Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.

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.

No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran.

BACKGROUND: Ximelagatran, an oral direct thrombin inhibitor, is currently in clinical development for the prevention and treatment of thromboembolic disease. Following oral administration, ximelagatran undergoes rapid bioconversion to its active form, melagatran, via two minor intermediates. Obesity, defined as body mass index (BMI) >30 kg/m(2), is a recognised risk factor for thrombosis. There is potential for differences in the pharmacokinetics and pharmacodynamics of drugs administered to obese versus non-obese patients, and some drugs may require alternative administration strategies in obese patients. OBJECTIVE: To investigate the effect of obesity on the pharmacokinetics and pharmacodynamics of melagatran after oral administration of ximelagatran. DESIGN AND PARTICIPANTS: This was an open-label, single-dose, group-matched study in which obese subjects (BMI 32-39 kg/m(2); six male and six female; age 21-40 years) were matched by sex and age (+/-2 years) with non-obese subjects (BMI 21-26 kg/m(2); six male and six female; aged 21-39 years). Each subject received a single oral dose of ximelagatran 24mg. Blood samples for determination of plasma concentrations of melagatran and activated partial thromboplastin times (APTT; a marker of melagatran pharmacodynamics) were collected up to 12 hours after administration. RESULTS: There were no statistically significant differences in the pharmacokinetic properties of melagatran between obese and non-obese subjects. Values of area under the melagatran plasma concentration-time curve, maximum plasma concentration (C(max)), time at which C(max) occurred and terminal elimination half-life were approximately 1 micromol. h/L, 0.2 micromol/L, 2 hours and 3 hours in both obese and non-obese subjects, respectively. In addition, there was no statistically significant difference between the obese and non-obese subjects in the amount of ximelagatran, melagatran or the minor intermediates ethyl-melagatran and melagatran hydroxyamidine excreted in urine. When relating the prolongation of APTT ratio to the square root of plasma concentration of melagatran and obesity status (no/yes), no statistically significant interaction between plasma concentration and obesity status was observed. Ximelagatran was well tolerated in both obese and non-obese subjects, and no bleeding events or serious adverse events occurred. CONCLUSIONS: No differences in the pharmacokinetics or pharmacodynamics of melagatran were detected between obese and non-obese subjects after oral administration of ximelagatran, suggesting that dose adjustment of ximelagatran in obesity (BMI up to 39 kg/m(2)) is not necessary.

Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial.

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

Effect of Gender and Menopausal Status on the Pharmacokinetics of Tirilazad Mesylate in Healthy Subjects.

The pharmacokinetics of tirilazad were assessed in men ages 40--60 years, women <40 years of age, premenopausal women ages 40--60, and postmenopausal ages 40--60. Eight subjects in each group received single 3.0 mg kg(minus sign1) intravenous infusions of tirilazad mesylate over 10 min. Plasma concentrations of tirilazad and U-89678, an active metabolite, were measured by high-performance liquid chromatography. Tirilazad administration was well tolerated in all groups. Mean tirilazad clearance was 59.6% higher in young women compared to the middle-aged men (35.6 plus minus 8.04 L h(minus sign1) vs. 22.3 plus minus 8.40 L h(minus sign1)). Mean tirilazad clearance in middle-aged women was 30.7% higher than in middle-aged men. Mean clearance in postmenopausal women (26.1 plus minus 4.21 L h(minus sign1)) was not significantly different than that in middle-aged men, but clearance corrected for body weight was significantly different between the men and postmenopausal women. Clearance in premenopausal middle-aged women (32.2 plus minus 7.60 L h(minus sign1)) was not significantly different from that in young women and was 44% greater than that in middle-aged men. Mean AUC(0minus signinfty infinity) and C(max) values for U-89678 were significantly higher in men than in all of the female groups. Among the women, values for U-89678 AUC(0minus signinfty infinity) were lowest in young women (467 plus minus 345 ng h ml(minus sign1), 8.8% of male value) and highest in postmenopausal women (1565 plus minus 1382 ng h ml(minus sign1), 29.4% of male value). The absolute values for U-89678 AUC(0minus signinfty infinity) must be interpreted with caution, as limited assay sensitivity and low plasma concentrations in the latter portion of the concentration-time profile in women precluded accurate determination of the terminal half-life and AUC(0minus signinfty infinity). Regardless, these results show that women, particularly premenopausal women, have lower concentrations of U-89678, an active metabolite of tirilazad, than are achieved in men. The gender differences in tirilazad and U-89678 pharmacokinetics are of sufficient magnitude that they may impact the clinical response of male and female patients to tirilazad treatment.