Primary and secondary prophylaxis of venous thromboembolism with low-molecular-weight heparins: prolonged thromboprophylaxis, an alternative to vitamin K antagonists

Low-molecular-weight heparins (LMWHs) are used widely in the treatment and prevention of venous thromboembolism (VTE). The LMWHs dalteparin and enoxaparin reduce the rate of VTE by at least 50% if administered for 4-5 weeks following major orthopedic surgery, compared with in-hospital prophylaxis for 7-15 days. Meta-analyses have confirmed that the size of the reduction is similar for both clinical and asymptomatic VTE. Vitamin K antagonists (VKAs) have been shown to be associated with significantly higher bleeding rates compared with LMWH when used as prolonged prophylaxis against VTE following major orthopedic surgery. Patients with cancer are a recognized group at high risk of VTE, and those undergoing major surgery for their malignancy are at particular risk. Evidence from clinical trials is amassing to show that prolonged prophylaxis with LMWH (dalteparin, enoxaparin) in these patients can significantly reduce the rate of postoperative VTE. In cancer patients with acute VTE, the traditional approach is to initiate acute treatment with unfractionated heparin or LMWH followed by long-term treatment with VKA to prevent recurrence. However, clinical trial data have confirmed that the LMWH dalteparin, when administered for 6 months, is significantly more effective than VKA in preventing recurrence, cutting the rate of VTE by 52% without increasing the risk of bleeding. A new and intriguing area of interest is whether LMWH can enhance survival in patients with cancer. Preliminary data suggest that a biological effect of LMWH may act to prolong survival in patients with cancer.     

Epidemiology and management of bleeding in patients using vitamin K antagonists

Summary.  Vitamin K antagonists are effective in the prevention and treatment of a variety of arterial and venous thrombotic disorders, but are associated with an increased risk of serious bleeding complications. According to well documented studies of patients using vitamin K antagonists, the incidence of major bleeding is 0.5% per year and the incidence of intracranial bleeding is 0.2% per year, however, in real life practice this incidence may be even higher. Risk factors for bleeding are the intensity of anticoagulation, the management strategy to keep the INR in the desired range, and patient characteristics. In case of serious bleeding complications in a patient who uses vitamin K antagonists, this anticoagulant treatment can be quickly reversed by administration of vitamin K or coagulation factor concentrates.     

Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without thromboprophylaxis. The SMART Study

Summary.  Background:  In Asian patients undergoing surgery, the incidence of venous thromboembolism (VTE) is thought to be low relative to Western patients, and the routine use of thromboprophylaxis is controversial. Objectives:  The aim of this work was to study the epidemiology of VTE in Asian patients undergoing orthopedic surgery without thromboprophylaxis. Patients and methods:  We performed a prospective observational study of a cohort of consecutive Asian patients hospitalized for total hip or knee replacement or hip fracture surgery without thromboprophylaxis. The primary study outcome was the incidence of the composite of symptomatic VTE or sudden death at hospital discharge. This outcome was also assessed at 1 month's follow-up. Results:  Between April 2001 and July 2002, 2420 patients were enrolled. Median age was 68 years and the median duration of hospital stay was 13 days. The rate of symptomatic VTE or sudden death as notified by investigators was 2.3%[55 patients, 99% confidence interval (CI) 1.6, 3.2] and 1.2% (28 patients, 99% CI 0.7, 1.8) after adjudication by an independent committee. Chronic heart failure, varicose veins and a history of VTE were independent risk factors ( P <  0.05) for the occurrence of the primary endpoint. At 1 month's follow-up, the incidence of adjudicated symptomatic VTE or sudden death was 1.5% (35/2264 patients). Conclusion:  In Asian patients, the incidence of symptomatic VTE after major orthopedic surgery is not low, consistent with the rates observed in Western countries. The use of thromboprophylaxis should be considered in Asian patients undergoing such high-risk surgical procedures.     

骨科大手术术后发生静脉血栓栓塞的影响因素分析

目的探讨骨科大手术术后发生静脉血栓栓塞(VTE)的影响因素。方法选取2017年2月至2019年2月在我院进行骨科大手术的患者120例为研究对象,术后4个月内发生VTE患者53例,采用多因素logistic回归分析发生VTE的高危因素。结果多因素logistic回归分析显示,肥胖、高血压病、糖尿病、血栓史、纤维蛋白原(FIB)、同型半胱氨酸(Hcy)、手术时间、手术体位是影响骨科大手术术后患者发生VTE的独立危险因素(P<0.05)。结论骨科大手术术后发生VTE是由多种危险因素共同导致的,医护人员进行术后护理需要掌握患者基本情况,针对性实施预防措施,降低发生VTE的风险。     

New oral anticoagulants versus vitamin K antagonists before cardioversion of atrial fibrillation: a meta-analysis of data from 4 randomized trials

Background: Scarce data are available about efficacy and safety of new oral anticoagulants (NOACs) for cardioversion (CV) of atrial fibrillation (AF). We performed a meta-analysis of data from randomized studies reporting outcomes of patients receiving NOACs, as compared to vitamin K antagonists (VKAs), and undergoing CV of AF. Methods: Data from four studies were selected, including 4268 CVs. The primary endpoints were the incidence of stroke or systemic embolism and the incidence of major bleeding within 30 days. Results: There was not any significant difference in the incidence of stroke or systemic embolism between NOACs and VKAs (RR 0.73, p = 0.47) nor in the incidence of major bleeding (RR 1.39, p = 0.13). Conclusions: We found no evidence of differential outcomes after CV of AF according to treatment with NOACs or VKAs. This finding warrants confirmation in larger clinical series and in the setting of properly powered randomized trials of newly diagnosed AF.     

Platelet aggregation inhibitors,vitamin K antagonists and risk of subarachnoid hemorrhage

Summary. Background: Use of platelet aggregation inhibitors and vitamin K antagonists has been associated with an increased risk of intracranial hemorrhage (ICH). Whether the use of these antithrombotic drugs is associated with an increased risk of subarachnoid hemorrhage (SAH) remains unclear, especially as confounding by indication might play a role. Objective: The aim of the present study was to investigate whether use of platelet aggregation inhibitors or vitamin K antagonists increase the risk of SAH. Methods: We applied population‐based case–control, case–crossover and case–time–control designs to estimate the risk of SAH while addressing issues both of confounding by indication and time varying exposure within the PHARMO Record Linkage System database. This system includes drug dispensing records from community pharmacies and hospital discharge records of more than 3 million community‐dwelling inhabitants in the Netherlands. Patients were considered a case if they were hospitalized for a first SAH (ICD‐9‐CM code 430) in the period between 1st January 1998 and 31st December 2006. Controls were selected from the source population, matched on age, gender and date of hospitalization. Conditional logistic regression was used to estimate multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of SAH during use of platelet aggregation inhibitors or vitamin K antagonists. In the case–crossover and case–time–control designs we selected 11 control periods preceding the index date in successive steps of 1 month in the past. Results: In all, 1004 cases of SAH were identified. In the case–control analysis the adjusted OR for the risk of SAH in current use of platelet aggregation inhibitors was 1.32 (95% CI: 1.02–1.70) and in current use of vitamin K antagonists 1.29 (95% CI: 0.89–1.87) compared with no use. In the case–crossover analysis the ORs for the risk of SAH in current use of platelet aggregation inhibitors and vitamin K antagonists were 1.04 (95% CI: 0.56–1.94) and 2.46 (95% CI: 1.04–5.82), respectively. In the case–time–control analysis the OR for platelet aggregation inhibitors was 0.50 (95% CI: 0.26–0.98) and for vitamin K antagonists 1.98 (95% CI: 0.82–4.76). Conclusion: The use of platelet aggregation inhibitors was not associated with an increased SAH risk; the modest increase observed in the case–control analysis could be as a result of confounding. The use of vitamin K antagonists seemed to be associated with an increased risk of SAH. The increase was most pronounced in the case–crossover analysis and therefore cannot be explained by unmeasured confounding.     

Non-fatal major bleeding during treatment with vitamin K antagonists: influence of soluble thrombomodulin and mutations in the propeptide of coagulation factor IX.

BACKGROUND AND OBJECTIVES: The key complication of treatment with vitamin K antagonists (VKAs) is bleeding. The major determinant of VKA-induced bleeding is the intensity of anticoagulation. Individual patient characteristics may also influence bleeding risk. In addition, soluble thrombomodulin (s-TM) levels and mutations in the propeptide of factor (F)IX are important candidate risk factors in this respect. PATIENTS AND METHODS: A matched case-control study was designed to search for risk factors that predict bleeding during VKA treatment. We selected cases that had experienced major bleeding during treatment with VKA and matched controls without bleeding complications from the databases of two Thrombosis Services. The controls were matched for indication of treatment, age, gender, type of anticoagulant used and whether or not treatment with VKA was stopped. DNA and plasma were stored of all cases and controls. RESULTS AND CONCLUSIONS: In total 110 patients and 220 controls consented to participate. The results indicate that s-TM levels, measured by ELISA, may be a risk indicator for bleeding [crude odds ratio 3.25 for the highest quartile vs. the lowest quartile (95% confidence interval 1.40, 7.51)]. Three novel mutations, determined by direct sequencing, in the gene portion encoding the propeptide of FIX were identified that do not seem to play an important role in bleeding risk during treatment with VKAs.     

Prevention of venous thromboembolism in the orthopedic surgery patient

Patients undergoing major orthopedic surgery--hip or knee arthroplasty, or hip fracture repair--are in the highest risk category for venous thromboembolism (VTE) solely on the basis of the orthopedic procedure itself. Despite this, nearly half of patients undergoing these procedures do not receive appropriate prophylaxis against VTE, often due to a disproportionate fear of bleeding complications in this population. Guidelines from the American College of Chest Physicians (ACCP) provide evidence-based recommendations for many aspects of VTE risk reduction in the setting of orthopedic surgery, as detailed in this review. The ACCP recommends the use of either low-molecular-weight heparin (LMWH), fondaparinux, or adjusted-dose warfarin as preferred VTE prophylaxis in patients undergoing either hip or knee arthroplasty. Fondaparinux is the preferred recommendation for patients undergoing hip fracture repair, followed by LMWH, unfractionated heparin, and adjusted-dose warfarin as alternative options. Extended-duration prophylaxis (for 4 to 5 weeks) is now recommended for patients undergoing hip arthroplasty or hip fracture repair. Patients undergoing knee arthroscopy do not require routine pharmacologic VTE prophylaxis.     

The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis.

Recent advances in the discovery of new functions for vitamin K-dependent (VKD) proteins and in defining vitamin K nutriture have led to a substantial revision in our understanding of vitamin K physiology. The only unequivocal function for vitamin K is as a cofactor for the carboxylation of VKD proteins which renders them active. While vitamin K was originally associated only with hepatic VKD proteins that participate in hemostasis, VKD proteins are now known to be present in virtually every tissue and to be important to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. The development of improved methods for analyzing vitamin K has shed considerable insight into the relative importance of different vitamin K forms in the diet and their contribution to hepatic vs. non-hepatic tissue. New assays that measure the extent of carboxylation in VKD proteins have revealed that while the current recommended daily allowance for vitamin K is sufficient for maintaining functional hemostasis, the undercarboxylation of at least one non-hemostatic protein is frequently observed in the general population. The advances in defining VKD protein function and vitamin K nutriture are described, as is the potential impact of VKD proteins on atherosclerosis. Many of the VKD proteins contribute to atherogenesis. Recent studies suggest involvement in arterial calcification, which may be influenced by dietary levels of vitamin K and by anticoagulant drugs such as warfarin that antagonize vitamin K action.     

The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery

Summary.  Background : The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. Objectives : To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. Patients/methods : A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. Results : In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are £27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. Results are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. Conclusions : Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.     

Management of idiopathic venous thromboembolism

Introduction: Idiopathic or unprovoked venous thromboembolism is an event occurring in the absence of any apparent provoking or triggering environmental risk factors, such as surgery, trauma, and immobilization.

Areas covered: Unprovoked VTE can be associated with occult cancer, but only limited, and not extensive cancer screening, may be warranted, as the rate of occult cancer is low in such patients. Routine thrombophilia testing is not currently recommended as it does not influence the management of the disease. The duration of anticoagulation for unprovoked VTE after the first three months is still debated as the disease tends to recur regardless of treatment duration.

Expert commentary: Prognostic scores incorporating patient related risk factors, such as age and sex, and global markers of hypercoagulability, such as D-dimer, have been proposed for identifying high risk patients who are candidates for extended anticoagulation beyond three months. Direct oral anticoagulants, aspirin and sulodexide could be alternative to vitamin K antagonists (VKA) for long term treatment in such patients. The most up to date guidelines suggest DOACs over VKA for non-cancer VTE in the first three months and also long-term in subjects at low or moderate risk of bleeding, albeit with grade 2B strength of recommendation.     

Therapeutic index of anticoagulants for prevention of venous thromboembolism following orthopedic surgery: a dose-response meta-analysis

Information on the comparative effectiveness of drugs is crucial for drug development decisions, in addition to being needed by regulators, prescribers, and payers. We have carried out a dose-response meta-analysis of three end points each for efficacy and bleeding for various anticoagulants evaluated for the prevention of venous thromboembolism (VTE) following orthopedic surgery to assess the comparative efficacy and safety of various classes of agents. Data obtained from 89 randomized controlled trials of 23 anticoagulants representing seven drug classes were analyzed. The analysis showed significant differences in the therapeutic index (TI), the ratio of the dose with an acceptable bleeding risk to the dose with a relevant risk reduction for VTE, across the drug classes but not for drugs within a class. The direct inhibitors of FXa, the activated form of factor X--also known as prothrombinase--were found to have a significantly higher TI than that of any other class of anticoagulants, including enoxaparin, suggesting that this mechanism of action provides the best safety-to-efficacy margin.     

“5A”护理对骨科手术患者术后下肢静脉血栓发生率的影响研究

目的研究5A护理的应用对骨科手术患者术后下肢静脉血栓发生率的影响。方法随机选取接受骨科手术治疗的患者110例,依据护理方法分为5A护理组和常规护理组各55例,对2组患者的下肢深静脉血栓(DVT)临床疗效、下床活动时间、住院时间、住院费用及并发症发生情况进行统计分析。结果 5A护理组患者的DVT总缓解率98.2%(54/55)显著高于常规护理组的83.6%(46/55)(P0.05),DVT发生率1.8%(1/55)显著低于常规护理组的16.4%(9/55)(P0.05),下床活动时间、住院时间均显著短于常规护理组(P0.05),并发症发生率5.5%(3/55)显著低于常规护理组的18.2%(10/55)(P0.05)。结论 5A护理的应用能够有效降低骨科手术患者术后下肢静脉血栓发生率,值得临床推广。     

Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study

BACKGROUND: The vitamin K epoxide reductase complex subunit 1 (VKORC1) recycles endogenous vitamin K, a cofactor for vitamin K-dependent coagulation factor synthesis. Common polymorphisms in VKORC1, the gene coding for VKORC1, have been found to affect the dose response to vitamin K antagonists, and to confer an increased risk of vascular diseases in a Chinese population. The aim of this study was to evaluate the association between the VKORC1 1173C > T polymorphism and venous thromboembolism (VTE). METHODS: We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We studied 439 cases hospitalized with a first venous thromboembolic event that was not related to a major acquired risk factor for VTE, and 439 matched controls. The VKORC1 1173C > T polymorphism was selected for genotyping as the tagging single-nucleotide polymorphism for previously identified VKORC1 haplotypes. RESULTS: The relationship between VTE and the VKORCI 1173C > T polymorphism was consistent with a recessive model. The frequency of the VKORCI TT genotype was lower in cases than in controls. The odds ratio (OR) (95% CI) was 0.62 (0.41-0.94) for the TT genotype as compared to CT/CC genotypes. Adjustment on cardiovascular diseases, body mass index, factor V (FV) and prothrombin gene mutations did not alter the results. CONCLUSIONS: In this case-control study, the frequency of the VKORCI TT genotype was lower in patients with VTE than in matched controls. The clinical consequence of these results remains to be determined, but gives new perspectives for exploration of the role of VKORCI polymorphism in the pathogenesis of VTE.