Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study

Abstract

Summary. Background: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10±15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the ef®cacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. Methods: This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received ®xed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7± 12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. Results: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (ef®cacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% con®dence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatrantreated patients and in 0.9% (eight of 910) of the enoxaparintreated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespeci®ed margin of 5% was not met, resulting in superiority of the enoxaparin regimen. Conclusions: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further re®nement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Prevention of Venous Thromboembolism in Surgical Patients

“…49 Venous thromboembolism was observed in 4.6% of the enoxaparin patients and 7.9% of the ximelagatran group, a statistically significant difference. Major bleeding was documented in less than 1% of patients in both groups.…”

“…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.…”

Thrombotic Complications of Central Venous Catheters in Cancer Patients

“…But it may be more fruitful to consider instead the use of newer factor Xa inhibitors, such as pentasaccharide [73][74][75][76], or direct thrombin inhibitors, such as ximelegatran [77][78][79][80][81]. The former appears to be a more effective prophylaxis of venous thromboembolism and is associated with less bleeding than LMWH.…”

The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants

“…Figure 1 shows that the noninferiority margins for the RDs from the trials were stricter than the 50% preserved-effects reference noninferiority margin (0.02-0.092 v. 0.115); thus, the conclusion of noninferiority in these trials does not change when using the reference noninferiority margin, with the exception of the trial by Colwell and colleagues. 11 The noninferiority margins in the RE-MODEL, 12 RE-MOBILIZE 13 and RE-NOVATE 14 trials were larger (i.e., less conservative) than the 67% preserved-effect reference noninferiority margin (0.092 and 0.077 v. 0.076). In the RE-MODEL trial, 12 dabigatran (150 mg) would not have been found noninferior to enoxaparin if the 67% preserved-effect reference noninferiority margin had been used.…”

“…One trial stated that an independent expert committee determined the margin, which was the same noninferiority margin that had been used in a previous active-controlled trial of enoxaparin versus tinzarapin. 11 Three trials used 67% preserved-effect of the (pooled) effect of 1 or 3 placebo-controlled trials. [12][13][14] Reference noninferiority margin We determined a reference noninferiority margin using the fixed-margin method recommended in the draft guideline.…”