Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent

Fondaparinux (Arixtra^®, Sanofi-Synthélabo/Organon) is the first of a new class of antithrombotic agents distinct from low molecular weight heparins (LMWHs) and heparin. It is a chemically synthetic pentasaccharide mimicking the site of heparin that binds to antithrombin III (AT). It exhibits only factor (F) Xa (FXa) inhibitor activity via binding to AT, which in turn inhibits thrombin generation. In contrast to heparin and LMWH, plasma anti-Xa activity corresponds directly to levels of fondaparinux. It does not release tissue factor pathway inhibitor (TFPI). There is nearly complete bioavailability by the sc. route, rapid onset of action, a prolonged half-life in both iv. and sc. (14 - 20 h) dosing regimens and no metabolism preceding renal excretion. Phase IIb clinical studies have identified a dose of 2.5 mg once-daily for prophylaxis of venous thrombosis. Four Phase III studies (n > 7000) have demonstrated a combined 50% relative risk reduction of venous thromboembolic events in orthopaedic surgery patients in comparison to the LMWH, enoxaparin. Haemmorrhagic complications for fondaparinux were either comparable to or higher than those for LMWH. The activated partial thromboplastin time (aPTT) is not affected by fondaparinux. At present, laboratory monitoring is not recommended. Clinical trials for treatment of established thrombosis, coronary syndromes and adjunct to thrombolytic therapy are in progress.     

Heparin in the prophylaxis and treatment of venous thromboembolism and other thrombotic diseases

In this chapter, we discuss the key-role of heparin in the prophylaxis and treatment of venous thromboembolism (VTE) and other thrombotic disorders. Heparin exerts its antithrombotic effects by facilitating the ability of antithrombin (AT), a plasma serum protease inhibitor, to inhibit thrombin (factor IIa) and factor Xa. Different heparin formulations can be used for the prophylaxis of thrombosis and treatment, going from unfractionated heparin (UFH), different low-molecular-weight heparin (LMWH) preparations, to the recently introduced synthetic pentasaccharide fondaparinux. All heparin formulations can be administrated only by the parenteral route, including the intravenous (iv) and the subcutaneous (sc) route. We will overview the clinical evidence for the use of different heparin formulations in the prophylaxis and treatment of venous thromboembolism, of superficial vein thrombosis and of acute coronary syndromes (ACS). Special issues, like the use of heparins in pregnancy or in children, will also be discussed. Although heparin is an almost one century-old drug it remains a cornerstone of antithrombotic treatment.     

Latest medical treatment strategies for venous thromboembolism

Anticoagulant therapy with unfractionated heparin (UFH) followed by warfarin prevents thrombus extension, reduces the risk of recurrent thrombosis and prevents death in patients with venous thromboembolism (VTE). Low-molecular-weight heparin (LMWH) has replaced UFH as the preferred initial anticoagulant therapy for VTE because it is as effective and safe as UFH, but does not require laboratory monitoring and is less likely to cause immune thrombocytopenia and osteoporosis. More recently, fondaparinux has been shown to be an effective and safe alternative to LMWH and several new parenteral anticoagulants are being evaluated. The most important unmet need in the anticoagulant management of VTE is a replacement for warfarin. New oral anticoagulants that selectively target individual steps in the coagulation cascade have been shown to be effective for the long-term treatment of VTE in Phase II and III trials and are likely to become available in the near future.     

Fondaparinux sodium

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.     

Studies comparing low molecular weight heparin with heparin for the treatment of thromboembolism: a literature review

The use of heparin for the prophylaxis and treatment of venous and arterial thrombosis had been the standard of care for clinicians until 1982. At that time the introduction of depolymerized heparin for the prophylaxis of deep vein thrombosis in surgical patients was introduced. A number of such products, low molecular weight heparins (LMWH) were patented and introduced as new drugs during the ensuing of 20 years. Each LMWH had to be given a clinical trial against standard heparin for the several thromboembolic disorders for which heparin was the standard of care. By definition LMWH had to have unequal factor Xa and IIa inhibitor potency, expressed as a Xa-IIa ratio of greater than 1. They also had a molecular weight reduction to about one third that of heparin. A major advantage of LMWH over heparin was the subcutaneous route of injection for treatment of thrombotic disorders in contrast to the intravenous route for heparin. They had greater bioavailability than heparin by the subcutaneous route, a longer half-life and better predictability of dose response. It was found that routine laboratory monitoring was unnecessary. When given a trial against heparin, LMWH was equally safe and effective for most venous and arterial disorders. A new synthetic version of (pentasaccharide) both heparin and LMWH has been at least if not more effective than one LMWH (enoxaparin).     

Short- and long-acting synthetic pentasaccharides as antithrombotic agents

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.     

Short- and long-acting synthetic pentasaccharides as antithrombotic agents

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.     

The safety of fondaparinux for the prevention and treatment of venous thromboembolism

Fondaparinux is the first synthetic selective Factor Xa inhibitor. Along with its antithrombotic efficacy, the safety of fondaparinux has been documented in several Phase II and III clinical trials, including the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery or high-risk abdominal surgery, or in acutely ill medical patients with restricted mobility, and the treatment of patients with deep-vein thrombosis and pulmonary embolism. In all these indications, the safety of fondaparinux used according to its registered regimen was similar to that of reference comparators. In conclusion, due to its superior efficacy and satisfactory safety, fondaparinux may substantially improve the prevention and treatment of venous thrombosis.     

The safety of fondaparinux for the prevention and treatment of venous thromboembolism

Fondaparinux is the first synthetic selective Factor Xa inhibitor. Along with its antithrombotic efficacy, the safety of fondaparinux has been documented in several Phase II and III clinical trials, including the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery or high-risk abdominal surgery, or in acutely ill medical patients with restricted mobility, and the treatment of patients with deep-vein thrombosis and pulmonary embolism. In all these indications, the safety of fondaparinux used according to its registered regimen was similar to that of reference comparators. In conclusion, due to its superior efficacy and satisfactory safety, fondaparinux may substantially improve the prevention and treatment of venous thrombosis.     

Low molecular weight heparin in acute stroke

Potential therapeutic strategies in acute ischaemic stroke include reperfusion, prevention of thrombus extension and rethrombosis and neuroprotection. Heparins inhibit thrombin and factor X and therefore may have useful effects on arterial and venous thrombosis; they are effective in the prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and in the prevention of myocardial infarction (MI) in patients with unstable angina. Low molecular weight heparins (LMWHs) and heparinoids are known to be more effective and have a safer profile than unfractionated heparins in patients with venous thromboembolic disease and coronary artery disease. However, their role in acute ischaemic stroke is less clear. The very large International Stroke Trial found that unfractionated heparin had no overall benefit in ischaemic stroke, whilst causing significant intracranial haemorrhage. A number of Phase II and III trials of LMWH have been assessed in acute ischaemic stroke. It remains unclear whether these agents are effective and safe in acute ischaemic stroke although they do reduce the risk of DVT and PE. A systematic review is now required in order to assess the safety and efficacy of LMWH in acute stroke.     

Low molecular weight heparin in acute stroke

Potential therapeutic strategies in acute ischaemic stroke include reperfusion, prevention of thrombus extension and rethrombosis and neuroprotection. Heparins inhibit thrombin and factor X and therefore may have useful effects on arterial and venous thrombosis; they are effective in the prevention and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and in the prevention of myocardial infarction (MI) in patients with unstable angina. Low molecular weight heparins (LMWHs) and heparinoids are known to be more effective and have a safer profile than unfractionated heparins in patients with venous thromboembolic disease and coronary artery disease. However, their role in acute ischaemic stroke is less clear. The very large International Stroke Trial found that unfractionated heparin had no overall benefit in ischaemic stroke, whilst causing significant intracranial haemorrhage. A number of Phase II and III trials of LMWH have been assessed in acute ischaemic stroke. It remains unclear whether these agents are effective and safe in acute ischaemic stroke although they do reduce the risk of DVT and PE. A systematic review is now required in order to assess the safety and efficacy of LMWH in acute stroke.     

Minimising the risk of heparin-induced osteoporosis during pregnancy

Unfractionated heparin (UFH) may lead to symptomatic vertebral fractures in up to 3 out of every 100 people on long-term therapy. Ten-times that many people will experience a significant reduction in bone density leading to osteopoenia or osteoporosis. Low molecular weight heparins (LMWH) have been shown to be as effective as UFH in the prevention and treatment of venous thromboembolism. Several well-established advantages of LMWH over UFH include increased bioavailability, more predictable dose response, less intensive coagulation monitoring, and a lower probability of causing immune-mediated thrombocytopenia. There is also some evidence that long-term LMWH therapy is less likely to cause osteoporotic fractures and significant reductions in bone mass than UFH. Both UFH and LMWH undergo pharmacokinetic changes during pregnancy, which sometimes necessitates dosage adjustments. Fondaparinux is a synthetic antithrombotic agent, which specifically binds to antithrombin. It has been shown to be comparable to, or even more effective than, LMWH in the management of both arterial and venous thrombosis. Fondaparinux does not appear to have a negative effect on bone metabolism. Therefore, fondaparinux may be a safe and effective alternative to UFH and LMWH in women who require anticoagulation during pregnancy.     

Minimising the risk of heparin-induced osteoporosis during pregnancy

Unfractionated heparin (UFH) may lead to symptomatic vertebral fractures in up to 3 out of every 100 people on long-term therapy. Ten-times that many people will experience a significant reduction in bone density leading to osteopoenia or osteoporosis. Low molecular weight heparins (LMWH) have been shown to be as effective as UFH in the prevention and treatment of venous thromboembolism. Several well-established advantages of LMWH over UFH include increased bioavailability, more predictable dose response, less intensive coagulation monitoring, and a lower probability of causing immune-mediated thrombocytopenia. There is also some evidence that long-term LMWH therapy is less likely to cause osteoporotic fractures and significant reductions in bone mass than UFH. Both UFH and LMWH undergo pharmacokinetic changes during pregnancy, which sometimes necessitates dosage adjustments. Fondaparinux is a synthetic antithrombotic agent, which specifically binds to antithrombin. It has been shown to be comparable to, or even more effective than, LMWH in the management of both arterial and venous thrombosis. Fondaparinux does not appear to have a negative effect on bone metabolism. Therefore, fondaparinux may be a safe and effective alternative to UFH and LMWH in women who require anticoagulation during pregnancy.     

Fondaparinux: a Factor Xa inhibitor for antithrombotic therapy

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 ～ 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.     

Fondaparinux: a Factor Xa inhibitor for antithrombotic therapy

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.     

Factor Xa inactivation in acute coronary syndrome

The increasing incidence of patients who develop acute coronary syndrome (ACS) stresses the importance of effective initial treatment to reduce morbidity and mortality. The recommended initial therapeutic regimen for patients with ACS includes both anticoagulants and antiplatelet agents to prevent excessive coronary thrombosis, stroke, and further coronary events. Most commonly, unfractionated heparin (UFH) is used for initial antithrombotic treatment of ACS, despite limited published evidence regarding effectiveness and safety (bleeding complications). Therefore, this treatment regimen is primarily based upon expert opinion rather than evidence-based medicine. Studies addressing the dilemma of effectiveness and increased risk of bleeding when using UFH and low molecular weight heparin (LMWH) in patients with ACS showed superior clinical outcome in patients treated with LMWH. Nevertheless, the concurrent increased risk of bleeding while using anticoagulants is a severe problem and negatively impacts upon clinical outcome. Furthermore, non-hemorrhagic side effects of heparin such as heparin-induced thrombocytopenia (HIT), and skin reactions at the site of subcutaneous injection are reduced but not abolished by replacing UFH with LMWH. The limitations of UFH and LWMH as outlined above provided the impetus for the development of a pentasaccharide, called fondaparinux, which inhibits factor Xa selectively. Fondaparinux has been shown to be as effective as enoxaparin in the prevention of thrombosis in patients undergoing orthopedic surgery and showed similar results compared to enoxaparin or UFH in patients with deep-vein-thrombosis or pulmonary embolism. Recently, a large clinical study addressed the dilemma of the effectiveness and adverse effects of anticoagulation in ACS by comparing fondaparinux and LMWH such as enoxaparin in patients with unstable angina or non ST-segment elevation myocardial infarction (NSTEMI).     

Pharmacological Prevention of Venous Thromboembolism in Medical Patients at Risk

Acutely ill general medical patients are at moderate-to-high risk of venous thromboembolism (VTE); approximately 10-30% may develop deep vein thrombosis or pulmonary embolism, the latter being a leading contributor to deaths in hospital. Medical conditions associated with a high risk of VTE include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, and infectious disease. Predisposing risk factors for VTE in medical patients include history of VTE, history of malignancy, complicating infections, increasing age, thrombophilia, prolonged immobility, and obesity. Unfractionated heparin (UFH), low-molecular weight heparin (LMWH), and fondaparinux sodium have been shown to be effective agents in the prevention of VTE in medical patients. In this setting, UFH has a higher rate of bleeding complications than LMWH. There is no evidence supporting the use of aspirin, warfarin, or mechanical methods to prevent VTE in medical patients. We recommend either LMWH or fondaparinux sodium as well tolerated and effective thromboprophylactic agents in medical patients.     

Fondaparinux Sodium

Fondaparinux sodium (fondaparinux) is a synthetic sulfated pentasaccharide anticoagulant developed from the antithrombin binding moiety of heparin. Through the activation of antithrombin it inhibits Factor Xa, the activation of thrombin, and the subsequent coagulation cascade. Fondaparinux is approved in Europe and the US for the treatment of acute venous thromboembolism (VTE), including both deep vein thrombosis (DVT) and pulmonary embolism (PE), when used in conjunction with warfarin. In phase III clinical trials, subcutaneous fondaparinux was noninferior to subcutaneous enoxaparin or intravenous unfractionated heparin (UFH) in the prevention of recurrent symptomatic VTE in patients with acute DVT and PE, respectively, and equally well tolerated. It thus provides a valuable alternative to UFH and low-molecular weight heparins in the treatment of acute VTE, particularly in the outpatient setting.     

Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases

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.     

Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases

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.