ximelagatran and Thromboembolism

This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date.. We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed.. A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban.. Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Hemorrhage; Humans; Myocardial Infarction; Odds Ratio; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

The standard effective treatment of venous and arterial thromboembolism includes unfractionated and low-molecular weight heparin as well as warfarin, which have major disadvantages. In recent years, new anticoagulants have been developed in an attempt to overcome the known limitations of established treatment and develop improved therapies. This chapter reviews pharmacological properties of the new anticoagulants, the most recent trials assessing their safety and efficacy as well as potential advantages and disadvantages of using these novel drugs in real life.

Topics: Anticoagulants; Antithrombins; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Thromboembolism; Warfarin

The most frequent cardiac arrhythmia and main cause for cardio-embolic stroke is atrial fibrillation. Prophylaxis for thrombembolic events is performed regarding individual risk of patients with either ASS or vitamin-K-antagonists. Efficacy and safety of oral anticoagulation is limited by a narrow therapeutical range as well as by inter- and intraindividual variability of INR-values due to genetic disposition, differences in alimentation, dosage errors, rare control of INR-levels and drug-interactions. New oral anticoagulants with different mechanisms of action may be a promising therapeutic option in future. This review addresses the new anticoagulants Apixaban, Rivaroxban and Dabigatranetexilat with the design and as available the results of the corresponding phase-III-trials in atrial fibrillation (ARISTOTLE, ROCKET-AF, RE-LY).

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

As the population ages, the burden of thromboembolic disease increases. The development of new anticoagulants that overcome the shortcomings of the vitamin K antagonists represents an important advance.Clinical evaluation of new anticoagulants typically begins in short-term indications, such as prophylaxis against venous thromboembolism in patients undergoing orthopaedic surgery, followed by investigation in chronic conditions, such as stroke prevention in patients with atrial fibrillation. Factors for consideration in clinical trials include methodological issues (blinded versus open-label; active-control statistical designs; patient selection, etc.). Despite its subsequent withdrawal, clinical trials of ximelagatran demonstrated the efficacy of fixed doses of an oral, direct thrombin inhibitor for prevention of thromboembolism. Direct and indirect inhibition of activated Factor X is another target for new anticoagulants. Evidence-based data from trials such as these will pave the way for new anticoagulants, with the goal of bringing optimum prophylactic therapy to those requiring anticoagulation.

Topics: Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Drugs, Investigational; Humans; Oligosaccharides; Pyridines; Thromboembolism; United States

Nonvalvular atrial fibrillation is the most common cardiac arrhythmia associated with a substantial risk of thromboembolism and stroke. Despite numerous disadvantages that limit its efficacy and safety, warfarin is widely used in the prevention and treatment of thromboembolism related with atrial fibrillation. Ximelagatran, an oral direct thrombin inhibitor has the potential to be an alternative choice in the prevention and therapy of thromboembolism related with atrial fibrillation. Studies compared ximelagatran with warfarin in nonvalvular atrial fibrillation at risk for stroke showed that fixed dose oral ximelagatran is effective as adjusted dose warfarin in stroke prevention. Ximelagatran has numerous advantages over warfarin in clinical practice. Although it seems as a promising option for the prevention and therapy of thromboembolism, its safety and efficacy need to be determined definitely by further clinical trials.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Stroke; Thromboembolism; Warfarin

Topics: Abciximab; Antibodies, Monoclonal; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Immunoglobulin Fab Fragments; Odds Ratio; Platelet Aggregation Inhibitors; Stroke; Thromboembolism; Thrombolytic Therapy

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

Ximelagatran is a new oral anticoagulant that acts by direct and reversible inhibition of thrombin and has the potential to replace warfarin. In 2004, the FDA Cardiovascular and Renal drug Advisory Committee (CRAC) reviewed the ximelagatran clinical program. Three indications were proposed: the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement surgery (TKR), the prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF), and the long-term secondary prevention of VTE after standard treatment of an episode of acute VTE. The database consisted of a total of 30,698 subjects and included five phase III pivotal studies. During the advisory panel debate, widely divergent analyses of the benefits and risks of ximelagatran were presented. Ximelagatran hepatic toxicity was a key feature leading the CRAC to conclude that the benefit risk ratio of ximelagtran was unfavorable for the three proposed indications. Some design issues also undermined the strength of efficacy data. This paper reviews the benefits and risks of ximelagatran and analyzes the reasons leading to conflicting conclusions among various experts. The aim of this review is to facilitate the interpretation of benefits and risks associated with a new drug product and to improve future clinical drug developments.

Topics: Advisory Committees; Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Humans; Liver; Risk Assessment; Thromboembolism; United States; United States Food and Drug Administration; Warfarin

Old burdens and new perspectives of the long-term anticoagulant therapy. Long-term anticoagulant therapy (LAT) has increasingly improved the prognosis in various diseases thus becoming an indispensable tool in our day-to-day therapeutic arsenal. However its use is influenced by various uncertainty factors. The optimal range of anticoagulation can unfortunately only be partially achieved due to the several factors influencing it. Thromboembolic and bleeding episodes occur mainly at times when the state of anticoagulation diverges from the ideally set therapeutic range. Quality of the ongoing therapy can only partially be improved by increasing the frequency of the controls. This however is also inherent partly in the treatment indication and also in the personality of the given patient (compliance). Heparin preparations are rarely used for long-term anticoagulant therapy due to the inevitable injectable form of administration. The more easily applicable LMWH-s' actions are also influenced by several uncertainty factors. In cases of idiopathic deep vein thrombosis, extension of the LAT therapy could be beneficial and is recommended beyond 6 months in order to prevent recurrence of the acute event and postthrombotic syndrome, irrespective of the proof of the genetic predisposition. Several clinical observations suggest that LAT could hinder propagation of malignant tumors and this presumption has already been supported by experimental data. The favourable effect has primarily been associated with and experienced with the use of LMWH-s. Prolonged LAT may even change the perspectives of thrombolytic therapy in venous thrombosis, improving its late efficacy. A new and simply applicable anticoagulant may help further spreading of LAT.

Topics: Anticoagulants; Azetidines; Benzylamines; Coumarins; Drug Administration Schedule; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Patient Compliance; Thromboembolism; Thrombolytic Therapy; Thrombosis

The coagulation cascade, and particularly thrombin, plays a very important role in arterial and venous thrombosis. Thereby, it is clear that thrombin inactivation is an optimal strategy for thrombotic disease prevention and treatment. The direct thrombin inhibitors are a new class of anticoagulant drugs directly binding thrombin and blocking its interaction with fibrinogen. The group of direct thrombin inhibitors includes recombinant hirudin (lepirudin and desirudin), bivalirudin, melagatran and its oral precursor, ximelagatran, argotraban and dabigatran. These drugs have several advantages compared to other anticoagulant drugs, and the particular pharmacokinetic properties of some of them could be very important for future management of thromboembolic prophylaxis. The efficacy and safety of these new drugs are evaluated in several clinical trials; however today only few clinical indications are available for the majority of them.

Topics: Anticoagulants; Antithrombins; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Therapy, Combination; Fibrinolytic Agents; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thromboembolism; Treatment Outcome

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

Chronic, nonvalvular atrial fibrillation occurs more frequently with increasing age, together with an increasing risk for ischemic stroke. Guidelines recommend oral anticoagulation with a vitamin K antagonist for patients >65 years without risk factors and patients <65 years with risk factors for cardiac diseases. Advancing age also increases the risk for bleeding complications under oral anticoagulants; thus, only a part of these patients receives anticoagulant therapy. The risk of falls in elderly patients is of advancing relevance for this therapeutic decision. Oral direct thrombin inhibitors like ximelagatran may be an alternative choice for therapy. Ischemic strokes and systemic embolism in the same frequency with 2x36 mg ximelagatran over 18 months (91/3664 patients: 1.6%/year, for study Sportif III and Sportif V) compared with warfarin (93/3665 patients: 1.6%/year for study Sportif III and Sportif V). All bleeding complications occurred less frequently under therapy with ximelagatran. This could be of importance for elderly patients with risk factors for bleeding or risk of falling.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cerebral Infarction; Clinical Trials as Topic; Hemorrhage; Humans; Risk Factors; Thromboembolism; Vitamin K; Warfarin

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

In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran.. The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]).. An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran.. Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Anticoagulants; Azetidines; Benzylamines; Female; Humans; Liver; Male; Middle Aged; Randomized Controlled Trials as Topic; Thromboembolism

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

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

Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4-12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelagatran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4-8 h) rather than later (8-12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Orthopedic Procedures; Premedication; Thromboembolism; Treatment Outcome

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; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Fibrinolytic Agents; Glycine; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Orthopedics; Random Allocation; Regression Analysis; Risk; Risk Factors; Thrombin; Thromboembolism

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

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

Antithrombotic agents have verified efficacy in reducing the thromboembolic risk associated with atrial fibrillation. This article focuses on the emergence of a new oral direct thrombin inhibitor, ximelagatran, into the arena of atrial fibrillation thromboprophylaxis. This review does not cover atrial fibrillation in the context of valvular heart disease. The efficacy of aspirin and warfarin will be discussed briefly.

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Humans; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thrombin; Thromboembolism; Warfarin

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

Chronic anticoagulation represents a clinical conundrum for the health care community that balances unquestionable morbidity and mortality benefits against interindividual variability, leading to drug interactions, adverse events, and thromoembolic events related to underdosing. Despite the growing data regarding the appropriate use and dosing of agents used for chronic anticoagulation, use in clinical practice remains low, thus leading to a theoretical reduction in the risk-to-benefit ratio in the clinical setting relative to that reported in the literature. Oral anticoagulants currently in development represent a heterogeneous group of compounds that are specific for the final common pathway in the coagulation cascade and show indications toward a reduced drug interaction profile, reduced interpatient variation in pharmacokinetic parameters, and morbidity and mortality benefits that might be similar to currently available treatment modalities. This review highlights the critical differences among oral anticoagulants in development and places their role in the context of the benefits and limitations of currently available anticoagulants.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Liver; Randomized Controlled Trials as Topic; Thrombin; Thromboembolism; 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

Thrombin plays a central role in thrombus formation through its conversion of fibrinogen to fibrin and activation of platelets as well as amplifying its own generation by feedback activation via factors V, VIII, and XI. Consequently, thrombin represents a logical and promising target for therapeutic interventions against arterial and venous thromboembolic disorders. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and is rapidly absorbed and bioconverted to the active moiety, melagatran, which inhibits fluid-phase and clot-bound thrombin with similar high potency. Binding to the active site of thrombin is direct and competitive and does not require the presence of co-factors. Inhibition of thrombin generation and platelet activation has been demonstrated in vitro with melagatran as well as ex vivo after oral administration of ximelagatran to healthy human volunteers. Oral ximelagatran dose dependently reduced the total thrombus area in an ex vivo flow chamber model of arterial thrombosis, reflecting the cumulative effect of inhibition of thrombin activity, thrombin generation, and platelet activation. Melagatran has also been shown to reduce thrombin-mediated inflammation in vitro. The combination of antithrombotic and anti-inflammatory activity with the practicality of oral dosing provided by ximelagatran represents an important new option for the treatment of arterial and venous thromboembolic disorders.

Topics: Administration, Oral; Anti-Inflammatory Agents; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Humans; Inflammation; Platelet Activation; Thrombin; Thromboembolism; 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

Ximelagatran has been approved in Europe for VTE prophylaxis in orthopedic surgery at fixed doses and without laboratory monitoring. Aim of the study was to evaluate safety and efficacy of ximelagatran in a meta-analysis of prophylaxis and/or treatment randomized controlled trials.. Absolute risk of events for ximelagatran and OR for its comparison with LMWH and coumarins were calculated. Subgroup analysis was performed for ximelagatran regimen, comparator agent, type of surgery, starting time of prophylaxis.. Twelve studies and 16,992 patients were meta-analysed. Ximelagatran showed an absolute risk of major VTE of 4.04% and 1.69% and of major bleedings of 1.68% and 1.03% in prophylaxis and treatment trials, respectively. In prophylaxis trials, a significant excess mortality (OR: 2.5; 95% CI: 1.02 - 6.13) and an excess in major bleedings (OR: 1.41; 95% CI: 0.93 - 2.14) was found in the whole ximelagatran group. No evidence of treatment effect for major VTE was seen in the comparison with LMWH (OR: 1.01; 95% CI: 0.52 - 1.97). The cohort of patients treated with 24 mg b.i.d. showed similar results. An increase in the absolute risk of bleeding (from 1.04% to 3.03%) was found between post and preoperative administration of ximelagatran. Major VTE risk was increased when ximelagatran was compared to b.i.d. LMWH.. Ximelagatran can be considered for its potential advantages for prevention and treatment of VTE. Future efforts are needed by researchers to prospectively investigate the best postoperatively starting time and by clinicians to monitor overall mortality in prophylactic use.

Topics: Anticoagulants; Azetidines; Benzylamines; Endpoint Determination; Humans; MEDLINE; Postoperative Hemorrhage; Prodrugs; Quality Control; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome

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

Topics: Administration, Oral; Animals; Anticoagulants; Azetidines; Benzylamines; Humans; Safety; Thrombin; Thromboembolism

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

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.

Topics: Administration, Oral; Animals; Antithrombins; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Thromboembolism

The oral direct thrombin inhibitor ximelagatran (Exanta, AstraZeneca) is rapidly absorbed, is efficiently bioconverted to the active form, melagatran (AstraZeneca) and has shown efficacy and relative safety as an anticoagulant for prophylaxis and therapy of thromboembolism. Two Phase III trials, Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF V), have tested the hypothesis that oral ximelagatran, administered 36 mg twice daily without coagulation monitoring or dose adjustment, prevents stroke and systemic embolism at least as effectively as adjusted-dose warfarin (international normalized ratio, 2.0-3.0) in patients with nonvalvular atrial fibrillation. Both were randomized, multicenter trials (n > 3000 per trial) with blinded end-point assessment. The open-label SPORTIF III trial confirmed the noninferiority of ximelagatran versus warfarin. Publication of the full results from SPORTIF V is pending.

Topics: Administration, Oral; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Fibrinolytic Agents; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Therapeutic Equivalency; Thromboembolism; Warfarin

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

The ideal anticoagulant agent would have a fixed oral dose without need for dose adjustment, a wider therapeutic window than that of warfarin, and acceptable bleeding risks without the need for routine coagulation monitoring. Ximelagatran is a new oral agent that, when converted to its active form, melagatran, directly inhibits thrombin, thus blocking its activity and modulating several of its key functions. For the prevention of venous thromboembolism after orthopedic surgery, treatment of venous thromboembolism, and prevention of stroke in patients with atrial fibrillation, clinical trials indicate that ximelagatran meets the criteria for a superior anticoagulant.

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

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

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

Non-rheumatic atrial fibrillation (NRAF) is one among the major public health problems, because it is associated with a high incidence of stroke or systemic thromboembolism. Warfarin significantly reduces cerebral/systemic events mainly in high-risk patients; unfortunately such drug is often as well under-used in eligible patients as under-dosed in treated patients. Traditional therapy with oral anticoagulants has several disadvatages: narrow therapeutic window, and often unpredictable dose-response so that frequent monitoring of the INR is required. It is therefore crucial that patients preferences and education be integrated into the decision-making process. Physicians often underprescribe oral anticoagulants since they perceive the risk of major bleeding as unacceptable because of some well known risk factors (e.g. previous bleedings, severe hypertension), and of qualms about drug interactions or alleged poor compliance. Therefore, the development of easy-to-use antithrombotic agents is still a challenge. New agents such as oral direct thrombin inhibitors are going to hold the promise for the next future. Ximelagatran is an orally active small molecule; being the first new oral anticoagulant used in large clinical trials. This molecule has many advantages in comparison to warfarin, such as the rapid onset/offset of action, the fixed oral dose, the no need of dose adjustment or of anticoagulation monitoring, as well the lack of food/alcohol intake interference as of drug interactions. The SPORTIF III and V trials have shown that ximelagatran is not inferior to warfarin in the prevention of strokes in patients with NRAF (both persistent and paroxysmal), but a side effect--consisting in the significant elevation of liver enzymes (> 3 times the upper limit of normal) in 6% of patients--was found. Further randomized trials are clearly needed, while current data suggest that ximelagatran will be able to represent a future viable therapeutic option for prevention of thromboembolism in patients with NRAF, offering huge advantages with respect to classic oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Combinations; Humans; Patient Education as Topic; Patient Satisfaction; Stroke; Thromboembolism; Treatment Outcome; Warfarin

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

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

The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (MElagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Humans; Orthopedic Procedures; Thromboembolism; Thrombosis; Treatment Outcome

There are many well-known drawbacks associated with the currently used antithrombotic agents, warfarin, heparin, and low-molecular-weight heparins (LMWHs). Because heparins can be administered only parenterally, their application is limited. Though warfarin can be administered orally, its unpredictable anticoagulant effect means that it must be regularly monitored. Ximelagatran (Exanta, AstraZeneca) is a novel, oral direct thrombin inhibitor (oral DTI) that is rapidly converted to its active form, melagatran, upon administration. The antithrombotic effects of melagatran have been demonstrated. Following the oral administration of ximelagatran, melagatran has stable and reproducible pharmacokinetic and pharmacodynamic properties that enable ximelagatran to be administered orally, twice daily, according to a fixed-dose regimen, with no need for routine coagulation monitoring. In view of its favourable profile, a clinical trial programme has been designed to evaluate the efficacy and tolerability of ximelagatran compared with standard therapies, for the prophylaxis and treatment of venous thromboembolism (VTE), the prevention of stroke in patients with atrial fibrillation (AF), and the prevention of cardiovascular events in patients with previous acute coronary syndromes. These studies show that oral ximelagatran is well tolerated at doses of up to 60 mg, twice daily (bid), and that it is as effective as standard therapy for the prevention of thromboembolic events in patients undergoing hip or knee replacement surgery, for the treatment of clinically verified acute deep vein thrombosis (DVT), and in patients with nonvalvular AF who have a moderate to high risk of stroke. The protocols and results of some of these studies--and a study that investigates the use of ximelagatran in combination with aspirin for the management of acute coronary artery disease--are described in this paper.

Topics: Azetidines; Benzylamines; Cardiovascular Diseases; Clinical Protocols; Clinical Trials as Topic; Glycine; Humans; Thromboembolism

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

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

By the use of conventional anticoagulants, significant improvements were achieved in all fields of medicine. Although efficacious and widely used, their use is limited in several respects. In particular, the use of vitamin K antagonists is restricted in the clinical routine setting. The main reasons are the delayed on- and off-set of action, the narrow therapeutic window, the necessity of individual laboratory-controlled dosing, and interactions with food ingredients and drugs. The search for new antithrombotics with an improved safety/efficacy profile led to the development of the direct oral thrombin-inhibitor ximelagatran. It can be administered without routine monitoring of coagulation parameters and does not possess any of the previously mentioned limitations. The results from clinical phase II studies obtained so far are very encouraging. After completion of the clinical development program focussing on prevention and treatment of venous thromboembolism, on stroke prevention in atrial fibrillation and on acute coronary syndromes, it is desirable to continue with investigations with regard to long-term prophylaxis in high risk surgery, in chronic peripheral artery disease, in patients with left ventricular thrombi, artificial heart valves, or thrombophilia, as an alternative anticoagulant in heparin induced thrombocytopenia and for prevention of thromboembolic complications in oncology. Because of the mitogenic effects of thrombin on the proliferation of tumour cells, additional experimental studies aiming at a potential inhibition of thrombin-triggered oncogenesis is of uttermost interest.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Humans; Prodrugs; Safety; Stroke; Thromboembolism

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

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

In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this.. In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated.. At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)).. The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cardiotonic Agents; Digitalis; Digitalis Glycosides; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Phytotherapy; Plant Preparations; Stroke; Thromboembolism; Warfarin

To test the hypothesis that stroke and systemic embolic events (SEE) in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V trials were related to blood pressure, and that differences in event rates (stroke and SEE, bleeding) could also be related to the degree of hypertension.. A cross-sectional, longitudinal analysis was conducted, using data from the SPORTIF III and V trials. Results showed an increasing rate of stroke and SEE with increasing quartiles of systolic blood pressure (SBP) in AF patients. For the top quartile of SBP compared with the lowest quartile, the hazard ratio (HR) for stroke and SEE was 1.83 (95% confidence intervals [CI]: 1.22-2.74), whereas mortality was lower in the top quartile (HR 0.64; 95% CI: 0.49-0.83). In the combined SPORTIF III and V cohort, the event rate for stroke/SEE increased markedly at mean SBP of > 140 mmHg. There was no relationship between bleeding and quartiles of BP. The proportion of subjects with mean systolic BP > or = 140 mmHg was 35.8% (1220/3407) in SPORTIF III and 20.6% (807/3922) in SPORTIF V (P < 0.0001).. Hypertension contributes to increased stroke and SEE in AF. Event rates markedly increase at SBP levels of > or = 140 mmHg. The higher stroke rates observed in SPORTIF III compared with SPORTIF V may be related to the greater proportion of subjects with SBP > or = 140 mmHg during the trial.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cross-Sectional Studies; Double-Blind Method; Female; Hemorrhage; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Risk Factors; Stroke; Thromboembolism; Warfarin

The risk of stroke is greater among women with atrial fibrillation (AF) than men. Warfarin protects against stroke, but treatment-related bleeding occurs more often in women than in men.. SPORTIF III (open label, n=3410) and V (double-blind, n=3922) included 2257 women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0-3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischaemic/haemorrhagic) and systemic embolic event. Women were older, on average, than men, 73.4+/-8.0 vs. 69.8+/-9.0 years (P<0.0001). More women were >75-years old and women had more risk factors than men had (P<0.0001). The INR on warfarin (mean 2.5+/-0.7) was within target range for 67% of follow-up regardless of gender. Women more often developed primary events [2.08%/year, 95% confidence interval (CI) 1.60-2.56%/year vs. 1.44%/year, 95% CI 1.18-1.71%/year in men; P=0.016). Major bleeding rates were similar (P=0.766) but women experienced more overall (major/minor) bleeding (P<0.001). Warfarin was associated with more overall bleeding in both genders and more major bleeding in women than in men (P=0.001).. When compared with men with AF, women in these studies were older and had more stroke risk factors. Women were more prone to anticoagulant-related bleeding; the higher rate of thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Double-Blind Method; Estrogen Replacement Therapy; Female; Hemorrhage; Humans; Male; Risk Factors; Sex Characteristics; Sex Factors; Stroke; Thromboembolism; 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

The oral direct thrombin inhibitor (oral DTI) ximelagatran (Exanta, AstraZeneca) is rapidly absorbed and bioconverted to its active form melagatran, which also can be administered subcutaneously (s.c.). Two large-scale clinical trials (MElagatran for THRombin inhibition in Orthopaedic surgery [METHRO] II and III) have evaluated the safety and efficacy of s.c. melagatran followed by oral ximelagatran compared with low-molecular-weight heparins (LMWH) for thromboprophylaxis following total hip (THR) and total knee replacement (TKR) surgery. In METHRO II, patients received either 5000 IU s.c. dalteparin once daily (od) or a combination of one of four doses (from 1 to 3 mg) of s.c. melagatran twice daily (bid) started immediately before surgery, followed by one of four doses (from 8 to 24 mg) of oral ximelagatran bid started 1-3 days after surgery. In METHRO III, patients were randomized to receive either 40 mg s.c. enoxaparin od or 3 mg s.c. melagatran bid started 4-12 h after surgery followed by 24 mg oral ximelagatran. In METHRO II, there was a highly significant dose-response relationship for s.c. melagatran plus oral ximelagatran, with the highest dose combination superior to dalteparin in the prevention of venous thromboembolism (VTE). In METHRO III, a dosing regimen in which s.c. melagatran was started postoperatively and followed by oral ximelagatran was not more effective than enoxaparin started preoperatively. Thus, the time interval between surgery and the first dose of anticoagulant may be important in ensuring optimal efficacy. The METHRO II and III studies demonstrate that s.c. melagatran combined with oral ximelagatran are well tolerated and effective for the prevention of VTE following major orthopaedic surgery.

Topics: Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Humans; Orthopedic Procedures; Thromboembolism; Thrombosis; Treatment Outcome

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

Ximelagatran is a novel, oral direct thrombin inhibitor under investigation as an alternative to warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation (AF). Two long-term studies in patients with AF and at least one additional risk factor for stroke are underway to compare the safety and efficacy of fixed-dose ximelagatran (36 mg bid) without coagulation monitoring with dose-adjusted warfarin (international normalized ratio 2.0-3.0).. SPORTIF III is a randomized, open-label, parallel-group study with blinded event assessment involving 3407 patients at 259 sites in 23 countries. SPORTIF V is similar, but with double-blind treatment allocation involving 3922 patients at 409 North American sites. The primary end point in each study is the incidence of all strokes and systemic embolic events, and the objective is to establish the noninferiority of ximelagatran relative to warfarin. Secondary end point constellations include (1) death, stroke, systemic embolism, and myocardial infarction; (2) ischemic stroke, transient ischemic attack, and systemic embolism; and (3) bleeding and treatment discontinuation. Blinded central committees adjudicate all end points and monitor patient safety. The studies commenced July 2000; enrollment ended in December 2001. Each study will accrue > or =4000 patient-years and > or =80 primary end points with a minimum per-patient exposure of 12 months. Combined analysis of both studies is also planned.. The demographics of the 2 patient populations are similar and should allow the studies to meet the objective.. The program, the largest conducted in this indication, will determine the safety and antithrombotic efficacy of ximelagatran as an alternative to warfarin for prevention of thromboembolism in patients with AF.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Prodrugs; Thromboembolism; 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

Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but dose adjustment, coagulation monitoring, and bleeding risk limit its use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative. We aimed to establish whether ximelagatran is non-inferior to warfarin, within a margin of 2% per year, for prevention of stroke and systemic embolism.. We randomised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin (adjusted-dose, international normalised ratio [INR] 2.0-3.0) or ximelagatran (fixed-dose, 36 mg twice daily); patients were recruited from 259 hospitals, doctor's offices, or health-care clinics. Primary analysis was based on masked event assessment and was by intention to treat. Primary endpoint was stroke or systemic embolism.. During 4941 patient-years of exposure (mean 17.4 months, SD 4.1), 96 patients had primary events (56 in the warfarin group vs 40 in the ximelagatran group). The primary event rate by intention to treat was 2.3% per year with warfarin and 1.6% per year with ximelagatran (absolute risk reduction 0.7% [95% CI -0.1 to 1.4], p=0.10; relative risk reduction 29% [95% CI -6.5 to 52]). Rates of disabling or fatal stroke, mortality, and major bleeding were similar between groups, but combined minor and major haemorrhages were lower with ximelagatran than with warfarin (29.8% vs 25.8% per year; relative risk reduction 14% [4 to 22]; p=0.007). Raised serum alanine aminotransferase was more common with ximelagatran.. In high-risk patients with atrial fibrillation, fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Male; Middle Aged; Prodrugs; Stroke; Thromboembolism; Warfarin

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

Ximelagatran (Exanta, AstraZeneca), which is still investigational, is the first of a new category of direct inhibitors of thrombin which can be administered orally. SPORTIF III and V trials are both randomized studies; the first is open-label; the second, double-blind. They involved patients aged 18 or over with a non-valvular atrial fibrillation and, at least, one additional risk factor fot stroke (St) or systemic embolism (SE). They compared traditional warfarin anticoagulation (INR = 2-3) with fixed dose ximelagatran (36 mg twice daily) for the prevention of St/SE. These studies are non-inferiority trials. In the intention-to-treat analysis, SPORTIF III (3,407 patients [1,704 on on ximelagatran and 1,703 on warfarin]; mean follow-up of 17.4 months) observed 40 cases of St/SE in the ximelagatran group and 56 in the warfarin group. These data demonstrated the non-inferiority of ximelagatran. In addition, the per protocol analysis showed a superiority of ximelagatran (0.018). SPORTIF V (3,992 patients; mean follow-up of 20 months) observed 88 cases of St/SE. The incidence of these events was similar in both treatment-groups with an absolute difference no greater than 0.5%/yr. The non-inferiority of ximelagatran was thus confirmed. In both studies, bleedings were observed on both therapies with a slight trend in favor of ximelagatran. Additionally, some 6% of patients treated by ximelagatran experienced an increase to greater than three times the upper limit of normal of the liver enzyme alanine aminotransferase (ALT), compared to 0.7-0.8% in the warfarin group. Nearly all enzyme rises occurred during the first six months of therapy and decreased with or without drug discontinuation. The potential breakthrough that these data represent for oral anticoagulation is briefly outlined.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Male; Middle Aged; Prodrugs; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thromboembolism; Warfarin

The efficacy and safety of the new oral, direct and selective thrombin inhibitor Ximelagatran and its active form Melagatran was analysed in patients undergoing total hip or knee replacement.. Methro II, a randomised, double-blind controlled dose-finding study, involved 1876 patients. Melagatran (1, 1.5, 2.25 or 3 mg; twice daily; start: immediately before surgery) was given subcutaneously, followed by orally administered Ximelagatran (8, 12, 18 or 24 mg, twice daily, day after surgery) and compared to subcutaneously administered dalteparin (5000 IE, once daily). Methro III was a randomised, double blind controlled study involving 2788 patients. The fixed dose of 3 mg Melagatran was given (start: 4-12 hours postoperatively) followed by oral Ximelagatran (24 mg, twice daily, day after surgery) compared to subcutaneous enoxaparin (40 mg, once daily). In both studies, dalteparin or enoxaparin was applied at the evening before operation; the treatment lasted 8 to 11 days. A bilateral venography was performed at the last day of treatment.. In the Methro II study, 1270 patients underwent total hip, 606 total knee replacement. In both groups the thromboembolism rate was reduced depending on the dose of Ximelagatran/Melagatran. Compared to dalteparin, it was significantly lower for the Ximelagatran/Melagatran group with the highest dose. In the Methro III study 1923 patients underwent a total hip, 865 a total knee replacement. The thromboembolism rate was 31% for the Ximelagatran/Melagatran group compared to 27% for the enoxaparin group. In both studies blood loss and transfusion requirement were in the same range as with low weight molecular heparins.. A fixed subcutaneously given dose of Melagatran, followed by orally administered Ximelagatran is effective and well tolerated as prophylaxis against venous thromboembolism.

Topics: Administration, Oral; Antithrombins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Humans; Postoperative Complications; Prodrugs; Thromboembolism

Heparins substantially reduce the risk of thromboembolic complications after total hip or knee replacement. However, they can be given only by injection and have several other drawbacks. We did a multicentre, randomised, double-blind study to examine the dose-response relation of subcutaneous melagatran, a direct thrombin inhibitor, followed by oral ximelagatran as thromboprophylaxis after total hip or knee replacement. We aimed to compare the efficacy and safety with that of dalteparin.. Of 1900 patients, 1495 were assigned to four dose categories of subcutaneous melagatran from just before surgery (1.00 mg, 1.50 mg, 2.25 mg, or 3.00 mg twice daily) followed from the day after surgery by oral ximelagatran (8 mg, 12 mg, 18 mg, or 24 mg twice daily). 381 patients were assigned subcutaneous dalteparin 5000 IU once daily, from the evening before surgery. Bilateral venography was done at 7-10 days, and clinically suspected venous thromboembolism (VTE) was confirmed radiologically. The primary endpoint was the rate of deep-vein thrombosis and pulmonary embolism (PE). Analyses were by intention to treat.. 1876 patients underwent total replacement of hip (n=1270) or knee (n=606); evaluable venograms were obtained in 1473 (79%). Four patients without evaluable venograms had PE. Overall, a significant dose-dependent decrease in VTE was seen with melagatran/ximelagatran (lowest to highest group: 111 [37.8%], 70 [24.1%], 71 [23.7%], and 43 [15.1%]; p=0.0001); there were also significant relations for both total hip and total knee replacement individually. The frequency of VTE was significantly lower with the highest dose of melagatran/ximelagatran than with dalteparin (15.1% vs 28.2%, p<0.0001). There were no reoperations due to bleeding and no critical organ bleeding. Excessive surgical bleeding was uncommon but more frequent in the highest dose group.. This sequential therapy was effective and safe in patients undergoing major joint replacement surgery. The findings should be confirmed in a large phase III trial.

Topics: Adult; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Dalteparin; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Glycine; Humans; Male; Middle Aged; Postoperative Complications; Prodrugs; Thromboembolism

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

The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin. Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability. Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Diet; Dietary Supplements; Food-Drug Interactions; Hemorrhage; Humans; Stroke; Thromboembolism; Vitamin K; Warfarin

The benefits and harms of oral anticoagulation therapy in patients with only one stroke risk factor (ie, CHA2DS2-VASc = 1 in males, or 2 in females) has been a subject of debate.. We analyzed all patients with only one stroke risk factor from the merged datasets of SPORTIF III and V trials. Anticoagulation control was defined according to time in therapeutic range (TTR).. Of the original trial cohort, 1097 patients had only one stroke risk factor. Stroke/systemic thromboembolic event had an incidence of 0.9 per 100 patient-years, with an incidence of 1.6 per 100 patient-years for all-cause death and 2.3%/patient-years for the composite outcome of stroke/systemic thromboembolic event/all-cause death. There were no significant differences in the risk for stroke/systemic thromboembolic event between sexes, nor between the different stroke risk factors amongst these atrial fibrillation patients with only one stroke risk factor. Cox regression analysis in patients treated with warfarin found only TTR to be inversely associated with stroke/systemic thromboembolic event (P = .034) and all-cause death (P = .015). Chronic heart failure was significantly associated with the outcome of all-cause death (P = .0019) and the composite outcome of stroke/systemic thromboembolic event/all-cause death (P = .021). There was a significant inverse linear association between TTR and the cumulative risk for both stroke/systemic thromboembolic event and all-cause death (both P <.001).. In atrial fibrillation patients with only one additional stroke risk factor (ie, CHA2DS2-VASc = 1 in males or 2 in females), rates of major adverse events (stroke/systemic thromboembolic event, mortality) were high, despite anticoagulation. TTR in warfarin-treated patients was inversely associated with the occurrence of both stroke/systemic thromboembolic event and all-cause death.

Topics: Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzylamines; Cause of Death; Chronic Disease; Comorbidity; Female; Heart Failure; Humans; Linear Models; Male; Middle Aged; Mortality; Prognosis; Proportional Hazards Models; Risk Factors; Stroke; Thromboembolism; 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

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had > or = 2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.

Topics: Antibodies, Anticardiolipin; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Biomarkers; Blood Coagulation Tests; Ethnicity; Europe; Factor V; Hemorrhage; Humans; Proportional Hazards Models; Protein S; Recurrence; Risk; Thromboembolism; Thrombophilia; Treatment Outcome

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Humans; Liver; Risk Assessment; Thromboembolism; United States; United States Food and Drug Administration

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cost-Benefit Analysis; Drug Costs; Humans; Safety; Thrombin; Thromboembolism; Warfarin

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

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

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Humans; International Normalized Ratio; Thromboembolism; Warfarin

Topics: Anticoagulants; Azetidines; Benzylamines; Humans; Research Design; Secondary Prevention; Thromboembolism

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Humans; Risk Factors; Thromboembolism; Tourniquets; Warfarin

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Humans; International Normalized Ratio; Thromboembolism; Warfarin

Topics: Anticoagulants; Azetidines; Benzylamines; Humans; Research Design; Risk; Secondary Prevention; Thromboembolism

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Prodrugs; Randomized Controlled Trials as Topic; Research Design; Risk; Stroke; Thromboembolism; Treatment Outcome; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Drug Therapy, Combination; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Randomized Controlled Trials as Topic; Research Design; Stroke; Thromboembolism; Treatment Outcome; Warfarin

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

While considering long-term oral anticoagulation one should assess benefit (i.e., reduction in thromboembolic events) and risks (i.e., bleeding complications) associated with therapy for each individual patient. The classic cardiac indications for oral anticoagulation include chronic atrial fibrillation, prosthetic heart valves, and left ventricular thrombus formation following anterior myocardial infarction. The value of anticoagulation in patients with impaired left ventricular function in stable sinus rhythm and in secondary prevention of coronary artery disease remains controversial. For decades warfarin has been the only compound available. Currently, promising results have been achieved with the oral thrombin inhibitor ximelagatran. In the future, oral anticoagulants, which are administered in fixed dose with no need for monitoring of the anticoagulation level, may replace warfarin. Safety and efficacy of double antiplatelet therapy (aspirin and clopidogrel) in the secondary prevention of thromboembolic events in patients with atrial fibrillation are currently being addressed in large-scale clinical trials.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Heart Valve Prosthesis Implantation; Heart Ventricles; Humans; Long-Term Care; Myocardial Infarction; Postoperative Complications; Risk Factors; Thromboembolism; Thrombosis

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Dissent and Disputes; Enoxaparin; Glycine; Humans; Orthopedic Procedures; Therapeutic Equivalency; Thromboembolism; Treatment Outcome; 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: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Enoxaparin; Fibrinolytic Agents; Glycine; Humans; Phenprocoumon; Placebos; Prodrugs; Thrombin; Thromboembolism; Thrombosis; Time Factors

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