Oral Direct Factor Xa Inhibitors Versus Low-Molecular-Weight Heparin to Prevent Venous Thromboembolism in Patients Undergoing Total Hip or Knee Replacement: A Systematic Review and Meta-Analysis

Study Questions:

What are the benefits and harms of oral direct factor Xa inhibitors versus low molecular weight heparin (LMWH) to prevent venous thromboembolism (VTE) in patients undergoing total hip or knee replacement surgery?


The authors performed a systematic review and meta-analysis, electronically searching the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. The authors included all studies that were randomized clinical trials of subjects undergoing hip or knee replacement surgery, evaluating direct oral factor Xa inhibitors with any of the following outcomes: mortality at the end of prophylaxis, mortality during follow-up, symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), major bleeding, intracranial bleeding, and bleeding leading to reoperation. Data were abstracted by two reviewers independently and assessed for risk of bias.


In reviewing 22 eligible trials, the authors reported that high-quality evidence suggests factor Xa inhibitors and LMWH do not differ in terms of all-cause mortality (risk difference [RD], 0 fewer deaths per 1,000 patients; 95% confidence interval [CI], 2 fewer to 1 more death) or nonfatal PE (RD, 0 events per 1,000 patients; CI, 1 fewer to 2 more events). Factor Xa inhibitors can prevent 4 instances of symptomatic DVT per 1,000 treated patients (CI, 3 to 6 fewer events), but was associated with increased risk of major bleeding by 2 more events per 1,000 patients (CI, 0 to 4 more events). High- but not low-dose factor Xa inhibitors increased bleeding compared with LMWH.


The authors concluded that, compared with LMWH, lower doses of oral factor Xa inhibitors can achieve the small absolute risk reduction in symptomatic DVT without increasing bleeding.


This important meta-analysis provides additional perspective on the relative benefits of factor Xa inhibitors versus LMWH for VTE prophylaxis after knee or hip replacement surgery. This is an important topic because the incidence of VTE after such surgery is historically high. The topic will remain controversial, however. The authors themselves point out that the very small number of events observed suggest that if there is any difference between these agents, it is quite small. Furthermore, the bleeding outcomes were often treated as a composite event, most often only ‘major bleeding,’ which may grossly undercount wound hematoma, or minor wound bleeding. This is a concern for the operating surgeons, as it may predispose to wound infections. Also, mandatory venographic screening was performed at the end of prophylaxis in all trials. This may have overcounted endpoints with the discovery of clinically silent DVT. (On the other hand, this may have resulted in the discovery of clinically minor DVTs which, because of treatment, never became symptomatic, resulting in an undercount of symptomatic DVT events.)

The most recent edition of the American College of Chest Physicians antithrombotic guidelines reflects the confusion in this field by recommending no fewer than 8 agents (including aspirin alone), as supportable by the literature for VTE prophylaxis in this situation. Given the cost of comparative effectiveness studies, and the conflicting concerns of interested parties, the controversy over best prophylaxis is unlikely to be resolved soon.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Lipid Metabolism, Novel Agents

Keywords: Arthroplasty, Replacement, Hip, Arthroplasty, Replacement, Knee, Follow-Up Studies, Confusion, Pulmonary Embolism, Heparin, Low-Molecular-Weight, Warfarin, Venous Thromboembolism, Wound Infection, Numbers Needed To Treat, Hematoma, Incidence, Reoperation, Cardiovascular Diseases, Venous Thrombosis, Confidence Intervals, Factor Xa, United States, Hemorrhage

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