 KNEE
The effect of aspirin and low-molecularweight heparin on venous thromboembolism
after knee replacement
S. S. Jameson,
P. N. Baker,
S. C. Charman,
D. J. Deehan,
M. R. Reed,
P. J. Gregg,
J. H. Van der
Meulen
From London School
of Hygiene and
Tropical Medicine,
London, United
Kingdom
 S. S. Jameson, MRCS,
Research Fellow
 P. N. Baker, MSc,
FRCS(Tr&Orth), Research Fellow
The National Joint Registry for
England and Wales, 15-17
Tavistock Place, London WC1H
9SH, UK.
 S. C. Charman, MSc, Lecturer in
Medical Statistics
 J. H. Van der Meulen, PhD,
FFPH, Professor of Clinical
Epidemiology
The London School of Hygiene
and Tropical Medicine, 15-17
Tavistock Place, London WC1H
9SH, UK.
 D. J. Deehan, MD, MSc,
FRCS(Tr&Orth), Consultant
Orthopaedic Surgeon
Newcastle Hospitals NHS
Foundation Trust, Freeman Road,
High Heaton, Newcastle upon
Tyne NE7 7DN, UK.
 M. R. Reed, MD,
FRCS(Tr&Orth), Consultant
Orthopaedic Surgeon
Northumbria Healthcare NHS
Foundation Trust, Woodhorn
Lane, Ashington,
Northumberland NE63 9JJ, UK.
 P. J. Gregg, FRCS(Ed),
FRCSEd(Orth), Consultant
Orthopaedic Surgeon
South Tees Hospitals NHS
Foundation Trust, The James
Cook Hospital, Marton Road,
Middlesbrough TS4 3BW, UK.
Correspondence should be sent
to Mr S. S. Jameson; e-mail:
simonjameson@doctors.org.uk
©2012 British Editorial Society of
Bone and Joint Surgery
doi:10.1302/0301-620X.94B7.
29129 $2.00
J Bone Joint Surg Br
2012;94-B:914–18.
Received 13 January 2012;
Accepted after revision 23
February 2012
914
A NON-RANDOMISED COMPARISON USING NATIONAL JOINT
REGISTRY DATA
We compared thromboembolic events, major haemorrhage and death after knee
replacement in patients receiving either aspirin or low-molecular-weight heparin (LMWH).
Data from the National Joint Registry for England and Wales were linked to an
administrative database of hospital admissions in the English National Health Service. A
total of 156 798 patients between April 2003 and September 2008 were included and
followed for 90 days. Multivariable risk modelling was used to estimate odds ratios adjusted
for baseline risk factors (AOR). An AOR < 1 indicates that risk rates are lower with LMWH
than with aspirin. In all, 36 159 patients (23.1%) were prescribed aspirin and 120 639 patients
(76.9%) were prescribed LMWH. We found no statistically significant differences between
the aspirin and LMWH groups in the rate of pulmonary embolism (0.49% vs 0.45%, AOR 0.88
(95% confidence interval (CI) 0.74 to 1.05); p = 0.16), 90-day mortality (0.39% vs 0.45%, AOR
1.13 (95% CI 0.94 to 1.37); p = 0.19) or major haemorrhage (0.37% vs 0.39%, AOR 1.01 (95% CI
0.83 to 1.22); p = 0.94). There was a significantly greater likelihood of needing to return to
theatre in the aspirin group (0.26% vs 0.19%, AOR 0.73 (95% CI 0.58 to 0.94); p = 0.01).
Between patients receiving LMWH or aspirin there was only a small difference in the risk of
pulmonary embolism, 90-day mortality and major haemorrhage.
These results should be considered when the existing guidelines for thromboprophylaxis
after knee replacement are reviewed.
Venous thrombosis is considered to be common
following knee replacement, with the incidence
of asymptomatic deep-vein thrombosis (DVT)
being estimated to be as high as 60%.1 However, the reported incidences of symptomatic
venous thromboembolism (VTE, 1.8%2) and
fatal pulmonary embolism (PE, 0.15%3) within
90 days of surgery are much lower. In order to
reduce the occurrence of VTE, the National
Institute for Health and Clinical Excellence
(NICE) recommend combined mechanical and
pharmacological prophylaxis post-operatively
for ten to 14 days for all patients undergoing
knee replacement, unless there are contraindications.1 Recommended agents include lowmolecular-weight heparins (LMWHs), direct
factor Xa inhibitors, fondaparinux sodium and
unfractionated heparin (UFH). NICE state that
the ‘protective effect of aspirin against VTE is
insufficient’, and therefore do not recommend
aspirin and other antiplatelet medications for
pharmacological prophylaxis. Although this
has also been the stance of the American College of Chest Physicians (ACCP)4 and the International Consensus Group,5 the American
Academy of Orthopaedic Surgeons (AAOS) in
their guidelines were unable to find conclusive
evidence to recommend one chemical prophylaxis agent over any other.6
Recommendations against the use of aspirin
are based on extrapolations from mostly small,
historical studies.7-9 Peri-operative care has
subsequently evolved, and this evidence may
now be outdated. More recent publications
with larger numbers have suggested that the
risk of VTE following either aspirin or injectable prophylaxis against VTE (LMWH/fondaparinux) is equivalent,10 and the routine use of
potent anticoagulants (LMWH/direct factor
Xa inhibitors) does not reduce the overall mortality or the proportion of deaths due to PE.11
Aspirin is an attractive method of prophylaxis
as it is inexpensive, orally administered, and
does not require laboratory monitoring. Prior
to the NICE guidance almost a quarter of all
patients undergoing knee replacement were
given aspirin for VTE prophylaxis.12
We have previously compared the effects of
aspirin and LMWH on VTE after hip replacement,13 showing a small survival benefit for
THE JOURNAL OF BONE AND JOINT SURGERY
THE EFFECT OF ASPIRIN AND LOW-MOLECULAR-WEIGHT HEPARIN ON VENOUS THROMBOEMBOLISM AFTER KNEE REPLACEMENT
those receiving LMWH, but no differences were seen for
the risk of VTE and bleeding events. We now examine the
role of these two chemical agents following total knee
replacement (TKR) in a similar national series of patients.
Patients and Methods
We used records from the National Joint Registry for
England and Wales (NJR) linked at patient level to records
from the Hospital Episode Statistics (HES) database. The
NJR aims to collect data prospectively on all patients who
undergo knee replacement in England and Wales.14 The
HES database includes all patients admitted to NHS hospitals in England, or to private hospitals funded by the NHS
(no Registry data from Wales was included in this analysis).15 HES records contain patient details and diagnostic
information coded using the International Classification of
Diseases, tenth revision (ICD-10),16 and operative procedure
codes using the United Kingdom Office for Population Censuses and Surveys classification, fourth revision (OPCS-4).17
The HES database also includes date of death from the
Office for National Statistics.
This analysis was based on data described in the Seventh
NJR Annual Report.12 We identified 227 668 patients for
whom a primary knee replacement (total, patellofemoral and
unicompartmental) was recorded in the NJR between 1 April
2003 and 30 September 2009, and who could be linked to
HES. The linkage was carried out based on a hierarchy of
deterministic criteria, including NHS number, year of birth
and gender, as detailed in the Seventh NJR Annual Report.12
Of these, 156 798 were given either aspirin or LMWH as the
sole chemical thromboprophylaxis, irrespective of whether
mechanical prophylaxis had also been used. Patients receiving more than one type of pharmacological prophylaxis were
excluded. All patients were followed for at least 90 days.
Information regarding the method of thromboprophylaxis was extracted from NJR records with relevant details
of the operation and patient characteristics that were considered risk factors for VTE or haemorrhage. We used the
Royal College of Surgeons Charlson Score18 to search the
HES database for comorbid conditions.
HES data were also used to identify thromboembolic
events (PE, DVT) and death within 90 days of surgery,
major haemorrhage (cerebrovascular accident or gastrointestinal haemorrhage) and return to theatre for wound
complications within 30 days of surgery. Minor haemorrhage was not considered, as it is unlikely to be accurately
coded in the HES database.
Statistical analysis. Logistic regression was used to assess
the effect of treatment on outcome, with adjustment for
patient characteristics that are risk factors for VTE or
haemorrhage. Results are presented as odd ratios (OR)
with 95% confidence intervals (CI); an OR < 1 indicates
that rates are lower with LMWH than with aspirin. The
likelihood ratio test was used as a basis for p-values, and
p < 0.05 was considered to indicate statistical significance.
All risk models included the type of pharmacological
VOL. 94-B, No. 7, JULY 2012
915
prophylaxis, age (grouped into three equal-sized categories
with cut-off values rounded to the nearest multiple of five),
gender, American Society of Anesthesiologists (ASA)
grade,19 number of comorbid conditions according to the
Charlson score, indication for surgery (osteoarthritis or
other), whether regional anaesthesia (epidural or spinal
procedures) was used, type of prosthesis type (cemented
TKR, cementless TKR, hybrid TKR, and unicompartmental or patellofemoral knee replacements), use of mechanical
thromboprophylaxis, and provider type (NHS hospital,
NHS treatment centre, independent hospital, or independent treatment centre).
Use of regional anaesthesia was the only variable with
missing values. In order to address this we used multiple
imputation by chained equations.20 Five datasets were created containing imputed values for missing values. Rubin’s
rules21 were used to combine the estimation results based
on each of these datasets.
Results
Of the 156 798 patients who were eligible for inclusion, aspirin was used as thromboprophylaxis in 36 159 (23.1%) and
LMWH in 120 639 (76.9%). Patients in the aspirin group
were more likely than those in the LMWH group to receive
mechanical prophylaxis and undergo treatment in an NHS
hospital, but were less likely to have regional anaesthesia
(Table I). The two groups were otherwise very similar.
Without adjustment for potential risk factors, there was
a significantly greater risk of return to theatre within
30 days in the aspirin group (OR 0.71 (95% CI 0.56 to
0.91)), although the absolute rate was low (aspirin 0.26%
vs LMWH 0.19%). We found no statistically significant
differences in the rate of thromboembolic events, 90-day
mortality or major haemorrhage between the two groups
(Table II). The rate of PE was 0.49% with aspirin and
0.45% with LMWH (unadjusted OR 0.91). The 90-day
mortality was 0.39% with aspirin and 0.45% with LMWH
(unadjusted OR 1.16). The differences in the other outcomes were small, and all unadjusted ORs varied around 1.
After risk adjustment, return to theatre within 30 days
remained significantly higher in the aspirin group (adjusted
OR 0.73; p = 0.01). The impact of the risk adjustment on
the differences in the other outcomes was small, and the
groups had similar outcomes in terms of PE, DVT, 90-day
mortality and major haemorrhage (Table II).
Discussion
In this large national cohort of patients undergoing knee
replacement no significant differences were observed in the
rates of VTE, 90-day mortality and major (cerebrovascular
and gastrointestinal) haemorrhage when aspirin was compared with LMWH for prophylaxis. Within the constraints
of the study design, we found that a significantly greater
number of patients in the aspirin group returned to theatre
for the management of wound complications within 30
days of the operation.
916
S. S. JAMESON, P. N. BAKER, S. C. CHARMAN, D. J. DEEHAN, M. R. REED, P. J. GREGG, J. H. VAN DER MEULEN
Table I. Characteristics of the patients and their treatment according to pharmacological prophylaxis with aspirin or low-molecular-weight heparin
(LMWH)
Aspirin (n = 36 159) LMWH (n = 120 639)
Gender (n, %)
Male
Female
Age group (n, %)
< 65 years
65 to 74 years
≥ 75 years
ASA* grade (n, %)
1
2
≥3
Charlson score (n, %)
0
1
2
3
Indication (n, %)
Osteoarthritis
Other
Type of replacement (n, %)
Cemented TKR
Cementless TKR
Hybrid TKR
Unicondylar
Patellofemoral
Regional anaesthesia† (n, %)
Yes
No
Missing data
Mechanical prophylaxis (n, %)
Yes
No
Provider type (n, %)
NHS hospital
NHS treatment centre
Independent hospital
Independent treatment centre
15 310 (42.3)
20 849 (57.7)
51 278 (42.5)
69 361 (57.5)
11 065 (30.6)
13 667 (37.8)
11 427 (31.6)
35 484 (29.4)
45 922 (38.1)
39 233 (32.5)
5465 (15.1)
25 387 (70.2)
5307 (14.7)
15 893 (13.2)
84 843 (70.3)
19 903 (16.5)
25 847 (71.5)
8569 (23.7)
1512 (4.2)
231 (0.6)
86 670 (71.8)
27 934 (23.2)
5252 (4.4)
783 (0.7)
34 874 (96.5)
1285 (3.5)
116 967 (97.0)
3672 (3.0)
29 480 (81.5)
2859 (7.9)
300 (0.8)
3004 (8.3)
516 (1.4)
102 544 (85.0)
8085 (6.7)
1427 (1.2)
7471 (6.2)
1112 (0.9)
19 090 (52.8)
15 670 (43.3)
1399 (3.9)
74 320 (61.6)
39 045 (32.4)
7274 (6.0)
30 189 (83.5)
5970 (16.5)
95 945 (79.5)
24 694 (20.5)
32 117 (88.8)
1282 (3.6)
2675 (7.4)
85 (0.2)
96 312 (79.8)
10 033 (8.3)
7038 (5.8)
7256 (6.0)
* ASA, American Society of Anesthesiologists
† spinal or epidural
The multivariable model included all available risk factors
that were thought to be associated with the outcome, including adjusting risk for the presence or absence of mechanical
prophylaxis. However, a number of unmeasured variables,
known to influence VTE risk, could confound this analysis:
obesity, cancer, previous VTE, family history, admission to
intensive care, smoking, dehydration, thrombophilia, contraceptive use, and post-operative immobility.1 If these
higher-risk patients were more likely to have LMWH our
results might underestimate the effect of LMWH. Unmeasured risk factors for bleeding may also influence the choice of
prophylaxis. In addition, the NJR collects thromboprophylaxis data immediately post-operatively on an ‘intention to
treat’ basis. The agent given is not recorded, nor the dose, the
duration of treatment or compliance. Data were unavailable
on patients’ use of gastro-protective drugs.
Patients who had a NJR record of knee replacement but
lacked a matching record in the HES were excluded,
thereby reducing the population studied. Furthermore,
there are limitations in the ICD-10 and OPCS-4 coding systems,22 and coding errors may underestimate event rates (as
missing an event is more likely than incorrectly identifying
one). Coding inaccuracies are especially relevant for DVT
and wound infection, both of which are difficult to diagnose within the current limitations of HES.23 We therefore
used ‘return to theatre’ codes as a surrogate for wound
complications, including infection. However, rates of minor
wound problems that did not require operative intervention, such as prolonged oozing, could not be quantified
using the data available. Results from administrative data
analyses must therefore be interpreted carefully. Regardless
of these coding limitations, mortality as an outcome is well
defined and therefore robust.
Although asymptomatic DVT may occur in most
patients after knee replacement, it is estimated that only
around 1 in 21 of these will result in symptomatic VTE.2
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THE EFFECT OF ASPIRIN AND LOW-MOLECULAR-WEIGHT HEPARIN ON VENOUS THROMBOEMBOLISM AFTER KNEE REPLACEMENT
917
Table II. Effect of aspirin and low-molecular-weight heparin (LMWH) on outcomes, with adjustment based on the multivariable risk model. An
odds ratio (OR) < 1 indicates that rates are lower with LMWH than with aspirin (CI, confidence interval)
Treatment group (n, %)
Outcome
Aspirin (n = 36 159)
LMWH(n = 120 639)
Unadjusted OR (95% CI)
Adjusted OR (95% CI)
p-value
Pulmonary embolus
Deep-vein thrombosis
Death
Cerebrovascular accident/
gastrointestinal haemorrhage
Return to theatre
178 (0.49)
239 (0.66)
140 (0.39)
134 (0.37)
539 (0.45)
762 (0.63)
540 (0.45)
465 (0.39)
0.91 (0.77 to 1.08)
0.96 (0.83 to 1.11)
1.16 (0.96 to 1.39)
1.04 (0.86 to 1.26)
0.88 (0.74 to 1.05)
0.93 (0.81 to 1.08)
1.13 (0.94 to 1.37)
1.01 (0.83 to 1.22)
0.16
0.37
0.19
0.94
94 (0.26)
224 (0.19)
0.71 (0.56 to 0.91)
0.73 (0.58 to 0.94)
0.01
Reported rates of symptomatic VTE within 90 days of knee
replacement are < 2%.2,3 We found lower risks of DVT and
PE, which may be explained by improvements in peri-operative care during the last decade. However, under-reporting
may have played a role, as many DVTs are diagnosed in the
outpatient clinic or in the community.
There is currently limited evidence on the effects of
thromboprophylaxis on the rates of PE following knee
replacement,10 and there is no significant evidence relating
to fatal PE and death.1 Moreover, no chemical thromboprophylaxis agent has been shown to be superior to others
in terms of either efficacy or safety.11 Guidelines are therefore based on evidence extrapolated from complex network analyses that provide indirect comparisons of
symptomatic DVT rates that are difficult to interpret, and
rely on the assumption that a reduction in DVT reduces
the risk of fatal PE. In an independent systematic review of
the same trials used by the ACCP to formulate their guidelines, Brown,24 in contrast to the ACCP, concluded that
aspirin was superior to LMWH. He found that the use of
potent anticoagulants significantly increased the risk of
post-operative bleeding without reducing clinically relevant symptomatic VTE and fatal PE rates compared to
aspirin. Many of the studies analysed are historical and
pre-date modern peri-operative care pathways. Admission
on the day of surgery, early mobilisation and reduction in
length of stay are all likely to contribute to a reduction in
the risk of VTE.10 The outcomes in these older VTE studies may not be representative of the current situation.
Owing to the decreased baseline risks, the balance
between harm and benefit of prophylaxis regimens will
have changed. In addition, PE is not the leading cause of
death after joint replacement, as was previously thought.
In Scottish patients who underwent knee replacement
between 1992 and 2001, acute myocardial infarction
accounted for 36% of deaths compared to 18% for PE,3
and when cause of death following almost 100 000 joint
replacements was analysed, cardiopulmonary disease
(excluding PE) accounted for 48%, compared with 25%
for PE, irrespective of thromboprophylaxis agent used.11
We have previously reported findings from a similar
comparison study of aspirin and LMWH in hip replacement patients.13 Although a very small survival benefit
VOL. 94-B, No. 7, JULY 2012
was seen in the LMWH group, no differences in VTE events
and major haemorrhage were found. There are only a few
direct comparisons of the effects of aspirin and LMWH.
Westrich et al9 reported a non-significant difference in DVT
rates in their randomised comparison of aspirin (DVT rate
17.8%) and LMWH (14.1%) when used in conjunction
with mechanical prophylaxis. More recently Bozic et al10
retrospectively compared rates of VTE, bleeding, infection
and mortality in 93 840 patients undergoing knee replacement using one of three pharmacological agents (aspirin
n = 4719; LMWH/fondaparinux n = 37 198; warfarin
n = 51 923). Once adjusted for case mix there were no significant differences for any outcomes between the aspirin
and LMWH/fondaparinux groups. In NICE’s network
analysis of the risk reduction (RR) for DVT, the indirect
comparison showed that aspirin and LMWH were equivalent when used in conjunction with mechanical devices
(aspirin RR = 0.15, LMWH RR = 0.14). Although aspirin
had the lowest bleeding risk of all prophylactic agents (aspirin: RR = 0.44 (95% CI 0.17 to 1.04); LMWH: RR = 1.23
(95% CI 0.91 to 1.68); fondaparinux: RR = 2.21 (95% CI
1.27 to 3.94)), the difference between aspirin and LMWH
was non-significant owing to the limited evidence on which
the calculations were based.1
In this large cohort study of over 150 000 knee replacements, patients receiving aspirin or LMWH had similar
risks of pulmonary embolus, 90-day mortality and major
haemorrhage. Despite a shift away from the use of aspirin
as thromboembolic prophylaxis over the last ten years, it
remains a viable alternative to LMWH for the prevention
of VTE and mortality after knee replacement. Despite the
limitations, this study provides further evidence for those
engaged in the review of thromboprophylaxis guidelines
for patients undergoing knee replacement.
Supplementary material
Two tables detailing i) the International Statistical
Classification of Diseases and Related Health Problems (10th revision) (ICD-10) and Office of Population,
Censuses and Surveys Classification of Surgical Operations
and Procedures (4th revision) (OPCS-4) codes and ii) the
Charlson score are available with the electronic version of
this article on our website www.bjj.boneandjoint.org.uk
918
S. S. JAMESON, P. N. BAKER, S. C. CHARMAN, D. J. DEEHAN, M. R. REED, P. J. GREGG, J. H. VAN DER MEULEN
The authors would like to thank the patients and staff of all the hospitals in England and Wales who have contributed data to the National Joint Registry. We
are grateful to the Healthcare Quality Improvement Partnership (HQIP), the NJR
steering committee and the staff at the NJR centre for facilitating this work.
The National Joint Registry for England and Wales is funded through a levy
raised on the sale of hip and knee replacement implants. The cost of the levy is
set by the NJR Steering Committee. The NJR Steering Committee is responsible for data collection. This work was funded by a fellowship from the National
Joint Registry. The authors have conformed to the NJR’s standard protocol for
data access and publication. The views expressed represent those of the
authors and do not necessarily reflect those of the National Joint Register
Steering committee or the Health Quality Improvement Partnership (HQIP) who
do not vouch for how the information is presented.
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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