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Clinician Article

Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair.



  • Forster R
  • Stewart M
Cochrane Database Syst Rev. 2016 Mar 30;3:CD004179. doi: 10.1002/14651858.CD004179.pub2. (Review)
PMID: 27027384
Read abstract Read evidence summary
Disciplines
  • Hospital Doctor/Hospitalists
    Relevance - 6/7
    Newsworthiness - 6/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Surgery - Orthopaedics
    Relevance - 6/7
    Newsworthiness - 6/7
  • Hemostasis and Thrombosis
    Relevance - 5/7
    Newsworthiness - 5/7
  • Hematology
    Relevance - 5/7
    Newsworthiness - 4/7

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 METHODS: 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 Clinical trials databases were searched for ongoing or unpublished studies.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).

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.


Clinical Comments

Hemostasis and Thrombosis

This Cochrane review compares symptomatic VTE rates (DVT, PE, or DVT + PE) during 5-7 weeks, compared with 7-14 days, of anticoagulant prophylaxis after major joint surgery. Relative to placebo, the review finds Odds Ratios of 0.18 - 0.25 for VTE, DVT or PE during extended DOAC prophylaxis (not significant for PE) and 0.59 - 0.73 (none significant) during extended heparin prophylaxis. Most heparin publications are 15-20 years old and earlier overviews of this data set concluded clinical benefit from extended heparin prophylaxis, with ORs of close to 0.4. So why the difference? The Cochrane analysis included fewer heparin studies (it excluded those with less than 5-7 weeks post-discharge prophylaxis, which one can argue was too rigid), and there were small differences between overviews in event rates extracted for some of these now aged studies. Conclusions from these old, small and fragile data sets remain uncertain. On balance, it is likely the heparins probably do work.

Hemostasis and Thrombosis

Nice summary of moderate significance. The necessity for further investigation is well understood among physicians.

Hospital Doctor/Hospitalists

This is an area of active controversy in my field; although, typically, the decisions regarding anticoagulation are made in cooperation with the primary surgical service. The lack of information about antiplatelet agents--especially aspirin--limits the applicability of these findings to my specific practice where they have become the preferred agent for prophylaxis.

Surgery - Orthopaedics

Given the continued debate and complexity around VTE prophylaxis in major orthopaedic surgery, this extensive and thorough Cochrane review is timely and provides an excellent summary of the evidence and a guide to the quality of that evidence.

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