1. Introduction
Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE),[ 1 ] with 10 million cases occurring every year,[ 2 ] represents the third most common acute cardiovascular syndrome (after myocardial infarction and stroke),[ 3 ] causes significant morbidity and mortality,[ 4 ] and places a substantial clinical and economic burden.[ 5 ] Total hip arthroplasty (THA) or total knee arthroplasty (TKA) is generally regarded as a highly successful surgical intervention that relieves pain, improves function, and enhances the quality of patients’ lives. However, VTE represents a major complication of this type of surgery. Among various methods of prophylaxis, the main approach involves anticoagulant prophylaxis. In addition, there are many kinds of anticoagulants, and there is no exact comparison of their anticoagulant effects. Therefore, in this study, we explored the effect of different anticoagulants on VTE prevention after THA or TKA through network meta-analysis, which is of great significance to guide clinical medical personnel to use scientific research results to prevent VTE.
2. Materials and methods
This review adhered to the Preferred Reporting in Systematic Reviews and Meta-Analysis 2020 guidelines,[ 6 ] and this review was registered in the International Prospective Register of Systematic Reviews (registration number, CRD42022357393).
3. Search strategy
A literature search was carried out by 2 independent reviewers. PubMed, Embase, The Cochrane Library, Web of Science, CBM, CNKI, WanFang Data, and VIP were explored from January 1, 2000, to January 27, 2022. To minimize the missing literature, references listed in the included studies were also traced to supplement relevant data.
4. Eligibility criteria
The inclusion criteria were as follows: administration of anticoagulants after THA or TKA (not limited by age, race, and nationality of patients); prospective or retrospective study design; direct or indirect availability of the results – responders and sample size.
The exclusion criteria were as follows: duplicate articles; articles with inconsistent research contents; review articles; conference abstracts; animal studies; case reports; study protocols; and non-English and non-Chinese articles.
4.1. Literature screening and data extraction
Two reviewers independently screened the literature and extracted and cross-checked the data. In case of disagreements, a third party was consulted to assist in the judgment. During literature screening, first, the title and abstract were read. Then, after the exclusion of irrelevant literature, the full text of the preliminarily relevant articles was read to determine whether to include them in the final analysis. Data extraction encompassed the basic characteristics of the included studies, such as author, publication year, country, anticoagulant, age, recipients, mean body mass index, duration of surgery, and surgery type. Results considered responders and sample size.
4.2. Statistical analysis
“Network” package of Stata 16.0 software was used to produce the network plot. The size of the nodes corresponds to the number of participants randomized to each treatment. Treatments with direct comparisons are linked with a line; its thickness corresponds to the number of trials evaluating the comparison. Frequentist network meta-analysis was conducted using the “netmeta” package in R 4.1.0 software. Transitivity was subjectively assessed by the basic characteristics of the included studies. I 2 was used to analyze the heterogeneity. If I 2 < 50%, there was little heterogeneity between the studies, and the fixed-effects model was used for pooling. If I 2 ≥ 50%, there was great heterogeneity between the studies. Meta-regression was used to identify the potential factors causing heterogeneity, and then subgroup analysis was performed. If the source of heterogeneity could not be found, the random-effects model was used for pooling. Inconsistency was divided into global inconsistency and local inconsistency. Global Wald test was used to evaluate global inconsistency, and the node-splitting test was used to evaluate local inconsistency. If there was no statistically significant difference between the results of direct comparison and indirect comparison (P > .05), the consistency was good, and the consistency model was used for pooling; otherwise, the inconsistent model was used. Relative risk (RR) and 95% confidence interval (CI) were used to evaluate the efficacy of anticoagulants in the league table. P score was used to rank and compare different anticoagulants. The higher the P score value, the higher the efficacy ranking of the anticoagulant, and vice versa. The stability of the research results was analyzed by sensitivity analysis. The included studies were excluded one by one, and then meta-analysis was performed again. The results were compared with those before exclusion. If the change was small, it indicated that the stability of the included literature was good and the results were credible. If there were significant changes, it indicated that the results were not credible. A funnel plot was used to evaluate the existence of publication bias. If the P values of Egger, Begg–Mazumdar, and Thompson–Sharp tests were >.05, there was no publication bias; otherwise, there was publication bias.
4.3. Evidence assessment of the included studies
The reviewers assessed the certainty of evidence contributing to network estimates of the main outcomes using the Confidence in Network Meta-Analysis (CINeMA) framework,[ 7 ] which includes 6 domains: within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. Within-study bias was assessed by the modified Jadad score.[ 8 ] Potential sources of bias include random sequence production, allocation concealment, blinding method, and withdrawals and dropouts. According to the modified Jadad score, studies with a score ≤2 were considered studies without concerns; studies with a score 3 to 5 were considered studies with some concerns; and studies with a score ≥6 were considered studies with major concerns. Reporting bias was assessed subjectively in accordance with unpublished studies, outcomes in the gray literature, and funnel plots. Indirectness was subjectively assessed by the basic characteristics of the included studies. For imprecision, heterogeneity, and incoherence, relative effect estimates <0.800 and >1.250 were considered clinically important.
5. Results
5.1. Literature search and characteristics of the included studies
Sixteen anticoagulants were searched preliminarily by referring to relevant literature, and a total of 4150 articles were identified by searching the databases. Additional 5 articles were identified during the screening of the reference sections of the included articles. The detailed information is shown in Supplemental Method S1, Supplemental Digital Content, https://links.lww.com/MD/I301 [ 9–69 ] on 11 anticoagulants were finally included. The process and the results of the literature screening are shown in Figure 1 . Detailed information on the included studies is shown in Table 1 . The 11 anticoagulants included were apixaban, aspirin, betrixaban, dabigatran, darexaban, edoxaban, fondaparinux, low-molecular-weight heparin (LMWH), rivaroxaban, unfractionated heparin (UFH), and warfarin.
Table 1 -
Characteristics of the included studies.
No.
Study
Country
Anticoagulant
Age
Recipients (m/f)
Mean body mass index (SD), kg/m2
Duration of surgery, h
Surgery type
1
Anderson 2013
Canada
LMWH
57.9 ± 12.2
400 (213/187)
27.9 ± 5.8
1.53 ± 0.82
THA
Aspirin
57.6 ± 11.9
385 (231/154)
29.3 ± 5.9
1.54 ± 0.62
2
Anderson 2018
Canada
Rivaroxaban
60.9 ± 11.0
902 (480/422)
29.4 ± 5.8
1.4 ± 0.6
THA
Aspirin
61.3 ± 11.1
902 (486/416)
29.4 ± 6.0
1.4 ± 0.6
3
Anderson 2018
Canada
Rivaroxaban
64.7 ± 8.4
815 (353/462)
32.7 ± 6.8
1.4 ± 0.5
TKA
Aspirin
64.6 ± 8.7
805 (318/487)
33.0 ± 7.2
1.4 ± 0.5
4
Argun 2013
Turkey
Fondaparinux
58.7 ± 13.6
55 (21/34)
NA
NA
THA & TKA
LMWH
60.0 ± 8.4
53 (20/33)
NA
NA
5
Bai 2018
China
Rivaroxaban
69.28 ± 10.42
98 (50/48)
23.12 ± 3.29
NA
THA
LMWH
68.33 ± 11.84
98 (49/49)
22.85 ± 2.85
NA
6
Bai 2020
China
Rivaroxaban
70 ± 7
42 (4/38)
27 ± 3
NA
TKA
LMWH
71 ± 8
42 (7/35)
27 ± 4
NA
7
Bai 2021
China
Rivaroxaban
61.2 ± 11.7 (27–83)
114 (42/72)
25.7 ± 3.2 (20.1–29.7)
NA
THA
LMWH
61.9 ± 9.6 (32–82)
114 (51/63)
24.6 ± 3.1 (21.2–29.2)
NA
8
Bauer 2001
USA
Fondaparinux
67.5 ± 10.7
517 (204/313)
31.5 ± 6.5
2.12 ± 0.65
TKA
LMWH
67.5 ± 10.2
517 (223/294)
30.9 ± 6.2
2.13 ± 0.7
9
Bonneux 2006
Belgium
Fondaparinux
66.9 ± 8.5
55 (12/43)
29.7 ± 5.2
NA
TKA
LMWH
65.7 ± 10.4
54 (11/43)
29.8 ± 7.8
NA
10
Colleoni 2008
Brazil
Aspirin
71.21 ± 6.35
14 (1/13)
NA
NA
TKA
Rivaroxaban
67.11 ± 7.65
18 (4/14)
NA
NA
11
Ding 2014
China
Rivaroxaban
56.5 ± 18.2 (35–72)
120 (78/42)
NA
NA
THA
LMWH
NA
NA
12
Eriksson 2005
Sweden
Dabigatran
65.9 (33–93)
393 (164/229)
NA
1.4 (0.5–3.6)
THA & TKA
LMWH
65.0 (20–86)
392 (151/241)
NA
1.5 (0.4–4.6)
13
Eriksson 2006
Sweden
Rivaroxaban
67 (51–87)
37 (16/21)
28 (21–38)
1.53 ± 0.55
THA
LMWH
65 (27–82)
132 (54/78)
28 (20–40)
1.37 ± 0.48
14
Eriksson 2007
Sweden
Dabigatran
67 ± 9
679 (238/441)
NA
1.52 ± 0.47
TKA
LMWH
68 ± 9
694 (216/478)
NA
1.5 ± 0.47
15
Eriksson 2007
Sweden
Dabigatran
67 ± 9
679 (238/441)
NA
1.52 ± 0.47
TKA
LMWH
68 ± 9
694 (216/478)
NA
1.5 ± 0.47
16
Eriksson 2007
Sweden
Dabigatran
65 ± 10
1146 (510/636)
NA
1.42 ± 0.48
THA
LMWH
64 ± 11
1154 (503/651)
NA
1.45 ± 0.48
17
Eriksson 2007
Sweden
Dabigatran
65 ± 10
1146 (510/636)
NA
1.42 ± 0.48
THA
LMWH
64 ± 11
1154 (503/651)
NA
1.45 ± 0.48
18
Eriksson 2007
Sweden
Rivaroxaban
66 (32–84)
77 (32/45)
28 (18–38)
NA
THA
LMWH
64 (30–92)
162 (74/88)
28 (19–44)
NA
19
Eriksson 2007
Sweden
Darexaban
NA
NA
NA
NA
THA
LMWH
NA
NA
NA
NA
20
Eriksson 2008
Sweden
Rivaroxaban
63.1 (18–91)
2209 (989/1220)
27.8 (16.2–53.4)
1.51 (0.45–8.00)
THA
LMWH
63.3 (18–93)
2224 (982/1242)
27.9 (15.2–50.2)
1.52 (0.42–5.75)
21
Eriksson 2010
Sweden
Darexaban
61.3 (24–84)
163 (73/90)
28.5 (18.3–40.8)
1.39 (0.4–4.0)
THA
LMWH
58.1 (22–85)
166 (80/86)
27.3 (18.4–41.4)
1.50 (0.5–3.4)
22
Eriksson 2011
Sweden
Dabigatran
62 ± 12
1010 (469/541)
27.8 ± 4.8
1.33 (0.25–5.50)
THA
LMWH
62 ± 11
1003 (502/501)
27.8 ± 4.8
1.32 (0.47–4.00)
23
Eriksson 2011
Sweden
Dabigatran
62 ± 12
1010 (469/541)
27.8 ± 4.8
1.33 (0.25–5.50)
THA
LMWH
62 ± 11
1003 (502/501)
27.8 ± 4.8
1.32 (0.47–4.00)
24
Fizgerald 2001
USA
Warfarin
NA
349 (153/196)
NA
NA
THA
LMWH
NA
NA
NA
25
Fuji 2014
Japan
Edoxaban
72,6 ± 7.5 (36–84)
299 (54/245)
NA
1.85 ± 0.63 (0.52–3.75)
TKA
LMWH
72.1 ± 7.8 (30–84)
295 (66/229)
NA
1.90 ± 0.53 (0.55–3.73)
26
Fuji 2014
Japan
Darexaban
62.1 ± 10.48
136 (23/113)
23.92 ± 3.168
1.79 ± 0.702
THA
LMWH
61.6 ± 10.99
82 (20/62)
23.70 ± 3.704
1.68 ± 0.710
27
Fuji 2014
Japan
Darexaban
71.2 ± 7.88
71 (9/62)
26.36 ± 3.850
1.82 ± 0.636
TKA
LMWH
72.3 ± 8.02
66 (9/57)
26.43 ± 3.407
1.80 ± 0.503
28
Fuji 2015
Japan
Edoxaban
62.8 ± 9.61
255 (35/220)
24.5 ± 3.52
THA
LMWH
62.8 ± 9.72
248 (36/212)
24.2 ± 3.60
29
Gao 2011
China
LMWH
66.1 (22–82)
166 (27/139)
26.79 ± 3.87
TKA
Aspirin
64.9 (40–84)
120 (21/99)
27.87 ± 3.62
30
Gao 2016
China
LMWH
59.2 ± 7.7 (36–74)
54 (30/24)
23.6 ± 4.8
THA
Rivaroxaban
59.5 ± 7.8 (35–78)
54 (31/23)
23.4 ± 4.5
31
Ginsberg 2009
Canada
Dabigatran
66.2 ± 9.5
857 (371/486)
NA
1.52 ± 0.47
TKA
LMWH
66.3 ± 9.6
868 (364/504)
NA
1.50 ± 0.47
32
Guo 2018
China
LMWH
63.6 ± 2.5 (52–82)
60 (27/33)
NA
NA
THA & TKA
Rivaroxaban
NA
NA
33
Hass 2006
Germany
LMWH
66.1 ± 9.3
1013 (337/676)
27.8 ± 3.8
1.42 (0.50–5.33)
THA & TKA
UFH
66.9 ± 9.8
1005 (350/655)
27.8 ± 3.9
1.42 (0.47–4.33)
34
Hosaka 2013
Japan
Fondaparinux
73.3 ± 7.3
277 (31/246)
26.4 ± 3.9
1.89 ± 0.51
TKA
LMWH
72.8 ± 7.7
298 (31/267)
26.4 ± 5.2
1.89 ± 0.48
35
Hull 2000
Canada
LMWH
64 ± 13
983 (467/516)
29 ± 6
THA
Warfarin
63 ± 13
489 (242/247)
28 ± 5
36
Jiang 2019
China
Apixaban
68.7 ± 5.7
110 (62/48)
24.5 ± 3.2
1.84 ± 0.39
TKA
LMWH
70.2 ± 6.1
110 (52/58)
25.1 ± 3.5
1.76 ± 0.33
37
Kakkar 2000
UK
LMWH
70.4 ± 10.9
149 (49/100)
25.3 ± 4.1
1.83 ± 0.92
THA
UFH
70.5 ± 9.2
149 (45/104)
25.6 ± 4.6
1.68 ± 0.98
38
Kakkar 2008
UK
Rivaroxaban
61.4 ± 13.2 (18–93)
1228 (561/667)
26.8 ± 4.8 (15.6–54.7)
1.58 (0.50–7.92)
THA
LMWH
61.6 ± 13.7 (19–93)
1229 (578/651)
27.1 ± 5.2 (15.5–59.0)
1.55 (0.47–9.92)
39
Kim 2016
South Korea
Rivaroxaban
55.9 ± 14.30
350 (163/187)
25.0 ± 3.20
1.22 ± 0.45
THA
LMWH
56.0 ± 15.17
351 (174/177)
25.0 ± 3.59
1.25 ± 0.51
40
Lassen 2002
Denmark
Fondaparinux
67 (30–90)
908 (396/512)
26 (15–45)
2·3 ± 0·80
THA
LMWH
67 (24–97)
919 (402/517)
26 (14–51)
2.4 ± 0.87
41
Lassen 2002
Denmark
Fondaparinux
66 (29–92)
1140 (493/647)
26 (15–45)
2.3 ± 0.82
THA
LMWH
67 (24–97)
1133 (473/660)
27 (14–51)
2·4 ± 0·83
42
Lassen 2007
Denmark
Apixaban
66.4 (46–84)
157 (54/103)
30.2 (22.5–50.2)
1.60 (0.62–7.73)
TKA
LMWH
66.5 (36–88)
152 (58/94)
30.4 (18.8–46.0)
1.60 (0.70–3.33)
Warfarin
66.8 (43–85)
153 (60/93)
30.4 (20.8–50.1)
1.61 (0.67–4.17)
43
Lassen 2008
Denmark
Rivaroxaban
67.6 (28–91)
1220 (363/857)
29.5 (16.3–51.1)
1.60 (0.43–8.33)
TKA
LMWH
67.6 (30–90)
1239 (418/821)
29.8 (16.0–54.3)
1.62 (0.47–5.25)
44
Li 2018
China
Rivaroxaban
NA (35–75)
50 (13/37)
NA
NA
THA & TKA
LMWH
NA (36–75)
50 (21/29)
NA
NA
45
Migita 2014
Japan
Fondaparinux
73.9 ± 8.0 (34–93)
1294 (221/1073)
25.4 ± 3.9 (14.5–44.0)
2.11 ± 0.62 (0.70–6.67)
TKA
LMWH
UFH
46
Migita 2014
Japan
Fondaparinux
66.7 ± 10.5 (23–94)
868 (128/740)
24.5 ± 3.9 (14.5–44.0)
2.06 ± 0.72 (0.58–5.53)
THA
LMWH
UFH
47
Mirdamadi 2014
Iran
LMWH
68.3 ± 10.1
45 (15/30)
NA
NA
TKA
Dabigatran
72.1 ± 9.3
45 (17/28)
NA
NA
48
Qin 2016
China
Rivaroxaban
60.5 ± 4.1 (36–79)
50 (29/21)
NA
NA
THA
LMWH
61.1 ± 4.2 (37–78)
50 (28/22)
NA
NA
49
Quan 2010
China
Rivaroxaban
63.9 ± 14.9
48 (13/35)
23.72 ± 2.61
NA
THA & TKA
LMWH
57.2 ± 16.9
36 (10/26)
24.50 ± 2.07
NA
50
Rahman 2020
Egypt
Rivaroxaban
42.95 ± 10.6
80 (36/44)
30.5 ± 4.80
1.67 ± 0.12
THA
LMWH
40.10 ± 14.7
80 (44/36)
29.8 ± 4.05
1.69 ± 0.13
51
Raskob 2010
USA
LMWH
57.6 ± 12.41
175 (68/107)
27.10 ± 4.27
1.36 ± 0.45
THA
Edoxaban
58.3 ± 11.55
187 (68/119)
28.53 ± 4.82
1.39 ± 0.45
52
Ren 2021
China
Aspirin
54.5 (40.8–62.3)
34 (13/21)
23.6 (20.7–25.5)
NA
THA
Rivaroxaban
50.0 (36.8–57.0)
36 (11/25)
23.5 (20.3–26.0)
NA
53
Senaran 2005
Turkey
LMWH
55.2 ± 8.4
50 (12/38)
NA
NA
THA
UFH
52.4 ± 11.2
50 (17/33)
NA
NA
54
Shi 2014
China
Rivaroxaban
65.14 ± 8.93
50 (10/40)
26.53 ± 3.56
NA
TKA
LMWH
66.84 ± 6.90
25 (7/18)
27.19 ± 3.71
NA
55
Turpie 2002
Canada
Fondaparinux
67 (26–92)
908 (386/401)
28 (14–73)
2.46 ± 0.95
THA
LMWH
67 (19–91)
919 (375/422)
27 (13–83)
2.42 ± 0.98
56
Turpie 2002
Canada
Fondaparinux
67 (18–92)
1128 (556/572)
28 (14–73)
2.48 ± 0.95
THA
LMWH
67 (19–91)
1129 (522/607)
28 (13–83)
2.45 ± 0.95
57
Turpie 2005
Canada
Rivaroxaban
67 (49–84)
103 (37/66)
31.8 ± 6.3
1.47 ± 0.57
TKA
LMWH
66 (47–83)
104 (47/57)
31.8 ± 6.0
1.51 ± 0.49
58
Turpie 2009
Canada
Rivaroxaban
64.4 ± 9.7
1526 (519/1007)
30.9 ± 6.2
1.67 ± 0.71
TKA
LMWH
64.7 ± 9.7
1508 (541/967)
30.7 ± 6.0
1.67 ± 0.70
59
Turpie 2009
Canada
Betrixaban
65 (47–75)
84 (32/52)
NA
NA
TKA
LMWH
62 (43–75)
43(21/22)
NA
NA
60
Wang 2014
China
Rivaroxaban
68.1 ± 0.5 (55–75)
60 (35/25)
NA
NA
TKA
LMWH
67.5 ± 0.3 (57–73)
60 (36/24)
NA
NA
61
Wang 2017
China
Rivaroxaban
69.3 ± 3.7
96 (27/69)
27.1 ± 4.4
1.43 ± 0.12
TKA
LMWH
70.7 ± 4.5
99 (34/65)
28.6 ± 3.9
1.51 ± 0.12
62
Wang 2020
China
Rivaroxaban
64.18 ± 8.56
89 (40/49)
23.13 ± 1.60
NA
THA
LMWH
63.70 ± 7.38
89 (44/45)
22.84 ± 1.45
NA
63
Weitz 2020
Canada
LMWH
67.0 ± 8.8
76 (21/55)
32.4 ± 5.5
1.42 (1.08–1.82)
TKA
Apixaban
64.9 ± 8.4
83 (18/65)
32.6 ± 5.8
1.42 (1.25–1.75)
64
Wu 2013
China
Rivaroxaban
72.1
64 (25/39)
NA
NA
THA
LMWH
74.7
64 (28/36)
NA
NA
65
Yang 2013
China
Rivaroxaban
57.64 ± 10.22
75 (40/35)
24.28 ± 4.59
NA
THA
LMWH
59.51 ± 10.65
70 (36/34)
23.80 ± 4.41
NA
66
Yokote 2011
Japan
Fondaparinux
63.0 ± 10.0
84 (14/70)
22.5 ± 4.8
NA
THA
LMWH
64.0 ± 11.0
83 (16/67)
23.0 ± 3.3
NA
67
Zhang 2017
China
LMWH
58.36 ± 9.64 (47–69)
45 (26/19)
NA
NA
THA
Rivaroxaban
56.68 ± 9.37 (45–68)
45 (27/18)
NA
NA
68
Zhang 2020
China
LMWH
57.44 ± 9.89
43 (18/25)
26.11 ± 4.53
NA
TKA
Rivaroxaban
59.72 ± 8.11
43 (21/22)
24.79 ± 3.48
NA
69
Zou 2014
China
Rivaroxaban
63.5 (50–82)
102 (32/70)
27.5 (18.0–39.5)
1.42 (1.32–1.45)
TKA
LMWH
65.7 (54–80)
112 (20/92)
27.0 (20.3–37.0)
1.41 (1.35–1.45)
Aspirin
62.7 (47–79)
110 (28/82)
27.8 (17.8–40.0)
1.51 (1.33–1.57)
LMWH = low molecular weight heparin, NA = , SD = standard deviation, THA = total hip arthroplasy, TKA = total knee arthroplasty, UFH = unfractionated heparin.
Figure 1.: Flow diagram of the literature search and selection processes.
5.2. Network meta-analysis
To visualize network geometry and node connectivity, network plots were produced for each outcome (Fig. 2 ). There was a similarity after carefully reviewing the included studies. Hence, the assumption of transitivity was likely to hold in the data. There was no heterogeneity for DVT outcome (I 2 = 43.9%) or PE outcome (I 2 = 0.0%); no global inconsistency for DVT outcome (global Wald test: P = .675) or PE outcome (global Wald test: P = .960); and no local inconsistency for DVT outcome (Table 2 ) or PE outcome (Table 3 ). Therefore, the consistency model and fixed model were used for pooling. Sixty-one articles with 67 studies were included for DVT outcome (Table 4 ). In terms of prevention of DVT, efficacy of apixaban was better than that of dabigatran (RR = 0.40, 95% CI [0.25–0.63]), LMWH (RR = 0.39, 95% CI [0.25–0.61]), aspirin (RR = 0.38, 95% CI [0.22–0.65]), UFH (RR = 0.36, 95% CI [0.23–0.58]), betrixaban (RR = 0.28, 95% CI [0.09–0.94]), and warfarin (RR = 0.22, 95% CI [0.14–0.35]); efficacy of edoxaban was better than that of dabigatran (RR = 0.43, 95% CI [0.28–0.65]), LMWH (RR = 0.42, 95% CI [0.28–0.63]), aspirin (RR = 0.40, 95% CI [0.24–0.68]), UFH (RR = 0.38, 95% CI [0.25–0.60]), betrixaban (RR = 0.30, 95% CI [0.09–0.99]), and warfarin (RR = 0.23, 95% CI [0.15–0.37]); efficacy of fondaparinux was better than that of dabigatran (RR = 0.57, 95% CI [0.47–0.69]), LMWH (RR = 0.56, 95% CI [0.48–0.66]), aspirin (RR = 0.54, 95% CI [0.38–0.77]), UFH (RR = 0.51, 95% CI [0.42–0.63]), and warfarin (RR = 0.31, 95% CI [0.24–0.40]); efficacy of rivaroxaban was better than that of dabigatran (RR = 0.58, 95% CI [0.49–0.69]), LMWH (RR = 0.57, 95% CI [0.50–0.65]), aspirin (RR = 0.55, 95% CI [0.39–0.77]), UFH (RR = 0.52, 95% CI [0.43–0.64]), and warfarin (RR = 0.32, 95% CI [0.25–0.40]); efficacy of darexaban was better than that of UFH (RR = 0.63, 95% CI [0.41–0.95]) and warfarin (RR = 0.38, 95% CI [0.25–0.59]); efficacy of dabigatran was better than that of warfarin (RR = 0.55, 95% CI [0.44–0.67]); efficacy of LMWH was better than that of warfarin (RR = 0.56, 95% CI [0.46–0.67]); efficacy of aspirin was better than that of warfarin (RR = 0.58, 95% CI [0.40–0.84]); and efficacy of UFH was better than that of warfarin (RR = 0.61, 95% CI [0.48–0.77]) (Fig. 3A ). The P score of the anticoagulants’ efficacy for the prevention of DVT was in the following order: apixaban > edoxaban > fondaparinux > rivaroxaban > darexaban > dabigatran > LMWH > aspirin > UFH > betrixaban > warfarin (Table 5 ). Thirty-nine articles with 42 studies were included in the analysis of PE outcome (Table 6 ). There was no significant difference in head-to-head comparisons of the efficacy of the 11 anticoagulants for the prevention of PE (Fig. 3B ). The P score of the anticoagulants’ efficacy for the prevention of PE was in the following order: warfarin > apixaban > aspirin > rivaroxaban > fondaparinux > edoxaban > darexaban > LMWH > dabigatran > betrixaban > UFH (Table 7 ). After the exclusion of individual studies one by one, the remaining studies were pooled and analyzed again. The results showed that each excluded study had a minor impact on the amount of pooling effect, indicating that the results of this meta-analysis were stable and reliable. The results of funnel plots showed that there was no publication bias for the outcome of DVT (Egger test P = .067, Begg–Mazumdar test P = .801, Thompson–Sharp test P = .296) (Fig. 4A ) or PE (Egger test P = .297, Begg–Mazumdar test P = .738, Thompson–Sharp test P = .554) (Fig. 4B ).
Table 2 -
Result of node-splitting test for DVT.
Comparison
P value
LMWH vs apixaban
.676
Warfarin vs apixaban
.619
Aspirin vs LMWH
.443
Aspirin vs rivaroxaban
.880
Fondaparinux vs LMWH
.469
Fondaparinux vs UFH
.716
LMWH vs rivaroxaban
.174
LMWH vs UFH
.615
LMWH vs warfarin
.655
DVT = deep vein thrombosis, LMWH = low molecular weight heparin, UFH = unfractionated heparin.
Table 3 -
Result of node-splitting test for PE.
Comparison
P value
LMWH vs apixaban
.579
Warfarin vs apixaban
1.000
Aspirin vs LMWH
.557
Aspirin vs rivaroxaban
.449
Fondaparinux vs LMWH
.711
Fondaparinux vs UFH
.740
LMWH vs rivaroxaban
.424
LMWH vs UFH
.914
LMWH vs warfarin
.580
LMWH = low molecular weight heparin, PE = pulmonary embolism, UFH = unfractionated heparin.
Table 4 -
Characteristics of anticoagulants’ efficacy for prevention of DVT.
Study
Treatment
Responder
Sample size
1
LMWH
2
398
1
Aspirin
1
380
2
Rivaroxaban
3
902
2
Aspirin
2
902
3
Rivaroxaban
3
815
3
Aspirin
4
805
4
Fondaparinux
0
55
4
LMWH
1
53
5
Rivaroxaban
4
98
5
LMWH
11
98
6
Rivaroxaban
14
42
6
LMWH
10
42
7
Rivaroxaban
2
114
7
LMWH
4
114
8
Fondaparinux
45
361
8
LMWH
98
361
9
Fondaparinux
2
55
9
LMWH
1
54
10
Aspirin
1
14
10
Rivaroxaban
2
18
11
Rivaroxaban
5
60
11
LMWH
6
60
12
Dabigatran
39
297
12
LMWH
72
300
13
Rivaroxaban
2
29
13
LMWH
18
106
14
Dabigatran
181
503
14
LMWH
184
511
15
Dabigatran
1
675
15
LMWH
8
685
16
Dabigatran
40
874
16
LMWH
56
894
17
Dabigatran
6
1137
17
LMWH
1
1142
18
Rivaroxaban
6
59
18
LMWH
18
107
19
Darexaban
5
27
19
LMWH
12
31
20
Rivaroxaban
12
1595
20
LMWH
53
1558
21
Darexaban
16
120
21
LMWH
24
127
22
Dabigatran
60
791
22
LMWH
67
783
23
Dabigatran
0
1001
23
LMWH
4
992
24
Warfarin
72
122
24
LMWH
41
108
25
Edoxaban
22
299
25
LMWH
41
295
26
Darexaban
4
136
26
LMWH
2
82
27
Darexaban
11
71
27
LMWH
14
66
28
Edoxaban
6
255
28
LMWH
17
248
29
LMWH
37
166
29
Aspirin
28
120
30
LMWH
5
54
30
Rivaroxaban
4
54
31
Dabigatran
188
604
31
LMWH
163
643
32
LMWH
3
30
32
Rivaroxaban
1
30
33
LMWH
200
813
33
UFH
204
815
34
Fondaparinux
13
275
34
LMWH
18
296
35
LMWH
80
673
35
Warfarin
81
338
36
Apixaban
6
110
36
LMWH
22
110
37
Rivaroxaban
14
864
37
LMWH
71
869
38
LMWH
9
101
38
UFH
24
116
39
Rivaroxaban
24
350
39
LMWH
23
351
40
Fondaparinux
36
908
40
LMWH
83
918
41
Apixaban
5
105
41
LMWH
15
109
41
Warfarin
29
109
42
Rivaroxaban
79
824
42
LMWH
160
878
43
Rivaroxaban
0
50
43
LMWH
4
50
44
Fondaparinux
60
360
44
LMWH
59
223
44
UFH
24
72
45
Fondaparinux
17
261
45
LMWH
17
148
45
UFH
5
32
46
LMWH
1
45
46
Dabigatran
1
45
47
Rivaroxaban
3
50
47
LMWH
5
50
48
Rivaroxaban
10
48
48
LMWH
9
36
49
Rivaroxaban
8
80
49
LMWH
0
80
50
LMWH
20
144
50
Edoxaban
2
158
51
Aspirin
3
34
51
Rivaroxaban
3
36
52
LMWH
2
50
52
UFH
2
50
53
Rivaroxaban
1
50
53
LMWH
0
25
54
Fondaparinux
44
784
54
LMWH
65
796
55
Rivaroxaban
14
60
55
LMWH
31
70
56
Rivaroxaban
61
965
56
LMWH
86
959
57
Betrixaban
9
65
57
LMWH
4
40
58
Rivaroxaban
8
96
58
LMWH
17
99
59
Rivaroxaban
1
89
59
LMWH
4
89
60
Rivaroxaban
1
60
60
LMWH
3
60
61
LMWH
21
76
61
Apixaban
12
83
62
Rivaroxaban
3
15
62
LMWH
4
15
63
Rivaroxaban
4
75
63
LMWH
3
70
64
Fondaparinux
6
84
64
LMWH
5
83
65
LMWH
6
45
65
Rivaroxaban
7
45
66
LMWH
6
43
66
Rivaroxaban
1
43
67
Rivaroxaban
3
102
67
LMWH
14
112
67
Aspirin
18
110
DVT = deep vein thrombosis, LMWH = low molecular weight heparin, UFH = unfractionated heparin.
Table 5 -
The
P score of anticoagulants’ efficacy for prevention of DVT.
Anticoagulants
P score
Rank
Apixaban
.940
1
Edoxaban
.917
2
Fondaparinux
.750
3
Rivaroxaban
.731
4
Darexaban
.621
5
Dabigatran
.392
6
LMWH
.358
7
Aspirin
.310
8
UFH
.233
9
Betrixaban
.216
10
Warfarin
.033
11
DVT = deep vein thrombosis, LMWH = low molecular weight heparin, UFH = unfractionated heparin.
Table 6 -
Characteristics of anticoagulants’ efficacy for prevention of PE.
Study
Treatment
Responder
Sample size
1
LMWH
3
398
1
Aspirin
0
380
2
Rivaroxaban
4
902
2
Aspirin
3
902
3
Rivaroxaban
4
815
3
Aspirin
4
805
4
Rivaroxaban
0
42
4
LMWH
0
42
5
Rivaroxaban
0
114
5
LMWH
0
114
6
Fondaparinux
1
517
6
LMWH
4
517
7
Rivaroxaban
0
60
7
LMWH
0
60
8
Dabigatran
0
297
8
LMWH
0
300
9
Dabigatran
0
675
9
LMWH
1
685
10
Dabigatran
5
1137
10
LMWH
3
1142
11
Rivaroxaban
0
59
11
LMWH
0
107
12
Rivaroxaban
4
1595
12
LMWH
1
1558
13
Darexaban
0
120
13
LMWH
0
127
14
Dabigatran
1
1001
14
LMWH
2
992
15
Dabigatran
1
1001
15
LMWH
2
992
16
Warfarin
0
122
16
LMWH
0
108
17
Edoxaban
0
299
17
LMWH
0
295
18
Edoxaban
0
255
18
LMWH
0
248
19
Dabigatran
6
604
19
LMWH
5
643
20
LMWH
1
813
20
UFH
1
815
21
Fondaparinux
1
277
21
LMWH
5
297
22
Rivaroxaban
1
864
22
LMWH
4
869
23
LMWH
1
125
23
UFH
2
134
24
Rivaroxaban
2
350
24
LMWH
1
351
25
Fondaparinux
2
1129
25
LMWH
2
1123
26
Apixaban
0
105
26
LMWH
2
109
26
Warfarin
0
109
27
Rivaroxaban
0
824
27
LMWH
4
878
28
Fondaparinux
1
360
28
LMWH
0
223
28
UFH
0
72
29
Fondaparinux
0
261
29
LMWH
0
148
29
UFH
0
32
30
LMWH
0
45
30
Dabigatran
0
45
31
Rivaroxaban
1
50
31
LMWH
2
50
32
Rivaroxaban
0
48
32
LMWH
0
36
33
Rivaroxaban
0
80
33
LMWH
0
80
34
LMWH
0
50
34
UFH
0
50
35
Fondaparinux
5
1126
35
LMWH
1
1128
36
Rivaroxaban
0
60
36
LMWH
0
70
37
Rivaroxaban
5
1526
37
LMWH
8
1508
38
Betrixaban
1
65
38
LMWH
0
40
39
LMWH
0
76
39
Apixaban
0
83
40
Rivaroxaban
0
15
40
LMWH
0
15
41
Fondaparinux
0
84
41
LMWH
0
83
42
Rivaroxaban
0
102
42
LMWH
0
112
42
Aspirin
0
110
LMWH = low molecular weight heparin, PE = pulmonary embolism, UFH = unfractionated heparin.
Table 7 -
The
P score of anticoagulants’ efficacy for prevention of PE.
Anticoagulants
P score
Rank
Warfarin
.716
1
Apixaban
.708
2
Aspirin
.671
3
Rivaroxaban
.580
4
Fondaparinux
.545
5
Edoxaban
.461
6
Darexaban
.455
7
LMWH
.400
8
Dabigatran
.395
9
Betrixaban
.325
10
UFH
.244
11
LMWH = low molecular weight heparin, PE = pulmonary embolism, UFH = unfractionated heparin.
Figure 2.: Network plots of overall efficacy. (A) DVT outcome. (B) PE outcome. The width of the lines is proportional to the number of trials comparing every pair of treatments, and the size of every node is proportional to the number of participants. DVT = deep vein thrombosis, PE = pulmonary embolism.
Figure 3.: League tables of results. (A) DVT outcome. (B) PE outcome. Results of the network meta-analysis are presented in the left lower half and results from pairwise meta-analysis in the upper right half, if available. DVT = deep vein thrombosis, PE = pulmonary embolism.
Figure 4.: Funnel plots of results. (A) DVT outcome. (B) PE outcome. DVT = deep vein thrombosis, PE = pulmonary embolism.
5.3. Grading the evidence of the network meta-analysis using CINeMA
After the assessment of 6 domains by CINeMA (Table S1, Supplemental Digital Content, https://links.lww.com/MD/I302 https://links.lww.com/MD/I303 https://links.lww.com/MD/I304 https://links.lww.com/MD/I305 https://links.lww.com/MD/I306 https://links.lww.com/MD/I307
6. Discussion
VTE is a frequent and increasing disease, which is associated with severe venous disease and high treatment costs.[ 70 ] The main reason for the occurrence of VTE is that after joint replacement, the human body is in a hypercoagulable state, where the coagulation mechanism is activated, procoagulant substances such as thromboxane and fibrinogen increase, and inflammation and edema of the surgical site tissue compress the blood vessels, resulting in slow local blood flow.[ 71 ] Therefore, to prevent the occurrence of VTE after THA or TKA, it is not enough to only rely on bed rest, use of pneumatic compression, wearing compression stockings, and other general measures; systematic anticoagulant therapy must be given.
In this study, we reviewed the efficacy of 11 anticoagulants in patients undergoing THA or TKA. Evidence was compiled from direct and indirect comparisons to evaluate the efficacy. For the prevention of DVT, the results of the league table and P score showed that apixaban, edoxaban, fondaparinux, rivaroxaban, and darexaban were the most effective anticoagulants for patients undergoing THA or TKA. Due to the relatively low incidence of PE, the results of the league table and P score showed that there was no difference in the efficacy among the anticoagulants for the prevention of PE. All these effective anticoagulants belong to new oral anticoagulants (NOACs) (apixaban, edoxaban, rivaroxaban, and darexaban). NOACs represent novel direct-acting medications that directly inhibit factor Xa or factor IIa.[ 72 ] These drugs have been approved for the prevention of VTE in patients after elective hip or knee arthroplasty in the European Union and many other countries worldwide.[ 73 ] Compared with other traditional anticoagulants, NOACs have various advantages, such as the absence of food interactions, few strong drug interactions, predictable pharmacokinetics and pharmacodynamics, rapid onset and offset of action, and absence of the need for laboratory monitoring.[ 74 , 75 ] However, NOACs have disadvantages, such as contraindication or dose reduction in patients with chronic kidney disease or hepatic disease, absence of a specific test, the potential for overuse, lack of a specific antidote in case of major bleeding, and high costs.[ 74 , 75 ]
At the same time, the short half-lives of NOACs can be considered both an advantage and a disadvantage under various circumstances. For example, the advantage of the short half-life of an NOAC may be relevant for emergency surgery and in cases of bleeding due to accumulation of the drug in the blood, whereas the short half-life is a disadvantage if the patient forgets to take the drug, which could put the patient at risk[ 74 ] ; therefore, many traditional anticoagulants can be replaced. This study showed that fondaparinux had a high efficacy for the prevention of DVT. Fondaparinux, a synthetic pentasaccharide, is the first drug in a new class of antithrombotic agents – selective factor Xa inhibitors.[ 76 ] Fondaparinux is completely absorbed following subcutaneous injection, and its activity is higher than that of LMWH (about 700 units/mg and 100 units/mg, respectively).[ 77 ] The half-life of fondaparinux is 17 hours, so it is suitable for daily dosing.[ 78 ] Fondaparinux undergoes renal clearance and therefore requires dose reduction or replacement in patients with poor renal function.[ 77 ]
This article had some limitations. First, studies in languages other than English and Chinese were excluded, which may have affected the comprehensiveness of the included studies. Second, the entire confidence in the collected evidence as assessed by CINeMA was low, so the results should be interpreted with caution.
7. Conclusion
In this study, we provided a useful reference for the selection of anticoagulants for the prevention of VTE after THA or TKA. Apixaban, edoxaban, fondaparinux, rivaroxaban, and darexaban showed the best efficacy. However, more high-quality studies are needed to confirm the above conclusions.
Author contributions
Conceptualization: Zhihao Huang, Xinru Xu, Dan Xu.
Formal analysis: Zhihao Huang, Xinru Xu, Miao Zou.
Investigation: Xinru Xu.
Methodology: Zhihao Huang, Pengfei Zhao.
Project administration: Zhihao Huang.
Software: Zhihao Huang.
Supervision: Zhihao Huang, Xinru Xu.
Visualization: Xinru Xu, Dan Xu.
Writing – original draft: Zhihao Huang, Xinru Xu.
Writing – review and editing: Zhihao Huang, Xinru Xu, Dan Xu, Pengfei Zhao, Miao Zou.
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