fondaparinux and Coronary-Disease

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

Hospital-acquired deep vein thrombosis (DVT) affects 10-25% of medical patients and up to 60% of surgical patients. While thromboprophylaxis is without a doubt under utilized in the hospital setting, there is also a need for more efficacious agents. Fondaparinux, the first of a new class of agents Factor Xa inhibitiors, has recently come into clinical use. It is a synthetic pentasaccharide and indirect Factor Xa inhibitor with a predictable antithrombotic action. Being a synthetic product, there are no concerns about supply, nor viral or prion protein contamination. Initial large international trials in orthopaedic patients demonstrated its superior efficacy to standard thromboprophylaxis. Further trials confirmed its superior efficacy in venous thromboembolism (VTE) prevention, both in medical and surgical patient groups, as well as treatment of pulmonary embolism and DVT. Its use has also recently been evaluated in acute coronary syndromes and angioplasty. Fondaparinux currently has licenses in the UK for thromboprophylaxis and treatment of VTE and a license for the management of acute coronary syndrome is likely to be forthcoming. It has a favourable side effect profile and if the price is acceptable, is likely to take over from low molecular weight heparins in these indications as the drug of choice on the grounds of efficacy and safety.

Topics: Anticoagulants; Antithrombin III; Coronary Disease; Fondaparinux; Humans; Polysaccharides; Thrombosis; 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

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

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

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

Acute coronary syndromes encompass a spectrum of conditions, including myocardial infarction and unstable angina. These syndromes are related to the formation and disruption of atherosclerotic plaque. Rupture of plaque leads to thrombin generation, fibrin deposition, and platelet aggregation, ultimately resulting in restriction of blood flow and ischemia of cardiac tissue. Percutaneous coronary intervention (PCI), including angioplasty and coronary stent placement, has been developed to open occluded arteries. The frequency with which these procedures are performed speaks to their largely successful outcomes. However, the mechanical manipulations of PCI result in additional plaque rupture and damage to the vessel wall, exposing subendothelial components to blood and resulting in the initiation of the clotting cascade and in platelet activation. Left unchecked, these intertwined processes lead to formation of arterial thrombi at the site of endothelial damage, and potentially to abrupt vessel closure or embolization of thrombi into the distal microcirculation. Thrombin plays a central role in thrombus formation and platelet activation, and its inhibition significantly reduces thrombus-related sequelae. Current antithrombotic strategies during PCI are based on the traditional indirect thrombin inhibitor heparin. Heparin has several limitations in efficacy and safety, due in part to its indirect mechanism of action. Bivalirudin, a direct thrombin inhibitor, offers significant improvement over heparin in the clinical outcomes and risks associated with PCI.

Topics: Angioplasty, Balloon, Coronary; Arginine; Clinical Trials as Topic; Coronary Disease; Coronary Thrombosis; Fibrinolytic Agents; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin

A recent randomized, controlled trial, the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS 5) trial, reported that major bleeding was 2-fold less frequent with fondaparinux than with enoxaparin in acute coronary syndromes (ACS). Renal dysfunction increases the risk for major bleeding.. To compare the efficacy and safety of fondaparinux and enoxaparin over the spectrum of renal dysfunction observed in the OASIS 5 trial.. Subgroup analysis of a randomized, controlled trial.. Patients presenting to the hospital with non-ST-segment elevation ACS.. 19,979 of the 20,078 patients in the OASIS 5 trial in whom creatinine was measured at baseline.. Death, myocardial infarction, refractory ischemia, and major bleeding were evaluated separately and as a composite end point at 9, 30, and 180 days. Glomerular filtration rate (GFR) was calculated by using the Modification of Diet in Renal Disease formula.. The absolute differences in favor of fondaparinux (efficacy and safety) were most marked in patients with a GFR less than 58 mL/min per 1.73 m2; the largest differences occurred in major bleeding events. At 9 days, death, myocardial infarction, or refractory ischemia occurred in 6.7% of patients receiving fondaparinux and 7.4% of those receiving enoxaparin (hazard ratio, 0.90 [95% CI, 0.73 to 1.11]); major bleeding occurred in 2.8% and 6.4%, respectively (hazard ratio, 0.42 [CI, 0.32 to 0.56]). Statistically significant differences in major bleeding persisted at 30 and 180 days. The rates of the composite end point were lower with fondaparinux than with enoxaparin in all quartiles of GFR, but the differences were statistically significant only among patients with a GFR less than 58 mL/min per 1.73 m2.. Subgroup analyses warrant caution; the study was powered to detect noninferiority at 9 days. Fondaparinux is not approved for use in patients with ACS in the United States.. The benefits of fondaparinux over enoxaparin when administered for non-ST-segment elevation ACS are most marked among patients with renal dysfunction and are largely explained by lower rates of major bleeding with fondaparinux.

Topics: Aged; Aged, 80 and over; Angina Pectoris; Anticoagulants; Coronary Disease; Death, Sudden, Cardiac; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Male; Middle Aged; Myocardial Infarction; Polysaccharides; Syndrome

Factor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial thrombosis. Fondaparinux, a synthetic pentasaccharide, is a factor Xa inhibitor, which has been shown to be superior to enoxaparin for the prevention of venous thrombosis. We designed a large, phase III, randomized trial to evaluate the efficacy and safety of fondaparinux compared with enoxaparin in acute coronary syndromes.. The OASIS-5 trial is a randomized, double-blind trial of fondaparinux versus enoxaparin in 20,000 patients with unstable angina or non-ST-segment elevation myocardial infarction. The primary objective is to determine whether fondaparinux is noninferior to enoxaparin in preventing the composite of death, new myocardial infarction, and refractory ischemia at 9 days (primary outcome) and at 30 days (secondary outcome) after randomization. There will be additional follow-up of all patients for 3 to 6 months after randomization. If noninferiority is established at 9 days, superiority will be tested. The primary safety outcome is to evaluate the rates of major bleeds in the 2 groups with the balance of benefit and risk assessed by comparing the impact on the composite of the primary and safety outcomes. Secondary outcomes are each component of the composite primary outcome separately at days 9, 30, and up to 6 months. The TIMACS, a major substudy using a partial 2x2 factorial design evaluating whether early angiography and intervention (within 24 hours) are superior to a more delayed approach (after 36 hours) in reducing major ischemic events at 6 months after randomization.. The MICHELANGELO OASIS 5 program will provide a comprehensive and reliable evaluation of fondaparinux in a broad spectrum of patients with ACS.

Topics: Acute Disease; Aged; Angina, Unstable; Anticoagulants; Coronary Disease; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Patient Selection; Polysaccharides

In this dose-finding study, we sought to compare fondaparinux with enoxaparin in patients with acute coronary syndromes (ACS).. Fondaparinux is a synthetic pentasaccharide that selectively inhibits activated clotting factor X. It has been demonstrated as effective in preventing thromboembolic complications in orthopedic surgery.. Four doses fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice daily) were compared, both given for three to seven days, in patients with ACS without persistent ST-segment elevation.. The rates of the combined primary end point of death, myocardial infarction, or recurrent ischemia after nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS). In the per-protocol analysis (929 patients who received adequate study drug and had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events.. This dose-finding study revealed no dose response for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and suggests that the efficacy and safety of fondaparinux may be similar to that of enoxaparin. Further studies with fondaparinux in ACS might include the lowest dose (2.5 mg) investigated in this study.

Topics: Acute Disease; Adrenergic beta-Antagonists; Adult; Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Coronary Artery Bypass; Coronary Disease; Creatine Kinase; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Enoxaparin; Female; Fibrinolytic Agents; Follow-Up Studies; Fondaparinux; Hemorrhage; Humans; Hypolipidemic Agents; Isoenzymes; Male; Middle Aged; Polysaccharides; Survival Analysis; Syndrome; Treatment Outcome; Troponin T

Topics: Anticoagulants; Coronary Disease; Enoxaparin; Fondaparinux; Humans; Kidney; Polysaccharides

Topics: Acute Disease; Anticoagulants; Antithrombin III; Coronary Disease; Drug Therapy, Combination; Electrocardiography; Fondaparinux; Hemorrhage; Heparin; Humans; Incidence; Myocardial Infarction; Platelet Aggregation Inhibitors; Polysaccharides; Registries; Severity of Illness Index; Syndrome; Thrombocytopenia

Low-molecular-weight heparins share many properties and are commonly referred to as a group, but structurally and pharmacologically they are dissimilar. The size spectrum of the heparin molecules varies between the different products and as assessed in vitro, their anticoagulant properties differ. In particular, the ratio anti-factor Xa : anti-factor IIa activities varies. The clinical consequences of these differences are unknown. The efficacy and safety of two different low-molecular-weight heparins have been compared in only a few clinical studies; no significant differences in outcome were shown. However, low-molecular-weight heparins should be used according to the approved indication for each product and in doses shown effective and safe in clinical studies. A change from one low-molecular-weight heparin to another in the same patient should be avoided. Fondaparinux is a synthetic penta-saccharide which may be regarded as an extreme low-molecular-weight heparin with a ratio of anti-factor Xa : anti-factor IIa activity as 1 : 0, and with a promising efficacy/safety profile. So far, the approved clinical indication for its use is limited to prophylaxis in orthopaedic surgery.

Topics: Anticoagulants; Coronary Disease; Dalteparin; Enoxaparin; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Molecular Structure; Polysaccharides; Thrombolytic Therapy; Tinzaparin; Venous Thrombosis

Topics: Acetanilides; Angina, Unstable; Anti-Arrhythmia Agents; Calcium Channel Blockers; Coronary Disease; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fibrinolytic Agents; Fondaparinux; Humans; Hydantoins; Imidazoles; Imidazolidines; Multicenter Studies as Topic; Myocardial Infarction; Nicorandil; Piperazines; Polysaccharides; Randomized Controlled Trials as Topic; Ranolazine; Treatment Outcome