Bleeding Indicators and Wound Complications with Ximelagatran and Warfarin after TKR: Findings from 3 Clinical Trials.
Authors: Berkowitz Scott D. , Francis Charles W. , McElhattan Jennifer , Colwell Clifford W. 
Published: October 2019

Introduction: Prophylaxis of venous thromboembolism (VTE) in patients undergoing total knee replacement (TKR) most often entails anticoagulation, yet minimization of excessive postoperative bleeding and wound complications is critical to attain an excellent functional result. Ximelagatran (Exanta®, AstraZeneca), the first oral alternative to warfarin, has a rapid onset of action and requires no coagulation monitoring or dose adjustment. Three randomized, double-blind trials of VTE prophylaxis after TKR comparing ximelagatran 24 and 36 mg BID with well-controlled warfarin (target INR 2.5) were completed: Study 236 (n=680), EXULT A (n=2301), and EXULT B (n=2303). When administered for 7–12 days, ximelagatran 36 mg BID was superior to well-controlled warfarin, while 24 mg yielded numerically better but not statistically superior efficacy over warfarin. Adjudicated bleeding rates did not differ significantly.

Objective: To assess the postoperative bleeding complications and overall surgical wound appearance during anticoagulation after TKR.

Methods: Two comparison pools were created: 36-mg pool (ximelagatran 36 mg and corresponding warfarin groups from EXULT A and B) and 24-mg pool (ximelagatran 24 mg and corresponding warfarin groups from Study 236 and EXULT A). Bleeding indicators, i.e., postoperative wound drainage, bleeding index, and transfusion requirements, were compared. A prespecified subjective assessment of the surgical wound was performed on postoperative Day 3, end of treatment (Day 7–12), and at follow-up (4–6 weeks). If wound appearance was rated “worse than expected” at any time point, wound characteristics of swelling, drainage, erythema, and bleeding were assessed. Intra-articular bleeding, unusual bruising or hematoma, and bleeding requiring an intervention were also recorded. Results:

36-mg Pool (n=3810) 24-mg Pool (n=2178) Bleeding Indicators Ximelagatran Warfarin Ximelagatran Warfarin Post-op wound drainage, mean in mL (95% CI) 697 (675, 718) 704 (682, 725) 659 (632, 686) 654 (626, 682) Bleeding Index, mean (95% CI) 3.4 (3.3, 3.4) 3.3 (3.2, 3.4) 3.2 (3.1, 3.3) 3.1 (3.0, 3.2) Transfusions Unplanned, % of Pts 8.9 8.1 Not Assessed Not Assessed Total, % of Pts 33.5 33.6 37.6 34.3 Vol. Transfused/Pt, mean (95% CI) 630 mL (602, 659) 606 mL (578, 635) 1.7 U (1.6, 1.8) 1.7 U (1.6, 1.8) Overall wound appearance (worse than expected), % 9.2 8.7 8.9 8.2 Wound characteristics (worse than expected) Swelling, % 5.1 4.5 5.7 4.6 Drainage, % 3.6 2.4 2.7 1.8 Erythema, % 3.9 3.7 2.8 3.5 Bleeding, % 1.7 1.2 Not Assessed Not Assessed

In the 36- and 24-mg pools the wound was assessed as “expected” or “better than expected” for ≥90% of the patients in the ximelagatran and warfarin groups. For the small number of patients with “worse than expected” wounds, the differences between the ximelagatran and warfarin groups were not statistically significant. Bleeding complications of the surgical wound, including intra-articular bleeding (<3.5%), unusual bruising or hematoma (<5.0%), and bleeding requiring an intervention (<0.9%), were few and comparable between treatment groups.

Conclusions: Analysis of bleeding indicators and complications of the surgical wound revealed no significant differences between treatment groups, supporting the safety of 36 mg for all patients undergoing TKR.