Anticoagulants taken for longer periods to prevent deep vein thrombosis or pulmonary embolism after hip or knee replacement

Background

Patients undergoing surgery have an increased risk of developing blood clots in their veins. These clots may be in the deep veins of the leg (deep vein thrombosis (DVT)) or travel to the lungs (pulmonary embolism (PE)). Venous thromboembolism (VTE) is the combined term for DVT and PE. Prevention of these blood clots (prophylaxis) after surgery may reduce the risk of postoperative vein clots. These potential benefits, however, have to be balanced against the associated risks of bleeding. The optimal duration of prophylaxis after total hip or knee replacement, or hip fracture repair remains controversial. It is common practice to administer prophylaxis using drugs such as low-molecular-weight heparin and unfractionated heparin (anticoagulants) until discharge from hospital and for a minimum of seven to 14 days after surgery. Current international guidelines recommend extending prophylaxis for up to 35 days following major orthopaedic surgery but recognise that the recommendation is weak due to moderate quality evidence. In addition, new oral anticoagulants (direct oral anticoagulants (DOAC)) show potential benefits such as taking tablets by mouth instead of injection, lack of frequent monitoring and few known drug interactions. Interest in this topic therefore remains high.

Study characteristics and key results

A total of 16 studies were included, with 24,930 randomised participants (current until May 2015). The main outcomes of interest were symptomatic (showing symptoms) VTE, including DVT and PE, and bleeding (major, clinically relevant non-major and minor bleeding). Six studies compared heparin with placebo, one compared the vitamin K antagonist (VKA) warfarin with placebo, two compared DOAC with placebo, one compared VKA with heparin, five compared DOAC with heparin and one study compared using a variety of anticoagulant treatments with placebo. Only three trials included participants undergoing knee replacement and no studies included participants undergoing hip fracture repair.

For the comparison heparin versus placebo (six studies) no differences were found between the study arms for symptomatic VTE, symptomatic DVT, symptomatic PE and major bleeding. Minor bleeding was increased in the heparin group. Clinically relevant non-major bleeding was not reported.

The comparison VKA versus placebo (one study) and the comparison placebo with anticoagulants chosen at the discretion of the investigators (one study) showed no differences between the study arms for symptomatic VTE, symptomatic DVT, symptomatic PE and major bleeding. Clinically relevant non-major bleeding and minor bleeding were not reported.

For the comparison DOACs versus placebo (two studies), reduced symptomatic VTE and symptomatic DVT were found in favour of the DOAC but no differences were found for symptomatic PE, major bleeding, clinically relevant non-major bleeding and minor bleeding.

Comparing extended-duration VKA with extended-duration LMWH (one study) there was no difference between the study arms for symptomatic VTE, symptomatic DVT, symptomatic PE, major bleeding and minor bleeding. Clinically relevant non-major bleeding was not reported.

Comparing extended-duration DOAC with extended-duration LMWH (five studies) there was no difference between the study arms for symptomatic VTE, symptomatic DVT, symptomatic PE, major bleeding, clinically relevant non-major bleeding and minor bleeding.

Quality of the evidence

Overall, the included studies were of good methodological quality, with the majority of studies having little risk of bias due to study design and reporting. The majority of concerns came from lack of reporting of specific details. The quality of the evidence was generally moderate, either because only one study was included in a comparison, because of few events or because there were a lot of differences between the findings of the studies meaning that the data were difficult to interpret. Further studies are needed to better understand the relationship between VTE and extended-duration oral anticoagulants for knee replacement and hip fracture repair as well as outcomes such as DVT below the knee and above the knee, reoperation, wound infection and healing.

Authors' conclusions: 

Moderate quality evidence suggests extended-duration anticoagulants to prevent VTE should be considered for people undergoing hip replacement surgery, although the benefit should be weighed against the increased risk of minor bleeding. Further studies are needed to better understand the association between VTE and extended-duration oral anticoagulants in relation to knee replacement and hip fracture repair, as well as outcomes such as distal and proximal DVT, reoperation, wound infection and healing.

Read the full abstract...
Background: 

The optimal duration of thromboprophylaxis after total hip or knee replacement, or hip fracture repair remains controversial. It is common practice to administer prophylaxis using low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) until discharge from hospital, usually seven to 14 days after surgery. International guidelines recommend extending thromboprophylaxis for up to 35 days following major orthopaedic surgery but the recommendation is weak due to moderate quality evidence. In addition, recent oral anticoagulants that exert effect by direct inhibition of thrombin or activated factor X lack the need for monitoring and have few known drug interactions. Interest in this topic remains high.

Objectives: 

To assess the effects of extended-duration anticoagulant thromboprophylaxis for the prevention of venous thromboembolism (VTE) in people undergoing elective hip or knee replacement surgery, or hip fracture repair.

Search strategy: 

The Cochrane Vascular Information Specialist searched the Specialised Register (last searched May 2015) and CENTRAL (2015, Issue 4). Clinical trials databases were searched for ongoing or unpublished studies.

Selection criteria: 

Randomised controlled trials assessing extended-duration thromboprophylaxis (five to seven weeks) using accepted prophylactic doses of LMWH, UFH, vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) compared with short-duration thromboprophylaxis (seven to 14 days) followed by placebo, no treatment or similar extended-duration thromboprophylaxis with LMWH, UFH, VKA or DOACs in participants undergoing hip or knee replacement or hip fracture repair.

Data collection and analysis: 

We independently selected trials and extracted data. Disagreements were resolved by discussion. We performed fixed-effect model meta-analyses with odds ratios (ORs) and 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity.

Main results: 

We included 16 studies (24,930 participants); six compared heparin with placebo, one compared VKA with placebo, two compared DOAC with placebo, one compared VKA with heparin, five compared DOAC with heparin and one compared anticoagulants chosen at investigators' discretion with placebo. Three trials included participants undergoing knee replacement. No studies assessed hip fracture repair.

Trials were generally of good methodological quality. The main reason for unclear risk of bias was insufficient reporting. The quality of evidence according to GRADE was generally moderate, as some comparisons included a single study, low number of events or heterogeneity between studies leading to wide CIs.

We showed no difference between extended-duration heparin and placebo in symptomatic VTE (OR 0.59, 95% CI 0.35 to 1.01; 2329 participants; 5 studies; high quality evidence), symptomatic deep vein thrombosis (DVT) (OR 0.73, 95% CI 0.39 to 1.38; 2019 participants; 4 studies; moderate quality evidence), symptomatic pulmonary embolism (PE) (OR 0.61, 95% CI 0.16 to 2.33; 1595 participants; 3 studies; low quality evidence) and major bleeding (OR 0.59, 95% CI 0.14 to 2.46; 2500 participants; 5 studies; moderate quality evidence). Minor bleeding was increased in the heparin group (OR 2.01, 95% CI 1.43 to 2.81; 2500 participants; 5 studies; high quality evidence). Clinically relevant non-major bleeding was not reported.

We showed no difference between extended-duration VKA and placebo (one study, 360 participants) for symptomatic VTE (OR 0.10, 95% CI 0.01 to 1.94; moderate quality evidence), symptomatic DVT (OR 0.13, 95% CI 0.01 to 2.62; moderate quality evidence), symptomatic PE (OR 0.32, 95% CI 0.01 to 7.84; moderate quality evidence) and major bleeding (OR 2.89, 95% CI 0.12 to 71.31; low quality evidence). Clinically relevant non-major bleeding and minor bleeding were not reported.

Extended-duration DOAC showed reduced symptomatic VTE (OR 0.20, 95% CI 0.06 to 0.68; 2419 participants; 1 study; moderate quality evidence) and symptomatic DVT (OR 0.18, 95% CI 0.04 to 0.81; 2459 participants; 2 studies; high quality evidence) compared to placebo. No differences were found for symptomatic PE (OR 0.25, 95% CI 0.03 to 2.25; 1733 participants; 1 study; low quality evidence), major bleeding (OR 1.00, 95% CI 0.06 to 16.02; 2457 participants; 1 study; low quality evidence), clinically relevant non-major bleeding (OR 1.22, 95% CI 0.76 to 1.95; 2457 participants; 1 study; moderate quality evidence) and minor bleeding (OR 1.18, 95% CI 0.74 to 1.88; 2457 participants; 1 study; moderate quality evidence).

We showed no difference between extended-duration anticoagulants chosen at investigators' discretion and placebo (one study, 557 participants, low quality evidence) for symptomatic VTE (OR 0.50, 95% CI 0.09 to 2.74), symptomatic DVT (OR 0.33, 95% CI 0.03 to 3.21), symptomatic PE (OR 1.00, 95% CI 0.06 to 16.13), and major bleeding (OR 5.05, 95% CI 0.24 to 105.76). Clinically relevant non-major bleeding and minor bleeding were not reported.

We showed no difference between extended-duration VKA and heparin (one study, low quality evidence) for symptomatic VTE (OR 1.64, 95% CI 0.85 to 3.16; 1279 participants), symptomatic DVT (OR 1.36, 95% CI 0.69 to 2.68; 1279 participants), symptomatic PE (OR 9.16, 95% CI 0.49 to 170.42; 1279 participants), major bleeding (OR 3.87, 95% CI 1.91 to 7.85; 1272 participants) and minor bleeding (OR 1.33, 95% CI 0.64 to 2.76; 1279 participants). Clinically relevant non-major bleeding was not reported.

We showed no difference between extended-duration DOAC and heparin for symptomatic VTE (OR 0.70, 95% CI 0.28 to 1.70; 15,977 participants; 5 studies; low quality evidence), symptomatic DVT (OR 0.60, 95% CI 0.11 to 3.27; 15,977 participants; 5 studies; low quality evidence), symptomatic PE (OR 0.91, 95% CI 0.43 to 1.94; 14,731 participants; 5 studies; moderate quality evidence), major bleeding (OR 1.11, 95% CI 0.79 to 1.54; 16,199 participants; 5 studies; high quality evidence), clinically relevant non-major bleeding (OR 1.08, 95% CI 0.90 to 1.28; 15,241 participants; 4 studies; high quality evidence) and minor bleeding (OR 0.95, 95% CI 0.82 to 1.10; 11,766 participants; 4 studies; high quality evidence).

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