fondaparinux and ximelagatran

Heparin, low molecular weight heparin (LMWH) and warfarin are well-established anticoagulants still in widespread use despite their well known drawbacks. Heparin requires continuous monitoring, has serious side-effects such as haemorrhage, thrombosis and osteoporosis, and lacks an oral route of administration. LMWH is a safer, more convenient anticoagulant to use but it cannot be given orally, does not have an antidote and may be difficult to administer in patients with renal failure. Warfarin has a narrow therapeutic window, interacts with other drugs and foods and requires monitoring like heparin. The limitations of all three of these established anticoagulants have prompted the search for better more convenient agents. The major examples of these newer anticoagulants are the direct and indirect factor Xa inhibitors and the direct thrombin inhibitors. These new agents tend to have more predictable pharmacokinetic properties, superior efficacy and safety and some can be administered orally. In this review, we summarise the advantages and disadvantages of three established anticoagulants (heparin, LMWH and warfarin) and the most promising new anticoagulants (fondaparinux, idraparinux, rivaroxaban, apixaban, dabigatran and ximelagatran) by discussing their pharmacodynamics and pharmacokinetics. We also discuss recent patents in the field of anticoagulation, which aim to improve the safety and effectiveness of antithrombotic agents currently in use or offer alternative ways for anticoagulation.

Topics: Animals; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Oligosaccharides; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Warfarin

Anticoagulation for thromboprophylaxis after THA and TKA has not been confirmed to diminish all-cause mortality. We determined whether the incidence of all-cause mortality and pulmonary embolism in patients undergoing total joint arthroplasty differs with currently used thromboprophylaxis protocols. We reviewed articles published from 1998 to 2007 that included 6-week or 3-month incidence of all-cause mortality and symptomatic, nonfatal pulmonary embolism. Twenty studies included reported 15,839 patients receiving low-molecular-weight heparin, ximelagatran, fondaparinux, or rivaroxaban (Group A); 7193 receiving regional anesthesia, pneumatic compression, and aspirin (Group B); and 5006 receiving warfarin (Group C). All-cause mortality was higher in Group A than in Group B (0.41% versus 0.19%) and the incidence of clinical nonfatal pulmonary embolus was higher in Group A than in Group B (0.60% versus 0.35%). The incidences of all-cause mortality and nonfatal pulmonary embolism in Group C were similar to those in Group A (0.4 and 0.52, respectively). Clinical pulmonary embolus occurs despite the use of anticoagulants. Group A anticoagulants were associated with the highest all-cause mortality of the three modalities studied.

Topics: Anesthesia, Conduction; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Azetidines; Benzylamines; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Intermittent Pneumatic Compression Devices; Morpholines; Platelet Aggregation Inhibitors; Polysaccharides; Pulmonary Embolism; Risk Assessment; Risk Factors; Rivaroxaban; Thiophenes; Treatment Outcome; Warfarin

Elderly patients immobilized because of an acute medical illness or surgery have a very high risk of developing venous thromboembolism (VTE). Aggressive pharmacologic prophylaxis is necessary and should be initiated either at admission for a medical condition or shortly after surgery. Aggressive prophylaxis may result in fewer patients developing VTE in the hospital and ultimately lead to fewer patients requiring full-dose anticoagulation for VTE. Mechanical prophylaxis can be used as an adjunct to an anticoagulant-based regimen but should only be used as primary prophylaxis when there is a contraindication, such as active bleeding. It is recommended that the clinician carefully evaluate the elderly patient's creatinine clearance and weight before prescribing anticoagulants, particularly when using fixed dosing regimens.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Elective Surgical Procedures; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Prodrugs; Pyridines; Risk Factors; Vena Cava Filters; Venous Thromboembolism

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Liver; Polysaccharides; Thrombocytopenia

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

Prevention and treatment of the venous thromboembolic phenomena should be modified in a near future. The arrival of two new classes of anticoagulants: antifactor Xa and anti-factor IIa, opens a new perspective in an area in which low molecular weight heparins and oral anticoagulants have the exclusivity. Fondaparinux has the approval for its introduction into the market as a maximum representative of this group and has begun to be used. Among the direct antithrombotics we find melagatran and its oral form, ximelagatran, that opts to be the substitute of oral anticoagulants.

Topics: Antithrombin III; Antithrombins; Azetidines; Benzylamines; Fibrinolytic Agents; Fondaparinux; Forecasting; Humans; Polysaccharides; Venous Thrombosis

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Blood Coagulation; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombosis; Warfarin

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

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

Patients undergoing major lower-extremity orthopedic surgery such as total hip replacement (THR) and total knee replacement (TKR) are at an increased risk of venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to potentially fatal pulmonary embolism and secondary complications such as postthrombotic syndrome, recurrent DVT, and chronic pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves anticoagulant treatment with either low-molecular-weight heparin (LMWH) or warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as obesity, cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter hospital stays, making practicality of treatment an important consideration. LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting. Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved anticoagulant, fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with LMWH, but this agent requires parenteral administration and does not overcome the convenience issue. Ximelagatran is the oral form of the direct thrombin inhibitor melagatran, which is available for subcutaneous administration. Ximelagatran has a consistent anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of melagatran/ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of melag

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Clinical Trials as Topic; Fondaparinux; Humans; Polysaccharides; Treatment Outcome; Venous Thrombosis

Patients with renal failure have an increased risk of both thrombotic and bleeding complications. A number of antithrombotic drugs undergo renal clearance. Therefore, estimation of renal function is necessary when prescribing these drugs to patients with renal dysfunction. Pharmacokinetic and clinical data in patients with chronic renal impairment are limited for several anticoagulants, and adequate administration information is often absent. Dose adjustment of anticoagulants may be indicated when the creatinine clearance falls below 30 mL/min. Unfractionated heparin, argatroban, and vitamin K antagonists generally do not require dose adjustment with renal dysfunction. However, smaller doses of warfarin may be required to achieve a particular target international normalized ratio. Close monitoring of anticoagulation is recommended when argatroban or high doses of unfractionated heparin are administered in patients with severe chronic renal impairment. Low-molecular weight heparins, danaparoid sodium, hirudins, and bivalirudin all undergo renal clearance. Lower doses and closer anticoagulation monitoring may be advisable when these agents are used in patients with chronic renal failure. We recommend that fondaparinux sodium and ximelagatran (not yet licensed) be avoided in the presence of severe renal impairment and be used with caution in patients with moderate renal dysfunction. While acknowledging the lack of pharmacokinetic data, this review provides specific recommendations for the use of anticoagulants in patients with chronic renal impairment.

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Fondaparinux; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Warfarin

Unfractionated heparin, derived from porcine intestine, is the prototype of a rapidly acting anticoagulant. It has been used for over 60 years to arrest or prevent thrombus growth. Low-molecular-weight heparins, available in the last 20 years, are manufactured from unfractionated heparin and have superior dose-response relationships because of fewer nonspecific reactions with plasma proteins and cells. Fondaparinux is a recently approved five-saccharide synthetic molecule that carries the evolution of heparin further. It is a pure Xa inhibitor, with minimal nonspecific interactions. It does not appear to elicit the antibody that leads to heparin-induced thrombocytopenia (HIT). All of these agents are given either intravenously or subcutaneously. They act indirectly by activating the natural plasma inhibitor, antithrombin III. Direct thrombin inhibitors bind directly to thrombin's active site without interaction with the cofactor, antithrombin III. Lepirudin (Refludan; Berlex, Wayne, NJ) and argatroban (Argatroban; GlaxoSmithKline, Research Triangle Park, NC) are given intravenously and are usually used in HIT and thrombosis associated with HIT. Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a parenteral direct thrombin used in place of heparin in percutaneous coronary interventions. Ximelagatran (Exanta; AstraZeneca, Wilmington, DE) is an oral direct thrombin inhibitor under development for both acute and chronic anticoagulation.

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Embolism; Enzyme Inhibitors; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia; Venous Thrombosis

In this paper, recent advances in new anticoagulants with the potential to be used for prevention or treatment of venous thrombosis are reviewed.. Numerous novel anticoagulants targeting specific stages of the coagulant pathway are in various stages of development. Fondaparinux, an indirect activated factor VII inhibitor, has been shown to be effective for initial treatment and prevention of venous thromboembolism, but still requires parenteral administration. Ximelagatran, an oral direct thrombin inhibitor, has also been shown to effective for treatment and prevention of venous thrombosis. Both agents are associated with bleeding, however, and ximelagatran is associated with hepatic toxicity with long-term use. Direct activated factor X inhibitors, orally available forms of heparin, and other direct thrombin inhibitors remain in early stages of development. Further data on the clinical utility of these agents are likely to emerge in the next few years, and uptake of their use will be affected by the cost considerations.. Numerous alternative anticoagulants are in varying stages of development. Clinical data have yet to show that these agents have a clearly superior risk-benefit ratio compared with currently used antithrombotics. Many drugs remain in initial stages of development. The ideal anticoagulant agent is being sought but has yet to be discovered.

Topics: Anticoagulants; Azetidines; Benzylamines; Factor VIIa; Fondaparinux; Heparin; Humans; Polysaccharides; Thrombin; Thrombocytopenia; 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

Antithrombotic drugs: heparins and oral vitamin K antimetabolites are connected with many side effects, which delimit their application in clinical practise. Continuous research has led to synthesis of new drugs which are safer and easier in use. Actually used antithrombotic drugs with their faults are discussed. Mechanism of action and data from trials relating to efficacy and safety of new drugs: fondaparinux, idraparinux and ximelagatran are presented.

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

Anticoagulation is highly effective in the prevention and treatment of venous thromboembolism (VTE). Since decades, vitamin K antagonists (VKA) were the only available oral anticoagulants. Even though VKA are very effective, they have numerous practical problems: Due to their narrow therapeutic window, highly variable dose requirements and drug interactions, close monitoring is mandatory, aiming towards an INR of 2-3 for most indications. At present, new oral anticoagulants are being studied, such as the oral direct thrombin inhibitor Ximelagatran, which in trials for prevention and treatment of VTE appears at least equivalent to heparin and VKA. Heparins have to be administered parenterally, and low molecular-weight heparins have been able to overcome some of the shortcomings of standard heparins, such as limited bioavailability, variable dose response and heparin induced thrombocytopenia (HIT). Heparinoids and hirudins are alternative anticoagulants to treat HIT. With the development of synthetic pentasaccharides, such as Fondaparinux an increase in efficacy could be achieved in high-risk thromboprophylaxis.

Topics: Anticoagulants; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Drug Therapy; Evidence-Based Medicine; Fondaparinux; Heparin; Humans; Patient Care Management; Polysaccharides; Practice Patterns, Physicians'; Thrombocytopenia; Treatment Outcome; Venous Thrombosis; Vitamin K

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

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Fondaparinux; Glycine; Heparin; Hirudin Therapy; Humans; Pipecolic Acids; Polysaccharides; Prodrugs; Sulfonamides; Thrombin; 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

Classic anticoagulant drugs, such as heparin and warfarin, are very effective. However, although in use for more than 50 years, they do have some clinical drawbacks. Heparin, now better termed unfractionated heparin, can only be used intravenously and its laboratory control is complicated. Warfarin is orally administered, but its therapeutic window is very narrow and patients need repeated laboratory tests. Moreover, both drugs are non-specific, as they inhibit the coagulation cascade at several steps. Pharmaceutic research has developed new drugs, some of which are already on the market, such as fondaparinux, a pentasaccharide that can interact with antithrombin, thus inhibiting factor Xa. This pentasaccharide is part of the parent heparin molecule and can be chemically synthesized, with the advantage of avoiding extractive compounds. Fondaparinux has a half-life compatible with once-a-day administration; modification of its structure (idraparinux) has led to more stable binding with antithrombin and to an increase in its half-life to allow once-a-week administration. Alternatives to oral anticoagulants have been developed following the study of some compounds like hirudin, which directly binds thrombin and blocks its catalytic site. One of these molecules, ximelagatran, is in advanced clinical development. Ximelagatran is converted into its active form, melagatran, in the circulation, and thrombin activity can be blocked by oral administration twice daily. There is no need for laboratory control and phase II and phase III studies are encouraging. The next few years should bring great changes to the treatment of patients with thromboembolic disorders.

Topics: Anticoagulants; Azetidines; Benzylamines; Blood Coagulation Disorders; Fondaparinux; Half-Life; Humans; Oligosaccharides; Polysaccharides

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

Every year, approximately 2 million people experience a deep venous thrombosis (DVT). Approximately 600,000 of these people are diagnosed with a pulmonary embolism and about 10% of these die. It has been established that surgery, anesthesia, and bed rest increase the risk of DVT, and therefore, patients who undergo a major lower-extremity procedure should receive prophylaxis. During the past 10 years, the choices of pharmacological and mechanical prophylaxis have increased greatly. Warfarin is probably the most widely used prophylactic method in the U.S., but low-molecular-weight heparin (LMWH) use has increased. Also available is a synthetic pentasaccharide that acts as an anti-Xa inhibitor to decrease DVT without increase in bleeding. All but warfarin are given by subcutaneous injection and require no laboratory management to adjust the medication. Another drug in clinical trials is a direct thrombin inhibitor taken orally in a fixed dose that does not require monitoring. Non-pharmacological prophylaxis and/or stacked modalities, although used, have not shown the efficacy of pharmacological prophylaxis. With the incidence of DVT reported in the range of 41% to 85% without prophylaxis in joint replacement and hip-fracture surgery, prophylaxis is warranted in all lower-extremity joint replacement and hip-fracture patients.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Venous Thrombosis; Warfarin

Several antithrombotic agents in development have the potential to greatly simplify the management of patients with AF or at risk for DVT/PE. Ximelagatran has already completed several phase 3 clinical studies in both of these high-risk, high-cost clinical settings and is poised to become the first practical alternative to warfarin. Although the exact therapeutic roles of ximelagatran and other novel antithrombotics further back in the pipeline remain to be determined, the impact of these nonwarfarin alternatives on the current labor-intensive system of anticoagulation clinics seems certain. Most important, the introduction of safer and equally effective oral anticoagulants that do not require monitoring may increase the percentage of high-risk patients who actually receive preventive therapy. If the institutional energy and resources previously spent on anticoagulation clinics, thrombotic disease management, and quality benchmarking can now be redirected to the delivery of the new generation of easier-to-administer and safer antithrombotic agents, the potential to increase rates of preventive therapy initiation and adherence in managed care populations may be within reach. Given the proven clinical value of anticoagulation, this potential increase in the rate of prophylaxis suggests the possibility that, even in the face of a rapidly aging US population, we are nonetheless entering into a period of reduced morbidity, mortality, and costs from stroke and DVT/PE.

Topics: Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clopidogrel; Fibrinolytic Agents; Fondaparinux; Humans; Oligosaccharides; Platelet Aggregation Inhibitors; Polysaccharides; Prodrugs; Pyridines; Stroke; Ticlopidine

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

The current management of thrombotic and vascular disorders has been strongly influenced by the introduction of several new drugs. 1. One of the major impact in the management of venous thromboembolic disorders has been the LMWHs. The newest, third generation heparin, the pentasaccharide inhibits specifically FXa. The elimination half-life of pentasaccharide is about 17 h, which allows a convenient once-daily dosing regime. The effects of pentasaccharide needs antithrombin. 2. Melagatran dipeptid is a specific, reversible direct thrombin inhibitor. It inhibits free and clot bound thrombin. Ximelagatran is a prodrug of melagatran. It is the first clinically used orally acting direct thrombin inhibitor. 3. Recombinant human activated protein C (rh-APC) has some advantages in patients with septic DIC. Qualities of the three new anticoagulants and clinical experiences with them have been summarized.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Glycine; Humans; Polysaccharides; Protein C; Pulmonary Embolism; Recombinant Proteins; 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

Treatment of deep venous thrombosis is founded on the association of low molecular heparins and oral anticoagulants for 3-6 months. In spite of their uncontested efficacy, these therapeutics bring an hemorrhagic risk and the need of regular laboratory controls for the whole duration of the treatment. The clinical need to extend the indications of anticoagulants have made necessary the development of new antithrombotic treatments.. Two new molecules, fondaparinux and ximelagatran, have been recently developed and are, at present, in very advanced phase of clinical research. Already published phase III studies on venous thromboembolism (VTE) prophylaxis show the efficacy of these new molecules towards this indication. The results of phase III study in patients with acute VTE have not been published yet.. The new anticoagulant molecules fondaparinux and ximelagatran could open the way to new therapeutic possibilities that could simplify the managing of patients under anticoagulant treatment.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Treatment Outcome; 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

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Fondaparinux; Heparin; Hirudin Therapy; Hirudins; Humans; Pipecolic Acids; Polysaccharides; Prodrugs; Recombinant Proteins; Sulfonamides; Thrombin; Thrombocytopenia

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Morpholines; Polysaccharides; Pulmonary Embolism; Research Design; Rivaroxaban; Thiophenes; Venous Thrombosis

Anticoagulant therapy plays an important role in current medical practice. The main types of anticoagulant agents are: heparins, hirudins and vitamin K antagonists. None of the drugs used as anticoagulants meet the criteria of an ideal anticoagulant because they have side effects and they interact with other compounds. The main side effect of anticoagulant therapy is bleeding. The choice of a certain anticoagulant is made by the doctor based on the clinical context and also on the desired effect.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Polysaccharides; Thrombocytopenia; Vitamin K; Warfarin

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Myocardial Ischemia; Oligosaccharides; Polysaccharides; Recurrence; Thrombin; Time Factors; Venous Thrombosis; Warfarin

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

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

Heparin and Vitamin K antagonists have been the only available anticoagulants for several decades. Their use has lead to significant achievements in all fields of medicine despite various shortcomings and bleeding complications. With the objective of an improved benefit-/risk ratio selective inhibitors of factor Xa (Fondaparinux) and factor IIa (Ximelagatran) have been developed. Ximelagatran can also be orally administered. The results obtained from various clinical trials with these compounds are extremely encouraging. Thus, a significant improvement of antithrombotic treatment may be expected by their future use in the clinical and out-patient setting.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Biological Availability; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Meta-Analysis as Topic; Polysaccharides; Prodrugs; Risk Factors; Stroke; 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; Azetidines; Benzylamines; Clinical Trials as Topic; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Venous Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin; History, 20th Century; Humans; Polysaccharides; Prodrugs; Thrombosis; Warfarin

Topics: Antineoplastic Agents; Azetidines; Benzylamines; Blood Coagulation Factors; Clinical Trials as Topic; Endothelium, Vascular; Fibrinolytic Agents; Fondaparinux; Hemostasis; Humans; Neoplasms; Neovascularization, Pathologic; Oligosaccharides; Polysaccharides; Stilbenes; Thrombosis

The main anticoagulants presently used have several drawbacks. Two new compounds (pentasaccharide and ximelagatran) have shown in recent studies several interesting properties and results. Both are of non animal origin, do not induce thrombocytopenia and do not require laboratory controls. Pentasaccharide has a better efficacy than low molecular weight heparin in major orthopaedic interventions; it will be registered soon in several countries. Ximelagatran, which can be given orally and is in phase III investigation, could replace vitamin K antagonist in the future.

Topics: Azetidines; Benzylamines; Fibrinolytic Agents; Fondaparinux; Humans; Polysaccharides