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

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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

Nowadays, total hip arthroplasty (THA) and total knee arthroplasty (TKA) has been widely used in the treatment of unrecovered disloca-tion, end-stage osteoarthritis, rheumatic arthri-tis and so on. But post-surgery complications, especially as venous thromboembolism (VTE), has been attracted more and more attention. A common type of venous thrombosis is deep vein thrombosis (DVT), which is a blood clot in the deep veins of the leg. If the thrombus

breaks off (embolizes) and flows towards the

lungs, it can become the life-threatening pul-monary embolism (PE), a blood clot in the lungs. According to Nature report, VTE has been the third cause of cardiovascular mortality [1] and

it has imposed a major health burden in the world for a substantial effect on patients’ qual-ity of life. Anderson et al. estimated that over 12 million patients, comprising 31% of hospital discharged patients were at risk of VTE in the US using the 2003 Nationwide Inpatient Sam- ple [2]. In 2007, Cohen et al. found the estimat-ed total number of symptomatic VTE events was 465,000 cases of deep-vein thrombosis, 296,000 cases of PE, and 370,000 VTE-related deaths in six EU countries [3]. Post-thrombotic syndrome and pulmonary hypertension, two major long-term complications of VTE, are not

only the significant causes of morbidity and

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VTE should be considered in THA and total knee arthroplasty TKA. According to clinical practice guideline, thromboprophylactic thera-py is recommended for 35 days after THA and more than 10 days after TKA [5]. There are three major types of the traditional anticoa- gulants for VTE prophylaxis: 1, low molecular weight heparins (such as enoxaparin); 2, indi-rect factor Xa inhibitors (such as fondaparinux, idraparinux, idrabiotaparinux); 3, vitamin Kan- tagonists (such as warfarin). Those three tradi-tional anticoagulants have been proven to be effective for theprophylaxis of VTE, but the par-enteral administration, routine laboratory moni-toring, post-operative bleeding and ongoing dose adjustment limit and complicate their use in clinic [6]. FactorXa (FXa) is a key factor in theintrinsic and extrinsic coagulant pathway and can analyze the conversion of prothrombin to thrombin [7]. So the blocking of FXa is an effective way to stopthe coagulative cascade. Oral direct factor Xa inhibitor is a new type of anticoagulant medicines, including apixa-ban, rivaroxaapixa-ban, dabigatran and endoxaapixa-ban, has been developed to overcome those

limita-tions of traditional anticoagulants and specifi -cally targets factor Xa. With the advantage of oral administration and a predictable pharma-cokinetics, oral direct factor Xa inhibitor pro-vides a promising future in the prophylaxis of post-major surgery VTE [8].

for thromboprophylaxis after total hip or knee replacement.

Materials and methods

Literature search strategy

Without language restriction, this paper se- arched the databases such as Pubmed, Me- dline, Web of Science and Embase databases by the terms (“venous thromboembolism” or “deep venous thrombosis” or “otal hip arthro-plasty” or “total knee arthroarthro-plasty” or “total knee replacement”, “enoxaparin” or “factor Xa inhibitor”, “apixaban” or “rivaroxaban” or “dabi-gatran”) to retrieve related studies and the last retrieval time was November, 30, 2015. The

flow diagram of retrieval process was shown

in Figure 1.

Inclusion and exclusion criteria

Inclusion criteria: (1) study focuses on Oral di- rect factor Xa inhibitor for thromboprophyla- xis; (2) RCT study; (3) Data reported was

avail-able; (4) published data was fit to this

meta-analysis.

[image:2.612.92.374.73.290.2]

The exclusion criteria: (1) animal studies; (2) the reported data was not adaptable; (3) the study focused on other thromboprophylaxis; (4) the surgery was not total hip or knee replace-ment; (5) daily dose of the oral direct factor Xa inhibitor was not reported.

Figure 1. A flow diagram of the study selection process.

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 ana-lyzed. With the aim to evalu-ate the suitable dose, this research conducted a

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[image:3.612.92.527.86.307.2]

Table 1. Summary of basic information of the studies included

Studies Year Drug participantsNumber of Dose daily included

Quantitative assessment by Jadad Scale

Random Blinding and dropoutsWith drawals Overall 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

The information about study design, first

author‘s name, published year, follow-up time, name of oral direct factor Xa inhibitor, daily

doses and the frequencies of primary efficacy

and safety endpoints in experimental group and control group were obtained based upon “Inclusion and exclusion criteria” mentioned above.

Statistical analysis

The statistical analysis was conducted by Stata 11.0 (StataCorp, College Station, TX) and

α=0.05 was considered as significance level. The risk ratio (RR) with a 95% confidence inter -val (CI) was used to describe the dichotomous data. Statistical heterogeneity was measured using the I2-statistic and Q-statistic (P≤0.05 was considered to be representative of

statisti-cally significant heterogeneity). When there was

no heterogeneity of the results of the studies,

then fixed effects model was used. Otherwise,

the random effects model was used. Publication bias was assessed by Begg’s rank correlation method and Egger weighted regression test. Endpoints measures

The primary efficacy endpoint included DVT,

non-fatal PE and death of all cause during the treatment period. The primary safety endpoints were the composite of major bleeding and non-major but clinically relevant bleeding.

Quality assessment

The Jadad scale was performed to evaluate quality of the studies included on three aspects: “random”, “blinding” and “Withdrawals and dropouts”. The overall scores of Jadad scale

were ranged from 0 to 5 (≥3 was generally con -sidered to be of high quality) [13].

Main results

Characteristics of studies

15 relevant studies with 28, 548 individuals and 3 different types of oral direct factor Xa inhibitor (apixaban, rivaroxaban and dabiga-tran) were employed for this meta-analysis. In those studies, 4 papers studied on the effect and safety of dabigatran, 7 papers were esti-mated the effect and safety of rivaroxaban and 4 paper focused on apixaban. The characteris-tics of each study were presented in Table 1. Quantitative data synthesis

Apixaban estimation: Primary efficacye valua -tion: compared to 40 mg daily of enoxaparin, all of 5 mg, 10 mg and 20 mg daily doses of apixa-ban could reduce the incidence of VTE (5 mg

daily: pooled RR=0.662, 95% CI=0.469-0.935, P=0.019; 10 mg daily: pooled RR=0.567, 95% CI=0.328-0.978, P=0.042; 20 mg daily: pool-ed RR=0.473, 95% CI=0.264-0.845, P=0.011), but there was no significant different among

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Primary safety evaluation: no significant differ -ent was found among 5 mg, 10 mg and 20 mg daily doses of apixaban in major or clinically

[image:4.612.90.520.96.393.2]

rel-evant non-major bleeding in this paper, but there was an interesting result that lower dos-age might be more safe than higher (RR value 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

Outcomes Daily dosage comparison RR (95% CI) Homogeneity Publication bias

RR CI P value Q Ph I² (%) PB PE

Primary efficacy outcomes 5 mg Apixabanvs

10 mg Apixaban 1.190 0.649-2.181 0.575 1.06 0.303 5.7 0.805 0.918 5 mg Apixabanvs

20 mg Apixaban 1.434 0.759-2.707 0.266 0.80 0.371 0.0 0.231 0.182 5 mg Apixabanvs

40 mg enoxaparin 0.662 0.469-0.935 0.019 16.43 0.002 75.7 0.532 0.371 10 mg Apixabanvs

20 mg Apixaban 1.231 0.631-2.399 0.543 3.08 0.079 67.5 0.343 0.433 10 mg Apixabanvs

40 mg enoxaparin 0.567 0.328-0.978 0.042 1.99 0.158 49.9 0.783 0.832 20 mg Apixabanvs

40 mg enoxaparin 0.473 0.264-0.845 0.011 0.40 0.527 0.0 1.000 0.276

Primary safety outcomes 5 mg Apixabanvs

10 mg Apixaban 0.828 0.239-2.873 0.767 3.81 0.051 73.8 0.49 0.558 5 mg Apixabanvs

20 mg Apixaban 0.479 0.157-1.454 0.194 1.56 0.212 35.9 0.621 0.733 5 mg Apixabanvs

40 mg enoxaparin 0.821 0.558-1.209 0.318 5.91 0.206 32. 0.850 0.660 10 mg Apixabanvs

20 mg Apixaban 0.556 0.188-1.640 0.287 1.59 0.208 37.0 1.000 0.829 10 mg Apixabanvs

40 mg enoxaparin 2.394 0.468-12.254 0.295 0.60 0.440 0.0 0.493 0.925 20 mg Apixabanvs

[image:4.612.94.518.198.633.2]

40 mg enoxaparin 4.314 1.040-19.800 0.032 0.883 0.02 0.0 0.390 0.615

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[image:5.612.94.522.94.722.2]

Table 3. Comparison results of different daily doses of rivaroxaban and 40 mg daily of enoxaparin in

primary efficacy and safety

Outcomes Daily dosage comparison RR (95% CI) Homogeneity Publication bias

RR CI P value Q Ph I² (%) PB PE

Primary efficacy outcomes 5 mg Rivaroxabanvs

10 mg Rivaroxaban 0.986 0.692-1.403 0.936 1.12 0.572 0.0 0.368 0.350 5 mg Rivaroxabanvs

20 mg Rivaroxaban 1.307 0.876-1.949 0.190 0.59 0.744 0.0 0.230 0.558 5 mg Rivaroxabanvs

30 mg Rivaroxaban 1.223 0.741-2.018 0.431 0.22 0.640 0.0 0.176 0.163 5 mg Rivaroxabanvs

40 mg Rivaroxaban 1.360 0.905-2.043 0.139 3.58 0.167 44.2 0.133 0.277 5 mg Rivaroxabanvs

60 mg Rivaroxaban 1.203 0.748-1.935 0.446 0.00 0.950 0.0 0.133 0.115 5 mg Rivaroxabanvs

40 mg Enoxaparin 0.833 0.604-1.148 0.263 2.42 0.299 17.3 0.368 0.346 10 mg Rivaroxabanvs

20 mg Rivaroxaban 1.321 0.890-1.962 0.167 0.39 0.822 0.0 0.652 0.631 10 mg Rivaroxabanvs

30 mg Rivaroxaban 0.786 0.608-1.015 0.065 3.43 0.180 41.7 0.368 0.154 10 mg Rivaroxabanvs

40 mg Rivaroxaban 1.395 0.934-2.084 0.104 1.65 0.438 0.0 0.293 0.189 10 mg Rivaroxabanvs

60 mg Rivaroxaban 1.373 0.866-2.177 0.178 0.03 0.858 0.0 0.293 0.383 10 mg Rivaroxabanvs

40 mg Enoxaparin 0.531 0.333-0.847 0.008 29.91 0.000 83.3 0.221 0.156 20 mg Rivaroxabanvs

30 mg Rivaroxaban 0.912 0.528-1.577 0.742 1.35 0.245 26.1 0.806 0.888 20 mg Rivaroxabanvs

40 mg Rivaroxaban 1.047 0.671-1.633 0.840 2.88 0.237 30.6 0.624 0.409 20 mg Rivaroxabanvs

60 mg Rivaroxaban 1.004 0.600-1.680 0.987 0.12 0.730 0.0 0.327 0.136 20 mg Rivaroxabanvs

40 mg Enoxaparin 0.633 0.440-0.910 0.014 4.77 0.092 58.1 0.462 0.937 30 mg Rivaroxabanvs

40 mg Rivaroxaban 1.692 0.879-3.259 0.116 0.25 0.620 0.0 0.230 0.255 30 mg Rivaroxabanvs

40 mg Enoxaparin 0.625 0.450-0.907 0.035 0.353 0.129 0.0 1.000 0.870 40 mg Rivaroxabanvs

60 mg Rivaroxaban 1.042 0.632-1.719 0.872 1.50 0.221 33.3 1.000 0.469 40 mg Rivaroxabanvs

40 mg Enoxaparin 0.602 0.414-0.870 0.008 4.63 0.099 56.8 0.602 0.527 60 mg Rivaroxabanvs

40 mg Enoxaparin 0.768 0.495-0.992 0.039 0.86 0.355 0.0 1.000 0.658

Primary safety outcomes 5 mg Rivaroxabanvs

10 mg Rivaroxaban 1.332 0.362-4.901 0.666 1.22 0.543 0.0 0.308 0.553 5 mg Rivaroxabanvs

20 mg Rivaroxaban 0.525 0.182-1.517 0.234 0.02 0.990 0.0 1.000 0.208 5 mg Rivaroxabanvs

30 mg Rivaroxaban 0.420 0.136-1.301 0.133 0.14 0.706 0.0 1.000 0.132 5 mg Rivaroxabanvs

40 mg Rivaroxaban 0.356 0.131-0.967 0.043 0.40 0.820 0.0 0.548 0.352 5 mg Rivaroxabanvs

60 mg Rivaroxaban 0.137 0.032-0.587 0.007 0.00 0.969 0.0 0.806 0.291 5 mg Rivaroxabanvs

40 mg Enoxaparin 1.073 0.337-3.417 0.905 0.60 0.739 0.0 0.734 0.649 10 mg Rivaroxabanvs

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10 mg Rivaroxabanvs

30 mg Rivaroxaban 0.295 0.084-1.037 0.057 0.98 0.322 0.0 1.000 0.831 10 mg Rivaroxabanvs

40 mg Rivaroxaban 0.266 0.089-0.793 0.018 0.61 0.736 0.0 0.806 0.436 10 mg Rivaroxabanvs

60 mg Rivaroxaban 0.661 0.329-1.330 0.246 8.74 0.013 77.1 0.308 0.278 10 mg Rivaroxabanvs

40 mg Enoxaparin 1.058 0.898-1.246 0.503 2.97 0.705 0.0 0.296 0.127 20 mg Rivaroxabanvs

30 mg Rivaroxaban 0.806 0.329-1.976 0.638 0.08 0.772 0.0 0.230 0.255 20 mg Rivaroxabanvs

40 mg Rivaroxaban 0.688 0.313-1.512 0.352 0.38 0.828 0.0 1.000 0.870 20 mg Rivaroxabanvs

60 mg Rivaroxaban 0.282 0.096-0.827 0.021 0.00 0.945 0.0 1.000 0.469 20 mg Rivaroxabanvs

40 mg Enoxaparin 2.040 0.764-5.442 0.155 0.98 0.613 0.0 0.602 0.527 30 mg Rivaroxabanvs

40 mg Rivaroxaban 0.858 0.387-1.904 0.707 0.13 0.716 0.0 1.000 0.658 30 mg Rivaroxabanvs

40 mg Enoxaparin 3.420 1.130-10.350 0.030 0.64 0.424 0.0 0.318 0.563 40 mg Rivaroxabanvs

60 mg Rivaroxaban 0.527 0.231-1.204 0.129 0.21 0.650 0.0 1.000 0.208 40 mg Rivaroxabanvs

40 mg Enoxaparin 3.129 1.268-7.722 0.013 1.79 0.409 0.0 0.122 0.132 60 mg Rivaroxabanvs

40 mg Enoxaparin 6.693 2.102-21.318 0.001 1.25 0.264 19.7 0.128 0.252

were all less than 1 in lower dosage compared with higher dosage). Compared with 40 mg daily of enoxaparin, this research found the safety of 5 mg daily doses of apixaban was not different, but 20 mgand 10 mg daily doses of

apixaban had higher risk of bleeding event

(20 mg daily: pooled RR=4.314, 95% CI= 1.040-19.800, P=0.032; 10 mg daily: pooled RR=2.394, 95% CI=0.468-12.254, P=0.295)

[image:6.612.186.518.75.363.2]

(Table 2 and Figure 2).

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Rivaroxaban estimation: Primary efficacye valu -ation: compared to 40 mg daily of enoxaparin, all of 10 mg, 20 mg, 30 mg, 40 mg and 60 mg daily doses of rivaroxaban could reduce the incidence of VTE except for 5 mg, (10 mg daily:

pooled RR=0.531, 95% CI=0.333-0.847, P= 0.008; 20 mg daily: pooled RR=0.633, 95% CI=0.440-0.910, P=0.014; 30 mg daily: pool-ed RR=0.625, 95% CI=0.450-0.907, P=0.035; 40 mg daily: pooled RR=0.602, 95% CI=0.414-0.870, P=0.008; 60 mg daily: pooled RR= 0.768, 95% CI=0.495-0.992, P=0.039), but there was no significant different among those

6 dosages of rivaroxaban.

Primary safety evaluation: Compared with 40 mg daily of enoxaparin, higher daily doses of rivaroxaban (eg. 30 mg, 40 mg and 60 mg) could increase the risk of incident of major or clinically relevant non-major bleeding event

(30 mg daily: pooled RR=3.420, 95% CI= 1.130-10.350, P=0.030; 40 mg daily: pooled RR=3.129, 95% CI=1.268-7.722, P=0.013; 60 mg daily: pooled RR=6.693, 95% CI=2.102-21.318, P=0.001). Meantime, higher daily

dosages seemed to be less safety than lower daily dosages of rivaroxaban too (5 mg vs. 40

mg: pooled RR=0.356, 95% CI=0.131-0.967, P=0.043; 5 mg vs. 60 mg: pooled RR=0.137, 95% CI=0.032-0.587, P=0.007; 10 mg vs. 40 mg: pooled RR=0.266, 95% CI=0.089-0.793, P=0.018; 20 mg vs. 60 mg: pooled RR=0.282, 95% CI=0.096-0.827, P=0.021) (Table 3 and Figure 3).

Darexaban estimation: Primary efficacye valua -tion: compared to 40 mg daily of enoxaparin and other daily doses of darexaban, 60 mg daily could reduce the incidence of VTE (10 mg

darexabanvs 60 mg darexaban: pooled RR= 1.673, 95% CI=1.059-2.642, P=0.027; 60 mg darexabanvs 40 mg enoxaparin: pooled RR= 0.742, 95% CI=0.574-0.959, P=0.022).

Primary safety evaluation: there were different among 10 mg, 30 mg and 60 mg daily doses of rivaroxaban and 40 mg daily of enoxaparin in incident of major or clinically relevant non-major bleeding event (Table 4 and Figure 4). Heterogeneity

the Q-statistic (Q>0.10) and the I2 statistic

(I=0.0%) were both used to calculated the het -erogeneity among subgroups analysis

quantita-tively. The heterogeneity was found in some subgroups, and the random-effects model was used.

Sensitivity analysis

The methods of “Influence analysis” and “Trim

and Filled analysis” were both conducted to investigate the sensitivity of the pooled RRs and the test results indicating that the pooled RRs were statistically robust.

Publication bias

This meta-analysis found no evidence of litera-ture publication bias by using Begg’s funnel plot and Egger’s test.

Discussion

The rate of THA is steadily increasing in parallel with the growing elderly population. In the United States, there are approximately 250,000 THAs per year, and this number will increase by 174% to 572,000 by 2030 [29]. Epidemiology study shown that the volume of primary and revision TKAs in England and Wales will have increased by 117% and 332%, respectively between 2012 and 2030 [30]. The most com-mon cause of re-admission after THA and TKA surgery is the venous thromboembolism. As previous reported, the incidence of deep vein thrombosis is almost 40% to 60% without any antithrombotic drugs [31]. Although the tradi-tional anticoagulants have been proven to be effective for the prevention of VTE, but the com-plex operation limited clinical application. In the past several decades, Vitamin-K antagonists, an oral anticoagulant, need laboratory monitor-ing and the interaction of food and drug is also complicated [32]. The major limitation of other traditional anticoagulants is that all of them need subcutaneous administration, so them are inconvenient for discharged patients and have low patient compliance [33]. The develop-ment of direct factor Xa inhibitor, which can be taken orally and had a predictable pharmacoki-netics, could overcome the limitations of tradi-tional anticoagulant drugs and be adopt widely in prevention of post-arthroplastic VTE [33]. Previous network meta-analysis had proven that apixaban, rivaroxaban and darexaban is better than edoxaban in primary safety

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[image:8.612.89.521.95.389.2]

Table 4. Comparison results of different daily doses of rivaroxaban and 40 mg daily of enoxaparin in

primary efficacy and safety

Outcomes Daily dosage comparison RR (95% CI) Homogeneity Publication bias

RR CI P value Q Ph I² (%) PB PE

Primary efficacy outcomes 10 mg Darexabanvs

30 mg Darexaban 1.382 0.906-2.109 0.133 0.47 0.493 0.0 0.301 0.478 10 mg Darexabanvs

60 mg Darexaban 1.673 1.059-2.642 0.027 2.44 0.118 59.1 0.585 0.463 10 mg Darexabanvs

40 mg Enoxaparin 1.215 0.819-1.802 0.334 3.69 0.055 72.9 0.125 0.805 30 mg Darexabanvs

60 mg Darexaban 1.224 0.962-1.556 0.100 1.43 0.698 0.0 0.794 0.364 30 mg Darexabanvs

40 mg Enoxaparin 0.955 0.749-1.217 0.709 1.80 0.614 0.0 0.883 0.771 60 mg Darexabanvs

40 mg Enoxaparin 0.742 0.574-0.959 0.022 0.75 0.861 0.0 0.288 0.064

Primary safety outcomes 10 mg Darexabanvs

30 mg Darexaban 1.069 0.513- 2.230 0.858 2.42 0.120 58.7 0.109 0.686 10 mg Darexabanvs

60 mg Darexaban 0.812 0.413-1.596 0.545 5.13 0.024 80.5 0.226 0.523 10 mg Darexabanvs

40 mg Enoxaparin 1.029 0.511- 2.074 0.936 3.11 0.078 67.9 0.110 0.720 30 mg Darexabanvs

60 mg Darexaban 0.844 0.513-1.387 0.502 0.77 0.856 0.0 0.560 0.312 30 mg Darexabanvs

40 mg Enoxaparin 0.773 0.457- 1.306 0.336 1.27 0.737 0.0 0.209 0. 432 60 mg Darexabanvs

40 mg Enoxaparin 0.965 0.593-1.569 0.886 2.88 0.410 0.0 0.483 0.292

best suitable dosages of the oral direct factor Xa inhibitor drugs are not described [12]. So the key purpose of this meta-analysis is to discuss the appropriate daily dose for those drugs by quantitative statistical analysis.

Safety and efficacy are the two contradictory elements. High dose may have better efficacy,

[image:8.612.97.517.292.620.2]
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of all causes as the primary efficacy outcomes,

and the events of major bleeding and non-major but clinically relevant bleeding as the pri-mary bleeding outcomes.

The three major results of this study are: 1, the

efficacy of 5 mg, 10 mg and 20 mg daily doses

of apixaban is superior to 40 mg daily of enoxa-parin, but 10 mg and 20 mg daily doses of apix-aban increase the risk of major bleeding and non-major but clinically relevant bleeding. This result indicates that 5 mg daily of apixaban may be the potential dose with higher effective and lower risk compared to enoxaparin. Diana M. Sobieraj et al. also found 5 mg daily of apixaban could reduce VTE recurrence when compared to placebo and aspirin [10]; 2, except the low-est daily dose of 5 mg, all of 10 mg, 20 mg, 30 mg, 40 mg and 60 mg daily doses of

rivaroxa-ban have superior efficacy than 40 mg daily of

enoxaparin, but higher doses of 30 mg, 40 mg and 60 mg show lower safety than enoxaparin and 10 mg and 20 mg of rivaroxaban. An phase II dose-ranging study found that 10 mg b.i.d.

dose of rivaroxaban with optimal potential effi

-cacy and an acceptable safety profile [28]. 3, 60 mg daily is better in efficacy than enoxapa -rin and other doses of darexaban. Meantime,

the risk of bleeding is not significantly increas -ing. This result is similar to a phase IIb study, that total daily doses of 60 mg appeared to be effective in preventing VTE and well toleration [19].

The papers included in this meta-analysis are high quality RCTs, but the data of those aborigi-nal articles is supported for detailed subgroup analysis. So some limitations of this paper are existed. Firstly, this paper only pooled the total daily dose of oral direct factor Xa inhibitor, the dosing regimen are not analyzed; secondly, sex and racial differences are not considered; third-ly, the duration of treatment and follow-up time are not considered.

Conclusion

Consider the safety and efficacy, 5 mg daily of

apixaban, 20 mg daily of rivaroxaban, 60 mg daily of darexaban are optimal potentialoral direct factor Xa inhibitor for thromboprophylax-is after total hip or knee replacement.

Disclosure of conflict of interest

None.

Address correspondence to: Chunli Yu, Department of Gynecology, Taian City Central Hospital, No. 29, Longtan Road, Taishan District, Taian 271000, Shandong Province, P. R. China. Tel: +86 538-6298551; E-mail: [email protected]

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Figure

Figure 1. A flow diagram of the study selection process.
Table 1. Summary of basic information of the studies included
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
Table 3. Comparison results of different daily doses of rivaroxaban and 40 mg daily of enoxaparin in primary efficacy and safety
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References

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