Key messages
• We do not know if classic anticoagulant medicines (commonly known as 'blood thinners') or newer blood-thinning medicines called 'direct factor Xa inhibitors' (DFXa inhibitors) are better at preventing death or the development of blood clots in the deep veins of the legs or in the lungs of people who have had hip or knee replacement surgery.
• Compared to classic anticoagulants, DFXa inhibitors may slightly reduce the number of people who experience blood clot symptoms (such as breathing difficulties or pain). One type of DFXa inhibitor, rivaroxaban, may slightly increase the number of people who have serious uncontrolled bleeding.
Why are blood clots a concern for people having major hip or knee surgery?
'Venous thromboembolism' is when a blood clot forms in a vein, the vessels that carry blood back to the heart. Clots can narrow or block veins, leading to tissue damage, stroke, and death. People having hip or knee replacement surgery, or an operation to fix a broken hip, are at a higher risk of developing a blood clot.
How can blood clots be prevented and treated?
People undergoing major hip or knee surgery are typically given an anticoagulant medicine, commonly known as a 'blood thinner', to help prevent blood clots from forming.
There are two main types of 'classic' anticoagulants: (1) low molecular weight heparins (LMWHs), which are injected with a needle at a fixed dose; and (2) vitamin K antagonists (VKAs), given by mouth in variable amounts.
Newer anticoagulant medicines known as direct factor Xa inhibitors have been developed. They are given by mouth in fixed doses. Rivaroxaban and apixaban are types of DFXa inhibitors.
What did we want to find out?
We wanted to find out if DFXa inhibitors were better than classic anticoagulants at reducing the number of people who (1) died from any cause after major hip or knee surgery, and (2) developed blood clots or symptoms of blood clots (e.g. breathing difficulties and pain).
We also wanted to find out if DFXa inhibitors were associated with any unwanted effects, including uncontrolled bleeding, serious liver disease, and other serious unwanted events.
What did we do?
We searched for studies that compared DFXa inhibitors with classic anticoagulants in people undergoing hip or knee surgery. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 53 studies that involved 44,371 adults who had hip or knee replacement surgery, and had a high risk of developing blood clots in their lungs, legs, or pelvis. They received anticoagulant treatment for 6 to 39 days, and follow-up lasted for an average of 42 days.
All 53 studies compared DFXa inhibitors with low molecular weight heparins (LMWHs). Just one study also investigated the VKA called warfarin.
The biggest study involved 5407 participants, and the smallest study, 50 participants. They were conducted in countries unevenly distributed around the world; most were done in high-income regions. Roughly one-third of participants (31%) were male. Participants' average age was 64 years. Pharmaceutical companies funded half of the studies (27 of 53).
Main results
Compared to LMWHs, we do not know if DFXa inhibitors reduce the number of people who:
• die from any cause after surgery, or
• develop blood clots in the lungs or deep veins of the leg or pelvis
because the evidence is very uncertain.
Compared to LMWHs, DFXa inhibitors may slightly reduce the number of people who have blood clot symptoms: between 2 and 5 fewer people out of every 1000 people given DFXa inhibitors would have blood clot symptoms compared to people given LMWHs.
The DFXa inhibitor rivaroxaban may slightly increase the number of people who have major uncontrolled bleeding compared to LMWHs. Between 1 and 7 more people out of every 1000 people given rivaroxaban may have uncontrolled bleeding compared to those given LMWHs.
The other DFXa inhibitors may have little to no effect on major bleeding, but the evidence is very uncertain.
Compared to LMWHs, DFXa inhibitors may have little to no effect on serious unwanted events affecting the liver, but the evidence is very uncertain.
They may slightly reduce other serious, non-liver-related events compared to LMWHs. Between 3 and 14 fewer people out of every 1000 people given DFXa inhibitors would have serious, non-liver-related events compared to people given LMWHs.
We did not find enough studies investigating VKAs to help us answer our questions.
What are the limitations of the evidence?
We have little confidence in the evidence because people in some studies were aware of which treatment they were getting. Most studies did not have a complete set of results for all participants. There were insufficient studies to be certain about the results of some outcomes.
How current is this evidence?
The evidence is current to November 2023.
Oral direct factor Xa inhibitors may have little to no effect on all-cause mortality, but the evidence is very uncertain.
Oral direct factor Xa inhibitors may slightly reduce symptomatic VTE events when compared with LMWH. They may make little or no difference to major VTE events, but the evidence is very uncertain.
In the evaluation of major bleeding, the evidence suggests rivaroxaban results in a slight increase in major bleeding events compared to LMWHs. The remaining oral direct factor Xa inhibitors may have little to no effect on major bleeding, but the evidence is very uncertain.
Oral direct factor Xa inhibitors may reduce serious non-hepatic adverse events slightly compared to LMWHs. They may have little to no effect on serious hepatic adverse events, but the evidence is very uncertain.
Due to the high rates of missing participants and selective outcome reporting, the effect estimates may be biased.
People undergoing major orthopaedic surgery are at increased risk of postoperative thromboembolic events. Low molecular weight heparins (LMWHs) are recommended for thromboprophylaxis in this population. New oral anticoagulants, including direct factor Xa inhibitors, are recommended as alternatives. They may have more advantages than disadvantages compared to LMWHs and vitamin K antagonists (VKAs, another type of anticoagulant).
To assess the benefits and harms of prophylactic anticoagulation with direct factor Xa inhibitors compared with low molecular weight heparins and vitamin K antagonists in people undergoing major orthopaedic surgery for elective total hip or knee replacement or hip fracture surgery.
We searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, two other databases, and two trial registers to 11 November 2023. We conducted reference checks to identify additional studies.
We included randomised controlled trials (RCTs) comparing the effects of direct factor Xa inhibitors to LMWHs or VKAs in people undergoing major orthopaedic surgery.
We used standard Cochrane methods. Our primary outcomes were all-cause mortality, major venous thromboembolism (VTE), symptomatic VTE, major bleeding, and serious hepatic and non-hepatic adverse events. We evaluated the risk of bias in the included studies using Cochrane's risk of bias 1 tool. We calculated estimates of treatment effects using risk ratios (RR) with 95% confidence intervals (CIs), and used GRADE criteria to assess the certainty of the evidence.
We included 53 RCTs (44,371 participants). Participants' average age was 64 years (range: 18 to 93 years). Only one RCT compared a VKA with direct factor Xa inhibitors. All 53 RCTs compared direct factor Xa inhibitors with LMWHs. Twenty-three studies included participants undergoing total hip replacement; 21 studies, total knee replacement; and three studies included people having hip fracture surgery. The studies' average duration was approximately 42 days (range: two to 720 days).
Compared to LMWHs, direct factor Xa inhibitors may have little to no effect on all-cause mortality, but the evidence is very uncertain (RR 0.83, 95% CI 0.52 to 1.31; I2 = 0%; 28 studies, 29,698 participants; very low-certainty evidence).
Direct factor Xa inhibitors may make little to no difference to major venous thromboembolic events compared to LMWHs, but the evidence is very uncertain (RR 0.51, 95% CI 0.37 to 0.71; absolute risk difference: 12 fewer major VTE events per 1000 participants, 95% CI 16 fewer to 7 fewer; I2 = 48%; 28 studies, 24,574 participants; very low-certainty evidence).
Compared to LMWHs, direct factor Xa inhibitors may reduce symptomatic VTE (RR 0.64, 95% CI 0.50 to 0.83; I2 = 0%; 33 studies, 31,670 participants; low-certainty evidence). The absolute benefit of substituting factor Xa inhibitors for LMWHs may be between two and five fewer symptomatic VTE episodes per 1000 patients.
In the meta-analysis with all studies pooled, direct factor Xa inhibitors appeared to make little or no difference to major bleeding compared to LMWHs, but the evidence was very uncertain (RR 1.05, 95% CI 0.86 to 1.30; I2 = 15%; 36 studies, 39,778 participants; very low certainty-evidence).
• In a subgroup analysis limited to studies comparing rivaroxaban to LMWHs, people given rivaroxaban may have had more major bleeding events (RR 1.94, 95% CI 1.26 to 2.98; I2 = 0%; 17 studies, 17,630 participants; low-certainty evidence). The absolute risk of substituting rivaroxaban for LMWH may be between one and seven more major bleeding events per 1000 patients.
• In a subgroup analysis limited to studies comparing direct factor Xa inhibitors other than rivaroxaban to LMWHs, people given these other direct factor Xa inhibitors may have had fewer major bleeding events, but the evidence was very uncertain (RR 0.80, 95% CI 0.63 to 1.02; absolute risk difference: 3 fewer major bleeding events per 1000 participants, 95% CI 5 fewer to 0 fewer; I2 = 0%; 19 studies, 22,148 participants; very low-certainty evidence).
Direct factor Xa inhibitors may make little to no difference in serious hepatic adverse events compared to LMWHs, but the evidence is very uncertain (RR 3.01, 95% CI 0.12 to 73.93; 2 studies, 3169 participants; very low-certainty evidence). Only two studies reported this outcome, with one death in the intervention group due to hepatitis reported in one study, and no events reported in the other study.
People given direct factor Xa inhibitors may have a lower risk of serious non-hepatic adverse events than those given LMWHs (RR 0.89, 95% CI 0.81 to 0.97; I2 = 18%; 15 studies, 26,246 participants; low-certainty evidence). The absolute benefit of substituting factor Xa inhibitors for LMWH may be between three and 14 fewer serious non-hepatic adverse events per 1000 patients.
Only one study compared a direct factor Xa inhibitor with a VKA. It reported outcome data with imprecise results due to the small number of events. It showed no difference in the effects of the study drugs.