Original Article
Comparison of Ximelagatran with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement
N Engl J Med 2003; 349:1703-1712October 30, 2003
- Abstract
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Media in This Article
Table 1
Patients Included in the Analyses, Those Excluded, and Reasons for Exclusion.Table 2
Base-Line Characteristics of Patients Included in the Safety Analysis.Article Activity
- Article
Venous thromboembolism occurs in 40 to 84 percent of patients who undergo total knee replacement and do not receive prophylactic drugs; in 9 to 20 percent of these patients the thrombosis is proximal,1 up to 7 percent have a pulmonary embolus,2,3 and in 0.2 to 0.7 percent the embolus is fatal.4-6 Prophylaxis with either warfarin or low-molecular-weight heparin is widely used in North America.1 Nevertheless, approximately 47 percent of patients treated with warfarin and 31 percent of those treated with low-molecular-weight heparin have thrombosis after total knee replacement.1 Warfarin has a slow onset of action, interacts with numerous foods and drugs, and requires monitoring of coagulation and dose adjustment. The low-molecular-weight heparins must be given parenterally, and they are associated with a higher rate of bleeding at the surgical site than is warfarin, especially if heparin therapy is started soon after surgery.1
Ximelagatran is an orally administered direct thrombin inhibitor under development as an anticoagulant agent for prophylaxis against and treatment of thromboembolism. It is rapidly absorbed and quickly converted into its active form, melagatran, a reversible, active-site inhibitor of both free and clot-bound thrombin7 that has stable and reproducible pharmacokinetic properties. No clinically relevant interactions with food or cytochrome P-450–metabolized drugs have been reported with ximelagatran.8-13 Initial studies have shown ximelagatran to have good efficacy and safety in the prevention of venous thromboembolism after total knee or total hip replacement.14-17 Results of a phase 2 trial15 suggested a wide range of doses with good efficacy and safety, and an initial phase 3 trial showed that treatment with ximelagatran at a dose of 24 mg twice daily was at least as effective as warfarin.14 The purpose of the present study was to determine whether a higher dose would be safe and more effective than warfarin.
Methods
Study Design
We conducted a prospective, randomized, double-blind trial at 116 centers in the United States, Canada, Israel, Mexico, and Brazil. The institutional review board at each center approved the protocol, and written informed consent was obtained from all patients before any study procedures were conducted. The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki. Patients were screened 1 to 30 days preoperatively, and they were randomly assigned after postoperative rescreening to receive ximelagatran at a dose of 24 mg twice daily, ximelagatran at a dose of 36 mg twice daily, or warfarin. Randomization was performed with the use of a computer-generated system, with stratification at each center according to whether patients underwent unilateral or bilateral surgery.
Patients
Eligible patients were women without childbearing potential and men who weighed between 40 and 136 kg. Only patients undergoing primary total knee replacement were included. The criteria for exclusion were pneumatic leg compression; immobilization for 3 or more days; major surgery, stroke, myocardial infarction, or receipt of any investigational drug within 30 days before surgery; intracranial, retroperitoneal, or intraocular bleeding or any other disorder associated with an increased risk of bleeding within 90 days before surgery; gastrointestinal bleeding within 90 days before surgery, ulcer disease verified by endoscopic examination within 30 days before surgery, or both; uncontrolled hypertension; cancer that required cytostatic treatment or was itself the reason for total knee replacement; an alanine or aspartate aminotransferase level greater than two times the upper limit of the normal range; thrombocytopenia; drug or alcohol abuse within the previous 6 months; allergy to contrast medium or iodine; a contraindication to warfarin therapy; impaired renal function (defined by an estimated creatinine clearance of less than 30 ml per minute)18; and traumatic epidural or lumbar puncture.
If the use of an epidural or spinal catheter continued into the treatment period, the catheter was to be removed during trough levels of melagatran (the active metabolite of ximelagatran). Treatment with thrombolytic, anticoagulant, or antiplatelet agents, including heparins, warfarin, direct thrombin inhibitors, dipyridamole, sulfinpyrazone, ticlopidine, clopidogrel, acetylsalicylic acid at a dose greater than 500 mg per day, and dextran, was not allowed within seven days before surgery or during the period of administration of the study drug.
Treatment Regimens
Warfarin (Coumadin, Bristol-Myers Squibb) or a warfarin placebo was administered each evening, with the first dose given on the evening of the day of surgery and with the dose adjusted to achieve an international normalized ratio (INR) of 2.5 (range, 1.8 to 3.0). Ximelagatran at a dose of 24 mg or 36 mg in tablet form (Exanta, AstraZeneca) or a ximelagatran placebo was given in the morning and evening starting 12 hours or more after surgery, when adequate hemostasis had been achieved. The treatment was continued until venography was performed. To guide the adjustment of the warfarin dosage, INR values were measured in a blinded fashion on days 1 to 3 after surgery, on the day when venography was performed, and as needed. INR values were measured either at participating centers, with the use of encrypted point-of-care devices provided by AstraZeneca, or at local laboratories equipped with a system that prevented access to the INR values by local personnel. All INR values were reported to an anticoagulation management center, which relayed real or sham values to local study personnel. A warfarin-dosing nomogram was provided, but the dose of either warfarin or warfarin placebo was chosen at the investigator's discretion. For patients receiving ximelagatran, sham INR values were generated to mimic the usual values in patients receiving warfarin. Compliance with oral treatment was assessed by counting tablets used in the hospital, dispensed at discharge, and returned after the treatment had ended.
Assessments of Efficacy
The composite primary end point for efficacy comprised total (distal and proximal) deep- vein thrombosis, pulmonary embolism, and death from all causes during treatment, as determined by an independent central adjudication committee. The composite secondary end point for efficacy comprised proximal deep-vein thrombosis, pulmonary embolism, and death from all causes during treatment.
Deep-vein thrombosis was evaluated by means of bilateral ascending venography19,20 7 to 12 days after the study treatment was initiated. In addition to central adjudication, venograms were assessed locally by personnel who had no knowledge of the assigned study treatment. The criterion for the diagnosis of deep-vein thrombosis was a consistent intraluminal filling defect on at least two images. To be considered adequate for evaluation, venograms had to show all deep veins except the deep femoral vein, the muscular veins of the calf, and the anterior tibial veins, although these were included in the evaluation if they were visible or if a clot was detected. Venograms were classified as indeterminate if they showed a lack of filling of a region of the deep-vein system without a filling defect in the same region. Symptomatic proximal deep-vein thrombosis could be diagnosed by compression ultrasonography, but a diagnosis of symptomatic distal deep-vein thrombosis required venography.
A diagnosis of pulmonary embolism was made if a lung scan showed one or more segmental perfusion defects in at least two views with corresponding normal ventilation, if pulmonary angiography showed a persistent intraluminal defect or an abrupt cutoff of a vessel that was greater than 2.5 mm in diameter, if a spiral computed tomographic scan showed a distinct filling defect in a large vessel, if embolectomy was performed, or if a pulmonary embolism was identified on autopsy. Deaths were classified as due to pulmonary embolism or a bleeding event or as not associated with venous thromboembolism or bleeding. All cases of confirmed symptomatic deep-vein thrombosis, suspected pulmonary embolism, and death from any cause were adjudicated centrally. Treatment of confirmed thrombosis was at the discretion of the attending physician.
Safety Assessments
The primary variables used to assess safety were major bleeding and major or minor bleeding occurring up to 48 hours after the last dose of the study drug had been administered. All bleeding events were reviewed by the independent central adjudication committee and classified as major if they were clinically overt, with one or more of the following findings: involvement of a critical site (intracranial, retroperitoneal, intraocular, intraspinal, or pericardial), a bleeding index of 2.0 or more (calculated as the hemoglobin level [in grams per liter] at the base-line visit minus the postbleeding hemoglobin level, plus the number of units of packed red cells or whole blood transfused), a need for medical or surgical intervention at the operative site, or fatal bleeding. Other episodes of clinically overt bleeding were classified as minor. The investigators also assessed the appearance and characteristics of the surgical wound (swelling, drainage, erythema, and bleeding) according to the following categories: as expected, better than expected, or worse than expected. Laboratory results were assessed at the time of screening for the study, on the last day of administration of the study drug, and at the follow-up examination four to six weeks after surgery.
Statistical Analysis
We estimated the size of the sample by assuming that the rate of venous thromboembolism with warfarin would be 30 percent and predicting a risk reduction of 33.3 percent with ximelagatran at a dose of 36 mg and of 25 percent with ximelagatran at a dose of 24 mg. To demonstrate these differences at a 5 percent level of significance would require the enrollment of 500 patients per treatment group (for 90 percent power) or 565 patients (for 80 percent power) for the high and low doses of ximelagatran, respectively. We planned to enroll approximately 2250 patients in order to detect a 25 percent risk reduction with the lower dose, given the assumption that 25 percent of venograms would be inadequate for evaluation.
The primary analysis was designed to test the superior efficacy of ximelagatran at a dose of 36 mg twice daily as compared with warfarin. If the difference was significant (as indicated by a two-tailed P value of <0.05), then ximelagatran at a dose of 24 mg twice daily was to be compared with warfarin. The efficacy analyses included all patients who had received at least one dose of a study medication and who had a venogram that was adequate for evaluation or had symptomatic, objectively confirmed deep- vein thrombosis or pulmonary embolism or died during treatment. Bilateral venography was required, but patients undergoing unilateral surgery in whom a clot was detected were included in the efficacy analysis even if a venogram that was adequate for evaluation could be obtained only in the leg that had undergone surgery or only in the contralateral side. For patients who underwent bilateral surgery, venograms that were adequate for evaluation were required in both legs, unless deep-vein thrombosis was found in one leg. Symptomatic venous thromboembolism and deaths that occurred within two days after venography, or up to day 12 if no venography was performed, were included in the analyses.
The frequency of bleeding events was estimated with the use of the observed proportions (with 95 percent confidence intervals) for each treatment group. Differences between each of the two groups receiving ximelagatran and the warfarin group were analyzed with the use of the Cochran–Mantel–Haenszel chi- square test. Differences in blood loss and transfusion requirements were tested with the use of analysis of variance. Differences in ratings of the appearance of the wound and bleeding complications at the surgical site were tested with the use of the Cochran–Mantel–Haenszel chi-square test.
The study was designed by the members of the executive committee of the EXULT A (Exanta Used to Lessen Thrombosis A) Study Group, who also analyzed and interpreted the data. The data were collected by Omnicare Clinical Research at the direction of the executive committee.
Results
Study Groups
Of 2656 patients who were enrolled, a total of 2301 patients were randomly assigned to a study group and 1851 were included in the analysis of efficacy (Table 1Table 1
Patients Included in the Analyses, Those Excluded, and Reasons for Exclusion.). Of the 450 patients not included, 16 underwent randomization but did not receive treatment; in the case of the remaining 434 patients, the presence or absence of an end point could not be determined because venography either was not performed or was indeterminate or because there was no confirmed symptomatic venous thromboembolic event or death. Base-line characteristics, details of the surgery, and the hospital course were similar in the three groups (Table 2Table 2Base-Line Characteristics of Patients Included in the Safety Analysis. and Table 3Table 3
Characteristics of Knee-Replacement Surgery in Patients Included in the Efficacy Analysis.). Characteristics of the 2285 patients included in the safety analysis and those of the 1851 patients included in the efficacy analysis did not differ significantly. Venography was adequate for evaluation in 80.7 percent of the patients. In the efficacy analysis, the mean time to the first dose of medication on day 1 was 20.4 hours for all three treatment groups combined; 89 percent of the patients received the assigned study medication for a period of 7 to 12 days. Approximately one third of the patients (701) received additional anticoagulant therapy after discontinuing the study medication at the discretion of the attending physician; in two thirds of these patients (478 patients) the purpose was extended prophylaxis, and in one third (223 patients) it was acute treatment of venous thromboembolism. Only two patients were lost to follow-up; 92 percent of the patients who underwent randomization completed the study, with a follow-up visit at weeks 4 to 6.Efficacy
The composite primary end point of total venous thromboembolism (deep-vein thrombosis and pulmonary embolism) and death from all causes occurred in 20.3 percent of patients in the group receiving 36 mg of ximelagatran (128 of 629) and in 27.6 percent of patients in the warfarin group (168 of 608) (relative risk reduction, 26.4 percent; P=0.003) (Table 4Table 4
Efficacy and Clinical End Points.). The incidence of the composite primary end point in the group receiving 24 mg of ximelagatran was 24.9 percent (153 of 614 patients; P=0.28 for the comparison with warfarin). Because only unilateral venograms were available for some patients, a sensitivity analysis that included only the patients with bilateral venograms (76.1 percent of the total) was performed, with a similar result. In the 4 percent of patients who had undergone bilateral surgery, the primary end point of total venous thromboembolism or death occurred in 22.2 percent of patients receiving the 36-mg dose of ximelagatran, 19.0 percent of patients receiving the 24-mg dose of ximelagatran, and 34.8 percent of patients receiving warfarin.The incidence of the combined end point of total venous thromboembolism and death from all causes, on the basis of local interpretation of the venograms, was somewhat higher, but the differences among the groups were similar — 29.6 percent of patients in the higher-dose ximelagatran group (P=0.002 for the comparison with warfarin), 33.4 percent of those in the lower-dose ximelagatran group (P=0.11 for the comparison with warfarin), and 37.7 percent of those in the warfarin group. The superior efficacy of ximelagatran at a dose of 36 mg was also consistently observed in the analyses of subgroups defined according to age, sex, race or ethnic group, country, weight, body-mass index, creatinine clearance, presence or absence of a history of venous thromboembolism, type of surgery, type of anesthesia, time to the first dose of study medication, and time to ambulation. There were no significant interactions between treatment and these subgroup variables.
The prespecified composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death from all causes occurred in 17 patients (2.7 percent) in the higher-dose ximelagatran group, 15 patients (2.5 percent) in the lower-dose ximelagatran group, and 25 patients (4.1 percent) in the warfarin group (P=0.17 for higher-dose ximelagatran vs. warfarin; P=0.10 for lower-dose ximelagatran vs. warfarin). Slightly more than 1 percent of patients in each group had symptomatic deep-vein thrombosis or died (Table 4).
The INR value was in the target range (1.8 to 3.0) or higher in 65 percent of patients in the warfarin group by postoperative day 3 (mean INR, 2.3) and in 76 percent of patients by the day of venography (mean INR, 2.4). There were no appreciable differences in mean INR values between patients with and those without venous thromboembolism on either day.
Safety
Major bleeding occurred during treatment in six patients in each of the two ximelagatran groups and in five patients in the warfarin group (Table 5Table 5
Bleeding Events during Treatment in the Patients Included in the Safety Analysis.). Additional major bleeding events occurred during follow-up in four patients in the lower-dose ximelagatran group and in one patient in the warfarin group. One bleeding complication was fatal; gastric-ulcer bleeding developed in a patient who had received two 36-mg doses of ximelagatran. The bleeding led to multiorgan-system failure and death on day 46. This patient had also received perioperative enoxaparin (as part of the anesthesia protocol) and diclofenac.Assessment of wound bleeding and of the appearance of the wound revealed no significant differences between either ximelagatran group and the warfarin group (Table 6Table 6
Evaluation of the Surgical Wound.), and there were no appreciable differences among the groups with respect to other adverse events. The most common postoperative complication was anemia, which occurred in 8 to 10 percent of patients in each of the three groups. Alanine aminotransferase levels were more than three times the upper limit of the normal range in 6 patients in the higher-dose ximelagatran group, 4 patients in the lower-dose ximelagatran group, and 12 patients in the warfarin group on the day of venography and in 4, 1, and 0 patients in the three groups, respectively, at follow-up at four to six weeks (Table 7Table 7
Cumulative Frequency of Elevated Alanine Aminotransferase Values in Patients Included in the Safety Analysis.).Discussion
Our results show that ximelagatran given orally at a dose of 36 mg twice daily starting postoperatively (a mean of 20.4 hours after surgery) was significantly more effective than warfarin in preventing venous thromboembolism after total knee replacement, with an absolute risk reduction of 7.3 percent and a relative risk reduction of 26.4 percent. The number needed to treat was 14. This benefit was due to a reduction in the rate of asymptomatic deep-vein thrombosis, whereas the rates of proximal deep-vein thrombosis and of symptomatic venous thromboembolism were low in all three treatment groups and did not differ significantly between the group receiving 36 mg of ximelagatran and the warfarin group. Studies of the natural history of venous thromboembolism suggest that asymptomatic deep-vein thrombosis identified by postoperative venography is a predictor of the development of symptomatic venous thromboembolism.1,21
As compared with the rates of total and proximal venous thrombosis in seven other multicenter trials of warfarin for prophylaxis after total knee replacement, all conducted in the past 10 years, the rates in our large study (27.4 percent and 3.8 percent, respectively) were among the lowest reported for warfarin. The other studies reported rates of 38 to 55 percent for deep-vein thrombosis and 7 to 12 percent for proximal deep-vein thrombosis.22-28 The low rates in our study may be related to improvements in general surgical care and to the strict, predefined guidelines used for central adjudication. Also, between two thirds and three quarters of the patients in our study had therapeutic INR values on day 3 and on the day of venography, which is a somewhat higher proportion than usual. Local interpretation of venograms, which was a secondary end point for efficacy, confirmed the superiority of ximelagatran at a dose of 36 mg twice daily, even though the rates of deep-vein thrombosis were higher with local interpretation, most likely because of less stringent application of diagnostic criteria.
The first large, randomized clinical trial of ximelagatran for the prevention of deep-vein thrombosis after total knee replacement in North America showed that a dose of 24 mg twice daily had an efficacy similar to that of warfarin; venous thromboembolism occurred in 19 percent of patients receiving this dose of ximelagatran and in 26 percent of those receiving warfarin (P=0.07).14 Because the rate of bleeding complications was low and ximelagatran was well tolerated over a range of doses, we chose a 36-mg dose, in addition to the 24-mg dose, for our study.
In six studies comparing low-molecular-weight heparin with warfarin after total knee replacement, the rates of venographically identified deep- vein thrombosis in the groups that received low-molecular-weight heparin ranged from 25 percent to 45 percent, with a mean of 31 percent, as compared with rates in the warfarin groups ranging from 38 percent to 55 percent, with a mean of 47 percent.1,22-27 In one study, which compared fondaparinux, a synthetic pentasaccharide, with enoxaparin in 724 patients, the fondaparinux group had a 12.5 percent rate of thromboembolism, whereas the rate with enoxaparin was 27.8 percent.29 The incidence of major hemorrhagic complications has been higher with low-molecular-weight heparins than with warfarin.23-25,27 A meta-analysis of four large clinical trials comparing fondaparinux with enoxaparin for prophylaxis after orthopedic surgery showed that major bleeding was significantly more frequent with fondaparinux.30
Warfarin is the single most commonly used pharmacologic form of prophylaxis prescribed after total knee replacement in North America.31,32 Among the many reasons for this preference are longer experience with the use of warfarin, oral administration, and a lower rate of early bleeding complications than with other agents. Nevertheless, warfarin has a delayed onset of action, requires monitoring of coagulation and dose adjustment, and has multiple interactions with food and drugs.33,34 The results of our study indicate that fixed-dose ximelagatran, administered without coagulation monitoring, was significantly more effective than warfarin and had similar safety. It could therefore be considered as an alternative to other available thromboprophylactic agents.
Supported by AstraZeneca.
Drs. Francis, Lieberman, Ginsberg, and Paiement report having served as paid consultants to AstraZeneca, Dr. Colwell reports having received lecture fees from the company, Drs. Colwell and Ginsberg report having received grant support from the company, and Ms. Roth reports owning equity in the company.
We are indebted to Joyce S. Weiner, Ph.D., an employee of AstraZeneca, for editorial support in the preparation of the manuscript.
Source Information
From the Department of Medicine, University of Rochester, Rochester, N.Y. (C.W.F.); the Department of Clinical Development, AstraZeneca, Wilmington, Del. (S.D.B., G.R.P., A.W.R., J.M.); the Department of Medicine, University of Oklahoma, Oklahoma City (P.C.C.); the Department of Orthopedic Surgery, University of California at Los Angeles, Los Angeles (J.R.L.); the Department of Medicine, McMaster University, Hamilton, Ont., Canada (J.S.G.); the Department of Orthopedic Surgery, University of California at Irvine, Irvine (G.P.); and the Department of Orthopaedic Surgery, Scripps Clinic, La Jolla, Calif. (C.W.C.).
Address reprint requests to Dr. Francis at the University of Rochester Medical Center, 610 Elmwood Ave., Box 610, Rochester, NY 14642, or at charles_francis@urmc.rochester.edu.
The members of the EXULT A (Exanta Used to Lessen Thrombosis A) Study Group are listed in Supplementary Appendix 1.
- References
References
1
Geerts WH ,Heit JA ,Clagett GP , et al. Prevention of venous thromboembolism. Chest 2001;119:Suppl 1:132S-175S
CrossRef | Web of Science | Medline2
Stulberg BN ,Insall JN ,Williams GW ,Ghelman B . Deep-vein thrombosis following total knee replacement: an analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg Am 1984;66:194-201
Web of Science | Medline3
Stringer MD ,Steadman CA ,Hedges AR ,Morley TR ,Kakkar VV . Deep vein thrombosis after elective knee surgery: an incidence study in 312 patients. J Bone Joint Surg Br 1989;71:492-497
Web of Science | Medline4
Mohr DN ,Silverstein MD ,Ilstrup DM ,Heit JA ,Morrey BF . Venous thromboembolism associated with hip and knee arthroplasty: current prophylactic practices and outcomes. Mayo Clin Proc 1992;67:861-870
Web of Science | Medline5
Khaw FM ,Moran CG ,Pinder IM ,Smith IR . The incidence of fatal pulmonary embolism after knee replacement with no prophylactic anticoagulation. J Bone Joint Surg Br 1993;75:940-941
Web of Science | Medline6
Ansari S ,Warwick D ,Ackroyd CE ,Newman JH . Incidence of fatal pulmonary embolism after 1,390 knee arthroplasties without routine prophylactic anticoagulation, except in high-risk cases. J Arthroplasty 1997;12:599-602
CrossRef | Web of Science | Medline7
Klement P ,Carlsson S ,Rak J , et al. The benefit-to-risk profile of melagatran is superior to that of hirudin in a rabbit arterial thrombosis prevention and bleeding model. J Thromb Haemost 2003;1:587-594
CrossRef | Web of Science | Medline8
Johansson LC ,Frison L ,Logren U ,Fager G ,Gustafsson D ,Eriksson UG . Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003;42:381-392
CrossRef | Web of Science | Medline9
Eriksson UG ,Johansson L ,Frison L , et al. Pharmacokinetics (PK) of melagatran (M) in young and elderly healthy subjects and orthopaedic surgery patients. Clin Pharmacol Ther 2001;69:P24-P24 abstract.
CrossRef | Web of Science10
Eriksson UG ,Fager G ,Eriksson-Lepkowska M , et al. Effect of acetylsalicylic acid (ASA) on the pharmacodynamics and pharmacokinetics (PK) of melagatran (M), active form of the oral direct thrombin inhibitor, H 376/95. Clin Pharmacol Ther 2001;69:P24-P24 abstract.
CrossRef | Web of Science11
Eriksson-Lepkowska M, Thuresson A, Bylock A, Frison L, Eriksson UG. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics of diazepam in healthy male volunteers. In: Proceedings of the 28th Congress of the International Society on Thrombosis and Haemostasis, Paris, July 6–12, 2001. abstract.
12
The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics and pharmacodynamics of diclofenac in healthy male volunteers. In: Proceedings of the 28th Congress of the International Society on Thrombosis and Haemostasis, Paris, July 6–12, 2001. abstract.
13
Johnasson S, Bylock A, Eriksson-Lepkowska M, Thuresson A, Frison L, Eriksson UG. The effect of the oral direct thrombin inhibitor, ximelagatran (pINN, formerly H 376/95), on the pharmacokinetics of nifedipine in healthy male volunteers. In: Proceedings of the 28th Congress of the International Society on Thrombosis and Haemostasis, Paris, July 6–12, 2001. abstract.
14
Francis CW ,Davidson BL ,Berkowitz SD , et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind trial. Ann Intern Med 2002;137:648-655
Web of Science | Medline15
Heit JA ,Colwell CW ,Francis CW , et al. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001;161:2215-2221
CrossRef | Web of Science | Medline16
Eriksson BI ,Agnelli G ,Cohen AT , et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thromb Haemost 2003;89:288-296
Web of Science | Medline17
Eriksson BI ,Bergqvist D ,Kalebo P , et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or total knee replacement: the METHRO II randomised trial. Lancet 2002;360:1441-1447
CrossRef | Web of Science | Medline18
Cockcroft DW ,Gault MH . Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41
CrossRef | Medline19
Rabinov K ,Paulin S . Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972;104:134-144
CrossRef | Web of Science | Medline20
Kalebo P ,Ekman S ,Lindbratt S , et al. Percentage of inadequate phlebograms and observer agreement in thromboprophylactic multicenter trials using standardized methodology and central assessment. Thromb Haemost 1996;76:893-896
Web of Science | Medline21
Cohen AT ,Bailey CS ,Alikhan R ,Cooper DJ . Extended thromboprophylaxis with low molecular weight heparin reduces symptomatic venous thromboembolism following lower limb arthroplasty -- a meta-analysis. Thromb Haemost 2001;85:940-941
Web of Science | Medline22
RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty: the RD Heparin Arthroplasty Group. J Bone Joint Surg Am 1994;76:1174-1185
Medline23
Heit JA ,Berkowitz SD ,Bona R , et al. Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Thromb Haemost 1997;77:32-38
Web of Science | Medline24
Fitzgerald RH Jr ,Spiro TE ,Trowbridge AA , et al. Prevention of venous thromboembolic disease following primary total knee arthroplasty: a randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin. J Bone Joint Surg Am 2001;83:900-906
Web of Science | Medline25
Hull R ,Raskob G ,Pineo G , et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993;329:1370-1376
Full Text | Web of Science | Medline26
Hamulyak K ,Lensing AWA ,van der Meer J ,Smid WM ,van Ooy A ,Hoek A . Subcutaneous low-molecular-weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Thromb Haemost 1995;74:1428-1431
Web of Science | Medline27
Leclerc JR ,Geerts WH ,Desjardins L , et al. Prevention of venous thromboembolism after knee arthroplasty: a randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996;124:619-626
Web of Science | Medline28
Francis CW ,Pellegrini VD Jr ,Leibert KM , et al. Comparison of two warfarin regimens in the prevention of venous thrombosis following total knee replacement. Thromb Haemost 1996;75:706-711
Web of Science | Medline29
Bauer KA ,Eriksson BI ,Lassen MR ,Turpie AGG . Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-1310
Full Text | Web of Science | Medline30
Turpie AG ,Bauer KA ,Eriksson BI ,Lassen MR . Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162:1833-1840
CrossRef | Web of Science | Medline31
Mesko JW ,Brand RA ,Iorio R , et al. Venous thromboembolic disease management patterns in total hip arthroplasty and total knee arthroplasty patients: a survey of the AAHKS membership. J Arthroplasty 2001;16:679-688
CrossRef | Web of Science | Medline32
Gross M ,Anderson DR ,Nagpal S ,O'Brien B . Venous thromboembolism prophylaxis after total hip or knee arthroplasty: a survey of Canadian orthopedic surgeons. Can J Surg 1999;42:457-461
Web of Science | Medline33
Hirsh J ,Dalen J ,Anderson DR , et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:Suppl 1:8S-21S
CrossRef | Web of Science | Medline34
Ansell J ,Hirsh J ,Dalen J , et al. Managing oral anticoagulant therapy. Chest 2001;119:Suppl 1:22S-38S
CrossRef | Web of Science | Medline
- Citing Articles (119)
Citing Articles
1
Sarkis Morales-Vidal, Michael J Schneck, Murray Flaster, José Biller. (2012) Direct thrombin inhibitors and factor Xa inhibitors in patients with cerebrovascular disease. Expert Review of Neurotherapeutics 12:2, 179-190
CrossRef2
A Hróbjartsson, I Boutron. (2011) Blinding in Randomized Clinical Trials: Imposed Impartiality. Clinical Pharmacology & Therapeutics 90:5, 732-736
CrossRef3
L. Bertoletti, P. Mismetti. (2011) Les nouveaux anticoagulants dans la maladie thrombo-embolique veineuse. Revue des Maladies Respiratoires 28:8, 1008-1016
CrossRef4
David Feinbloom, John Fani Srour. 2011. Heparin-Induced Thrombocytopenia. , 331-359.
CrossRef5
A. RUPIN, I. MARX, M. O. VALLEZ, P. MENNECIER, P. GLOANEC, G. DE NANTEUIL, T. J. VERBEUREN. (2011) S35972, a direct-acting thrombin inhibitor with high oral bioavailability and antithrombotic efficacy. Journal of Thrombosis and Haemostasis 9:7, 1375-1382
CrossRef6
K. A. BAUER. (2011) Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa. Journal of Thrombosis and Haemostasis 9, 12-19
CrossRef7
Andrew Cunningham, C. Michael Stein, Cecilia P. Chung, James R. Daugherty, Walter E. Smalley, Wayne A. Ray. (2011) An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiology and Drug Safety 20:6, 560-566
CrossRef8
E J Do, P Lenzini, C S Eby, A R Bass, G A McMillin, S M Stevens, S C Woller, R C Pendleton, J L Anderson, P Proctor, R M Nunley, V Davila-Roman, B F Gage. (2011) Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. The Pharmacogenomics Journal
CrossRef9
Jeffrey I. Weitz. (2011) Factor Xa and thrombin as targets for new oral anticoagulants. Thrombosis Research 127, S5-S12
CrossRef10
Honorio T. Benzon. 2011. Anticoagulants and neuraxial and peripheral nerve blocks. , 629-640.
CrossRef11
Stephan H. Schirmer, Magnus Baumhäkel, Hans-Ruprecht Neuberger, Stefan H. Hohnloser, Isabelle C. van Gelder, Gregory Y.H. Lip, Michael Böhm. (2010) Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation. Journal of the American College of Cardiology 56:25, 2067-2076
CrossRef12
Timothy K. Liem, Thanh M. Huynh, Shannon E. Moseley, Renee C. Minjarez, Gregory J. Landry, Erica L. Mitchell, Thomas G. DeLoughery, Gregory L. Moneta. (2010) Symptomatic perioperative venous thromboembolism is a frequent complication in patients with a history of deep vein thrombosis. Journal of Vascular Surgery 52:3, 651-657
CrossRef13
Catherine J. Lee, Gauri Badhwar, Jack E. Ansell. (2010) Oral IIa Inhibitors. Hematology/Oncology Clinics of North America 24:4, 739-753
CrossRef14
Eric M. Bershad, Jose I. Suarez. (2010) Prothrombin Complex Concentrates for Oral Anticoagulant Therapy-Related Intracranial Hemorrhage: A Review of the Literature. Neurocritical Care 12:3, 403-413
CrossRef15
Rohtesh S Mehta. (2010) Novel oral anticoagulants. Part II: direct thrombin inhibitors. Expert Review of Hematology 3:3, 351-361
CrossRef16
Carlos A Salazar, German Malaga, Giuliana Malasquez, Carlos A Salazar. 2010. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement. .
CrossRef17
Robin Som, James A. Gossage, Anna Crane, Paul H. Rowe. (2010) Surgical workload, risk factors and complications in patients on warfarin with gastrointestinal bleeding. International Journal of Surgery 8:1, 52-55
CrossRef18
Alejandro González Della Valle, Francis Jeshira Reynoso, Judith Ben Ari, Eduardo Salvati. (2009) The Multimodal Approach for the Prevention of Thromboembolic Disease After Total Joint Arthroplasty. Seminars in Arthroplasty 20:4, 241-250
CrossRef19
Lassen, Michael Rud, Raskob, Gary E., Gallus, Alexander, Pineo, Graham, Chen, Dalei, Portman, Ronald J., . (2009) Apixaban or Enoxaparin for Thromboprophylaxis after Knee Replacement. New England Journal of Medicine 361:6, 594-604
Full Text20
Farhad Kamali, Peter Wood, Alan Ward. (2009) Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety. Annals of Hematology 88:2, 141-149
CrossRef21
Brooke E Baetz, Sarah A Spinler. (2008) Dabigatran Etexilate: An Oral Direct Thrombin Inhibitor for Prophylaxis and Treatment of Thromboembolic Diseases. Pharmacotherapy 28:11, 1354-1373
CrossRef22
Kenneth A Bauer. (2008) New anticoagulants. Current Opinion in Hematology 15:5, 509-515
CrossRef23
Lassen, Michael R., Ageno, Walter, Borris, Lars C., Lieberman, Jay R., Rosencher, Nadia, Bandel, Tiemo J., Misselwitz, Frank, Turpie, Alexander G.G., . (2008) Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty. New England Journal of Medicine 358:26, 2776-2786
Full Text24
Monica R. McClain, Glenn E. Palomaki, Margaret Piper, James E. Haddow. (2008) A Rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. Genetics in Medicine 10:2, 89-98
CrossRef25
Katharine He Xing, Gareth Morrison, Wendy Lim, James Douketis, Adefowope Odueyungbo, Mark Crowther. (2008) Has the incidence of deep vein thrombosis in patients undergoing total hip/knee arthroplasty changed over time? A systematic review of randomized controlled trials. Thrombosis Research 123:1, 24-34
CrossRef26
L. Testa, F. Andreotti, G.G.L. Biondi Zoccai, F. Burzotta, F. Bellocci, F. Crea. (2007) Ximelagatran/melagatran against conventional anticoagulation: A meta-analysis based on 22,639 patients. International Journal of Cardiology 122:2, 117-124
CrossRef27
K. A. BAUER. (2007) Targeted inhibition of coagulation: oral agents show promise in phase III trials. Journal of Thrombosis and Haemostasis 5:11, 2175-2177
CrossRef28
Qing Ma. (2007) Development of oral anticoagulants. British Journal of Clinical Pharmacology 64:3, 263-265
CrossRef29
D. J. QUINLAN, J. W. EIKELBOOM, O. E. DAHL, B. I. ERIKSSON, P. S. SIDHU, J. HIRSH. (2007) Association between asymptomatic deep vein thrombosis detected by venography and symptomatic venous thromboembolism in patients undergoing elective hip or knee surgery. Journal of Thrombosis and Haemostasis 5:7, 1438-1443
CrossRef30
Luca Testa, Ravinai Bhindi, Pierfrancesco Agostoni, Antonio Abbate, Guiseppe GL Biondi Zoccai, William J van Gaal. (2007) The direct thrombin inhibitor ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile. Expert Opinion on Drug Safety 6:4, 397-406
CrossRef31
Stephen H. McKellar, Jess L. Thompson, Hartzell V. Schaff. (2007) A Model of Heterotopic Aortic Valve Replacement for Studying Thromboembolism Prophylaxis in Mechanical Valve Prostheses. Journal of Surgical Research 141:1, 1-6
CrossRef32
Alex C Spyropoulos. (2007) Investigational treatments of venous thromboembolism. Expert Opinion on Investigational Drugs 16:4, 431-440
CrossRef33
M.-M. Samama, G. Gerotziafas. (2007) Les nouveaux anticoagulants. Annales Pharmaceutiques Françaises 65:2, 85-94
CrossRef34
Peter D. Asnis, Michael J. Gardner, Anil Ranawat, Anne H. Leitzes, Margaret G.E. Peterson, Anne R. Bass. (2007) The Effectiveness of Warfarin Dosing from a Nomogram Compared with House Staff Dosing. The Journal of Arthroplasty 22:2, 213-218
CrossRef35
Matthew L. Ortman, Todd E.H. Hecht. 2007. Prevention of Venous Thromboembolism in the Surgical Patient. , 151-222.
CrossRef36
Bruno Tribout, Florence Colin-Mercier. (2007) New versus Established Drugs in Venous Thromboprophylaxis. American Journal of Cardiovascular Drugs 7:1, 1-15
CrossRef37
David Bergqvist. (2006) Venous Thromboembolism: A Review of Risk and Prevention in Colorectal Surgery Patients. Diseases of the Colon & Rectum 49:10, 1620-1628
CrossRef38
Stefan Kuhle, Alice Lau, Laszlo Bajzar, Patsy Vegh, Jacqueline Halton, Irene Cherrick, Ron Anderson, Sunil Desai, Patricia McCusker, John Wu, Thomas Abshire, Donald Mahoney, Lesley Mitchell. (2006) Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with l-asparaginase: an in vitro study. British Journal of Haematology 134:5, 526-531
CrossRef39
Shannon M. Bates, Jeffrey I. Weitz. (2006) The status of new anticoagulants. British Journal of Haematology 134:1, 3-19
CrossRef40
Serge Motte, Charles Marc Samama, Joanne Guay, Jeanne Barrê, Jeanne-Yvonne Borg, Nadia Rosencher. (2006) Prevention of postoperative venous thromboembolism. Risk assessment and methods of prophylaxis. Canadian Journal of Anesthesia/Journal canadien d'anesthésie 53:S2, S68-S79
CrossRef41
Carlos A Salazar, German Malaga, Giuliana Malasquez, Carlos A Salazar. 2006. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparin for prevention of venous thromboembolism following total hip or knee replacement or hip repair. .
CrossRef42
Rakesh P. Mehta, Matthew S. Johnson. (2006) Update on Anticoagulant Medications for the Interventional Radiologist. Journal of Vascular and Interventional Radiology 17:4, 597-612
CrossRef43
Job Harenberg, Ingrid Jörg, Christel Weiss. (2006) Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran. European Journal of Clinical Pharmacology 62:3, 173-177
CrossRef44
Cedric Hermans, Donald Claeys. (2006) Review of the rebound phenomenon in new anticoagulant treatments. Current Medical Research and Opinion 22:3, 471-481
CrossRef45
Johann Motsch, Andreas Walther, Matthias Bock, Bernd W. B??ttiger. (2006) Update in the prevention and treatment of deep vein thrombosis and pulmonary embolism. Current Opinion in Anaesthesiology 19:1, 52-58
CrossRef46
Enrique Ginzburg, Kresimir Banovac, Bryce Epstein, Kester Nedd, Murray Rolnick, Scott Tannenbaum. (2006) Thromboprophylaxis in Medical and Surgical Patients Undergoing Physical Medicine and Rehabilitation. American Journal of Physical Medicine & Rehabilitation 85:2, 159-166
CrossRef47
Doruk Erkan, Michael D. Lockshin. (2006) New Treatments for Antiphospholipid Syndrome. Rheumatic Disease Clinics of North America 32:1, 129-148
CrossRef48
Kenneth A. Bauer. (2006) New Anticoagulants: Anti IIa vs Anti Xa—Is One Better?. Journal of Thrombosis and Thrombolysis 21:1, 67-72
CrossRef49
Deepak Thatai, Vineeta Ahooja, Patrick M Pullicino. (2006) Pharmacological Prevention of Thromboembolism in Patients with Left Ventricular Dysfunction. American Journal of Cardiovascular Drugs 6:1, 41-49
CrossRef50
Bengt I Eriksson, Daniel J Quinlan. (2006) Oral Anticoagulants in Development. Drugs 66:11, 1411-1429
CrossRef51
Linda C Wernevik, Per Nystr??m, Magnus Andersson, Gillis Johnsson, Anders Bylock, Takashi Nakanishi, Ulf G Eriksson. (2006) Comparable Pharmacokinetics and Pharmacodynamics of Melagatran in Japanese and Caucasian Volunteers after Oral Administration of the Direct Thrombin Inhibitor Ximelagatran. Clinical Pharmacokinetics 45:1, 85-94
CrossRef52
Hans-Christoph Diener. (2006) Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Non-Valvular Atrial Fibrillation. Cerebrovascular Diseases 21:4, 279-293
CrossRef53
Margareta Elg, David Gustafsson. (2006) A combination of a thrombin inhibitor and dexamethasone prevents the development of experimental disseminated intravascular coagulation in rats. Thrombosis Research 117:4, 429-437
CrossRef54
Shaker A. Mousa, Hikmat N. Abdel-Razeq. (2005) Ximelagatran, the New Oral Anticoagulant: Would Warfarin Survive the Challenge?. Cardiovascular Drug Reviews 23:4, 331-344
CrossRef55
David Garcia, Walter Ageno, Edward Libby. (2005) Update on the diagnosis and management of pulmonary embolism. British Journal of Haematology 131:3, 301-312
CrossRef56
A. T. Cohen, C. Hirst, B. Sherrill, P. Holmes, D. Fidan. (2005) Meta-analysis of trials comparing ximelagatran with low molecular weight heparin for prevention of venous thromboembolism after major orthopaedic surgery. British Journal of Surgery 92:11, 1335-1344
CrossRef57
Lisa Kwok, Dana Molckovsky, Michel Boucher. (2005) Ximelagatran: A new type of oral anticoagulant. International Journal of Technology Assessment in Health Care 21:04,
CrossRef58
Ting-Ting Hong, Jinbao Huang, Edward Driscoll, Benedict R Lucchesi. (2005) The Antithrombotic Effect of Melagatran in Combination With Clopidogrel and/or Aspirin (carotid artery primary thrombosis study). Journal of Cardiovascular Pharmacology 46:4, 526-533
CrossRef59
Di Nisio, Marcello, Middeldorp, Saskia, Büller, Harry R., . (2005) Direct Thrombin Inhibitors. New England Journal of Medicine 353:10, 1028-1040
Full Text60
Thomas M. Hyers. (2005) Heparin and Other Rapidly Acting Anticoagulants. Seminars in Vascular Surgery 18:3, 130-133
CrossRef61
D. R. PHILLIPS, P. B. CONLEY, U. SINHA, P. ANDRE. (2005) Therapeutic approaches in arterial thrombosis. Journal of Thrombosis and Haemostasis 3:8, 1577-1589
CrossRef62
J. I. WEITZ, S. M. BATES. (2005) New anticoagulants. Journal of Thrombosis and Haemostasis 3:8, 1843-1853
CrossRef63
Christopher J Boos, Gregory YH Lip. (2005) Ximelagatran for stroke prevention in atrial fibrillation. Expert Review of Cardiovascular Therapy 3:4, 551-563
CrossRef64
Deepak Voora, Howard L McLeod, Charles Eby, Brian F Gage. (2005) The pharmacogenetics of coumarin therapy. Pharmacogenomics 6:5, 503-513
CrossRef65
Stefan Carlsson, Margareta Elg. (2005) The effects of ximelagatran and warfarin on the prophylaxis of a caval vein thrombosis and bleeding in the anaesthetized rat. Blood Coagulation & Fibrinolysis 16:4, 245-249
CrossRef66
M. Hellgren, S. Johansson, U.G. Eriksson, K. Wåhlander. (2005) The oral direct thrombin inhibitor, ximelagatran, an alternative for anticoagulant treatment during the puerperium and lactation. BJOG: An International Journal of Obstetrics & Gynaecology 112:5, 579-583
CrossRef67
P. ZUFFEREY, S. LAPORTE, S. MOLLIEX, C. AUBOYER, P. MISMETTI. (2005) Ximelagatran and melagatran vs. low-molecular-weight heparin in major orthopedic surgery: relationship between efficacy and safety and timing of initial administration*. Journal of Thrombosis and Haemostasis 3:5, 1104-1107
CrossRef68
Susanne Johansson, Lis Ohlsson, Helene Stenhoff, Karin W
hlander, Marie Cullberg. (2005) No effect of encapsulation on the pharmacokinetics of warfarin. Biopharmaceutics & Drug Disposition 26:3, 121-127
CrossRef69
P. Bramlage, D. Pittrow, W. Kirch. (2005) Current concepts for the prevention of venous thromboembolism. European Journal of Clinical Investigation 35:s1, 4-11
CrossRef70
Marnix R. Hoppener, Harry R. B
CrossRef71
Paul A Kyrle, Sabine Eichinger. (2005) Deep vein thrombosis. The Lancet 365:9465, 1163-1174
CrossRef72
Michael H Huo, Ryan Stuckey. (2005) Thromboembolism after total hip arthroplasty. Current Opinion in Orthopaedics 16:1, 25-28
CrossRef73
Eugene P. Frenkel, Yu-Min Shen, Barbara B. Haley. (2005) The Direct Thrombin Inhibitors: Their Role and Use for Rational Anticoagulation. Hematology/Oncology Clinics of North America 19:1, 119-145
CrossRef74
Lori-Ann Linkins, Jeffrey I. Weitz. (2005) New Anticoagulant Therapy. Annual Review of Medicine 56:1, 63-77
CrossRef75
Masahiko Nishiguchi, Noboru Takamura, Yasuyo Abe, Masafumi Kono, Hiroyuki Shindo, Kiyoshi Aoyagi. (2005) Pilot study on the use of tourniquet: a risk factor for pulmonary thromboembolism after total knee arthroplasty?. Thrombosis Research 115:4, 271-276
CrossRef76
Ola E Dahl, Bengt I Eriksson, Giancarlo Agnelli, Alexander T Cohen, Patrick Mouret, Nadia Rosencher, Seva Panfilov, Anders Bylock, Magnus Andersson. (2005) Postoperative Melagatran/Ximelagatran for the Prevention of Venous Thromboembolism following Major Elective Orthopaedic Surgery. Clinical Drug Investigation 25:1, 65-77
CrossRef77
Giancarlo Agnelli. (2005) Current Issues in Anticoagulation. Pathophysiology of Haemostasis and Thrombosis 34:1, 2-9
CrossRef78
Stefan C. Carlsson, Christer Mattsson, Ulf G. Eriksson, Troy C. Sarich, Karin Wåhlander, Åsa Eliasson, Björn W. Karlson, Sunita B. Sheth, Peter Held. (2005) A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays. Thrombosis Research 115:1-2, 9-18
CrossRef79
Jonathan L. Halperin. (2005) Ximelagatran: Oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation. Journal of the American College of Cardiology 45:1, 1-9
CrossRef80
Bengt Eriksson. (2005) Ximelagatran in Orthopaedic Surgery. Pathophysiology of Haemostasis and Thrombosis 34:1, 10-17
CrossRef81
William M Lee, Dominique Larrey, Rolf Olsson, James H Lewis, Marianne Keisu, Laurent Auclert, Sunita Sheth. (2005) Hepatic Findings in Long-Term Clinical Trials of Ximelagatran. Drug Safety 28:4, 351-370
CrossRef82
Mike Ufer. (2005) Comparative Pharmacokinetics of Vitamin K Antagonists. Clinical Pharmacokinetics 44:12, 1227-1246
CrossRef83
Anne Grand???Maison, Andre F Charest, William H Geerts. (2005) Anticoagulant Use in Patients with Chronic Renal Impairment. American Journal of Cardiovascular Drugs 5:5, 291-305
CrossRef84
Eva Ersdal, Kajs-Marie Sch??tzer, Carina L??nnerstedt, Lis Ohlsson, Ulrika Wall, Ulf G Eriksson. (2005) No Influence of Food on the Pharmacokinetics, Pharmacodynamics or Tolerability of the 24mg and 36mg Oral Tablet Formulations of Ximelagatran. Clinical Drug Investigation 25:7, 425-433
CrossRef85
Brian T. Feeley, Jay R. Lieberman. (2004) Warfarin Prophylaxis following Total Hip and Knee Arthroplasty. Techniques in Orthopaedics 19:4, 266-274
CrossRef86
Christopher J Boos, Gregory YH Lip. (2004) Novel therapies for the prevention of stroke. Expert Opinion on Investigational Drugs 13:12, 1615-1630
CrossRef87
A. Planes. (2004) Prevention of venous thromboembolism after orthopedic surgery: the EXPRESS study. Journal of Thrombosis and Haemostasis 2:11, 2037-2039
CrossRef88
Howard C. Cook. (2004) Alternatives to Heparin Infusion. Journal of Infusion Nursing 27:6, 413-424
CrossRef89
David Bergqvist. (2004) Bleeding profiles of anticoagulants, including the novel oral direct thrombin inhibitor ximelagatran: definitions, incidence and management. European Journal of Haematology 73:4, 227-242
CrossRef90
David Hawkins. (2004) The Role of Oral Direct Thrombin Inhibitors in the Prophylaxis of Venous Thromboembolism. Pharmacotherapy 24:10 Part 2, 179S-183S
CrossRef91
Palle Petersen. (2004) New approaches to anticoagulation in atrial fibrillation. Current Cardiology Reports 6:5, 354-364
CrossRef92
Lisa M. Tong. (2004) Ximelagatran-An Oral Direct Thrombin Inhibitor. Progress in Cardiovascular Nursing 19:4, 168-173
CrossRef93
N. Rosencher. (2004) Ximelagatran, a new oral direct thrombin inhibitor, for the prevention of venous thromboembolic events in major elective orthopaedic surgery. Efficacy, safety and anaesthetic considerations. Anaesthesia 59:8, 803-810
CrossRef94
G. Di Minno, A. Tufano. (2004) Challenges in the prevention of venous thromboembolism in the elderly. Journal of Thrombosis and Haemostasis 2:8, 1292-1298
CrossRef95
David Gustafsson, Ruth Bylund, Thomas Antonsson, Ingemar Nilsson, Jan-Erik Nyström, Ulf Eriksson, Ulf Bredberg, Ann-Catrine Teger-Nilsson. (2004) Case history: A new oral anticoagulant: the 50-year challenge. Nature Reviews Drug Discovery 3:8, 649-659
CrossRef96
A. Iorio. (2004) Prevention of venous thromboembolism after major orthopedic surgery: summing up evidence about old and new antithrombotic agents. Journal of Thrombosis and Haemostasis 2:7, 1055-1057
CrossRef97
David E. Kandzari. (2004) Current concepts in the antithrombotic management of non-ST-elevation acute coronary syndromes. Current Cardiology Reports 6:4, 279-286
CrossRef98
Gary E. Sander, Thomas D. Giles. (2004) Ximelagatran: Light at the End of the Tunnel or the Next Tunnel?. The American Journal of Geriatric Cardiology 13:4, 221-224
CrossRef99
Amar M Salam, Eyas N Al-Mousa. (2004) The therapeutic potential of ximelagatran to become the anticoagulant of choice in medicine: a review of recently completed clinical trials. Expert Opinion on Pharmacotherapy 5:6, 1423-1430
CrossRef100
Cabot, Richard C.Harris, Nancy Lee, Shepard, Jo-Anne O., Ebeling, Sally H.Ellender, Stacey M.Peters, Christine C., Goldhaber, Samuel Z., Nadel, Eric S., King, Mary Etta, Sharma, Amita, . (2004) Case 17-2004. New England Journal of Medicine 350:22, 2281-2290
Full Text101
Juan F. Viles-Gonzalez, Sunil X. Anand, M. Urooj Zafar, Valentin Fuster, Juan J. Badimon. (2004) Tissue Factor Coagulation Pathway: A New Therapeutic Target in Atherothrombosis. Journal of Cardiovascular Pharmacology 43:5, 669-676
CrossRef102
Aline Charabaty Pishvaian, Bradley W. Trope, James H. Lewis. (2004) Drug-induced liver disease in 2003. Current Opinion in Gastroenterology 20:3, 208-219
CrossRef103
James S Kalus, Michael F Caron. (2004) Novel uses for current and future direct thrombin inhibitors: focus on ximelagatran and bivalirudin. Expert Opinion on Investigational Drugs 13:5, 465-477
CrossRef104
Mark A Crowther, Jeffrey I Weitz. (2004) Ximelagatran: the first oral direct thrombin inhibitor. Expert Opinion on Investigational Drugs 13:4, 403-413
CrossRef105
Shuwei Gao, Carmen Escalante. (2004) Venous thromboembolism and malignancy. Expert Review of Anticancer Therapy 4:2, 303-320
CrossRef106
Craig M Kessler. (2004) Antidotes to haemorrhage: recombinant factor VIIa. Best Practice & Research Clinical Haematology 17:1, 183-197
CrossRef107
Charles W Francis. (2004) Ximelagatran: a new oral anticoagulant. Best Practice & Research Clinical Haematology 17:1, 139-152
CrossRef108
Victor J Marder, Michael H Rosove, Dena M Minning. (2004) Foundation and sites of action of antithrombotic agents. Best Practice & Research Clinical Haematology 17:1, 3-22
CrossRef109
Jonathan L Halperin. (2004) Antithrombotic therapy in atrial fibrillation: ximelagatran, an oral direct thrombin inhibitor. Expert Review of Cardiovascular Therapy 2:2, 163-174
CrossRef110
Theodore E Warkentin. (2004) Bivalent direct thrombin inhibitors: hirudin and bivalirudin. Best Practice & Research Clinical Haematology 17:1, 105-125
CrossRef111
(2004) Ximelagatran versus Warfarin after Total Knee Replacement. New England Journal of Medicine 350:6, 616-617
Full Text112
Stig L Boström, Göran F.H Hansson, Troy C Sarich, Michael Wolzt. (2004) The inhibitory effect of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, compared with enoxaparin and r-hirudin on ex vivo thrombin generation in human plasma. Thrombosis Research 113:1, 85-91
CrossRef113
William Simonson, Bob L. Lobo, Bruce Davidson. (2004) Venous Thromboembolism: Optimizing Clinical Outcomes for the Elderly. The Consultant Pharmacist 19:0, 1-24
CrossRef114
Kajs-Marie Schützer, Ulrika Wall, Carina Lönnerstedt, Lis Ohlsson, Renli Teng, Troy C. Sarich, Ulf G. Eriksson. (2004) Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation. Current Medical Research and Opinion 20:3, 325-331
CrossRef115
Hannah C Evans, Caroline M Perry, Diana Faulds. (2004) Ximelagatran/Melagatran. Drugs 64:6, 649-678
CrossRef116
Henry Eriksson. (2004) Treatment of Venous Thromboembolism and Long-Term Prevention of Recurrence. Drugs 64:Supplement 1, 37-46
CrossRef117
Doruk Erkan, Michael D. Lockshin. (2004) How much warfarin is enough in APS related thrombosis?. Thrombosis Research 114:5-6, 435-442
CrossRef118
Lenka Hrebickova, James J. Nawarskas, Joe R. Anderson. (2003) Ximelagatran. Heart Disease 5:6, 397-408
CrossRef119
Shapiro, Sandor S., . (2003) Treating Thrombosis in the 21st Century. New England Journal of Medicine 349:18, 1762-1764
Full Text
- Letters
