ximelagatran and Pulmonary-Embolism

After arthroplasty treatment, some complications commonly occur, such as early revision, infection/dislocation, and venous thromboembolism (VTE). This study aims to use a network meta-analysis to compare effects of 9 anticoagulant drugs (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, ximelagatran, and enoxaparin) in preventing postoperative complications in arthroplasty patients.. After retrieving PubMed, Embase, and Cochrane Library database from the inception to November 2016, randomized controlled trials were enrolled. The integration of direct and indirect evidences was performed to calculate odd ratios and the surface under the cumulative ranking curves. Nineteen eligible randomized controlled trials were included.. The network meta-analysis results showed that compared with warfarin, edoxaban, apixaban, and rivaroxaban had a lower incidence rate in asymptomatic deep venous thrombosis, which indicated that edoxaban, apixaban, and rivaroxaban had better effects on prevention. Similarly, in comparison to enoxaparin, edoxaban and rivaroxaban had better effect; rivaroxaban was better than ximelagatran in preventive effects. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence rate in clinically relevant non-major bleeding, which showed that preventive effects were relatively poor. In addition, the results of the surface under the cumulative ranking curves showed that rivaroxaban and bemiparin worked best on symptomatic deep venous thrombosis and pulmonary embolism. In terms of bleeding, apixaban and warfarin had better preventive effects.. Our findings suggested that rivaroxaban may work better in terms of symptomatic deep venous thrombosis and pulmonary embolism, whereas apixaban had better preventive effects in bleeding.

Topics: Anticoagulants; Arthroplasty; Azetidines; Benzylamines; Dabigatran; Enoxaparin; Heparin; Heparin, Low-Molecular-Weight; Humans; Network Meta-Analysis; Postoperative Complications; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Treatment Outcome; Venous Thromboembolism; Warfarin

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

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

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

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

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

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

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: 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

Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of thrombin. These agents produce a predictable anticoagulant response; thus, routine coagulation monitoring is unnecessary. Because they do not bind to platelets or platelet factor 4, fondaparinux and idraparinux do not cause heparin-induced thrombocytopenia (HIT). Unlike vitamin K antagonists, ximelagatran has a rapid onset of action, thereby obviating the need for concomitant administration of a parenteral anticoagulant when starting treatment. The lack of an antidote for these new agents is a drawback, particularly for idraparinux, which has a long half-life.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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