Supplementary Online Content
Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical
effectiveness and safety of aspirin for venous thromboembolism prophylaxis after
total hip and knee replacement: a systematic review and meta-analysis of
randomized clinical trials. JAMA Intern Med. Published online February 3, 2020.
doi:10.1001/jamainternmed.2019.6108
eTable 1. Search Strategy and Terms
eFigure 1. Risk of Bias
eFigure 2. Summary of the Pooled Effect of Aspirin Compared With Other
Anticoagulants on Adverse Events in Randomized Controlled Trials of Patients
Undergoing Total Hip and Knee Replacement
eFigure 3. Funnel Plots for Publication Bias
eTable 2. GRADE Summary of Findings
This supplementary material has been provided by the authors to give readers
additional information about their work.
© 2020 American Medical Association. All rights reserved.
eTable 1. Search strategy and terms
Database: Ovid MEDLINE(R) <1946 to present>
Search Strategy:
-------------------------------------------------------------------------------1 exp Arthroplasty, Replacement, Hip/ (23697)
2 exp Hip Joint/ (25689)
3 exp Hip Prosthesis/ (21720)
4 hip prosthes$.mp. (22931)
5 exp Arthroplasty, Replacement, Knee/ (20294)
6 exp Knee Joint/ (55377)
7 exp Knee Prosthesis/ (10735)
8 exp ASPIRIN/ (42867)
9 acetylsalicylic acid.mp. (9253)
10 exp HEPARIN/ (62526)
11 unfractionated heparin.mp. (5399)
12 exp WARFARIN/ (18169)
13 Coumadin.mp. (999)
14 exp DABIGATRAN/ (2563)
15 Pradaxa.mp. (129)
16 exp RIVAROXABAN/ (2372)
17 Xarelto.mp. (115)
18 exp Anticoagulants/ (205780)
19 exp Factor Xa Inhibitors/ (5134)
20 exp Antithrombins/ (20306)
21 direct thrombin inhibitor.mp. (1448)
22 exp Enoxaparin/ (3192)
23 Clexane.mp. (111)
24 Lovenox.mp. (132)
25 Fondaparinux.mp. (1818)
26 Arixtra.mp. (95)
27 exp Heparin, Low-Molecular-Weight/ (11748)
28 exp DALTEPARIN/ (850)
29 fragmin.mp. (366)
30 Tinzaparin.mp. (449)
31 Innohep.mp. (21)
32 Pentasaccharide.mp. (1907)
33 vitamin k antagonist.mp. (2058)
34 Apixaban.mp. (2697)
35 Eliquis.mp. (48)
36 Edoxaban.mp. (1080)
37 Lixiana.mp. (13)
38 Clopidogrel.mp. (12882)
39 Plavix.mp. (285)
40 Ximelagatran.mp. (588)
41 Exanta.mp. (23)
42 Otamixaban.mp. (49)
43 Betrixaban.mp. (120)
44 Bevyxxa.mp. (6)
45 exp Pulmonary Embolism/ (36820)
46 PE.mp. (36822)
47 VTE.mp. (9038)
48 DVT.mp. (9197)
49 pulmonary emboli.mp. (3196)
50 Deep vein thrombosis.mp. (15093)
51 Deep-vein thrombosis.mp. (15093)
52 exp THROMBOSIS/ (123024)
53 exp Venous Thrombosis/ (52250)
54 exp Venous Thromboembolism/ (8792)
55 exp THROMBOEMBOLISM/ (52424)
© 2020 American Medical Association. All rights reserved.
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
Thromboembolic disease.mp. (3902)
Thromboembolic event.mp. (1280)
blood flow stasis.mp. (67)
vein stasis.mp. (22)
venous stasis.mp. (1732)
blood clot.mp. (2689)
bleeding.mp. (180928)
bleed$.mp. (187443)
haemorrhage.mp. (32627)
exp HEMORRHAGE/ (307965)
exp MORTALITY/ (350654)
exp DEATH/ (140152)
exp INFECTION/ (746321)
superficial infection.mp. (955)
deep infection.mp. (2807)
haematoma.mp. (8593)
exp HEMATOMA/ (33464)
wound haematoma.mp. (114)
wound hematoma.mp. (297)
haemarthrosis.mp. (427)
exp HEMARTHROSIS/ (2175)
return to theatre.mp. (170)
exp REOPERATION/ (80111)
further surgery.mp. (2962)
revision surgery.mp. (8948)
exp Myocardial Infarction/ (166157)
heart attack.mp. (3966)
wound complication.mp. (1002)
exp Wound Infection/ (44161)
wound drainage.mp. (737)
wound ooze.mp. (13)
wound dehiscence.mp. (9799)
exp THROMBOCYTOPENIA/ (45263)
Anaemia.mp. (31018)
exp ANEMIA/ (153887)
transfusion.mp. (129910)
exp Blood Transfusion/ (81416)
transient ischaemic attack.mp. (1651)
exp Ischemic Attack, Transient/ (19576)
cerebrovascular accident.mp. (4062)
cerebrovascular haemorrhage.mp. (8)
cerebrovascular hemorrhage.mp. (32)
exp Cerebral Hemorrhage/ (32019)
cerebrovascular bleed$.mp. (27)
intracerebral haemorrhage.mp. (1805)
intracerebral hemorrhage.mp. (10189)
intracerebral bleed$.mp. (428)
intracranial haemorrhage.mp. (1728)
exp Intracranial Hemorrhages/ (66556)
intracranial bleed$.mp. (1844)
exp STROKE/ (118070)
gastrointestinal bleed$.mp. (15960)
gastrointestinal haemorrhage.mp. (1219)
exp Gastrointestinal Hemorrhage/ (48777)
intraabdominal bleed$.mp. (317)
intraabdominal haemorrhage.mp. (27)
intraabdominal hemorrhage.mp. (204)
abdominal bleed$.mp. (755)
abdominal haemorrhage.mp. (130)
abdominal hemorrhage.mp. (656)
© 2020 American Medical Association. All rights reserved.
116 allergy.mp. (75995)
117 exp HYPERSENSITIVITY/ (326235)
118 allergic reaction.mp. (6154)
119 exp ANAPHYLAXIS/ (19958)
120 intraspinal bleed$.mp. (19)
121 intraspinal haemorrhage.mp. (4)
122 intraspinal hemorrhage.mp. (49)
123 intraocular bleed$.mp. (80)
124 intraocular bleed$.mp. (80)
125 intraocular haemorrhage.mp. (44)
126 intraocular hemorrhage.mp. (240)
127 retroperitoneal bleed$.mp. (422)
128 retroperitoneal haemorrhage.mp. (168)
129 retroperitoneal hemorrhage.mp. (686)
130 intraarticular bleed$.mp. (32)
131 intraarticular haemorrhage.mp. (1)
132 intraarticular hemorrhage.mp. (8)
133 pericardial bleed$.mp. (54)
134 pericardial haemorrhage.mp. (5)
135 pericardial hemorrhage.mp. (33)
136 intramuscular bleed$.mp. (50)
137 intramuscular haemorrhage.mp. (8)
138 intramuscular hemorrhage.mp. (45)
139 exp Compartment Syndromes/ (5464)
140 compartment syndrome.mp. (6180)
141 1 or 2 or 3 or 4 or 5 or 6 or 7 (120257)
142 8 or 9 (45945)
143 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26
or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or
44 (221261)
144 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61
or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76 or 77 or 78 or
79 or 80 or 81 or 82 or 83 or 84 or 85 or 86 or 87 or 88 or 89 or 90 or 91 or 92 or 93 or 94 or 95 or 96
or 97 or 98 or 99 or 100 or 101 or 102 or 103 or 104 or 105 or 106 or 107 or 108 or 109 or 110 or 111
or 112 or 113 or 114 or 115 or 116 or 117 or 118 or 119 or 120 or 121 or 122 or 123 or 124 or 125 or
126 or 127 or 128 or 129 or 130 or 131 or 132 or 133 or 134 or 135 or 136 or 137 or 138 or 139 or
140 (2677546)
145 141 and 142 and 143 and 144 (166)
146 limit 145 to humans (166)
***************************
Each part was specifically translated for searching the other databases (Embase and The Cochrane
library)
© 2020 American Medical Association. All rights reserved.
eFigure 1. Risk of bias
Author, year
Anderson, 2018 1
Jiang, 2014 2
Zou, 2014 3
Anderson, 2013 4
Westrich, 2006 5
Gelfer, 2006 6
Kim, 1998 7
Woolson, 1991 8
Josefsson, 1987 9
Harris, 1985 10
Lotke, 1996 11
Salzman, 1971 12
Alfaro, 1986 13
+
?
-
Random
sequence
generation
+
+
+
+
?
+
?
+
?
?
?
+
?
Allocation
concealment
+
?
?
+
+
+
?
Blinding of
participants
& personnel
+
+
-
Blinding of
outcome
assessments
+
+
+
?
+
-
Incomplete
outcome
data
+
+
?
+
+
+
?
?
+
+
?
?
?
Selective
reporting
+
+
+
+
+
+
+
+
+
?
?
-
Other
bias
+
+
+
+
?
+
?
?
?
?
?
?
?
Low risk of bias
Unclear risk of bias
High risk
of bias
© 2020 American Medical Association. All rights reserved.
eFigure 2. Summary of the pooled effect of aspirin compared with other anticoagulants on
adverse events in randomized controlled trials of patients undergoing total hip and knee
replacement
Outcome
No. of studies
Aspirin
Events / Participants
RR (95% CI)
Comparator
Events / Participants
Any bleeding
2
23 / 1836
17 / 1,852
1.35 (0.73, 2.49)
Major bleeding
3
11 / 2135
10 / 2,160
1.11 (0.47, 2.59)
Minor bleeding
2
12 / 428
22 / 443
0.57 (0.28, 1.15)
GI bleeding
2
3 / 428
3 / 443
0.97 (0.07, 12.88)
Wound haematoma
5
15 / 235
24 / 234
0.67 (0.38, 1.19)
Wound infection
3
57 / 2135
68 / 2,160
0.85 (0.60, 1.20)
Other wound complication
3
9 / 336
14 / 308
0.59 (0.26, 1.37)
Bruising
2
55 / 495
78 / 502
0.68 (0.54, 0.84)
Oedema
2
25 / 171
41 / 162
0.57 (0.37, 0.88)
Myocardial infarction
2
2 / 2092
2 / 2,117
1.07 (0.16, 7.29)
Death
1
0 / 385
1 / 400
0.35 (0.01, 8.48)
.01
.1
Favours aspirin
.25
.5
1
2.5
5
Favours control
CI, confidence interval (bars); RR, relative risk
© 2020 American Medical Association. All rights reserved.
15
eFigure 3. Funnel plots for publication bias
Deep vein thrombosis
0
0
.2
.5
.4
s.e. of lnrr
.6
s.e. of lnrr
1
.8
1
1.5
Venous thromboembolism
.13
.2
.4
.6
1
1.8
Relative risk (log scale)
3.2
4.8
6.4
9.2
.1
.2
.4
.6
1
1.8
Relative risk (log scale)
3.2
The dotted lines show 95% confidence intervals around the overall summary estimate
calculated using a fixed effect model; p-values for bias calculated using Egger’s test were
0·92 and 0·61 for venous thromboembolism and deep vein thrombosis respectively.
© 2020 American Medical Association. All rights reserved.
4.8 6.4 8.4 11
eTable 2. GRADE Summary of findings:
Clinical effectiveness and safety of aspirin for venous thromboembolism prophylaxis after total hip and knee
replacement: a systematic review and meta-analysis of randomized clinical trials.
Patient or population: Hip and knee replacement
Setting: Post-operative
Intervention: Aspirin
Comparison: Other anticoagulants
Anticipated absolute effects* (95% CI)
Certainty of the
evidence
(GRADE)
Risk with aspirin
Relative effect
(95% CI)
№ of participants
(studies)
Venous
thromboembolism 72 per 1,000
(VTE)
81 per 1,000
(56 to 116)
RR 1.13
(0.78 to 1.62)
5787
(13 RCTs)
MODERATE a
Deep vein
54 per 1,000
thrombosis (DVT)
57 per 1,000
(39 to 82)
RR 1.04
(0.72 to 1.51)
5700
(12 RCTs)
MODERATE b
Outcomes
Risk with
comparator
Comments
⨁⨁⨁?
⨁⨁⨁?
Pulmonary
embolism (PE)
16 per 1,000
16 per 1,000
(11 to 24)
RR 1.01
(0.68 to 1.48)
5295
(9 RCTs)
⨁⨁⨁⨁
Wound
hematoma
(Hematoma)
103 per 1,000
69 per 1,000
(39 to 122)
RR 0.67
(0.38 to 1.19)
469
(5 RCTs)
⨁⨁??
HIGH
LOW c,d
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially
different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
Explanations
a. I-squared= 63%
b. I-squared=46%
c. Concerns about bias in the domains of allocation concealment, blinding of outcome assessment and selective reporting.
d. Concerns about width of confidence interval and number of participants.
© 2020 American Medical Association. All rights reserved.
Reference list for Supplementary Online Content
1. Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or
knee arthroplasty. N Engl J Med. 2018;378(8):699-707. Medline:29466159
doi:10.1056/NEJMoa1712746
2. Jiang Y, Du H, Liu J, Zhou Y. Aspirin combined with mechanical measures to prevent venous
thromboembolism after total knee arthroplasty: a randomized controlled trial. Chin Med J (Engl).
2014;127(12):2201-2205. Medline:24931228
3. Zou Y, Tian S, Wang Y, Sun K. Administering aspirin, rivaroxaban and low-molecular-weight heparin
to prevent deep venous thrombosis after total knee arthroplasty. Blood Coagul Fibrinolysis.
2014;25(7):660-664. Medline:24695091 doi:10.1097/MBC.0000000000000121
4. Anderson DR, Dunbar MJ, Bohm ER, et al. Aspirin versus low-molecular-weight heparin for extended
venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med.
2013;158(11):800-806. Medline:23732713 doi:10.7326/0003-4819-158-11-201306040-00004
5. Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP. VenaFlow plus Lovenox vs
VenaFlow plus aspirin for thromboembolic disease prophylaxis in total knee arthroplasty. J
Arthroplasty. 2006;21(6)(suppl 2):139-143. Medline:16950076 doi:10.1016/j.arth.2006.05.017
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molecular weight dextran in Korean patients undergoing total hip replacement: a randomized controlled
trial. Int Orthop. 1998;22(1):6-10. Medline:9549575 doi:10.1007/s002640050199
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compression and aspirin, and compression and low-dose warfarin. J Bone Joint Surg Am.
1991;73(4):507-512. Medline:2013589 doi:10.2106/00004623-199173040-00005
9. Josefsson G, Dahlqvist A, Bodfors B. Prevention of thromboembolism in total hip replacement: aspirin
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doi:10.3109/17453678709146500
10. Harris WH, Athanasoulis CA, Waltman AC, Salzman EW. Prophylaxis of deep-vein thrombosis after
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aspirin daily. J Bone Joint Surg Am. 1985;67(1):57-62. Medline:2578469 doi:10.2106/00004623198567010-00008
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12. Salzman EW, Harris WH, DeSanctis RW. Reduction in venous thromboembolism by agents affecting
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doi:10.1056/NEJM197106102842303
13. Alfaro MJ, Páramo JA, Rocha E. Prophylaxis of thromboembolic disease and platelet-related changes
following total hip replacement: a comparative study of aspirin and heparin-dihydroergotamine. Thromb
Haemost. 1986;56(1):53-56. Medline:3535158 doi:10.1055/s-0038-1661602
© 2020 American Medical Association. All rights reserved.