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Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: A meta-analysis of 6 randomized clinical trials
Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: A meta-analysis of 6 randomized clinical trials Guofeng Ma, Ruifeng Zhang, Xiaohong Wu, Dan Wang, Kejing Ying PII: DOI: Reference:
S0049-3848(15)00063-8 doi: 10.1016/j.thromres.2015.02.008 TR 5850
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
7 November 2014 29 December 2014 8 February 2015
Please cite this article as: Ma Guofeng, Zhang Ruifeng, Wu Xiaohong, Wang Dan, Ying Kejing, Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: A meta-analysis of 6 randomized clinical trials, Thrombosis Research (2015), doi: 10.1016/j.thromres.2015.02.008
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ACCEPTED MANUSCRIPT Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: a
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Running title: Rivaroxaban/apixaban vs. enoxaparin in VTE
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meta-analysis of 6 randomized clinical trials
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Guofeng Ma1 MM, Ruifeng Zhang1 MD, Xiaohong Wu1 MD, Dan Wang2 MD, Kejing Ying1* MM 1
Department of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang
Radiology Department, Sir Run Run Shaw Hospital, Zhejiang University School of
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2
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University School of Medicine, Hangzhou, 310020, China
Medicine, Hangzhou, China. 310020 *
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Email: [email protected]
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Corresponding author: Kejing Ying
Address: Department of Respiratory Diseases, Sir Run Run Shaw Hospital, No.3 East
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Qingchun Road, Jianggan District, Hangzhou, China. 310020
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Tel: +86-57186006196; Fax: +86-57186006192
ACCEPTED MANUSCRIPT Abstract Objective: A meta-analysis of randomized controlled trials (RCTs) was performed to
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compare the efficacy and safety of direct factor Xa inhibitors (rivaroxaban and
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apixaban) with enoxaparin for the prevention of venous thromboembolism (VTE)
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after total knee replacement.
Methods: A systematic literature search in Medline, EMBASE, EBSCO, Springer, Ovid and Cochrane library databases was performed to identify RCTs comparing
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rivaroxaban/apixaban with enoxaparin for the prevention of VTE after total knee
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replacement. The outcomes including deep vein thrombosis (DVT), pulmonary embolism (PE) and major bleeding were pooled using risk ratios (RRs) with their
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95% confidence intervals (95% CIs) as statistic.
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Results: A total of 6 RCTs with 13,790 patients were included in this meta-analysis. Overall, the incidence of DVT was significantly decreased with the use of direct Xa
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inhibitors (both twice daily [b.i.d] and once daily [q.d.] regimes) comparing with the enoxaparin treatment (P < 0.01); however, there was no significant influencing
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difference between direct Xa inhibitors (b.i.d. regime) and enoxaparin on the incidence of PE (P = 0.06), while significantly lower rate was found for q.d. regime of direct Xa inhibitors (P = 0.02). With respect to major bleeding, the pooled analysis did not demonstrate a significant difference between direct Xa inhibitors (b.i.d. and q.d. regimes) and enoxaparin (30 mg and 40 mg b.i.d.). Conclusion: In conclusion, our results confirmed that direct Xa inhibitors (rivaroxaban and apixaban) were more effective for prevention of VTE after total knee replacement as compared with enoxaparin, without increasing major bleeding risk. Key words: Venous thromboembolism, factor Xa inhibitor, rivaroxaban, apixaban,
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enoxaparin, total knee replacement
ACCEPTED MANUSCRIPT Introduction Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and
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pulmonary embolism (PE), represents one of the most common complications of
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major orthopedic surgery such as total knee replacement, and is associated with
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substantial short/long-term morbidity, mortality and costs [1, 2].
Although the traditional anticoagulants, such as low molecular weight heparins (LMWHs, e.g. enoxaparin), indirect factor Xa inhibitors (e.g. fondaparinux,
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idraparinux, idrabiotaparinux) and vitamin K antagonists (e.g. warfarin), have been
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proven to be effective for the management of VTE, the limitations including parenteral administration, need for laboratory monitoring, and ongoing dose
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adjustment complicate their use [3]. Over the past several years, new anticoagulants
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including the oral direct factor Xa inhibitors, which act to limit fibrin-antagonists formation through their exclusive inactivation of factor Xa, have been developed to
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overcome these drawbacks [4-6].
Apixaban, rivaroxaban, dabigatran and endoxaban are all belong to the new oral
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anticoagulants. As selective and reversible direct factor Xa inhibitor, apixaban, rivaroxaban and endoxaban exhibit promising role for the prevention of VTE [7]. Apixaban is usually administrated with fix doses, as there is a rapid action onset as well as predictable pharmacokinetics, without extra laboratory monitoring [8]. For rivaroxaban, the oral bioactivity was approximately 80% [9]. Although there is no significant efficacy differences of all the four drugs, endoxaban could increase the risk of major bleeding comparing with apixaban, similar result have been found in the direct thrombin inhibitor of dabigatran when compared with apaixaban [10, 11]. Additionally, there are better venographic outcomes of apixaban and rivaroxaban treatment than dabigatran treatment [12].
ACCEPTED MANUSCRIPT Therefore, the pooled estimation on effects and safety of apixaban and rivaroxaban for the prevention of VTE after total knee replacement, comparing with
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enoxaparin (an agent for the global clinical use and recommended primarily to
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prevent VTE in knee replacement surgery), were conducted in this study. To date, six
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randomized controlled trials (RCTs) have made such comparison [13, 9, 14-17]. The evidence from these RCTs appeared to support the use of rivaroxaban/apixaban for preventing VTE after total knee replacement, but the sample size of single trial was
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limited to draw a conclusive conclusion. Moreover, comprehensive comparison of
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medication frequency and doses in previous studies are scarce. Therefore, we performed this meta-analysis of available RCTs to better elucidate the efficacy and
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safety of direct factor Xa inhibitors (rivaroxaban and apixaban) comparing with
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Methods
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enoxaparin for the prevention of VTE after total knee replacement.
Literature search
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A systematic literature search in Medline, EMBASE, EBSCO, Springer, Ovid and Cochrane library databases was performed to identify RCTs that comparing rivaroxaban/apixaban and enoxaparin in preventing VTE after total knee replacement. The search was up to August 2014 and limited to English publication, using the following terms: (“rivaroxaban” OR “apixaban”) AND (“total knee replacement”) AND (“randomized controlled trial” OR “RCT”). In addition, reference lists of eligible articles were screened for additional articles.
Study selection and data extraction Studies were included if they met the following inclusion criteria: (1) RCTs that
ACCEPTED MANUSCRIPT comparing rivaroxaban/apixaban and enoxaparin for preventing VTE in patients after total knee replacement; and (2) provided sufficient information regarding the
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treatment outcome (DVT and PE) and adverse effect (major bleeding or hemorrhoea).
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The exclusion criteria were as follows: (1) Non RCTs or quasi RCT. (2) Patients had
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dysfunction of blood coagulation. (3) Patients had serious diseases such as cancer, congestive heart failure and renal failure. For studies with multiple publications focusing on the same study population or studies with the same results published in
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different journals, the most recent and complete study was collected. Furthermore,
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retrospective studies, reviews, animal studies, and studies did not provide sufficient data were excluded.
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Two investigators independently extracted the following data from each study:
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name of first author, publication year, sample size, relevant data about treatment and follow-up. Any discrepancies were resolved by discussion. Quality assessment of the
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included studies was determined by Jadad scoring system with full score of five [18].
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Statistical analysis
Risk ratios (RR) with their 95% confidence intervals (95% CI) were calculated using random effects model or fixed effects model in accordance with heterogeneity level. The heterogeneity across studies was examined by the Cochran’s Q statistic and the I2 statistic [19]. The fixed effects model was selected for the homogeneous outcomes (P ≥ 0.05 and I2 < 50%) and the random effects model was applied for heterogeneous outcomes (P < 0.05 or I2 ≥ 50%). Subgroup analyses by direct factor Xa inhibitors and therapy regimes were performed. A p-value less than 0.05 was considered to be statistically significant. Data analyses were performed with the Review Manger 5.2 version software (Cochrane Library Software, Oxford, UK).
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Results
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Search results
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The process of study selection is shown in Figure 1. A total of 125 articles were
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potentially relevant to the searching terms, 58 of which were excluded after screening the titles and abstracts. Subsequently, another 61 articles were excluded since they were not accord with the inclusion criteria (25 were review articles, 32 were non
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RCTs and 4 did not provided sufficient information). No additional eligible articles
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were obtained via screening the reference lists of identified primary studies. Thus, 6 articles, published between 2005 and 2010, with 13,790 patients were finally included
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in the present meta-analysis [13, 9, 14-17].
Characteristics of included studies
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The characteristics of included studies are depicted in Table 1. Three studies compared the outcomes of apixaban with enoxaparin on DVT, PE and major bleeding
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[13-15], while another 3 studies investigated rivaroxaban [9, 16, 17]. In addition, the twice-daily (b.i.d.) regime of enoxaparin was used in 3 studies [14-16]; the once-daily (q.d.) regime was used in 2 studies [9, 17], and both regimes were used in the remaining one study [13]. Further, the dose of enoxaparin used in 4 studies was 30 mg b.i.d [13, 15-17], while 40 mg q.d. of enoxaparin was used for another 2 studies [9, 14]. According to the Jadad scoring evaluation, 5 of 6 included studies obtain full score [9, 14-17] and the remaining one had 4 scores [13], indicating high quality of these eligible studies.
Efficacy
ACCEPTED MANUSCRIPT Deep vein thrombosis Overall, the incidence of DVT was significantly decreased with the use of direct
heterogeneity
= 0.03, I2 = 66%, Figure 2). Subgroup analysis of 3 apixaban
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< 0.01; P
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Xa inhibitors (b.i.d. regime) other than enoxaparin (RR = 0.68, 95% CI: 0.59-0.78, P
heterogeneity
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studies [13-15] yielded similar result (RR = 0.68, 95% CI: 0.59-0.79, P < 0.01; P = 0.01, I2 = 78%). However, further analysis stratified by the regime of
enoxaparin did not find a significant difference between apixaban and 30 mg b.i.d
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dose of enoxaparin (RR = 0.85, 95% CI: 0.66-1.10, P < 0.01; P heterogeneity = 0.03, I2 =
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78%). Pooled analysis of three studies [13, 9, 17] that used direct Xa inhibitors with q.d. regime demonstrated a significantly lower incidence of DVT as compared with heterogeneity
= 0.29, I2 = 20%,
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enoxaparin (RR = 0.60, 95% CI: 0.50-0.73, P < 0.01; P
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Figure 3), and similar result was obtained from the pooled analysis of two studies [9,
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17] for rivaroxaban (RR = 0.59, 95% CI: 0.48-0.72, P < 0.01; P heterogeneity = 0.17, I2 =
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Pulmonary embolism
Overall, there was no significant difference between direct Xa inhibitors (b.i.d. regime) with enoxaparin on PE (RR = 1.94, 95% CI: 0.96-3.92, P = 0.06; P heterogeneity = 0.15, I2 = 44%, Figure 4). Similar results were obtained with respect to the stratification analyses: apixaban and enoxaparin (RR = 2.00, 95% CI: 0.97-4.12, P = 0.06; P heterogeneity = 0.07, I2 = 62%); apixaban and 30 mg b.i.d dose of enoxaparin (RR = 1.65, 95% CI: 0.77-3.54, P = 0.20; P heterogeneity = 0.04 I2 = 75%). Pooled analysis of three studies [13, 9, 17] that used direct Xa inhibitors with q.d. regime demonstrated a significantly lower incidence of PE as compared with enoxaparin (RR = 0.33, 95% CI: 0.12-0.87, P = 0.02; P
heterogeneity
= 0.55, I2 = 0%, Figure 5), however, subgroup
ACCEPTED MANUSCRIPT analysis did not find a significant difference between rivaroxaban (q.d. regime) and
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enoxaparin (RR = 0.36, 95% CI: 0.12-1.07, P = 0.07; P heterogeneity = 0.37, I2 = 0%).
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Safety
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Major bleeding
The pooled analysis revealed that there was no significant difference between direct Xa inhibitors (apixaban and rivaroxaban; b.i.d. and q.d. regimes) with
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enoxaparin (30 mg and 40 mg b.i.d.) in terms of major bleeding (Figure 6 and 7).
Discussion
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The postoperative regimen of 30 mg b.i.d. dose of enoxaparin (initiated 12-24 h
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postsurgery) is approved by the Food and Drug Administration (FDA), and this regimen was selected as the comparator in 4 studies included in our study [13, 15-17].
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On the other hand, the preoperative regime of 40 mg q.d. dose of enoxaparin (initiated 12 h before surgery) is approved for use in Europe, and this regime was selected as
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the comparator in 2 studies included in our study [9, 14]. Overall, the incidence of DVT was significantly decreased with the use of direct Xa inhibitors (both b.i.d. and q.d. regimes) other than enoxaparin, which was supported by the stratification analysis regarding apixaban/rivaroxaban with both regimes (30 mg b.i.d. and 40 mg q.d.) of enoxaparin. However, comparable result was found between apixaban and 30 mg b.i.d. dose of enoxaparin. With respect to PE, no significant difference was found between Xa inhibitors (b.i.d. regime) and enoxaparin (both 30 mg and 40 mg q.d. regimes); while Xa inhibitors with q.d. regime had a significantly lower incidence, but the subgroup analysis of rivaroxaban did not confirm a significant difference. The reduction of VTE risk is believed to be related with the pharmacokinetic properties
ACCEPTED MANUSCRIPT (eg. the fluctuations of plasma concentrations) of direct factor Xa inhibitors [20]. Usually, the pharmacokinetic and pharmacodynamic characters of apixaban are not
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influenced by gender, age and weight, as well as food intake during medication [21].
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The AUC0-24 of rivaroxaban under 5 mg b.i.d administration is 30% inferior to 10 q.d
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administration, which causes the reduced drug exposure and then the decreased VTE risk [22].
In respect of safety, the pooled analysis did not show a significant difference
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between direct Xa inhibitors (both b.i.d. and q.d. regimes) with enoxaparin (both 30
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mg and 40 mg q.d. regimes) in terms of major bleeding. In their study of 3,195 patients, Lassen et al. did not find a significant difference between 2.5 mg b.i.d. dose
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of apixaban and 30 mg b.i.d. dose of enoxaparin for prevention of VTE after total
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knee replacement with respect to efficacy and safety, although favorable result regarding the incidence of major bleeding was obtained in patients received apixaban
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as compared with those received enoxaparin (0.7% vs. 1.4%, P = 0.053) [15]. Several factors would have led to this observation, such as the high initial dose of apixaban
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which favor lower bleeding risk [10]. Notably, the incidence of the primary efficacy outcome, comprising adjudicated asymptomatic and symptomatic DVT, non-fatal PE and all-cause death, in patients treated with apixaban was 9.0%; while in those treated with enoxaparin was 8.8% that was only approximately 55% of the predicted rate (15.6%) in clinic [13]. In their previous study of 1,238 patients, the efficacy and safety of six doses of apixaban (5, 10 or 20 mg q.d. or 2.5, 5 or 10 mg b.i.d.) was compared with the one of 30 mg b.i.d. dose of enoxaparin. The results showed that all apixaban groups had lower primary outcome rate than enoxaparin and the rate decreased with increasing apixaban dose; however, the incidence of total adjudicated bleeding events increased significantly with increasing apixaban dose [13]. With
ACCEPTED MANUSCRIPT regard to the difference of outcome rates between clinical trials, a plausible explanation was offered that the decreased rates perhaps attributed to improved
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anesthetic and surgical techniques and patient care, but the authors could not explain
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the source for 8.8% rate. In their recent study of 3,057 patients, 40 mg q.d. dose of
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enoxaparin was selected as the comparator for 2.5 mg b.i.d. dose of apixaban [14]. A significantly decreased incidence of primary outcome and favorable safety benefit appeared with the use of apixaban. With respect to the different results of enoxaparin
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between the two regimes, the authors emphasized that 30 mg b.i.d. dose of enoxaparin
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could be more effective with more bleeding, whereas 40 mg q.d. dose of enoxaparin could be less effective with more safety [14]. Indeed, the issue that whether
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enoxaparin timing and total daily dose are clinically important remains to be
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investigated.
In the study of Turpie et al., 30 mg b.i.d. dose of enoxaparin was selected as
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comparator for rivaroxaban in preventing VTE after total knee replacement [16, 17]. Their phase II dose-ranging study compared the efficacy and safety of five dose of
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rivaroxaban (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery) with enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery) to show that the optimal regime was 10 mg b.i.d. dose of rivaroxaban with potential efficacy and an acceptable safety profile [16]. In their phase III study of 3,148 patients, 10 mg b.i.d. dose of rivaroxaban initiated 6-8 h postsurgery was demonstrated to be significantly superior to 30 mg b.i.d. dose of enoxaparin, without significantly increased major bleeding risk [17]. Similar result was obtained in the study of Lassen et al., in which 10 mg b.i.d. dose of rivaroxaban (initiated 6-8 h postsurgery) was compared with 40 mg q.d. dose of enoxaparin in 2,531 patients [9]. The evidence from these RCTs appeared to support the 10 mg b.i.d. dose of rivaroxaban as an alternative to the recommend
ACCEPTED MANUSCRIPT regime of enoxaparin for treatment of VTE after total knee replacement. Notably, our finding that there was no significant difference between apixaban
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and 30 mg b.i.d. dose of enoxaparin with respect to efficacy is consistent with the
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recent meta-analysis of 3 RCTs, which also yielded a preferable performance of
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rivaroxaban for the treatment of VET after total knee replacement as compared with enoxaparin considering the efficacy and safety [23]. Nevertheless, limitations in our study should be considered. First, we did not evaluate the publication bias since the
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eligible studies for subgroup analysis was limited to make a practical evaluation, thus
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the potential publication bias should be taken into account for the interpretation of the result. Second, we only evaluated the primary efficacy/safety outcomes including
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DVT, PE and major bleeding; the secondary outcomes such as all-cause mortality,
Conclusion conclusion,
our
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In
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clinically relevant non-major bleeding and liver function were not evaluated.
results
confirmed
that
direct
Xa
inhibitors
(rivaroxaban/apixaban) were more effective for prevention of VTE after total knee
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replacement as compared with enoxaparin, without increasing major bleeding risk. However, the optimal regime of direct Xa inhibitors is needed to be investigated for improved clinical outcome especially in respect of major bleeding. Conflict of interest: none declared.
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ACCEPTED MANUSCRIPT Figure legends Figure 1 Process of study selection.
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Figure 2 The incidence of deep vein thrombosis (DVT) between direct factor Xa
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inhibitors (b.i.d regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin,
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(B) apixaban vs. enoxaparin, and (C) apixaban vs. 30 mg b.i.d. dose of enoxaparin. b.i.d., twice daily.
Figure 3 The incidence of deep vein thrombosis (DVT) between direct factor Xa
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inhibitors (q.d. regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin
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and (B) rivaroxaban vs. enoxaparin. q.d., once daily.
Figure 4 The incidence of pulmonary embolism (PE) between direct factor Xa
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inhibitors (b.i.d regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin,
b.i.d., twice daily.
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(B) apixaban vs. enoxaparin, and (C) apixaban vs. 30 mg b.i.d. dose of enoxaparin.
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Figure 5 The incidence of pulmonary embolism (PE) between direct factor Xa inhibitors (q.d. regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin
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and (B) rivaroxaban vs. enoxaparin. q.d., once daily. Figure 6 The incidence of major bleeding between direct factor Xa inhibitors (b.i.d regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin, (B) apixaban vs. enoxaparin, and (C) apixaban vs. 30 mg b.i.d. dose of enoxaparin. b.i.d., twice daily. Figure 7 The incidence of major bleeding between direct factor Xa inhibitors (q.d. regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin and (B) rivaroxaban vs. enoxaparin. q.d., once daily.
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therapy
Follow-up
(days)
(N)
Lassen
2007
1238
Controlled
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Experimental therapy
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Patients
Apixaban
5, 10, 20 mg q.d.
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Year
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Author
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Table 1 Characteristics of studies included in the meta-analysis.
Enoxaparin
30 mg b.i.d.
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or 2.5, 5, 10 mg b.i.d. 2009
3195
Apixaban
2.5 mg b.i.d.
Enoxaparin
30 mg b.i.d.
70-84
Lassen
2010
3057
Apixaban
2.5 mg b.i.d.
Enoxaparin
40 mg q.d.
70-84
Turpie
2005
621
30 mg b.i.d.
37-67
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Rivaroxaban
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Lassen
2.5, 5, 10, 20, 30 mg Enoxaparin
Lassen
2008
2531
Rivaroxaban
Turpie
2009
3148
Rivaroxaban
q.d., once daily; b.i.d., twice daily.
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b.i.d.
10 mg q.d.
Enoxaparin
40 mg q.d.
41-50
10 mg q.d.
Enoxaparin
30 mg b.i.d.
40-49
ACCEPTED MANUSCRIPT Highlights A total of 6 RCTs with 13,790 patients were included in this meta-analysis.
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Direct Xa inhibitors were more effective for the prevention of VTE.
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Comparable major bleeding existed between direct Xa inhibitors and enoxaparin.
S0049-3848(15)00063-8 doi: 10.1016/j.thromres.2015.02.008 TR 5850
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
7 November 2014 29 December 2014 8 February 2015
Please cite this article as: Ma Guofeng, Zhang Ruifeng, Wu Xiaohong, Wang Dan, Ying Kejing, Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: A meta-analysis of 6 randomized clinical trials, Thrombosis Research (2015), doi: 10.1016/j.thromres.2015.02.008
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: a
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Running title: Rivaroxaban/apixaban vs. enoxaparin in VTE
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meta-analysis of 6 randomized clinical trials
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Guofeng Ma1 MM, Ruifeng Zhang1 MD, Xiaohong Wu1 MD, Dan Wang2 MD, Kejing Ying1* MM 1
Department of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang
Radiology Department, Sir Run Run Shaw Hospital, Zhejiang University School of
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2
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University School of Medicine, Hangzhou, 310020, China
Medicine, Hangzhou, China. 310020 *
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Email: [email protected]
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Corresponding author: Kejing Ying
Address: Department of Respiratory Diseases, Sir Run Run Shaw Hospital, No.3 East
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Qingchun Road, Jianggan District, Hangzhou, China. 310020
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Tel: +86-57186006196; Fax: +86-57186006192
ACCEPTED MANUSCRIPT Abstract Objective: A meta-analysis of randomized controlled trials (RCTs) was performed to
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compare the efficacy and safety of direct factor Xa inhibitors (rivaroxaban and
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apixaban) with enoxaparin for the prevention of venous thromboembolism (VTE)
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after total knee replacement.
Methods: A systematic literature search in Medline, EMBASE, EBSCO, Springer, Ovid and Cochrane library databases was performed to identify RCTs comparing
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rivaroxaban/apixaban with enoxaparin for the prevention of VTE after total knee
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replacement. The outcomes including deep vein thrombosis (DVT), pulmonary embolism (PE) and major bleeding were pooled using risk ratios (RRs) with their
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95% confidence intervals (95% CIs) as statistic.
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Results: A total of 6 RCTs with 13,790 patients were included in this meta-analysis. Overall, the incidence of DVT was significantly decreased with the use of direct Xa
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inhibitors (both twice daily [b.i.d] and once daily [q.d.] regimes) comparing with the enoxaparin treatment (P < 0.01); however, there was no significant influencing
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difference between direct Xa inhibitors (b.i.d. regime) and enoxaparin on the incidence of PE (P = 0.06), while significantly lower rate was found for q.d. regime of direct Xa inhibitors (P = 0.02). With respect to major bleeding, the pooled analysis did not demonstrate a significant difference between direct Xa inhibitors (b.i.d. and q.d. regimes) and enoxaparin (30 mg and 40 mg b.i.d.). Conclusion: In conclusion, our results confirmed that direct Xa inhibitors (rivaroxaban and apixaban) were more effective for prevention of VTE after total knee replacement as compared with enoxaparin, without increasing major bleeding risk. Key words: Venous thromboembolism, factor Xa inhibitor, rivaroxaban, apixaban,
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enoxaparin, total knee replacement
ACCEPTED MANUSCRIPT Introduction Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and
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pulmonary embolism (PE), represents one of the most common complications of
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major orthopedic surgery such as total knee replacement, and is associated with
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substantial short/long-term morbidity, mortality and costs [1, 2].
Although the traditional anticoagulants, such as low molecular weight heparins (LMWHs, e.g. enoxaparin), indirect factor Xa inhibitors (e.g. fondaparinux,
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idraparinux, idrabiotaparinux) and vitamin K antagonists (e.g. warfarin), have been
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proven to be effective for the management of VTE, the limitations including parenteral administration, need for laboratory monitoring, and ongoing dose
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adjustment complicate their use [3]. Over the past several years, new anticoagulants
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including the oral direct factor Xa inhibitors, which act to limit fibrin-antagonists formation through their exclusive inactivation of factor Xa, have been developed to
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overcome these drawbacks [4-6].
Apixaban, rivaroxaban, dabigatran and endoxaban are all belong to the new oral
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anticoagulants. As selective and reversible direct factor Xa inhibitor, apixaban, rivaroxaban and endoxaban exhibit promising role for the prevention of VTE [7]. Apixaban is usually administrated with fix doses, as there is a rapid action onset as well as predictable pharmacokinetics, without extra laboratory monitoring [8]. For rivaroxaban, the oral bioactivity was approximately 80% [9]. Although there is no significant efficacy differences of all the four drugs, endoxaban could increase the risk of major bleeding comparing with apixaban, similar result have been found in the direct thrombin inhibitor of dabigatran when compared with apaixaban [10, 11]. Additionally, there are better venographic outcomes of apixaban and rivaroxaban treatment than dabigatran treatment [12].
ACCEPTED MANUSCRIPT Therefore, the pooled estimation on effects and safety of apixaban and rivaroxaban for the prevention of VTE after total knee replacement, comparing with
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enoxaparin (an agent for the global clinical use and recommended primarily to
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prevent VTE in knee replacement surgery), were conducted in this study. To date, six
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randomized controlled trials (RCTs) have made such comparison [13, 9, 14-17]. The evidence from these RCTs appeared to support the use of rivaroxaban/apixaban for preventing VTE after total knee replacement, but the sample size of single trial was
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limited to draw a conclusive conclusion. Moreover, comprehensive comparison of
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medication frequency and doses in previous studies are scarce. Therefore, we performed this meta-analysis of available RCTs to better elucidate the efficacy and
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safety of direct factor Xa inhibitors (rivaroxaban and apixaban) comparing with
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Methods
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enoxaparin for the prevention of VTE after total knee replacement.
Literature search
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A systematic literature search in Medline, EMBASE, EBSCO, Springer, Ovid and Cochrane library databases was performed to identify RCTs that comparing rivaroxaban/apixaban and enoxaparin in preventing VTE after total knee replacement. The search was up to August 2014 and limited to English publication, using the following terms: (“rivaroxaban” OR “apixaban”) AND (“total knee replacement”) AND (“randomized controlled trial” OR “RCT”). In addition, reference lists of eligible articles were screened for additional articles.
Study selection and data extraction Studies were included if they met the following inclusion criteria: (1) RCTs that
ACCEPTED MANUSCRIPT comparing rivaroxaban/apixaban and enoxaparin for preventing VTE in patients after total knee replacement; and (2) provided sufficient information regarding the
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treatment outcome (DVT and PE) and adverse effect (major bleeding or hemorrhoea).
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The exclusion criteria were as follows: (1) Non RCTs or quasi RCT. (2) Patients had
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dysfunction of blood coagulation. (3) Patients had serious diseases such as cancer, congestive heart failure and renal failure. For studies with multiple publications focusing on the same study population or studies with the same results published in
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different journals, the most recent and complete study was collected. Furthermore,
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retrospective studies, reviews, animal studies, and studies did not provide sufficient data were excluded.
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Two investigators independently extracted the following data from each study:
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name of first author, publication year, sample size, relevant data about treatment and follow-up. Any discrepancies were resolved by discussion. Quality assessment of the
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included studies was determined by Jadad scoring system with full score of five [18].
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Statistical analysis
Risk ratios (RR) with their 95% confidence intervals (95% CI) were calculated using random effects model or fixed effects model in accordance with heterogeneity level. The heterogeneity across studies was examined by the Cochran’s Q statistic and the I2 statistic [19]. The fixed effects model was selected for the homogeneous outcomes (P ≥ 0.05 and I2 < 50%) and the random effects model was applied for heterogeneous outcomes (P < 0.05 or I2 ≥ 50%). Subgroup analyses by direct factor Xa inhibitors and therapy regimes were performed. A p-value less than 0.05 was considered to be statistically significant. Data analyses were performed with the Review Manger 5.2 version software (Cochrane Library Software, Oxford, UK).
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Results
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Search results
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The process of study selection is shown in Figure 1. A total of 125 articles were
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potentially relevant to the searching terms, 58 of which were excluded after screening the titles and abstracts. Subsequently, another 61 articles were excluded since they were not accord with the inclusion criteria (25 were review articles, 32 were non
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RCTs and 4 did not provided sufficient information). No additional eligible articles
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were obtained via screening the reference lists of identified primary studies. Thus, 6 articles, published between 2005 and 2010, with 13,790 patients were finally included
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in the present meta-analysis [13, 9, 14-17].
Characteristics of included studies
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The characteristics of included studies are depicted in Table 1. Three studies compared the outcomes of apixaban with enoxaparin on DVT, PE and major bleeding
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[13-15], while another 3 studies investigated rivaroxaban [9, 16, 17]. In addition, the twice-daily (b.i.d.) regime of enoxaparin was used in 3 studies [14-16]; the once-daily (q.d.) regime was used in 2 studies [9, 17], and both regimes were used in the remaining one study [13]. Further, the dose of enoxaparin used in 4 studies was 30 mg b.i.d [13, 15-17], while 40 mg q.d. of enoxaparin was used for another 2 studies [9, 14]. According to the Jadad scoring evaluation, 5 of 6 included studies obtain full score [9, 14-17] and the remaining one had 4 scores [13], indicating high quality of these eligible studies.
Efficacy
ACCEPTED MANUSCRIPT Deep vein thrombosis Overall, the incidence of DVT was significantly decreased with the use of direct
heterogeneity
= 0.03, I2 = 66%, Figure 2). Subgroup analysis of 3 apixaban
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< 0.01; P
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Xa inhibitors (b.i.d. regime) other than enoxaparin (RR = 0.68, 95% CI: 0.59-0.78, P
heterogeneity
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studies [13-15] yielded similar result (RR = 0.68, 95% CI: 0.59-0.79, P < 0.01; P = 0.01, I2 = 78%). However, further analysis stratified by the regime of
enoxaparin did not find a significant difference between apixaban and 30 mg b.i.d
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dose of enoxaparin (RR = 0.85, 95% CI: 0.66-1.10, P < 0.01; P heterogeneity = 0.03, I2 =
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78%). Pooled analysis of three studies [13, 9, 17] that used direct Xa inhibitors with q.d. regime demonstrated a significantly lower incidence of DVT as compared with heterogeneity
= 0.29, I2 = 20%,
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enoxaparin (RR = 0.60, 95% CI: 0.50-0.73, P < 0.01; P
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Figure 3), and similar result was obtained from the pooled analysis of two studies [9,
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17] for rivaroxaban (RR = 0.59, 95% CI: 0.48-0.72, P < 0.01; P heterogeneity = 0.17, I2 =
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Pulmonary embolism
Overall, there was no significant difference between direct Xa inhibitors (b.i.d. regime) with enoxaparin on PE (RR = 1.94, 95% CI: 0.96-3.92, P = 0.06; P heterogeneity = 0.15, I2 = 44%, Figure 4). Similar results were obtained with respect to the stratification analyses: apixaban and enoxaparin (RR = 2.00, 95% CI: 0.97-4.12, P = 0.06; P heterogeneity = 0.07, I2 = 62%); apixaban and 30 mg b.i.d dose of enoxaparin (RR = 1.65, 95% CI: 0.77-3.54, P = 0.20; P heterogeneity = 0.04 I2 = 75%). Pooled analysis of three studies [13, 9, 17] that used direct Xa inhibitors with q.d. regime demonstrated a significantly lower incidence of PE as compared with enoxaparin (RR = 0.33, 95% CI: 0.12-0.87, P = 0.02; P
heterogeneity
= 0.55, I2 = 0%, Figure 5), however, subgroup
ACCEPTED MANUSCRIPT analysis did not find a significant difference between rivaroxaban (q.d. regime) and
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enoxaparin (RR = 0.36, 95% CI: 0.12-1.07, P = 0.07; P heterogeneity = 0.37, I2 = 0%).
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Safety
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Major bleeding
The pooled analysis revealed that there was no significant difference between direct Xa inhibitors (apixaban and rivaroxaban; b.i.d. and q.d. regimes) with
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enoxaparin (30 mg and 40 mg b.i.d.) in terms of major bleeding (Figure 6 and 7).
Discussion
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The postoperative regimen of 30 mg b.i.d. dose of enoxaparin (initiated 12-24 h
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postsurgery) is approved by the Food and Drug Administration (FDA), and this regimen was selected as the comparator in 4 studies included in our study [13, 15-17].
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On the other hand, the preoperative regime of 40 mg q.d. dose of enoxaparin (initiated 12 h before surgery) is approved for use in Europe, and this regime was selected as
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the comparator in 2 studies included in our study [9, 14]. Overall, the incidence of DVT was significantly decreased with the use of direct Xa inhibitors (both b.i.d. and q.d. regimes) other than enoxaparin, which was supported by the stratification analysis regarding apixaban/rivaroxaban with both regimes (30 mg b.i.d. and 40 mg q.d.) of enoxaparin. However, comparable result was found between apixaban and 30 mg b.i.d. dose of enoxaparin. With respect to PE, no significant difference was found between Xa inhibitors (b.i.d. regime) and enoxaparin (both 30 mg and 40 mg q.d. regimes); while Xa inhibitors with q.d. regime had a significantly lower incidence, but the subgroup analysis of rivaroxaban did not confirm a significant difference. The reduction of VTE risk is believed to be related with the pharmacokinetic properties
ACCEPTED MANUSCRIPT (eg. the fluctuations of plasma concentrations) of direct factor Xa inhibitors [20]. Usually, the pharmacokinetic and pharmacodynamic characters of apixaban are not
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influenced by gender, age and weight, as well as food intake during medication [21].
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The AUC0-24 of rivaroxaban under 5 mg b.i.d administration is 30% inferior to 10 q.d
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administration, which causes the reduced drug exposure and then the decreased VTE risk [22].
In respect of safety, the pooled analysis did not show a significant difference
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between direct Xa inhibitors (both b.i.d. and q.d. regimes) with enoxaparin (both 30
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mg and 40 mg q.d. regimes) in terms of major bleeding. In their study of 3,195 patients, Lassen et al. did not find a significant difference between 2.5 mg b.i.d. dose
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of apixaban and 30 mg b.i.d. dose of enoxaparin for prevention of VTE after total
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knee replacement with respect to efficacy and safety, although favorable result regarding the incidence of major bleeding was obtained in patients received apixaban
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as compared with those received enoxaparin (0.7% vs. 1.4%, P = 0.053) [15]. Several factors would have led to this observation, such as the high initial dose of apixaban
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which favor lower bleeding risk [10]. Notably, the incidence of the primary efficacy outcome, comprising adjudicated asymptomatic and symptomatic DVT, non-fatal PE and all-cause death, in patients treated with apixaban was 9.0%; while in those treated with enoxaparin was 8.8% that was only approximately 55% of the predicted rate (15.6%) in clinic [13]. In their previous study of 1,238 patients, the efficacy and safety of six doses of apixaban (5, 10 or 20 mg q.d. or 2.5, 5 or 10 mg b.i.d.) was compared with the one of 30 mg b.i.d. dose of enoxaparin. The results showed that all apixaban groups had lower primary outcome rate than enoxaparin and the rate decreased with increasing apixaban dose; however, the incidence of total adjudicated bleeding events increased significantly with increasing apixaban dose [13]. With
ACCEPTED MANUSCRIPT regard to the difference of outcome rates between clinical trials, a plausible explanation was offered that the decreased rates perhaps attributed to improved
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anesthetic and surgical techniques and patient care, but the authors could not explain
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the source for 8.8% rate. In their recent study of 3,057 patients, 40 mg q.d. dose of
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enoxaparin was selected as the comparator for 2.5 mg b.i.d. dose of apixaban [14]. A significantly decreased incidence of primary outcome and favorable safety benefit appeared with the use of apixaban. With respect to the different results of enoxaparin
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between the two regimes, the authors emphasized that 30 mg b.i.d. dose of enoxaparin
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could be more effective with more bleeding, whereas 40 mg q.d. dose of enoxaparin could be less effective with more safety [14]. Indeed, the issue that whether
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enoxaparin timing and total daily dose are clinically important remains to be
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investigated.
In the study of Turpie et al., 30 mg b.i.d. dose of enoxaparin was selected as
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comparator for rivaroxaban in preventing VTE after total knee replacement [16, 17]. Their phase II dose-ranging study compared the efficacy and safety of five dose of
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rivaroxaban (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery) with enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery) to show that the optimal regime was 10 mg b.i.d. dose of rivaroxaban with potential efficacy and an acceptable safety profile [16]. In their phase III study of 3,148 patients, 10 mg b.i.d. dose of rivaroxaban initiated 6-8 h postsurgery was demonstrated to be significantly superior to 30 mg b.i.d. dose of enoxaparin, without significantly increased major bleeding risk [17]. Similar result was obtained in the study of Lassen et al., in which 10 mg b.i.d. dose of rivaroxaban (initiated 6-8 h postsurgery) was compared with 40 mg q.d. dose of enoxaparin in 2,531 patients [9]. The evidence from these RCTs appeared to support the 10 mg b.i.d. dose of rivaroxaban as an alternative to the recommend
ACCEPTED MANUSCRIPT regime of enoxaparin for treatment of VTE after total knee replacement. Notably, our finding that there was no significant difference between apixaban
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and 30 mg b.i.d. dose of enoxaparin with respect to efficacy is consistent with the
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recent meta-analysis of 3 RCTs, which also yielded a preferable performance of
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rivaroxaban for the treatment of VET after total knee replacement as compared with enoxaparin considering the efficacy and safety [23]. Nevertheless, limitations in our study should be considered. First, we did not evaluate the publication bias since the
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eligible studies for subgroup analysis was limited to make a practical evaluation, thus
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the potential publication bias should be taken into account for the interpretation of the result. Second, we only evaluated the primary efficacy/safety outcomes including
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DVT, PE and major bleeding; the secondary outcomes such as all-cause mortality,
Conclusion conclusion,
our
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In
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clinically relevant non-major bleeding and liver function were not evaluated.
results
confirmed
that
direct
Xa
inhibitors
(rivaroxaban/apixaban) were more effective for prevention of VTE after total knee
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replacement as compared with enoxaparin, without increasing major bleeding risk. However, the optimal regime of direct Xa inhibitors is needed to be investigated for improved clinical outcome especially in respect of major bleeding. Conflict of interest: none declared.
ACCEPTED MANUSCRIPT References 1. Selby R, Geerts W. Prevention of venous thromboembolism: consensus,
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controversies, and challenges. ASH Education Program Book. 2009, 2009:286-292.
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2. Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation.
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2003, 107:I-9-I-16.
3. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. CHEST Journal. 2004,
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6. Deftereos S, Hatzis G, Kossyvakis C, Bouras G, Panagopoulou V, Kaoukis A et al. Prevention and treatment of venous thromboembolism and pulmonary embolism: the
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role of novel oral anticoagulants. Current clinical pharmacology. 2012, 7:175-194. 7. Ufer M. Comparative efficacy and safety of the novel oral anticoagulants
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randomised double-blind trial. The Lancet. 2010, 375:807-815. 15. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or
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enoxaparin for thromboprophylaxis after knee replacement. New England Journal of Medicine. 2009, 361:594-604. 16. Turpie A, Fisher W, Bauer K, Kwong L, Irwin M, Kälebo P et al. BAY 59‐7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose‐ranging study. Journal of Thrombosis and Haemostasis. 2005, 3:2479-2486. 17. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. The Lancet. 2009, 373:1673-1680. 18. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ et al.
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19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
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20. Nieto JA, Espada NG, Merino RG, González TC. Dabigatran, Rivaroxaban and Apixaban versus Enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thrombosis
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ACCEPTED MANUSCRIPT Figure legends Figure 1 Process of study selection.
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Figure 2 The incidence of deep vein thrombosis (DVT) between direct factor Xa
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inhibitors (b.i.d regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin,
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(B) apixaban vs. enoxaparin, and (C) apixaban vs. 30 mg b.i.d. dose of enoxaparin. b.i.d., twice daily.
Figure 3 The incidence of deep vein thrombosis (DVT) between direct factor Xa
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inhibitors (q.d. regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin
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and (B) rivaroxaban vs. enoxaparin. q.d., once daily.
Figure 4 The incidence of pulmonary embolism (PE) between direct factor Xa
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inhibitors (b.i.d regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin,
b.i.d., twice daily.
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(B) apixaban vs. enoxaparin, and (C) apixaban vs. 30 mg b.i.d. dose of enoxaparin.
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Figure 5 The incidence of pulmonary embolism (PE) between direct factor Xa inhibitors (q.d. regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin
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and (B) rivaroxaban vs. enoxaparin. q.d., once daily. Figure 6 The incidence of major bleeding between direct factor Xa inhibitors (b.i.d regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin, (B) apixaban vs. enoxaparin, and (C) apixaban vs. 30 mg b.i.d. dose of enoxaparin. b.i.d., twice daily. Figure 7 The incidence of major bleeding between direct factor Xa inhibitors (q.d. regime) versus enoxaparin: (A) rivaroxaban/apixaban vs. enoxaparin and (B) rivaroxaban vs. enoxaparin. q.d., once daily.
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therapy
Follow-up
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(N)
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Year
MA N
Author
T
Table 1 Characteristics of studies included in the meta-analysis.
Enoxaparin
30 mg b.i.d.
42
or 2.5, 5, 10 mg b.i.d. 2009
3195
Apixaban
2.5 mg b.i.d.
Enoxaparin
30 mg b.i.d.
70-84
Lassen
2010
3057
Apixaban
2.5 mg b.i.d.
Enoxaparin
40 mg q.d.
70-84
Turpie
2005
621
30 mg b.i.d.
37-67
CE P
Rivaroxaban
TE D
Lassen
2.5, 5, 10, 20, 30 mg Enoxaparin
Lassen
2008
2531
Rivaroxaban
Turpie
2009
3148
Rivaroxaban
q.d., once daily; b.i.d., twice daily.
AC
b.i.d.
10 mg q.d.
Enoxaparin
40 mg q.d.
41-50
10 mg q.d.
Enoxaparin
30 mg b.i.d.
40-49
ACCEPTED MANUSCRIPT Highlights A total of 6 RCTs with 13,790 patients were included in this meta-analysis.
IP
T
Direct Xa inhibitors were more effective for the prevention of VTE.
AC
CE P
TE
D
MA
NU
SC R
Comparable major bleeding existed between direct Xa inhibitors and enoxaparin.