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Multicentre hospital drug utilization study on the prophylaxis of venous thromboembolism. The Venous Thromboembolism Study Group of the Spanish Society of Clinical Pharmacology.

1. Thromboembolic disease (TED) is an important cause of in-hospital morbidity and mortality. Although different prophylactic approaches have been shown to be effective and cost-effective, surveys have suggested that they are underused. The aim of this study was to estimate the prevalence of use of TED prophylaxis in our hospitals. 2. All patients admitted on a specified day to the Internal Medicine and General Surgery wards of seven Spanish university hospitals were included in the study. They were identified cross-sectionally and followed up until discharge or for 15 days. Information about the following variables was collected: risk factors for venous thromboembolism, prophylactic measures used (if any), contraindications to the use of each specific drug or other prophylactic measure, and dosage schedule of the drug used, if any. 3. Nine hundred and thirty-nine patients (53% men) were studied. The most common risk factors for venous thromboembolism were: age > or = 40 years (802; 85%), major surgery (298; 32%), immobilization > or = 6 days (285; 30%), obesity (241; 26%), and cancer (202; 22%). 4. Prophylactic measures were used in 320 patients (34%). Of these, 297 (93%) received heparin, mainly as low molecular weight heparins (248, 78%); physical measures were rarely used. 5. Five hundred and eighty-three patients (62%) fulfilled criteria for moderate or high risk of venous thromboembolism; only 275 (47%) of them received any form of prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Heparin and low-molecular-weight heparin in the treatment of venous thromboembolism.

Venous thromboembolism (deep vein thrombosis and pulmonary embolism) continues to constitute a major clinical challenge. Effective and safe prophylactic measures against venous thromboembolism are now available for most high risk patients. In spite of this, pulmonary embolism is responsible for approximately 150,000 to 200,000 deaths per year in the United States alone. Over the past 20 years, based on a number of high quality (Level I) clinical trials, patterns of practice with respect to the treatment of venous thromboembolism have changed dramatically. The standard treatment of venous thromboembolism has been the use of unfractionated heparin by continuous intravenous infusion, with laboratory monitoring using the activated partial thromboplastin time (APTT), with warfarin starting on day 1 or 2 and continued for 3 months. Unfractionated heparin has withstood the test of time and has been shown to be safe and effective in preventing recurrent venous thromboembolism and death in numerous clinical trials. The response of individual patients to heparin is highly variable, requiring frequent laboratory monitoring. Heparin has a number of other troublesome side effects including bleeding, heparin-induced thrombocytopenia and osteoporosis. The low-molecular-weight heparins have a number of advantages over unfractionated heparin. In particular, their increased bio-availability and prolonged half-life permit once daily subcutaneous injections and their predictable antithrombotic response based on body weight permits treatment without laboratory monitoring. Low-molecular-weight heparin in therapeutic doses causes less bleeding than unfractionated heparin and evidence is accumulating that the incidence of heparin-induced thrombocytopenia and osteoporosis are decreased as well. In individual clinical trials and meta-analyses, low-molecular-weight heparin treatment results in decreased recurrent thromboembolism, major bleeding and death when compared with unfractionated heparin in the treatment of deep vein thrombosis and pulmonary embolism. These agents have also been shown to be both effective and safe for the out-of-hospital treatment of venous thrombosis. Therefore, in many countries, low-molecular-weight heparin has replaced unfractionated heparin for the treatment of venous thromboembolism.

Anticoagulants↗

Risk factors for venous thromboembolism.

Venous thromboembolism is a common and potentially lethal disease. Patients who have pulmonary embolism are at especially high risk for death. Death owing to pulmonary embolism is independent of other comorbid conditions (e.g., cancer, chronic heart disease, or lung disease). Sudden death is often the first clinical manifestation. Only a reduction in the incidence of venous thromboembolism can reduce sudden death owing to pulmonary embolism and venous stasis syndrome owing to deep vein thrombosis. The incidence of venous thromboembolism has been relatively constant since about 1980. Improvement in the incidence of venous thromboembolism will require better recognition of persons at risk, improved estimates of the magnitude of risk, the avoidance of risk exposure when possible, more widespread use of safe and effective prophylaxis when risk is unavoidable, and targeting of prophylaxis to those persons who will benefit most. Recognition of venous thromboembolism as a multifactorial disease with genetic and genetic-environmental interaction has provided significant insights into its epidemiology and offers the possibility of improved identification of persons at risk for incident and recurrent venous thromboembolism.

Humans↗

Risk factors in venous thromboembolism.

Venous thromboembolism is a serious disorder because of its potential complications, such as pulmonary embolism and the post-thrombotic syndrome. Inherited determinants of venous thromboembolism are only in part known, but in the past decades considerable progress has been made in the understanding of risk factors for the disease and their clinical impact. In particular, the development of molecular biology techniques and the increasing interest in their application, allowed an identification of two causes of inherited thrombophilia, i.e., factor V Leiden and the prothrombin G20210A mutation. Their recent discovery provided a new approach for improving the knowledge of inherited thrombophilia. In contrast to deficiencies of the naturally occurring anticoagulant proteins antithrombin, protein C and protein S, these two mutations cannot be considered true genetic defects, since they are nucleotide substitutions resulting in a more efficient coagulation process. Since they are rather common in the general populations of Caucasian descent and are associated with a moderate increased risk of venous thromboembolism, the effect of the interaction between inherited and environmental risk factors for venous thromboembolism has become an even greater field of interest. Prevention of first events and recurrences of venous thromboembolism can be optimized only through a knowledge of the main risk factors, their effect, and their interaction with environmental factors.

Female↗

Prevention of venous thromboembolism.

Venous thromboembolism is the most common cause of preventable death among hospitalised patients. Systematic prophylaxis with antithrombotic agents in patients at risk for venous thromboembolism is the most effective approach to reduce morbidity and mortality. Despite this evidence, antithrombotic prophylaxis is still underused, due to the underestimation of incidence of venous thromboembolism and to the unjustified fear of bleeding complications. Both the characteristics of the individual patient and the clinical setting contribute to the definition of the risk for venous thromboembolism. Patient-related risk factors include clinical and molecular abnormalities. The grade of risk for venous thromboembolism is defined better by the clinical setting than by the patient characteristics. Prophylactic studies have been extensively carried out in surgical patients and, only more recently, in medical patients. Prophylactic methods include pharmacological agents, such as heparin, low molecular weight heparins, warfarin, and hirudin, as well as mechanical methods such as compression stockings and intermittent pneumatic compression.

Anticoagulants↗

Fondaparinux versus enoxaparin for the prevention of venous thromboembolism.

Venous thromboembolism is a frequent, life-threatening, postoperative complication of hip-fracture and total-knee-replacement surgery. Fondaparinux is a synthetic polysaccharide that selectively binds to antithrombin, the primary endogenous regulator of blood coagulation. Low molecular weight heparins, such as enoxaparin, are less specific inhibitors of coagulation. In patients undergoing hip-fracture surgery, fondaparinux is more effective than once-daily enoxaparin as prophylaxis for venous thromboembolism. Fondaparinux (25 mg/day sc.) was also more effective than enoxaparin (30 mg sc. b.i.d.) as prophylaxis for venous thromboembolism in elective knee surgery. These differences may be explained by the fact that there is less prophylaxis cover with enoxaparin, as it has a much shorter duration of action than fondaparinux. Thus, with the present dosing regimens, fondaparinux is probably preferable to enoxaparin for the prevention of venous thromboembolism.

Arthroplasty, Replacement, Hip↗

Pathophysiology of venous thromboembolism.

Venous thromboembolism is complex with a multifactorial etiology. The Virchow triad (changes in blood flow, changes in vessel wall, and changes in the properties of blood) gives the main factors involved in venous thromboembolism. Venous stasis during immobilization in general anesthesia, stroke with hemiparesis, and heart failure plays a central role. The thromboembolic process can be initiated by a disturbance in the normal "hemostatic balance," with an increased thrombogenic potential, due to release of thromboplastin and collagen exposure during vessel wall injury by stasis and hypoxia, decreased fibrinolysis during surgery, malignancy, among others. Many substances modify these processes, including heparan sulfate, AT III, protein C, t-PA inhibitor, and alpha 2-antiplasmin.

Blood Coagulation↗

Perioperative prophylaxis of venous thromboembolism.

Venous thromboembolism is an important cause of morbidity and mortality in hospitalized patients, causing 100,000 to 200,000 deaths per year in the United States. Patients undergoing surgery are at the highest risk of venous thromboembolism. The magnitude of this risk in a patient depends on the surgical procedure performed and the presence of other risk factors that predispose to venous thromboembolism. The clinical diagnosis of both deep vein thrombosis and pulmonary embolism is notoriously inaccurate. Furthermore, two thirds of all fatal pulmonary emboli cause death within 30 minutes of the embolic episode, leaving little time for diagnostic work-up and effective treatment. Prophylactic treatment for prevention of venous thromboembolism is therefore important in these patients, and several effective mechanical and chemical methods for this purpose are available. The pathogenesis of deep vein thrombosis in the surgical patients, the predisposing risk factors, and the available prophylactic modalities are discussed in this article. Recommendations for the use of various approaches in different risk categories are provided.

Humans↗

Cancer and venous thromboembolism.

Venous thromboembolism occurs commonly in patients with cancer. The pathogenetic mechanisms of thrombosis involve a complex interaction between tumour cells, the haemostatic system, and characteristics of the patient. Among risk factors for thromboembolism are long-term immobilisation, especially in hospital, surgery, and chemotherapy with or without adjuvant hormone therapy. Although prophylaxis and treatment of thromboembolism in patients with cancer draw on the agents that are commonly used in those without cancer, there are many special features of patients with cancer that make use of these drugs more challenging. Low-molecular-weight heparins are the cornerstone of prophylaxis and treatment of venous thromboembolism in patients with cancer. These drugs have the potential to increase survival, at least in patients with more favourable outlook. About 10% of patients with idiopathic venous thromboembolism have an underlying malignant disorder that can be detected by extensive diagnostic investigation. However, the issue of whether screening for occult malignant disease ultimately improves prognosis and survival remains to be resolved.

Anticoagulants↗

Oral direct thrombin inhibition: an effective and novel approach for venous thromboembolism.

Venous thromboembolism is a serious illness that affects patient morbidity and mortality and presents a significant management challenge to healthcare providers world-wide. Despite major achievements in the significant reduction of thromboembolic complications, the most common therapies currently used for prevention and treatment of venous thromboembolism--heparins and vitamin K antagonists such as warfarin--have several limitations. In particular, unfractionated heparin and warfarin show significant inter-patient variability in pharmacokinetics and pharmacodynamics, which makes regular coagulation monitoring necessary. Furthermore, only warfarin is suitable for long-term use, as it is administered orally. A new class of anticoagulants has been developed that directly target thrombin, a key enzyme in the blood coagulation cascade. Unlike warfarin and heparin, these direct thrombin inhibitors are able to inhibit fibrin-bound thrombin and so produce more effective inhibition of coagulation. Importantly, some members of this class of drugs have been developed for oral administration. Ximelagatran, which is converted to its active form melagatran, has predictable pharmacokinetics and pharmacodynamics. Therefore, ximelagatran can be administered in fixed doses with no need for coagulation monitoring. Its efficacy and safety profile have been demonstrated in preclinical and clinical studies. As the first oral agent in the new class, direct thrombin inhibitors, ximelagatran has significant potential for improving the prevention and treatment of venous thromboembolism.

Administration, Oral↗

Thrombophilia: disorders predisposing to venous thromboembolism.

Venous thromboembolism continues to present a challenge to clinicians. Over the years, a number of risk factors which predispose to venous thromboembolism have been identified, and these risk factors are taken into account in the formulation of recommendations for the prevention and treatment of these disorders. In more recent years, there have been major advances in our understanding of congenital or acquired defects that predispose to thrombosis leading to these so-called acquired or inherited forms of thrombophilia. The list of acquired forms of thrombophilia now includes anti-thrombin, protein C, protein S, activated protein C resistance, the prothrombin 20210A mutant, homocysteinemia and a number of rare defects which either enhance coagulation or interfere with fibrinolysis. In spite of these advances, there are numerous families with thrombophilia in whom none of the known defects can be demonstrated. The challenge for the future is to discover some of these as yet unknown factors and to determine the most appropriate methods for the prevention and treatment of venous thromboembolism in susceptible individuals with thrombophilia.

Activated Protein C Resistance↗

[Current status of postoperative venous thromboembolism].

Venous thromboembolism has been a common illness even in Japan and gets increased social as well as medical attention, especially during postoperative period. The most effective way of reducing unexpected death from postoperative venous thromboembolism is to institute a comprehensive institutional policy of primary prophylaxis in patients at risk. Since the clinical experience has shown that there are ethnic differences between Japanese and westerners in coagulability, it will be inappropriate to assume that the results of western studies are fully applicable to the clinical situation in Japan. Although it is difficult to prepare the guideline for prophylaxis of venous thromboembolism based on reliable evidence for Japanese currently, available epidemiologic information has been obtained in orthopedic or gynecologic fields.

Anticoagulants↗

Current concepts for the prevention of venous thromboembolism.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide and the annual incidence of VTE is 1 per 1000. The individual risk for venous thromboembolism may be substantially higher and is determined by expositional and dispositional factors. Unfractionated heparin and warfarin have been the mainstays for the prevention of VTE until the early 1980s. Bleeding complications and side effects limited the use of these agents and subsequently low molecular weight heparins (LMWH) were introduced into clinical practice. These are most commonly used for the prophylaxis and treatment of VTE today. In the last decade, the pace of development of further anticoagulants has accelerated with the introduction of new treatment regimens and new substances. In this context, novel drugs directed against clotting factor Xa (such as fondaparinux) and direct thrombin inhibitors (such as melagatran/ximelagatran) have been developed. Fondaparinux shows a favourable efficacy/safety profile and has been documented to be cost-effective compared to enoxaparin in the US and the UK.

Anticoagulants↗

Prospective assessment of a nomogram for the initiation of oral anticoagulation therapy for outpatient treatment of venous thromboembolism.

Venous thromboembolism is a common medical problem. Recently, the emphasis has been on a switch to outpatient low molecular weight heparin therapy. Previous warfarin nomograms have been developed only for inpatients. We prospectively assessed a warfarin initiation nomogram in 105 consecutive outpatients; the nomogram requires International Normalized Ratio (INR) testing on only days 3, 5, and 8. Eighty-three percent had a therapeutic INR by day 5 and 98% by day 8. There were no major bleeds and only 6 instances of INR >4.5. This outpatient warfarin nomogram appears to be safe and efficacious in obtaining timely therapeutic levels of warfarin and deserves further study.

Adult↗

Pathophysiology of venous thromboembolism.

Venous thromboembolism remains an important cause of morbidity and mortality for surgical and non-surgical patients, and its pathophysiology in acutely ill, non-surgical patients is not well understood. The clinically silent nature of thromboembolism makes it a significant threat to hospital patients.

Death, Sudden↗

Current and emerging options in the management of venous thromboembolism.

Venous thromboembolism (VTE) is a common disease whose diagnosis is challenging. The best diagnostic approaches combine the patient's pretest clinical probability of disease with D-dimer testing and/or diagnostic imaging. In light of several advantages, low-molecular-weight heparins are now recommended over unfractionated heparin for most patients with acute VTE. Newer anticoagulants such as the factor Xa inhibitor fondaparinux also show promise for acute VTE. For chronic management, the duration and intensity of warfarin therapy should be tailored to the individual patient.

Anticoagulants↗

Treatment of venous thromboembolism.

Venous thromboembolism (VTE) is a disease entity composed of pulmonary embolism (PE) and deep vein thrombosis (DVT). Anticoagulation, initiated as soon as the diagnosis is suspected, is the treatment of choice. Traditionally, anticoagulation is started with intravenous heparin, and changed to warfarin for long-term treatment. The introduction of unmonitored, subcutaneously administered, low molecular weight heparin has resulted in shorter hospitalizations, reduced the incidence of major bleeding as a complication, and shifted the treatment of VTE for selected patients to the outpatient setting. Thrombolytic therapy has been recommended for patients with life-threatening PE. Technologic advances in catheter embolectomy and fragmentation permit clot resolution in patients in whom thrombolytic therapy is contraindicated. Inferior cava filters can be placed percutaneously in patients at high risk for VTE or those in whom anticoagulation is contraindicated. Because VTE is often clinically silent, prevention of VTE is therefore the most effective means to reduce associated morbidity and mortality. Strategies to prevent VTE have been studied and validated for specific clinical circumstances.

Anticoagulants↗

[Epidemiology and risk factors of venous thromboembolism].

Venous thromboembolism (deep venous thrombosis (DVT) and pulmonary embolism (PE)) is a serious and quite frequent disease. In this review, we summarize the present state of knowledge regarding clinical epidemiology and risk factors. These features should allow the general practitioner to assign each individual patient to a particular risk group and to order an personalized prophylaxis.

Cross-Sectional Studies↗