Original Article Efficacy and Safety of Oral Direct Factor Xa Inhibitor for Thromboprophylaxis After Total Hip Or Knee Replacement: a Meta-Analysis

Int J Clin Exp Med 2016;9(6):10695-10705 www.ijcem.com /ISSN:1940-5901/IJCEM0021469

Original Article Efficacy and safety of oral direct factor Xa inhibitor for thromboprophylaxis after total hip or knee replacement: a meta-analysis

Zhen Wang1*, Li Zhao2*, Shankun Liu3, Chuanyu Li4, Peng Zhang1, Chunli Yu3

1Department of Spinal and Joint Surgery, Taian City Central Hospital, No. 29, Longtan Road, Taishan District, Taian Shandong Province, P. R. China; 2Department of Reproductive Genetics, Taian City Central Hospital, No. 29, Longtan Road, Taishan District, Taian Shandong Province, P. R. China; 3Department of Gynecology, Taian City Central Hospital, No. 29, Longtan Road, Taishan District, Taian, Shandong Province, P. R. China; 4Department of Rehabilitation Medicine, Taian City Central Hospital, No. 29, Longtan Road, Taishan District, Taian, Shandong Province, P. R. China. *Equal contributors and co-first authors. Received December 8, 2015; Accepted March 19, 2016; Epub June 15, 2016; Published June 30, 2016

Abstract: Objective: The aim of this meta-analysis is to estimate efficacy and safety of different daily doses of oral direct factor Xa inhibitor for thromboprophylaxis after total hip or knee replacement. Methods: This paper searched the databases such as Pubmed, Medline, Web of Science and Embase databases. 15 RCT studies were included and dichotomousdata were presented as the risk ratio (RR) with a 95% confidence interval (CI). Results: 15 relevant studies with 28, 548 individuals and 3 different types of oral direct factor Xa inhibitor (apixaban, rivaroxaban and dabigatran) were employed for this meta-analysis. The efficacy of 5 mg, 10 mg and 20 mg daily doses of apixaban was superior to 40 mg daily of enoxaparin, but 10 mg and 20 mg daily doses of apixaban increased the risk of major bleeding and non-major but clinically relevant bleeding. Except the lowest daily dose of 5 mg, 10 mg, 20 mg, 30 mg, 40 mg and 60 mg daily doses of rivaroxaban had superior efficacy than 40 mg daily of enoxaparin, but higher doses of 30 mg, 40 mg and 60 mg showed lower safety than enoxaparin and 10 mg and 20 mg of rivaroxaban. 60 mg daily was better in efficacy than enoxaparin and other doses of darexaban. Meantime, the risk of bleeding was not significantly increasing. Conclusion: Consider the safety and efficacy, 5 mg daily of apixaban, 20 mg daily of rivaroxaban, 60 mg daily of darexaban were optimal potential oral direct factor Xa inhibitor for thromboprophylaxis after total hip or knee replacement.

Keywords: Thromboprophylaxis, total hip or knee replacement, oral direct factor Xa inhibitor, efficacy and safety, meta-analysis

Introduction it has imposed a major health burden in the world for a substantial effect on patients’ qual- Nowadays, total hip arthroplasty (THA) and ity of life. Anderson et al. estimated that over total knee arthroplasty (TKA) has been widely 12 million patients, comprising 31% of hospital used in the treatment of unrecovered disloca- discharged patients were at risk of VTE in the tion, end-stage osteoarthritis, rheumatic arthri- US using the 2003 Nationwide Inpatient Sam- tis and so on. But post-surgery complications, ple [2]. In 2007, Cohen et al. found the estimat- especially as venous thromboembolism (VTE), has been attracted more and more attention. A ed total number of symptomatic VTE events common type of venous thrombosis is deep was 465,000 cases of deep-vein thrombosis, vein thrombosis (DVT), which is a blood clot in 296,000 cases of PE, and 370,000 VTE-related the deep veins of the leg. If the thrombus deaths in six EU countries [3]. Post-thrombotic breaks off (embolizes) and flows towards the syndrome and pulmonary hypertension, two lungs, it can become the life-threatening pul- major long-term complications of VTE, are not monary embolism (PE), a blood clot in the lungs. only the significant causes of morbidity and According to Nature report, VTE has been the mortality, but also lead to high long-term treat- third cause of cardiovascular mortality [1] and ment costs [4]. Efficacy and safety of oral direct factor Xa inhibitor

Most of existing reviews and/ or meta-analysis focused on the efficacy and safety of direct factor Xa inhibitor with enoxaparin conducted in THA and TKA, but the comparing of different daily doses of direct factor Xa inhibitors was ignored [9-12]. As we know, the anticoagulation effect and the bleeding complication are contradictory elements for the anticoagulant medicines, so the dose-related efficacy and bleeding complication should be statistically analyzed. With the aim to evaluate the suitable dose, this research conducted a meta- Figure 1. A flow diagram of the study selection process. analysis on efficacy and safety of different daily doses of oral direct factor Xa inhibitor VTE should be considered in THA and total for thromboprophylaxis after total hip or knee knee arthroplasty TKA. According to clinical replacement. practice guideline, thromboprophylactic therapy is recommended for 35 days after THA and Materials and methods more than 10 days after TKA [5]. There are Literature search strategy three major types of the traditional anticoagulants for VTE prophylaxis: 1, low molecular Without language restriction, this paper se- weight heparins (such as enoxaparin); 2, indi- arched the databases such as Pubmed, Me- rect factor Xa inhibitors (such as fondaparinux, dline, Web of Science and Embase databases idraparinux, idrabiotaparinux); 3, vitamin Kan- by the terms (“venous thromboembolism” or tagonists (such as warfarin). Those three tradi- “deep venous thrombosis” or “otal hip arthro- tional anticoagulants have been proven to be plasty” or “total knee arthroplasty” or “total effective for theprophylaxis of VTE, but the par- knee replacement”, “enoxaparin” or “factor Xa enteral administration, routine laboratory moni- inhibitor”, “apixaban” or “rivaroxaban” or “dabi- toring, post-operative bleeding and ongoing gatran”) to retrieve related studies and the last dose adjustment limit and complicate their use retrieval time was November, 30, 2015. The flow diagram of retrieval process was shown in clinic [6]. FactorXa (FXa) is a key factor in in Figure 1. theintrinsic and extrinsic coagulant pathway and can analyze the conversion of prothrombin Inclusion and exclusion criteria to thrombin [7]. So the blocking of FXa is an effective way to stopthe coagulative cascade. Inclusion criteria: (1) study focuses on Oral di- Oral direct factor Xa inhibitor is a new type rect factor Xa inhibitor for thromboprophyla- of anticoagulant medicines, including apixa- xis; (2) RCT study; (3) Data reported was avail- ban, rivaroxaban, dabigatran and endoxaban, able; (4) published data was fit to this meta- has been developed to overcome those limita- analysis. tions of traditional anticoagulants and specifi- The exclusion criteria: (1) animal studies; (2) cally targets factor Xa. With the advantage of the reported data was not adaptable; (3) the oral administration and a predictable pharma- study focused on other thromboprophylaxis; (4) cokinetics, oral direct factor Xa inhibitor pro- the surgery was not total hip or knee replace- vides a promising future in the prophylaxis of ment; (5) daily dose of the oral direct factor Xa post-major surgery VTE [8]. inhibitor was not reported.

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Table 1. Summary of basic information of the studies included Quantitative assessment by Jadad Scale Number of Dose daily Studies Year Drug With drawals Overall participants included Random Blinding and dropouts score Eriksson [14] 2007 Darexaban 174 3, 10, 30, 60 mg 1 1 1 3 Eriksson [15] 2006 Rivaroxaban 873 5, 10, 20, 30, or 40 mg 2 2 0 4 Lassen [16] 2009 Apixaban 3195 5 mg 2 2 1 5 Lassen [17] 2010 Apixaban 3057 5 mg 2 2 1 5 Lassen [18] 2010 Apixaban 5407 5 mg 2 2 1 5 Eriksson [19] 2013 Darexaban 2,235 30 mg, 60 mg 2 2 1 5 Fuji [20] 2014 Darexaban 662 30 mg, 60 mg 2 2 0 4 Eriksson [21] 2007 Rivaroxaban 625 20, 40, 30 and 60 mg 2 2 0 4 Eriksson [22] 2010 Darexaban 1017 5, 10, 30, 60 and 120 mg 2 1 1 4 Turpie [23] 2009 Rivaroxaban 3148 10 mg 2 2 1 5 Eriksson [24] 2008 Rivaroxaban 4541 10 mg 2 2 1 5 Lassen [25] 2008 Rivaroxaban 2531 10 mg 2 2 1 5 Lassen [26] 2007 Apixaban 1238 5, 10 or 20 mg 2 2 1 5 Kakkar [27] 2008 Rivaroxaban 2509 10 mg 2 2 1 5 Turpie [28] 2005 Rivaroxaban 613 5, 10, 20, 40 and 60 mg 2 1 1 4

Data extraction Quality assessment

The information about study design, first The Jadad scale was performed to evaluate author‘s name, published year, follow-up time, quality of the studies included on three aspects: name of oral direct factor Xa inhibitor, daily “random”, “blinding” and “Withdrawals and doses and the frequencies of primary efficacy dropouts”. The overall scores of Jadad scale and safety endpoints in experimental group were ranged from 0 to 5 (≥3 was generally con- and control group were obtained based upon sidered to be of high quality) [13]. “Inclusion and exclusion criteria” mentioned above. Main results

Statistical analysis Characteristics of studies

The statistical analysis was conducted by Stata 15 relevant studies with 28, 548 individuals 11.0 (StataCorp, College Station, TX) and and 3 different types of oral direct factor Xa α=0.05 was considered as significance level. inhibitor (apixaban, rivaroxaban and dabiga- The risk ratio (RR) with a 95% confidence inter- tran) were employed for this meta-analysis. In val (CI) was used to describe the dichotomous those studies, 4 papers studied on the effect data. Statistical heterogeneity was measured and safety of dabigatran, 7 papers were esti- using the I2-statistic and Q-statistic (P≤0.05 mated the effect and safety of rivaroxaban and was considered to be representative of statisti- 4 paper focused on apixaban. The characteris- cally significant heterogeneity). When there was tics of each study were presented in Table 1. no heterogeneity of the results of the studies, then fixed effects model was used. Otherwise, Quantitative data synthesis the random effects model was used. Publication Apixaban estimation: Primary efficacye valua- bias was assessed by Begg’s rank correlation tion: compared to 40 mg daily of enoxaparin, all method and Egger weighted regression test. of 5 mg, 10 mg and 20 mg daily doses of apixa- Endpoints measures ban could reduce the incidence of VTE (5 mg daily: pooled RR=0.662, 95% CI=0.469-0.935, The primary efficacy endpoint included DVT, P=0.019; 10 mg daily: pooled RR=0.567, 95% non-fatal PE and death of all cause during the CI=0.328-0.978, P=0.042; 20 mg daily: pool- treatment period. The primary safety endpoints ed RR=0.473, 95% CI=0.264-0.845, P=0.011), were the composite of major bleeding and non- but there was no significant different among major but clinically relevant bleeding. those 3 dosages.

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Table 2. Comparing results of 5 mg, 10 mg and 20 mg daily doses of apixaban and 40 mg daily of enoxaparin in primary efficacy and safety Daily dosage RR (95% CI) Homogeneity Publication bias Outcomes comparison RR CI P value Q Ph I² (%) PB PE Primary efficacy outcomes 5 mg Apixabanvs 1.190 0.649-2.181 0.575 1.06 0.303 5.7 0.805 0.918 10 mg Apixaban 5 mg Apixabanvs 1.434 0.759-2.707 0.266 0.80 0.371 0.0 0.231 0.182 20 mg Apixaban 5 mg Apixabanvs 0.662 0.469-0.935 0.019 16.43 0.002 75.7 0.532 0.371 40 mg enoxaparin 10 mg Apixabanvs 1.231 0.631-2.399 0.543 3.08 0.079 67.5 0.343 0.433 20 mg Apixaban 10 mg Apixabanvs 0.567 0.328-0.978 0.042 1.99 0.158 49.9 0.783 0.832 40 mg enoxaparin 20 mg Apixabanvs 0.473 0.264-0.845 0.011 0.40 0.527 0.0 1.000 0.276 40 mg enoxaparin Primary safety outcomes 5 mg Apixabanvs 0.828 0.239-2.873 0.767 3.81 0.051 73.8 0.49 0.558 10 mg Apixaban 5 mg Apixabanvs 0.479 0.157-1.454 0.194 1.56 0.212 35.9 0.621 0.733 20 mg Apixaban 5 mg Apixabanvs 0.821 0.558-1.209 0.318 5.91 0.206 32. 0.850 0.660 40 mg enoxaparin 10 mg Apixabanvs 0.556 0.188-1.640 0.287 1.59 0.208 37.0 1.000 0.829 20 mg Apixaban 10 mg Apixabanvs 2.394 0.468-12.254 0.295 0.60 0.440 0.0 0.493 0.925 40 mg enoxaparin 20 mg Apixabanvs 4.314 1.040-19.800 0.032 0.883 0.02 0.0 0.390 0.615 40 mg enoxaparin

Figure 2. Forest plot of the efficacy estimation of 5 mg daily of apixabancompared to 40 mg daily of enoxaparin.

Primary safety evaluation: no significant differ- evant non-major bleeding in this paper, but ent was found among 5 mg, 10 mg and 20 mg there was an interesting result that lower dos- daily doses of apixaban in major or clinically rel- age might be more safe than higher (RR value

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Table 3. Comparison results of different daily doses of rivaroxaban and 40 mg daily of enoxaparin in primary efficacy and safety Daily dosage RR (95% CI) Homogeneity Publication bias Outcomes comparison RR CI P value Q Ph I² (%) PB PE Primary efficacy outcomes 5 mg Rivaroxabanvs 0.986 0.692-1.403 0.936 1.12 0.572 0.0 0.368 0.350 10 mg Rivaroxaban 5 mg Rivaroxabanvs 1.307 0.876-1.949 0.190 0.59 0.744 0.0 0.230 0.558 20 mg Rivaroxaban 5 mg Rivaroxabanvs 1.223 0.741-2.018 0.431 0.22 0.640 0.0 0.176 0.163 30 mg Rivaroxaban 5 mg Rivaroxabanvs 1.360 0.905-2.043 0.139 3.58 0.167 44.2 0.133 0.277 40 mg Rivaroxaban 5 mg Rivaroxabanvs 1.203 0.748-1.935 0.446 0.00 0.950 0.0 0.133 0.115 60 mg Rivaroxaban 5 mg Rivaroxabanvs 0.833 0.604-1.148 0.263 2.42 0.299 17.3 0.368 0.346 40 mg Enoxaparin 10 mg Rivaroxabanvs 1.321 0.890-1.962 0.167 0.39 0.822 0.0 0.652 0.631 20 mg Rivaroxaban 10 mg Rivaroxabanvs 0.786 0.608-1.015 0.065 3.43 0.180 41.7 0.368 0.154 30 mg Rivaroxaban 10 mg Rivaroxabanvs 1.395 0.934-2.084 0.104 1.65 0.438 0.0 0.293 0.189 40 mg Rivaroxaban 10 mg Rivaroxabanvs 1.373 0.866-2.177 0.178 0.03 0.858 0.0 0.293 0.383 60 mg Rivaroxaban 10 mg Rivaroxabanvs 0.531 0.333-0.847 0.008 29.91 0.000 83.3 0.221 0.156 40 mg Enoxaparin 20 mg Rivaroxabanvs 0.912 0.528-1.577 0.742 1.35 0.245 26.1 0.806 0.888 30 mg Rivaroxaban 20 mg Rivaroxabanvs 1.047 0.671-1.633 0.840 2.88 0.237 30.6 0.624 0.409 40 mg Rivaroxaban 20 mg Rivaroxabanvs 1.004 0.600-1.680 0.987 0.12 0.730 0.0 0.327 0.136 60 mg Rivaroxaban 20 mg Rivaroxabanvs 0.633 0.440-0.910 0.014 4.77 0.092 58.1 0.462 0.937 40 mg Enoxaparin 30 mg Rivaroxabanvs 1.692 0.879-3.259 0.116 0.25 0.620 0.0 0.230 0.255 40 mg Rivaroxaban 30 mg Rivaroxabanvs 0.625 0.450-0.907 0.035 0.353 0.129 0.0 1.000 0.870 40 mg Enoxaparin 40 mg Rivaroxabanvs 1.042 0.632-1.719 0.872 1.50 0.221 33.3 1.000 0.469 60 mg Rivaroxaban 40 mg Rivaroxabanvs 0.602 0.414-0.870 0.008 4.63 0.099 56.8 0.602 0.527 40 mg Enoxaparin 60 mg Rivaroxabanvs 0.768 0.495-0.992 0.039 0.86 0.355 0.0 1.000 0.658 40 mg Enoxaparin Primary safety outcomes 5 mg Rivaroxabanvs 1.332 0.362-4.901 0.666 1.22 0.543 0.0 0.308 0.553 10 mg Rivaroxaban 5 mg Rivaroxabanvs 0.525 0.182-1.517 0.234 0.02 0.990 0.0 1.000 0.208 20 mg Rivaroxaban 5 mg Rivaroxabanvs 0.420 0.136-1.301 0.133 0.14 0.706 0.0 1.000 0.132 30 mg Rivaroxaban 5 mg Rivaroxabanvs 0.356 0.131-0.967 0.043 0.40 0.820 0.0 0.548 0.352 40 mg Rivaroxaban 5 mg Rivaroxabanvs 0.137 0.032-0.587 0.007 0.00 0.969 0.0 0.806 0.291 60 mg Rivaroxaban 5 mg Rivaroxabanvs 1.073 0.337-3.417 0.905 0.60 0.739 0.0 0.734 0.649 40 mg Enoxaparin 10 mg Rivaroxabanvs 0.806 0.329-1.976 0.638 0.08 0.772 0.0 1.000 0.786 20 mg Rivaroxaban

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10 mg Rivaroxabanvs 0.295 0.084-1.037 0.057 0.98 0.322 0.0 1.000 0.831 30 mg Rivaroxaban 10 mg Rivaroxabanvs 0.266 0.089-0.793 0.018 0.61 0.736 0.0 0.806 0.436 40 mg Rivaroxaban 10 mg Rivaroxabanvs 0.661 0.329-1.330 0.246 8.74 0.013 77.1 0.308 0.278 60 mg Rivaroxaban 10 mg Rivaroxabanvs 1.058 0.898-1.246 0.503 2.97 0.705 0.0 0.296 0.127 40 mg Enoxaparin 20 mg Rivaroxabanvs 0.806 0.329-1.976 0.638 0.08 0.772 0.0 0.230 0.255 30 mg Rivaroxaban 20 mg Rivaroxabanvs 0.688 0.313-1.512 0.352 0.38 0.828 0.0 1.000 0.870 40 mg Rivaroxaban 20 mg Rivaroxabanvs 0.282 0.096-0.827 0.021 0.00 0.945 0.0 1.000 0.469 60 mg Rivaroxaban 20 mg Rivaroxabanvs 2.040 0.764-5.442 0.155 0.98 0.613 0.0 0.602 0.527 40 mg Enoxaparin 30 mg Rivaroxabanvs 0.858 0.387-1.904 0.707 0.13 0.716 0.0 1.000 0.658 40 mg Rivaroxaban 30 mg Rivaroxabanvs 3.420 1.130-10.350 0.030 0.64 0.424 0.0 0.318 0.563 40 mg Enoxaparin 40 mg Rivaroxabanvs 0.527 0.231-1.204 0.129 0.21 0.650 0.0 1.000 0.208 60 mg Rivaroxaban 40 mg Rivaroxabanvs 3.129 1.268-7.722 0.013 1.79 0.409 0.0 0.122 0.132 40 mg Enoxaparin 60 mg Rivaroxabanvs 6.693 2.102-21.318 0.001 1.25 0.264 19.7 0.128 0.252 40 mg Enoxaparin

Figure 3. Forest plot of the efficacy estimation of 10 mg daily ofrivaroxaban compared to 40 mg daily of enoxaparin. were all less than 1 in lower dosage compared apixaban had higher risk of bleeding event with higher dosage). Compared with 40 mg (20 mg daily: pooled RR=4.314, 95% CI= daily of enoxaparin, this research found the 1.040-19.800, P=0.032; 10 mg daily: pooled safety of 5 mg daily doses of apixaban was not RR=2.394, 95% CI=0.468-12.254, P=0.295) different, but 20 mgand 10 mg daily doses of (Table 2 and Figure 2).

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Rivaroxaban estimation: Primary efficacye valu- tively. The heterogeneity was found in some ation: compared to 40 mg daily of enoxaparin, subgroups, and the random-effects model was all of 10 mg, 20 mg, 30 mg, 40 mg and 60 mg used. daily doses of rivaroxaban could reduce the incidence of VTE except for 5 mg, (10 mg daily: Sensitivity analysis pooled RR=0.531, 95% CI=0.333-0.847, P= 0.008; 20 mg daily: pooled RR=0.633, 95% The methods of “Influence analysis” and “Trim CI=0.440-0.910, P=0.014; 30 mg daily: pool- and Filled analysis” were both conducted to ed RR=0.625, 95% CI=0.450-0.907, P=0.035; investigate the sensitivity of the pooled RRs 40 mg daily: pooled RR=0.602, 95% CI=0.414- and the test results indicating that the pooled 0.870, P=0.008; 60 mg daily: pooled RR= RRs were statistically robust. 0.768, 95% CI=0.495-0.992, P=0.039), but there was no significant different among those Publication bias 6 dosages of rivaroxaban. This meta-analysis found no evidence of litera- Primary safety evaluation: Compared with 40 ture publication bias by using Begg’s funnel mg daily of enoxaparin, higher daily doses of plot and Egger’s test. rivaroxaban (eg. 30 mg, 40 mg and 60 mg) Discussion could increase the risk of incident of major or clinically relevant non-major bleeding event The rate of THA is steadily increasing in parallel (30 mg daily: pooled RR=3.420, 95% CI= with the growing elderly population. In the 1.130-10.350, P=0.030; 40 mg daily: pooled United States, there are approximately 250,000 RR=3.129, 95% CI=1.268-7.722, P=0.013; 60 THAs per year, and this number will increase by mg daily: pooled RR=6.693, 95% CI=2.102- 174% to 572,000 by 2030 [29]. Epidemiology 21.318, P=0.001). Meantime, higher daily study shown that the volume of primary and dosages seemed to be less safety than lower revision TKAs in England and Wales will have daily dosages of rivaroxaban too (5 mg vs. 40 increased by 117% and 332%, respectively mg: pooled RR=0.356, 95% CI=0.131-0.967, between 2012 and 2030 [30]. The most com- P=0.043; 5 mg vs. 60 mg: pooled RR=0.137, mon cause of re-admission after THA and TKA 95% CI=0.032-0.587, P=0.007; 10 mg vs. 40 surgery is the venous thromboembolism. As mg: pooled RR=0.266, 95% CI=0.089-0.793, previous reported, the incidence of deep vein P=0.018; 20 mg vs. 60 mg: pooled RR=0.282, thrombosis is almost 40% to 60% without any 95% CI=0.096-0.827, P=0.021) (Table 3 and antithrombotic drugs [31]. Although the tradi- Figure 3). tional anticoagulants have been proven to be Darexaban estimation: Primary efficacye valua- effective for the prevention of VTE, but the com- tion: compared to 40 mg daily of enoxaparin plex operation limited clinical application. In the and other daily doses of darexaban, 60 mg past several decades, Vitamin-K antagonists, daily could reduce the incidence of VTE (10 mg an oral anticoagulant, need laboratory monitor- darexabanvs 60 mg darexaban: pooled RR= ing and the interaction of food and drug is also 1.673, 95% CI=1.059-2.642, P=0.027; 60 mg complicated [32]. The major limitation of other darexabanvs 40 mg enoxaparin: pooled RR= traditional anticoagulants is that all of them 0.742, 95% CI=0.574-0.959, P=0.022). need subcutaneous administration, so them are inconvenient for discharged patients and Primary safety evaluation: there were different have low patient compliance [33]. The develop- among 10 mg, 30 mg and 60 mg daily doses ment of direct factor Xa inhibitor, which can be of rivaroxaban and 40 mg daily of enoxaparin taken orally and had a predictable pharmacoki- in incident of major or clinically relevant non- netics, could overcome the limitations of tradi- major bleeding event (Table 4 and Figure 4). tional anticoagulant drugs and be adopt widely in prevention of post-arthroplastic VTE [33]. Heterogeneity Previous network meta-analysis had proven the Q-statistic (Q>0.10) and the I2 statistic that apixaban, rivaroxaban and darexaban is (I=0.0%) were both used to calculated the het- better than edoxaban in primary safety out- erogeneity among subgroups analysis quantita- comes and primary efficacy outcomes, but the

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Table 4. Comparison results of different daily doses of rivaroxaban and 40 mg daily of enoxaparin in primary efficacy and safety Daily dosage RR (95% CI) Homogeneity Publication bias Outcomes comparison RR CI P value Q Ph I² (%) PB PE Primary efficacy outcomes 10 mg Darexabanvs 1.382 0.906-2.109 0.133 0.47 0.493 0.0 0.301 0.478 30 mg Darexaban 10 mg Darexabanvs 1.673 1.059-2.642 0.027 2.44 0.118 59.1 0.585 0.463 60 mg Darexaban 10 mg Darexabanvs 1.215 0.819-1.802 0.334 3.69 0.055 72.9 0.125 0.805 40 mg Enoxaparin 30 mg Darexabanvs 1.224 0.962-1.556 0.100 1.43 0.698 0.0 0.794 0.364 60 mg Darexaban 30 mg Darexabanvs 0.955 0.749-1.217 0.709 1.80 0.614 0.0 0.883 0.771 40 mg Enoxaparin 60 mg Darexabanvs 0.742 0.574-0.959 0.022 0.75 0.861 0.0 0.288 0.064 40 mg Enoxaparin Primary safety outcomes 10 mg Darexabanvs 1.069 0.513- 2.230 0.858 2.42 0.120 58.7 0.109 0.686 30 mg Darexaban 10 mg Darexabanvs 0.812 0.413-1.596 0.545 5.13 0.024 80.5 0.226 0.523 60 mg Darexaban 10 mg Darexabanvs 1.029 0.511- 2.074 0.936 3.11 0.078 67.9 0.110 0.720 40 mg Enoxaparin 30 mg Darexabanvs 0.844 0.513-1.387 0.502 0.77 0.856 0.0 0.560 0.312 60 mg Darexaban 30 mg Darexabanvs 0.773 0.457- 1.306 0.336 1.27 0.737 0.0 0.209 0. 432 40 mg Enoxaparin 60 mg Darexabanvs 0.965 0.593-1.569 0.886 2.88 0.410 0.0 0.483 0.292 40 mg Enoxaparin

Figure 4. Forest plot of the efficacy estimation of 6 mg daily of darexabancompared to 40 mg daily of enoxaparin. best suitable dosages of the oral direct factor Safety and efficacy are the two contradictory Xa inhibitor drugs are not described [12]. So the elements. High dose may have better efficacy, key purpose of this meta-analysis is to discuss but them often bring lower safety. In this paper, the appropriate daily dose for those drugs by we adopt composite of deep venous thrombo- quantitative statistical analysis. sis, non-fatal pulmonary embolism and death

10702 Int J Clin Exp Med 2016;9(6):10695-10705 Efficacy and safety of oral direct factor Xa inhibitor of all causes as the primary efficacy outcomes, Address correspondence to: Chunli Yu, Department and the events of major bleeding and non- of Gynecology, Taian City Central Hospital, No. 29, major but clinically relevant bleeding as the pri- Longtan Road, Taishan District, Taian 271000, mary bleeding outcomes. Shandong Province, P. R. China. Tel: +86 538- 6298551; E-mail: [email protected] The three major results of this study are: 1, the efficacy of 5 mg, 10 mg and 20 mg daily doses References of apixaban is superior to 40 mg daily of enoxaparin, but 10 mg and 20 mg daily doses of apix- [1] Mackman N. Triggers, targets and treatments aban increase the risk of major bleeding and for thrombosis. Nature 2008; 451: 914-918. non-major but clinically relevant bleeding. This [2] Anderson FA Jr, Zayaruzny M, Heit JA, Fidan D result indicates that 5 mg daily of apixaban may and Cohen AT. Estimated annual numbers of be the potential dose with higher effective and US acute-care hospital patients at risk for ve- lower risk compared to enoxaparin. Diana M. nous thromboembolism. Am J Hematol 2007; Sobieraj et al. also found 5 mg daily of apixaban 82: 777-782. [3] Cohen AT, Agnelli G, Anderson FA, Arcelus JI, could reduce VTE recurrence when compared Bergqvist D, Brecht JG, Greer IA, Heit JA, to placebo and aspirin [10]; 2, except the low- Hutchinson JL, Kakkar AK, Mottier D, Oger E, est daily dose of 5 mg, all of 10 mg, 20 mg, 30 Samama MM, Spannagl M; VTE Impact mg, 40 mg and 60 mg daily doses of rivaroxa- Assessment Group in Europe (VITAE). Venous ban have superior efficacy than 40 mg daily of thromboembolism (VTE) in Europe. The num- enoxaparin, but higher doses of 30 mg, 40 mg ber of VTE events and associated morbidity and 60 mg show lower safety than enoxaparin and mortality. Thromb Haemost 2007; 98: and 10 mg and 20 mg of rivaroxaban. An phase 756-764. II dose-ranging study found that 10 mg b.i.d. [4] O’Brien JA and Caro JJ. Direct medical cost dose of rivaroxaban with optimal potential effi- of managing deep vein thrombosis according cacy and an acceptable safety profile [28]. 3, to the occurrence of complications. Pharma- 60 mg daily is better in efficacy than enoxapa- coeconomics 2002; 20: 603-615. [5] Johanson NA, Lachiewicz PF, Lieberman JR, rin and other doses of darexaban. Meantime, Lotke PA, Parvizi J, Pellegrini V, Stringer TA, the risk of bleeding is not significantly increas- Tornetta P 3rd, Haralson RH 3rd and Watters ing. This result is similar to a phase IIb study, WC 3rd. Prevention of symptomatic pulmon- that total daily doses of 60 mg appeared to be ary embolism in patients undergoing total effective in preventing VTE and well toleration hip or knee arthroplasty. J Am Acad Orthop [19]. Surg 2009; 17: 183-196. [6] Hirsh J and Raschke R. Heparin and low- The papers included in this meta-analysis are molecular-weight heparin: the Seventh ACCP high quality RCTs, but the data of those aborigi- Conference on Antithrombotic and Thrombo- nal articles is supported for detailed subgroup lytic Therapy. Chest 2004; 126: 188S-203S. analysis. So some limitations of this paper are [7] Mann KG, Brummel K and Butenas S. What existed. Firstly, this paper only pooled the total is all that thrombin for? J Thromb Haemost daily dose of oral direct factor Xa inhibitor, the 2003; 1: 1504-1514. dosing regimen are not analyzed; secondly, sex [8] Weitz JI, Hirsh J, Samama MM; American and racial differences are not considered; third- College of Chest Physicians. New antithrombotic drugs: American College of Chest Phy- ly, the duration of treatment and follow-up time sicians Evidence-Based Clinical Practice Gui- are not considered. delines (8th Edition). Chest 2008; 133: 234S-256S. Conclusion [9] Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N and Jin C. A systematic review of rivaroxaban Consider the safety and efficacy, 5 mg daily of versus enoxaparin in the prevention of venous apixaban, 20 mg daily of rivaroxaban, 60 mg thromboembolism after hip or knee replace- daily of darexaban are optimal potentialoral ment. Thromb Res 2011; 127: 525-534. direct factor Xa inhibitor for thromboprophylax- [10] Sobieraj DM, Coleman CI, Pasupuleti V, De- is after total hip or knee replacement. shpande A, Kaw R and Hernandez AV. Com- parative efficacy and safety of anticoagulants Disclosure of conflict of interest and aspirin for extended treatment of venous thromboembolism: a network meta-analysis. None. Thromb Res 2015; 135: 888-896.

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