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Low Molecular Weight Heparin Versus Other Anti-Thrombotic Agents For Lu and Lin BMC Musculoskeletal Disorders (2018) 19:322 https://doi.org/10.1186/s12891-018-2215-3 RESEARCH ARTICLE Open Access Low molecular weight heparin versus other anti-thrombotic agents for prevention of venous thromboembolic events after total hip or total knee replacement surgery: a systematic review and meta-analysis Xin Lu and Jin Lin* Abstract Background: Venous thromboembolism (VTE) is an important complication following total hip replacement (THR) and total knee replacement (TKR) surgeries. Aim of this study was to comprehensively compare the clinical outcomes of low-molecular-weight heparin (LMWH) with other anticoagulants in patients who underwent TKR or THR surgery. Methods: Medline, Cochrane, EMBASE, and Google Scholar databases were searched for eligible randomized controlled studies (RCTs) published before June 30, 2017. Meta-analyses of odds ratios were performed along with subgroup and sensitivity analyses. Results: Twenty-one RCTs were included. In comparison with placebo, LMWH treatment was associated with a lower risk of VTE and deep vein thrombosis (DVT) (P values < 0.001) but similar risk of pulmonary embolism (PE) (P =0.227)in THR subjects. Compared to factor Xa inhibitors, LMWH treatment was associated with higher risk of VTE in TKR subjects (P < 0.001), and higher DVT risk (P < 0.001) but similar risk of PE and major bleeding in both THR and TKR. The risk of either VTE, DVT, PE, or major bleeding was similar between LMWH and direct thrombin inhibitors in both THR and TKR, but major bleeding was lower with LMWH in patients who underwent THR (P =0.048). Conclusion: In comparison with factor Xa inhibitors, LMWH may have higher risk of VTE and DVT, whereas compared to direct thrombin inhibitors, LMWH may have lower risk of major bleeding after THR or TKR. Keywords: Low molecular weight heparin, Total knee replacement, Total hip replacement, Bleeding, Thrombosis Background aged ≥40 years had a significantly higher relative risk of Venous thromboembolism (VTE) is an important com- developing DVT, proximal DVT and PE [4]. plication following total hip replacement (THR) and Anticoagulants are routinely used and recommended total knee replacement (TKR) surgeries. The risk of after major orthopedic surgery to prevent VTE Anticoagu- postoperative thromboembolic events was estimated to lants has been found to reduce the risk of thromboembolic be approximately 50% for an asymptomatic event and events by approximately 50% to 80% when prescribed 15% to 30% for a symptomatic event in the absence of prophylactically [1]. Both the American College of Chest prophylactic treatment [1, 2]. These procedures can also Physicians (ACCP) and American Association of Ortho- result in deep venous thrombosis (DVT), pulmonary pedic Surgeons (AAOS) guidelines for VTE prophylaxis embolism (PE), infection, and death [3]. Asian patients recommend antithrombotic prophylaxis following THR or TKR [2, 4]. However, although pharmacologic thrombopro- * Correspondence: [email protected] phylaxis in patients with THR or TKR may decrease the Department of Orthopaedics, Peking Union Medical College Hospital, incidence of VTE and other thrombus related events, it can Chinese Academy of Medical Sciences and Peking Union Medical College, cause increased risk of major bleeding [2, 5]. A strong Beijing, China © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lu and Lin BMC Musculoskeletal Disorders (2018) 19:322 Page 2 of 19 relationship between major bleeding and poor outcome Eligibility irrespective of the study drug used has been demonstrated Eligible studies had to have investigated patients undergo- [6]. Hence, the trade-offs between fewer symptomatic PE ing hip or knee arthroplasty or replacement, and to have and DVT with thromboprophylaxis versus increased major compared patients receiving LMWH (enoxaparin) with bleeding should be considered [2, 7]. placebo, factor Xa inhibitors or direct thrombin inhibitors. Current guidelines for thromboprophylaxis recom- Included studies had to have reported outcomes of inter- mend the use of vitamin K antagonists (e.g. warfarin), ests (given below). Retrospective studies, one arm studies, low-molecular-weight heparins (LMWH), aspirin, or in- letters, commentaries, editorials, case reports, proceed- directinhibitoroffactorXa[8]. The efficacy and safety ings, and personal communications were excluded. Also of LMWH is well established [5, 9]. It has a long half-life excluded were studies that evaluated anticoagulants other with good bioavailability [9] and is administered once daily than direct thrombin and factor Xa inhibitors (e.g. aspirin subcutaneous dose without laboratory monitoring or dose or warfarin). adjustment. It is safe and effective for extended out-of- hospital prophylaxis after TKR or THR surgery [10]. Dis- Quality assessment advantages associated with LMWH include parenteral The quality of the included studies was assessed using administration, expense, potential thrombocytopenia, and Quality in Prognostic Studies (QUIPS), which consists of poor patient adherence [11, 12]. In a previous meta-ana- six domains (study participation, study attrition, prognostic lysis, patients who received LMWH (e.g. enoxaparin) factor measurement, outcome measurement, confounding prophylaxis had lower incidence of DVT after knee arthro- measurement and account, analysis) [15, 16]. scopic surgery compared to patients who did not receive LMWH prophylaxis [13]. Data and statistical analysis New generation of oral anticoagulants, such as dabigatran The following information/data was extracted from studies etexilate, ximelagatran, rivaroxaban, and apixaban, are now that met the inclusion criteria: the name of the first author, available for prophylaxis against VTE in patients undergo- year of publication, study design, number of participants in ing TKR or THR surgery [14]. Factor Xa inhibitors (i.e., each group, participants’ age and gender, and major out- rivaroxaban, darexaban, and apixaban) and direct throm- comes. The outcomes of interest were the risk or odds of bin inhibitors (i.e., ximelagatran and dabigatran etexilate) thrombotic events (VTE, DVT, PE, major bleeding). Basic have more predictable anticoagulant effects compared to characteristics of the included studies were summarized as LMWH which also overcome the need to monitor patients mean ± standard deviations (SD), mean (range: min., max.), receiving short-term thromboprophylaxis [6]. However, dis- or median (min., max.) for age, and n (%) for gender and advantages associated with these drugs include costs and patient number. The outcomes were summarized as n/N lack of antidotes for timely reversal of bleeding [6]. (patients with events out of total number of patients) for Currently, there is no comprehensive review to summarize given intervention as LMWH vs controls (placebo, or factor the relative effectiveness of LMWH by comparing it with Xa inhibitor, or a direct thrombin inhibitor). When assess- placebo, factor Xa inhibitors or direct thrombin inhibitors in ment of an outcome included ≥3studies,aneffectsizeodd preventing VTE and incidence of major bleeding when used ratio (OR) with corresponding 95% confidence intervals as thromboprophylaxis agent in TKR or THR surgical inter- (95% CI) was calculated for each individual study and ventions. The aim of this meta-analysis was to assess the then overall effect size was generated . Meta-analyses in-patient clinical outcomes of LMWH compared to factor was not performed when ≤2 studies reported an out- Xa inhibitors and direct thrombin inhibitors in TKR or come of interest. Odds ratios >1 implied patients with THR surgery subjects. LMWH treatment had a higher rate of a given outcome than those treated with control; OR < 1 indicated patients with LMWH treatment had a lower rate of a specific out- Methods come than patients receiving control therapy; OR = 1 sug- Search strategy gested the rate of an outcome was similar between LMWH The study was performed in accordance with the PRISMA and control treatments. guidelines. Following databases were searched for studies A χ2 test for homogeneity was conducted, and an in- published before June 30, 2017: Medline, Cochrane, consistency index (I2) and Q statistics were determined EMBASE, and Google Scholar. The search term (Hip [17]. If the I2 statistic was > 50%, a random-effects model OR Knee), (replacement OR arthroplasty), (low molecular (Der Simonian–Laird method) was used [18]. Otherwise, weight heparin OR enoxaparin), (Venous Thromboembol- a fixed-effects model (Mantel-Haenszel method) was ism OR Pulmonary Embolism OR Vein Thrombosis) AND employed. Combined effects were calculated, and a (inhibitor of factor Xa OR direct thrombin inhibitor) and two-sided P value of < 0.05 was considered significant. Randomized controlled trial (RCTs) were used. Sensitivity analyses were performed using a leave-one-out Lu and Lin BMC Musculoskeletal Disorders (2018) 19:322 Page 3 of 19 approach. Publication bias was
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