THE EFFICACY AND SAFETY OF ORAL DIRECT FACTOR XA INHIBITING ANTICOAGULANTS IN ELECTIVE TOTAL HIP AND KNEE ARTHROPLASTY: META-ANALYSES OF 16203 CASES

Abstract

Background: The recognised risk of post-operative venous thromboembolism (VTE), presenting as deep vein thrombosis (DVT) and/or pulmonary embolism (PE), after elective total hip and knee arthroplasty (THA and TKA) has always made the selection of suitable thromboprophylaxis treatment a clinical priority for orthopaedic surgeons. Over recent years there has been the emergence of new oral direct Factor Xa (FXa) inhibiting anticoagulants, which may replace the widely used low-molecular-weight heparins (LMWHs).

Methods: A systematic review of published English-language literature (completed in July 2009) and surgical type meta-analyses were conducted to compare the efficacy (risk of any DVT, PE and all-cause mortality) and safety (risk of major bleeding requiring clinical intervention) of oral direct FXa inhibiting anticoagulants with LMWHs in THA and TKA.

Results: Five eligible THA randomised-controlled trials (RCTs) with total of 9286 patients and three eligible TKA RCTs with 6917 patients were identified. The Der-Simonian-Laird random effects model was employed for each meta-analysis and heterogeneity between trials was explored statistically using the Mantel-Haenszel χ² test. The efficacy meta-analysis of THA RCTs revealed an odds ratio (OR) 0.46 (95% confidence interval (c.i.) 0.23, 0.92), which was significantly (P = 0.03) in favour of the oral FXa inhibitors but there was sizable heterogeneity amongst trials (P = 0.0002). Although the safety meta-analysis of THA RCTs showed an increase incidence of major bleeding with the use of oral FXa inhibitors, OR 1.71 (95% c.i. 0.67, 4.39), this risk was not statistically significant (P = 0.26) with little heterogeneity between trials (P = 0.44). The efficacy meta-analysis of TKA RCTs demonstrated an efficacy OR 0.56 (95% c.i. 0.42, 0.73), in favour of the oral FXa inhibitors (P = 0.0001) with no significant heterogeneity (P = 0.21). The safety meta-analysis of TKA RCTs showed an increased occurrence of major bleeding with oral FXa inhibitors, OR 1.79 (95% c.i. 0.83, 3.87), but this was not statistically significant (P = 0.14) and heterogeneity between trials was low (P = 0.54).

Conclusions: This review demonstrated an overall better efficacy for oral FXa inhibitors compared with LMWHs in thromboprophylaxis for both THA and TKA. Although it also revealed that oral FXa inhibitors were statistically as safe as LMWHs, there was clinically higher incidence of major bleeding with their use in both THA and TKA. These safety results coupled with the fact that currently no specific antidote exists, highlights the urgent need for further research and large RCTs to prove the clinical safety of all new oral direct FXa inhibiting anticoagulants.