There is currently limited information available on the benefits and risks of extended thromboprophylaxis after hip fracture surgery. SAVE-HIP3 was a randomised, double-blind study conducted to evaluate the efficacy and safety of extended thromboprophylaxis with the ultra-low molecular-weight heparin semuloparin compared with placebo in patients undergoing hip fracture surgery. After a seven- to ten-day open-label run-in phase with semuloparin (20 mg once daily subcutaneously, initiated post-operatively), patients were randomised to once-daily semuloparin (20 mg subcutaneously) or placebo for 19 to 23 additional days. The primary efficacy endpoint was a composite of any venous thromboembolism (VTE; any deep-vein thrombosis and non-fatal pulmonary embolism) or all-cause death until day 24 of the double-blind period. Safety parameters included major and clinically relevant non-major bleeding, laboratory data, and treatment-emergent adverse events (TEAEs). Extended thromboprophylaxis with semuloparin demonstrated a relative risk reduction of 79% in the rate of any VTE or all-cause death compared with placebo (3.9% vs 18.6%, respectively; odds ratio 0.18 (95% confidence interval 0.07 to 0.45), p < 0.001). Two patients in the semuloparin group and none in the placebo group experienced clinically relevant bleeding. TEAE rates were similar in both groups. In conclusion, the SAVE-HIP3 study results demonstrate that patients undergoing hip fracture surgery benefit from extended thromboprophylaxis.

Cite this article: Bone Joint J 2013;95-B:459–66.

Patients who have undergone total hip or knee replacement (THR and TKR, respectively) are at high risk of venous thromboembolism. We aimed to determine the time courses of both the incidence of venous thromboembolism and effective prophylaxis. Patients with elective primary THR and TKR were enrolled in the multi-national Global Orthopaedic Registry. Data on the incidence of venous thromboembolism and prophylaxis were collected from 6639 THR and 8326 TKR patients.

The cumulative incidence of venous thromboembolism within three months of surgery was 1.7% in the THR and 2.3% in the TKR patients. The mean times to venous thromboembolism were 21.5 days (sd 22.5) for THR, and 9.7 days (sd 14.1) for TKR. It occurred after the median time to discharge in 75% of the THR and 57% of the TKA patients who developed venous thromboembolism. Of those who received recommended forms of prophylaxis, approximately one-quarter (26% of THR and 27% of TKR patients) were not receiving it seven days after surgery, the minimum duration recommended at the time of the study.

The risk of venous thromboembolism extends beyond the usual period of hospitalisation, while the duration of prophylaxis is often shorter than this. Practices should be re-assessed to ensure that patients receive appropriate durations of prophylaxis.

Aims: To investigate the efficacy and safety of a new dosage regimen of the oral direct thrombin inhibitor ximelagatran, and its subcutaneous (sc) form melagatran, started in close proximity to surgery. Methods: In a randomised, double-blind, parallel-group study, duration 8–11 days, patients undergoing total hip or knee replacement (THR, n= 1856; TKR, n= 908) received either sc melagatran 2 mg immediately before surgery followed by sc 3 mg in the evening after surgery, and then by oral ximelagatran 24 mg bid as a fixed dose (the ximelagatran group), or sc enoxaparin 40 mg od, started the evening before surgery. Bilateral venography was performed on the final day of treatment. Results: The rate of proximal deep vein thrombosis plus pulmonary embolism was 2.3% in the ximelagatran group vs. 6.3% in the enoxaparin group (p< 0.000002; RRR 63.2%). The total rates of venous thromboembolism (VTE) were 20.3% vs. 26.6%, respectively (p< 0.0003; RRR 23.6%). Cases with symptomatic VTE were rare: 8 in the ximelagatran group and 12 in the enoxaparin group. Bleeding events were more common in the ximelagatran group compared with the enoxaparin group (3.3% vs. 1.2%) as were the transfusion rates (66.8% vs. 61.7%). Importantly, there were no differences in fatal bleeding, critical organ bleeding or bleeding requiring re-operation. Conclusion: Pre-operatively initiated sc melagatran followed by oral ximelagatran was superior in efficacy to enoxaparin in preventing VTE in patients undergoing THR or TKR.

Ximelagatran is an oral direct thrombin inhibitor intended for the prophylaxis and treatment of thrombo-embolic complications. Purpose: The efficacy and safety of ximelagatran, and its subcutaneous (sc) form melagatran, were evaluated in patients undergoing total hip or knee replacement (THR, TKR). Study 1 was a randomised, double-blind, controlled, dose–response study in which patients received 2-6 doses of sc melagatran (1, 1.5, 2.25, or 3 mg bid) followed by oral ximelagatran (8, 12, 18, or 24 mg bid), or sc dalteparin (5000 IU od). Melagatran treatment was initiated immediately before surgery. Study 2 was a randomized, double-blind, controlled study in which patients received 1–5 doses of sc melagatran (3 mg bid) initiated 4–12 h after surgery followed by oral ximelagatran (24 mg bid), or sc enoxaparin (40 mg od). In both studies, low-molecular-weight heparin (LMWH) was started the evening before surgery, and all treatment regimens were continued for 8–11 days. Bilateral venography was performed on the final day of treatment.

Results: In Study 1, 1876 patients underwent THR (n=1270) or TKR (n=606). A significant dose-dependent reduction in venous thromboembolism (VTE) was seen with melagatran + ximelagatran for both THR (P< 0.0001) and TKR (P=0.0014). The rate of VTE was significantly lower with the highest dose of melagatran + ximelagatran (15.1%) when compared with dalteparin (28.2%) (P< 0.0001). In Study 2, 2788 patients underwent THR (n=1923) or TKR (n=865). The VTE rate was 31% in the melagatran + ximelagatran group and 27% in the enoxaparin group (P=0.053). Total bleeding volume was not significantly different between treatment groups. Conclusion: Fixed-dose sc melagatran followed by oral ximelagatran are efficacious and well tolerated for the prophylaxis of VTE following THR or TKR.