Idraparinux: review of its clinical efficacy and safety for prevention and treatment of thromboembolic disorders

Background: Idraparinux is a synthetic pentasaccharide that binds to antithrombin with high affinity. In view of its long half-life, it is suitable for once-a-week administration. Objective: To review the evidence favoring the use of idraparinux for the acute and long-term treatment of patients with venous thromboembolism (VTE) and for the prevention of thromboembolic events in patients with atrial fibrillation (AF). Methods: All preclinical and clinical studies carried out with the use of idraparinux were sought through electronic searches of MEDLINE from January 1, 1999 up to December 31, 2007. Results: The administration of idraparinux in subcutaneous fixed doses of 2.5 mg once weekly was found to be as effective and safe as conventional antithrombotic therapy in the initial treatment of patients with deep vein thrombosis, but less effective than standard therapy in the initial treatment of patients with primary pulmonary embolism. During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent VTE but was associated with an increased risk of bleeding versus placebo. Finally, in patients with AF the long-term treatment with idraparinux was as effective as vitamin K antagonists, but caused more bleeding. Conclusions: In its current formulation, idraparinux can be recommended only for the initial treatment of patients with deep vein thrombosis. The bioequipotency of a biotinylated version of idraparinux (idrabiotaparinux), whose effects can be reversed by a neutralizing agent (avidin), is under investigation in the treatment of VTE at present, as is the use of lower doses in patients with AF.     

The discovery of dabigatran etexilate for the treatment of venous thrombosis

ABSTRACT

Introduction: Venous thromboembolism (VTE) can be life-threatening and requires anticoagulant treatment; for many years, vitamin K antagonists, e.g. warfarin, were the only oral anticoagulants available for long-term treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug–drug and drug–food interactions, and a narrow therapeutic range. These limitations spurred the search for non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran etexilate.

Areas covered: The authors illustrate the progression of preclinical and clinical studies leading to the development of dabigatran, the only approved NOAC to act by direct thrombin inhibition. They focus on molecule discovery, animal models of thrombosis, clinical trials and post-launch activities in VTE treatment.

Expert opinion: Dabigatran demonstrated comparable efficacy to the highly effective warfarin, and a more favourable safety profile in trials of VTE treatment. A favourable anticoagulant safety profile in addition to efficacy is essential for VTE treatment. Availability of the dabigatran-specific reversal agent, idarucizumab, provides a means of rapidly reversing the anticoagulant effect if required. Future investigations into the optimal duration of VTE treatment and an evaluation of the impact of idarucizumab, in real-world studies, could provide valuable information to help optimise treatment for selected patients.     

Direct oral anticoagulants in the treatment of pulmonary embolism

Objective: The objective of this review is to examine the management strategies for pulmonary embolism (PE) with an emphasis of the role of direct oral anticoagulants (DOACs).

Methods: PubMed was searched to identify relevant journal articles published through April 2017. Additional references were obtained from articles discovered during the database search.

Results: Initial heparinization followed by long-term anticoagulation with vitamin K antagonists has been considered the mainstay for the treatment of PE. However, DOACs now offer comparably effective and potentially safer alternatives for both acute and long-term treatment of PE using a monotherapy approach without the need for initial heparinization for rivaroxaban or apixaban. Advantages to using DOACs include oral availability, rapid onset of action, minimal drug and food interactions, predictable pharmacokinetics, and lack of need for routine monitoring. Limitations of using these agents include a limited availability of assays to quickly and efficiently measure their anticoagulant effects and the lack of widely available reversal agents for the direct oral factor Xa inhibitors; although idarucizumab has recently been approved for the reversal of dabigatran’s anticoagulant effects.

Conclusions: Advantages to using DOACs render them an attractive alternative to conventional therapy in PE treatment that may simplify acute and long-term treatment paradigms, improve patient outcomes, and increase patient compliance. However, questions remain pertaining to the use of DOACs in PE patients with high-risk features and in cancer patients and fragile populations. Clinical studies are under way to address many of these issues.     

Clinical management of rivaroxaban-treated patients

Introduction: Until recently, only vitamin K antagonists (VKAs) were used for long-term anticoagulation. New oral anticoagulants, with pharmacokinetic and pharmacodynamic characteristics different to VKAs, are now available for some indications. Rivaroxaban (Xarelto®) is an oral Factor Xa inhibitor approved in many countries for long-term treatment of patients with atrial fibrillation or venous thromboembolism. This article is addressed to all professionals involved in the management of treated patients to highlight the characteristics of rivaroxaban and provide practical guidance on management of treated patients.

Areas covered: This article is based on a consensus of specialists involved in the management of anticoagulant treatment, including thrombosis experts, cardiologists, neurologists, emergency medicine specialists, and general practitioners. The authors performed a nonsystematic review of the literature, and expressed guidance statements based on the results of the review as well as personal experience.

Expert opinion: Availability of new anticoagulant drugs, including rivaroxaban, is an important step forward to allow easier, more effective, and safer long-term anticoagulation in patients in whom adequate anticoagulation is currently denied due to the limitations of VKAs. However, given their totally new properties, associated risks, and expected broad clinical use, expert professionals and manufacturers must urgently tackle a series of issues.     

The evolving role of dabigatran etexilate in clinical practice

Introduction: Stroke and venous thromboembolism (VTE) affect millions of patients. The vitamin K antagonist, warfarin, has been the main oral anticoagulant used to treat these conditions despite many limitations associated with its use. Recently, multiple novel oral anticoagulants have been approved and are reshaping how patients with atrial fibrillation (AF) at risk of stroke and patients with VTE are treated. The direct thrombin inhibitor, dabigatran etexilate, is among these novel agents that have been developed to overcome limitations with warfarin.

Areas covered: In this article, authors describe the pharmacokinetic and pharmacodynamic properties of dabigatran etexilate and summarize the clinical evidence and controversy surrounding its use in the US, Canada and Europe.

Expert opinion: Dabigatran has demonstrated similar efficacy and safety to enoxaparin for VTE prevention in patients undergoing hip and knee arthroplasty, and to warfarin for the treatment of VTE. Dabigatran (110 mg) is noninferior and dabigatran (150 mg) is superior to warfarin for stroke prevention in patients with nonvalvular AF, with a lower rate of intracranial hemorrhage reported at both doses. Apixaban, rivaroxaban and edoxaban provide alternate anticoagulant options to dabigatran. While there are many similarities, there are also significant differences to consider in agent selection based on patient-specific characteristics.     

Inhibitors of propagation of coagulation: factors V and X

Cardiovascular diseases are still the most important cause of morbidity and mortality in western countries and antithrombotic treatment is nowadays widely used. Drugs able to reduce coagulation activation are the treatment of choice for a number of arterial and/or venous thromboembolic conditions. Some of the drugs currently used for this purpose, such as heparins (UFH or LMWH) and VKA, have limitations consisting of a narrow therapeutic window and an unpredictable response with the need of laboratory monitoring in order to assess their efficacy and safety. These drawbacks have stimulated an active research aimed to develop new drugs able to act on single factors involved in the coagulation network, with predictable response. Intense experimental and clinical work on new drugs has focused on synthetic agents, which could preferably be administered orally and at fixed doses. The most advanced clinical development with new anticoagulants has been achieved for those inhibiting FXa and some of them, like fondaparinux, are already currently used in clinical practice. Other agents, such as rivaroxaban, apixaban, otamixaban and edoxaban are under development and have already been studied or are currently under investigation in large scale phase III clinical trials for prevention and treatment of venous thromboembolism, atrial fibrillation and acute coronary syndromes. Some of them have proved to be more effective than conventional therapy. Data on some agents inhibiting FVa are still preliminary and some of these drugs have so far been considered only in patients with disseminated intravascular coagulation secondary to sepsis.     

The therapeutic potential of ximelagatran to become the anticoagulant of choice in medicine: a review of recently completed clinical trials

Ximelagatran (Exanta^?, AstraZeneca) is a novel oral direct thrombin inhibitor that inhibits the final step in the coagulation process – namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Recently completed large clinical trials have evaluated the efficacy and safety of ximelagatran compared to standard anticoagulation therapy with warfarin and heparins in several thrombotic disorders including the treatment and prevention of venous thromboembolism following major orthopaedic surgery; stroke prevention in atrial fibrillation; and after acute myocardial infarction. This article reviews these recent clinical trials and explores the therapeutic potential of ximelagatran to become the oral anticoagulant of first choice in medicine.     

Treatment of thromboembolism in cancer patients

Importance of the field: Cancer patients are at increased risk of developing venous thromboembolism (VTE). The occurrence of VTE predicts worse prognosis in cancer patients: whereas the 1-year survival in cancer patients free of thrombosis is 36%, in patients with diagnosed VTE it is 12%. The management of VTE in cancer patients is challenging because the anticoagulant treatment in these patients can be less effective and carry considerable morbidity.

Areas covered in this review: This review covers the treatment strategies for cancer patients with VTE and highlights the new anticoagulant agents and their potential use in oncology. In writing this review, a literature search was performed using the PUB MED database with the following subject headings: cancer, venous thromboembolism and anticoagulant treatment.

What the reader will gain: A comprehensive overview of the current recommendations for prevention and treatment of VTE in cancer patients. In addition, this review provides an insight into the new anticoagulant drugs potentially suitable for use in oncology, in particular idraparinux, apixaban, rivaroxaban and dabigatran etexilate.

Take home message: Low-molecular-weight heparin remains the best treatment option for initial and long term treatment of VTE in cancer patients.     

短尾蝮蛇毒磷脂结合抗凝蛋白对动物血栓的抗栓作用

目的从短尾蝮蛇毒中分离纯化磷脂结合抗凝蛋白(PBAP),研究其对动物血栓的抗栓作用。方法用Chandler法制备家兔体外血栓和半体内血栓模型;用Reyers法制备大鼠静脉血栓模型;用Nowork法制备家兔肺动脉栓塞模型。测定PBAP对家兔体外血栓、半体内血栓、肺动脉栓塞和大白鼠静脉血栓的抗栓效应。结果短尾蝮蛇毒PBAP对家兔体外血栓、半体内血栓、肺动脉栓塞和大白鼠静脉血栓干湿重均有明显减轻作用,与生理盐水对照组比较,差异均有统计学意义(P<0.05或P<0.01)。结论PBAP抗凝蛋白对动物血栓具有明显的抗栓作用,具有潜在的临床应用价值。     

Recent advances in the development of haemoglobin-based blood substitutes

Dyslipidaemia may be a risk factor for venous thromboembolism and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may be protective. The current review outlines the cumulative evidence from both the basic and epidemiologic sciences for why this might be so and offers some directions for future research.     

Dalteparin sodium

Dalteparin sodium (Fragmin?, Pharmacia Corporation) is a low molecular weight heparin (LMWH) with a mean molecular weight of approximately 5000 Da. As with the other LMWHs, dalteparin sodium has certain advantages over unfractionated heparin (UFH), most important of which are improved bio-availability by sc. injection, a prolonged antithrombotic activity which is highly correlated with body weight permitting the o.d. administration of the drug. Dalteparin sodium has been subjected to a large number of well-designed randomised clinical trials for the prevention and treatment of thrombotic disorders. Based on data from the randomised clinical trials, dalteparin sodium has been approved internationally for a wide spectrum of clinical indications (e.g., prevention of thromboembolic events after surgery). Dalteparin sodium has also been studied in randomised controlled trials in the maintenance of graft patentcy following peripheral vascular surgery, in place of warfarin for the long-term treatment of patients presenting with deep vein thrombosis (DVT), in the prevention of upper extremity thrombosis in patients with indwelling portacath devices and in pregnant patients with a history of previous venous thromboembolism with or without thrombophilia. Dalteparin sodium has been compared with heparin for the prevention of thrombotic complications during haemodyalisis and haemofiltration. These studies have shown promising results but further work is required before dalteparin sodium can be recommended for these indications.     

Pharmacotherapy with oral Xa inhibitors for venous thromboembolism

Introduction: Venous thromboembolism (VTE) causes substantial morbidity and mortality worldwide. The traditional treatment of VTE, with an initial therapy with (low molecular weight) heparin or fondaparinux and a continued treatment with vitamin K antagonists, is effective but has limitations.

Areas covered: The current review summarizes the results of the Phase III trials with the new oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and provides a meta-analysis of these trials in the subgroups of elderly patients (> 75 years) and patients with impaired renal function.

Expert opinion: The practical use of direct Xa inhibitors in the treatment of VTE in general and in specific subgroups is discussed. For elderly patients, patients with extremes of body weight, cancer patients or patients with moderate renal impairment, pooled data suggest that the direct oral Xa inhibitors are a reasonable alternative to standard therapy. For other indications, such as treatment of VTE in children, during pregnancy or in the context of heparin-induced thrombocytopenia, further data from clinical trials are needed.     

阿加曲班治疗下肢深静脉血栓及其并发症肺栓塞的临床疗效观察

目的 比较阿加曲班和普通肝素治疗下肢深静脉血栓及其并发症肺栓塞的临床疗效和不良反应。方法 将200例下肢深静脉血栓形成患者随机分成治疗组（100例）和对照组（100例）,对照组患者入院后绝对卧床休息,患肢制动、抬高,忌按压、热敷;使用肝素钠抗凝,肝素钠注射液2 mL＋生理盐水10 mL,用微量泵以2 mL/h持续静脉泵入,治疗7 d后停用普通肝素,改为口服华法令治疗;使用注射用纤溶酶溶栓;合并肺栓塞者给予3 L/min吸氧及前列地尔扩张支气管。治疗组患者给予阿加曲班注射液抗凝,开始2 d,60 mg/d,持续静脉泵入;后5 d,20 mg/d,3 h内泵入,2 次/d。治疗7 d后改为口服华法令,其他治疗方案同对照组患者。治疗时间为2周,比较两组患者治疗前后症状和体征的变化,并在治疗过程中监测凝血酶原时间、活化部分凝血活酶时间及血小板。结果 治疗2周后,两组患者患肢疼痛、肿胀,肺栓塞患者咳嗽、咯血、呼吸困难等症状均有好转,治疗组患者症状改善更明显,且患肢周径较治疗前明显减小（P＜0.05）,治疗组和对照组总有效率分别为98%、90%,两组比较差异有统计学意义（P＜0.05）。治疗组无血小板减少症（HIT）发生,对照组发生1例;对照组与治疗组相比,PT及APTT波动较大,差异有统计学意义（P＜0.05）。结论 阿加曲班治疗下肢深静脉血栓及其并发的肺栓塞与常规普通肝素治疗相比临床疗效及安全性均有提高,值得临床推广。     

Rivaroxaban,a new,oral, direct factor Xa inhibitor for thromboprophylaxis after major joint arthroplasty

The new oral, antithrombotic drug rivaroxaban is a direct factor Xa inhibitor, which can restrict thrombin generation both in vitro and in vivo. It has a predictable dose-dependent pharmacokinetic and pharmacodynamic profile and is well tolerated. In patients undergoing total hip or knee arthroplasty, rivaroxaban, 10 mg once daily started 6 – 8 h after the operation, had a significantly better antithrombotic efficacy and a comparable safety when compared with enoxaparin. Furthermore in all studies performed the drug had no adverse influence on the liver function in comparison with enoxaparin. In conclusion, rivaroxaban is a potent and safe new compound for antithrombotic prophylaxis in orthopaedic surgery.     

Tinzaparin in the treatment of venous thromboembolism

Low molecular weight heparin (LMWH) has been widely used for the initial treatment of patients presenting with venous thromboembolism. The LMWH, tinzaparin, has been shown in randomised clinical trials to be as effective and safe as unfractionated heparin for the initial treatment of venous thromboembolism and in clinical trials, it has been used in place of warfarin for the long-term treatment of deep vein thrombosis. Tinzaparin can safely be given to patients with significant renal impairment (creatinine clearance of ≥ 20 ml/min) and the dose of tinzaparin does not need to be altered in patients with a body mass index of > 25.     

Review of enoxaparin and its clinical applications in venous and arterial thromboembolism

Venous and arterial thromboembolic disorders are common medical conditions that are associated with considerable morbidity and mortality. Unfractionated heparin (UFH) and its derivatives, the low molecular weight heparins (LMWHs), are the anticoagulants of choice when a rapid anticoagulant effect is required. LMWHs have several advantages over UFH, including a longer plasma halflife and higher bioavailability; a predictable dose response, which enables once- or twice-daily dosing; and a more convenient route of administration (subcutaneous instead of intravenous), which enables patients to self-inject in an out-patient setting. Enoxaparin is a LMWH prepared by alkaline hydrolysis of the benzylin ester of UFH. The efficacy of enoxaparin in the management of venous and arterial thromboembolism has been shown in a wide range of patient groups using doses ranging from fixed doses of 20 – 60 mg o.d. and 0.75 – 1.5 mg/kg b.i.d. Other doses, such as 80 mg/day for pregnant women with combined thrombophilic defects, have also been studied. The use of subcutaneous enoxaparin as an effective and safe home treatment for patients with acute proximal deep vein thrombosis (DVT) has been demonstrated. The benefits of preventing venous thromboembolic events with enoxaparin include reducing the costs associated with investigating the symptoms of DVT, acute treatment and hospitalisation, and potentially preventing the development of post-thrombotic syndrome, while improving quality of life and so making the treatment cost effective. In contrast to other LMWHs, enoxaparin has been shown to provide better outcomes than UFH in the treatment of unstable angina and non-ST-segment elevation myocardial infarction, without increasing major bleeding. Adverse events with enoxaparin are infrequent; the most common events are minor bleeding complications. It should be noted that different doses or indications are approved in each country.     

Minimizing the risk of hemorrhagic stroke during anticoagulant therapy for atrial fibrillation

Introduction: Oral anticoagulation (OAC) is given for ischemic stroke prevention in patients with nonvalvular atrial fibrillation. OAC’s most serious complications are major bleeding and, in particular, hemorrhagic stroke. Together with vitamin K antagonists (VKAs), direct oral anticoagulants (DOAC) are now available which have a more rapid onset/offset of action and more predictable anticoagulant effect. The advent of DOAC has given to the clinician an opportunity to tailor OAC therapy in order to maximize advantages and minimize complications.

Areas covered: This review covers data published in literature regarding the risk of hemorrhagic stroke in patients taking OAC. Bleeding risk assessment is discussed and different bleeding risk factors are presented. The paper will also review clinical studies comparing DOAC against standard anticoagulation, in regard to the risk of hemorrhagic stroke.

Expert opinion: Bleeding assessment is mandatory in order to select patients at high hemorrhagic risk who will benefit the most from close monitoring. Blood pressure, alcohol intake, concomitant medication and comorbidities should be constantly evaluated and treated accordingly. During VKA therapy, adherence and intensity of anticoagulation must be strictly monitored. DOAC are associated with lower risk of hemorrhagic stroke than VKA. However, periodic hepatic and renal checks as well as careful evaluation of time adherence are necessary to reduce the risk of bleeding.     

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.     

北京地区患者使用抗凝血药物的分析

目的:了解北京地区患者使用抗凝血药物的需求,并对抗凝血药进行分析.方法:采用<医院处方分析>课题(北京地区)2002年第4季度～2003年第3季度门诊、病房对抗凝血药物的处方数据进行比较.结果与结论:通过统计,北京地区使用抗凝血药物的患者人数基本稳定.在临床应用中,口服制剂以华法林、蚓激酶,注射制剂仍然为肝素类用量居主导地位.