Proficient and cost-effective approaches for the prevention and treatment of venous thrombosis and thromboembolism

Thrombosis is clearly a common cause of death in the US. It is obviously of major importance to define the aetiology of deep vein thrombosis (DVT) as (i) many of these events are preventable if appropriate therapy, dependent upon the risk factors known is utilised; (ii) appropriate antithrombotic therapy will decrease risks of recurrence; (iii) the type of defect(s) and risk(s) will determine length of time the patient should remain on therapy for secondary prevention and (iv) if the defect is hereditary appropriate family members can be assessed. Aside from mortality, significant additional morbidity occurs from DVT including, but not limited to, stasis ulcers and other sequelae of post-phlebitic syndrome. Numerous studies have provided evidence that medical patients and patients undergoing surgery or trauma are at significant risk for developing DVT, including pulmonary embolism (PE). Thus, an important task for the clinician is to prevent DVT and its complications. It is important to define risk groups where prophylaxis must be considered. The attitudes and beliefs towards prophylaxis show great regional variations. This is true for the definition of risk groups, the proportion of patients receiving prophylaxis and prophylactic modalities used. For this reason, various 'consensus conference' groups have attempted to alleviate these problems; the primary mission of consensus guidelines is to provide optimal direction to the clinician in the setting of clinical practice. If the practice guidelines generated are successful they will assist clinicians in decision-making for their patients, and they will also provide protection against unjustified malpractice actions. Therapy may be complex, as clinical studies continue to identify more effective treatments. This review includes currently accepted approaches to the treatment of DVT. The clinical course of DVT is highly dynamic. When the response to therapy is not as expected, more than one cause of DVT may be present in a patient. Treatment must address the primary coagulopathy as well as any precipitating factors. The risk of pharmacological intervention must be balanced against potential benefit. If the incidence of DVT in a given disorder is low and if the mortality rate is similarly low, therapy with an agent known to be associated with a high risk for complications, such as warfarin, would not be indicated. If DVT is seen primarily after surgery or in other high-risk situations, therapy might be limited to a fixed time period. However, if the ongoing risk of DVT remains high or if a history of recurrent DVT dictates, lifelong therapy might be indicated. The recommendations presented are based upon published controlled trials; however, indications for therapy and therapeutic agents of choice will continually evolve. By applying the principles outlined in this review, substantial cost savings, reduction in morbidity and reductions in mortality should occur.     

骨科手术后深静脉血栓形成的预防和治疗进展

深静脉血栓形成是骨科术后严重的并发症,如得不到及时预防和治疗,致残率和致死率较高。随着医疗技术的发展,骨科手术患者的危险性越来越受到人们的重视,预防和治疗围手术期静脉血栓栓塞病尤为重要。本文就近几年来对骨科手术后深静脉血栓形成的预防和治疗进展概况进行综述。     

Ticagrelor for the treatment of arterial thrombosis

Importance of the field: High platelet reactivity has been linked to recurrent ischemic events in patients treated with conventional dual antiplatelet therapy, in patients with arterial diseases and particularly in patients treated with coronary artery stenting. The limitations of clopidogrel have served as a major rationale for the development of new P2Y₁₂ blockers that have superior pharmacodynamic profiles uninfluenced by concomitant therapies or specific genotypes. Ticagrelor is the first direct-acting reversibly binding oral P2Y₁₂ receptor antagonist. Extensive Phase II investigations have addressed the pharmacokinetic, pharmacodynamic and safety-related properties of ticagrelor compared with clopidogrel. The recently completed PLATO trial demonstrated promise for ticagrelor as a major treatment strategy for a wide spectrum of patients with acute coronary syndromes. Ticagrelor is now being reviewed by the FDA as a P2Y₁₂ receptor blocker to treat patients with coronary artery disease and, once accepted, will be in widespread use as an antiplatelet agent. Thus, it is both appropriate and timely to review available data and provide a comprehensive review of ticagrelor.

Areas covered in this review: We discuss the rationale for the development of ticagrelor, a reversible and potent P2Y₁₂ receptor blocker. The data regarding ticagrelor based on preclinical and clinical studies are examined. We researched articles about ‘AZD6140’ and ‘ticagrelor’ in PubMed from 2006 to 2010 and also reviewed data presented at recent cardiology meetings.

What the reader will gain: This is an updated and comprehensive review of ticagrelor. The advantages and disadvantages of ticagrelor and available P2Y₁₂ receptor blockers such as clopidogrel and prasugrel are discussed, thus providing a clear picture to readers.

Take home message: Ticagrelor has an important role as an antiplatelet agent in the settings of acute coronary syndrome and percutaneous coronary intervention and once accepted will be in widespread use.     

Detection and prevention of deep venous thrombosis

Deep venous thrombosis (DVT) is a significant problem in the postoperative course of high-risk patients. Risk factors that further predispose patients to DVT include obesity, age over 40 years, smoking, dehydration, and a prior history of thromboembolism. Diagnosis of DVT by physical examination and medical history is difficult; objective diagnostic techniques are often required. Considerable emphasis has been placed on the cost-effectiveness of implementing prophylactic measures in patients who are at high risk for developing DVT. Physical maneuvers attempt to reduce stasis and enhance venous return and pharmacologic approaches alter blood coagulability. The drug therapy used in preventing DVT consists of dextran, low-dose heparin, a combination of low-dose heparin and dihydroergotamine, and warfarin. Effective prophylactic regimens differ according to the type of patients at risk. Prophylactic therapy should be tailored according to the patient's disease and degree of risk.     

Emerging therapies for the treatment and prevention of otitis media

Otitis media is one of the most common disorders occurring in children, and there is growing concern that bacteria are quickly becoming resistant to antimicrobials. As a result, global antibiotic treatment is no longer the standard of care and treatment of otitis media has changed dramatically in the last decade. In addition to new antimicrobials currently in development, the effects of the pneumococcal conjugate vaccine are just beginning to be understood. Furthermore, new surgical techniques are for the first time being tested as alternatives for tympanostomy tubes for recurrent acute otitis media. This review discusses current and emerging otitis media therapeutics, with particular attention to acute otitis media. Topics include antimicrobial use, antimicrobial resistance, effects of vaccination and new surgical techniques.     

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.     

新型冠状病毒肺炎相关静脉血栓防治的药学服务

目的：介绍新型冠状病毒肺炎（COVID-19）治疗期间，静脉血栓（VTE）防治的药学监护策略。方法：通过查阅不同人群（如儿童、孕妇、老年患者） VTE防治的文献和指南，结合临床药师实践工作经验和对应的药品相关信息，给出不同COVID-19患者人群防治VTE的监护要点和用药参考。结果：对于所有确诊的COVID-19住院患者均应进行VTE风险评估，并根据评估结果采取预防措施。对于儿童COVID-19患者，药物预防VTE可选择达肝素钠和依诺肝素钠；对于妊娠和哺乳期COVID-19患者，建议首选低分子肝素（LMWH）；对于肝肾功能不全患者，应根据肝肾功能状态评估，进行药物选择和剂量调整。结论：COVID-19患者并发VTE是临床较为严重的情况之一，严重影响患者的治疗和预后，因此进行及时的VTE风险评估和防治，并提供实时的药学监护服务是十分必要的。     

脑肿瘤术后患者下肢深静脉血栓形成的诊治及预防

目的探讨对脑肿瘤术后下肢深静脉血栓形成（DVT）的诊治及预防。方法回顾性分析我院2005年7月～2008年1月38例脑肿瘤术后下肢深静脉血栓形成患者临床资料。结果38例患者行抗凝治疗26例，溶栓治疗8例，下腔静脉滤器置入4例，36例患者下肢肿胀疼痛症状缓解，下肢血管彩色多普勒超声检查示血栓全部再通痊愈者10例，部分再通有效者26例。结论脑肿瘤术后患者为下肢DVT中高危患者，血浆D-二聚体的检测及血管彩色多普勒超声检查相结合能够有效地诊断DVT的发生，抗凝治疗为主要方法，下腔静脉滤器置入对防止肺栓塞发生有重要作用。     

Bemiparin: a review of its use in the prevention of venous thromboembolism and treatment of deep vein thrombosis

Bemiparin (bemiparin sodium; Hibor, Ivor, Zibor, Badyket) is a low molecular weight heparin (LMWH) with a lower mean molecular weight (3600 D) and a higher anti-Xa/IIa ratio (8:1) than other LMWHs. Bemiparin was effective as thromboprophylaxis in surgical patients in well controlled clinical trials. No cases of venous thromboembolism (VTE) were reported in low- to moderate-risk patients receiving prophylaxis with bemiparin 2500 anti-Xa IU/day for 7 days or unfractionated heparin (UFH) 5000 anti-Xa IU twice daily for 7 days. In high-risk patients, bemiparin 3500 anti-Xa IU/day for > or =8 days was more effective than UFH 5000 anti-Xa IU twice daily for > or =8 days in the prevention of VTE in patients undergoing total hip replacement. Postoperative bemiparin 3500 anti-Xa IU/day for 10 days was as effective as enoxaparin 4000 anti-Xa IU/day for 10 days commenced 12 hours before surgery in high-risk patients undergoing total knee replacement. As a short-term treatment for acute established deep vein thrombosis (DVT), bemiparin 5000-10 000 anti-Xa IU/day (dependent on bodyweight) for 7 or 10 days was more effective than intravenous UFH (5000 anti-Xa IU bolus followed by 30,000 or 40,000 anti-Xa IU/day for 7 days) in reducing thrombus size from baseline. Bemiparin 3500 anti-Xa IU/day was also as effective as oral warfarin (10 mg/day for the first 3 days, then adjusted to achieve an international normalised ratio between 2 and 3) for the long-term (12 weeks) treatment of DVT, although data are limited. Subcutaneous bemiparin was generally well tolerated. The most commonly reported adverse events in clinical trials were postoperative bleeding complications (similar incidence to that with UFH or enoxaparin in high-risk patients, lower incidence in low- to moderate-risk patients). CONCLUSIONS: Bemiparin is a new LMWH which has shown efficacy in a small number of well controlled trials in the prevention of postoperative VTE in low- to moderate- and high-risk patients and in the treatment of established DVT. It can be initiated pre- or post-operatively, whereas recommendations for other LMWHs in Europe primarily involve preoperative initiation. Additional comparative studies would be beneficial in determining the overall place of bemiparin, particularly with respect to the relative incidence of bleeding complications. In the meantime, available data suggest that bemiparin is an effective and useful addition to the available range of LMWHs for the prevention of VTE and treatment of DVT.     

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.     

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.     

Targeted oral therapies in the treatment of pulmonary arterial hypertension

Recent advances in our understanding of the pathophysiology of pulmonary arterial hypertension (PAH) have led to the US FDA's approval of eight drugs for its treatment. Although guidelines for the use of PAH therapies are available and regularly updated, there is a lack of information on how these agents differ and what characteristics may enable one agent to be of greater relative clinical utility than another. Oral agents may be compared across a variety of measures, including clinical efficacy, safety and tolerability, dosing and pharmacology, potential for drug interactions, treatment adherence and suitability for use in combination regimens. Although no large, prospective, head-to-head trial has been conducted with oral agents for PAH, data from placebo-controlled studies indicate that the enrolled patient populations were remarkably homogeneous with respect to demographic and disease severity parameters. In general, data suggest that these agents improve functional capacity, delay disease progression and improve haemodynamics. Additionally, long-term sustainability of response has been demonstrated. However, there was no consistently superior agent across the primary and secondary endpoints assessed in these trials, and the magnitudes of improvements were in a fairly defined range across agents. Consequently, treatment choice may shift to other aspects such as drug safety and tolerability, potential for drug interactions, dosing convenience, treatment adherence, effect on quality of life and access to medication. In this review, the four targeted oral agents approved for the treatment of PAH in the US are reviewed, and clinical results are placed into context.     

肠系膜上静脉血栓形成的诊治分析

目的:探讨肠系膜上静脉血栓形成(SMVT)的诊断与治疗。方法:回顾分析2003～2007年间收治的8例SMVT患者临床资料,总结SMVT的临床特点、诊断和治疗。结果:手术治疗6例,保守治疗2例,无死亡病例。结论:SMVT的早期症状与体征不符,极易误诊,B超、CT及MRI是诊断SMVT的主要手段。早期诊断,及时手术治疗,术后抗凝是降低手术死亡率和复发的关键。     

Novel therapies for the prevention of malaria

Background: Malaria continues to exact a huge toll on the health of residents of endemic countries. Thus, new approaches to prevention and treatment are needed. Objective: To provide an update on novel therapies for the prevention of malaria. Methods: Systematic MEDLINE search from 1956 to 2008 using the search term ‘malaria’ (with the subheadings ‘intermittent preventive treatment’, ‘mass drug administration’, ‘chemotherapy’, ‘artemisinin-based combination therapy’ and ‘home-based management of malaria’). Conclusions: Chemoprophylaxis is used as a short-term protective measure for non-immune visitors to malaria-endemic countries. However, in malaria-endemic areas, chemoprophylaxis has not been implemented widely because of concerns related to sustainability, cost-effectiveness, appropriate delivery systems and development of drug resistance. Intermittent preventive treatment, a novel approach to malaria control, has the potential to provide some of the benefits of sustained chemoprophylaxis without some of its drawbacks.     

Novel therapies for the prevention of stroke

The health and economic burden of stroke to society is enormous. Pharmacological therapies remain the primary stroke prevention strategy for the vast majority. Several existing and newer pharmacological agents aimed at the treatment of hypertension and lowering cholesterol are proving to be effective. For example, the antiplatelet agent clopidogrel has reduced end points in the secondary prevention of stroke, as have combinations of aspirin with traditional therapies, including dipyramidole. The direct oral thrombin inhibitor ximelagatran is a novel oral anticoagulant that has shown significant potential as a possible replacement to warfarin therapy, for the prevention of stroke for patients with non-valvular atrial fibrillation. Additional novel agents with hypothetical, although not yet proven, benefits in stroke prevention include fish oils, homocysteine-lowering therapy and anti-inflammatory agents. Finally, a controversial novel polypill, which would include fixed combinations of several pharmacological agents, may yet become a realistic and promising stroke prevention option.     

Novel therapies for the prevention of stroke

The health and economic burden of stroke to society is enormous. Pharmacological therapies remain the primary stroke prevention strategy for the vast majority. Several existing and newer pharmacological agents aimed at the treatment of hypertension and lowering cholesterol are proving to be effective. For example, the antiplatelet agent clopidogrel has reduced end points in the secondary prevention of stroke, as have combinations of aspirin with traditional therapies, including dipyramidole. The direct oral thrombin inhibitor ximelagatran is a novel oral anticoagulant that has shown significant potential as a possible replacement to warfarin therapy, for the prevention of stroke for patients with non-valvular atrial fibrillation. Additional novel agents with hypothetical, although not yet proven, benefits in stroke prevention include fish oils, homocysteine-lowering therapy and anti-inflammatory agents. Finally, a controversial novel polypill, which would include fixed combinations of several pharmacological agents, may yet become a realistic and promising stroke prevention option.     

Current therapies for the treatment of systemic sclerosis-related pulmonary arterial hypertension: efficacy and safety

Introduction: Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. Patients with limited SSc typically develop pulmonary arterial hypertension (PAH). TNF-α, VEGF, platelet-derived growth factor and endothelin-1 play a key role in the development of PAH.

Areas covered: This paper addresses the efficacy and safety of current drugs used for the treatment of PAH.

Expert opinion: Bosentan, ambrisentan, sildenafil, tadalafil, iloprost, epoprostenol and treprostinil were associated with hemodynamic improvements in PAH patients. Ambrisentan has a better safety profile compared with bosentan, regarding the risk of increase in hepatic transaminases. Flushing, dyspepsia and diarrhea were the most frequent adverse events in patients treated with sildenafil, while headache, myalgia and flushing were the adverse events in those receiving tadalafil. Inhaled iloprost is also effective, but it requires multiple daily nebulizations up to 15 min each and may induce cough, flushing, jaw pain and headache. Epoprostenol is considered the most effective approved therapy for severe PAH in WHO functional class III and class IV. TNF-α inhibitors reduce the systemic inflammation in patients with chronic immune-mediated diseases and improve the endothelial function, decreasing the risk of PAH progression.