep.espacenet.com/ and Google websites were used as the main sources for literature retrieving, and > 100 patents filed between 2006 and April 2009, reviewed and discussed herein, highlight the variety among the P1 and P4 moieties on suitable scaffolds.

What the reader will gain. The replacement of the benzamidine P1 moiety, which characterizes the first generation, with less basic bioisosteric or nonpolar neutral P1 groups led to the disclosure of numerous fXa inhibitors with high potency, selectivity and oral bioavailability. Novel selective fXa inhibitors with stable pharmacokinetics, better therapeutic windows and ease-of-use than the existing anticoagulants are currently under advanced stage clinical trials.

Take-home message. Available data from Phase II and Phase III studies reflect the drive towards fXa inhibitors as potentially more effective and safer antithrombotic drugs. Their development is expected to address two major needs for anticoagulation, namely safety and ease-of-use, and to significantly affect the anticoagulant market.     

Antithrombotic therapy for venous thromboembolism in patients with cancer: expert guidance

Introduction: Most of the current clinical guidelines recommend the use of Low-Molecular-Weight Heparins (LMWHs) for cancer-associated thrombosis (CAT). The Hokusai VTE-cancer trial reported the first results of a direct comparison between a direct oral anticoagulant (DOAC), edoxaban, and LMWH in this setting.

Areas covered: This review aims to critically appraise the currently available evidence on the efficacy and safety of anticoagulant agents for the long-term treatment of CAT and to provide an expert opinion and guidance in this field.

Expert opinion: Based on the available evidence, DOACs represent a valid alternative to LMWH for the treatment of CAT for the majority of patients with active cancer. Currently, most solid evidence comes from the Hokusai VTE-cancer study, which showed that edoxaban is non-inferior to the LMWH dalteparin, with a trend toward fewer recurrent venous thromboembolic events, but with more major bleeding events. Similar findings were reported with rivaroxaban, although the study was not sufficiently powered to allow definitive conclusions. The majority of bleeding events occurred in the upper gastrointestinal tract and in patients with gastrointestinal cancer. Thus, LMWH remains the preferred option for patients with gastrointestinal cancer. Additional studies aimed to confirm these findings with other DOACs are now warranted.     

Short- and long-acting synthetic pentasaccharides as antithrombotic agents

Fondaparinux sodium (Arixtra?; GlaxoSmithKline) is the first of a new class of antithrombotic agents. It is a chemically synthesised pentasaccharide mimicking the site of heparin that binds to antithrombin. It is purely a factor Xa inhibitor and an inhibitor of thrombin generation that requires binding to antithrombin. Fondaparinux sodium differs from heparin, low-molecular-weight heparin and heparinoids, and cannot be used interchangeably. It has been approved in the US and Europe for the prophylaxis of venous thrombosis after orthopaedic surgery by a fixed dose of 2.5 mg/day without monitoring. Using this pentasaccharide as a backbone, other structures have been synthesised. Idraparinux sodium (Sanofi-Aventis) differs structurally from fondaparinux sodium as it has additional methyl groups, a long half-life, and once-weekly administration. Both drugs are being developed as antithrombotics for venous and arterial thrombosis, acute coronary syndrome, stroke and as adjuncts to thrombolytic therapy.     

凝血因子Xa抑制药研究进展

凝血因子Xa是内源性凝血系统和外源性凝血系统的交汇点。针对凝血因子Xa的新型抗凝药物具有疗效显著、使用方便、不需实验室监测、出血不良反应少等优点。间接凝血因子Xa抑制药璜达肝素、艾屈肝素、idrabiotaparinux、SR123781和直接凝血因子Xa抑制药利伐沙班、apixaban、betrixaban、edoxaban、eribaxaban、LY517717、YM150、letaxaban、奥米沙班是目前研究较多的药物。     

Treatment dosing of low-molecular-weight heparins and the dose cap dilemma: considerations for patients in Canada

Background:

In Canada, there is a dose cap for weight-based treatment with low-molecular-weight (LMW) heparins.

Objective:

To review whether capping of LMW heparin doses is warranted for patients with obesity.

Methods:

English-language publications concerning the use of LMW heparin in Canada were reviewed, and the literature regarding use of these drugs at treatment doses in patients with obesity was assessed.

Results:

Five pharmacokinetic or pharmacodynamic studies meeting the inclusion criteria were identified. The evidence in those studies pointed toward no excess accumulation of LMW heparin in patients with obesity. In addition, 5 trials involving patients with acute coronary syndromes and 6 trials involving patients with venous thromboembolism and other indications were identified, but only 7 of these 11 trials included sufficient information for review. Subgroup analysis of patients with acute coronary syndrome whose LMW heparin dose was not capped showed no increased risk of bleeding for obese patients treated with enoxaparin. For patients with venous thromboembolism and other indications, the best evidence was for dalteparin, with anti-Xa levels used as a surrogate end point. In this setting, excess accumulation did not occur when there was no dose cap.

Discussion:

There is little literature dedicated to the dosing of LMW heparin for obese patients. In particular, there are few data for those with body weight above 150 kg. Despite the limitations of these studies, there appears to be little justification for capping the doses of these drugs. On the basis of the available literature, it is suggested that treatment doses of LMW heparin be based on body weight up to 150 kg.     

口服Xa因子直接抑制剂阿哌沙班的临床研究进展

阿哌沙班是口服Xa因子直接抑制剂,继达比加群酯和利伐沙班后上市,用于择期髋关节或膝关节置换手术的成年患者,以预防静脉血栓形成。本文主要介绍这个新药的研发背景、作用机制、药动学和临床试验。     

冠状动脉介入术后发生肝素诱导的血小板减少症抗栓治疗的药学监护

目的 探讨临床药师在急性心肌梗死（AMI）患者经皮冠脉介入术（PCI）后发生肝素诱导的血小板减少症（heparin-induced thrombocytopenia,HIT）抗栓治疗方案制定及药学监护。方法 临床药师利用急性冠脉综合征临床风险评分（GRACE）及抗血小板、抗凝治疗出血风险评分（Crusade）进行死亡风险及缺血、出血风险评估,及时调整抗栓治疗方案。出现HIT后分析血小板减少的原因及凝血功能,确定可能的相关药物因素,选择阿加曲班替代抗凝治疗,并及时监测活化部分凝血活酶时间（APTT）进行剂量调整。从药物的作用机制,不良反应,安全经济性,阐述出院带药选择华法林对患者的用药优势。结果 选择阿加曲班替代抗凝治疗,维持双联抗血小板（阿司匹林+氯吡格雷）方案,患者情况控制平稳,未出现出血及血栓栓塞并发症,顺利出院。结论 临床药师需要充分了解药理学及药动学变化,可协助临床发现药物治疗相关问题。同时需加强监测,以便及时调整用药方案,提高临床用药的安全性和合理性,为患者提供更好的药学服务。     

Rivaroxaban,an oral direct factor Xa inhibitor

Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists. Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis. A broad search of Medline, clinicaltrials.gov and the annual proceedings of the American Society of Hematology and the International Society on Thrombosis and Hemostasis was conducted. This review addresses the findings of this systematic search, including the need for new oral anticoagulants, the development and pharmacology of rivaroxaban, and the results of completed as well as ongoing trials with rivaroxaban. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The drug may have its greatest impact in providing a much-needed and attractive alternative to warfarin. Further data (especially large Phase III trials) are required.     

Measuring Anti–Factor Xa Activity to Monitor Low-Molecular-Weight Heparin in Obesity: A Critical Review

Background:The choice of whether to monitor anti–factor Xa (anti-Xa) activity in patients who are obese and who are receiving low-molecular-weight heparin (LMWH) therapy is controversial. To the authors’ knowledge, no systematic review of monitoring of anti-Xa activity in such patients has been published to date.Objective:To systematically ascertain the utility of monitoring anti-Xa concentrations for LMWH therapy in obese patients.Conclusions:Routinely determining anti-Xa concentrations in obese patients to monitor the clinical effectiveness of LMWH is not warranted on the basis of the current evidence. Circumstances where measurement of anti-Xa concentration may help in clinical decision-making in either obese or non-obese patients would be cases where elimination of LMWH is impaired or there is an unexpected clinical response, as well as to confirm compliance with therapy or to identify deviation from predicted pharmacokinetics.     

The emergence of factor Xa inhibitors for the treatment of cardiovascular diseases: a patent review

Classical cancer treatments have focused on the use of cytotoxic agents and/or radiation therapy that target both tumour and normal cells. Consequently, current cancer treatments with chemotherapeutic agents are subject to limitations associated with high toxicity and resistance. There is a need to develop new agents and therapies that will permit long-term administration without compromising the patient. The individual steps of angiogenesis and metastasis during cancer progression are now well understood and present new targets for chemotherapy. The cysteine protease cathepsin B has been linked to the invasive steps during the metastatic process and provides a new target for drug development. Cathepsin B has also been implicated in other disease states with aberrant protein turnover such as muscular dystrophy, inflammatory airway diseases, bone and joint disorders and pancreatitis. Examination of the x-ray crystal structure of cathepsin B reveals the presence of an insertion loop extending for 18 residues that obstructs part of the active-site cleft. This ‘occluding loop’ is a unique feature that can be targeted for the development of specific inhibitors of cathepsin B as potential therapeutic agents. Inhibitors can be classified as to whether they act in a reversible or irreversible manner. This review details members of both of these classes of inhibitors and their therapeutic applications.     

Synthesis of a stable‐isotope‐labeled biotinylated pentasaccharide conjugate (EP217609), a dual‐effect anticoagulant drug

EP217609 is a neutralizable dual‐effect anticoagulant under clinical investigation in cardiopulmonary bypass during cardiac surgery. Stable‐isotope‐labeled EP217609 was synthesized as an internal standard for mass spectrometry in support of bioassays. EP217609 was obtained in six steps starting from three building blocks in an overall yield of 42%, with a chemical purity of >99%. Thus, coupling between the N‐protected labeled biotin‐lysine 4 , prepared in three steps from [¹³C,¹⁵N]‐l ‐lysine 2 , and the pentasaccharide‐spacer‐amine 6 was first performed. Removal of the Cbz protective group to 8 followed by coupling of the activated peptidomimetic building‐block 10 gave the immediate precursor of EP217609, which could be obtained after catalytic hydrogenolysis of 1,2,4‐oxadiazol‐5(2H)‐one into amidine.     

磺达肝素预防术后肺血栓栓塞的荟萃分析

目的:评估磺达肝素对术后发生肺血栓栓塞(PTE)的预防作用,并系统分析磺达肝素和一般低分子肝素(LMWH)疗效和安全性的差异。方法:从Medline、Cochrane图书馆和中国生物医学文献数据库(CBM)检索公开发表的文章(2000年1月—2007年6月),以磺达肝素或LMWH类药物(对照)预防术后PTE的随机对照试验(RCT)为研究对象,采用Rev Man 4.2软件进行统计分析。结果:对符合纳入标准的5篇文献共10 271例病人进行荟萃分析,根据意向性分析(ITT)磺达肝素组和对照组术后PTE发病率分别为0.31%和0.25%,2组比数比(OR)为1.23(95%CI为0.59～2.57),差异无显著意义(P>0.05)。2组术后严重出血发生率分别为2.82%和1.89%,OR值为1.51(95%CI为0.73～1.83),差异有显著意义(P<0.01)。2组术后轻微出血发生率分别为2.73%和2.37%,OR值为1.15(95%CI为0.90～1.48),差异无显著意义(P>0.05)。结论:磺达肝素预防术后PTE的疗效与一般LMWH相当,两者术后轻微出血发生率相似,但磺达肝素引起术后严重出血的危险性相对较高。