Anticoagulation in patients with venous thromboembolism

Deep venous thrombosis and pulmonary embolism are considered to be two variants of one disease--'venous thromboembolism'. Pathogenesis, therapy and prognosis of these both entities are very similar and therefore the term 'venous thromboembolism' has been used in recent literature. The cornerstone of therapy is anticoagulation and initially consists of heparin for at least five days. Because of pharmacokinetic advantages low molecular weight heparins are the therapy of choice. They are as efficient and save as unfractionated heparins and allow weight-adapted dosing with daily subcutaneous injections in most patients. Low molecular weight heparins do not require regularly laboratory monitoring with few exceptions, e.g. renal failure. Therefore outpatient treatment of deep venous thrombosis is possible in most patients. Although there are promising data about outpatient treatment of pulmonary embolism, this is still being studied and can not be recommended outside clinical trials. Introduction of coumarin therapy for venous thromboembolism should be started on day 1 of diagnosis, keeping the total duration of heparin therapy at no more than five days and therefore minimizing the incidence of heparin-induced thrombocytopenia. Evidence from multiple studies indicates that effective coumarin therapy in venous thromboembolism is usually reflected by an INR of 2.0 to 3.0. In patients with massive and hemodynamically relevant thromboembolism alternative therapeutic approaches such as thrombolytic therapy, thrombectomy or insertion of intravenous filters may be useful. Adequately fit compression stockings can reduce the risk of post-thrombotic syndrome after deep venous thrombosis.     

关注妊娠期静脉血栓栓塞症

肺血栓栓塞症(PTE)和深静脉血栓形成(DVT)合称为静脉血栓栓塞症(VTE)。妊娠期女性由于存在高凝状态、静脉淤滞、血管损伤等特殊的生理变化,VTE发生风险增高。对存在VTE症状或体征的孕产妇,除非存在明确的抗凝禁忌,否则均应尽快行客观检查同时给予抗凝治疗直到完全排除VTE诊断。低分子肝素(LMWH)不通过胎盘,且无哺乳禁忌,是妊娠及产褥期VTE患者抗凝治疗的最佳选择。一旦开始LMWH初始治疗,应该在余下孕程持续使用,直到产后6周,且总疗程不少于3个月。     

Dalteparin in emergency patients to prevent admission prior to investigation for venous thromboembolism

A 15-month prospective cohort study of emergency department (ED) patients with suspected venous thromboembolism was conducted to assess the role of low molecular weight heparin (dalteparin) in an emergency setting in suspected venous thromboembolism prior to diagnostic confirmation. Patients were given a therapeutic dose of dalteparin and were discharged home; they then returned the next day for diagnostic testing. All patients were followed for 3 months. Of 128 patients, 44 had positive test results and 84 had negative test results. Four patients required admission for other reasons. Seventeen had continuing symptoms after initial negative testing; 10 returned to the ED and 9 had repeat Doppler ultrasound, all of which remained negative. None of the 84 negative patients were diagnosed with venous thromboembolism subsequent to an initial negative test. There were no serious adverse effects. This study suggests that treatment with low molecular weight heparin pending outpatient investigation for suspected venous thromboembolism in emergency patients is safe and effective. This could lead to substantial cost savings in the management of this problem. Further study is warranted.     

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.     

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.     

Role of heparin and low-molecular-weight heparins in the management of acute ischemic stroke

The numerous large-scale randomized clinical trials performed during the last decade on either unfractionated heparin, or low molecular weight heparin have not been able to demonstrate undisputed benefits in patients with acute ischemic stroke, compared with no treatment or aspirin. However, a large number of these trials, including the International Stroke Trial and Chinese Acute Stroke Trial, exhibit severe methodological limitations and need to be interpreted with caution. Knowledge of thromboembolism pathophysiology and clinical experience leads to the theory that heparins will prevent red thrombus formation, propagation and embolism. Heparins effectively prevent venous thrombosis and pulmonary embolism. More trials are needed to test heparins in patients whose cardiocerebrovascular lesions are better defined by newer neuroimaging techniques. The efficacy of heparins has not been adequately tested in patients with defined stroke subtypes and occlusive vascular lesions. Heparins should not be indiscriminately given to all patients with acute ischemic stroke. High-quality, randomized trials that adequately study heparin use in patients using modern technology for vascular lesions and stroke subtypes are lacking, and need to be performed.     

Where do we go now with low molecular weight heparin use in obstetric care?

Summary.  The use of low molecular weight heparins (LMWH) in obstetric care has grown considerably since their introduction into clinical practice in the early 1990s. However, because of the physiological changes of pregnancy, the predictable pharmacokinetic profile of LMWH is lost and some uncertainty exists around the optimal dosing regimen for LMWH in obstetric care. Two recent United Kingdom prospective surveys of the management of acute venous thromboembolism (VTE) suggest that despite recommendations from the Royal College of Obstetricians and Gynaecologists (RCOG) for a twice daily LMWH regimen, a once daily regimen is acceptable for the treatment of venous thromboembolism; and that accepted thromboprophylactic doses licensed for non-pregnant individuals may not be applicable during the second and third trimester for VTE thromboprophylaxis. Accepting that randomized clinical studies are difficult in obstetric care, future advances could be made through population-based multi-center studies, coupled with pharmacokinetic modeling studies, which have the potential to determine the optimal dosing regimen for the various obstetric indications.     

News on antithrombotic therapy and pregnancy

Objectives. State of the art of antithrombotics and their use recommendations during pregnancy. Methods. A review Results. Aspirin and heparins remain the safest molecules during pregnancy, and oral anticoagulants are still used for mechanical valves. Heparinoids are the methods of choice in case of heparin-induced thrombopenia but other molecules could find their place: fondaparinux at first and possibly the direct thrombin inhibitors. Thrombolysis may be used in case of life-threatening incident. At present, the new oral forms can not be used during pregnancy Conclusions. During pregnancy, all antithrombotics, except the oral forms, can be used, but the low molecular weight heparins replacing the unfractionated ones in the treatment and prevention of venous thromboembolism remain the treatment of choice.     

Venous thromboembolism after trauma

PURPOSE OF REVIEW: The trauma population is at increased risk of venous thromboembolic disease, a potentially preventable cause of mortality and morbidity. Although the association between trauma and venous thromboembolism has been recognized for more than a century, there is still great variability in the clinical practices with respect to prophylaxis. This thorough review of recent literature aims to clarify the incidence and risk factors for deep venous thrombosis and pulmonary embolism after trauma, review options and recommendations for detection of deep venous thrombosis and pulmonary embolism, and give evidence-based recommendations for prophylaxis. Special attention is paid to patients with spinal cord injury, patients with head injury, and pediatric trauma patients. RECENT FINDINGS: Highlights in this field during the past year include stratification of venous thromboembolism risk factors after trauma using a large national database, the expanded use of venous duplex ultrasound surveillance in the ICU and during rehabilitation, and investigations into the safety of low molecular weight heparins in patients with solid organ and traumatic brain injuries. Additionally, two new classes of anticoagulant drugs have been introduced for venous thromboembolism prophylaxis, and there are some preliminary studies on a temporary vena cava filter for the prevention of pulmonary embolism. SUMMARY: Venous thromboembolism remains an area of active clinical research focusing on evolving diagnostic techniques, newer methods of chemical and mechanical prophylaxis, and improved understanding of the etiologic factors of posttraumatic venous thromboembolism. These efforts will undoubtedly decrease the posttraumatic morbidity and mortality associated with venous thromboembolism.     

Current perspectives on the treatment of venous thromboembolism: need for effective, safe and convenient new antithrombotic drugs

Treatment of venous thromboembolism (VTE) has evolved significantly over the last decade. Low-molecular-weight heparins have largely replaced unfractionated heparin in the treatment of deep-vein thrombosis (DVT) but the majority of patients with pulmonary embolism (PE) continue to be treated with unfractionated heparin. Fondaparinux is the first synthetic selective inhibitor of factor Xa. It has recently been proved to be more effective than, and as safe as, a low-molecular-weight heparin for the prevention of VTE after major orthopaedic surgery. The two large randomised MATISSE trials demonstrated that fondaparinux was at least as effective and as safe as previous reference heparin therapies in the treatment of VTE. Fondaparinux should further simplify the treatment of this frequent disease since a single once-daily fixed dosage regimen may effectively and safely treat both DVT and PE, an important point especially considering the frequent though clinically silent concomitance of these two thrombotic events.     

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.     

Fondaparinux (Arixtra): a new anticoagulant

Fondaparinux is a promising new antithrombotic agent. This pentasaccharide selectively and specifically inhibits coagulation factor Xa, and requires antithrombin as co-factor It is entirely synthetic, in contrast to conventional heparin and low molecular heparins which are derived from animal tissues. Fondaparinux exhibits a high bioavailability and is convenient to use as it only needs to be given once daily by subcutaneous injection. Peak plasma levels are achieved within two hours of dosing and the plasma half-life of fondaparinux is approximately 17 hours. There is no specific antidote for fondaparinux: it is not neutralised by protamine sulphate. Fondaparinux shows no cross-reactivity with antibodies associated with heparin-induced thrombocytopenia. Several randomised, double-blind studies have demonstrated superiority with respect to a low molecular weight heparin (enoxaparin) in preventing venous thromboembolism in the setting of orthopaedic surgery. The results of clinical trials of fondaparinux in the treatment of deep vein thrombosis and acute coronary syndrome are also presented.     

New oral anticoagulants to revolutionise venous thromboembolism (VTE) management

Warfarin, a vitamin K antagonist has been the mainstay of venous thromboembolism treatment for over 60 years. However, it has significant limitations in relation to achieving a safe and therapeutic efficacy. Evolution in the development of oral anticoagulants to offset the drawbacks of warfarin, has led to the introduction of two new oral anticoagulants, namely dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor. This paper examines the potential of the two new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. In seven randomized clinical trials, dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, The National Institute of Clinical Excellence (NICE) have now endorsed its clinical efficacy as a serious alternative to low molecular weight heparin and fondaparinux.Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopaedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban within its marketing authorisation was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery.     

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

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

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

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

AFFECT: a prospective,open-label,multicenter trial to evaluate the feasibility and safety of a short-term treatment with subcutaneous certoparin in patients with persistent non-valvular atrial fibrillation

BACKGROUND: Patients with persistent atrial fibrillation (AF) scheduled for electrical cardioversion need immediate anticoagulation. Unfractionated heparin (UFH) is often used for early anticoagulation in these patients before oral anticoagulation becomes effective. However, dose adjustment is required to achieve a two- to three-fold prolongation of the activated partial thromboplastin. Low molecular weight heparins, given in body weight-adjusted or independent fixed dosage, require less laboratory monitoring and are also effective within hours of first dosing. They seem to be an attractive alternative to UFH. Previous evidence has shown that these drugs are safe and effective in this indication. PATIENTS AND METHODS: In this prospective, open-label, multicenter pilot study, 203 patients were enrolled with persistent non-valvular AF scheduled for electrical cardioversion. Patients received a fixed dose of 8000 U anti-Xa certoparin twice daily starting immediately after enrolment and before cardioversion was performed. Patients with AF > 48 h underwent transoesophageal echocardiography (TEE) before cardioversion to exclude intra-atrial thrombi. After cardioversion, overlapping oral anticoagulation was started. Treatment with certoparin was stopped only after two consecutive days with INR values >2. OBJECTIVES: The objective was to document the feasibility and safety of a short-term treatment with a fixed, body weight-independent certoparin regimen (2 x 8000 U anti-Xa). RESULTS: Out of 203 patients enrolled, 200 received at least one dose of certoparin and were included in the analysis (safety population). Median treatment duration with certoparin was 7 days. Bleedings were observed in 8 patients (4.0%) and were classified as major (1.5%) or minor (2.5%). Cerebral ischemia was reported for 1 patient (0.5%). One patient showed mild thrombocytopenia (0.5%). There were no reports of venous thromboembolism or death during the treatment period. CONCLUSION: Certoparin administered at 8000 U anti-Xa twice daily independent of body weight was safe and appeared to be effective in patients with non-valvular AF undergoing electrical cardioversion. Its ease of use and the possibility of treatment on an outpatient basis make it an attractive option for early anticoagulation in AF.     

Low molecular weight heparin in chronic renal failure: clinical use

Low molecular weight heparin offers several advantages concerning therapeutic efficacy and safety as compared to unfractionated heparin. Due to renal clearance of low molecular weight heparin problems with the use of low molecular weight heparins may occur in patients with renal failure. Current experience using low molecular weight heparin in patients with renal failure is based on single-dose pharmacokinetic studies, on retrospective analysis and on non-randomized prospective studies. Large randomized studies investigating the use of low molecular weight heparin (e. g. in acute coronary syndrome) have excluded patients with renal failure. Based on the findings mentioned above, treatment with low molecular weight heparin in patients with severe renal failure should follow only under special conditions. In moderate to severe renal failure monitoring anti-Xa activity may be useful to avoid bleeding complications. A definite cut-off level for a potential increase of bleeding complications with the use of low molecular weight heparins in renal failure has not been defined.     

Pharmacologic therapy for the management of thrombosis: unfractionated heparin or low-molecular-weight heparin?

Heparin and heparin-derived drugs play a major therapeutic role in thrombotic and cardiovascular disorders. Infusion of unfractionated heparin (UFH) followed by warfarin has traditionally been the standard pharmacologic therapy for treatment of venous thromboembolism (VTE), which includes both deep vein thrombosis and pulmonary embolism, and for initial therapy of non-ST-elevation (NSTE) acute coronary syndrome (ACS). More recently, low-molecular-weight heparins (LMWHs) have been shown to provide at least as good efficacy and safety outcomes as UFH regimens for prevention of these conditions. In addition to good efficacy outcomes with LMWHs compared with UFH, LMWHs have other advantages over UFH, including improved bioavailability, QD administration, more predictable anticoagulant response, lack of the need for monitoring, and suitability for outpatient use, thereby increasing convenience, reducing cost, and improving cost-to-benefit ratios. In carefully screened and managed patients, LMWH offers a cost-effective, convenient, and safe alternative to UFH for thrombosis management. The aim of this article is to summarize efficacy, safety, and pharmacoeconomic considerations when selecting LMWH versus UFH for thrombosis management in VTE and NSTE ACS.     

A cost analysis of fondaparinux versus enoxaparin in total knee arthroplasty

Several hundred thousand total knee replacement (TKR) surgeries are performed in the United States each year. The American College of Chest Physicians has classified TKR patients in the "highest-risk" category for developing venous thromboembolic events. Recommended prophylactic agents following TKR surgery include unfractionated heparin and low-molecular weight heparins. Fondaparinux is a selective inhibitor of factor Xa and has recently received approval for the prophylaxis of venous thromboembolism in TKR patients. In November 2001, an efficacy study comparing fondaparinux with enoxaparin as deep vein thrombosis prophylaxis in TKR surgery was published by Bauer et al. The purpose of the current study was to perform an incremental cost analysis for fondaparinux versus enoxaparin using the efficacy and safety data of the Bauer et al study. Specific comparisons evaluated included cost per venous thromboembolic event avoided, cost per death averted, and cost per life-year gained with fondaparinux and enoxaparin. All analyses were performed from an institutional perspective and projected to 1000 patients. The incremental cost analysis indicates an USD $1081.33 cost savings with fondaparinux over enoxaparin per venous thromboembolic event avoided. Cost per death averted in the enoxaparin group is USD $88,943.54; cost per death averted in the fondaparinux groups is USD $81,157.94. Cost per life-year gained of USD $5437 for enoxaparin and USD $4925 for fondaparinux.     

低分子肝素对慢性阻塞性肺疾病及血液流变学的影响

目的探讨应用低分子肝素对慢性阻塞性肺疾病及血液流变学的影响。方法将162例慢性阻塞性肺疾病患者随机分为观察组（84例）和对照组（78例）,162例患者均积极控制呼吸道感染、改善呼吸功能、纠正酸碱平衡及电解质紊乱、治疗并发症。观察组加用低分子肝素,每次使用4000U,隔日1次,皮下注射,总疗程20d。结果观察组总有效率为92．86％,对照组总有效率为74．36％,前者显著改善全血粘度和红细胞压积等血液流变学指标,两组差异有统计学意义（P〈0．05）。结论低分子肝素治疗慢性阻塞性肺疾病可改善血液循环障碍和心肺功能,纠正低氧血症。