REVIEW ARTICLE

ANZJSurg.com

Safety and effectiveness of aspirin and enoxaparin for venous

thromboembolism prophylaxis after total hip and knee arthroplasty: a
systematic review

Sinan Nadi ,*† Thomas D. Vreugdenburg ,* Yasoba Atukorale ,* Ning Ma ,* Guy Maddern *‡ and
Maroeska Rovers †
*Research and Evaluation, Incorporating ASERNIP-S, Royal Australasian College of Surgeons, Adelaide, South Australia, Australia
†Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands and
‡Discipline of Surgery, The University of Adelaide and The Queen Elizabeth Hospital, Adelaide, South Australia, Australia

Key words Abstract

arthroplasty, aspirin, deep vein, enoxaparin,
thromboembolism, thrombosis.
Correspondence
Mr Sinan Nadi, Royal Australasian College of
Surgeons, 199 Ward Street, North Adelaide, SA
5006, Australia. Email: college.asernip@surgeons.org
S. Nadi BSc; T. D. Vreugdenburg PhD;
Y. Atukorale MD, AFCHSM; N. Ma BHSc,
BMaCompSc; G. Maddern PhD, FRACS;
M. Rovers MSc, PhD.
Accepted for publication 30 January 2019.
doi: 10.1111/ans.15122
Background: Patients undergoing total hip arthroplasty (THA) or total knee arthroplasty
(TKA) are at risk of venous thromboembolism (VTE). Australian orthopaedic guidelines
recommend aspirin and low-molecular-weight heparin (e.g. enoxaparin) for VTE prophy-
laxis; however, there is debate in the international literature around the use of aspirin as
VTE prophylaxis. This review assesses the risks and benefits of aspirin compared to enoxa-
parin as VTE prophylaxis for patients undergoing THA or TKA.
Methods: A systematic review was conducted to identify relevant randomized controlled
trials. Studies comparing enoxaparin, aspirin and/or placebo for VTE prophylaxis in THA
or TKA patients were included. Network meta-analysis (NMA) was performed to calculate
risk ratios (RRs) and confidence intervals (CIs). Quality appraisal was conducted by asses-
sing risk of bias and the strength of the evidence.
Results: Nine randomized controlled trials were eligible for inclusion. The NMA found no
statistically significant differences for the investigated outcomes: total DVT rates
(RR = 1.21, 95% CI 0.86, 1.72), symptomatic pulmonary embolism (PE) rates (RR = 1.02,
95% CI 0.02, 50.86), major haemorrhage (RR = 0.97, 95% CI 0.02, 50.99) and wound
complication (RR = 0.73, 95% CI 0.17, 3.20). The occurrence of PE was rare. Due to lim-
ited data, sub-group analysis was not possible. The overall quality of evidence in the NMA
is considered to be very low.
Conclusion: This review did not find statistically significant differences between aspirin
and enoxaparin. Future studies should identify more evidence, particularly for rare outcomes
such as PE, as this might help decision-makers to get consensus on the use of aspirin as
VTE prophylaxis.

increased risk of bleeding and wound infection.3 Therefore, deci-

Introduction
The risk of venous thromboembolism (VTE), including deep vein
thrombosis (DVT) and pulmonary embolism (PE) is high for
patients undergoing total hip arthroplasty (THA) and total knee
arthroplasty (TKA).1 Prophylactic strategies, including compression
devices and anticoagulation agents, are used to reduce the incidence
of VTE. Commonly used anticoagulation agents in Australia
include low-molecular-weight heparin (e.g. enoxaparin) and anti-
platelets (e.g. aspirin).2 VTE prophylaxis is intended to reduce the
incidence of VTE after THA or TKA, but is also associated with an
sion making around an appropriate treatment strategy remains a
clinical dilemma of balancing the postoperative risks of VTE with
prophylactic complications.4
A recent Australian guideline outlines patient-specific risk factors
that are used to inform clinicians on appropriate prophylactic treat-
ment strategies for patients undergoing THA or TKA.2 However,
despite the presence of this guideline expert opinion in Australia
suggests the choice between enoxaparin and aspirin is a contentious
issue in the clinical field. The ambiguity around aspirin is empha-
sized by the fact that the current Australian guideline recommends

© 2019 Royal Australasian College of Surgeons ANZ J Surg (2019)

2 Nadi et al.
aspirin as an appropriate prophylaxis for VTE,2 while the current
guideline from the National Institute for Health and Care Excel-
lence (NICE) does not.5 Therefore, the aim of this systematic
review is to assess the risks and benefits of aspirin compared to
enoxaparin for patients undergoing total hip or knee arthroplasty.
Methods
A systematic literature search was conducted. The Population,
Intervention, Comparator, Outcome (PICO) and study selection cri-
teria were defined a priori (Table 1), as defined in a research proto-
col (PROSPERO id CRD42018090050).
Search strategy and study selection
Searches were conducted in the PubMed, Embase and Cochrane
Library databases up to 21 February 2018. All citations were
reviewed by the first author (SN) based on title and abstract; full-
text screening was performed by two independent reviewers
(SN and BH). Disagreements were resolved by discussion with a
third reviewer (TDV).
The TRIP database, clinicaltrials.gov, Cochrane central register
of trials, current controlled trials metaRegister and the Australian
New Zealand Clinical trials registry were searched to identify ongo-
ing or unpublished randomized controlled trials (RCTs). Reference
lists of included studies were pearled to identify relevant articles
that may have been missed by the searches.6
Data extraction and management
Data extraction was completed by one author (SN) and checked for
accuracy by a second reviewer (BH). Discrepancies settled via con-
sensus. The following information was extracted from the articles:
Table 1 PICO and study selection criteria
Population Patients who have undergone elective total hip or
knee arthroplasty
Intervention Two commonly used drugs in Australian clinical
practice:
• Low-molecular-weight heparin (i.e. enoxaparin,
traded as clexane)
• Antiplatelet (i.e. aspirin)
Comparator Effectiveness and safety outcomes of both aspirin
and enoxaparin will be compared with each
other, placebo and no treatment
Outcomes Safety outcomes: bleeding events, wound
infections or other adverse events
Primary effectiveness outcomes: mortality, rates of
symptomatic DVT or PE
Secondary effectiveness outcomes: radiological
evidence of DVT or PE
Design RCTs
Publication date All RCTs published in the last 20 years, from 1998
and type† to 2018
Grey literature resources for unpublished RCTs
All languages
†Literature searches for EMBASE and PubMed databases were performed
on 20 February 2018 and the search in the Cochrane database was per-
formed on 21 February 2018. DVT, deep vein thrombosis; PE, pulmonary
embolism; PICO, Population, Intervention, Comparator, Outcome; RCT,
randomized controlled trial.
• Study characteristics: study design, country, setting, funding
and conflicts of interest.
• Population: sample size, losses to follow up, age, gender, body
mass index, risk factors.
• Interventions: prophylactic agent used (e.g. dose, duration),
concomitant interventions.
• Outcomes: safety (bleeding events, wound infections, other
adverse events), primary effectiveness outcomes (mortality,
rates of symptomatic DVT or PE), secondary effectiveness out-
comes (radiological evidence of asymptomatic PE or DVT).
Data analyses
We conducted a random-effects network meta-analysis (NMA)
(software: R version 3.5.0). The NMA combines direct and indirect
evidence across a network of RCTs into a single effect size, under
the assumptions it can increase the precision in the estimates. risk
ratios (RRs) and 95% confidence intervals (CIs) were produced to
estimate the pairwise comparative treatment effect, and I2 was cal-
culated to indicate overall heterogeneity. Netrank p-scores were
generated in the NMA, which is an indicator for the ‘best’ treatment
by ranking the treatments on a continuous scale from 0 to 1. By
taking into account treatment superiority, certainty, homogeneity
and consistency, p-scores measure the mean extent of certainty that
a treatment is better than the competing treatment.
Subgroup analysis and sensitivity analysis
This study planned to perform subgroup analysis and search for
heterogeneity for the primary outcomes in the following subgroups:
• VTE risk (high risk versus low risk based on: age, mobiliza-
tion, history of VTE, revision procedure)
• Treatment duration (up to 10 days versus 10–14 days versus
15 days or more)
• Dosage (depending on the dosages from the included studies)
• Type of surgery (knee versus hip arthroplasty)
This study also planned to conduct sensitivity analysis to identify
influential studies and factors that affect the direction and the size
of the reported effects.
Publication bias
Publication bias was planned to be investigated using funnel plot
asymmetry testing for meta-analysis with greater than 10 studies.7
In addition, clinical trial databases were searched to identify can-
celled or unpublished clinical trials.
Risk of bias and level of evidence (quality
appraisal)
Two reviewers (SN and BH) independently assessed the risk of bias
using the Cochrane ‘Risk of bias’ tool for RCTs.8 Any discrepan-
cies were discussed with a third reviewer (TDV).
The strength of the body of evidence was assessed per outcome
using the GRADE approach.9 Scores for the five domains in the
GRADE approach for direct and indirect evidence were combined
to get a GRADE score to indicate the strength of the body of
© 2019 Royal Australasian College of Surgeons
Venous thromboembolism prophylaxis 3

evidence for the NMA. Scoring was performed in the online GRA-
DEpro tool.10
Results
Study selection
The flowchart of the search strategy is shown in Figure 1. After the
full-text assessment of all citations, 13 RCTs were excluded and
only nine RCTs were eligible for inclusion in the quantitative anal-
ysis. No additional references were identified through pearling the
reference lists of the included studies.
Study characteristics
The nine studies included a total of 2336 patients receiving aspi-
rin, 897 patients receiving enoxaparin and 2625 patients receiving
placebo (Table 2). Two studies were direct comparisons,11,12 that
investigated the effect of enoxaparin compared to aspirin. The
other seven studies compared enoxaparin with placebo13–17 or
aspirin with placebo.18,19 Although fewer trials investigated aspi-
rin the sample size investigating aspirin is significantly larger.
From the aspirin trials, only two studies reported the use of enteric
coating.12,19 All studies excluded high-risk patients and therefore
all the evidence is based on low risk patient groups. High-risk
patients were mostly excluded due to history of VTE, history of
haemorrhagic stroke or gastro-intestinal bleeding, severe periph-
eral vascular diseases; chronic heart failure or severe varicose
veins.
Total studies identified
Identification
Quantitative analysis
Sufficient data were only available for total DVT rates (combining
both symptomatic and asymptomatic DVT rates), symptomatic PE
rates, major haemorrhage and wound complication; hence the
NMA was performed on the four outcomes. All the comparisons
investigated by the NMA are based on data combining THA
and TKA.
Total DVT rates
There was no statistical significance in total DVT rates between
aspirin and enoxaparin (RR = 1.27 (0.84, 1.96)) reported within the
direct evidence (Table 3). Also, no statistical significance was
observed for indirect evidence (RR = 1.09 (0.56, 2.12)) or the
NMA, incorporating direct and indirect evidence (RR = 1.21 (0.86,
1.72)) on total DVT. The I2 is zero (P-value = 0.48) indicating
reported outcomes are very consistent (Table 3). For total DVT
rates, the Netrank p-score was higher for aspirin (p-score = 0.94)
than enoxaparin (p-score = 0.55). The higher the p-score, the more
likely the treatment is more reliable overall regarding superiority,
consistency and certainty.
Symptomatic PE rates
For direct evidence RRs and 95% CIs could not be calculated due to
zero events. For indirect evidence RR and 95% CI could not be cal-
culated as no trial comparing aspirin with placebo reported symptom-
atic PE rates. The NMA did not find a significant difference between
aspirin compared to enoxaparin (RR = 1.02 (0.00, 242.90)). The evi-
dence base for aspirin in the NMA is based on one study,11 reporting
zero events. The wide range of the CI implies the point estimate is
very uncertain. There was moderate heterogeneity for symptomatic
PE rates (I2 = 58.6, P-value = 0.06). Assessment of heterogeneity
‘between designs’ was not applicable because the outcome was not
sufficiently reported in the direct evidence. The Netrank p-score was

(N=5158)
0.68 for aspirin and 0.44 for enoxaparin.
EMBASE (n=3267)
PubMed (n=1199) Total studies excluded
Cochrane (n=692) (N = 1205)
Wound complication
Duplicates
(n = 708) Wound complication was only reported in one direct RCT
Studies prior 1998 (RR = 0.68 (0.12, 3.98)),11 and the indirect evidence (RR = 0.66
(n=497)
Screening

Total studies screened by title (0.05, 8.86)). Neither of the RRs were statistically significant. The
and abstract NMA, incorporating direct and indirect evidence, non-significant
(N= 3953) Total studies excluded
(N = 3931) differences were observed between aspirin compared to enoxaparin
Non RCT ( n= 43) (RR = 0.73 (0.17, 3.20)). Heterogeneity was low (I2 = 19.6%, P-
Cost analysis ( n= 104) value = 0.29). The highest Netrank p-score was found for aspirin
Reviews ( n=271)
Guidelines ( n= 24) (p-score = 0.79) compared to enoxaparin (p-score = 0.46).
Eligibility

Total studies assessed by

full-text for eligibility Irrelevant ( n=3489)
(N=22)
Total studies excluded
Major haemorrhage
(N=13) Major haemorrhage was not reported within the direct evidence.
Reasons for excluding are
The RR for major haemorrhage for aspirin was not significant (0.97
Included

Total studies included in
quantitative analysis
(N= 9)
Fig. 1. PRISMA study selection flowchart.
reported (0.09, 50.99)). The wide range of the 95% CI indicates the point
estimate is highly uncertain.
There was no evidence of heterogeneity (I2 = 0%, P-value =
0.6). No differences were found between the Netrank p-scores for
aspirin (p-score = 0.51) and enoxaparin (p-score = 0.50).

© 2019 Royal Australasian College of Surgeons

 4

Table 2 Characteristics of the included randomized controlled trials

Author, year Total Type of Age mean (range) BMI mean (range) Daily dose in mg Follow Funding and Conflict of
Country no. patients procedure up, support interest†
randomized weeks
Intervention Comparator Intervention Comparator Intervention Comparator

Direct comparisons, aspirin versus enoxaparin

Zou et al., 2014 324 TKA Aspirin: 62.7 Enoxaparin: 65.7 Aspirin: 27.8 Enoxaparin: 27.0 Aspirin: 100 mg Enoxaparin: 4000 4 NR No
China (range 47–79) (range 54–80) (range (range daily AxaIU
17.8–40.0) 20.3–37.0) (0.4 mL)/day
Westrich et al., 275 TKA Aspirin: 69.0 Enoxaparin: NR NR Aspirin: 325 mg Enoxaparin: 4–6 Aventis Yes
2006 (SD 12.1) 68.9 (SD 9.6) twice daily 40–60 mg daily Bridgewater
United States
Indirect comparisons, enoxaparin versus placebo
Intiyanaravut et al., 50 TKA Enoxaparin: Placebo: Enoxaparin: Placebo: Enoxaparin: Placebo 12–24 None No
2017 72 (SD 6.9) 70 (SD 6.8) 29.1 (SD 8.8) 26.9 (SD 4.7) 40 mg daily
Thailand
Chin et al., 2009 220 TKA Enoxaparin: Placebo: Enoxaparin: 25.7 Placebo: 25.6 Enoxaparin: Placebo 4 NR NR
Singapore 67 (range 65 (range 40 mg daily
52–78) 47–77)
Fuji et al.,‡ 2008 421 THA Enoxaparin: Placebo: Enoxaparin: Placebo: Enoxaparin: Placebo 13 Sanofi-Aventis Yes
Japan 62.4 (SD 9.9) 62 (SD 10.3) 23.6 (SD 3.6) 24 (SD 3.4) 20 mg daily or K.K
40 mg daily
382 TKA Enoxaparin: Placebo: Enoxaparin: Placebo: Enoxaparin: Placebo 13 Sanofi-Aventis Yes
69.0 (SD 9.0) 68.7 (SD 9.5) 25 (SD 4.2) 25.4 (SD 3.7) 20 mg daily or K.K
40 mg daily
Indirect comparisons, enoxaparin versus placebo
Jain et al., 2004 40 THA Enoxaparin: 48 Placebo: 46 Enoxaparin: 25 Placebo: 24 Enoxaparin: Placebo NR NR NR
India 40 mg daily
Kim et al., 2016 400 THA Enoxaparin: Placebo: Enoxaparin: Placebo: Enoxaparin: Placebo 6 NR No
Korea 43.9 (SD 9.4) 43.4 (SD 9.9) 25.4 (SD 3.8) 24.3 (SD 3.4) 40 mg daily
Indirect comparisons, aspirin versus placebo
Rodgers et al., 4088 THA Enoxaparin and placebo NR NR Aspirin: 160 mg Placebo 4–5 Public and Yes
2000 and combined: 67 daily private
Australia, TKA organizations
New Zealand,
South Africa,
Sweden and UK
Kim et al., 1998 150 THA Enoxaparin and placebo NR NR Aspirin: 1200 mg Placebo NR NR NR
Korea combined: (21–81) daily

†Conflict of interest is based on the reported acknowledgement of conflict of interest reported and reported funding and support. ‡Fuji et al. investigated THA and TKA and reported results separately.
NR, not reported; SD, standard deviation; THA, total hip arthroplasty; TKA, total knee arthroplasty; UK, United Kingdom.

© 2019 Royal Australasian College of Surgeons

Nadi et al.
Venous thromboembolism prophylaxis 5

Table 3 Inconsistency for total, within design and between design comparisons for effectiveness and safety outcomes

Total DVT rates Symptomatic PE rates Wound complication Major haemorrhage

Total I † = 0%
2 2
I = 58.6% 2
I = 19.6% I2 = 0%
Q = 6.56(7) Q = 7.25(3) Q = 6.22(5) Q = 3.69(5)
P-value = 0.48 P-value = 0.06 P-value = 0.29 P-value = 0.60
Within design Q = 6.38(6) Q = 7.25(3) Q = 6.16(4) Q = 3.69(5)
P-value = 0.38 P-value = 0.06 P-value = 0.19 P-value = 0.60
Between design Q = 0.18(1) Q = 0.00(0) Q = 0.05(1) Q = 0.00(0)
P-value = 0.67 P-value = NA P-value = 0.82 P-value = NA

†I2 indicates high (75%), moderate (50%) and low (25%) heterogeneity. DVT, deep vein thrombosis; NA, not applicable; PE, pulmonary embolism; Q, degrees of
freedom.

Risk of bias compared all low-molecular-weight heparin (e.g. enoxaparin, dalte-

Risk of bias was often difficult to assess due to poor reporting
(Fig. 2). Risk of bias was particularly high for blinding, as blinding
was rarely done and was reportedly difficult to maintain because
enoxaparin was given subcutaneously and aspirin was given by tab-
lets. Three studies blinded effectively13,17,19 by giving the patients
both (placebo) injections and (placebo) tablets.
For one study,16 an extra risk of bias was added because data
from the tables and text were not consistent. We consulted the
authors for clarification but did not receive a reply.
parin) with aspirin while we only used enoxaparin as the active
comparator.20 Also, they did not report p-scores. The Netrank
p-scores in this review rank aspirin as the ‘best’ treatment for all
four outcomes which indicates that the evidence for aspirin is ‘the
best’ when combining treatment superiority, certainty, homogeneity
and consistency. Due to the limited data, with only four trials inves-
tigating aspirin, it is questionable how accurate this p-score is.
Although results partly overlap, our review is more relevant to
the Australian context. Prophylactic options which are not com-
monly used in Australian clinical practices were excluded in this

Quality of the evidence (GRADE)

Table 4 shows the GRADE scores for direct evidence, indirect evi-
dence and the NMA separately. GRADE scores for the NMA are a
combination of scores on the five domains for direct and indirect evi-
dence and are scored very low for all outcomes. Reasons for scoring
and results for scoring separately per outcome are shown in
Appendix H.

Subgroup analysis and sensitivity analysis

This study intended to perform subgroup analysis and sensitivity
analysis but did not identify sufficient evidence to compare the sub-
groups mentioned in the methods section of this review.

Publication bias
Because of the low number of studies that are incorporated in the
NMA it was inappropriate to perform funnel plot asymmetry testing
to investigate publication bias. Two trials identified on clinical trial
databases were noted as completed; however, no publication was
found indicating possible publication bias. Details for the trials are
shown in Appendix I.

Discussion
The NMA did not find statistically significant differences for the
four outcomes comparing aspirin with enoxaparin.

Comparison with previous literature

A previous review performed a comprehensive NMA investigating
available RCTs to assess the effectiveness of VTE prophylaxis after
THA and TKA.20 Different from our review, Kapoor et al. Fig. 2. Risk of bias in the included trials.

© 2019 Royal Australasian College of Surgeons

6 Nadi et al.

Table 4 Summary and strength of the included evidence

Outcome Direct evidence (two studies) Indirect evidence‡ (seven studies) Network meta-analysis (nine studies)
Relative risk ratio GRADE scores§ Relative risk ratio GRADE scores§ Relative risk ratio GRADE scores§
(95% CI) (95% CI) (95% CI)

Total DVT rates 1.27 1.09 1.21

(0.84, 1.96) Very low (0.56, 2.12) Very low (0.86, 1.72) Very low
Symptomatic NA† NA†† 1.02
PE rates Low Moderate (0.0, 242.90)¶ Very low
Major NA NA 0.97 0.97
haemorrhage No study (0.02, 50.99) Very low (0.02, 50.99) Very low
available
Wound 0.68 0.66 0.73
complication (0.12, 3.98) Moderate (0.05, 8.86) Very low (0.17, 3.20) Very low

†Only one study was available; event rates were 0 so a RR could not be calculated. ‡Risk ratios and the quality of evidence for indirect evidence were generated
by combining enoxaparin versus placebo and aspirin versus placebo using R statistical package §GRADE scores are based on evidence graded according to the
GRADE approach including the following components: risk of bias, inconsistency, indirectness and imprecision. The GRADE scores for these components are
obtained separately for all three comparisons investigated in this study. For grading evidence of the NMA scores for those five components are combined accord-
ing to the GRADE approach to obtain a new GRADE score. ¶The network meta-analysis included one direct study of clexane versus aspirin, and one indirect study
of clexane versus placebo ††One study comparing clexane to placebo was identified; an indirect RR could not be calculated. CI, confidence interval; DVT, deep
vein thrombosis; NA, not applicable; PE, pulmonary embolism. RR values <1 indicate the size of a protective effect of the treatment described compared to enoxa-
parin. RR values >1 indicate the size of a certain risk of the treatment described compared to enoxaparin.

study. The exclusion of other drugs also minimizes the risk of
including potentially heterogeneous populations from other trials.
Even though Kapoor et al.20 included more comparative arms
and used all low-molecular-weight heparin as the active compara-
tor, which made them able to expand their evidence base, they were
not able to draw firm conclusions about aspirin. This corresponds
with our findings, which showed that the evidence base around
aspirin as a VTE prophylaxis is limited.
Strengths and limitations
This review did not find sufficient data for symptomatic DVT rates
and was forced to investigate total DVT rates (including both
symptomatic and asymptomatic DVT rates). Debate on the clinical
relevance of asymptomatic DVT is ongoing,21 and disagreement
exists on the relationship between asymptomatic DVT and clini-
cally important VTE. This is the main issue leading to conflicting
recommendations on the use of aspirin.22 Struijk-Mulder et al.
stated that disagreement on the relevance of different endpoint
(e.g. asymptomatic DVT) should be solved before agreement
around aspirin as a VTE prophylaxis can be reached. This review
was not able to distinguish between both outcomes.
Although this review investigated both effectiveness (e.g. DVT)
and safety (e.g. major haemorrhage) outcomes, it does not place a
greater emphasis on one or the other when comparing aspirin with
enoxaparin. Current guidelines, which consider both effectiveness
and safety outcomes to be important, have different views on the
weight of importance when looking at effectiveness and safety.22
This review did not find any evidence for the effectiveness and
safety of aspirin in the prevention of PE. Interestingly, evidence
around PE was also absent for enoxaparin. This can be explained
by the rare occurrence of PE; according to two register-based
studies,23,24 the 90-day non-fatal PE rate after THA and TKA with-
out prophylaxis is 0.93% and 0.41% respectively. According to the
American Academy of Orthopaedic Surgeons (AAOS) rates of PE
cannot be assessed adequately.25 Results from this review support
this statement; the largest trial included in this review (n = 4088)
comparing aspirin with placebo was not able to detect sufficient PE
events.19
Due to the limited data available, the planned subgroup analyses
could not be performed. Future studies investigating the use of aspi-
rin without an enteric coating would also be valuable, as only two
aspirin trials reported the use of enteric coating,12,19 which reduces
the bio availability of aspirin.26
We encountered the same restrictions for type of procedure, drug
dose, treatment duration, ethnicity, conflict of interest and the use
mechanical prophylaxis.
It would be clinically valuable to compare the effects between
high and low risk populations. However, high-risk populations were
systematically excluded from all current RCTs, meaning the results
cannot be extrapolated to patients at high-risk for VTE or complica-
tions due to prophylactic treatments. While this review only looked
at RCTs, future reviews should consider the inclusion of other levels
of evidence to identify data from patients at greater risk of VTE. Risk
levels for VTE and postoperative complications, based on patient-
specific comorbidities, will likely affect clinical decisions as to which
drug to use in specific risk groups. The individual complexity of
weighing the best approach for managing VTE depends on each
patient, which makes this area of research open for interpretation.
Although the data are limited, this review does show a lack of a
statistical significant difference between aspirin and enoxaparin for
VTE prophylaxis after THA and TKA. This is an important finding
as it directly contributes to the current discussion around whether to
or not to use aspirin as a prophylactic agent. Also, this review
offers insights in the possible reasons for not finding statistical sig-
nificance, which is necessary in helping future studies to obtain bet-
ter and more convincing evidence.
Conclusion
This review did not find statistical significant results when compar-
ing aspirin with enoxaparin as a VTE prophylaxis. No evidence

© 2019 Royal Australasian College of Surgeons

Venous thromboembolism prophylaxis
was identified for PE and subgroup analysis was not possible due
to limited data. Future studies should identify more evidence, par-
ticularly for PE and high-risk groups. This might help decision-
makers to get consensus on the use of aspirin as VTE prophylaxis.
Acknowledgements
Funding support for this project was provided by the Royal Austral-
asian College of Surgeons. Sinan Nadi was supported by a research
scholarship by the Royal Australasian College of Surgeons. The
authors are grateful to Dr Alun Cameron and Dr David Tivey for
their assistance during the preparation of this manuscript. Also, the
authors offer their special thanks to Bridget Heijkoop, who has
been the second reviewer in this manuscript.
Conflicts of interest
None declared.
References
1. White RH, Henderson MC. Risk factors for venous thromboembolism
after total hip and knee replacement surgery. Curr. Opin. Pulm. Med.
2002; 8: 365–71.
2. Arthroplasty Society of Australia. Arthroplasty Society of Australia
Guidelines for VTE Prophylaxis for Hip and Knee Arthroplasty. 2017.
[Cited 20 Jan 2018.] Available from URL: https://www.aoa.org.au/
3. Ricket AL, Stewart DW, Wood RC et al. Comparison of postoperative
bleeding in total hip and knee arthroplasty patients receiving rivaroxa-
ban or enoxaparin. Ann. Pharmacother. 2016; 50: 270–5.
4. Guijarro R, Montes J, San Roman C et al. Venous thromboembolism
and bleeding after total knee and hip arthroplasty. Findings from the
Spanish National Discharge Database. Thromb. Haemost. 2011;
105: 610–5.
5. National Institute of Clinical Excellence. Venous Thromboembolism:
Reducing the Risk for Patients in Hospital. 2015. [Cited 22 Jan 2018.]
Available from URL: https://www.nice.org.uk/Guidance/CG92
6. Cooke A, Smith D, Booth A. Beyond PICO: the SPIDER tool for quali-
tative evidence synthesis. Qual. Health Res. 2012; 22: 1435–43.
7. Sterne J, Becker B, Egger M. The funnel plot. In: Publication Bias in
Meta-Analysis: Prevention, Assessment and Adjustments. Chichester,
UK: John Wiley & Sons, 2005.
8. Higgins J, Sterne J, Savovic J et al. A revised tool for assessing risk of
bias in randomized trials. Cochrane Database Syst. Rev. 2016; 10
(Suppl 1): 29–31.
9. Balshem H, Helfand M, Schunemann HJ et al. GRADE guidelines:
3. Rating the quality of evidence. J. Clin. Epidemiol. 2011; 64: 401–6.
10. GRADEpro GDT: GRADEpro Guideline Development Tool [Soft-
ware]. McMaster University, 2015 (developed by Evidence Prime,
Inc.). Available from gradepro.org
11. 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: 660–4.
12. Westrich GH, Bottner F, Windsor RE, Laskin RS, Haas SB, Sculco TP.
VenaFlow plus Lovenox vs VenaFlow plus aspirin for thromboembolic
© 2019 Royal Australasian College of Surgeons
7
disease prophylaxis in total knee arthroplasty. J. Arthroplasty 2006; 21:
139–43.
13. Chin PL, Amin MS, Yang KY, Yeo SJ, Lo NN. Thromboembolic pro-
phylaxis for total knee arthroplasty in Asian patients: a randomised con-
trolled trial. J. Orthop. Surg. (Hong Kong) 2009; 17: 1–5.
14. Fuji T, Ochi T, Niwa S, Fujita S. Prevention of postoperative venous
thromboembolism in Japanese patients undergoing total hip or knee arthro-
plasty: two randomized, double-blind, placebo-controlled studies with
three dosage regimens of enoxaparin. J. Orthop. Sci. 2008; 13: 442–51.
15. Intiyanaravut T, Thongpulsawasdi N, Sinthuvanich N, Teavirat S,
Kunopart M. Enoxaparin versus no anticoagulation prophylaxis after
total knee arthroplasty in Thai patients: a randomized controlled trial.
J. Med. Assoc. Thai. 2017; 100: 42–9.
16. Jain V, Dhal AK, Dhaon BK, Pradhan G. Deep vein thrombosis after
total hip arthroplasty in Indian patients with and without enoxaparin.
J. Orthop. Surg. (Hong Kong) 2004; 12: 173–7.
17. Kim SM, Moon YW, Lim SJ, Kim DW, Park YS. Effect of oral factor
Xa inhibitor and low-molecular-weight heparin on surgical complica-
tions following total hip arthroplasty. Thromb. Haemost. 2016;
115: 600–7.
18. Kim YH, Choi IY, Park MR, Park TS, Cho JL. Prophylaxis for deep
vein thrombosis with aspirin or low molecular weight dextran in Korean
patients undergoing total hip replacement. A randomized controlled
trial. Int. Orthop. 1998; 22: 6–10.
19. Rodgers A, MacMahon S, Collins R, Prentice C. Prevention of pulmo-
nary embolism and deep vein thrombosis with low dose aspirin: pulmo-
nary embolism prevention (PEP) trial. Lancet 2000; 355: 1295–302.
20. Kapoor A, Ellis A, Shaffer N et al. Comparative effectiveness of venous
thromboembolism prophylaxis options for the patient undergoing total
hip and knee replacement: a network meta-analysis. J. Thromb. Haemost.
2017; 15: 284–94.
21. Quinlan DJ, Eikelboom JW, Dahl OE, Eriksson BI, Sidhu PS, Hirsh J.
Association between asymptomatic deep vein thrombosis detected by
venography and symptomatic venous thromboembolism in patients under-
going elective hip or knee surgery. J. Thromb. Haemost. 2007; 5: 1438–43.
22. Struijk-Mulder MC, Ettema HB, Verheyen CC, Buller HR. Comparing
consensus guidelines on thromboprophylaxis in orthopedic surgery.
J. Thromb. Haemost. 2010; 8: 678–83.
23. Katz JN, Losina E, Barrett J et al. Association between hospital and sur-
geon procedure volume and outcomes of total hip replacement in the United
States medicare population. J. Bone Joint Surg. Am. 2001; 83-a: 1622–9.
24. SooHoo NF, Lieberman JR, Ko CY, Zingmond DS. Factors predicting
complication rates following total knee replacement. J. Bone Joint Surg.
Am. 2006; 88: 480–5.
25. American Academy of Orthopedic Surgeons Clinical Guideline on Pre-
vention of Symptomatic Pulmonary Embolism in Patients Undergoing
Total Hip or Knee Arthroplasty. 2007. [Cited 22 Jan 2018.] Available
from URL: http://www.aaos.org/Research/guidelines/PE_guideline.pdf
26. James MJ, Foreman RK, Burnett JR, Cleland LG. Inhibition of human
endothelial prostacyclin synthesis by different aspirin formulations.
Aust. N. Z. J. Surg. 1991; 61: 849–52.
Supporting information
Additional Supporting Information may be found in the online ver-
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Appendix S1. Supporting Information.