ximelagatran and Venous-Thrombosis

Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT.. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT.. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations.. We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT.. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).. We included 11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta-analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life.. NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

Topics: Administration, Oral; Antithrombins; Azetidines; Benzylamines; Dabigatran; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Venous Thrombosis

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. For several decades, anticoagulant options for the treatment and prevention of thrombosis have been limited mainly to agents such as unfractionated heparin and oral vitamin K antagonists, such as warfarin. Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clinical practice. A variety of novel anticoagulants with improved pharmacologic and clinical profiles are in development, offering benefits over traditional therapies. Specifically, progress has been made in the development of small molecule factor Xa inhibitors and thrombin inhibitors. With their potentially consistent and predictable clinical profile, oral formulation, and decreased need for coagulation monitoring, these new agents will likely increase the use and duration of anticoagulation treatment in thromboembolic disorders and reduce the burden associated with long-term management.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Drug Approval; Humans; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; United States; Venous Thrombosis

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 infinity 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 infinity 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.

Topics: Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Humans; International Normalized Ratio; Prospective Studies; Pulmonary Embolism; Randomized Controlled Trials as Topic; Recurrence; Thrombin; Venous Thrombosis

Despite the significant advances over the last 50 years with regard to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in at-risk patients, except those with acute coronary syndromes, in which antiplatelets are preferred. Ximelagatran, a prodrug of melagatran, is an orally administered direct thrombin inhibitor whose therapeutic potential has been investigated in venous thromboembolism, acute coronary syndromes and prevention of stroke in atrial fibrillation. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to the oral vitamin K antagonist warfarin and low molecular weight heparin for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Double-blind trials have also revealed the efficacy of ximelagatran in the secondary prevention of venous thromboembolism and shown the agent to be as effective as enoxaparin/warfarin in treating patients with acute deep vein thrombosis. Adverse effects with ximelagatran include elevations in alanine transaminase (ALT), which may require monitoring, and bleeding complications. Bleeding complications appear to be less than or at least comparable to those occurring with standard anticoagulant treatments like warfarin or low molecular weight heparin. In addition to its favorable efficacy and safety profile in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration without the need for anticoagulation monitoring might help encourage a wider use of appropriate anticoagulation using ximelagatran across the population at risk, reducing the incidence of thromboembolic events.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Drug Administration Schedule; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Secondary Prevention; Stroke; Thrombin; Thromboembolism; Venous Thrombosis; Warfarin

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

Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Heart Diseases; Hemostasis; Humans; Molecular Structure; Orthopedic Procedures; Patient Compliance; Patient Satisfaction; Platelet Aggregation; Prodrugs; Stroke; Syndrome; Thrombin; Thromboembolism; Treatment Outcome; Venous Thrombosis

Ximelagatran has been recently studied for prophylaxis in surgical orthopedic cases.. We proposed to establish whether interventions involving ximelagatran, as compared with warfarin, would increase thromboembolic prophylaxis in patients undergoing major orthopedic knee surgery.. Studies with random assignment were identified by an electronic search of the medical literature up to 2006. Data were double-entered into the Review Manager software, version 4.2.5.. We included three well-conducted clinical trials involving 4,914 participants. Sub-groups with two dosages of ximelagatran (24 mg and 36 mg, b.i.d.), were defined. Ximelagatran showed significantly lower frequency of total venous thromboembolism (VTE) than warfarin, but only with the 36-mg dosage (risk relative, RR: 0.72; 95% confidence interval, CI: 0.64-0.81; p < 0.00001). For the 24-mg subgroup, total VTE frequency was similar (RR: 0.86; 95% CI: 0.73-1.01; p = 0.06). No significant differences were shown with either ximelagatran dosage for deep vein thrombosis (DVT), pulmonary embolism, any bleeding or severe bleeding. At the end of the treatment, alanine aminotransferase (ALT) elevation was less frequent in the 24-mg ximelagatran sub-group (RR: 0.33; 95% CI: 0.12-0.91; p = 0.03], but during the follow-up period, the ALT elevation rate was greater in the 36-mg ximelagatran group (RR: 6.97; 95% CI: 1.26-38.50; p = 0.03].. Ximelagatran appears to be more effective than warfarin when used in higher dosages (36 mg b.i.d.), but at the expense of increased frequency of ALT elevation during the follow-up period.

Topics: Aged; Anticoagulants; Azetidines; Benzylamines; Brazil; Epidemiologic Methods; Hemorrhage; Humans; Knee; Orthopedic Procedures; Pulmonary Embolism; Thromboembolism; Venous Thrombosis; Warfarin

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Disease; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thromboembolism; Thrombosis; Venous Thrombosis

Ximelagatran is an oral direct thrombin inhibitor (DTI), the active form of which is melagatran. Approximately 20% of an oral ximelagatran dose becomes bioavailable as melagatran, which binds noncovalently and reversibly to both fibrin-bound and freely circulating thrombin. Oral ximelagatran dosing not only inhibits thrombin activity rapidly, competitively, and potently, but also delays and suppresses thrombin generation. In humans, oral ximelagatran exhibits anticoagulant, antiplatelet, and profibrinolytic effects, with only minor prolongation of the capillary bleeding time. Oral ximelagatran exhibits a stable and predictable pharmacokinetic profile during repeated dosing, with low intra- and inter-individual variation, and a low potential for interaction with other medications. It is excreted primarily as melagatran via the kidney, without unexpected bioaccumulation. Dosing requirements do not vary with age, gender, ethnicity, obesity, or food or alcohol intake. Clinical trials (total n>30,000) have evaluated oral ximelagatran in four indications: the prevention of venous thromboembolism (VTE, comprising deep venous thrombosis with or without and pulmonary embolism) after elective hip- or knee-replacement surgery (with approval granted by France, as the Reference Member State for the European Union); treatment and long-term secondary prevention of VTE; the prevention of stroke and other systemic embolic events associated with nonvalvular atrial fibrillation; and the prevention of cardiovascular events after an acute myocardial infarction. The results of these trials suggest that the benefit-risk profile of oral ximelagatran therapy, administered at a fixed-dose without coagulation monitoring, compares favorably with that of currently approved standard therapy.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Glycine; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Thrombin; Thromboembolism; Venous Thrombosis

Clinical-based evidence demonstrates that long-term oral anticoagulant therapy with the vitamin K antagonists is highly effective for the secondary prevention of venous thromboembolism (VTE). However, owing to fear of bleeding complications and the inconvenience of coagulation monitoring, many patients do not receive the required duration of treatment. This can lead to a high incidence of recurrent VTE events and has prompted the evaluation of alternative treatment strategies and the development of new anticoagulants for VTE management. For patient groups in which it is particularly difficult to maintain the target intensity of anticoagulation, low-molecular-weight heparin (LMWH) has been found to significantly reduce the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of LMWH, however, is a drawback for long-term use in the outpatient setting. Long-term warfarin use at a lower intensity (international normalized ratio [INR] 1.5-2.0) has also been assessed as a possible strategy to reduce bleeding complications and the need for monitoring, but results were disappointing when compared with conventional-intensity warfarin (INR 2.0-3.0). New therapies in development that may potentially offer a more favourable benefit-risk profile and greater consistency and predictability of response include the synthetic pentasaccharides, fondaparinux and idraparinux. These par enterally administered indirect factor Xa inhibitors have a predictable pharmacokinetic profile, allowing use without coagulation monitoring. Fondaparinux to date has only been evaluated in the initial treatment (5-7 days) of symptomatic deep vein thrombosis. In contrast, idraparinux, with its longer half-life (80 h) allowing once-weekly parenteral dosing, has the potential for long-term treatment and is currently being assessed in phase III trials for the secondary prevention of VTE. Currently, the most promising new therapeutic option is the first of the oral direct thrombin inhibitors, ximelagatran. The THRombin Inhibitor in VEnous thromboembolism (THRIVE) clinical trial programme has demonstrated that this agent is as effective as standard therapy for the acute treatment (THRIVE Treatment) and secondary prevention (THRIVE lll) of VTE events and is well tolerated when used for 6 months or over extended periods up to 1.5 years. Furthermore, with oral administration, fixed dosing and no requirement for anticoagulation monitoring, ximelagatran has the potential

Topics: Anticoagulants; Azetidines; Benzylamines; Humans; Secondary Prevention; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Prodrugs; Stroke; Venous Thrombosis; Vitamin K

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

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed.. Ximelagatran is the first orally active direct thrombin inhibitor to be tested in Phase III clinical trials. After oral administration, ximelagatran is rapidly converted to its active metabolite, melagatran. Melagatran (after oral ximelagatran administration) predictably inhibits thrombin function without need for routine anticoagulation monitoring. Melagatran effectively inhibits both free and clot-bound thrombin-a potential pharmacodynamic advantage over heparin products. Melagatran has a half-life of 2.4-4.6 hours, necessitating twice-daily administration. Melagatran is primarily eliminated by the kidneys and has not been studied clinically in patients with severe renal failure. Ximelagatran has undergone 10 Phase III trials (6 for prophylaxis of venous thromboembolism [VTE] due to orthopedic surgery, 1 for initial treatment of VTE, 1 for long-term prevention of VTE recurrence, and 2 for stroke prophylaxis due to atrial fibrillation). Results were generally positive. AstraZeneca applied in December 2003 for marketing approval of ximelagatran for prevention of VTE after total knee replacement surgery, long-term prevention of VTE recurrence after standard therapy, and stroke prevention due to atrial fibrillation. FDA denied approval of ximelagatran for all indications, mainly because of increased rates of coronary artery disease events in ximelagatran recipients in some studies and the possibility of hepatic failure when the medication is used for long-term therapy.. Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Biological Availability; Clinical Trials, Phase III as Topic; Drug Interactions; Half-Life; Humans; Metabolic Clearance Rate; Stroke; Thrombin; Thromboembolism; Venous Thrombosis; Warfarin

Ximelagatran is a direct thrombin inhibitor that offers numerous potential advantages compared with traditional anticoagulants. It is given orally, has a rapid onset of action, does not require laboratory monitoring, and is not associated with immune-mediated thrombocytopenia. Numerous phase III trials with ximelagatran focusing on deep vein thrombosis prophylaxis and treatment, stroke prevention in patients with atrial fibrillation, and secondary prevention after acute myocardial infarction have been conducted. Results of these trials indicate that ximelagatran has similar efficacy and risk of bleeding compared with currently used anticoagulants. Accordingly, the potential of this agent to replace warfarin therapy for a variety of indications has been widely touted. Ximelagatran has already been approved in Europe for prophylaxis of venous thromboembolism in patients undergoing hip or knee surgery. However, an adverse effect of ximelagatran is liver enzyme elevation, which has been observed in 5% to 10% of patients with chronic administration of the drug. Although initially felt to be transient in nature, subsequent data presented to the Federal Drug Administration suggest a small but real risk of significant hepatotoxicity. These data led the advisory committee to the Federal Drug Administration to recommend against immediate approval of ximelagatran pending further information. The consistent results of completed trials with ximelagatran suggest that it has the potential to be used in many conditions that currently require treatment with warfarin and heparin products. The potential benefit that may be achieved by the replacement of these historically problematic narrow therapeutic index agents must be weighed against as yet undetermined long-term risks of hepatotoxicity.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Humans; Myocardial Infarction; Stroke; Thrombin; Thromboembolism; Venous Thrombosis; Warfarin

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.

Topics: Animals; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Blood Coagulation; Blood Coagulation Factors; Dabigatran; Factor IX; Fibrinolytic Agents; Humans; Models, Biological; Protein C; Pyridines; Thrombin; 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

Several case studies are briefly introduced, followed by a description of the clinical problem from an epidemiological point of view. The evidence for established management strategies is reviewed and, finally, practical handling of the case is considered.

Topics: Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Male; Stroke; Venous Thrombosis

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

Use of low molecular weight heparin (LMWH) is standard practice for preventing postoperative venous thromboembolism (VTE). Ximelagatran is a new direct thrombin inhibitor for this indication.. A systematic review was conducted to compare the efficacy and safety of LMWH with ximelagatran in orthopaedic surgery.. Six eligible, well conducted clinical trials (10 051 patients) were identified. Overall, the risk of VTE (OR (odds ratio) 1.22 (95 per cent confidence interval (c.i.) 0.89 to 1.67)) and serious bleeding (OR 0.70 (95 per cent c.i. 0.42 to 1.18)) was not significantly different for LMWH compared with ximelagatran. Exploratory analyses to investigate statistical heterogeneity found that results varied by surgical subtype and treatment regimen. Compared with postoperative ximelagatran, LMWH had a significantly lower rate of VTE (OR 0.68 (95 per cent c.i. 0.56 to 0.82); P < 0.001), with no significant difference in bleeding rate (OR 1.09 (95 per cent c.i. 0.62 to 1.94); P = 0.76), in hip surgery, and no significant differences in knee surgery. When ximelagatran was started immediately before surgery, LMWH had a significantly higher rate of VTE in both hip (OR 1.87 (95 per cent c.i. 1.20 to 2.92); P = 0.006) and knee (OR 1.49 (95 per cent c.i. 1.14 to 1.93); P = 0.003) surgery, but less bleeding: hip OR 0.30 (95 per cent c.i. 0.17 to 0.53; P < 0.001); knee OR 0.71 (95 per cent c.i. 0.30 to 1.67; P = 0.43).. This review demonstrated no overall advantage for either LMWH or ximelagatran in thromboprophylaxis following orthopaedic surgery. Benefits in VTE prevention with ximelagatran were gained at the expense of an increased risk of serious bleeding.

Topics: Adult; Anticoagulants; Arthroplasty, Replacement; Arthroplasty, Replacement, Hip; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Postoperative Complications; Postoperative Hemorrhage; Randomized Controlled Trials as Topic; Thromboembolism; Venous Thrombosis

Current antithrombotic agents include anticoagulants (unfractionated and low-molecular-weight heparin, and antivitamin K) and platelet aggregation inhibitors (aspirin, ticlopidine, clopidogrel). Two areas are under particular investigation: specific inhibition, direct or indirect, of factor Xa and factor IIa. Pentasaccharide, an indirect anti-Xa, has proved effective in curing deep-vein thrombosis and more effective than enoxaparin for prophylactic treatment after orthopedic surgery. Administered in a single subcutaneous injection daily, it has no risk of thrombocytopenia; laboratory surveillance is based on anti-Xa activity. Hirudin and melagatran act by direct thrombin inhibition. Unlike hirudin (which requires monitoring of active coagulation time or ecarin clotting time), melagatran requires no laboratory monitoring. It is not associated with an increased risk of hemorrhage. But there is no true antidote at this time. If its efficacy is confirmed, ximelagatran, the orally active prodrug of melagatran, may facilitate the long-term treatment now reserved for antivitamin K. Three antagonists of the tissue factor-factor VIIa complex are also under development: rNAPc2 (Recombinant Nematode Anticoagulant Protein C2), ASIS (Active Site Inhibitor Factor Seven) and recombinant TFPI (Tissue Factor Pathway Inhibitor). Antiplatelet drugs are the reference antithrombotic agents for the prevention and treatment of arterial thrombosis. Aspirin remains in first place (75 to 300 mg/d) but the modest superiority of the thienopyridines (clopidogrel and ticlopidine) is established. Hemogram monitoring is no longer necessary for clopidogrel. Use of aspirin + a thienopyridine after placement of a coronary stent has been validated. Laboratory monitoring of antiplatelet treatments has not been codified.

Topics: Administration, Oral; Angioplasty, Balloon, Coronary; Anticoagulants; Aspirin; Azetidines; Benzylamines; Clopidogrel; Fibrinolytic Agents; Glycine; Hirudins; Humans; Injections, Subcutaneous; Platelet Aggregation Inhibitors; Polysaccharides; Prodrugs; Randomized Controlled Trials as Topic; Stents; Thrombosis; Ticlopidine; Time Factors; 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

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

Atrial fibrillation is the most frequently encountered tachyarrhythmia requiring therapy. Treatment issues include therapy for any reversible cause; the identification and treatment of any underlying structural disorder; control of the ventricular rate, both for symptom reduction and prevention of tachycardic-induced cardiomyopathy; restoration and maintenance of sinus rhythm when symptoms persist despite rhythm control; and anticoagulation in patients with high-risk markers for systemic embolization: age over 65 years, hypertension, diabetes, ventricular failure, rheumatic valvular disease, and prior stroke or other embolic event. In such patients, anticoagulation with warfarin is currently recommended. Warfarin therapy carries significant risks (especially bleeding), inconveniences (the cost of prothrombin time monitoring, the need for rigid dietary stability, the concerns of drug and herbal interactions), and other concerns (the issue of generic formulation substitution).. Under development are oral thrombin inhibitors. The first to reach clinical approval will likely be ximelagatran. In clinical trials to date, ximelagatran has proven to be equal to or superior to warfarin in the prevention and treatment of thrombophlebitis. In atrial fibrillation patients, the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials completed so far appear to show a similar or better efficacy for ximelagatran versus warfarin as regards both prevention of embolic events and lower risks of major bleeding, with no serious adverse effects except for apparently reversible alterations in liver function tests in approximately 6% of subjects, all occurring early in therapy to date. If the remaining SPORTIF trial (SPORTIF V) is confirmatory (results to be available in late 2003), it is expected that this exciting new product will be submitted this winter to the Food and Drug Administration for approval. Recent findings also include the observations in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and Rate Control Versus Electrical Cardioversion (RACE) trials that anticoagulation should not be discontinued despite the restoration and maintenance of sinus rhythm.. Oral direct thrombin inhibitors, such as ximelagatran, appear likely to replace the use of warfarin in most patients in the near future, because of a better risk-benefit profile.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Embolism; Fibrinolytic Agents; Humans; Prothrombin Time; Randomized Controlled Trials as Topic; Stroke; Venous Thrombosis; Warfarin

Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and its active form, melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement. After oral administration ximelagatran is rapidly bioconverted to melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time. The efficacy of subcutaneous melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials. In a dose-ranging European study, preoperatively initiated subcutaneous melagatran 3 mg twice daily followed by oral ximelagatran 24 mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous melagatran 3 mg administered after surgery followed by ximelagatran 24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the US, four studies showed that postoperatively initiated ximelagatran 24 mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.Ximelagatran alone or after melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients.. Oral ximelagatran alone or in conjunction with subcutaneous melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.

Topics: Anticoagulants; Azetidines; Benzylamines; Drug Interactions; Drug Therapy, Combination; Enoxaparin; Glycine; Humans; Orthopedic Procedures; Randomized Controlled Trials as Topic; Thrombin; Thromboembolism; Venous Thrombosis; Warfarin

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

Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that inhibits the final step in the coagulation process - namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Recently completed large clinical trials have evaluated the efficacy and safety of ximelagatran compared to standard anticoagulation therapy with warfarin and heparins in several thrombotic disorders including the treatment and prevention of venous thromboembolism following major orthopaedic surgery; stroke prevention in atrial fibrillation; and after acute myocardial infarction. This article reviews these recent clinical trials and explores the therapeutic potential of ximelagatran to become the oral anticoagulant of first choice in medicine.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Artery Disease; Drug Therapy, Combination; Glycine; Humans; Prodrugs; Stroke; Thrombin; Thromboembolism; Venous Thrombosis

Vitamin K antagonists are effective oral anticoagulants, but they have limitations related to a narrow therapeutic range, food and drug interactions, slow onset of action and the need for routine coagulation monitoring. Ximelagatran is a promising new oral anticoagulant under investigation in advanced clinical trials. It is a prodrug that is converted after oral administration to melagatran, a direct thrombin inhibitor, with a peak effect after 2 hours and a half-life of approximately 3 hours with primarily renal excretion. Administration results in prolongation of coagulation tests, but routine monitoring is not required because of reliable absorption and predictable effects. A large clinical trials program has demonstrated effectiveness in prophylaxis of deep vein thrombosis (DVT) following major orthopedic surgery, treatment of symptomatic DVT, prevention of embolism in patients with atrial fibrillation, and prophylaxis of recurrent events after acute myocardial infarction. Bleeding complications have been similar to those with standard therapy, with no unexpected adverse effects except for elevation of serum transaminase levels in over 6% of patients beginning after 1 month of therapy. Ximelagatran may be an alternative oral anticoagulant for patients currently taking vitamin K antagonists.

Topics: Anticoagulants; Azetidines; Benzylamines; Heart Diseases; Hemorrhage; Humans; Liver Function Tests; Venous Thrombosis

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

Topics: Azetidines; Benzylamines; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Postoperative Complications; Therapeutic Equivalency; Thromboembolism; Venous Thrombosis; Vitamin K

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

The oral direct thrombin inhibitor ximelagatran shows great promise for prevention of venous thromboembolic events following major elective orthopaedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In orthopaedic surgery clinical trials, ximelagatran was effective and well tolerated compared with standard therapy, with dose and timing relative to surgery important factors in determining its optimal profile. In European trials, an initial 3-mg postoperative dose of subcutaneous melagatran, the active form of ximelagatran, followed by oral ximelagatran 24 mg twice daily achieved similar efficacy and safety to enoxaparin. Although the risk of spinal haematoma following neuraxial anaesthesia is rare, it is increased by the concomitant use of anticoagulants. In orthopaedic surgery trials with ximelagatran to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of ximelagatran suggests that concurrent use with neuraxial anaesthesia should require no further precautions than those currently necessary with low-molecular-weight heparin.

Topics: Administration, Oral; Anesthesia; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Orthopedic Procedures; Postoperative Complications; Thrombin; Thromboembolism; 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

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

The trypsin-like serine protease thrombin is a multifunctional key enzyme at the final step of the coagulation cascade and is involved in the regulation of hemostasis and thrombosis. An increased activation of coagulation can result in severe thromboembolic disorders, one of the major reasons responsible for mortality and morbidity in western world. Therefore, an effective, safe, and orally available thrombin inhibitor could be a useful anticoagulant drug for the daily prophylaxis of venous and arterial thrombosis and prevention of myocardial infarction for high-risk patients. Synthetic thrombin inhibitors have a long history; initial compounds were derived from electrophilic ketone- and aldehyde-analogs of arginine. First potent leads of non-covalent inhibitors were developed in the early eighties, which were further optimised in the nineties, after the X-ray structure of thrombin became available. In the meantime a huge number of highly active and selective inhibitors has been published, however, only a few of them have an appropriate pharmacokinetic and pharmacodynamic overall profile, which could justify their further development. Very recently, with Ximelagatran a first orally available thrombin inhibitor has been approved in France for the prevention of venous thromboembolic events in major orthopaedic surgery after successful clinical phase III. However, it still has to be awaited, whether the extensive clinical use of Ximelagatran can demonstrate for the first time that direct thrombin inhibitors offer a real benefit in terms of efficacy and safety over established antithrombotic therapies. This review summarizes the current status of synthetic thrombin inhibitors with a focus on more recently published and promising new compounds.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Binding Sites; Drug Design; Humans; Myocardial Infarction; Thrombin; Thromboembolism; Thrombosis; Vascular Diseases; Venous Thrombosis

To present the chemistry, pharmacology, and pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor (DTI), and to review available comparative clinical trial data evaluating its efficacy and safety relative to other antithrombotic agents in the prevention and treatment of thromboembolism.. A search of the PubMed and Cochrane databases (1995-August 2004), supplemented by a manual search of article bibliographies, conference abstracts, and data on file from the manufacturer, was conducted. Key search terms were ximelagatran, melagatran, H376/95, and direct thrombin inhibitors.. Pertinent information from available clinical trials, including study design, patient demographics, dosing regimens, anticoagulant comparators, methods for evaluating effectiveness, treatment outcomes, adverse events, and pharmacokinetic and pharmacodynamic evaluations, was extracted.. Ximelagatran is an orally administered DTI under development for use in the treatment of venous thromboembolism (VTE), long-term prevention of a second VTE event, stroke secondary to atrial fibrillation, prevention of VTE after orthopedic procedures, and recurrent ischemic events after acute myocardial infarction.. Ximelagatran, in twice-daily doses of 24 or 36 mg, is an alternative to low-molecular-weight heparins or warfarin in thromboprophylaxis following orthopedic knee replacement, atrial fibrillation, or initial treatment of VTE. Improved outcomes versus placebo were seen in the long-term prevention of VTE in patients who completed an initial 6 months of treatment. Liver-related effects need further clarification.

Topics: Adult; Anticoagulants; Area Under Curve; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Biological Availability; Clinical Trials as Topic; Food-Drug Interactions; Half-Life; Humans; Male; 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

Melagatran is a synthetic, small-peptide direct thrombin inhibitor with anticoagulant activity. Ximelagatran, an oral prodrug, undergoes rapid enzymatic conversion to melagatran. Melagatran has rapid onset of action, fixed twice-daily dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring drug levels or dose adjustment. There is no specific antidote, but the drug has a short plasma elimination half-life (about 4 hours). In clinical studies, melagatran/ximelagatran is not inferior to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, to heparin-warfarin for acute treatment and extended secondary prevention of deep vein thrombosis, and superior to warfarin for prevention of venous thromboembolism after major orthopaedic surgery. Major bleeding with melagatran/ximelagatran occurred at rates similar to those in patients treated with warfarin. 6%-12% of patients taking ximelagatran develop asymptomatic elevated liver enzyme levels (predominantly alanine aminotransferase) after 1-6 months of therapy; this usually resolves with cessation of therapy. Less than 1% of patients develop abnormal liver function while taking ximelagatran; this rarely persists or develops into clinical illness.

Topics: Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Glycine; Humans; Myocardial Infarction; Secondary Prevention; Stroke; Thrombin; Treatment Outcome; Venous Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Humans; Myocardial Infarction; Orthopedic Procedures; Postoperative Complications; Stroke; Venous Thrombosis

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

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Biological Availability; Blood Coagulation; Blood Coagulation Factor Inhibitors; Half-Life; Heparin; Humans; Venous Thrombosis

Patients who undergo orthopaedic surgery are at substantially increased risk for venous thromboembolic events. These include proximal and distal deep vein thrombosis, with the former more likely to lead to pulmonary embolism and fatal complications. Anticoagulants are routinely used for venous thromboembolism prophylaxis in patients undergoing total hip or total knee replacement surgery. Although current treatments offer effective prophylaxis, they have disadvantages. Warfarin is limited by the requirement for coagulation monitoring to ensure effective and safe use. Similarly, low-molecular-weight heparins (LMWHs) have disadvantages, including the need for parenteral administration. This article brings together data from clinical trials of the novel oral direct thrombin inhibitor, ximelagatran, in the prevention of venous thromboembolism in patients undergoing elective total hip or total knee replacement. The ximelagatran clinical trial programme in orthopaedic surgery has focused primarily on five large multicentre studies in Europe (the Melagatran Thromboprophylaxis in Orthopaedic surgery II and III and Expanded Prophylaxis Evaluation Surgery Study studies) and in the United States (the Exanta Used to Lessen Thrombosis A and B studies), which enrolled more than 8000 patients. In addition, the USA clinical trial programme included three other trials that investigated ximelagatran in orthopaedic surgery; two of these studies focused on prevention of venous thromboembolism after total knee replacement, and one study investigated prevention of venous thromboembolism after total hip replacement. These studies compared ximelagatran with the LMWHs dalteparin and enoxaparin and with warfarin, and were designed to reflect regional differences in venous thromboembolism prophylaxis and to build on findings from previous studies. Generally, ximelagatran has been shown to possess comparable or greater efficacy relative to comparators. The timing and dose of ximelagatran have been shown to be important determinants of its efficacy and safety. As ximelagatran can be given in fixed oral dosing without coagulation monitoring, it is an attractive choice for the prevention of venous thromboembolism in major elective orthopaedic surgery.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Clinical Trials as Topic; Heparin, Low-Molecular-Weight; Humans; Multicenter Studies as Topic; Postoperative Complications; Pulmonary Embolism; Thrombin; Venous Thrombosis

Despite the effectiveness of anticoagulant therapy for the treatment of acute venous thromboembolism and the prevention of recurrent venous thromboembolism, existing antithrombotic therapies are suboptimal. Unfractionated heparin, low-molecular-weight heparin (LMWH) and warfarin have practical limitations and carry the risk of treatment-related adverse events that restrict their clinical benefits and reduce cost-effectiveness. Efforts to achieve optimal venous thromboembolism prophylaxis by modifying the intensity of oral warfarin treatment have produced equivocal results, and there is a need for new, efficacious antithrombotic drugs providing predictable, well-tolerated oral dosing without the need for coagulation monitoring. Such agents would ideally have no significant food or drug interactions, and be suitable for both short- and long-term treatment. Ximelagatran, the first oral direct thrombin inhibitor, has the potential to fulfill many of the unmet needs in the management of venous thromboembolism.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Heparin, Low-Molecular-Weight; Humans; Secondary Prevention; Thrombin; Venous Thrombosis; Warfarin

Current antithrombotic therapies are associated with various practical limitations and risks that restrict their utility in the management of venous thromboembolism. The coagulation factor, thrombin, has been the focus of extensive investigation as a pharmacological target in efforts to improve the management of venous thromboembolism. Hirudin, desirudin, bivalirudin and argatroban are direct thrombin inhibitors that have been launched for limited indications as anticoagulants. Their usefulness for long-term prophylaxis is limited by a requirement for parenteral administration, restricted licensing and bleeding/tolerability profile. Ximelagatran--which, after oral administration, is rapidly converted to its active form, melagatran--is the first oral direct thrombin inhibitor and the first new oral anticoagulant to become available in 60 years. Clinical studies have shown that melagatran/ximelagatran, without coagulation monitoring, is effective and well tolerated for the prevention of venous thromboembolism after hip replacement and knee replacement surgery. Ximelagatran is also effective in the acute treatment of venous thromboembolism and long-term secondary prevention of recurrent venous thromboembolism, the prevention of stroke in patients with atrial fibrillation and in the prevention of cardiovascular events after myocardial infarction. Oral direct thrombin inhibitors have a promising role in the management of venous thromboembolism and other associated medical conditions.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Orthopedic Procedures; Postoperative Complications; Thrombin; Venous Thrombosis

Unfractionated heparin and warfarin have been the mainstay of treatment of venous thromboembolism (VTE) for approximately half a century. However, both agents are difficult to dose accurately, require frequent blood testing and dosage adjustment, and can cause serious adverse effects. Oral direct thrombin inhibitors may provide more predictable anticoagulation with oral dosing, without the need for frequent blood test monitoring and without the adverse effects seen with conventional agents. The oral direct thrombin inhibitor closest to being marketed is ximelagatran, which has been through phase III trials. Available data thus far suggest that the efficacy and safety of this agent may allow it to replace both heparin (and low-molecular-weight heparin) and warfarin for VTE treatment and long-term prophylaxis. Concerns about ximelagatran that require further study are a 5-9% rate of transient elevation in liver enzyme levels, drug interactions, how patient adherence can be ensured in the absence of blood tests, and whether alterations in renal or hepatic function will require dosage adjustments. Although there is more to learn about ximelagatran, available data suggest that it is likely to be the most significant therapeutic advance in this area in over 50 years.

Topics: Administration, Oral; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fibrinolytic Agents; Humans; Meta-Analysis as Topic; Thrombin; Venous Thrombosis

Venous thromboembolism, which is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a significant cause of death, disability, and discomfort. Two million people/year are affected by VTE, making it the third most common cardiovascular disease after coronary heart disease and stroke. The rationale for VTE prophylaxis stems from the clinically silent presentation of the disease and its prevalence among hospitalized patients. At greatest risk are patients undergoing major orthopedic surgery and those admitted to the intensive care unit with acute myocardial infarction, heart failure, ischemic stroke, respiratory disease, systemic infection, or other medical conditions that immobilize patients for 5 days or longer. Several anticoagulant regimens have been effective in reducing the risk of VTE after major orthopedic surgery. For patients undergoing total hip or knee replacement, treatment with adjusted-dose warfarin, low-molecular-weight heparins, or fondaparinux may be used. Warfarin, which has been around for more than 50 years, is the only oral anticoagulant available for VTE prophylaxis. Ximelagatran, a new low-molecular-weight oral prodrug of the direct thrombin inhibitor melagatran, has advantages over warfarin that may make it the drug of choice for prevention of VTE.

Topics: Administration, Oral; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Double-Blind Method; Fibrinolytic Agents; Humans; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Thrombin; Venous Thrombosis

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

Venous thromboembolism is a common and potentially fatal complication among hospital in-patients, particularly those undergoing orthopaedic surgery. Current prophylactic strategies utilise low molecular weight heparins (LMWHs) and warfarin. However, painful subcutaneous injections for LMWHs and delays in achieving target anticoagulation for warfarin pose significant problems clinically. The Melagatran for THRombin inhibition in Orthopaedic surgery (METHRO) trial represents a landmark step in the sequential combination of subcutaneous and oral anticoagulation with melagatran and ximelagatran, respectively, for surgical venous thromboprophylaxis. These agents have proven to be as effective and safe as LMWHs. Furthermore, with no need for dosage adjustment or therapeutic drug monitoring there is emerging evidence that ximelagatran may replace warfarin as the anticoagulant of choice.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Humans; Orthopedic Procedures; Prodrugs; Thrombin; Venous Thrombosis

Thrombin has long been a target for development of oral anticoagulants but it has been difficult to find synthetic inhibitors with a desirable combination of pharmacodynamic and pharmacokinetic properties. However, there are now two oral direct thrombin inhibitors (DTIs) in clinical development, ximelagatran (ExantaTM) and BIBR 1048. Both are prodrugs with two protecting groups that are eliminated after absorption from the gastrointestinal tract. Their main active substances, melagatran and BIBR 953, are both potent and selective DTIs. In experimental models of thrombosis, melagatran has been shown to have a shallower dose-response curve than warfarin and, therefore, a better separation between efficacy and bleeding. Oral bioavailability, measured as the plasma concentration of the active metabolite, seems to be higher for ximelagatran (20%) than for BIBR 1048 (estimated to 5%). BIBR 953 has a longer half-life (about 12 h) than does melagatran (3-5 h) after oral administration of BIBR 1048 and ximelagatran, respectively. Both melagatran and BIBR 953 are mainly eliminated via the renal route. The variability of the plasma concentration of melagatran after oral administration of ximelagatran is low. There are no clinically relevant interactions with food or cytochrome P450 metabolized drugs and ximelagatran. In clinical studies, ximelagatran has been administered in a twice-daily fixed-dose regimen without coagulation monitoring. Results of published clinical studies are encouraging, both with regard to efficacy and bleeding. Major indications in Phase III studies with ximelagatran are the prevention of venous thromboembolism (VTE) in hip and knee replacement surgery, treatment and long-term secondary prevention of VTE and prevention of stroke in patients with nonvalvular atrial fibrillation. It is anticipated that with a favourable outcome of the Phase III clinical studies new oral DTIs, with the oral fixed-dose regimen without routine coagulation monitoring, will ease the use of today's anticoagulant therapy.

Topics: Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Glycine; Hemostasis; Humans; Prodrugs; Pyridines; Stroke; Thrombin; Thrombosis; Venous Thrombosis; Vitamin K

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

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action. Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1). reviews the limitations of vitamin K antagonists, (2). lists the characteristics of an ideal anticoagulant, (3). rationalizes thrombin as a target for new anticoagulants, (4). reviews the preclinical and clinical data with ximelagatran, and (5). provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Blood Coagulation; Drug Monitoring; Glycine; Humans; International Normalized Ratio; Postoperative Complications; Prodrugs; Stroke; Thrombin; Thrombosis; Venous Thrombosis; Vitamin K

Acute venous thromboembolism including asymptomatic and symptomatic pulmonary embolism without respiratory or cardiac failure is currently treated for 6 months, initially with subcutaneous low-molecular-weight heparin followed by oral anticoagulation. The main drawback of oral anticoagulation is caused by severe bleeding complications. Oral Ximelagatran has shown to be as effective and safe for the initial treatment of acute deep venous thrombosis compared to subcutaneous low-molecular-weight heparin followed by oral warfarin over a period of 4 weeks. Currently, oral ximelagatran is investigated versus subcutaneous low-molecular-weight heparin and oral warfarin over 6 months to demonstrate an almost equal efficacy and safety. The study is performed on a double blind and double dummy basis. Six months after oral anticoagulation of patients with acute deep venous thrombosis, recurrent venous thromboembolism may occur in up to 25% within 2 years. Ximelagatran is currently investigated versus placebo to demonstrate a reduced recurrence rate of venous thromboembolism over a period of 18 months.

Topics: Anticoagulants; Azetidines; Benzylamines; Humans; Prodrugs; Thromboembolism; 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

AstraZeneca (formerly Astra) is developing ximelagatran, an orally active thrombin inhibitor and prodrug of melagatran, for the potential prevention and treatment of venous thromboembolism (VTE) in hip and knee replacement, for prevention of stroke in atrialfibrillation (AF) and for post acute coronary syndrome. As of December 1999, the compound was undergoing phase III trials for the prevention of VTE [349551]; these were ongoing in December 2001. By December 2000, ximelagatran had entered phase III trials for the prevention of stroke in atrial fibrillation [395212]. In September 2000, the company expected global NDA filing for this indication to take place in the middle of 2001 [383469]; however, in December 2000 this was revised to the second half of 2002 [395212], and in March 2001, to the second quarter of 2003 [402040], [416882], [431673]. By December 2000, a phase II trial was underway of ximelagatran as a potential treatment following myocardial infarction [395237]. In December 2001, early phase clinical trials were ongoing for post acute coronary syndrome [431673]. By December 2001, EU and US filings for VTE prevention were anticipated in the third quarter of 2002 and the second quarter of 2003, respectively [3144721, [350050], [431673]. Exanta is the trade name for both melagatran and ximelagatran. In 1998, marketing of ximelagatran in the US was to be assigned to the Astra/Merek joint marketing venture, prior to the merger [276577]. In April 1999, ABN predicted sales of 4 pounds million in 2003 [328676], [394606]. In December 2000, Lehman Brothers estimated peak sales to be $1.4 billion [394606]. At the same time, ABN-AMRO predicted peak sales of more than $1 billion [395237]. In June 2000, Deutsche Bank predicted sales of $70 million in 2002, rising to $245 million in 2003 [374500]. In September 2000, Merrill Lynch predicted sales of 125 pounds million in 2002, rising to 625 pounds million in 2004 [383742]. In February 2001, Merrill Lynch estimated that peak sales would reach $924 million in 2005 [429697].

Topics: Azetidines; Benzylamines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Industry; Drugs, Investigational; Female; Fibrinolytic Agents; Humans; Male; Prodrugs; Structure-Activity Relationship; Thrombin; Treatment Outcome; Venous Thrombosis

Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran.. Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2x36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2x24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed.. In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups.. The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran.

Topics: Administration, Oral; Anticoagulants; Arteries; Azetidines; Benzylamines; Drug Therapy, Combination; Enoxaparin; Follow-Up Studies; Germany; Hemorrhage; Humans; Incidence; International Normalized Ratio; Muscle, Skeletal; Prospective Studies; Recurrence; Retinal Vein Occlusion; Time Factors; Venous Thrombosis; Warfarin

Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism.. To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.. Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.. Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.. Recurrent venous thromboembolism, bleeding, and mortality.. Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], -1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, -1.0%; 95% CI, -2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, -1.1%; 95% CI, -2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).. Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Drug Therapy, Combination; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Prodrugs; Pulmonary Embolism; Recurrence; Treatment Outcome; Venous Thrombosis; Warfarin

Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.. A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.. The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.. The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Area Under Curve; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Severity of Illness Index; Sweden; Treatment Outcome; Venous Thrombosis

Warfarin, which requires coagulation monitoring, is associated with relatively high rates of thromboembolism despite providing adequate prophylaxis. This study compared an oral direct thrombin inhibitor, ximelagatran, with warfarin in order to evaluate the safety and efficacy of the medication for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.. Following surgery, patients were randomly assigned to fixed-dose oral ximelagatran (36 mg twice daily) or warfarin (target international normalized ratio, 2.5), both administered for seven to twelve days in a double-blind, double-dummy design. Warfarin was initiated on the evening of the day of surgery, and ximelagatran, on the morning after surgery. The primary efficacy end point was the incidence of asymptomatic deep-vein thrombosis determined by bilateral venography, objectively confirmed symptomatic deep-vein thrombosis or pulmonary embolism, and death from all causes during treatment.. Adequate venograms or confirmed symptomatic events (efficacy population) were obtained for 1949 patients. Venous thromboembolism and death from all causes occurred in 22.5% (221) of 982 ximelagatran-treated patients and in 31.9% (308) of 967 warfarin-treated patients (p < 0.001). Proximal deep-vein thrombosis and pulmonary embolism were observed in 3.1% (thirty) and 0.2%, respectively, of the patients in the ximelagatran group and in 3.4% (thirty-three) and 0.4%, respectively, of the patients in the warfarin group. The six deaths from all causes included 0.3% (four) of the ximelagatran-treated patients and 0.2% (two) of the warfarin-treated patients. Major bleeding was noted in 1% (twelve) of the ximelagatran-treated patients and in 0.4% (five) of the warfarin-treated patients (p = 0.09).. Oral ximelagatran (36 mg twice daily), administered without coagulation monitoring or dose adjustment and started the day after total knee arthroplasty, demonstrates superior efficacy compared with warfarin prophylaxis, with no wound complications and no significant difference with respect to bleeding events, although the rate of major bleeding events was greater with ximelagatran than with warfarin.. Therapeutic Level I.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Female; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Treatment Outcome; Venous Thrombosis; Warfarin

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

Topics: Adult; Aged; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Pulmonary Embolism; Recurrence; Risk Factors; Sex Factors; Thromboembolism; Time Factors; Venous Thrombosis

In the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13 patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and one VTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36; P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36; P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36, 1.93; P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.

Topics: Administration, Oral; Adolescent; Adult; Anticoagulants; Azetidines; Benzylamines; Follow-Up Studies; Humans; Incidence; Prodrugs; Proportional Hazards Models; Risk Factors; Thromboembolism; Treatment Outcome; Venous Thrombosis

We evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Glycine; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Postoperative Complications; Prodrugs; Prospective Studies; Pulmonary Embolism; Safety; Thrombin; Treatment Outcome; Venous Thrombosis

Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined.. Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model.. The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT.. The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.

Topics: Administration, Cutaneous; Administration, Oral; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Biological Availability; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Glycine; Humans; Metabolic Clearance Rate; Partial Thromboplastin Time; Postoperative Complications; Sweden; Thromboembolism; Venous Thrombosis; Whole Blood Coagulation Time

This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low-molecular-weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24- and 36-mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Azetidines; Benzylamines; Dalteparin; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Leg; Male; Middle Aged; Phlebography; Prodrugs; Radionuclide Imaging; Treatment Outcome; Venous Thrombosis; Warfarin

Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR.. This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis.. Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen.. Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Azetidines; Benzylamines; Double-Blind Method; Enoxaparin; Female; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Prodrugs; Random Allocation; Thrombin; Thromboembolism; Venous Thrombosis; Wound Healing

In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of ximelagatran is superior to warfarin.. This randomized, double-blind trial compared a regimen of 7 to 12 days of oral ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. The composite end point of venous thromboembolism and death from all causes and the incidence of bleeding were the primary outcome measures.. Among the 1851 patients in the efficacy analysis, oral ximelagatran at a dose of 36 mg twice daily was superior to warfarin with respect to the primary composite end point of venous thromboembolism and death from all causes (20.3 percent vs. 27.6 percent; P=0.003). There were no significant differences between these two groups with respect to major bleeding (incidence, 0.8 percent and 0.7 percent, respectively), perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death (2.7 percent vs. 4.1 percent; P=0.17).. The efficacy of oral ximelagatran, administered starting the morning after total knee replacement, was superior to that of warfarin for prevention of venous thromboembolism. Rates of hemorrhagic complications with the two drugs were similar.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Middle Aged; Prodrugs; Pulmonary Embolism; Thromboembolism; Treatment Outcome; Venous Thrombosis; Warfarin

For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding.. In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed.. Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001).. Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Prodrugs; Pulmonary Embolism; Risk; Secondary Prevention; Thrombin; Thromboembolism; Venous Thrombosis

Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease.. In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8-11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding.. The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin.. In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Enoxaparin; Female; Glycine; Hemorrhage; Humans; Male; Middle Aged; Preoperative Care; Therapeutic Equivalency; Thrombin; Thromboembolism; Venous Thrombosis

Warfarin is used for prophylaxis of venous thromboembolism in patients undergoing total knee arthroplasty. However, it is associated with rates of deep venous thrombosis (DVT) of approximately 38% to 55% and requires routine coagulation monitoring and frequent dose adjustment. Ximelagatran, an oral direct thrombin inhibitor, has shown promising efficacy and tolerability in patients undergoing total hip or knee arthroplasty.. To compare the efficacy and safety of ximelagatran and warfarin for prophylaxis of venous thromboembolism after total knee arthroplasty.. Randomized, double-blind, parallel-group trial.. 74 North American hospitals.. 680 patients who had undergone total knee arthroplasty.. 7 to 12 days of treatment with oral ximelagatran, 24 mg twice daily, starting on the morning after surgery, or warfarin (target international normalized ratio, 2.5 [range, 1.8 to 3.0]), starting on the evening of the day of surgery.. Principal end points were asymptomatic DVT on mandatory venography; symptomatic DVT confirmed by ultrasonography or venography; symptomatic, objectively proven pulmonary embolism; and bleeding. All were assessed by blinded adjudication locally and at a central study laboratory.. On central adjudication, incidence of venous thromboembolism was 19.2% (53 of 276 patients) in the ximelagatran group and 25.7% (67 of 261 patients) in the warfarin group (difference, -6.5 percentage points [95% CI, -13.5 to 0.6 percentage points]; P = 0.070). On local assessment, incidence was 25.4% in the ximelagatran group and 33.5% in the warfarin group (P = 0.043). In the ximelagatran and warfarin groups, respectively, major bleeding occurred in 1.7% and 0.9% of patients and minor bleeding occurred in 7.8% and 6.4% of patients. No variables related to bleeding differed significantly between the two groups.. For prophylaxis of venous thromboembolism, fixed-dose ximelagatran started the morning after total knee arthroplasty is well tolerated and at least as effective as warfarin, but it does not require coagulation monitoring or dose adjustment.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Female; Hemorrhage; Humans; Male; Phlebography; Thrombin; Venous Thrombosis; Warfarin

Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE).. In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6-9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded.. Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6-9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment.. Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.

Topics: Administration, Oral; Adult; Aged; Azetidines; Benzylamines; Female; Fibrinolytic Agents; Glycine; Humans; Male; Middle Aged; Partial Thromboplastin Time; Pharmacokinetics; Prodrugs; Pulmonary Embolism; Thrombin; Treatment Outcome; Venous Thrombosis

Venous thromboembolic diseases are treated initially with low molecular weight heparin followed by oral coumarins.. To investigate an orally available direct thrombin inhibitor for the acute treatment of venous thromboembolism as well as for prophylaxis of recurrent events.. The direct thrombin inhibitor ximelagatran was compared with subcutaneous LMW heparins followed by oral warfarin in a double-blind randomized prospective multicenter trial in patients with acute VTE. A pharmacokinetic study was performed in the VTE patients. For assessing the prevention of recurrent VTE, double-blind prospective randomized studies were conducted as follows: a) ximelagatran compared to warfarin for 6 months, and b) prolonged anticoagulation of ximelagatran vs. placebo for 18 months after termination of 6 months coumarin therapy.. Two dose-finding studies and the pharmacokinetic analysis of ximelagatran in acute VTE were completed. About 2,500 patients were randomized to investigate 2 x 36 mg ximelagatran versus 2 x 1 mg/kg body weight enoxaparin followed by warfarin. The study hypothesized that the efficacy was equal in both treatment regimens for recurrent VTE documented by objective methods. The second study, with 1,234 patients, aimed to demonstrate a reduced incidence of recurrent thromboembolic events documented by objective methods after 18 months of treatment with 2 x 24 mg ximelagatran daily compared to placebo.. These large-scale clinical trials will soon yield the results of the comparison between oral ximelagatran and subcutaneous LMW heparin for treatment of acute VTE, and of warfarin for prophylaxis of recurrent events for 6 months and for a prolonged prophylaxis for another 18 months.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Drug Administration Schedule; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Venous Thrombosis; Warfarin

The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (s.c.). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received s.c. melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU s.c. once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received s.c. melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the s.c. melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.

Topics: Administration, Oral; Adolescent; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dalteparin; Female; Glycine; Humans; Incidence; Injections, Subcutaneous; Male; Middle Aged; Partial Thromboplastin Time; Postoperative Complications; Prodrugs; Safety; Sweden; Thrombin; Thromboembolism; Treatment Outcome; Venous Thrombosis

Patients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

Topics: Activated Protein C Resistance; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dalteparin; DNA Mutational Analysis; Double-Blind Method; Europe; Factor V; Female; Genetic Predisposition to Disease; Genotype; Glycine; Humans; Male; Middle Aged; Postoperative Complications; Promoter Regions, Genetic; Prospective Studies; Prothrombin; Pulmonary Embolism; Risk Factors; Thrombophilia; Venous Thrombosis

Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin.. We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding.. A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily.. Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Drug Administration Schedule; Enoxaparin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Postoperative Complications; Prodrugs; Pulmonary Embolism; Thrombin; Treatment Outcome; Venous Thrombosis

Thrombin amplifies the blood coagulation via factor V (FV)-mediated positive feedback loop. We hypothesised that factor Xa (FXa) inhibitors would interfere more gradually with this feedback activation loop than thrombin inhibitors, thereby achieving a better balance between haemostasis and prevention of thrombosis. In this study, we compared the effects of TAK-442, a novel FXa inhibitor, versus ximelagatran, a thrombin inhibitor, on FV-mediated positive feedback, venous thrombosis and bleeding. In normal plasma, TAK-442 delayed the onset of tissue factor-induced thrombin generation and prolonged prothrombin time (PT) with more gradual concentration-response curve than melagatran, the active form of ximelagatran. The effect of melagatran on the onset of thrombin generation decreased in an FVa-concentration-dependent manner in FV-deficient plasma supplemented with FVa. Furthermore, in FV-deficient plasma, the PT-prolonging potency of melagatran was markedly increased with a change in its concentration-response curve from steep to gradual. In the rat venous thrombosis model, TAK-442 (10 mg/kg, p.o.) prevented thrombus formation by 55% with 1.2 times prolongation of PT; a similar effect was observed in ximelagatran-treated (3 mg/kg, p.o.) rats. TAK-442 at 100 mg/kg prolonged PT by only 2.1 times with no change in bleeding time (BT), whereas ximelagatran at 10 mg/kg prolonged PT by 3.9 times and significantly increased BT. These results suggest that the differential effects of the two agents on FV-mediated amplification of thrombin generation may underlie the observation of a wider therapeutic window for TAK-442 than for ximelagatran.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Blood Coagulation; Disease Models, Animal; Dose-Response Relationship, Drug; Factor V; Factor Xa; Factor Xa Inhibitors; Feedback, Physiological; Hemorrhage; Humans; Male; Phospholipids; Prothrombin Time; Pyrimidinones; Rats; Rats, Sprague-Dawley; Risk Assessment; Sulfones; Thrombin; Thromboplastin; Venous Thrombosis

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

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dabigatran; Drug Delivery Systems; Drug Design; Enoxaparin; Factor Xa Inhibitors; Humans; Morpholines; Postoperative Hemorrhage; Pyridines; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Orthopedic Procedures; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Orthopedic Procedures; Thromboembolism; Venous Thrombosis

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Humans; Pulmonary Embolism; Treatment Failure; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Artery Disease; Humans; Prodrugs; Risk; Stroke; Venous Thrombosis

To determine the excretion of the oral direct thrombin inhibitor (oral DTI), ximelagatran, and its active form, melagatran, in human milk, and to thus evaluate the potential exposure of breastfed infants to melagatran.. An open, single dose, single centre study.. Department of Antenatal Care, Primary Health Care South Bohuslän and Institute for the Health of Women and Children, Göteborg University, Sweden.. Seven healthy Caucasian breastfeeding women who were at least two months postpartum were studied.. The concentrations of ximelagatran, its two intermediates, and melagatran were determined using liquid chromatography-mass spectrometry, with the limit of quantification of 2 nmol L(-1) for human milk and 10 nmol L(-1) for plasma concentrations.. Concentrations of ximelagatran, its intermediates and melagatran were measured in breast milk over 72 hours, and in plasma over 12 hours, after a single oral 36 mg dose of ximelagatran.. Neither ximelagatran nor its intermediates were detected in human breast milk. Only trace amounts of melagatran were detected. The mean cumulative amount of melagatran excreted into breast milk over the 72-hour period after dosing with oral ximelagatran was 0.00091% of the administered dose of ximelagatran. Ximelagatran was well tolerated, with no clinically relevant changes in laboratory variables or vital signs.. Trace levels of melagatran are excreted in human breast milk following administration of the oral DTI ximelagatran. The exposure of breastfed infants to melagatran appears to be low and is therefore unlikely to be of clinical concern.

Topics: Administration, Oral; Adult; Anticoagulants; Azetidines; Benzylamines; Breast Feeding; Female; Glycine; Humans; Lactation; Milk, Human; Postpartum Period; Puerperal Disorders; Thrombin; Thromboembolism; Venous Thrombosis

The antithrombotic and bleeding properties of the oral direct thrombin inhibitor ximelagatran and of warfarin were investigated in an experimental venous thrombosis and bleeding model in anaesthetized rats. Rats were randomized to receive ximelagatran (1-20 micromol/kg), warfarin (0.20-0.82 micromol/kg), or vehicle (tap water) once daily orally for 4 days before surgery. Thrombosis was induced by partial stenosis and application of ferric chloride to the wall of the abdominal vena cava under anaesthesia. Sixty minutes after thrombus induction, rats were sacrificed, thrombi harvested, and their fresh weight determined. Bleeding was determined as haemoglobin in fluid collected from the abdominal cavity. Blood samples were taken before thrombus induction and sacrifice for determination of coagulation parameters and plasma concentrations of melagatran, the active form of ximelagatran. Ximelagatran and warfarin dose-dependently reduced thrombus formation. The highest doses of ximelagatran and warfarin almost completely prevented thrombus formation; however, the increase in bleeding (versus vehicle) was significantly lower with the highest dose of ximelagatran than with the highest dose of warfarin. The oral direct thrombin inhibitor ximelagatran is thus as at least as effective as warfarin in the prevention of thrombus formation in this animal model, but with a wider separation between antithrombotic effects and bleeding.

Topics: Animals; Azetidines; Benzylamines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glycine; Hemorrhage; Male; Rats; Rats, Sprague-Dawley; Venae Cavae; Venous Thrombosis; 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; Clinical Trials as Topic; Dissent and Disputes; Enoxaparin; Glycine; Humans; Orthopedic Procedures; Therapeutic Equivalency; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Advisory Committees; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Embolism; Humans; Randomized Controlled Trials as Topic; Stroke; United States; United States Food and Drug Administration; Venous Thrombosis

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Consensus Development Conferences as Topic; Humans; Venous Thrombosis

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

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

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Fondaparinux; Humans; Orthopedic Procedures; Polysaccharides; Venous Thrombosis

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Female; Hemorrhage; Humans; Male; Thrombin; Venous Thrombosis; Warfarin

Topics: Animals; Azetidines; Benzylamines; Humans; Prodrugs; Rats; Thromboembolism; Venous Thrombosis