The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study

Abstract

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

Epidemiology of post-operative venous thromboembolism in Asian patients. Results of the SMART venography study

“…[5][6][7] In addition, as in modern large Western studies, all venograms were reviewed centrally. The proportion of evaluable patients (84.5%) was high compared with the percentages of patients evaluable for primary efficacy (69.0 to 82.0%) recently reported in large multicenter studies using venography in orthopedic surgery, [11][12][13][14][15][16] and the vast majority of patients (92.7%) underwent clinical follow-up. We found a rate of asymptomatic or symptomatic venous thromboembolism or sudden death (primary outcome) of 36.5% (99% CI: 29.7-43.7) and a rate of proximal deep-vein thrombosis of 9.8% at hospital discharge.…”

“…1 Chronic heart failure, varicose veins and a history of venous thromboembolism were found to be independent risk factors (p<0.05) for the occurrence of the primary outcome. 1 In a recent review of published studies in Asian patients undergoing surgery and not receiving thromboprophylaxis, the adjusted incidence of total (symptomatic and asymptomatic) deep-vein thrombosis was 13% (95% CI: 10-16) in general surgery, 16% (95% CI: [13][14][15][16][17][18][19][20] after total hip replacement, 50% (95% CI: 44-55) after total knee replacement, and 18% (95% CI: 12-24) after hip fracture surgery. The adjusted incidence of symptomatic pulmonary embolism was 1% (95% CI: 0-2) in general surgery and 1.4% (95% CI: 1-3) after total hip replacement.…”

Prevention of Venous Thromboembolism in Surgical Patients

“…48,49 In the most recent of the European studies, patients undergoing elective hip or knee replacement were randomly assigned to prophylaxis with subcutaneous melagatran at the dose of 2 mg immediately before surgery and 3 mg on the evening of surgery, followed by oral ximelagatran at the dose of 24 mg twice a day versus enoxaparin at the dose of 40 mg started on the evening before surgery. 48 The rate of overall and proximal DVT was significantly lower in the melagatran/ximelagatran group, although bleeding and transfusion rates were greater.…”

Ximelagatran, the New Oral Anticoagulant: Would Warfarin Survive the Challenge?

“…However, the incidences of major and symptomatic VTE events were comparable in the two treatment groups. The two medications had a similar safety profile and were well tolerated (9).…”