fondaparinux and Thromboembolism

The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007.. To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications.. For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings.. Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein.. Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach.. We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects.. Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Rivaroxaban; Stockings, Compression; Thrombectomy; Thromboembolism; Thrombophlebitis; Venous Thromboembolism

Heparin, whose discovery goes back one hundred years, was first detected as a thromboplastin from liver tissue, and its anticoagulant action was only identified later. The procoagulant action of heparin, which was later characterized as an immunologic reaction by binding to platelet-factor IV, presenting as heparin-induced thrombocytopenia, remains as a side effect. For more than 60 years heparin has been the immediate anticoagulant of choice in many clinical indications. Further development of heparins resulted in the production of low-molecular weight heparins and Fondaparinux, which substituted heparin for many indications and has received many more new indications, including administration for non-anticoagulant purposes. This development is still ongoing and has resulted in more than 300 registered clinical trials at the end of 2015. All types of heparins are still investigated in patients with impairment of renal function to improve the safety of treatment. New therapeutic strategies for the prevention and treatment of thromboembolism, as well as of the non-anticoagulant actions of natural and modified types of heparins, are studied intensively. The clinical study designs include treatment with vitamin-K and non-vitamin K oral anticoagulants. Consequently, heparins, low-molecular weight heparins and Fondaparinux play an important role in the human health care system.

Topics: Anticoagulants; Clinical Trials as Topic; Drug Design; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Renal Insufficiency; Thromboembolism; Vitamin K

The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the second update of a review first published in 2007.. To assess the efficacy and safety of topical, medical, and surgical treatments in patients presenting with ST of the legs.. For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11). We handsearched the reference lists of relevant papers and conference proceedings.. Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included participants with a clinical diagnosis of ST of the legs or an objective diagnosis of a thrombus in a superficial vein.. Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus.. We identified four additional trials (986 patients), so this update considered 30 studies involving 6507 participants with ST of the legs.Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), non-steroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. Only a minority of trials compared treatment with placebo rather than an alternative treatment, none evaluated the same treatment comparisons on the same study outcomes (which precluded meta-analysis), and many of the studies were small and of poor quality. In one large, placebo-controlled RCT of about 3000 patients, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), ST extension (RR 0.08; 95% CI 0.03 to 0.22), and ST recurrence (RR 0.21; 95% CI 0.08 to 0.54) with comparable rates of major bleeding (RR 0.99; 95% CI 0.06 to 15.86) relative to placebo. In a further placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (RR 0.40; 95% CI 0.22 to 0.72 and RR 0.42; 95% CI 0.23 to 0.75, respectively) and NSAIDs (RR 0.41; 95% CI 0.23 to 0.75) reduced the extension and recurrence of ST in comparison to placebo, with no significant effects on symptomatic VTE nor major bleeding. Overall, topical treatments improved local symptoms compared with placebo but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatment, topical treatment, or surgery did not report VTE, ST progression, adverse events, or treatment side effects.. Prophylactic dose fondaparinux given for six weeks appears to be a valid therapeutic option for ST of the legs. The evidence on oral treatments, topical treatment, or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE and ST progression. Further research is needed to assess the role of the new oral direct thrombin and activated factor-X inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Thrombophlebitis; Venous Thromboembolism

The Authors describe diagnosis, treatment and therapy of deep venous thrombosis in Emergency Department following the last guidelines indications.. Deep venous thrombosis of the legs, ranges from asymptomatic, incidentally discovered emboli to massive embolism causing immediate death. Chronic sequelae of venous thromboembolism (deep venous thrombosis and pulmonary embolism) include the post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. Acute pulmonary embolism may occur rapidly and unpredictably and may be difficult to diagnose. Diagnosis and treatment can reduce the risk of death, and appropriate primary prophylaxis is usually effective. Patients treated for acute pulmonary embolism appear to be more times as likely to die of recurrent thromboembolism in the next year.

Topics: Anticoagulants; Antifibrinolytic Agents; Emergency Medical Services; Emergency Service, Hospital; Fibrin Fibrinogen Degradation Products; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Risk Factors; Stockings, Compression; Thrombectomy; Thromboembolism; Thrombolytic Therapy; Tomography, Spiral Computed; Ultrasonography; Vena Cava Filters; Venous Thrombosis; Vitamin K

Anticoagulants are the mainstay of treatment of venous thromboembolic and acute coronary events. Improvements of new over established anticoagulants are targeted to achieve more favorable pharmacokinetics, minimal hemorrhagic side effects, a predictable dose response that obviates the need for coagulation monitoring, and more appropriate dose selection for the indication of interest. New parenteral anticoagulants are free of the complications of HIT, can be selected so that they are safe in patients with impaired renal or hepatic function, and can be administered once daily without the need for coagulation monitoring. Drug development has been focused on two key targets: factor Xa and factor IIa (thrombin). Fondaparinux is the first selective inhibitor of the coagulation factor Xa which is commercially available for clinical use. It has been approved for the prevention of venous thromboembolism in patients undergoing orthopedic surgery, abdominal surgery and for the initial therapy of deep venous thrombosis and venous thromboembolism. Fondaparinux sodium injection has been accepted for priority review by the United States Food and Drug Administration based on positive results from two pivotal, Phase III trials (OASIS 5 and 6) that evaluated its role in the treatment of a broad spectrum of patients with acute coronary syndromes (ACS). In this article, we review the available literature that provides evidence for the efficacy of fondaprinux in management of thromboembolic disease as well as acute coronary syndromes.

Topics: Acute Disease; Animals; Anticoagulants; Coronary Disease; Fondaparinux; Humans; Polysaccharides; Thromboembolism

Disorders of coagulation are common adverse drug events encountered in critically ill patients and present a serious concern for intensive care unit (ICU) clinicians. Dosing strategies for medications used in the ICU are typically developed for use in noncritically ill patients and, therefore, do not account for the altered pharmacokinetic and pharmacodynamic properties encountered in the critically ill as well as the increased potential for drug-drug interactions, given the far greater number of medications ordered. This substantially increases the risk for coagulation-related adverse reactions, such as a bleeding or prothrombotic events. Although many medications used in the ICU have the potential to cause coagulation disorders, the exact incidence will vary based on the specific medication, dose, concomitant drug therapy, ICU setting, and patient-specific comorbidities. Clinicians must strongly consider these factors when evaluating the risk/benefit ratio for a particular therapy. This review surveys recent literature documenting the risk for adverse drug reactions specific to bleeding and/or clotting with commonly used medications in the ICU.

Topics: Anti-Infective Agents; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Colloids; Critical Care; Deamino Arginine Vasopressin; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Estrogens, Conjugated (USP); Factor VIIa; Fibrinolytic Agents; Fondaparinux; Hemostatics; Humans; Polysaccharides; Protein C; Recombinant Proteins; Thrombin; Thromboembolism; Vitamin K

Fondaparinux, a pentasaccharide which selectively binds to antithrombin III, has negligible to no cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies in in vitro studies. The lack of cross-reactivity suggests a potential role in the management of HIT, and indeed, there are several such case reports and small studies. These published data have used both the prophylactic and weight-based treatment doses. However, due to the small possibility of developing HIT with thromboembolic complications while receiving fondaparinux, it is suggested that the appropriate weight-based treatment dose be used. In all these reports, fondaparinux provided adequate anticoagulation, prevented further thromboembolic events, and platelet counts returned to normal. However, there have been a couple of case reports on possible HIT or HIT-like syndrome secondary to fondaparinux use.. Fondaparinux is an attractive anticoagulant therapy in patients with HIT. There is still the need for larger randomized trials evaluating the true efficacy, appropriate dose, safe duration of treatment, and the true incidence of HIT associated with fondaparinux.

Topics: Adult; Anticoagulants; Clinical Trials as Topic; Female; Fondaparinux; Heparin; Humans; Male; Polysaccharides; Thrombocytopenia; Thromboembolism

The use of anticoagulants in the prophylaxis and treatment of arterial and venous thrombosis has substantially expanded during the last years. Increasing knowledge about the inherited and acquired thrombophilia and the risk factors predisposing to the recurrency of thromboembolic events result in a new indications for primary and secondary thromboprophylaxis with prolonged or even life-long duration. The limitations of classical anticoagulans, heparin and vitamin K antagonists support the development of medicaments with a specific antithrombotic action. The new generation anticoagulants inhibit in a specific way either particular coagulation enzyme or hemostasis activation step. Based on the in vitro studies and extensive clinical observations the activated factor Xa (FXa) seems to be one of the most advantageous targets for a specific action of perspective antithrombotic agents. Two selective F Xa inhibitors have been approved for clinical use: fondaparinux is an indirect parenteral F Xa inhibitor, and most recently approved rivaroxaban is the first oral anti-Xa inhibitor. Other anti-Xa molecules are under development for either parenteral (idraparinux, DX-9065a) or oral use (razaxaban, apixaban, rivaroxaban, LY-51, 7717, BMS-56247 a DU-176b).

Topics: Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Humans; Morpholines; Polysaccharides; Rivaroxaban; Thiophenes; Thromboembolism

Selective inhibitors of specific coagulation factors represent a new class of antithrombotic agents, designed to overcome the limitations of traditional anticoagulants. Available clinical studies indicate that the most promising new anticoagulants are those selectively targeting factor Xa and thrombin. Typically, the standard steps for clinical evaluation of new anticoagulants are thromboprophylaxis in high risk orthopedic surgery, followed by treatment of established venous thromboembolism, nonvalvular atrial fibrillation and acute coronary syndromes. These agents - that have the potential to be more effective and easier to use than conventional drugs such as heparins and vitamin K antagonists - will greatly expand our armamentarium for the prevention and treatment of arterial and venous thromboembolism. The current knowledge on these antithrombotic agents is summarized in this review, particularly focusing on the early results of clinical trials.

Topics: Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Humans; Polysaccharides; Thrombin; Thromboembolism

A review of current literature discussing thromboprophylaxis in the multiple-trauma patient to provide insight on the type of treatment and its duration of use. AMEDLINE search was conducted in May 2009 using keywords associated with thromboprophylactic measures in multiple-trauma patient care, including inferior vena cava (IVC) filters, mechanical-compression devices and anticoagulants. Abstracts were evaluated for relevance to this study and full-text articles were then examined individually. Fourteen full text articles were evaluated including guidelines published by the American College of Chest Physicians (ACCP) and the Eastern Association for the Surgery of Trauma (EAST) and other studies dealing with multiple-trauma patients, including those in hip-fracture surgery, lower-leg trauma and head trauma. Limited research has been performed for the multiple-trauma patient and recommendations regarding the type of treatment and its duration of use cannot be suggested beyond what has been extrapolated from existing trauma and major surgery patients. IVC filters, mechanical compression devices and anticoagulants therefore remain the standard, but their duration of use in the multiple-trauma patient is not well described. New oral anticoagulants that inhibit factor Xa or thrombin directly show promising qualities but have not been evaluated for multiple-trauma applications. Therefore, optimal thromboprophylaxis and its duration after multiple trauma is largely based on rational, clinical decision making on a case-by-case basis.

Topics: Anticoagulants; Clinical Trials, Phase III as Topic; Device Removal; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Intermittent Pneumatic Compression Devices; Morpholines; Multiple Trauma; Polysaccharides; Practice Guidelines as Topic; Rivaroxaban; Thiophenes; Thromboembolism; Time Factors; Vena Cava Filters

Thromboembolic complications are increasing in children and the use of anticoagulation has seen a dramatic increase despite the lack of randomized clinical trials. The most widely used agents in children are heparin, low-molecular-weight heparins (LMWH), and warfarin. These agents, however, have significant limitations that are exaggerated in children. Novel anticoagulants such as direct thrombin inhibitors and the selective factor Xa inhibitor, fondaparinux, have been approved for use in adults and have properties that suggest they may be safer and more efficacious than the standard agents; however, until recently, publications using these agents in children were limited to case reports. Recently, clinical trials for two direct thrombin inhibitors, bivalirudin and argatroban, have been completed and a clinical trial of fondaparinux is under way. This review will compare the standard agents with the novel agents and briefly review the results of the clinical trials.

Topics: Adult; Age Factors; Anticoagulants; Child; Clinical Trials as Topic; Fondaparinux; Heparin, Low-Molecular-Weight; History, 20th Century; Humans; Polysaccharides; Safety; Thromboembolism; Warfarin

The overall thromboembolic risk is the resultant of patient-related risk and surgical risk. The surgical risk is decreasing, especially with the introduction of new procedures (fast-track surgery). The value of prophylaxis has been firmly established. Mechanical prophylaxis is to be used as first-line prophylaxis when there is a risk of bleeding. Combining this with drugs increases the antithrombotic efficacy. However, the effectiveness of prophylaxis on pulmonary embolism and mortality has not been demonstrated. Renal function needs to be evaluated when low molecular weight heparins, fondaparinux, rivaroxaban or dabigatran are prescribed. An age of over 75 years and low body weight (<50 kg) have to be taken into account. There is a risk of spinal or epidural hematoma in patients receiving anticoagulants. Caution should be taken especially when administering the newer agents. Patients undergoing surgery that involves a moderate or high overall risk should receive prophylaxis until full mobilization. Patients who have undergone a total hip replacement, surgery for hip fracture, or major abdominal surgery should receive prophylaxis for about 5 weeks longer. The relevance of distal vein thromboses is debated. Surrogate venographic end-points should be gradually replaced by a combination of ultrasound and clinical criteria. The new antithrombotic agents will probably modify prevention in the years to come but currently there are very few long-term data for these products for which - it should be reminded - no antagonists are available.

Topics: Adult; Aged; Anticoagulants; Combined Modality Therapy; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Morpholines; Polysaccharides; Postoperative Complications; Preanesthetic Medication; Pulmonary Embolism; Risk Factors; Rivaroxaban; Stockings, Compression; Thiophenes; Thromboembolism; Thrombophlebitis; Vitamin K

Topics: Anticoagulants; Chemoprevention; Combined Modality Therapy; Fondaparinux; Heparin; Hospitalization; Humans; Male; Middle Aged; Polysaccharides; Practice Guidelines as Topic; Pulmonary Embolism; Risk Assessment; Thromboembolism; Venous Thrombosis; Walking

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Arthroscopy; Drug Administration Schedule; Fondaparinux; Hematoma, Epidural, Spinal; Hematoma, Subdural, Spinal; Heparin; Heparin, Low-Molecular-Weight; Hip Fractures; Humans; Polysaccharides; Postoperative Complications; Practice Guidelines as Topic; Premedication; Punctures; Soft Tissue Injuries; Thromboembolism; Venous Thrombosis; Wounds and Injuries

The long-term complications of deep vein thrombosis (DVT), assessment of risk for venous thromboembolism (VTE) in medical and surgical patients, recommendations in evidence-based guidelines for VTE prophylaxis in surgical and medical patients and the treatment of VTE, and a new alternative for VTE prophylaxis and treatment are discussed.. Pulmonary embolism (PE) is an acute complication of DVT, and recurrent DVT, post-thrombotic syndrome, and death are long-term complications of DVT. The need to assess VTE risk and provide VTE prophylaxis are well recognized in surgical patients. However, VTE prophylaxis is underutilized in medical patients despite the fact that DVT is common and guidelines for prophylaxis are available, partly because the condition often is asymptomatic in these patients. The risk for VTE increases as the number of risk factors increases, so the aggressiveness of VTE prophylaxis in medical and surgical patients increases as the risk of VTE increases. The most recent American College of Chest Physicians (ACCP) guidelines recommend low-dose unfractionated heparin or low-molecular-weight heparin (LMWH) for VTE prophylaxis in acutely ill medical patients. The treatment of VTE recommended by ACCP involves short-term LMWH or unfractionated heparin therapy plus long-term oral warfarin therapy. The pentasaccharide, factor Xa inhibitor, fondaparinux is a new alternative for VTE prophylaxis and treatment. Reducing LMWH doses for patients with severe renal impairment may offer a safety advantage. Fixed doses of LMWH are customarily used for VTE prophylaxis regardless of body weight or body mass index, but weight-based dosing with larger doses for obese patients may be more effective than fixed doses.. Efforts to assess VTE risk and apply evidence-based guidelines for VTE prophylaxis and treatment in medical patients as well as surgical patients can improve patient care and outcomes. Findings from recent clinical research provide clinicians with clarification about the optimal prophylactic and treatment strategies, and future guidelines will reflect these findings.

Topics: Adult; Aged; Anticoagulants; Clinical Protocols; Drug Therapy, Combination; Evidence-Based Medicine; Female; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Outcome Assessment, Health Care; Polysaccharides; Pulmonary Embolism; Risk; Thromboembolism; Venous Thrombosis; Warfarin

Thromboembolic complications are one of the most severe complications after orthopaedic or trauma surgery. More than 50% of patients undergoing total knee replacement are at risk of suffering deep-vein thrombosis if not provided sufficient prophylaxis. The former standard prophylaxis with unfractionated heparin has been changed over the few last years to low molecular weight heparin or heparinoids, due to the increased incidence of heparin-induced thrombocytopenia under therapy with unfractionated heparin. Risk management is based on different risk levels: highest risk, high risk, intermediate risk and low risk. The probabilities of suffering from deep-vein thrombosis have been determined dependent on the risk level. In patients with total knee replacement, which are at highest risk, a higher dose for the prevention of thromboembolism has been recommended. The synthetic, selective antithrombin-binding pentasaccharide fondaparinux has been successfully used in prophylaxis for the prevention of thrombosis in highest risk patients. However, because of a higher risk of bleeding, this pentasaccharide can be only given 6-8 h after surgery. Low molecular weight heparins and the pentasaccharide are the standard pharmacological prophylaxis for the prevention of venous thromboembolism. Physical therapy, pneumatic compression, A-V impulse systems, passive ankle motion systems and graduated compression stockings are an additional, effective prophylaxis without side effects.

Topics: Adult; Age Factors; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Orthopedic Procedures; Physical Therapy Modalities; Polysaccharides; Postoperative Complications; Risk Assessment; Risk Factors; Stockings, Compression; Thrombocytopenia; Thromboembolism; Time Factors; Venous Thrombosis

Type-2 heparin-induced thrombocytopenia (HIT) is a not infrequent complication of treatment with heparins which can lead to fatal outcomes if not recognized and timely treated. Over the last years new epidemiological knowledge, new diagnostic approaches and new therapeutic options have become available. In the present review such novelties will be briefly discussed in the frame of Italian Health System. In Italy only one drug is approved for use in HIT patients differently from other countries. Alternative possible therapeutic options will be discussed based on the scarce available evidence.

Topics: Fondaparinux; Heparin; Hirudins; Humans; Italy; Platelet Activation; Platelet Factor 4; Polysaccharides; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Thromboembolism

Factor Xa (FXa) is a key enzyme that is positioned at the convergence of the intrinsic and extrinsic pathways in the blood coagulation cascade, and inactivation by a specific FXa inhibitor effectively prevents the generation of thrombin. Various types of low molecular weight (LMW) heparin, which function as semi-selective and indirect FXa inhibitors, are replacing unfractionated heparin (UFH) as agents for the prevention and treatment of venous thromboembolism (VTE), as well as in initial treatment for coronary events. Of those, heparinoid has been shown to be safer and more effective for the prevention of postoperative VTE than UFH, especially for treatment of heparin-induced thrombocytopenia (HIT). Further, synthetic pentasaccharide has been found to offer advantages over current thromboprophylactic regimens in a number of patients undergoing major orthopedic surgery. Other studies have shown that pentasaccharide is more effective for overall VTE in comparison with LMW heparin, though it was also associated with an increased rate of major bleeding. Synthetic, selective, and direct inhibitors to FXa, such as DX-9065a, are highly potent and orally bioavailable antithrombotic agents that have demonstrated an improved side effect profile, probably by allowing sufficient thrombin to remain for platelet activation and normal hemostasis, while preventing pathological thrombus formation. For thrombosis therapy, the most desirable type of antithrombotic agent is an orally active drug that has a broad range of effective doses and no hemorrhagic side effects. Presently, many types of direct inhibitors are in various stages of clinical trials and expected to provide significant benefits as compared to currently utilized therapy strategies.

Topics: Animals; Anticoagulants; Bleeding Time; Blood Coagulation; Chondroitin Sulfates; Clinical Trials as Topic; Dermatan Sulfate; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemostasis; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Models, Biological; Models, Chemical; Platelet Aggregation; Platelet Aggregation Inhibitors; Polysaccharides; Thromboembolism

Elderly patients require special consideration when administered anticoagulants because of age-related alterations in renal function, protein binding, and increased bleeding risk. Unfractionated heparin can be used in most patients but difficulties with dosing and monitoring often lead to inadequate anticoagulation. Low-molecular-weight heparin has more predictable pharmacokinetics than conventional heparin, but requires dose adjustments in renal impairment and obesity. Fondaparinux is a synthetic pentasaccharide that is being used increasingly for both treatment and prophylaxis of venous thromboembolism. The immune-mediated form of heparin-induced thrombocytopenia is a syndrome with thrombocytopenia or thrombosis in the setting of heparin use. Heparin-induced thrombocytopenia must be identified early, and treated with argatroban or lepirudin to avoid life-threatening complications.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fondaparinux; Geriatric Assessment; Half-Life; Heparin, Low-Molecular-Weight; Humans; Male; Maximum Tolerated Dose; Monitoring, Physiologic; Polysaccharides; Prognosis; Thrombocytopenia; Thromboembolism

Topics: Anticoagulants; Fondaparinux; Forecasting; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Pulmonary Embolism; Risk Factors; Thromboembolism; Thrombolytic Therapy; Venous Thrombosis; Vitamin K

Heparin-induced thrombocytopenia (HIT) is a clinicopathologic condition and adverse drug reaction caused by immunoglobulin G (IgG) antibodies directed against the heparin-platelet factor 4 complex. In most patients, the onset of thrombocytopenia begins while the patient is receiving heparin. In less than 5% of patients, the onset of thrombocytopenia begins several days following heparin discontinuation and has been termed "delayed-onset" HIT. This review summarizes the presentation and clinical course of published reports of delayed-onset HIT occurring in 30 patients. The diagnosis of delayed-onset HIT should be considered in all patients presenting with venous thromboembolism (VTE) and all patients with recent heparin exposure (within the past 14 days) who present with a low platelet count. Most patients with HIT are treated with direct thrombin inhibitors and transitioned to warfarin oral anticoagulation. Administration of direct thrombin inhibitors requires close monitoring for bleeding, dose adjustments based upon coagulation monitoring and is costly. Fondaparinux, a synthetic pentasaccharide and indirect-acting factor-Xa inhibitor, has little to no cross-reactivity with the heparin-platelet factor 4 antibody in in vitro testing. This review summarizes dosing, monitoring and outcomes of preliminary reports of fondaparinux successfully administered to 13 patients with subacute HIT and 22 patients with acute HIT. While several reports have described the treatment and prophylaxis of thrombosis in patients with HIT using fondaparinux, clinical trials should be conducted and reported before fondaparinux becomes a therapy of choice for HIT.

Topics: Anticoagulants; Clinical Trials as Topic; Fondaparinux; Heparin; Humans; Polysaccharides; Thrombocytopenia; Thromboembolism

To review the epidemiology and pathogenesis of venous thromboembolism (VTE) in surgical cancer patients, in addition to the use of thromboprophylaxis in major abdominal surgery, such as low-molecular-weight heparin (LMWH) and fondaparinux.. Systematic review of the literature, focussing on risk factors for VTE, parenteral methods of thromboprophylaxis, approaches to prolonged prophylaxis, and effects on patient survival.. Patients with cancer undergoing abdominal surgery are at substantially higher risk for VTE than patients without cancer. Furthermore, prolonged thromboprophylaxis for up to 4 weeks is more effective than short-term administration in these high-risk patients. The concurrent use of graduated compression stockings has a synergistic effect on the reduction in VTE risk.. Thromboprophylaxis with LMWH has been shown to minimise the incidence of thromboembolic events, and is a well-established therapy worldwide. The American College of Chest Physicians recommends the routine use of thromboprophylaxis, with LMWH or unfractionated heparin, in patients with cancer who are undergoing surgical procedures, and the appropriate use of these thromboprophylactic agents has significant implications for the clinical care and quality of life of surgical patients with cancer.

Topics: Abdomen; Anticoagulants; Bandages; Combined Modality Therapy; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Polysaccharides; Postoperative Complications; Thromboembolism

This article summarizes the published data on the prevention of venous thromboembolism. Routine thromboprophylaxis is the best way to lower the risk. It is recommended to sort patients according the thrombosis risk and to make use of the standard prophylactic modes. In low risk patients, no specific thromboprophylaxis is needed. Patients with moderate risk levels are candidates for administration of subcutaneous low molecular weight heparin (LMWH) at doses under 3 400 anti-Xa units a day and patients with increased risk at doses higher than 3400 anti-Xa units a day during the period of higher risk. In order to decrease the risk of bleeding, a half dose 2 hours prior or 4-6 hours after the operation can be administered. Under the highest risk conditions, there is a recommendation to combine LMWH over 3 400 anti-Xa units with elastic panty-hose or, alternatively, with intermittent pneumatic compression. At moderate risk levels, subcutaneous administration of unfractionated heparin at the doses of 5 000 units twice a day is also possible and at increased risk levels, a TID administration over the increased risk period. In patients with a significant bleeding risk, the physical method of thromboprophylaxis can be used and pharmacological prophylaxis can set in after the risk of bleeding has passed. Fondaparinux is the alternative to LMWH in people after major orthopaedic surgeries and with a history of heparin induced thrombocytopenia over the past three months. An alternative to the administration of LMWH even after the end of the hospitalization can be warfarin in certain situations. The sole use of acetylsalicylic acid or Rheodextran is not recommended. While undertaking epidural anaesthesia or analgesia, it is necessary to follow strictly the guidelines of the use of pharmacological thromboprophylaxis.

Topics: Anticoagulants; Bandages; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Intermittent Pneumatic Compression Devices; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Risk Factors; Thromboembolism; Venous Thrombosis

The incidence of venous thromboembolism in orthopaedic patients is high and its prevention deserves special attention. In patients with total hip and knee replacements and with the proximal femur fractures, low molecular weight heparin should be administered at higher prophylactic dosages. Following its approval, pentasaccharide (fondaparinux) should become the drug of choice, especially in patients with proximal femur fractures. Pharmacological prophylaxis should take at least 10 days in case of total knee replacements and longer in patients with increased risk of venous thromboembolism. In patients with total hip replacements or with proximal femur fractures, LMWH or pentasaccharide prophylaxis is indicated over a period of 28-35 days. Under the conditions of well working infrastructure for anticoagulation treatment, there is an alternative of warfarin treatment, lasting consequently 6-8 weeks. In patients with proximal femur fracture that bleed or are in a very increased risk of bleeding, a possible alternative is represented by intermittent pneumatic compression and shift to antithrombotic treatment after bleeding stops. In patients with knee arthroscopies displaying no risk factors of venous thromboembolism where tourniquet was used no longer than 60 minutes, pharmacological prophylaxis is not necessary. Only timely mobilisation is recommended. In patients displaying risk factors of venous thromboembolism or with tourniquet use surpassing 60 minutes, it is advisable to administer low molecular weight heparin in lower prophylactic dosage. In patients with lower extremity fractures treated with osteosynthesis, LMWH administration of 7-10 days is indicated. In patients with lower extremity injuries requiring plaster casting or other type of fixation reaching below the knee, LMWH administration is indicated over the whole period of fixation in persons with higher risk (people with venous thromboembolism in their histories, in direct relative's histories, people with thrombophilic conditions including poeple with malignancies, women using hormonal contraceptives or their substitutions). Aspirin is not a suitable drug for separate administration in the prophylaxis of venous thromboembolism in orthopaedic patients.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Femoral Fractures; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Practice Guidelines as Topic; Risk Factors; Thromboembolism; Venous Thrombosis

Shortcomings of the existing anticoagulants, vitamin K antagonists and heparins, have led to the development of newer anticoagulant therapies. In particular, Vitamin K antagonists' slow onset of action, numerous drug interactions, narrow therapeutic window and need for frequent monitoring make it the most obvious target for replacement. Targeting specific coagulation enzymes or steps in the coagulation pathway, new anticoagulants have been or are under evaluation in clinical trials for a number of clinical indications, namely the prevention and treatment of venous thromboembolism, the prevention of ischemic stroke in patients with atrial fibrillation, and in acute coronary syndromes. Following a brief review of pharmacological aspects, this article will summarize the results of Phase III clinical trials evaluating the novel anticoagulants fondaparinux, ximelagatran and idraparinux. At present, most attention is directed at developing an oral anticoagulant to replace vitamin K antagonists for prevention of systemic thromboembolism. A number of newer agents are in both early and advanced stages of investigation.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

Venous thromboembolism (VTE) is a major problem in non-surgical patients admitted to the hospital, both during the hospitalization period and after discharge. Risk factors for VTE are well known and scoring systems have been published. Nevertheless, prophylaxis against VTE is in many hospitals used less often than ideal and also inappropriately. Electronic tools to alert the physicians to provide prophylaxis and suggest suitable measures have shown promising results with a reduction of clinically relevant VTE. Large randomized clinical trials have demonstrated efficacy of low molecular-weight heparin (LMWH), pentasaccharide(fondaparinux) and unfractionated heparin. The results were, however, driven by asymptomatic deep vein thrombosis (DVT), including distal DVT in some studies. A reduction of pulmonary embolism is achieved, but without any significant effect on the mortality. The agents are generally safe, with only a small increase of major bleeding, less with LMWH than with unfractionated heparin. The challenge is still to direct the efforts to the most appropriate patients.

Topics: Clinical Trials as Topic; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Premedication; Thromboembolism; Thrombosis; Treatment Outcome; Venous Thrombosis

Novel anticoagulants to replace unfractionated heparins, low molecular weight heparins and vitamin K antagonists, are needed urgently. Coagulation factor Xa is an attractive target for drug development because of its position at the convergence of the intrinsic and extrinsic clotting pathways. There are two differing strategies of inhibiting factor Xa that are being pursued: indirect inhibition by compounds such as fondaparinux and idraparinux, requiring antithrombin as a cofactor; and direct inhibition by compounds such as rivaroxaban (BAY 597939), DX-9065a, otamixaban, LY517717 and YM150. Of these compounds, fondaparinux is approved for the prevention and treatment of venous thromboembolism, and idraparinux is in Phase III for venous thromboembolism treatment and stroke prevention in patients with atrial fibrillation. Rivaroxaban has undergone extensive Phase II studies for venous thromboembolism prevention after orthopaedic surgery, and Phase III studies have begun. In this review, we will discuss the pharmacological effects of factor Xa inhibitors and the latest clinical developments.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Humans; Injections, Intravenous; Injections, Subcutaneous; Morpholines; Naphthalenes; Oligosaccharides; Polysaccharides; Propionates; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thromboembolism

Anticoagulant therapy is the cornerstone of treatment of venous thromboembolism (VTE). Such treatment is divided into two stages. Rapid initial anticoagulation is given to minimize the risk of thrombus extension and fatal pulmonary embolism, whereas extended anticoagulation is aimed at preventing recurrent VTE, thereby reducing the risk of postphlebitic syndrome. With currently available drugs, immediate anticoagulation can only be achieved with parenteral agents, such as heparin, low-molecular-weight heparin, or fondaparinux. Extended treatment usually involves the administration of vitamin K antagonists, such as warfarin. Emerging anticoagulants have the potential to streamline VTE treatment. These agents include idraparinux, a long-acting synthetic pentasaccharide that is given subcutaneously on a once-weekly basis, and new oral anticoagulants that target thrombin or factor Xa. This paper i) reviews the pharmacology of these agents, ii) outlines their potential strengths and weaknesses, iii) describes the results of clinical trials with these new drugs, and iv) identifies the evolving role of new anticoagulants in the management of VTE.

Topics: Anticoagulants; Fondaparinux; Glycosaminoglycans; Heparin, Low-Molecular-Weight; Humans; Models, Chemical; Oligosaccharides; Polysaccharides; Postphlebitic Syndrome; Pulmonary Embolism; Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

Patients with clinical conditions such as surgery, trauma, and acute medical illness have a transiently increased risk of venous thromboembolism and merit consideration for adequate thromboprophylaxis. The choice of an appropriate pharmacologic or physical means of prophylaxis should be made taking into account both the thrombotic and bleeding risk associated with patient-related factors and the type of surgery or other disease state involved. A large number of randomized clinical trials, meta-analyses, and guidelines developed by scientific societies worldwide have addressed this issue and have provided information and recommendations that should be considered carefully. The aim of this review is to provide the practicing physician with a brief updated summary of the subject, stratifying those patients at low thrombotic risk who do not require specific thromboprophylaxis apart from early ambulation, from those at moderate or higher thrombotic risk. Patients at moderate thrombotic risk face a 10 to 20% risk of deep vein thrombosis (DVT) and require prophylaxis with low-dose unfractionated heparin or low molecular weight heparins (LMWHs) at a dosage < 3400 U once daily, or with graduated elastic stockings if their bleeding risk is high. Patients with an expected 20 to 40% DVT rate without prophylaxis are considered at high thrombotic risk and should be treated preferentially with LMWHs at high prophylactic dosage (> 3400 U). Patients undergoing major orthopedic surgery face a DVT rate > 40%, are considered at very high risk of venous thromboembolism, and should be given either LMWHs at high prophylactic dosage, fondaparinux, or vitamin K antagonists--either alone or in association with intermittent pneumatic compression devices.

Topics: Anticoagulants; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Male; Polysaccharides; Stockings, Compression; Thromboembolism; Venous Thrombosis

The antithrombin binding sequence of heparin, a pentasaccharide, has been synthesized as fondaparinux, an indirect, selective, and reversible factor Xa inhibitor. It can be administered subcutaneously, is well absorbed, and has a half-life of c. 17 hours permitting once-daily injection. It has been evaluated in an extensive study program in major orthopedic surgery, including hip fracture, and in major abdominal surgery with a large proportion of surgery for cancer. The effect is at least as effective as for low-molecular-weight heparins and it has also been shown effective for extended prophylaxis in hip fracture patients. Several thousands of patients have been studied and the substance is safe, although a slightly higher frequency of bleedings is found than in patients on low-molecular-weight heparins. There is no specific antidote but if necessary, recombinant activated factor VII can be used. Other side-effects are rare. Fondaparinux is cost saving and sometimes cost neutral when compared with enoxaparin.

Topics: Abdomen; Anticoagulants; Cost-Benefit Analysis; Drug Costs; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Orthopedic Procedures; Polysaccharides; Surgical Procedures, Operative; Thromboembolism; Treatment Outcome; Venous Thrombosis

The design and synthesis of new antithrombotic agents have led to numerous recent clinical trials to investigate their efficacy and safety. Analysis of the data from these trials, especially when the results were not totally expected, has provided interesting information, allowing a better understanding of the pathophysiology of thrombosis in various clinical situations. The aim of the present manuscript is to present the hypotheses on thrombogenesis generated by some of these recent clinical trials, notably those investigating the antithrombotic efficacy of a new synthetic and selective factor Xa inhibitor, fondaparinux. The antithrombotic efficacy of fondaparinux was recently investigated in a number of trials in the prevention and treatment of venous and arterial thrombotic disorders. In each case, the concept of the clinical efficacy of a selective factor Xa inhibitor has been proven. These trials have also clarified the implication and mode of action of factor Xa in these various types of thrombotic events. In the light of these trials, we discuss the clinical efficacy of such a selective factor Xa inhibitor, and other specific points such as the apparent lack of dose-dependency of its antithrombotic effect.

Topics: Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Polysaccharides; Postoperative Complications; Thrombin; Thromboembolism; Venous Thrombosis

Fondaparinux (Arixtra) is the first selective factor Xa inhibitor approved for use in thromboprophylaxis after orthopaedic surgery. New recently completed trials have also demonstrated the potential of fondaparinux in the prevention of venous thromboembolism (VTE) in other surgical and medical settings and in the treatment of established VTE. In the randomized double-blind PEGASUS study in high-risk abdominal surgery patients, fondaparinux reduced the incidence of VTE from 6.1% with dalteparin to 4.6% (odds ratio reduction = 25.8%, P = 0.14), without increasing the bleeding risk. In the randomized double-blind ARTEMIS trial in acutely ill medical patients, fondaparinux reduced the incidence of VTE from 10.5% with placebo to 5.6% (odds ratio reduction = 49.5%, P = 0.029), without increasing the bleeding risk; there was no pulmonary embolism in the fondaparinux group compared with five, all fatal, in the placebo group (P = 0.029). In the two MATISSE trials, both the efficacy and safety of once daily fondaparinux were at least as good as enoxaparin in the treatment of deep-vein thrombosis (MATISSE-DVT) and unfractionated heparin in the treatment of pulmonary embolism (MATISSE-PE). In patients with coronary artery disease, promising results were obtained in phase II trials and large phase III trials are ongoing. In conclusion, fondaparinux may further improve and simplify the prevention and treatment of thrombosis in a large range of medical and surgical settings.

Topics: Angina, Unstable; Angioplasty, Balloon, Coronary; Anticoagulants; Antithrombin III; Fondaparinux; Humans; Myocardial Infarction; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Fondaparinux is the first drug from the pentassaccharide factor X inhibitor class of anticoagulants to be approved for clinical use. It has been shown to be effective in the prevention of deep vein thrombosis in patients undergoing major orthopaedic surgery of the lower limbs. The drug is also being evaluated for use in the acute coronary syndromes and established thromoboembolic events. The pharmacology of fondaparinux is discussed in this review, as well as the major clinical trials involving this drug. Arguments for (and against) the use of this drug are also summarised.

Topics: Anticoagulants; Clinical Trials as Topic; Coronary Disease; Factor X; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Thromboembolism

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Anticoagulants; Antineoplastic Agents; Azetidines; Body Weight; Cannabinoid Receptor Antagonists; Cetuximab; Drug Therapy; Ezetimibe; Fondaparinux; Humans; Hypoglycemic Agents; Insulin; Osteoporosis, Postmenopausal; Piperidines; Polysaccharides; Pyrazoles; Rimonabant; Smoking Cessation; Teriparatide; Thromboembolism

During the last decade low molecular weight heparins have been the dominating methodology to prevent postoperative venous thromboembolism. They are effective and safe but in high risk surgery (major orthopaedic and abdominal/pelvic cancer) there is still a significant thrombotic problem. Recently two new thromboprophylactic principles have appeared--one Xa inhibitor in the form of the pentasaccharide fondaparinux and one direct thrombin inhibitor in the form of melagatran with an orally absorbable prodrug--ximelagatran. Both have been evaluated in extensive research programmes and both have been approved for use in major orthopaedic surgery by the European health care authorities.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Humans; Polysaccharides; Thromboembolism

Because the costs of anticoagulation therapy are substantial and the difference between the risks and benefits of this therapy are often narrow, economic analyses are particularly valuable when weighing anticoagulation options. Economic analyses to date suggest that anticoagulation is most effective and results in the greatest cost savings when applied to populations at highest risk for thrombotic events. They also suggest that in situations where a more costly anticoagulant agent is available, that agent is cost-effective only if it is clearly more efficacious or if it substantially reduces costs in other areas, such as hospitalization. These principles should guide clinicians' choices of anticoagulation strategies.

Topics: Anticoagulants; Cost-Benefit Analysis; Drug Costs; Fondaparinux; Health Care Costs; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis; Warfarin

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.

Topics: Anticoagulants; Antithrombins; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Probability; Risk Assessment; Risk Factors; Thromboembolism; Venous Thrombosis

Venous thromboembolic disease (VTE) is a major cause of morbidity and mortality. Unfractioned heparin, low-molecular weight heparins and vitamin K antagonists, currently used in the prophylaxis and treatment of VTE, are effective and relatively safe. Otherwise, they have some important limitations (narrow therapeutic window, highly variable dose-response relationship; limitation by the need of parenteral administration for heparins and the risk of heparin-induced thrombocytopenia) which provide opportunities for new antithrombotic drugs. These drugs include: inhibitors of factors IXa and factor VIIa/tissue factor complex, agents that enhance the protein C anticoagulant pathway, direct and antithrombin-dependent Xa inhibitors, direct and indirect thrombin inhibitors. Fondaparinux and idraparinux, two new indirect parenteral factor Xa inhibitors, have been studied in well conducted trials, showing interesting results both in the prevention and in the treatment of VTE. Ximelagatran, the first orally available thrombin inhibitor, represents a promising new anticoagulant drug for the prophylaxis of VTE after major orthopedic surgery and for the treatment of deep vein thrombosis.

Topics: Anticoagulants; Azetidines; Benzylamines; Fibrinolytic Agents; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

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.

Topics: Anticoagulants; Clinical Trials as Topic; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Risk Factors; Thromboembolism; Venous Thrombosis

Fondaparinux sodium (Arixtra; GlaxoSmithKline) is the first of a new class of antithrombotic agents. It is a chemically synthesised pentasaccharide mimicking the site of heparin that binds to antithrombin. It is purely a factor Xa inhibitor and an inhibitor of thrombin generation that requires binding to antithrombin. Fondaparinux sodium differs from heparin, low-molecular-weight heparin and heparinoids, and cannot be used interchangeably. It has been approved in the US and Europe for the prophylaxis of venous thrombosis after orthopaedic surgery by a fixed dose of 2.5 mg/day without monitoring. Using this pentasaccharide as a backbone, other structures have been synthesised. Idraparinux sodium (Sanofi-Aventis) differs structurally from fondaparinux sodium as it has additional methyl groups, a long half-life, and once-weekly administration. Both drugs are being developed as antithrombotics for venous and arterial thrombosis, acute coronary syndrome, stroke and as adjuncts to thrombolytic therapy.

Topics: Animals; Antithrombin III; Delayed-Action Preparations; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Thromboembolism

Heparin has been the mainstay of treatment and prevention of venous and arterial thromboembolism for many years. Its use, however, is associated with a serious and potentially fatal immunological drug reaction termed heparin-induced thrombocytopenia (HIT). Current treatment consists of discontinuing heparin therapy and the administration of an alternate anticoagulant (e.g. danaparoid, lepirudin, bivalirudin or argatroban). Fondaparinux is a novel synthetic heparin pentasaccharide capable of inhibiting factor Xa via the action of antithrombin (AT) but devoid of anti-factor IIa (thrombin) activity. Although the drug is identical in structure to the pentasaccharide domain found on unfractionated heparin (UH), it is too small to be recognized by the majority of heparin-reactive antibodies. It is theoretically an excellent candidate agent for the treatment of HIT. Currently, fondaparinux is licensed for orthopaedic venous thromboprophylaxis but not for the treatment of HIT. Successes in the use of fondaparinux in the treatment of HIT, as demonstrated in recent published case reports, warrant further study in larger controlled trials for this indication.

Topics: Anticoagulants; Female; Fondaparinux; Heparin; Humans; Male; Polysaccharides; Thrombocytopenia; Thromboembolism; Venous Thrombosis

Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality in hospitalized patients with acute medical illness. The high prevalence of VTE in this patient population, its clinically silent nature, and associated morbidity and mortality indicate that prophylactic therapy is appropriate in those determined to be at increased risk. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have been shown to reduce the incidence of VTE and are the primary therapies used for prophylaxis in these patients. Although both UFH and LMWH have received grade 1A recommendations for the prevention of VTE in at-risk medical patients in the 2004 American College of Chest Physicians consensus conference statements, LMWH has advantages over UFH in its once-daily dosing scheme, reduced incidence of major and minor bleeding events, and reduced incidence of heparin-induced thrombocytopenia. Fondaparinux is a novel antithrombotic agent characterized by specificity for factor Xa and a lack of platelet interaction. A recent clinical trial in hospitalized patients with acute medical illness found that fondaparinux significantly reduced the incidence of both VTE and fatal pulmonary embolism compared with placebo, without increased major bleeding. Despite the availability of effective thromboprophylactic therapies, VTE prophylaxis continues to be underutilized in hospitalized medical patients.

Topics: Anticoagulants; Fondaparinux; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Polysaccharides; Risk Factors; Thromboembolism; Venous Thrombosis

Modern approaches to prevention of venous thromboembolic complications in patients with chronic heart failure are analyzed in this review which contains results of large studies of low molecular weight heparins. In MEDENOX trial the use of enoxaparin in medical patients was associated with 63% reduction of risk of thrombosis. The authors own experience showed that 2 weeks of therapy with enoxaparin in patients with chronic stage IIB-III heart failure caused significant lowering of soluble fibrin-monomer complexes, fibrinogen, and index of turbo-dynamic potential. These changes evidenced for decreased intravascular blood coagulation. Thus enoxaparin can be effectively used for prevention of thrombosis and thromboembolism in patients with chronic heart failure. Novel antithrombotic agents fondaparinux, idraparinux, ximelagatran, recombinant thrombomodulin are perspective medications for prevention of venous thromboses and embolism in medical patients.

Topics: Anticoagulants; Azetidines; Benzylamines; Dalteparin; Double-Blind Method; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heart Failure; Humans; Multicenter Studies as Topic; Oligosaccharides; Placebos; Polysaccharides; Randomized Controlled Trials as Topic; Risk Factors; Thromboembolism; Thrombomodulin; Thrombosis; Time Factors; Venous Thrombosis

Autopsies and clinical studies have shown that venous thromboembolism (VTE) is a common cause of morbidity and mortality in medical patients. Prophylaxis of VTE has been less extensively studied in medical patients than in surgical patients, and the results of recent practice audits indicate that the use of thromboprophylaxis is uncommon in medical patients. In the past few years, 3 large randomized clinical trials have demonstrated the efficacy and safety of prophylaxis of VTE in the medical setting. The prophylaxis in MEDical patients with ENOXaparin (MEDENOX), Prospective Evaluation of Dalteparin Efficacy for PREVENTion of VTE in Immobilized Patients Trial (PREVENT), and ARixta for ThromboEmbolism Prevention in a Medical Indications Study (ARTEMIS) studies have compared the low-molecular-weight heparins enoxaparin and dalteparin, and the specific factor Xa inhibitor fondaparinux, respectively, with placebo in acutely ill medical patients hospitalized with heart failure, respiratory failure, infectious disease, or inflammatory disease. All studies showed both a statistically significant reduction in the rate of venous thromboembolic events (as assessed by venography or compression ultrasonography) and a rate of major bleeding events that were comparable to placebo. The results of these studies support the evidence-based recommendations for systematic use of thromboprophylaxis in this setting.

Topics: Aged; Anticoagulants; Dalteparin; Enoxaparin; Fondaparinux; Humans; Middle Aged; Polysaccharides; Pulmonary Embolism; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

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.

Topics: Animals; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Factor VII; Factor Xa Inhibitors; Fondaparinux; Helminth Proteins; Humans; Oligosaccharides; Polysaccharides; Recombinant Proteins; Thrombin; Thromboembolism; Thrombomodulin; Thromboplastin; Treatment Outcome; Venous Thrombosis

Fondaparinux (Arixtra) is the first of a new class of antithrombotic compounds - Factor Xa inhibitors. This synthetic pentasaccharide acts by inhibiting Factor Xa selectively. Its efficacy and safety have been demonstrated in animal models of venous and arterial thromboses and bleeding risk. In humans, its pharmacokinetic profile after subcutaneous injection shows a rapid onset of antithrombotic activity and an elimination half-life that reliably allows once-daily dosing. As the inter-subject variability is limited, no laboratory monitoring of coagulation parameters is needed. The efficacy and safety of fondaparinux have been examined in several Phase II and III clinical trials. So far, the largest programme has involved approximately 9000 patients undergoing major orthopaedic surgery of the lower limbs. In the setting of short-term prophylaxis, the efficacy of fondaparinux for preventing venous thromboembolism was significantly superior to that of the low-molecular-weight heparin, enoxaparin (common reduction in risk: 50.6%; p < 0.001). The benefit of extended thromboprophylaxis with fondaparinux in hip fracture surgery patients was also demonstrated. Fondaparinux also showed benefit in the prevention of venous thromboembolism in other surgical and medical settings and in the treatment of patients with venous thromboembolism. Overall, fondaparinux therapy was as well-tolerated as currently available treatments. In conclusion, selective inhibition of Factor Xa is an effective antithrombotic strategy. Fondaparinux may substantially improve the prevention and treatment of thrombosis. Fondaparinux 2.5 mg once-daily s.c. has been approved for the prevention of venous thromboembolism after major orthopaedic surgery. Fondaparinux use in extended prophylaxis (4 weeks) after hip fracture surgery has also been recently approved.

Topics: Clinical Trials as Topic; Drug Interactions; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Drug Design; Factor Xa Inhibitors; Follow-Up Studies; Fondaparinux; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Recurrence; Thromboembolism; Thrombophilia; Venous Thrombosis; Vitamin K

The fondaparinux trials in venous thromboembolism (VTE) prevention after orthopaedic surgery have been subject to methodological criticisms recently summarised in this journal. These criticisms merit comments and corrections. Fondaparinux reduced the risk of VTE and of proximal deep-vein thrombosis by more than 55% compared with enoxaparin, based on the efficacy endpoint that supported the registration and use of low-molecular-weight heparins (LMWH) in all their prophylactic indications, an endpoint endorsed by international consensus statements and health authorities. Fondaparinux is the only antithrombotic agent that significantly reduced the rate of symptomatic VTE in a single orthopaedic surgery trial that was powered to detect this effect. In contrast to the paucity of data available on LMWH, the relationship between the timing of first administration and efficacy and safety has been well documented for fondaparinux. Fondaparinux used according to its approved regimen provides a simple, easy-to-use, effective and safe post-operative regimen for all orthopaedic surgery patients.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Enoxaparin; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Care; Preoperative Care; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome; Venous Thrombosis

Aging itself is a risk factor for venous thromboembolism, and the prevalence in the elderly of additional risk factors (e.g. cancer, orthopedic surgery, immobility) increase its intrinsic risk. Many in the medical community are reluctant to prescribe anticoagulation (for primary and secondary prevention of venous thromboembolism) to their geriatric patients for the fear that bleeding complications may outweigh the benefits. A thorough analysis of the data support the concept that the under-use of heparin in primary prevention in the elderly is more related to medical beliefs than to facts. The risk of bleeding due to oral anticoagulants (secondary prevention) is greatly reduced by keeping the International Normalized Ratio (INR) values within therapeutic ranges and carefully avoiding conditions/drugs that may interfere with such treatment. The oral direct thrombin inhibitor ximelagatran has been studied for primary (hip and knee replacement surgery) and for secondary prophylaxis of venous thromboembolism, and for acute venous thromboembolism treatment. The selective factor Xa inhibitor fondaparinux has been approved for primary prophylaxis of venous thromboembolism in hip and knee replacement surgery and in hip fracture surgery. Studies on the latter drugs, where most of the patients were > 65 years of age, further show that the fear of bleeding complications due to anticoagulation in the elderly is largely unjustified.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; International Normalized Ratio; Polysaccharides; Risk Factors; Thromboembolism; Time Factors; Venous Thrombosis

The aim of this review is to perform a critical analysis of all completed studies evaluating pentasaccharides-synthetically derived, selective inhibitors of activated factor X-in prophylaxis in major orthopedic surgery and the treatment of venous thromboembolism.. Venous thromboembolism is a disorder with considerable morbidity when left untreated. New antithrombotic agents have been developed that selectively inhibit components of the coagulation system, thereby avoiding the difficulties associated with current anticoagulants. The pentasaccharides fondaparinux and idraparinux are the first of a new class of synthetic selective inhibitors of activated factor X. Fondaparinux has been extensively investigated in two areas: orthopedic surgery and venous thromboembolism. It is clear from four thromboprophylaxis studies in major orthopedic surgery that fondaparinux is 50% more effective in reducing venous thromboembolism than enoxaparin. This superior efficacy led to an overall increase in major bleeding, which was however primarily due to more fondaparinux-treated patients with bleeding indexes of 2 or greater. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two groups. In the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, fondaparinux was equally effective as low molecular weight heparins and unfractionated heparin, respectively, without a different incidence in major bleeding in fondaparinux and comparator heparin groups.. Fondaparinux, one of the first of a new class of synthetic selective factor Xa inhibitors, is overall 50% more effective in reducing venous thromboembolism than enoxaparin in major orthopedic surgery, with an overall 1% increased rate of major bleeding, when compared with enoxaparin. The incidence of fatal bleeding, critical organ bleeding, or bleeding leading to reoperation did not differ significantly between the two treatment groups. Fondaparinux is equally effective as low molecular weight heparins and unfractionated heparin in the initial treatment of patients with proximal vein thrombosis and pulmonary embolism, respectively. Finally, as with any new drug, fondaparinux should be used cautiously and only in patients who reflect the population of the clinical trials in which the drug was evaluated.

Topics: Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Humans; Oligosaccharides; Orthopedic Procedures; Polysaccharides; Thromboembolism; Venous Thrombosis

Venous thromboembolism is a multifactorial silent disease and tends not to be suspected by physicians, especially in medical patients. Pulmonary embolism is the most preventable cause of death among hospitalized patients. It is of major importance to assess the risk for venous thromboembolism and to adapt the prophylactic strategy with the aim of improving the risk-benefit ratio of the prophylaxis.. Prophylaxis of venous thromboembolism can be done by either mechanical means or pharmacologic agents or both. The Medenox trial, the Prime study, the Prince study, the Prevent study, and the Artemis trial demonstrated that acutely ill medical patients are at increased risk of venous thromboembolism and that low molecular weight heparins (enoxaparin 40 mg or dalteparin 5000 IU subcutaneously once daily for 10 days) as well as fondaparinux 2,5 mg subcutaneously once daily for 10 days have a favorable risk-benefit ratio in the prevention of venous thromboembolism in acutely ill medical patients. The publication of the results of the Exclaim study is expected to clarify the optimal duration of prophylaxis in this group of patients. Patients hospitalized in medical intensive care units as well as patients with active cancer or central venous catheters are at increased risk of venous thromboembolism, and the studies published so far demonstrate the favorable risk-benefit ratio of thromboprophylaxis with either low molecular weight heparins or low-dose warfarin.. Acutely ill medical patients are at increased risk of venous thromboembolism. Prophylaxis with low molecular weight heparins and fondaparinux is effective and safe. Initiatives to improve venous thromboembolism prophylaxis should be based on the education of physicians regarding the individualized risk assessment.

Topics: Anticoagulants; Dalteparin; Enoxaparin; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Risk Factors; Thromboembolism; Venous Thrombosis; Warfarin

Patients undergoing orthopedic surgery represent one of the highest risk groups for the development of venous thromboembolism (VTE). Evidence shows that this risk extends beyond the period in which the patient is hospitalized, especially for patients undergoing hip surgery. Clinical trials have shown that extended prophylaxis with the low-molecular-weight heparins is effective in reducing the rate of total VTE, and a meta-analysis demonstrated a reduction in symptomatic VTE with extended prophylaxis after total hip replacement surgery. Based on these results, the American College of Chest Physicians gives a grade 2A recommendation for the use of extended prophylaxis after orthopedic surgery. Until recently, data evaluating the role of prophylaxis in patients undergoing hip fracture surgery were limited. Subsequently, a novel anticoagulant, fondaparinux, demonstrated significant benefit in these patients and has become the first and only agent approved by the United States Food and Drug Administration (FDA) for use in patients undergoing hip fracture surgery Despite the limitations of the older trials, their findings supported the need to evaluate extended prophylaxis in patients undergoing hip fracture surgery. In the first well-conducted trial of extended prophylaxis for hip fracture surgery, fondaparinux provided impressive results in reducing total and symptomatic VTE. The results of this trial have once again led to fondaparinux being the first and only agent to be granted FDA approval for the indication of extended prophylaxis in patients undergoing hip fracture surgery.

Topics: Anticoagulants; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

In four randomized, controlled studies of patients undergoing orthopedic surgery, the antithrombotic efficacy and safety of subcutaneous fondaparinux 2.5 mg once/day were compared with those of subcutaneous enoxaparin regimens that were approved by the United States Food and Drug Administration. In patients undergoing elective hip replacement surgery, fondaparinux significantly reduced the frequency of venous thromboembolism (VTE). However, in a second trial that compared fondaparinux with enoxaparin 30 mg twice/day beginning 12-24 hours after surgery, a 26% risk reduction in favor of fondaparinux was not statistically significant. In patients undergoing elective knee replacement surgery, fondaparinux significantly reduced the risk of VTE compared with enoxaparin without increasing the risk of clinically relevant bleeding, although the risk of major bleeding defined by the bleeding index was significantly higher with fondaparinux. Fondaparinux was superior to enoxaparin 40 mg once/day in the setting of hip fracture surgery, with no increased risk of major bleeding. Meta-analysis of the four studies confirms the superior antithrombotic efficacy of fondaparinux over enoxaparin in orthopedic surgery and suggests that the risk of major bleeding is similar to that of enoxaparin when the first dose of fondaparinux is given at least 6 hours after surgery.

Topics: Anticoagulants; Enoxaparin; Fondaparinux; Humans; Meta-Analysis as Topic; Orthopedic Procedures; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

Anticoagulation is an essential component of the care of patients with venous thromboembolism (VTE). Traditional anticoagulants for the treatment of VTE include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the oral vitamin K antagonist, warfarin. A variety of anticoagulant agents with improved pharmacologic and clinical profiles are emerging and offer benefits over the traditional therapies. One of the most recent advances has been the development of new agents, such as oral direct thrombin inhibitors and factor Xa inhibitors, that have a more selective and targeted effect on the coagulation cascade. Recent clinical trials have evaluated fondaparinux, the first commercially available factor Xa inhibitor, in the treatment of patients with deep vein thrombosis and pulmonary embolism and indicate efficacy and safety as compared with traditional options such as UFH and LMWH. Fondaparinux is a welcomed addition to the available antithrombotic options.

Topics: Anticoagulants; Antithrombin III; Clinical Trials as Topic; Fondaparinux; Humans; Polysaccharides; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Venous thromboembolism (VTE) is the cause of significant morbidity and mortality and may lead to other complications, including recurrent VTE and long-term postthrombotic syndrome. Venous thromboembolism represents a huge health economic burden of nearly 500 million dollars/year in the United States. Without adequate prophylaxis, patients undergoing major orthopedic surgery are at high risk of developing VTE. Prophylaxis with either unfractionated heparin or warfarin not only substantially reduces the risk of VTE after orthopedic surgery, but also is more cost-effective than no prophylaxis. Low-molecular-weight heparins (LMWHs) have been shown to be superior to unfractionated heparin or warfarin, and despite the fact that they are more expensive, they are cost-effective. Large-scale clinical trials have shown that fondaparinux further reduces the likelihood of VTE complications after major orthopedic surgery. A review of the pharmacoeconomic evaluations of fondaparinux leads to the conclusion that fondaparinux is a cost-effective alternative to LMWHs in VTE prophylaxis.

Topics: Cost-Benefit Analysis; Fibrinolytic Agents; Fondaparinux; Heparin; Humans; Orthopedic Procedures; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

Venous thromboembolism VTE remains a common but preventable disease. The last decade has witnessed major advances in VTE treatment and prophylaxis. Low molecular weight heparins LMWH became the agents of choice in the treatment of deep venous thrombosis DVT and are increasingly used in the treatment of stable pulmonary embolism PE. Increasing focus on simplicity and efficacy has led to the discovery of the synthetic pentasaccharides, substances that specifically inhibit factor Xa activity, producing an antithrombotic effect without affecting other coagulation factors or platelets. Fondaparinux, the first pentasaccharide introduced into the market, was first tried as a prophylactic agent against VTE in patients undergoing major orthopedic procedures, such as hip fracture, total hip and knee replacements, such approach appeared to be more effective than LMWH. Fondaparinux was also used, with promising results, in prophylaxis in patients undergoing major abdominal surgery and high risk medical patients. Pentasaccharides were recently tried in the treatment of both DVT and PE. The largest clinical investigation program ever undertaken in this therapeutic area, has shown that pentasaccharides are as safe and as effective as either unfractionated heparin UFH or LMWH, with the added convenience of once daily injection, no need for monitoring the anticoagulant effect and no major side effects such as thrombocytopenia. Therefore, the efficacy, the safety profile and the added convenience for both patients and physicians alike, will probably keep pentasaccharides as the front runner among new anticoagulants of the future. This article focuses on the use of fondaparinux as a prophylactic agent against VTE in patients undergoing major orthopedic and abdominal surgery along with high risk medical patients; it will also discuss the recent promising data on its use to treat active DVT and PE.

Topics: Anticoagulants; Enoxaparin; Female; Fondaparinux; Humans; Male; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Sensitivity and Specificity; Thromboembolism

Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of thrombin. These agents produce a predictable anticoagulant response; thus, routine coagulation monitoring is unnecessary. Because they do not bind to platelets or platelet factor 4, fondaparinux and idraparinux do not cause heparin-induced thrombocytopenia (HIT). Unlike vitamin K antagonists, ximelagatran has a rapid onset of action, thereby obviating the need for concomitant administration of a parenteral anticoagulant when starting treatment. The lack of an antidote for these new agents is a drawback, particularly for idraparinux, which has a long half-life.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Fondaparinux is a novel synthetic antithrombotic that has been evaluated for the prevention of venous thromboembolism (VTE). In four large trials in patients who underwent major hip or knee surgery, fondaparinux was found to have a good safety profile and be more effective than enoxaparin. To generate Canadian pharmacoeconomic data for fondaparinux, an internationally developed cohort deterministic model was used to estimate the costs and consequences of prophylaxis with fondaparinux compared with enoxaparin in the Canadian orthopedic surgical setting.. A health economic advisory group was assembled to guide the pharmacoeconomic evaluation. Efficacy and safety data for fondaparinux relative to enoxaparin were abstracted from a meta-analysis of four randomized trials. Canadian cost data to populate the model were obtained from a resource-use survey of four large Canadian hospitals, from the Canadian Institute for Health Information (CIHI), and from the Canadian economic literature. Case-mix information obtained from CIHI was incorporated into the cohort deterministic model, which predicted the number of VTEs and bleeds following prophylaxis with fondaparinux or enoxaparin within 90 days of surgery, and the associated overall cost difference. The stability of the base-case findings was evaluated with sensitivity analyses.. Canadian healthcare system perspective.. Assuming a case mix of 50,693 major hip or knee surgeries performed in Canada in 1999/2000 (as reported by CIHI), the model predicted that prophylaxis with fondaparinux would avoid an additional 16 symptomatic VTEs per 1000 patients over the first 90 days, with an average cost savings of Can 55 dollars per patient. These findings were stable when key economic and clinical parameters were varied, including bleeding events.. Our results suggest that in Canada, prophylactic fondaparinux compared with enoxaparin avoids VTEs and is associated with lower costs in patients who undergo major hip or knee surgery.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Canada; Cost-Benefit Analysis; Economics, Pharmaceutical; Enoxaparin; Fondaparinux; Hospital Costs; Humans; Models, Econometric; Orthopedic Procedures; Polysaccharides; Randomized Controlled Trials as Topic; Safety; Thromboembolism

Significant advances in the pharmacological prophylaxis of venous thromboembolism have occurred since warfarin and unfractionated heparin were introduced for this indication nearly 60 years ago. Despite these advances, coumarin derivatives such as warfarin remain the only orally active anticoagulants available for prophylaxis in venous thromboembolism. Although administered orally, coumarin derivatives are not convenient to use, because they have narrow therapeutic indexes and require routine coagulation monitoring and dose adjustment. This is inconvenient for patients and physicians and costly for the healthcare system. Low-molecular-weight heparins, which are administered in fixed or weight-adjusted doses and do not require monitoring, are widely used for the prevention of venous thromboembolism in patients in both the hospital and the outpatient setting. However, these drugs must be given subcutaneously, which can be difficult for outpatients and resource-intensive for in-hospital use. Likewise, fondaparinux, the synthetic pentasaccharide, must be administered subcutaneously. Consequently, there remains a need for new orally active anticoagulants that can be given in fixed doses and do not have a narrow therapeutic index, so that coagulation monitoring is unnecessary. Because such agents would be more convenient for patients and physicians, they would probably expand the use of prophylaxis in venous thromboembolism in those at risk, and would simplify treatment of patients with established venous thromboembolism.

Topics: Administration, Oral; Anticoagulants; Coumarins; Fondaparinux; Heparin; Humans; Injections, Subcutaneous; Polysaccharides; Thrombocytopenia; Thromboembolism

The results of studies of the comparative efficacy, safety, feasibility, and costs of using low molecular weight heparin (LMWH) or unfractionated heparin (UFH) for the treatment of venous thromboembolism (VTE) are reviewed. Cost-effectiveness research comparing LMWH with warfarin or UFH and comparing the activated factor X inhibitor fondaparinux with LMWH for VTE prophylaxis also is discussed.. The greater ease of administration, fewer laboratory monitoring requirements, and feasibility of using LMWH safely on an outpatient basis instead of on an inpatient basis facilitate earlier hospital discharge and make LMWH more cost-effective than UFH for the treatment of DVT. The use of LMWH instead of warfarin to prevent VTE increases costs, but it is more effective for preventing DVT and death at a relatively small incremental cost per DVT event avoided and cost per death averted. The total expected costs are higher, but the expected cost per DVT event avoided is lower when enoxaparin is used instead of UFH for VTE prophylaxis.. Fondaparinux is more cost-effective than enoxaparin for VTE prophylaxis, with a cost saving that increases progressively over time.

Topics: Clinical Trials as Topic; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

A new generation of antithrombotic agents that target a single enzyme within the procoagulant cascade is making its way into mainstream clinical practice. Borrowing selectively from the properties of their parent anticoagulant, unfractionated heparin, as well as from those of peptide anticoagulants from reptile or insect venoms, designers of the new drugs have created targeted inhibitors of thrombin, factor Xa, or other specific factors in the procoagulant pathways. These new agents promise efficacy and safety profiles far more favorable than those of conventional anticoagulants for thromboprophylaxis after major orthopedic surgery and require no laboratory monitoring of drug efficacy in this setting. Ximelagatran, the oral "prodrug" of the direct thrombin inhibitor melagatran, is in phase III of clinical development. Clinical trials using various dosages of ximelagatran, sometimes preceded by subcutaneous melagatran, as thromboprophylaxis after total hip or knee replacement surgery have suggested efficacy equal to or better than that of warfarin and enoxaparin. The best dosing regimen and optimal timing of first dose for melagatran and ximelagatran remain to be determined, as do the mechanism and impact of drug disturbance of hepatic function. Fondaparinux, a selective, synthetic inhibitor of factor Xa, has been shown in large clinical trials to be superior to low-molecular-weight heparins and is approved as a fixed once-daily subcutaneous 2.5-mg dose for thromboprophylaxis for hip or knee replacement surgery and after hip fracture repair. Fixed-dose fondaparinux 2.5 mg initiated 6 to 8 hours after surgery achieved superior efficacy and comparable safety in head-to-head comparisons with enoxaparin for the prevention of venous thromboembolism after major orthopedic surgery. Fondaparinux is the only agent approved for use in hip fracture patients in the United States at this time and has recently gained approval for extended prophylaxis in this patient population.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Glycine; Heparin; Heparin, Low-Molecular-Weight; Humans; Models, Biological; Orthopedics; Polysaccharides; Postoperative Complications; Thromboembolism; Thrombolytic Therapy

Fondaparinux (Arixtra, GlaxoSmithKline, Philadelphia, PA.) is the first synthetic selective factor Xa inhibitor. A worldwide phase III program, that consists of four randomized, double-blind trials, in patients who underwent surgery for hip fracture, and elective hip replacement and elective major knee surgery was conducted to compare the benefit-to-risk ratio of a subcutaneous 2.5 mg once-daily regimen of fondaparinux starting postoperatively versus enoxaparin in preventing venous thromboembolism. The overall incidence of venous thromboembolism up to day 11 was reduced from 13.7% in the enoxaparin group, to 6.8% in the fondaparinux group, with a relative risk reduction of 50.6% in favor of fondaparinux (95% confidence interval: 40.9% to 59.1%, p<0.001). The overall incidence of clinically relevant bleeding was low and did not differ between the two groups. The benefit of fondaparinux was consistent across all types of surgery and all subgroups. The further randomized, double-blind PENTHIFRA-PLUS trial showed that extending fondaparinux prophylaxis from one to four weeks after hip fracture surgery was well tolerated and, compared to one-week fondaparinux, dramatically reduced delayed venous thromboembolism events from 35.0% to 1.4% (p<0.001). Four-week fondaparinux could become the standard thromboprophylaxis after hip fracture surgery. Fondaparinux is the first selective factor Xa inhibitor approved for use in thromboprophylaxis after orthopedic surgery.

Topics: Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Clinical Trials, Phase III as Topic; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Follow-Up Studies; Fondaparinux; Humans; Incidence; Injections, Subcutaneous; Male; Odds Ratio; Polysaccharides; Postoperative Complications; Randomized Controlled Trials as Topic; Risk Assessment; Thromboembolism; Treatment Outcome; Venous Thrombosis

Factor X plays a central role in coagulation, being the point of convergence of the extrinsic and intrinsic pathways of blood clotting. It may also act as one of the links between the coagulation and inflammatory pathways. These findings suggest that factor X may represent an attractive target for a new antithrombotic drug. Indeed, a factor X inhibitor, fondaparinux, has already been approved for clinical use to prevent post-operative deep vein thrombosis. Factor X inhibitors are also being evaluated for use in the treatment of the acute coronary syndromes, pulmonary embolism and deep vein thrombosis. Oral factor X inhibitors are also being developed, which may be of use in the outpatient prevention and/or treatment of stroke and thromboembolism.

Topics: Anticoagulants; Clinical Trials as Topic; Factor X; Factor Xa Inhibitors; Fondaparinux; Humans; Polysaccharides; Postoperative Complications; Stroke; Thromboembolism; Venous Thrombosis

Venous thromboembolism is a serious, frequent, and potentially fatal complication of major orthopedic surgery. Currently available pharmacologic agents for the prevention of venous thromboembolism in this high-risk population consist of the oral anticoagulants and the heparin family of antithrombotic agents (unfractionated heparin, low-molecular-weight heparin, heparinoids). These classes of agents interfere with the activity of both thrombin and factor Xa (or their respective zymogens) to varying degrees. Newer antithrombotic agents in various stages of development exert their antithrombotic effect through a more targeted mechanism of action. Direct factor Xa inhibitors and the newest class of antithrombotic agents, the indirect factor Xa inhibitors, the prototype of which is the synthetic pentasaccharide fondaparinux sodium, limit fibrin formation through their exclusive inactivation of factor Xa. Clinical data from venous thromboembolism prophylaxis trials in hip and knee replacement and hip fracture surgeries, including the recently completed fondaparinux phase II and phase III trials, indicate that selective antifactor Xa activity may improve the efficacy:safety ratio of antithrombotic therapies for the prevention of venous thromboembolism in high-risk major orthopedic surgery.

Topics: Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thromboembolism

Fondaparinux (Arixtra, Sanofi-Synthelabo, Paris, France) is a pentasaccharide that selectively inhibits factor Xa; it is the first of a new class of synthetic antithrombotic agents. Fondaparinux has a linear pharmacokinetic profile allowing once-daily subcutaneous administration. Absence of metabolism, complete bioavailability, and lack of nonspecific binding in plasma contribute to the predictability of its effect. Fondaparinux has been approved for use in the prophylaxis of venous thromboembolism following orthopedic surgery. In this setting, it was found to reduce VTE risk by more than 50% in comparison with the low molecular weight heparin enoxaparin, with an incidence of clinically important bleeding not significantly different from that of standard low molecular weight heparin regimens. Furthermore, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery was shown to reduce the risk of venous thromboembolism by 96% compared with 1-week prophylaxis. Finally, the efficacy and safety of fondaparinux in the treatment of venous thromboembolism and acute coronary syndromes appears promising.

Topics: Acute Disease; Antithrombin III; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coronary Disease; Double-Blind Method; Female; Fondaparinux; Humans; Injections, Subcutaneous; Male; Meta-Analysis as Topic; Orthopedic Procedures; Polysaccharides; Pregnancy; Pregnancy Complications, Cardiovascular; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome; Venous Thrombosis

Hip fracture surgery carries a high risk of venous thromboembolism and, until recently, was poorly investigated. The efficacy and safety of fondaparinux, a new synthetic antithrombotic, were investigated in two large, thromboprophylaxis studies. Results of the Penthifra study, which was a randomized, double-blind phase III trial, showed that 1 week of fondaparinux, compared with enoxaparin, significantly reduced venous thromboembolic events from 19.1% to 8.3% (relative risk reduction: 56.4%; P<.001) without increasing bleeding risk. Penthifra Plus results showed that extending fondaparinux prophylaxis from 1 to 4 weeks was well tolerated and, compared to placebo, significantly reduced delayed venous thromboembolism events from 35% to 1.4% (relative risk reduction: 95.9%; P<.001). Based on these findings, 4-week fondaparinux treatment may become the standard thromboprophylaxis after hip fracture surgery.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Enoxaparin; Female; Fondaparinux; Fracture Fixation, Internal; Hip Fractures; Humans; Incidence; Injury Severity Score; Male; Middle Aged; Polysaccharides; Postoperative Care; Postoperative Complications; Postoperative Hemorrhage; Primary Prevention; Prognosis; Radiography; Randomized Controlled Trials as Topic; Sex Factors; Survival Rate; Thromboembolism; Treatment Outcome

Inhibition of activated coagulation factor X (FXa) is an attractive target for antithrombotic treatment strategies, because of the central position of FXa in the coagulation cascade. Most of the now available anticoagulant drugs have inhibitory effects not only on FXa, but also on thrombin. With the development of pentasaccharides, a new class of antithrombotic agents has emerged that acts by specific inhibition of FXa and lacks activity against FIIa. Fondaparinux, the first synthetic short-acting pentasaccharide, has been evaluated, in a large phase II and III clinical programme concerning prophylaxis and treatment of venous thromboembolism and also in phase II studies in patients with acute coronary syndromes. Idraparinux, the long-acting pentasaccharide, has been studied in a dose-finding study in patients with established deep-vein thrombosis and phase III studies are now planned in patients with venous thromboembolism and in patients with atrial fibrillation.

Topics: Acute Disease; Anticoagulants; Blood Coagulation; Coronary Disease; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

Two new classes of anticoagulants are actually developed which would change in the near future our strategies for the prevention and the treatment of venous thromboembolic events. These two classes are the anti-factor Xa and anti-factor IIa (direct antithrombin) agents. Among the anti factor Xa, the pentasaccharides are initiating their clinical use. Fondaparinux is a synthetic form of the natural pentasaccharide, its pharmacokinetics allows one s.c. administration/24 hours. It is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. A modified form (idraparinux) whose pharmacokinetics allows one administration only once a week should have the same type of efficacy. Among direct antithrombin agents, hirudin and derivatives have been developed in the past decade with a limited use due to several drawback. More recently synthetic direct antithrombins modified to allow oral route have been developed, the most advanced in development, melagatran, is active in the prevention and treatment of venous thromboembolic and coronary thrombotic events. It could allow (if confirmed by clinical trials) a complete oral treatment of deep vein thrombosis without any biological monitoring. Melagatran is also active in the prevention of arterial thromboembolic events on atrial fibrillation. But other molecular forms of synthetic orally active direct antithrombin are also in development. Besides these important changes in our therapeutics which should appear in a near future, molecules aimed at other target are also tested: the most advanced are those antagonizing the initial phase of tissue factor activation of factor VII but other strategies are being tested such as stimulation of fibrinolysis. These new drugs at our disposal to treat venous thromboembolism should modify completely our handling of the patients. But additionally the numerous clinical trials necessary to prove the efficacy of the drugs, modify our understanding in the implication of the coagulation and in the physiopathogeny of thrombotic events.

Topics: Administration, Oral; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Thrombosis; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Hirudin Therapy; Humans; Orthopedics; Polysaccharides; Prodrugs; Prothrombin; Research; Thrombin; Thromboembolism; Time Factors; Venous Thrombosis

To review clinical information related to fondaparinux, a synthetic pentasaccharide recently approved for the prevention of deep-vein thrombosis (DVT) in patients undergoing major orthopedic surgeries and for extended DVT prophylaxis after hip fracture surgery.. Primary and review articles were identified by MEDLINE (1983-June 2003) using the key words pentasaccharide, Org31540, SR90107A, DVT prophylaxis, and fondaparinux. Additional sources were found listed in articles, abstracts, and unpublished data on file from the manufacturer. Articles selected were based on their coverage of the pharmacology, pharmacokinetics, safety, and efficacy of fondaparinux.. All of the articles identified were evaluated and all information deemed relevant was included.. Fondaparinux is a selective antithrombin-dependent, indirect inhibitor of activated factor Xa. It has a favorable and predictable pharmacokinetic profile when administered subcutaneously, and has a long half-life, allowing once-daily dosing. Fondaparinux lacks in vitro cross-reactivity with heparin-induced antibodies. Major Phase III studies have demonstrated that subcutaneous fondaparinux sodium 2.5 mg given at least 6 hours postoperatively resulted in a 55% reduction in the risk of venous thromboembolism (VTE) in patients undergoing hip fracture surgery, total hip replacement surgery, or knee replacement surgery compared with standard enoxaparin therapy. It has a safety profile similar to that of enoxaparin with respect to clinically relevant major bleeding, including fatal bleeding, nonfatal bleeding, and bleeding requiring repeat surgery. The use of fondaparinux for prolonged prophylaxis after hip fracture has demonstrated further reduction in VTE events without increasing the risk of bleeding.. Fondaparinux is the first of a new class of synthetic factor Xa inhibitors that demonstrated greater efficacy compared with enoxaparin for the prevention of VTE in major orthopedic surgery without an increase in clinically relevant bleeding. Given the favorable cost-effectiveness analysis and improved efficacy profile, fondaparinux should be considered for formulary addition for DVT prophylaxis in patients undergoing hip and knee replacement surgery. In patients undergoing hip fracture surgery, fondaparinux should be considered the DVT prophylaxis of choice. Extended thromboprophylaxis up to 28 days resulted in additional reduction in VTE (both symptomatic and venography-proven DVT) in patients with hip fracture surgery.

Topics: Adult; Aged; Factor Xa Inhibitors; Female; Fondaparinux; Formularies as Topic; Humans; Male; Middle Aged; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

Despite widespread use of antithrombotic agents, major orthopedic surgery (total hip arthroplasty, major knee surgery, fracture of the femoral neck) still raises a high risk of deep vein thrombosis and pulmonary embolism. Proper understanding of thromboprophylaxis in orthopedic surgery requires good knowledge of the mechanisms of coagulation and the point of action of different antithrombotic agents. Sodium fondaparinux is the first synthetic inhibitor selective for factor Xa. It is composed of five saccharide units obtained by chemical synthesis, thus eliminating the risk of contamination by a pathogenic agent of animal origin and batch variability. Clinical trials using sodium fondaparinux for the prevention of venous thromboembolism after major orthopedic surgery have demonstrated its superiority over low-molecular-weight heparin without increased risk of clinically pertinent bleeding if the first injection is given at the proper time. We present the main results of clinical trials.

Topics: Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Orthopedic Procedures; Polysaccharides; Risk Factors; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Fondaparinux; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

black triangle Fondaparinux sodium, a selective factor Xa inhibitor, is the first in a new class of antithrombotics. It binds selectively with high affinity to antithrombin III and specifically catalyses the inactivation of factor Xa. The elimination half-life of fondaparinux sodium permits once daily treatment. black triangle A randomised, double-blind, parallel-group, dose-ranging, multicentre phase IIb study in 933 eligible patients established that a subcutaneous dose of between 1.5 and 3mg of fondaparinux sodium has the optimum efficacy and safety profile for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. black triangle Fondaparinux sodium, given to more than 3600 patients undergoing major orthopaedic surgery who participated in prospective, randomised, double-blind, multicentre phase III clinical trials, significantly reduced the incidence of venous thromboembolism, with an overall risk reduction of 55.2% compared with enoxaparin. black triangle Fondaparinux sodium was well tolerated by patients undergoing major orthopaedic surgery, and at the recommended clinical dose of 2.5mg has a similar tolerability profile, including bleeding events, to standard enoxaparin regimens. Fondaparinux sodium has not been reported to cause antibody-induced thrombocytopenia.

Topics: Animals; Antithrombin III; Biological Availability; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Fondaparinux; Humans; Male; Polysaccharides; Thromboembolism; Treatment Outcome

Fondaparinux sodium is the first in a new class of antithrombotic agents possessing selective inhibitory activity against factor Xa. The agent was designed and developed with the objective of overcoming the limitations of currently available therapies for the prevention and treatment of venous and arterial thromboembolic disease. Extensive data from preclinical and clinical trials demonstrate fondaparinux's favorable pharmacokinetic profile combined with promising efficacy and safety results in the prevention of venous thromboembolism following major orthopedic surgery, in the treatment of deep venous thrombosis, and in acute coronary syndromes.

Topics: Animals; Factor Xa Inhibitors; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Venous Thrombosis

Venous thromboembolism (VTE) is a life-threatening complication following orthopedic surgery. Selective factor Xa inhibition is a new antithrombotic approach designed to avoid difficulties associated with heparins and other current anticoagulants. Several antifactor Xa compounds are in early investigation, but fondaparinux (Arixtra; NV Organon, Oss, The Netherlands; Sanofi-Synthelabo, Paris, France) is the first and most advanced compound in the development of a new class of synthetic antithrombotic agents--the selective factor Xa inhibitors. Fondaparinux has a highly favorable pharmacokinetic profile; four large phase 3 trials comparing subcutaneous fondaparinux 2.5 mg once daily with the low molecular weight heparin (LMWH) enoxaparin in doses approved by regulatory bodies showed that fondaparinux reduced the overall risk of VTE in major orthopedic surgery by > 50% without increasing clinically relevant bleeding. Fondaparinux also appears to be a very promising candidate for the treatment of patients with existing VTE.

Topics: Animals; Anticoagulants; Clinical Trials, Phase III as Topic; Enoxaparin; Factor Xa Inhibitors; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Polysaccharides; Thromboembolism; Venous Thrombosis

Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments.. A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding.. Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; P<.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P =.008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups.. In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Confidence Intervals; Double-Blind Method; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Fracture Fixation, Internal; Hip Fractures; Humans; Incidence; Male; Middle Aged; Multicenter Studies as Topic; Orthopedic Procedures; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Treatment Outcome; Venous Thrombosis

Fondaparinux (Arixtra), a synthetic pentasaccharide, is the first in a new class of antithrombotic agents that selectively inhibit coagulation factor Xa. In vitro experiments demonstrated that it is a selective inhibitor of factor Xa. In plasma, fondaparinux selectively binds to antithrombin, catalyzes factor Xa inhibition, and thereby inhibits thrombin generation. Its antithrombotic efficacy has been demonstrated in various animal models mimicking venous and arterial thrombosis. In humans, its pharmacokinetic profile is favorable, with a rapid onset of antithrombotic activity and an elimination half-life allowing a convenient once-daily dosing regimen. In several clinical trials, fondaparinux was more effective than the reference drug, enoxaparin, in preventing venous thromboembolism after hip fracture, major knee, and elective hip replacement surgeries. The overall reduction in the risk of venous thromboembolism ranged between 26.3 and 56.4%, depending on the trial. This superior efficacy was achieved without increasing the risk of clinically relevant bleeding. Fondaparinux also showed promising results in the treatment of patients with venous thromboembolism and acute coronary syndromes. Thus, it is now established that selective factor Xa inhibition is an efficient way to prevent venous thrombosis. The advent of fondaparinux offers an opportunity to improve substantially the management of venous thromboembolism.

Topics: Animals; Clinical Trials as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Thromboembolism

Traditional and modern anticoagulant therapies for the management, prophylaxis, and treatment of venous thromboembolism (VTE) and acute coronary syndrome (ACS) and key findings of primary studies are summarized. Significant advances have been made during the past decade in the prevention and treatment of VTE and the treatment of ACS. Numerous trials have demonstrated that low-molecular-weight heparins (LMWHs) are at least as effective as and have challenged unfractionated heparins (UFHs) as the standard of care for the treatment of VTE and ACS. For VTE, a number of new antithrombotic agents have been developed and are currently under development, including oral direct thrombin inhibitors and synthetic pentasaccharides, such as fondaparinux, in addition to LMWHs. For ACS, various new treatment modalities, such as the broader use of percutaneous transluminal coronary angioplasty and stents, are available, in addition to new pharmacologic agents, such as glycoprotein IIb/IIIa inhibitors and innovative thrombolytics. Most of these agents and treatment modalities require the use of an anticoagulant as adjuvant therapy. Evidence suggests that LMWHs can be used safely and, in addition to being more practical, have been shown to improve outcomes compared with traditional anticoagulants in certain patient populations. LMWHs demonstrate superior clinical outcomes over traditional anticoagulants for VTE prophylaxis and treatment and ACS treatment. Primary studies of new agents, including oral direct thrombin inhibitors and synthetic pentasaccharides for the treatment of ACS are promising; however, more data are needed on their safety and efficacy.

Topics: Anticoagulants; Azetidines; Benzylamines; Coronary Disease; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

The synthetic pentasaccharide fondaparinux is the first in a novel class of antithrombotic agents. By selectively inactivating factor Xa in an antithrombin-dependent mechanism of action, fondaparinux exerts its anticoagulant effect through inhibition of thrombin generation, without any direct effect on thrombin activity. Unlike unfractionated heparin and low-molecular-weight heparins, fondaparinux is a single molecular entity produced by total chemical synthesis. Its favorable pharmacokinetic profile and pharmacodynamics allow for safe and effective once-daily dosing in the majority of populations. Initial clinical development of fondaparinux has focused on the prevention of venous thromboembolism following major orthopedic surgery--that is, hip and knee replacement and hip fracture. Results of the largest phase III clinical trial program to date in these major hip and knee surgeries demonstrate comparable safety, in terms of clinically relevant bleeding, and an overall 55% reduction in risk of venous thromboembolism with fondaparinux relative to the low-molecular-weight heparin enoxaparin.

Topics: Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

A unique antithrombotic agent, fondaparinux, selectively inhibits factor Xa and, therefore, thrombin generation, without affecting activity of the thrombin molecule. Its efficacy and safety in preventing venous thromboembolism following major orthopedic surgery, that is, hip and knee replacement and hip fracture, were demonstrated in 4 phase III clinical trials involving 7433 patients. Fondaparinux produced an overall 55% reduction in the risk of venous thromboembolism relative to the low-molecular-weight heparin enoxaparin without increasing the incidence of clinically relevant bleeding, which was similarly low for both agents. However, the incidence of overt bleeding with a bleeding index > or = 2 was higher for fondaparinux. First-dose timing according to the protocol for the 4 phase III trials was fondaparinux, 6 +/- 2 hours postoperatively, and enoxaparin, following the manufacturers' recommendations--either 12 hours preoperatively or 12 to 24 hours postoperatively. Whether the first-dose timing may explain the observed differences in efficacy and safety between the drugs was addressed in post-hoc analyses. Post-hoc analyses of the phase III trial data indicate that the superior efficacy of fondaparinux is maintained independent of the timing of the first dose. These analyses also indicate that administration of fondaparinux earlier than 6 hours postoperatively is associated with an increased incidence of a bleeding index > or = 2. Thus, when fondaparinux is administered according to the manufacturers recommended regimen, that is, not earlier than 6 hours postoperatively, the incidence of a bleeding index > or = 2 decreases to a rate similar to that found in the enoxaparin group. The superior efficacy of fondaparinux relative to enoxaparin is the result of its unique mechanism of action, clinical pharmacology, and dose selection rather than early timing of first administration.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Drug Administration Schedule; Factor Xa Inhibitors; Fondaparinux; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Safety; Thromboembolism

It has become increasingly well documented that, compared with general anesthesia, neuraxial anesthesia reduces the risk of venous thromboembolism after joint replacement surgery. The concurrent use of anticoagulants with neuraxial anesthesia, however, has raised some safety concerns. Recent large-scale, prospective, randomized experience indicates that the selective factor Xa inhibitor fondaparinux does not increase the risk of epidural hematoma when used in combination with neuraxial anesthesia.

Topics: Anesthesia, Epidural; Anesthesia, Spinal; Anticoagulants; Drug Administration Schedule; Factor Xa Inhibitors; Fondaparinux; Hematoma; Humans; Orthopedic Procedures; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism

Fondaparinux (Org-31540 / SR-90107A) is a new drug chemically synthesized for treatment and prophylaxis of thromboembolic disease. Fondaparinux is a selective inhibitor of activated factor X. Its structure is the copy of the heparin pentasaccharide sequence, the shortest chain required for antithrombin inhibition of activated factor X without antithrombin action. Fondaparinux has no effect on coagulation tests and does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. Fondaparinux inhibits thrombin generation and the growth of thrombi in in vitro and in vivo models. Phase I trials have shown a 100% bioavailability after subcutaneous (s.c.) administration, a rapid onset of action and an approximate half-life of 13.5 h. Fondaparinux is cleared as an active substance by the kidneys. In elderly patients, renal clearance is reduced and the half-life is longer. The phase II Pentathlon trial demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism in total hip-replacement patients and the optimal dose was determined to be 2.5 mg s.c./24 h. Four phase III trials have evaluated fondaparinux starting 6 hours after surgery compared with enoxaparin for prevention of venous thromboembolism following orthopedic surgery in 7,344 patients. The risk of thrombosis was reduced by 50% with fondaparinux and no differences were observed in death or severe bleeding. In a phase II trial, similar efficacy and incidence of major bleeding were seen with fondaparinux s.c. compared with dalteparin s.c. in the treatment of deep venous thrombosis. In patients with acute myocardial infarction, the efficacy of fondaparinux during fibrinolytic therapy was assessed in 326 patients who had acute coronary syndromes of less than a 6 hour duration, showing a slight but statistically not significant advantage for fondaparinux over unfractionated heparin in the coronary angiographies. There is currently no antidote for fondaparinux.

Topics: Animals; Blood Coagulation; Fibrinolytic Agents; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thromboembolism; Thrombosis; Vascular Diseases; Venous Thrombosis

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.

Topics: Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Enoxaparin; Fondaparinux; Humans; Polysaccharides; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Despite currently available antithrombotic therapies, venous thromboembolism (VTE) remains a major cause of morbidity and mortality. Fondaparinux sodium (pentasaccharide), the first in a new class of antithrombotic agents developed for the prevention and treatment of VTE, inhibits thrombin generation by selectively inhibiting factor Xa. Fondaparinux exhibits complete bioavailability by the subcutaneous route and is rapidly absorbed, reaching its maximum concentration approximately 2 h post dosing. It has a terminal half-life of 13 to 21 h, permitting once-daily dosing. Fondaparinux's reproducible linear pharmacokinetic profile exhibits minimal intrasubject and intersubject variability, suggesting that individual dose adjustments will not be required for the vast majority of the population and that there will be no need for routine hemostatic monitoring. At therapeutic concentrations (<2 mg/L), fondaparinux exhibits >94% binding to its target protein, antithrombin. Within this same concentration range there is no specific binding by fondaparinux to plasma proteins commonly involved in drug binding, indicating a low potential for drug-drug interactions by protein displacement. Unlike antithrombotic agents prepared from animal extracts (heparins), fondaparinux is chemically synthesized; this leads to batch-to-batch consistency and the absence of potential risk of contamination problems. In recently completed phase III clinical trials in VTE prevention in major orthopedic surgery, fondaparinux showed significant superiority over the low-molecular-weight heparin enoxaparin, providing an overall >50% (P < 0.001) reduction in VTE risk without increasing clinically important bleeding. Additional clinical data support its potential benefits in other venous and arterial thrombotic disorders. In view of these collective findings, fondaparinux is expected to play a major role in the prevention and treatment of venous and arterial thrombotic disease.

Topics: Animals; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Pregnancy; Pregnancy Complications, Hematologic; Thromboembolism

Thrombotic events contribute significantly to the morbidity, mortality, and health care costs of patients undergoing major orthopedic surgery. Despite therapy with unfractionated heparin, low-molecular-weight heparin, or warfarin, thrombotic events continue to occur at an unacceptably high rate in populations at risk. The need for improved prophylaxis against venous thromboembolism has resulted in the development of several new antithrombotics, both recently approved and investigational, that target specific steps in the hemostatic pathway. These include direct thrombin inhibitors, agents that inhibit the factor VIIa-tissue factor complex, and selective factor Xa inhibitors. Fondaparinux is the first of the selective factor Xa inhibitors. It was evaluated in the most comprehensive drug development program ever in major orthopedic surgery, culminating in four phase III trials involving more than 7000 enrollees, and is the first agent in its class to be approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. It has been suggested that fondaparinux's superior efficacy may be related to its ability to initiate selective inhibition of factor Xa and its predictable linear pharmacokinetics.

Topics: Arthroplasty, Replacement; Clinical Trials as Topic; Dose-Response Relationship, Drug; Enoxaparin; Fondaparinux; Humans; Polysaccharides; Premedication; Thromboembolism

Antithrombotic therapy with unfractionated heparin (UFH) and warfarin for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) became widely accepted in the early 1960s. Subsequent clinical trials have focused on the importance of early intravenous UFH in the treatment of venous thromboembolic events, the method of heparin administration, the importance of rapid anticoagulation to prevent recurrent venous thromboembolism (VTE), and the optimal duration of UFH administration. Low-molecular-weight heparin (LMWH) represents a significant advance over UFH therapy for VTE. Developed in the late 1980s, LMWH has become an excellent alternative to UFH because it offers superior efficacy and safety, improved pharmacokinetics, longer half-life, and once- or twice-daily subcutaneous administration without the need for laboratory monitoring. Fondaparinux is the first of a new class of antithrombotic agents that targets factor Xa. Based on studies of the heparin binding site of antithrombin, this novel pentasaccharide has superior pharmacokinetics and bioavailability when compared with LMWH and can be administered once daily. Studies in patients undergoing major orthopedic surgery and in those with proximal DVT indicate that the efficacy and safety of fondaparinux may represent an improvement over those of LMWH.

Topics: Double-Blind Method; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Polysaccharides; Pulmonary Embolism; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome

Trials of the new antithrombotic agent fondaparinux sodium in patients undergoing orthopedic surgery are discussed. Phase II studies conducted in more than 900 hip-replacement and 400 knee-replacement patients demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism. Phase III trials evaluated the efficacy and safety of fondaparinux sodium 2.5 mg s.c. once daily starting six hours after surgery compared with enoxaparin for prevention of venous thromboembolism (VTE). Four multicenter, randomized, comparative, double-blind Phase III trials were conducted: two in total hip replacement patients (Ephesus and Pentathlon 2000), one in knee surgery patients (PentaMaks), and one in hip fracture surgery patients (Penthifra). All four studies followed the same design template, and the comparator was one of two regimens of enoxaparin approved for this indication. Enoxaparin sodium 30 mg s.c. every 12 hours starting postoperatively was used in Pentathlon 2000 and PentaMaks, and enoxaparin sodium 40 mg s.c. once daily starting preoperatively was used in Ephesus and Penthifra. The primary efficacy endpoint was the occurrence of VTE up to day 11, as determined by venography or confirmation of symptoms. The main safety outcome was occurrence of major bleeding. In total, 7344 patients were randomized and efficacy was evaluated in 5385 (73.3%). Risk of VTE was reduced by 50% in patients receiving fondaparinux compared with those receiving enoxaparin. Safety profiles for clinically relevant bleeding were similar between the two drugs. Fondaparinux sodium, a novel antithrombotic agent, is effective for the prevention of VTE, with a favorable safety profile, in patients undergoing major orthopedic surgery.

Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin; Humans; Polysaccharides; Thromboembolism; Veins; Warfarin

Topics: Clinical Trials, Phase III as Topic; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Survival Rate; Therapeutic Equivalency; Thromboembolism; Treatment Outcome; Venous Thrombosis

We aimed to assess the safety and efficacy of fondaparinux (FPNX) for patients undergoing laparoscopic colorectal surgery (LAC).. Patients scheduled for LAC received once-daily subcutaneous injections of FPNX 1.5-2.5 mg for 4-8 days. The primary endpoint was the incidence of bleeding events. The secondary endpoint was the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE).. Among 128 patients evaluable for efficacy, 119 patients were administered FPNX. Nine patients were excluded owing to intraoperative events, including conversion to open surgery among others. Thirteen patients discontinued treatment owing to anastomotic bleeding (n = 5), anastomotic leakage (n = 3), bleeding at drain insertion site (n = 2), subcutaneous bleeding (n = 1), drug-induced rash (n = 1), and sepsis (n = 1). Among the FPNX discontinuations, there were eight cases of bleeding (6.7%), and two cases of major bleeding (1.7%). In multivariate analysis, operative time >300 min was identified as a risk factor for bleeding events (p = 0.001) secondary to FPNX. The incidence rate of DVT was 2.5% (3/119 cases); these patients were asymptomatic.. There were no cases of PE. It is necessary to establish strict criteria for VTE prophylaxis with FPNX after LAC for Japanese patients considering the incidence of bleeding events.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Humans; Laparoscopy; Male; Middle Aged; Polysaccharides; Postoperative Complications; Prospective Studies; Thromboembolism; Venous Thrombosis

Current guidelines recommend unfractionated heparin (UFH) or low-molecular-weight heparin plus an oral anticoagulant for the prevention of thromboembolism in patients undergoing electric cardioversion of atrial fibrillation (AF). Selective factor Xa inhibitors, such as fondaparinux, which has a favourable benefit-risk profile in the prevention and treatment of venous thromboembolism and the management of acute coronary syndromes, have not been systematically evaluated in this setting.. To evaluate the efficacy and safety of fondaparinux versus standard treatment in patients undergoing echocardiographically-guided cardioversion of AF.. In this multicentre, randomized, open-label, controlled, two-parallel-group, phase II pilot study, patients with AF undergoing electric cardioversion following transoesophageal echocardiography (TEE) were randomized to fondaparinux or standard therapy (UFH plus vitamin K antagonist [VKA]). Patients showing an atrial thrombus in the first TEE (clot-positive) were randomized to treatment with fondaparinux or standard care for 4 weeks before cardioversion.. The primary endpoint (combined rate of cerebral neurological events, systemic thromboembolism, all-cause death and major bleeding events) occurred in 3 of 174 (1.7%) patients on fondaparinux and 2 of 170 (1.2%) patients on UFH+VKA. The rate of thrombus disappearance among clot-positive patients was higher in the fondaparinux arm (11 of 14; 78.6%) than in the UFH+VKA arm (7 of 14; 50.0%). Incidences of adverse events were similar (45.4% with fondaparinux and 46.5% with UFH+VKA).. In this pilot study in patients with TEE-guided cardioversion, the use of fondaparinux appeared to be well tolerated, with similar efficacy to UFH+VKA. Furthermore, a trend to greater thrombus resolution was observed.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Echocardiography, Transesophageal; Electric Countershock; Factor X; Female; Fondaparinux; Humans; Male; Middle Aged; Pilot Projects; Polysaccharides; Surgery, Computer-Assisted; Thromboembolism

Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse.. To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients.. Primary outcomes were compared in subsets composed of patients weighing < or = and > 100 kg and with body mass index (BMI) < 30 and > or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding.. Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed > 100 kg and 1216 (28%) had a BMI > or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar.. The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients.

Topics: Adult; Aged; Anticoagulants; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Male; Middle Aged; Obesity; Polysaccharides; Recurrence; Thromboembolism; Treatment Outcome; Venous Thrombosis

The benefit of combined mechanical and pharmacologic methods for venous thromboembolism prevention after abdominal surgery has not been clearly established.. To compare the efficacy and safety of fondaparinux in conjunction with intermittent pneumatic compression vs. intermittent pneumatic compression alone in this context.. This was a randomized, double-blind, placebo-controlled superiority trial. Patients aged at least 40 years undergoing abdominal surgery were randomized to receive either fondaparinux 2.5 mg or placebo s.c. for 5-9 days, starting 6-8 h postoperatively. All patients received intermittent pneumatic compression. The primary efficacy outcome was venous thromboembolism up to day 10. The main safety outcomes were major bleeding and all-cause mortality. Follow-up lasted 32 days.. Of the 1309 patients randomized, 842 (64.3%) were evaluable for efficacy. The venous thromboembolism rate was 1.7% (7/424) in the fondaparinux-treated patients and 5.3% (22/418) in the placebo-treated patients (odds ratio reduction 69.8%; 95% confidence interval 27.9-87.3; P = 0.004). Fondaparinux significantly reduced the proximal deep vein thrombosis rate from 1.7% (7/417) to 0.2% (1/424; P = 0.037). Major bleeds occurred in 1.6% (10/635) and 0.2% (1/650) of fondaparinux-treated and placebo-treated patients, respectively (P = 0.006), none being fatal or involving a critical organ. By day 32, eight patients (1.3%) receiving fondaparinux and five (0.8%) receiving placebo had died.. In patients undergoing abdominal surgery and receiving intermittent pneumatic compression, fondaparinux 2.5 mg reduced the venous thromboembolism rate by 69.8% as compared to pneumatic compression alone, with a low bleeding risk as compared to placebo.

Topics: Abdomen; Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Female; Fondaparinux; Humans; Intermittent Pneumatic Compression Devices; Male; Middle Aged; Placebos; Polysaccharides; Surgical Procedures, Operative; Thromboembolism; Treatment Outcome

To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism.. Double blind randomised placebo controlled trial.. 35 centres in eight countries.. 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days.. 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days.. The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month.. 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died.. Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.

Topics: Acute Disease; Aged; Anticoagulants; Bed Rest; Chronic Disease; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Fondaparinux; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Polysaccharides; Thromboembolism; Treatment Outcome; Venous Thrombosis

Venous thromboembolism (VTE) is a common complication of total joint arthroplasty. Fondaparinux VTE prophylaxis is currently begun 6 to 8 hours after surgery. Flexible dosing may reduce bleeding risk and allow easier use by starting the morning after surgery instead of staggered hours on the surgery day. This study examined flexible timing of the first dose of fondaparinux. Whether the first dose was administered 8 +/- 2 hours after surgery or the morning after surgery, no significant difference was observed in incidence of symptomatic VTE (2.0% and 1.9%, respectively, P = .89). Major and minor bleeding events were similar between groups (1.2% and 0.7% [P = .19], and 1.4% and 2.0% [P = .31], respectively). Delaying initiation of fondaparinux prophylaxis provides an option after total joint arthroplasty with preserved efficacy and safety.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Chi-Square Distribution; Drug Administration Schedule; Female; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Thromboembolism; Treatment Outcome

There remains considerable controversy regarding optimal initial warfarin dosing in patients with acute venous thromboembolism. Therefore, an open-label, randomized trial comparing 2 warfarin initiation nomograms (5 vs 10 mg) was conducted in patients with acute venous thromboembolism. All participants received fondaparinux for > or = 5 days as a "bridge" to warfarin. The primary end point was defined as the number of days necessary to achieve 2 consecutive international normalized ratio laboratory test values > 1.9. A total of 50 patients were enrolled and randomly assigned to each of the treatment arms. The median time to 2 consecutive international normalized ratios was 5 days in the 2 groups. There was no statistical difference in achieving the primary end point using either the 5- or the 10-mg nomogram (p = 0.69). These results should provide clinicians with increased warfarin dosing options in patients presenting with acute venous thromboembolism.

Topics: Acute Disease; Anticoagulants; Dose-Response Relationship, Drug; Factor X; Female; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Thromboembolism; Treatment Outcome; Warfarin

The aim of this study was to assess whether the synthetic factor Xa inhibitor fondaparinux reduced the risk of venous thromboembolism more efficiently than the low molecular weight heparin dalteparin in patients undergoing major abdominal surgery.. In a double-blind double-dummy randomized study, patients scheduled for major abdominal surgery under general anaesthesia received once-daily subcutaneous injections of fondaparinux 2.5 mg or dalteparin 5000 units for 5-9 days. Fondaparinux was started 6 h after surgery. The first two doses of dalteparin, 2500 units each, were given 2 h before surgery and 12 h after the preoperative administration. The primary outcome measure was a composite of deep vein thrombosis detected by bilateral venography and symptomatic, confirmed deep vein thrombosis or pulmonary embolism up until day 10. The main safety outcome measure was major bleeding during treatment.. Among 2048 patients evaluable for efficacy, the rate of venous thromboembolism was 4.6 per cent (47 of 1027) with fondaparinux compared with 6.1 per cent (62 of 1021) with dalteparin, a relative risk reduction of 24.6 (95 per cent confidence interval -9.0 to 47.9) per cent (P = 0.144), which met the predetermined criterion for non-inferiority of fondaparinux. Major bleeding was observed in 49 (3.4 per cent) of 1433 patients given fondaparinux and 34 (2.4 per cent) of 1425 given dalteparin (P = 0.122).. Postoperative fondaparinux was at least as effective as perioperative dalteparin in patients undergoing high-risk abdominal surgery.

Topics: Abdomen; Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Female; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Postoperative Complications; Risk Factors; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Factor Xa Inhibitors; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

The targeted mechanism of factor Xa inhibition has been studied extensively, initially as prophylaxis for venous thromboembolism (VTE) in the orthopedic surgical setting. Future therapeutic directions for selective factor Xa inhibition in the management of other thrombotic diseases are discussed. Thromboembolic diseases can occur in the venous or arterial sides of the circulatory system. Factor Xa inhibition is a targeted approach to anticoagulation that resulted from significant advances in our understanding of the coagulation cascade. The factor Xa inhibitor fondaparinux has been studied extensively in the orthopedic surgical setting for the prophylaxis of VTE. Current investigations that are under way or completed evaluate the efficacy and safety of fondaparinux for the management of various thrombotic diseases. The future development of fondaparinux resides primarily in three therapeutic areas: prevention of VTE, treatment of VTE, and treatment of acute coronary syndromes. For the prevention of VTE, fondaparinux has been studied as extended prophylaxis following hip fracture surgery (PENTHIFRA Plus), for use in high-risk abdominal surgical patients (PEGASUS and APOLLO), and for use in medical patients (ARTEMIS). Studies evaluating fondaparinux for the treatment of VTE are part of the large MATISSE clinical program (MATISSE DVT and MATISSE PE). Fondaparinux was investigated in phase 2 studies for the treatment of acute coronary syndromes, including acute ST-segment myocardial infarction (PENTALYSE) and unstable angina (PENTUA). Encouraging data from these trials are the basis for phase 3 programs in this area (MICHELANGELO). The orthopedic prophylactic and nonorthopedic clinical programs for fondaparinux in the management of thrombosis support the concept that targeted inhibition of coagulation is an effective advance in antithrombotic therapy.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Female; Fondaparinux; Forecasting; Humans; Male; Middle Aged; Polysaccharides; Postoperative Complications; Thromboembolism

Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk.. In a double-blind study, were randomly assigned 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily, initiated postoperatively, or 40 mg of enoxaparin once daily, initiated preoperatively, for at least five days. The primary efficacy outcome was venous thromboembolism up to postoperative day 11. Venous thromboembolism was defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was six weeks.. The incidence of venous thromboembolism by day 11 was 8.3 percent (52 of 626 patients) in the fondaparinux group and 19.1 percent (119 of 624 patients) in the enoxaparin group (P<0.001). The reduction in risk with fondaparinux was 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent). There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding.. In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and equally safe.

Topics: Aged; Double-Blind Method; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Hip Fractures; Humans; Incidence; Injections, Subcutaneous; Male; Mortality; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk.. In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding.. The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ.. In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.

Topics: Aged; Double-Blind Method; Drug Administration Schedule; Elective Surgical Procedures; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Incidence; Injections, Subcutaneous; Knee; Male; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Heparin-induced thrombocytopenia (HIT) is a serious complication of the administration of heparin and its derivatives. Non-heparin anticoagulants such as argatroban and fondaparinux are widely used in the management of HIT to compare the effectiveness of argatroban and fondaparinux in the resolution of thrombocytopenia and to compare clinical outcomes in patients with isolated HIT. A retrospective cohort analysis was performed at King Abdulaziz Medical City (KAMC) on patients diagnosed with isolated HIT between 31 Jan, 2014 and 30 June, 2017. Demographics data, non-heparin anticoagulants, related laboratory results, and clinical outcomes were retrieved and analysed. The cohort comprised a total of 95 adult patients who received either argatroban (56 patients) or fondaparinux (39 patients) for isolated HIT. The median age and sex distribution were similar in both argatroban and fondaparinux groups. The mean (+ SD) time (in days) for the resolution of thrombocytopenia was 3.5 (± 1.8) for patients who received argatroban and 3.7 (± 1.7) for patients administered fondaparinux (p = 0.843). Thromboembolic events occurred in five patients (8.9%) administered argatroban and in three patients (7.7%) administered fondaparinux (p = 0.382). There was no significant difference in the rates of bleeding or death (p = 0.829); however, the small number of cases limits our ability to draw conclusions about these outcomes. In this retrospective study, fondaparinux and argatroban were similarly effective in resolving thrombocytopenia, preventing further thromboembolic events, and maintaining safety in patients with confirmed HIT. To confirm this observation, larger prospective studies are needed.

Topics: Aged; Arginine; Fondaparinux; Heparin; Humans; Middle Aged; Pipecolic Acids; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism

Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label.. The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.. In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.. Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.. Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238).

Topics: Anticoagulants; Arginine; Chondroitin Sulfates; Dermatan Sulfate; Factor Xa Inhibitors; Female; Fondaparinux; Hemorrhage; Heparin; Heparitin Sulfate; Hirudins; Hospital Mortality; Hospitalization; Humans; Male; Necrosis; Off-Label Use; Partial Thromboplastin Time; Patient Safety; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Registries; Retrospective Studies; Sulfonamides; Thrombocytopenia; Thromboembolism; Treatment Outcome

The prevalence of medical conditions representing a risk for thromboembolic complications and requiring antithrombotic therapy increases gradually with age. Two cases of fatal noncritical organ bleeding complication that occurred during the conversion period from initial fondaparinux to vitamin K antagonist are presented. An 81-year-old obese female patient (body mass index 43 kg/m(2)) with previous postoperative thrombosis underwent uneventful total knee replacement under spinal anesthesia. She presented with popliteal hematoma during conversion to oral anticoagulant. A 92-year-old female patient (body mass index 33 kg/m(2)) with left lower limb thrombosis was referred to our orthopedics department from her senior citizens' home for right lower limb hematoma and ischemia that occurred during conversion to oral anticoagulant. Thromboembolic and bleeding events in the elderly are real public health problems. Specific guidelines dedicated to this particular population are needed, which will improve the management of anticoagulation and decrease risk of complications.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Fatal Outcome; Female; Fondaparinux; Hemorrhage; Humans; Obesity; Polysaccharides; Risk Factors; Thromboembolism; Thrombosis; Vitamin K

Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinux-associated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P = .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ≥1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to www.umin.ac.jp/ctr as #UMIN000001366.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Autoantibodies; Autoantigens; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Intermittent Pneumatic Compression Devices; Male; Middle Aged; Platelet Factor 4; Polysaccharides; Stockings, Compression; Thromboembolism

Topics: Blood Coagulation; Drug Administration Schedule; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Risk Factors; Thromboembolism; Treatment Outcome; Venous Thrombosis

Fondaparinux is an antithrombin-dependent factor Xa inhibitor that is used for thromboprophylaxis of patients undergoing hip fracture surgery, hip or knee replacement, or abdominal surgery. It is cleared by the kidney and should be used with caution in patients with renal impairment and avoided in patients with severe renal insufficiency. Recently, several studies have demonstrated that a lower dose of fondaparinux in patients with moderate renal impairment appears to be safe and effective. The purpose of this study was to obtain pharmacokinetic and clinical data on the use of prophylactic fondaparinux in patients with renal insufficiency undergoing major abdominal surgery for cancer (n=8) or orthopedic surgery (n=1). Anti-factor Xa levels were obtained, and a published population pharmacokinetic model for fondaparinux was fit to the data. The data were analyzed using NONMEM software. Fondaparinux did not appear to accumulate in these patients, even when the drug was administered for up to twelve days. Pharmacokinetic analysis revealed that the apparent clearance in this population, who were primarily undergoing cancer surgery, was similar to prior studies in orthopedic surgery patients. In contrast, lower estimates were obtained for volume of distribution and absorption rate constant parameters. None of the patients sustained a hemorrhagic complication attributable to fondaparinux. One patient developed hypoxia in the setting of transient atrial fibrillation and clinical suspicion for pulmonary embolism, but this was not confirmed radiographically. These results support the use of 1.5mg of fondaparinux every 24hours for thromboprophylaxis in patients with renal insufficiency undergoing high-risk surgical procedures.

Topics: Aged; Aged, 80 and over; Anticoagulants; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Postoperative Period; Prospective Studies; Renal Insufficiency; Risk Factors; Thromboembolism

Thromboembolic complications such as systemic embolization and valve thrombosis are a major concern early after mechanical valve replacement; however, the benefit of anticoagulation must be weighed against the risk of early postoperative bleeding complications. Thromboembolic risk is also higher in the early postoperative period (less than 6 mo) compared with the risk in the late postoperative period. Current evidence supports the use of unfractionated heparin or low-molecular-weight heparin early after valve replacement to prevent valve thrombosis or systemic embolization but provides no recommendations for the management of patients with a history of heparin-induced thrombocytopenia (HIT), in which heparin products are contraindicated. We describe the use of fondaparinux early after aortic mechanical valve replacement in a 63-year-old, 95-kg woman with a history of HIT. Fondaparinux was initiated on postoperative day 2 at a prophylactic dose of 2.5 mg subcutaneously daily; the dose was increased to a therapeutic weight-based dose of 7.5 mg subcutaneously daily on postoperative day 3. Warfarin was initiated on postoperative day 1, and fondaparinux was continued until a therapeutic international normalized ratio was achieved. The patient was discharged from the hospital receiving warfarin alone on postoperative day 6. No signs or symptoms of thrombosis or bleeding were noted during or after fondaparinux therapy or at hospital follow-up visits. To our knowledge, this is the first case report to describe the use of fondaparinux within the first 48 hours after mechanical valve replacement in a patient with a history of HIT. This case suggests that fondaparinux may be a safe and effective option to prevent thromboembolic complications early after mechanical valve replacement when heparin products are contraindicated.

Topics: Anticoagulants; Aortic Valve; Female; Follow-Up Studies; Fondaparinux; Heart Valve Prosthesis Implantation; Heparin; Humans; International Normalized Ratio; Middle Aged; Polysaccharides; Postoperative Complications; Thrombocytopenia; Thromboembolism; Treatment Outcome; Warfarin

Today, there is a small number of studies on the effects of Enoxaparin and Fondaparinux used commonly in the prevention of venous thromboembolism on healing of fracture cases.. The aim of this study was to investigate clinically, radiologically and histopathologically, the effects of Enoxaparin, Fondaparinux and Rivaroxaban used in thromboembolism prophylaxis on fracture healing in a rat model of femur fracture.. Thirty-two male Sprague Dawley rats were randomized into four groups (n=8): the control group (Group 1), the Enoxaparin group (Group 2), the Fondaparinux group (Group 3), and Rivaroxaban group (Group 4). Under general anesthesia, a standard closed fracture was created in the left femur of each rat using an osteotome. Group 1 was given saline solution (1 cc/day, sc), Group 2 Enoxaparin (100 anti Xa IU/kg/day, sc), Group 3 Fondaparinux (0.2 mg/kg/day, sc), and Group 4 Rivaroxaban (3 mg/kg/day, po) for 21 days. After all rats were sacrificed at the end of day 21, their left femurs were disarticulated at the level of the hip and knee. The bony union was radiologically, clinically, and histopathologically evaluated.. No differences were found between the groups in terms of clinical, radiological, and histopathological findings in fracture healing (p = 0.849, p = 0.731, and p = 0.395, respectively).. Enoxaparin, Fondaparinux and Rivaroxaban used in thromboembolism prophylaxis cause no significant changes in fracture healing with short term follow up. Thus, they can be safely used in cases of fractures.

Topics: Animals; Enoxaparin; Femoral Fractures; Fibrinolytic Agents; Fondaparinux; Fracture Healing; Male; Morpholines; Polysaccharides; Rats; Rats, Sprague-Dawley; Rivaroxaban; Thiophenes; Thromboembolism; Tomography, X-Ray Computed

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Contraindications; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; Kidney Failure, Chronic; Polysaccharides; Renal Dialysis; Thromboembolism; Vascular Calcification; Vitamin K; Warfarin

Thromboembolic complications are the most common preventable cause of mortality and morbidity in trauma and arthroplasty patients. Therefore, this group of patients receive a prophylaxis for thromboemboli by mechanical or pharmacological methods. This study was designed to evaluate the effect of enoxaparin, nadroparin, dalteparin and fondaparinux on fracture healing in an experimental rat femur fracture model.. Thirty male, Wistar-Albino rats were divided randomly into five groups. A retrograde intramedullary kirschner wire was inserted under general anesthesia and then standard closed femoral shaft fractures were produced. After the production of fractures, treatment groups received enoxaparin, nadroparin, dalteparin and fondaparinux via subcutaneous injections and the control group received placebo injections for four weeks. The formation and healing of the bones were determined by clinical manual evaluation, radiographic and histopathological analyses.. Histological callus formation scores were found to be significantly increased in the fondaparinux group when compared to the control group at the end of the fourth week. Other treatment groups' histological scores did not show any significant difference with the control group. The histological scores of all groups were compared and the fondaparinux group histological score was found to be significantly increased. The clinical and radiological scores between the groups did not show any significant difference.. A positive histological effect of fondaparinux on fracture healing was observed in this study. This enhancing effect of fondaparinux may be related to its synthetic and selective composition and non-inhibitory effects on osteoblasts and growth factors.

Topics: Animals; Dalteparin; Enoxaparin; Femoral Fractures; Femur; Fondaparinux; Fracture Healing; Heparin, Low-Molecular-Weight; Male; Models, Animal; Nadroparin; Osteoblasts; Polysaccharides; Rats; Rats, Wistar; Thromboembolism

To report a case of successful use of fondaparinux for bridging early after aortic and mitral mechanical heart valve replacement (MHVR).. A 71-year-old female underwent aortic and mitral valve replacements with St. Jude medical bileaflet prostheses, as well as DeVega tricuspid annuloplasty and coronary artery bypass graft. Anticoagulation was initially withheld following the procedure because of thrombocytopenia, large amount of chest tube drainage (~1 L/day), and concerns regarding postoperative bleeding. The thrombocytopenia (baseline platelet count 183 x 10(3)/μL; postoperative platelet count 44 × 10(3)/μL) was thought to be a consequence of the cardiopulmonary bypass; there was a low probability of heparin-induced thrombocytopenia. However, the care team preferred to avoid heparin products and initiated fondaparinux 7.5 mg subcutaneously once daily on postoperative day 8 once the patient's platelet count had recovered to >100 x 10(3)/μL. The treatment was bridged to warfarin on postoperative day 13 and the patient was discharged home after receiving 8 days of fondaparinux. Throughout the patient's hospitalization and upon follow-up on postoperative day 31, there were no signs or symptoms of thromboembolic events or bleeding.. Unfractionated heparin and low-molecular-weight heparins are the standard of care for bridging to warfarin in patients with MHVR. The use of fondaparinux following MHVR has not been studied in randomized controlled trials. In vitro studies support the effectiveness of fondaparinux in preventing thrombus formation on mechanical heart valves. However, the only data available in humans as of December 2011 are 3 case reports. Two of these case reports described the successful use of fondaparinux for anticoagulation in a patient with an aortic valve replacement. In the third case report, the patient had an aortic and mitral valve replacement. Our case report is novel because it describes the use of fondaparinux early after MHVR, which is the most critical time period for effective thromboprophylaxis.. The use of fondaparinux for postoperative bridging in our patient early after combined aortic and mitral MHVR was effective. However, until studies evaluate the efficacy and safety of fondaparinux in patients with MHVR, its use should be considered only when heparin products are contraindicated.

Topics: Aged; Anticoagulants; Aortic Valve; Female; Fondaparinux; Heart Valve Prosthesis; Humans; Mitral Valve; Polysaccharides; Thromboembolism

Thromboembolism is an infrequent, yet serious cause of both maternal and fetal morbidity and death during pregnancy and the puerperium. Antithrombotic treatment and prophylaxis both before and during pregnancy are based on unfractionated heparin (UH), low-molecularweight heparin (LMWH), Warfarin and Aspirin. The prevalence and severity of thromboembolism during pregnancy and puerperium warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. This paper assesses the safety and efficacy of antithrombotic therapy during pregnancy and the peripartum period. Its cardiovascular and obstetric indications, the evidence of association between thrombophilias and adverse pregnancy outcome, regimens and maternal and fetal side-effects are also discussed.

Topics: Anticoagulants; Aspirin; Bone Density; Breast Feeding; Chondroitin Sulfates; Dermatan Sulfate; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Humans; Infant, Newborn; Polysaccharides; Pregnancy; Pregnancy Complications, Hematologic; Thromboembolism; Thrombophilia; Warfarin

Venous thromboembolism is a common problem in the intensive care unit (ICU). To decrease its incidence, prophylactic pharmacologic interventions are part of the ICU routine. However, common ICU conditions may impair the bioavailability of subcutaneously administered agents. The present study evaluates the bioavailability of prophylactic subcutaneous fondaparinux to critically ill patients.. The purpose of the study was to evaluate vasopressor effect on the bioavailability of subcutaneously administered fondaparinux.. A 2-center, prospective, observational study was performed. Forty patients were enrolled and divided into 2 groups depending on their vasopressor requirements. All subjects were critically ill patients admitted to a medical ICU for an anticipated stay of more than 72 hours.. All patients received subcutaneous fondaparinux 2.5 mg/d, and serum anti-Xa factor was serially assessed during the first 100 hours of medical ICU stay.. Therapeutic anti-factor Xa levels among patients receiving vasopressors were observed. In hemodynamically normal patients, subtherapeutic concentrations were detected during the first 48 hours of fondaparinux administration.. Vasopressor therapy does not appear to affect fondaparinux bioavailability or to reduce anti-factor Xa levels. Subtherapeutic concentrations were detected during the first 48 hours of fondaparinux administration in hemodynamically stable patients. The clinical significance of reduced levels during the first 2 days of fondaparinux administration remains unknown.

Topics: Anticoagulants; Biological Availability; Critical Illness; Factor Xa Inhibitors; Female; Fondaparinux; Humans; Male; Middle Aged; Polysaccharides; Prospective Studies; Thromboembolism

Topics: Anticoagulants; Aortic Valve Stenosis; Aspirin; Drug Therapy, Combination; Fondaparinux; Heart Valve Prosthesis; Hemorrhage; Humans; Male; Middle Aged; Obesity; Platelet Aggregation Inhibitors; Polysaccharides; Postoperative Complications; Risk Factors; Thromboembolism; Time Factors; Treatment Outcome

Topics: Antibodies; Anticoagulants; Chondroitin Sulfates; Dermatan Sulfate; Female; Fondaparinux; Heparin; Heparitin Sulfate; Humans; Male; Platelet Activation; Platelet Factor 4; Polysaccharides; Serotonin; Thrombocytopenia; Thromboembolism

The development of new antithrombotic molecules which induced an inhibition of activated factor X (fondaparinux, Arixtra) shows effectiveness and safety in prevention of thromboembolic disease in surgery, but also in the treatment of the pulmonary embolism and major venous thromboses and acute myocardial infarction. Recent clinical trials show that new anti-Xa inhibitors also have interesting properties in antithrombotic therapy. Fondaparinux could offer new therapeutic possibilities that could simplify the management of patients under anticoagulant treatment.

Topics: Anticoagulants; Blood Coagulation; Cysteine Endopeptidases; Drug Interactions; Fondaparinux; Humans; Neoplasm Proteins; Polysaccharides; Thromboembolism

Development of post-thrombotic syndrome (PTS) is increasingly being recognized as a complication of deep venous thrombosis (DVT) in children.. To determine the prevalence, clinical characteristics, and predictors of moderate to severe PTS in children.. A retrospective chart review was performed on those children who were followed in the coagulation clinic for objectively confirmed DVTs from December 2004 to December 2006. The scoring system used by Kuhle et al was used to grade the severity of PTS as: mild, moderate, and severe.. PTS developed in 20% (11/55; 95% confidence interval 9.4-30.1) of children, in which 8/11 were moderate and 3/11 were severe. Median interval between diagnosis of PTS and DVT was 90 days (range, 46 d to 3 y). The majority (72.7%) of patients in the non-PTS group received treatment intervention within 48 hours of diagnosis of DVT. Delay in treatment initiation (>48 h) and recurrence of DVT were associated with the development of PTS (P<0.05). Variables including occlusive thrombus, location and number of vessels involved with DVT, age at diagnosis, underlying thrombophilia, intensity of anticoagulation, and body mass index were not associated with the development of PTS. Other debilitating consequences of DVT requiring intervention included portal hypertension (n=2), chylothorax (n=1), and reflux sympathetic dystrophy (n=1). The small sample size and limited follow up restricted the statistical analysis.. PTS is a significant problem in children with symptomatic DVTs. Early treatment intervention within the first 48 hours of diagnosis of DVT and prevention of thrombosis recurrence may prevent development of PTS. Although PTS refers to consequences of intravenous hypertension owing to extremity DVTs, sequlae of nonextremity DVTs require special consideration in pediatric PTS classification.

Topics: Adolescent; Anticoagulants; Child; Child, Preschool; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Infant; Infant, Newborn; Male; Polysaccharides; Postphlebitic Syndrome; Recurrence; Retrospective Studies; Thromboembolism; Warfarin

Topics: Anticoagulants; Drug Hypersensitivity; Female; Fondaparinux; Heparin; Humans; Lupus Erythematosus, Systemic; Polysaccharides; Pregnancy; Pregnancy Complications, Hematologic; Skin Tests; Thromboembolism

Topics: Adult; Disease Management; Disease Progression; Fatal Outcome; Female; Fondaparinux; Humans; Lung Neoplasms; Polysaccharides; Recurrence; Thromboembolism; Venous Thrombosis

Topics: Adult; Anticoagulants; Drug Hypersensitivity; Female; Fondaparinux; Heparin, Low-Molecular-Weight; Heparinoids; Humans; Polysaccharides; Pregnancy; Pregnancy Complications, Hematologic; Risk Factors; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Drug Administration Schedule; Factor Xa Inhibitors; Female; Fibrin; Fondaparinux; Humans; Middle Aged; Perioperative Care; Phenprocoumon; Polysaccharides; Postoperative Hemorrhage; Surgical Procedures, Operative; Thromboembolism; Thrombophilia; Venous Thrombosis; Vitamin K

Initial treatment of venous thromboembolic events is currently based on antithrombotics. This treatment is validated and identical for deep vein thrombosis (DVT) and pulmonary embolism. For distal DVT, this treatment has still to be validated. This reference therapeutic strategy is firstly parenteral and based on low-molecular-weight heparins (LMWH) or fondaparinux, subcutaneously prescribed at fixed dosage based on body weight without any systematic dose adjustment on hemostasis tests. Unfractionated heparin is steel the reference treatment in case of severe renal insufficiency. This parenteral treatment has to be relieved by vitamin K antagonists (VKA). VKA has to be co-administrated for at least 3 days, without any loading dose and can be early initiated. VKA dose needs to be adjusted in order to maintain INR between 2 and 3. However, in case of cancer, LMWH have to be carried on for 6 months. A part this antithrombotic treatment, thrombolytics are recommended in case of massive PE and vena cava filter should be used in case of recurrence despite adequate antithrombotic treatment or in case of contraindication to antithrombotic.

Topics: Anticoagulants; Antifibrinolytic Agents; Factor X; Fibrinolytic Agents; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Intravenous; Injections, Subcutaneous; International Normalized Ratio; Polysaccharides; Pulmonary Embolism; Renal Insufficiency; Thromboembolism; Vena Cava Filters; Venous Thrombosis; Vitamin K

Topics: Aged; Anticoagulants; Fondaparinux; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Fondaparinux; Humans; Polysaccharides; Thromboembolism

Topics: Aged; Anticoagulants; Drug Eruptions; Fondaparinux; Humans; Hypersensitivity, Delayed; Injections, Subcutaneous; Male; Nadroparin; Polycythemia Vera; Polysaccharides; Thromboembolism; Treatment Outcome

The risk of venous thromboembolism in patients following arthroplasty may be reduced by continuing chemical thromboprophylaxis for up to 35 days post-operatively. This prospective cohort study investigated the compliance of 40 consecutive consenting patients undergoing lower limb arthroplasty with self-administration of a recommended subcutaneous chemotherapeutic agent for six weeks after surgery. Compliance was assessed by examination of the patient for signs of injection, number of syringes used, and a self-report diary at the end of the six-week period. A total of 40 patients, 15 men and 25 women, were recruited. One woman was excluded because immediate post-operative complications prevented her participation. Self-administration was considered feasible in 87% of patients (95% confidence interval (CI) 76 to 98) at the time of discharge. Among this group of 34 patients, 29 (85%) were compliant (95% CI 73 to 97). Patients can learn to self-administer subcutaneous injections of thromboprophylaxis, and compliance with extended prophylaxis to six weeks is good.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Feasibility Studies; Female; Fondaparinux; Hand; Humans; Injections, Subcutaneous; Male; Patient Compliance; Polysaccharides; Postoperative Care; Postoperative Complications; Prospective Studies; Self Administration; Thromboembolism; Venous Thrombosis

Topics: Animals; Anticoagulants; Fondaparinux; Humans; Islam; Polysaccharides; Swine; Thromboembolism

Topics: Anticoagulants; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Glycine; Humans; Morpholines; Piperazines; Polysaccharides; Rivaroxaban; Thiophenes; Thromboembolism

Heparin is the drug of choice for the treatment or the prevention of thromboembolic disease during pregnancy. However, treatment options are limited when heparin cannot be used because of hypersensitivity skin reactions. Despite the recent availability of new anticoagulant agents, data relating to their use during pregnancy are lacking. This report describes the successful management with fondaparinux, during 150 days, of a pregnant patient with protein S deficiency and prior deep vein thrombosis (DVT) who developed heparin and danaparoid hypersensitivity.

Topics: Adult; Female; Fondaparinux; Heparin; Humans; Polysaccharides; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Protein S Deficiency; Thromboembolism

Topics: Acute Disease; Anticoagulants; Bed Rest; Disease-Free Survival; Fondaparinux; Humans; Inpatients; Polysaccharides; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Anticoagulants; Clinical Trials as Topic; Ethics, Research; Fondaparinux; Guidelines as Topic; Humans; Placebos; Polysaccharides; Research Design; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Clinical Trials as Topic; Ethics, Research; Fondaparinux; Guidelines as Topic; Humans; Placebos; Polysaccharides; Research Design; Thromboembolism; Venous Thrombosis

The prolonged administration of heparin for prevention and treatment of venous thromboembolism has been associated with a risk of heparin-induced osteoporosis. Fondaparinux is a new antithrombotic drug that specifically inhibits factor Xa. Because of the known interactions of other antithrombotic agents with bone remodelling, the effects of fondaparinux on human osteoblasts were analysed in vitro.. Primary human osteoblast cell cultures were incubated with either the low molecular weight heparin dalteparin at concentrations of 30, 300 and 900 microg/ml or with fondaparinux at concentrations of 25, 50, 100, 150, 200 and 250 microg/ml. Cellular proliferation rate and protein synthesis were measured. Expression of genes encoding osteocalcin, collagen type I and alkaline phosphatase was examined by reverse transcriptase-polymerase chain reaction.. Incubation with dalteparin led to a significant, dose-dependent inhibition of osteoblast proliferation, inhibition of protein synthesis, and inhibited expression of phenotype markers (osteocalcin and alkaline phosphatase genes) after 3 and 7 days. No inhibitory effects were observed in the fondaparinux-treated cells.. Fondaparinux did not inhibit osteoblast proliferation in vitro and may reduce the risk of heparin-induced osteoporosis associated with long-term heparin administration.

Topics: Alkaline Phosphatase; Anticoagulants; Cells, Cultured; Dalteparin; Fluoresceins; Fondaparinux; Gene Expression; Humans; Osteoblasts; Osteocalcin; Osteoporosis; Polysaccharides; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Thromboembolism

Patients undergoing major orthopedic surgery face considerable risk of venous thromboembolism (VTE), which may be fatal unless they receive prophylactic treatment. Fondaparinux sodium is a new antithrombotic agent that is indicated for prophylaxis of VTE after major orthopedic surgery. This paper presents a cost-effectiveness analysis of fondaparinux sodium and enoxaparin sodium, the latter being the most commonly used agent for prophylaxis of VTE.. The analysis is based on an international simulation model, using Norwegian unit costs, and Norwegian data of 55 000 patients undergoing orthopedic surgery between 1999 and 2001. We estimated the expected incidence of VTE and VTE-related deaths, and expected costs of VTE-related care for each of the two prophylactic agents for different periods.. The results indicate that fondaparinux sodium is likely to be more effective than enoxaparin sodium in preventing the incidence of VTE. By day 90, fondaparinux sodium is expected to avoid 180 more VTE events, and between 8 and 33 more VTE-related deaths per 10,000 patients than enoxaparin sodium. Fondaparinux sodium is also a cost-saving option in short follow-up periods for hip fracture surgery. For extended follow-up periods (i.e. 5 years), fondaparinux sodium is also likely to represent the lower cost treatment option after total knee and hip replacement. The sensitivity analyses show that the main results are robust to changes in the most important parameters. Results are, however, sensitive to the price difference between the two drugs.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Cost-Benefit Analysis; Enoxaparin; Female; Follow-Up Studies; Fondaparinux; Hip Fractures; Humans; Inpatients; Insurance, Health, Reimbursement; Length of Stay; Linear Models; Male; Norway; Polysaccharides; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Contraindications; Drug Interactions; Factor Xa Inhibitors; Female; Fondaparinux; Humans; Male; Polysaccharides; Postoperative Complications; Thromboembolism

Topics: Anesthesia, Spinal; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thromboembolism

Patients undergoing hip arthroplasty are at high risk for developing venous thromboembolic events (VTE) postoperatively in the absence of prophylaxis. In this study, a cost analysis comparing efficacy and safety data from a published trial evaluating fondaparinux and enoxaparin as VTE prophylaxis in hip replacement patients was performed. Incremental cost effectiveness ratios were calculated to determine cost per VTE avoided. Additionally, cost per death averted and cost per life year gained were calculated. Fondaparinux proved to offer minor cost savings when compared with 30 mg enoxaparin every 12 h for costs per VTE avoided, costs per death averted, and costs per life year gained. Sensitivity analyses support these findings.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Costs and Cost Analysis; Elective Surgical Procedures; Enoxaparin; Fondaparinux; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

Topics: Adult; Age Factors; Aged; Anticoagulants; Azetidines; Benzylamines; Dalteparin; Female; Fibrinolytic Agents; Fondaparinux; Humans; Male; Middle Aged; Multicenter Studies as Topic; Oligosaccharides; Placebos; Polysaccharides; Prodrugs; Pulmonary Embolism; Randomized Controlled Trials as Topic; Thromboembolism; Thrombomodulin; Time Factors; Warfarin

Fondaparinux and enoxaparin are both effective and safe in preventing post-operative venous thromboembolism. However, neither of them significantly influence the conventional clotting tests. We compared the influence of clinically relevant concentrations of fondaparinux and enoxaparin on normal whole blood (WB) thromboelastographic profiles after triggering TF-pathway with minimal amount of thromboplastin. Diluted thromboplastin was added to WB samples supplemented with buffer (control), fondaparinux (0.25; 0.5; 1 microg/ml), or enoxaparin (0.1; 0.5; 1 anti-Xa IU/ml). Four parameters were analyzed, R: clotting time, K: time required to reach an amplitude of 20 mm, alpha angle: measurement reflecting clot development kinetics and MA: maximal amplitude. At concentrations used in prophylaxis, both enoxaparin (0.1 anti-Xa IU/ml) and fondaparinux (0.25 microg/ml which correspond to 0.27 anti-Xa IU/ml) significantly prolonged the R and K times, but did not significantly modify the alpha angle as compared to the control. At concentrations observed after administration of curative doses for the treatment of DVT (> or = 0.5 anti-Xa IU/ml for enoxaparin and > or = 0.5 microg/ml for fondaparinux) both drugs induced a significant increase of R and K times, and a significant decrease of the alpha angle (p < 0.05). In contrast to fondaparinux, enoxaparin at concentrations equal to or higher than 0.5 anti-Xa IU/ml significantly reduced MA. The present study provides evidence that the whole blood TF-triggered TEG assay is sensitive to the presence of clinically relevant concentrations of enoxaparin or fondaparinux. Moreover, the angle may be used in order to distinguish the effect of prophylactic and therapeutic concentrations, since it was significantly reduced by the later ones. Further studies are needed to evaluate the clinical usefulness of whole blood TF-triggered TEG assay for the monitoring of treatment with enoxaparin or fondaparinux.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Dose-Response Relationship, Drug; Enoxaparin; Fondaparinux; Humans; In Vitro Techniques; Kinetics; Polysaccharides; Thrombelastography; Thrombin; Thromboembolism; Thromboplastin; Time Factors; Venous Thrombosis

Drug prevention and treatment of venous thromboses and thromboembolism remain a serious problem in the management of surgical and therapeutic patients. Pentasaccharides, novel anticoagulants selectively blocking Xe factor have a great potential for their use in the given area. It has been demonstrated at the preliminary stages of the study of these antithrombotic agents that their pharmacokinetics permits subcutaneous drug injection once a day (for fondaparinux) and once for 7 days (for indraparinux) without the necessity of making routine coagulologic control. The drugs are marked by bioavailability approximating 100%, linear dose-dependent pharmacokinetic profile at subcutaneous injection; they do not undergo metabolism and are excreted largely with urine. Fondaparinux, the first representative of this class anticoagulants, has evidence for the effectiveness and safety, obtained in large randomized studies carried out in orthopedic and traumatologic patients. The given paper reports the new positive data on evaluation of the preventive action of fondaparinux in therapeutic subjects end patients who had undergone abdominal surgical interventions. Moreover, in large comparative studies , this anticoagulant did yield to the standard agents applied to the treatment of thrombosis of the deep veins and thromboembolism of pulmonary artery branches. Being more handy in use fondaparinux is capable of replacing antithrombotic agents (without efficacy and safety loss) used nowadays for preventive and therapeutic purposes. In the event of successful completion of the evaluation of idraparinux, another pentasaccharide intended for many months of anticoagulant treatment, the goal-oriented use of pentasaccharides is potentially capable of supplanting all the "old" antithrombotic agents from the schedule of the short-term and prolonged prevention and treatment of venous thromboses and thromboembolism.

Topics: Adult; Anticoagulants; Complement Factor H; Dalteparin; Fondaparinux; Humans; Middle Aged; Polysaccharides; Postoperative Complications; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

Topics: Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Fondaparinux; Fracture Fixation, Internal; Hip Fractures; Humans; Polysaccharides; Thromboembolism; United Kingdom; Venous Thrombosis

Two new classes of anticoagulants in development at the present time [anti-factor Xa and anti-factor IIa (direct antithrombin) agents] should change our future strategies for prevention and treatment of venous thromboembolic events. Among the anti-factor Xa, the pentasaccharides are initiating their clinical use. Fondaparinux, the synthetic form of the natural pentasaccharide is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. A modified form (idraparinux) whose pharmacokinetics allows one administration only once a week should have the same type of efficacy. Among direct antithrombin agents, hirudin and derivatives have been developed in the past decade burt are not routinely used. Synthetic direct antithrombins allowing oral route are currently developed: Exanta with the most advanced development, is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. It could allow (if confirmed by clinical trials) a complete oral treatment of deep vein thrombosis without any biological monitoring. Exanta is also active in the prevention of arterial thromboembolic events on atrial fibrillation. Other molecular forms of synthetic per os direct antithrombin are also in development. But molecules aimed at other targets are also tested: the most advanced are those antagonizing the initial phase of tissue factor activation of factor VII but other strategies are being tested such as stimulation of fibrinolysis.

Topics: Antithrombins; Azetidines; Benzylamines; Fibrinolytic Agents; Fondaparinux; Forecasting; Humans; Insect Proteins; Polysaccharides; Salivary Proteins and Peptides; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Arthroplasty, Replacement; Clinical Trials as Topic; Fondaparinux; Humans; Orthopedic Procedures; Osteoarthritis, Hip; Osteoarthritis, Knee; Polysaccharides; Postoperative Complications; Research Design; Thromboembolism; Treatment Outcome; Venous Thrombosis

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.. 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.. 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.. 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 pound 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.. 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.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Cohort Studies; Cost-Benefit Analysis; Enoxaparin; Fondaparinux; Hip Fractures; Humans; Models, Theoretical; Orthopedics; Polysaccharides; Sensitivity and Specificity; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Anticoagulants; Enoxaparin; Evidence-Based Medicine; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thromboembolism

Topics: Clinical Trials as Topic; Drug Approval; Drug Industry; Fibrinolytic Agents; Financing, Organized; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Research Design; Research Support as Topic; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Fibrinolytic Agents; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Research Design; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Clinical Trials as Topic; Drug Industry; Fibrinolytic Agents; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Research Design; Research Support as Topic; Thromboembolism; Venous Thrombosis

Topics: Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Controlled Clinical Trials as Topic; Fondaparinux; Fracture Fixation, Internal; Hip Fractures; Humans; Polysaccharides; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Clinical Trials, Phase III as Topic; Fondaparinux; Hip Prosthesis; Humans; Knee Prosthesis; Polysaccharides; Postoperative Complications; Thromboembolism; Treatment Outcome

Topics: Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Leg; Orthopedic Procedures; Polysaccharides; Postoperative Complications; Thromboembolism

Topics: Arthroplasty, Replacement, Hip; Drug Administration Schedule; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Topics: Arthroplasty, Replacement, Hip; Drug Administration Schedule; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Topics: Arthroplasty, Replacement, Hip; Drug Administration Schedule; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Factor Xa Inhibitors; Fondaparinux; Guidelines as Topic; Humans; Orthopedic Procedures; Polysaccharides; Thromboembolism

Many clinicians recommend long-term, postoperative thromboprophylaxis for patients who undergo major hip or knee replacement or hip fracture surgery. However, special care must be taken when administering pharmacoprophylaxis to such patients, as they commonly exhibit characteristics that are different from those of the general population and can affect their responses to certain drugs. Among the currently available thromboprophylactic agents are warfarin, the heparins, and the recently introduced selective factor Xa inhibitor, fondaparinux. One feature of fondaparinux is that it can be administered safely and efficaciously in a wide variety of patient populations, without the need for dosage modification.

Topics: Adult; Age Factors; Aged; Anticoagulants; Antithrombins; Body Mass Index; Body Weight; Contraindications; Factor Xa Inhibitors; Female; Fondaparinux; Frail Elderly; Humans; Kidney; Liver; Male; Middle Aged; Orthopedic Procedures; Polysaccharides; Pregnancy; Racial Groups; Sex Factors; Thromboembolism

Topics: Drug Administration Schedule; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Hip Fractures; Humans; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Topics: Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Postoperative Complications; Thromboembolism; Venous Thrombosis

Topics: Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thromboembolism; Venous Thrombosis

Venous thromboembolism (VTE) is a major health problem. Anticoagulation can significantly decrease the morbidity and mortality associated with VTE. Heparin and coumarin derivatives have been the standard of care for the last 50 years, and the development of low-molecular-weight heparin preparations has significantly improved the prevention and treatment of venous thromboembolic disease. With these advances, investigators are now able to address some of the unresolved issues in antithrombotic therapy, including the search for the optimal antithrombotic agent in high-risk patients, the optimal timing of thromboprophylaxis initiation in the surgical population, and the duration of prophylaxis for the prevention of initial and recurrent VTE events. Clinical trials have begun to investigate many of these issues, and the resulting data have already contributed to improving the management of patients with a high risk of VTE.

Topics: Clinical Trials as Topic; Dalteparin; Double-Blind Method; Drug Administration Schedule; Factor VIIa; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides; Risk Factors; Thrombin; Thromboembolism

Topics: Antithrombin III; Clinical Trials as Topic; Drug Design; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Substrate Specificity; Thrombin; Thromboembolism

Topics: Angina, Unstable; Anticoagulants; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis