Ximelagatran: direct thrombin inhibitor

Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.     

Ximelagatran: a new type of oral anticoagulant

OBJECTIVES: This assessment sought to evaluate the comparative benefit and adverse effect profile of ximelagatran, as well as the clinical issues surrounding its potential use. METHODS: We performed a Dialog OneSearch across BIOSIS Previews, EMBASE, MEDLINE, PASCAL, and ToxFile to identify published literature. PubMed and The Cochrane Library were also searched. Gray literature was identified by searching a variety of Web sites of health technology assessment and related agencies and their associated databases. The manufacturer's Canadian office, AstraZeneca, was invited to submit information. RESULTS: Ximelagatran is the first oral agent from a new class of anticoagulants called direct thrombin inhibitors. Other oral anticoagulants require routine blood monitoring; ximelagatran does not. Ximelagatran has been evaluated in the areas of venous thromboembolism management, particularly after orthopedic surgery, and stroke prevention in patients with atrial fibrillation. Overall, ximelagatran's efficacy appears comparable to other anticoagulants in these clinical settings. Also, bleeding rates were generally similar between ximelagatran and comparators but, as for warfarin, bleeding risk increases with higher ximelagatran doses. In addition, there is no specific antidote to help manage ximelagatran-induced bleeding. Finally, significantly more patients exposed to long-term ximelagatran developed elevated liver enzymes more than three times the upper normal limit, compared with patients on comparator anticoagulants. CONCLUSIONS: Given its apparent simplicity of use, ximelagatran carries the potential to replace, at least in part, anticoagulants currently used in the management of venous thromboembolism or for preventing stroke in atrial fibrillation patients. However, the safety of ximelagatran will not be fully known without further evaluation and surveillance for potential liver toxicity. There is also a need to evaluate its use in special populations such as patients with renal failure and patients using several concurrent medications.     

Dabigatran etexilate: a possible replacement for heparinoids and vitamin K antagonists?

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet-drug interactions, and has fewer clinically significant drug-drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.     

Index Volume 5 January- December 1970

Abstract

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet–drug interactions, and has fewer clinically significant drug–drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.     

阿加曲班联合尿激酶治疗急性创伤性下肢深静脉血栓的临床疗效观察

目的研究阿加曲班联合尿激酶治疗急性创伤性下肢深静脉血栓（traumatic dee pvein thrombosis,TDVT）的临床疗效。方法 40例急性TDVT患者随机分为两组,研究组（20例）采用阿加曲班联合尿激酶（urokinase,UK）行溶栓抗凝治疗;对照组（20例）采用低分子肝素钙联合UK行溶栓抗凝治疗。观察研究过程中的疗效、并发症及不良反应;通过血管彩超了解血管再通情况。结果研究组及治疗组总有效率分别为100%和80.0%,统计学结果差异显著性（P〈0.05）,两组均无严重出血并发症发生。结论阿加曲班联合UK治疗急性TDVT疗效显著,安全性好。     

Pregnancy and the mechanical prosthetic valve: dilemmas about the choice of antithrombotic prophylaxis

Two pregnant women aged 32 and 34, both of whom had mechanical prosthetic mitral valves, for which they were using low molecular weight heparin. One developed orthopnoea and dyspnoea at 36 weeks amenorrhoea, and the other suffered an acute myocardial infarction at 18 weeks. Both had valvular thrombosis. Following effective treatment, both women delivered at term and one week later after an uncomplicated course, were discharged home from hospital. Clinicians caring for pregnantwomen with mechanical prosthetic valves are faced with a dilemma when trying to provide optimal treatment. Inadequate anticoagulant therapy can result in thrombosis of the mechanical prosthetic valve while, on the other hand, anticoagulant therapy is associated with foetal and maternal bleeding and teratogenic effects. Pregnant women with mechanical prosthetic valves should be thoroughly counselled before or shortly after the confirmation of pregnancy regarding the risks associated with available anticoagulant options, allowing them to make an informed decision concerning the best management plan. This is an algorithm for optimal care of these patients.     

A multicentre randomised clinical trial to evaluate the benefit of testing for thrombophilia following a first venous thromboembolism: the NOSTRADAMUS study

It is unknown whether testing patients for thrombophilia after a first episode of venous thromboembolism (VTE) and prolonging anticoagulant treatment in those with thrombophilia is justified. The NOSTRADAMUS trial, a multicentre randomised controlled trial, is being conducted to assess whether this strategy is beneficial in terms of clinical outcomes, quality of life and costs. Patients with a first VTE will be randomly assigned to one of two groups. The first group will be tested for thrombophilia and subsequently receive the test results; those in the second group will be tested but the results will not be disclosed. A total of 1336 patients will be included. Additional anticoagulant treatment for a predefined period will be initiated in patients found to have thrombophilia, while others will receive a standard predefined duration oftreatment. Primary outcomes are the risk of recurrent VTE, clinically important bleeding and the composite outcome of both. Other outcomes include overall quality of life and costs associated with outcome measures 18 months after the initial episode of VTE.     

重症急性胰腺炎并发脓毒血症患者治疗过程中抗凝的应用

目的:研究抗凝剂在重症急性胰腺炎并发的脓毒血症患者当中的临床疗效以及对患者产生的影响。方法:选取本院重症急性胰腺炎并发脓毒血症的患者80例,把80例患者按照数学随机数字的方法分为实验组40例与空白组35例。空白组患者给予抗重症急性胰腺炎并发脓毒血症治疗,实验组在此基础之上采用低分子肝素钠进行治疗,比对治疗效果。结果:最后一共有76例患者完成了临床研究,实验组40例与空白组36例。实验组显效患者共36例,有效患者共4例,无效患者共0例;空白组显效患者共25例,有效患者共11例,无效患者共0例,差异在统计学当中具有意义(P<0.05)。进行治疗之后和空白组进行对比,实验组的血清WBC、CRP水平以及APACHEⅡ评分与手术率都有明显的降低,差异在统计学中均具有意义(P<0.05)。实验组和对照组相比较,接受治疗之后实验组的NK细胞、B细胞以及CD4%+/CD8%+值、CD4%+、CD3%+、CD8%+T细胞都有明显升高,但是差异不具有统计学意义(P<0.05)。结论:重症急性胰腺炎的并发的脓毒血症患者采用抗凝治疗,临床治疗效果比较好,并且对免疫功能可能物明显影响。     

New anticoagulants for the prevention and treatment of venous thromboembolism

Anticoagulant therapy is effective at preventing the development of venous thromboembolism in high-risk patients, and reduces morbidity and mortality in individuals with established thromboembolic disease. Vitamin K antagonists and heparins are currently the most commonly used anticoagulant drugs, but they have practical limitations. Therefore, new antithrombotic agents with predictable dose-responses (thereby decreasing the need for monitoring without compromising efficacy or safety), ideally available in an oral formulation and with a rapidly reversible anticoagulant effect, are needed. New drugs fulfilling some of the above criteria have been developed and have proven to be effective agents for the treatment and prevention of venous thromboembolism.     

New anticoagulants

A large number of newly developed platelet aggregation inhibitors and anticoagulants are currently being investigated in clinical studies. Most of these new agents are targeted to haemostatic pathways that have recently been shown to be of importance in vivo and usually have a higher efficacy than the currently available anticoagulants. The new platelet aggregation inhibitors can be divided into thienopyridine derivatives (ticlopidine, clopidogrel) and glycoprotein IIb/IIIa receptor antagonists (abciximab, eptifibatide, tirofiban). The new inhibitors of fibrin synthesis can be divided into direct thrombin inhibitors (hirudine, melagatran, ximelagatran), specific factor Xa inhibitors (pentasaccharides: fondaparinux, idraparinux) and inhibitors of the tissue thromboplastin factor VIIa complex (recombinant nematode anticoagulant protein c2, inactivated factor VIIa, recombinant tissue factor pathway inhibitor). In some cases this also results in a (relatively modest) increase in the risk of bleeding. The clinical use of the new compounds is often much more convenient than that of the presently available anticoagulants.     

丁胺卡那霉素对抗凝剂依赖性血小板假性减少症血小板的解离作用及血小板功能的影响

目的研究丁胺卡那霉素对抗凝剂依赖的假性血小板减少症血小板聚集的解离作用及其功能的影响。方法①在确诊为抗凝剂依赖的假性血小板减少症患者的EDTA-K2抗凝血和枸橼酸钠抗凝血内加入丁胺卡那霉素(6.5mg/ml血),在不同时间段作血小板计数,以原液(不加丁胺卡那霉素的抗凝血)作对照。②观察血小板聚集释放的情况:在不加丁胺卡那霉素、抽血后即加丁胺卡那霉素和1小时后加丁胺卡那霉素,用胶原、ADP、花生四烯酸诱导血小板聚集释放。结果用EDTA-K2、枸橼酸钠抗凝的血小板计数随着时间的延长呈下降趋势,观察血片均有血小板聚集现象,在上述两种抗凝剂中加入丁胺卡那霉素(6.5mg/ml血),血小板计数2小时内稳定;加入丁胺卡那霉素的血小板聚集释放试验比不加丁胺卡那霉素的聚集释放试验的结果稍高。结论丁胺卡那霉素可以抑制和解离由于EDTA-K2、枸橼酸钠依赖引起的血小板聚集,对血小板的聚集释放没有影响。     

Use of anticoagulant therapy in non-valvular atrial fibrillation. Analysis of a Hungarian cohort

In nonvalvular atrial fibrillation stroke prevention by anticoagulation is clearly recommended by evidence based medicine. Underusage of coumarin treatment however is a general problem. The aim of this study was the analysis of prehospital and hospital practice of anticoagulant therapy in a Hungarian cohort. 106 consecutive patients hospitalized in a Budapest medical department with chronic non-valvular atrial fibrillation were included. Mean age was 76 years, the percentage of males was 30%. High stroke risk factors were found in all patients, at least two of them in 72%. 70% of patients were 75 years old or more. Thus anticoagulant treatment was indicated in all patients, however at admission only 30% were anticoagulated, moreover therapeutic range was achieved in only 28% of them. At discharge in 77% of all patients and in 82% without contraindications coumarin treatment could be started, practically independently of age. CONCLUSIONS: In the Hungarian prehospital practice anticoagulant treatment of nonvalvular atrial fibrillation is underused and inefficient, but excellent rates even in international comparison can be achieved by adequate medical approach even in the elderly.     

Telemedicine improves the monitoring process in anticoagulant treatment

We compared the INR (International Normalized Ratio) monitoring process using a telemedicine device with the conventional approach in which blood samples were sent to the hospital for analysis. We conducted a randomized controlled trial. We enrolled 40 patients on chronic warfarin therapy from two primary healthcare centres (PHCs). Half were monitored using the telemedicine device and half were monitored conventionally. Each patient received three INR measurements. The total processing time was measured from blood sampling until warfarin dosing was performed in the anticoagulant clinic. The median total processing time was significantly shorter with telemedicine than usual care (34 vs. 260 min, P < 0.001). This was mainly because sample transport was avoided using the point-of-care device and automatic data transmission. Telemedicine reduced the total processing time for INR monitoring and has the potential to improve the management of patients undergoing anticoagulant treatment at PHCs.     

Testing for factor V Leiden in patients with pulmonary or venous thromboembolism: a cost-effectiveness analysis.

BACKGROUND: Survivors of venous thromboembolism who have the factor V Leiden mutation have an increased risk of recurrent venous thromboembolism (VTE), but the cost-effectiveness of testing for factor VLeiden has not been assessed. METHODS: We used a Markov state transition decision model to evaluate the cost-effectiveness of factor V Leiden testing and treatment strategies in survivors of VTE using a societal perspective for costs, effectiveness-measured in quality-adjusted life years, and incremental cost-effectiveness. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles. Cost estimates were derived from Medicare reimbursement and other sources. The analysis examined 3 hypothetical cohorts of 35-year-old women having suffered their 1st episode of VTE. Interventions included oral anticoagulant therapy for 6 months versus testing. Patients found to have the factor V Leiden mutation were then treated with either 3 years or lifelong oral anticoagulant therapy. RESULTS: Total costs for testing followed by 3 years of treatment were $9,676, whereas those for no testing were $10,392 and those for testing followed by lifelong therapy were $13,179. Testing followed by 3 years of treatment increased quality-adjusted life expectancy by roughly 0.15 years. In sensitivity analyses using a more plausible constant risk model of recurrent VTE, testing followed by lifelong anticoagulation was the favored strategy. However, the marginal cost-effectiveness ratio was highly dependent on the rate of recurrent VTE, the risk of major hemorrhage, prevalence of factor V Leiden, patient age, and the efficacy of anticoagulation therapy. CONCLUSIONS: Testing followed by lifelong anticoagulation is unlikely to be a cost-effective strategy in patient populations with a very low prevalence of factor V Leiden; for those with a lower risk for recurrent VTE, such as patients with a clear precipitant; or for patients with risk factors for bleeding while receiving anticoagulant therapy. The only patients for whom testing followed by lifelong anticoagulant therapy may be a reasonable strategy are those with no obvious precipitant for VTE (i.e., idiopathic VTE) who are at low risk for bleeding complications from oral anticoagulant therapy. These results highlight the need for further clinical investigation and the development of multivariable models predicting the risk of recurrent VTE based on factor V Leiden status, idiopathic versus precipitated VTE, treatment, and the coinheritance of other common thrombophilias, such as the prothrombin gene mutation.     

Anticoagulant treatment of patients with chronic atrial fibrillation in primary health care in Sweden--a retrospective study of incidence and quality in a registered population

BACKGROUND: The number of patients receiving anticoagulant treatment is increasing. Chronic atrial fibrillation is the most common treatment diagnosis. The literature indicates a variable level of treatment control. Estimates of time within the therapeutic range have been recommended as a measurement of quality. Electronic patient records are providing clinical data that are useful for audits concerning anticoagulant treatment in real-life practice. OBJECTIVE: Our aim was to assess warfarin treatment for chronic atrial fibrillation in primary health care with regard to prevalence, incidence and quality. METHODS: A 2 year retrospective study was carried out of electronic patient records up to April 2002 in primary health care in Stockholm, including 12 primary health care centres with a registered population of 203 407. Main outcome measures were the number of new patients on wafarin treatment for chronic atrial fibrillation, and time within the therapeutic prothrombin range in the first 90 days of treatment using a linear interpolation method. RESULTS: In total, 827 patients were on warfarin treatment for chronic atrial fibrillation, giving a prevalence of 0.41%. Of these, 144 patients (study group) started treatment with warfarin for chronic atrial fibrillation during the study period, giving a yearly incidence of 0.07%. Their mean age was 73.1 years and 61.1% were men. There were 1721 prothrombin monitoring episodes registered in the first 90 days of treatment, on average once a week per patient. The average proportion of time within the therapeutic range was 54.1% (95% confidence interval (CI) 50.1-58.1), and the proportion of therapeutic tests was 50.2% (95% CI 47.8-52.6). CONCLUSIONS: During the first, second and third months of warfarin treatment for chronic atrial fibrillation, patients were outside the therapeutic range time nearly half the time. There was a gender difference favouring men regarding initiation of treatment.     

Anticoagulant therapy and referral form. Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology

Many hospitals use the recommendations contained in the British Committee for Standards in Haematology anticoagulant guideline documents to develop local protocols for anticoagulant management. A combined anticoagulant treatment chart and referral form has been produced to help incorporate the recently updated recommendations for oral anticoagulation into day-to-day practice.     

华法林对围产期心肌病抗凝治疗的临床观察

目的通过对比接受华法林治疗3个月与6个月时的临床效果,以探讨华法林对围产期心肌病患者的影响。方法选择2010年12月-2012年12月住院的42例围产期心肌病患者作为研究对象．按照入院顺序将上述患者随机分为两组．两组患者均予以抗心力衰竭治疗,20例（A组）使用华法林治疗3个月,22例（B组）使用华法林治疗6个月,调整华法林剂量将国际标准化比值维持在2．0～3．0,观察比较两组血浆D-二聚体、深静脉血栓和出血率。结果两组治疗后D-二聚体水平显著下降,B组的下降效果明显好于A组,随访发现B组的深静脉血栓形成率明显低于A组,两组出血率比较不存在显著性差异。结论华法林对围产期心肌病抗凝效果明显。持续治疗时间可能是影响抗凝效果的重要因素。     

Referral of patients to an anticoagulant clinic: implications for better management.

The quality of anticoagulant treatment of ambulatory patients is affected by the content of referral letters and administrative processes. To assess these influences a method was developed to audit against the hospital standard the referral of patients to one hospital anticoagulant clinic in a prospective study of all (80) new patients referred to the clinic over eight months. Administrative information was provided by the clinic coordinator, and the referral letters were audited by the researchers. Referral letters were not received by the clinic for 10% (8/80) of patients. Among the 72 referral letters received, indication for anticoagulation and anticipated duration of treatment were specified in most (99%, 71 and 81%, 58 respectively), but only 3% (two) to 46% (33) reported other important clinical information (objective investigations, date of starting anticoagulation, current anticoagulant dose, date and result of latest international normalised ratio, whether it should be the anticoagulant clinic that was eventually to stop anticoagulation, patients' other medical problems and concurrent treatment. Twenty two per cent (16/80) of new attenders were unexpected at the anticoagulant clinic. Most patients' case notes were obtained for the appointment (61%, 47/77 beforehand and 30% 23/77 on the day), but case notes were not obtained for 9% (7/77). The authors conclude that health professionals should better appreciate the administrative and organisational influences that affect team work and quality of care. Compliance with a well documented protocol remained below the acceptable standard. The quality of the referral process may be improved by using a more comprehensive and helpful referral form, which has been drawn up, and by educating referring doctors. Measures to increase the efficiency of the administrative process include telephoning the clinic coordinator directly, direct referrals through a computerised referral system, and telephone reminders by haematology office staff to ward staff to ensure availability of the hospital notes. The effect of these changes will be assessed in a repeat audit.     

Les thromboses veineuses en nutrition parentérale à domicile : de la prévention au traitement

The objective of this review is to summarize the literature and to look at epidemiology, prevention and treatment of catheter-associated venous thrombosis in home parenteral nutrition patients. The rate of this complication is between 0.01 to 0.03 episodes per catheter year. Several risk factors have been identified, such as the position of the catheter tip, the type of material used and a history of catheter-associated infections. Systematic anticoagulant prophylaxis has largely been ineffective. Good insertion technique and catheter cares remain important preventives measures. Moreover, the optimal anticoagulant treatment is unclear due to lack of well-designed studies. In case of catheter-associated venous thrombosis in home parenteral nutrition patients, removal of the catheter is not mandatory. If it is functional, necessary and without associated infection, long-term systemic anticoagulation will be indicated.