Article

Prevention of VTE in Orthopedic Surgery Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Department of Medicine, School of Medicine, Case Western Reserve University, Case and VA Medical Center, 10701 East Blvd, Cleveland, OH 44106, USA.
Chest (Impact Factor: 7.48). 02/2012; 141(2 Suppl):e278S-325S. DOI: 10.1378/chest.11-2404
Source: PubMed

ABSTRACT

VTE is a serious, but decreasing complication following major orthopedic surgery. This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and DVT.
The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
In patients undergoing major orthopedic surgery, we recommend the use of one of the following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux; dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a minimum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharmacologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recommend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava filter placement for primary prevention in patients with contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex) ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B). For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophylaxis (Grade 2B).
Optimal strategies for thromboprophylaxis after major orthopedic surgery include pharmacologic and mechanical approaches.

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e278S
CHEST
Supplement
Prevention of VTE in Orthopedic Surgery Patients
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
Background: VTE is a serious, but decreasing complication following major orthopedic surgery.
This guideline focuses on optimal prophylaxis to reduce postoperative pulmonary embolism and
DVT.
Methods: The methods of this guideline follow those described in Methodology for the Develop-
ment of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines in this supplement.
Results: In patients undergoing major orthopedic surgery, we recommend the use of one of the
following rather than no antithrombotic prophylaxis: low-molecular-weight heparin; fondaparinux;
dabigatran, apixaban, rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip
fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin
(all Grade 1B); or an intermittent pneumatic compression device (IPCD) (Grade 1C) for a min-
imum of 10 to 14 days. We suggest the use of low-molecular-weight heparin in preference to the other
agents we have recommended as alternatives (Grade 2C/2B), and in patients receiving pharma-
cologic prophylaxis, we suggest adding an IPCD during the hospital stay (Grade 2C). We suggest
extending thromboprophylaxis for up to 35 days (Grade 2B). In patients at increased bleeding risk, we
suggest an IPCD or no prophylaxis (Grade 2C). In patients who decline injections, we recom-
mend using apixaban or dabigatran (all Grade 1B). We suggest against using inferior vena cava
lter placement for primary prevention in patients with contraindications to both pharmacologic
and mechanical thromboprophylaxis (Grade 2C). We recommend against Doppler (or duplex)
ultrasonography screening before hospital discharge (Grade 1B). For patients with isolated lower-
extremity injuries requiring leg immobilization, we suggest no thromboprophylaxis (Grade 2B).
For patients undergoing knee arthroscopy without a history of VTE, we suggest no thromboprophy-
laxis (Grade 2B).
Conclusions: Optimal strategies for thromboprophylaxis after major orthopedic surgery include
pharmacologic and mechanical approaches. CHEST 2012; 141(2)(Suppl):e278S–e325S
Abbreviations: DUS 5 Doppler (or duplex) ultrasonography; GCS 5 graduated compression stockings; HFS 5 hip
fracture surgery; INR 5 international normalized ratio; IPCD 5 intermittent pneumatic compression device; IVC 5 infe-
rior vena cava; LDUH 5 low-dose unfractionated heparin; LMWH 5 low-molecular-weight heparin; PE 5 pulmonary
embolism; PEP 5 Pulmonary Embolism Prevention trial; RCT 5 randomized controlled trial; RR 5 risk ratio; THA 5 total hip
arthroplasty; TKA 5 total knee arthroplasty; UFH 5 unfractionated heparin; VFP 5 venous foot pump; VKA 5 vitamin
K antagonist
Prevention of VTE in Orthopedic
Surgery Patients
Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines
Yngve Falck-Ytter , MD ; Charles W. Francis , MD ; Norman A. Johanson , MD ;
Catherine Curley , MD ; Ola E. Dahl , MD ; Sam Schulman , MD, PhD ;
Thomas L. Ortel , MD, PhD ; Stephen G. Pauker , MD ; and Clifford W. Colwell Jr , MD
Page 1
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CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e
279S
reporting proper wear time on a daily basis for inpa-
tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. One panel member
believed strongly that aspirin alone should not be
included as an option.
2.1.2. In patients undergoing hip fracture sur-
gery (HFS), we recommend use of one of the
following rather than no antithrombotic prophy-
laxis for a minimum of 10 to 14 days: LMWH,
fondaparinux, LDUH, adjusted-dose VKA, aspi-
rin (all Grade 1B) , or an IPCD (Grade 1C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpa-
tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. One panel member
believed strongly that aspirin alone should not be
included as an option.
2.2. For patients undergoing major orthopedic
surgery (THA, TKA, HFS) and receiving LMWH
as thromboprophylaxis, we recommend starting
either 12 h or more preoperatively or 12 h or
more postoperatively rather than within 4 h or
less preoperatively or 4 h or less postoperatively
(Grade 1B) .
2.3.1. In patients undergoing THA or TKA, irre-
spective of the concomitant use of an IPCD
or length of treatment, we suggest the use of
LMWH in preference to the other agents we have
recommended as alternatives: fondaparinux,
apixaban, dabigatran, rivaroxaban, LDUH (all
Grade 2B) , adjusted-dose VKA, or aspirin (all
Grade 2C) .
Remarks: If started preoperatively, we suggest adminis-
tering LMWH 12 h before surgery. Patients who
place a high value on avoiding the inconvenience of
daily injections with LMWH and a low value on the
limitations of alternative agents are likely to choose
an alternative agent. Limitations of alternative agents
include the possibility of increased bleeding (which
may occur with fondaparinux, rivaroxaban, and VKA),
possible decreased effi cacy (LDUH, VKA, aspirin, and
IPCD alone), and lack of long-term safety data (apixa-
ban, dabigatran, and rivaroxaban). Furthermore, patients
who place a high value on avoiding bleeding compli-
cations and a low value on its inconvenience are likely
to choose an IPCD over the drug options.
2.3.2. In patients undergoing HFS, irrespective
of the concomitant use of an IPCD or length
of treatment, we suggest the use of LMWH in
preference to the other agents we have recom-
mended as alternatives: fondaparinux, LDUH
Revision accepted August 31, 2011.
Affi liations: From the Department of Medicine (Dr Falck-Ytter),
School of Medicine, Case Western Reserve University, Cleveland,
OH; Hematology/Oncology Unit (Dr Francis), University of Roches-
ter Medical Center, Rochester, NY; Department of Orthopaedic
Surgery (Dr Johanson), Drexel University College of Medicine,
Philadelphia, PA; Division of Hospital Medicine (Dr Curley),
MetroHealth Medical Center, Case Western Reserve University,
Cleveland, OH; Innlandet Hospitals (Dr Dahl), Brumunddal,
Norway; Thrombosis Research Institute (Dr Dahl), Chelsea,
London, England; Department of Medicine (Dr Schulman), Divi-
sion of Hematology and Thromboembolism, McMaster University,
Hamilton, ON, Canada; Hemostasis and Thrombosis Center
(Dr Ortel), Duke University Health System, Durham, NC; Tufts
Medical Center (Dr Pauker), Boston, MA; and Shiley Center for
Orthopaedic Research and Education at Scripps Clinic (Dr Colwell),
La Jolla, CA.
Funding/Support : The Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines received support from
the National Heart, Lung, and Blood Institute [R13 HL104758]
and Bayer Schering Pharma AG. Support in the form of educa-
tional grants was also provided by Bristol-Myers Squibb; Pfi zer,
Inc; Canyon Pharmaceuticals; and sanofi -aventis US.
Disclaimer: American College of Chest Physician guidelines
are intended for general information only, are not medical advice,
and do not replace professional medical care and physician advice,
which always should be sought for any medical condition. The
complete disclaimer for this guideline can be accessed at http://
chestjournal.chestpubs.org/content/141/2_suppl/1S.
Correspondence to: Yngve Falck-Ytter, MD, Department of
Medicine, School of Medicine, Case Western Reserve University,
Case and VA Medical Center, 10701 East Blvd, Cleveland, OH
44106; e-mail: Yngve.Falck-Ytter@case.edu
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians ( http://www.chestpubs.org/
site/misc/reprints.xhtml ).
DOI: 10.1378/chest.11-2404
Summary of Recommendations
Note on Shaded Text: Throughout this guideline,
shading is used within the summary of recommenda-
tions sections to indicate recommendations that are
newly added or have been changed since the pub-
lication of Antithrombotic and Thrombolytic Therapy:
American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines (8th Edition). Rec-
ommendations that remain unchanged are not shaded.
2.1.1. In patients undergoing total hip arthro-
plasty (THA) or total knee arthroplasty (TKA),
we recommend use of one of the following for a
minimum of 10 to 14 days rather than no anti-
thrombotic prophylaxis: low-molecular-weight
heparin (LMWH), fondaparinux, apixaban, dab-
igatran, rivaroxaban, low-dose unfractionated
heparin (LDUH), adjusted-dose vitamin K antag-
onist (VKA), aspirin (all Grade 1B) , or an inter-
mittent pneumatic compression device (IPCD)
(Grade 1C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
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Prevention of VTE in Orthopedic Surgery Patients
2.7. In patients undergoing major orthopedic
surgery and who decline or are uncooperative with
injections or an IPCD, we recommend using
apixaban or dabigatran (alternatively rivaroxa-
ban or adjusted-dose VKA if apixaban or dabig-
atran are unavailable) rather than alternative
forms of prophylaxis (all Grade 1B) .
2.8. In patients undergoing major orthopedic
surgery, we suggest against using inferior vena
cava (IVC) fi lter placement for primary pre-
vention over no thromboprophylaxis in patients
with an increased bleeding risk or contraindi-
cations to both pharmacologic and mechanical
thromboprophylaxis (Grade 2C) .
2.9. For asymptomatic patients following major
orthopedic surgery, we recommend against Dopp-
ler (or duplex) ultrasound (DUS) screening before
hospital discharge (Grade 1B) .
3.0. We suggest no prophylaxis rather than phar-
macologic thromboprophylaxis in patients with
isolated lower-leg injuries requiring leg immo-
bilization (Grade 2C) .
4.0. For patients undergoing knee arthroscopy
without a history of prior VTE, we suggest no
thromboprophylaxis rather than prophylaxis
(Grade 2B) .
T
otal hip arthroplasty (THA) and total knee arthro-
plasty (TKA) are performed with increasing fre-
quency, with close to 200,000 procedures for THA
alone in the United States each year.
1
The risk for
VTE in major orthopedic surgery, in particular THA
and hip fracture surgery (HFS), is among the highest
for all surgical specialties, and deaths from VTE still
occur, albeit very infrequently. This article discusses
prophylaxis of VTE in patients undergoing ortho-
pedic surgery, including THA, TKA, and HFS; below-
knee injuries; and arthroscopic procedures. We have
included only the drugs that have been approved by
regulatory agencies in more than one country.
1.0 Methods
1.1 Outcomes of Interest
All recommendations are based on the use of prophylaxis to
reduce the patient-important outcomes of fatal and symptomatic
pulmonary embolism (PE) and symptomatic DVT balanced against
the hazard of an increase in symptomatic bleeding events. The
design and reporting of clinical trials creates challenges in applying
this approach. Studies have used varying defi nitions of important
bleeding, and it was sometimes diffi cult to extract data regarding
patient-important bleeding outcomes (those that led to trans-
fusion or an intervention, such as reoperation). Additionally, most
(Grade 2B) , adjusted-dose VKA, or aspirin (all
Grade 2C) .
Remarks: For patients in whom surgery is likely to be
delayed, we suggest that LMWH be initiated during
the time between hospital admission and surgery but
suggest administering LMWH at least 12 h before
surgery. Patients who place a high value on avoiding
the inconvenience of daily injections with LMWH
and a low value on the limitations of alter native agents
are likely to choose an alternative agent. Limita-
tions of alternative agents include the possibility of
increased bleeding (which may occur with fonda-
parinux) or possible decreased effi cacy (LDUH, VKA,
aspirin, and IPCD alone). Furthermore, patients who
place a high value on avoiding bleeding complica-
tions and a low value on its inconvenience are likely
to choose an IPCD over the drug options.
2.4. For patients undergoing major orthopedic
surgery, we suggest extending thromboprophy-
laxis in the outpatient period for up to 35 days
from the day of surgery rather than for only
10 to 14 days (Grade 2B) .
2.5. In patients undergoing major orthopedic
surgery, we suggest using dual prophylaxis with
an antithrombotic agent and an IPCD during
the hospital stay (Grade 2C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpa-
tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. Patients who place
a high value on avoiding the undesirable consequences
associated with prophylaxis with both a pharmaco-
logic agent and an IPCD are likely to decline use of
dual prophylaxis.
2.6. In patients undergoing major orthopedic
surgery and increased risk of bleeding, we sug-
gest using an IPCD or no prophylaxis rather
than pharmacologic treatment (Grade 2C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpa-
tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. Patients who place
a high value on avoiding the discomfort and inconve-
nience of IPCD and a low value on avoiding a small
absolute increase in bleeding with pharmacologic agents
when only one bleeding risk factor is present (in par-
ticular the continued use of antiplatelet agents) are
likely to choose pharmacologic thromboprophylaxis
over IPCD.
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Table 1—[Introduction] Structured Clinical Questions
PICO Question
Section Informal Question Population Interventions Comparator Outcome Methodology
Major orthopedic
surgery (THA,
TKA, HFS)
Whether to use VTE
prophylaxis (drugs)
Patients undergoing
THA, TKA, HFS
Any drug (LMWH,
LDUH, fondaparinux,
VKA, ASA, dabigatran,
rivaroxaban, apixaban)
No anticoagulation Asymptomatic DVT,
symptomatic DVT, nonfatal PE,
fatal PE, bleeding, reoperation,
readmission, total mortality
RCT
Whether to use VTE
prophylaxis (mechanical)
Same Any mechanical device No device Same RCT
Choice of thromboprophylaxis
drugs
Same Any drug Any drug Same RCT
Choice of mechanical devices
vs medications
Same Mechanical devices Any drug Same RCT
Choice of combining different
medication or mechanical
methods with drugs
Same Combination of multiple
agents or devices
Single intervention or
combinations
Same RCT
Timing of starting
thromboprophylaxis
Same 10-12 h preoperatively 2-4 h preoperatively; or
different time points
postoperatively
Same RCT
Choice of duration Same
30 d
7-14 d Same RCT
Role of predischarge
ultrasound DVT screening
Same Predischarge ultrasound
DVT screening (plus
treatment if positive)
No screening Same RCT
Whether IVC fi lter should be
used in defi ned populations
Same IVC fi lter for primary
prevention
No fi lter, any other mechanical
thromboprophylaxis
Same (plus any IVC fi lter
related effects)
RCT, observa tional
studies
Knee arthroscopy,
isolated distal to
the knee injuries
Whether to use VTE
prophylaxis (drugs)
Patients undergoing
arthroscopic procedures,
patients with isolated
distal-to-knee injuries
Any drug No anticoagulation Asymptomatic DVT,
symptomatic DVT,
nonfatal PE, fatal PE,
bleeding, reoperation,
readmission, total mortality
RCT
Whether to use VTE
prophylaxis (mechanical)
Same Any mechanical device No device Same RCT
Choice of thromboprophylaxis
drugs
Same Any drug Any drug Same RCT
Choice of mechanical
devices vs medications
Same Mechanical devices Any drug Same RCT?
ASA 5 aspirin; HFS 5 hip fracture surgery; IVC 5 inferior vena cava; LDUH 5 low-dose unfractionated heparin; LMWH 5 low-molecular-weight heparin; PE 5 pulmonary embolism; PICO 5 population,
intervention, comparator, outcome; RCT 5 randomized controlled trial; THA 5 total hip arthroplasty; TKA 5 total knee arthroplasty; VKA 5 vitamin K antagonist.
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Prevention of VTE in Orthopedic Surgery Patients
bleeding defi nition of the study but recorded any bleeds requiring
reoperation in a separate category to avoid double counting.
Because patients undergoing surgery have some blood loss
and surgeons may have a low threshold for transfusing blood when
autologous blood is used (with perioperative transfusion rates
of 40% not being unusual),
4
drop in hemoglobin level and trans-
fusion requirements are hard to interpret. The effect of such
transfusion practices on the signifi cance of the outcome of major
bleeding is unknown. However, major bleeding that followed the
above defi nition appears to have a clinical impact. A regression
analysis of major bleeding events involving . 13,000 patients
enrolled in fondaparinux trials demonstrated a hazard ratio of
death of close to 7 (8.6% vs 1.7%), demonstrating a strong rela-
tionship between major bleeding and poor outcome irrespective
of the study drug used.
5
Whether this fi nding can be generalized
to other populations and interventions is unknown.
The major advantage of our outlined approach is that the evi-
dence summaries allow for direct trade-off of undesirable events.
These trade-offs are fewer symptomatic PE and DVT with throm-
boprophylaxis vs increased major bleeding.
2
1.3 Deriving Baseline Risks
1.3.1 Baseline Risk for VTE: We made considerable effort to
determine the baseline risk of symptomatic VTE and bleeding in
the absence of prophylaxis. For this purpose, we analyzed all con-
trolled trials that had a placebo or no-treatment group extending
back to 1959.
6
This has obvious limitations because of important
changes in surgical care, including changes in operative tech-
nique, earlier ambulation, and earlier discharge that have had an
impact on rates of thrombosis and bleeding. For instance, although
the average length of stay after HFS in the 1960s was 35 days,
7
current averages of 3.2 days have been reported in a large cohort
after arthroplasties,
8
and early mobilization starts at 2 to 4 h after
surgery.
8
Randomized controlled trial (RCT) data typically showed
a symptomatic VTE event rate of 15% to 30% without prophylaxis
prior to 1980,
6,9-12
and observational data suggest a further drop
from around 5% to 1% to 2% in the years from 1989 to 2001.
13
In recent years, there have been no large placebo controlled
trials, and we did not identify any large, well-designed cohort stud-
ies to provide a baseline risk relevant to current practice. However,
there are several large RCTs that have used low-molecular-weight
heparin (LMWH), and we have estimated baseline risk by apply-
ing the observed risk of symptomatic VTE in patients treated with
LMWH and adjusting it by the relative risk reduction in symp-
tomatic VTE from prior randomized trials of LMWH compared
with placebo.
First, we estimated contemporary average on-prophylaxis
rates with LMWH for symptomatic DVT to be 0.8% and for PE
to be 0.35% by averaging the LMWH event rates from trials
enrolling . 16,000 patients since 2003.
4,14-26
We selected the year
2003 because of a shift in surgical technique since that time to
be less invasive and possibly less thrombogenic. Concerns that
those rates could be too low given the sometimes highly selected
nature of clinical trials, we compared this rate with older data
from a large observational study.
27
The investigators identifi ed
133 of 19,586 (0.7%) VTE events during the initial hospitalization
for patients receiving prophylaxis (estimated prophylaxis compli-
ance, 88%), suggesting that the symptomatic VTE rate of 1.15%
we used is not too low.
Second, if we assume the effect of LMWH is similar in asymp-
tomatic and symptomatic DVT, then the best evidence suggests
that LWMH reduces the risk for DVT by 50% to 60% and PE by
about two-thirds.
3
Using this estimate, the contemporary off-
prophylaxis rates are 1.8% for symptomatic DVT and 1% for PE
for the fi rst 7 to 14 days (the initial prophylaxis period most RCTs
used and that correspond to the nonextended prophylaxis period).
trials before 2000 used asymptomatic DVT detected by screening
tests as a primary end point. When symptomatic DVTs were not
reported, we used the relative risk estimate from asymptomatic
DVT. Pulmonary embolisms (PEs) were assumed to be symp-
tomatic unless the study described systematic screening for PE.
2
Table 1 summarizes the questions we addressed.
1.2 Evaluating and Summarizing Evidence
If available, we used existing systematic reviews as the basis of
evidence. If existing reviews were unavailable or not up to date or
the outcomes of interest were not reported, we performed addi-
tional analyses. For example, we relied on a recent, well-done sys-
tematic review
3
to inform relative effects of low-dose unfractionated
heparin (LDUH) vs no prophylaxis because studies were per-
formed in the 1970s and 1980s and critical appraisal of the search
strategy made it unlikely that studies would have been missed.
However, we performed an update of the same comprehensive
literature search for all interventions listed in Table 1 to include
the time frame from January 2008 to December 2010. Sources
included Medline, the Cochrane Library (including the Cochrane
database of controlled trials), meeting abstracts, conference
proceedings, and reference lists of studies that were manually
reviewed. No language restriction was applied.
For additional analyses, we pooled the data using a random-
effects model for three or more studies (fi xed-effects model for
two studies). When the analysis showed a similar relative effect
for THA, TKA, and HFS, we used this single best relative risk
estimate to inform absolute risk differences in VTE reduction
and bleeding risk increase. When effects differed, we used effects
specifi c to the surgery.
For our own analyses, we excluded studies that failed to con-
rm VTE with accurate methods, such as pulmonary angiogram,
CT scan, ventilation/perfusion scanning, venography, and com-
pression Doppler (or duplex) ultrasonography (DUS), and instead
used clinical signs and symptoms, plethysmography, or fi brinogen
uptake as the sole detection method. However, for well-done sys-
tematic reviews, we accepted the authors’ choice of study selec-
tion, even if a less-reliable detection method was used in some of
the studies.
Where possible, we removed doubly counted events from the
outcomes presented in the evidence summaries. For instance, if a
patient died of a PE, the event would only be counted in mortality
and would not appear again under PE. We report deaths from PE
together with all other mortal events, but a footnote presents a
description of those events as deaths from VTE, deaths from
unexplained causes (unable to rule out PE), fatal bleeding, and
death from other causes. Because studies often presented out-
comes as composites, the number of events in our analysis may
at times differ from the result highlighted in the publication.
Different categories of bleeding events have very different
impacts on patients. Trials, therefore, have separated bleeding
into categories, of which traditionally there have been two: major
bleeding and minor bleeding. More recent trials have introduced
another, intermediate category: clinically relevant nonmajor bleed-
ing. However, clinically relevant nonmajor bleeding remains
hard to defi ne, and we decided not to include this outcome in
our evidence summaries, instead exclusively focusing on major
bleeding.
Studies usually defi ned major bleeding events as any fatal bleed-
ing, bleeding into a critical organ (eg, retroperitoneal, intracra-
nial, intraocular, or intraspinal), clinically overt (eg, GI) bleeding
associated with a 2 g/dL drop in hemoglobin level or requir-
ing 2 units of blood transfused, and bleeding leading to reop-
eration. We separated fatal bleeding and bleeding requiring
reoperation from other major bleeding events because these out-
comes are the least ambiguous. We usually accepted the major
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CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e
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The median rate was 1.5%, but because of the low event rate
in the LMWH trials, variability in the defi nitions of major bleed-
ing across trials makes this estimate uncertain . This is, however,
consistent with a systematic review that estimated the absolute
untreated bleeding risk to be between 1% and 2%.
3
Second, we selected the major bleeding event rate for LMWH
from a recent review that examined the reporting defi nitions and
event rates from the enoxaparin control arm of recent trials.
40
We
chose a rate of 1.5%, which was slightly higher than the average
(1.4%) and higher than 12 of 14 trials that enrolled . 16,000 patients
since 2003 that we included in the estimate of baseline VTE risk
(median, 0.91%; maximum, 1.9%).
4,14-26
Recognizing the some-
times highly selective process of RCTs in enrolling patients with
low bleeding risk, we believe that a selected bleeding rate that
is somewhat higher than the median is therefore close to what
would be observed in clinical practice. The baseline major bleed-
ing rate of 1.5% (15 of 1,000) and that expected with LMWH
are shown in Table 3 and Table S1 and are very close. (Tables and
gures that contain an “S” before the number denote supplementary
information not contained in the body of the article and available
instead in an online data supplement; see the “Acknowledgments”
for more information.) Intuitively, a greater bleeding rate might
be expected with the use of LMWH, but this increased risk is
likely within the large CI.
1.4 VTE and Bleeding Risk Assessment
Individual risk factor assessment for VTE focuses on patient-
specifi c characteristics, incorporating surgery-specifi c risk in
addition to medical factors. Alternatively, group-specifi c recom-
mendations for thromboprophylaxis, such as major orthopedic
surgery, exist. Although individualized risk factor assessment carries
considerable appeal, it is limited by lack of validation in orthope-
dic surgery. In addition, although we can fi nd ORs for individual
risk factors for VTE, the interaction of these factors in a given
patient is not well understood. Such risk factors include (multivar-
iate ORs): previous VTE (OR, 3.4-26.9),
41-43
cardiovascular disease
(OR, 1.4-5.1),
41,42
Charlson comorbidity index 3 (OR, 1.45-2.6),
41,44
BMI . 25 kg/m
2
(OR, 1.8),
43
age (OR, 1.1 for each 5-year increment
The untreated baseline risk for the extended, out-of-hospital
period, defi ned as the time period starting at around postopera-
tive day 15 and extending up to 35 days, is likely to be somewhat
lower because the VTE risk is highest close to surgery and the
median time of diagnosis for thromboembolic events is 7 days
after TKA and 17 days after THA.
27
We found only one trial that
enrolled patients after 2003 that examined extended, out-of-
hospital prophylaxis using a placebo group control to estimate the
baseline risk for this time period.
4
Extracting events from the time-
to-event graph and from the text, 11 of 1,207 (0.91%) symptomatic
VTE events were observed up to postoperative day 39, starting
from the time enoxaparin was stopped at an average of 12 days
postoperation. A trial that enrolled patients slightly before our
cutoff years (2001 and 2002) found a higher rate in the placebo
arm (symptomatic VTE, 8/330 [2.4%]).
28
In summary, we have estimated a symptomatic VTE rate that is
about one-half the rate observed in the immediate postoperative
period (1.5%; symptomatic DVT, 1%; PE, 0.5%). For this guide-
line, we therefore estimated a combined 35-day untreated base-
line risk for symptomatic VTE of 4.3%.
Although epidemiologic data from the early 1990s suggest that
the cumulative 90-day symptomatic VTE risk for THA is higher
than that for TKA (2.8% vs 2.1%, respectively),
27
randomized trials
fail to confi rm this fi nding. Follow-up epidemiologic data from
the mid-1990s also demonstrated that cumulative 90-day symp-
tomatic VTE rates after HFS did not exceed those reported for
arthroplasty (HFS, 1.9%; THA, 2.4%; TKA, 1.7).
29
We therefore
concluded that a 4.3% combined symptomatic VTE untreated
baseline risk for the fi rst 35 days is the best approximation for all
three major orthopedic surgeries. Table 2 and Figure 1 present a
sum mary of the estimated symptomatic VTE rates for this guideline.
Because VTE-related deaths were rarely observed in trials
since 2003, the data were insuffi cient to estimate current baseline
risk. In addition, competing risks, such as cardiovascular and
infectious causes of death, often outnumber the risk of death
from VTE, particularly in HFS. When pooling study data, total
mortality—because this outcome includes fatal bleeding—was
selected to better represent the overall balance of fatal events.
The majority of mortal events were seen in HFS populations that
are elderly and experience considerable comorbidity.
1.3.2 Baseline Risk for Major Bleeding Events: The risk for
major bleeding with LMWH, and in particular without treatment,
remains diffi cult to estimate because better operative techniques
make deriving the untreated bleeding event rate from the placebo
group of past RCTs in major orthopedic surgery problematic. To
estimate untreated bleeding risk, we fi rst determined the median
major bleeding event rate from the placebo (or graduated com-
pression stockings [GCS]) arm of LMWH trials and the Pul-
monary Embolism Prevention (PEP) trial (subgroup that did not
receive any heparin) because those trials were more recent.
30-39
Table 2—[Section 1.3.1] Estimated Nonfatal, Symptomatic
VTE Rates After Major Orthopedic Surgery
Initial
Prophylaxis,
Postoperative
Days 0-14
Extended
Prophylaxis,
Postoperative
Days 15-35
Cumulative,
Postoperative
Days 0-35
No pro phylaxis VTE 2.80%
(PE 1.00%,
DVT 1.80%)
VTE 1.50%
(PE 0.50%,
DVT 1.00%)
VTE 4.3%
(PE 1.50%,
DVT 2.80%)
LMWH VTE 1.15%
(PE 0.35%,
DVT 0.80%)
VTE 0.65%
(PE 0.20%,
DVT 0.45%)
VTE 1.8%
(PE 0.55%,
DVT 1.25%)
See Table 1 legend for expansion of abbreviations.
Figure 1. [Section 1.3.1] Schematic of estimated incidence rates
for LMWH and no prophylaxis for major orthopedic surgery used
for this guideline. Additional example data are from observational
studies (dashed line), which usually represents a cumulative inci-
dence rate resulting from high rates of prophylaxis in the fi rst 7 to
14 days and low rates or no prophylaxis during the extended pro-
phylaxis period. LMWH 5 low-molecular-weight heparin.
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Prevention of VTE in Orthopedic Surgery Patients
Table 3—[Section 2.1.1] Summary of Findings: LMWH vs No LMWH (With or Without GCS in Both Groups) for Major Orthopedic Surgery (Initial Prophylaxis
Period Up to 14 Days)
31-39,47-50
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No LMWH GCS
Risk Difference With
LMWH GCS (95% CI)
Nonfatal PE 2,025 (11 studies) High RR 0.58 (0.22-1.47) Study population
11 per 1,000
Contemporary population (initial prophylaxis)
a
10 per 1,000 4 fewer per 1,000
(from 8 fewer to 5 more)
Symptomatic DVT (as inferred from
asymptomatic DVT)
2,250 (14 studies) Moderate
b
due
to indirectness
RR 0.5 (0.43-0.59) Study population
463 per 1,000
Contemporary population (initial prophylaxis)
a
18 per 1,000 9 fewer per 1,000
(from 7 fewer to 10 fewer)
Bleeding requiring reoperation 0 (0)
Major nonfatal bleeding 1,977 (11 studies) Moderate
c
due
to imprecision
RR 0.81 (0.38-1.72) 15 per 1,000 3 fewer per 1,000
(from 9 fewer to 11 more)
Total mortality
d
971 (6 studies) Moderate
c
due
to imprecision
RR 0.9 (0.3-2.67) 14 per 1,000 1 fewer per 1,000
(from 10 fewer to 24 more)
GCS 5 graduated compression stockings; GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; RR 5 risk ratio. See Table 1 legend for expansion of other abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
Inferred from asymptomatic DVT.
c
CI includes benefi ts as well as harms.
d
Deaths placebo GCS: two from VTE, none from bleeding, one from unexplained causes, and four from other causes. Deaths LMWH: one from VTE, none from bleeding, none from unexplained causes,
and four from other causes.
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Table 4—[Sections 1.4, 2.6, 2.8] General Risk Factors
for Bleeding
• Previous major bleeding (and previous bleeding risk similar to
current risk)
• Severe renal failure
• Concomitant antiplatelet agent
• Surgical factors: history of or diffi cult-to-control surgical bleeding
during the current operative procedure, extensive surgical
dissection, and revision surgery
plasty
31-39,47,48
and HFS.
49,50
Our analysis included all
studies of LMWH vs no prophylaxis whether GCS
were used in both groups because this would not
affect the relative risk observed for LMWH. This
allowed us to make more-precise estimates for risk
reduction of VTE and bleeding. We decided against
pooling across other patient groups, such as nonor-
thopedic surgery patients, because of differences in
risk and technique. In those trials, LMWH usually
was continued for 6 to 14 days, which coincided with
discharge from the hospital at the time those trials
were conducted.
For THA or TKA, LMWH consistently reduces asymp-
tomatic DVT by 50% (combined risk ratio [RR],
0.50; 95% CI, 0.43-0.59). Similar results were seen in
two studies in HFS involving 218 patients.
49,50
Com-
bining results from all relevant studies failed to dem-
onstrate or to exclude a benefi cial effect of LMWH
on PE (RR, 0.58; 95% CI, 0.22-1.47). On the basis of
moderate-quality evidence, the use of LMWH for the
initial prophylaxis period (10-14 days) is expected to
prevent 13 VTE per 1,000 patients undergoing major
orthopedic surgery, assuming a baseline risk of 1% for
PE and 1.8% for symptomatic DVT.
The defi nition and reporting of major bleeding was
inconsistent across studies, and the results failed to
demonstrate or to exclude a detrimental effect of
LMWH on the occurrence of major bleeding (RR,
0.81; 95% CI, 0.38-1.72); the 95% CI was nine fewer
to 11 more major bleeding events per 1,000. Few deaths
occurred, and these were mainly seen in HFS patients;
two VTE-associated deaths were seen in the placebo
groups compared with one in the LMWH arm ( Table 3 ,
Figs S1-S4, Table S1).
Extended Prophylaxis With LMWH Observational
data suggest that the incidence of VTE after TKA and
THA returns to the presurgical risk levels at about
3 months postoperation.
13,27
Extending thrombopro-
phylaxis beyond 10 to 14 days, which coincided with
the duration of hospital stay in older trials, is now
used often, and recent trials have included prophy-
laxis for . 30 days, particularly after THA.
Three systematic reviews
51-53
have examined the
effect of extended-use LMWH vs placebo from seven
trials enrolling . 2,600 patients mainly after THA
54-60
;
one trial also included TKA patients.
55
Most trials
randomized patients at discharge (which occurred
6-14 days postoperation) to continue with LMWH
vs placebo until postoperative days 27 to 35. Because
most studies screened patients at discharge and only
enrolled patients without asymptomatic DVT, some
authors have argued that the absolute event rate
may be inaccurate.
51
However, as discussed in the
Methods section, the relative VTE risks should not
be affected. Additionally, we are providing baseline
risks based on contemporary practice.
vs age , 40 years),
29
advanced age 85 years (OR, 2.1),
43
vari-
cose veins (OR, 3.6),
42
and ambulation before day 2 after surgery
(OR, 0.7).
42
However, for major orthopedic surgery, the surgery-specifi c
risk far outweighs the contribution of the patient-specifi c factors.
For instance, a population-based case-control study looked at
635 patients with fi rst-time VTE during a period from 1976 to
1990 compared with controls.
45
The factor hospitalized with recent
surgery resulted in an OR of 22 (95% CI, 9-50). In our view, indi-
vidual risk estimation is not suffi ciently secure to mandate different
recommendations for different risk strata.
Similarly, we did not fi nd any bleeding risk assessments that
have been suffi ciently validated in the orthopedic surgery pop-
ulation. Table 4 lists general risk factors for bleeding in the setting
of orthopedic surgery, but specifi c thresholds for using mechan-
ical compression devices or no prophylaxis instead of anticoagu-
lant thromboprophylaxis have not been established.
1.5 Values and Preferences
Both symptomatic VTE and bleeding are important, unwanted
outcomes from the perspective of a patient. There is little infor-
mation available on the opinion of patients regarding the relative
disutility of these two outcomes. This is, however, a very impor-
tant consideration because many of the approaches to reducing
postoperative VTE use anticoagulants, and these all increase the
risk of bleeding. Therefore, it is critical to judge the relative bal-
ance of disutility between an episode of symptomatic VTE and
of bleeding. To do this, we used available literature and the results
of a rating exercise of physicians involved in developing the
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines recommendations.
46
On balance, it was
believed that the adverse consequences of a major postoperative
bleeding event were approximately equal to those of symptomatic
VTE. In developing recommendations, we therefore considered
these as equivalent in their aversiveness or disutility.
2.0 Patients Undergoing Major
Orthopedic Surgery: THA, TKA, HFS
2.1 Thromboprophylaxis Compared
With No Prophylaxis
2.1.1 LMWH vs No Prophylaxis—Initial and
Extended-Period Prophylaxis: LMWH has become
the thromboprophylaxis agent against which newer
drugs are compared. Several studies published in the
mid-1980s, during the 1990s, and as recently as 2008
have investigated LMWH compared with no prophy-
laxis in . 2,000 patients to test the hypothesis that
LMWH decreases the incidence of VTE after arthro-
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Prevention of VTE in Orthopedic Surgery Patients
with a trend toward increased bleeding (RR, 1.50;
95% CI, 0.92-2.43), which was described as wound
hematomas, wound bleeding, wound leakage, hema-
turia, and hematemesis. There was also more blood
transfused and one intracerebral hemorrhage in the
VKA group.
61
Results showed a trend toward a mor-
tality reduction (RR, 0.76; 95% CI, 0.54-1.07). Based on
moderate-quality evidence, VKA prophylaxis for 10 to
14 days would result in 18 fewer VTEs and seven more
major bleeding events per 1,000 ( Table 7 , Table S4).
2.1.4 Aspirin vs No Prophylaxis—Initial Plus
Extended Prophylaxis Period: Aspirin is inexpen-
sive, orally administered, and widely available. In the
1970s and 1980s, a number of studies investigated
the use of aspirin in THA,
10,62-65
TKA,
66
and HFS.
67-72
Those studies used high doses of aspirin of up to
3.8 g daily. They suffer from serious methodologic
limitations, including the use of an unreliable method
for DVT screening, such as fi brinogen uptake; lack
of blinding; and lack of allocation concealment. Addi-
tionally, there was strong evidence of reporting and
publication bias.
Because of this low quality of evidence, a subse-
quent trial, PEP, was initiated to study the effects of
160 mg of aspirin given for 35 days against placebo in
a routine practice setting that allowed for additional
antithrombotic intervention if deemed necessary.
30
This multicenter trial enrolled 17,444 patients pre-
dominantly after HFS in the mid-1990s and included
patients after hip arthroplasty. This study has been
criticized because of perceived changes in the pri-
mary outcome and adjustments of sample size. There
were additional problems with the presentation of
the results that made evaluation of the bleeding end
point diffi cult. The PEP study, however, had consid-
erable strengths, including concealment of allocation
through remote randomization; blinding of patients,
caregivers, and investigators; and an independent,
blinded adjudication committee that interpreted objec-
tively confi rmed end points, such as venographically or
DUS-confi rmed DVT, high probability ventilation/
perfusion scans, or pulmonary angiograms. In addi-
tion, there was near-complete follow-up (99.6%).
Although the combined results (arthroplasty and
HFS) failed to demonstrate or exclude a benefi cial
effect of aspirin on nonfatal PE, there was a modest
28% relative risk reduction in symptomatic DVT (RR,
0.72; 95% CI, 0.53-0.96). The upper boundary of the
CI crosses a threshold of 10% that clinicians con-
sider the desirable minimum clinical effect, and the
CI of the absolute effect includes as few as one less
DVT in 1,000. The results, therefore, are impre-
cise, despite the large number of patients enrolled.
Although there were 19 VTE-associated deaths in
the aspirin group compared with 45 in the placebo
No PE was observed in the LMWH group compared
with fi ve of 1,104 in the placebo group. Symptom-
atic DVT was reduced by more than one-half (RR, 0.46;
95% CI, 0.26-0.82). Results failed to demonstrate
or exclude an effect of LMWH on major bleeding
(RR, 0.43; 95% CI, 0.11-1.65) or on total mortality
(RR, 0.39; 95% CI, 0.08-1.98), although the only two
deaths from VTE were in the placebo group. On
the basis of high-quality evidence, extending throm-
boprophylaxis up to 35 days postoperation compared
with 10 to 14 days will result in nine fewer symptomatic
VTE per 1,000 without an appreciable increase in
major bleeding ( Table 5 , Figs S5-S8, Table S2).
2.1.2 LDUH vs No Prophylaxis—Initial Prophylaxis
Period: Numerous RCTs examined LDUH vs no
prophylaxis throughout the 1970s and early 1980s.
A systematic review involving close to 7,000 patients
demonstrated a relative risk reduction of 58% (RR,
0.42; 95% CI, 0.36-0.50) in the incidence of asymp-
tomatic DVT found by screening across 57 trials from
surgical and nonsurgical populations.
3
Only four of the
12 studies in orthopedic surgery used venography to
confi rm thrombotic events; the others used fi brinogen
uptake . The relative effect estimates were similar for
the eight studies involving . 500 patients under-
going elective hip replacement (RR, 0.53; 95% CI,
0.32-0.89) and six trials in HFS (RR, 0.56; 95% CI,
0.39-0.81) compared with the entire population.
A signifi cant reduction in PE was observed by pool-
ing all trials from surgical and nonsurgical popula-
tions (RR, 0.69; 95% CI, 0.49-0.99). Unfractionated
heparin (UFH) was associated with a trend toward an
increased risk of major bleeding (RR, 1.26; 95% CI,
0.99-1.6). Using our estimates of baseline risk, the
relative effect translates into a reduction of 13 symp-
tomatic VTEs per 1,000 with UFH, with an increase
in major bleeding events of four per 1,000. Mortal
events in major orthopedic surgery were only reported
for HFS trials (RR, 0.96; 95% CI, 0.55-1.67), and across
all patient groups, UFH appeared to have little or no
effect on overall mortality (RR, 0.91; 95% CI, 0.8-1.04).
The underlying quality of evidence was moderate
( Table 6 , Table S3).
2.1.3 Vitamin K Antagonist vs No Prophylaxis—
Initial Prophylaxis Period: Evidence for use of vita-
min K antagonists (VKAs) comes from eight RCTs
involving 703 patients, most with hip fracture, that
demonstrated a 55% relative risk reduction in primarily
asymptomatic DVT (RR, 0.45; 95% CI, 0.32-0.62).
3
PEs were reduced by almost 80% (RR, 0.21; 95% CI,
0.08-0.53), although this result is based on only
32 events. Although patients and clinicians in those
trials were not blinded, two trials blinded the throm-
bosis outcome adjudicators. VKA use was associated
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Table 5—[Section 2.1.1] Summary of Findings: LMWH for Extended Prophylaxis vs Placebo After Major Orthopedic Surgery (Up to 35 Days)
52,53
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With Placebo
Risk Difference With LMWH for
Extended Prophylaxis (95% CI)
Nonfatal PE 2,423 (6 studies) High RR 0.24 (0.04-1.4) Study population
5 per 1,000
Contemporary population (extended prophylaxis)
a
5 per 1,000 4 fewer per 1,000
(from 5 fewer to 2 more)
Symptomatic DVT 2,647 (7 studies) High RR 0.46 (0.26-0.82)
b
Study population
33 per 1,000
Contemporary population (extended prophylaxis)
a
10 per 1,000 5 fewer per 1,000
(from 2 fewer to 7 fewer)
Bleeding requiring reoperation 0 (0)
Major nonfatal bleeding 2,725 (7 studies
c
) High
d
RR 0.43 (0.11-1.65) 5 per 1,000
e
3 fewer per 1,000
(from 4 fewer to 3 more)
Total mortality
f
2,725 (7 studies
c
) High
d
RR 0.39 (0.08-1.98) 2 per 1,000 1 fewer per 1,000
(from 2 fewer to 2 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
Number of events taken directly from Hull et al
52
but relative risk recalculated using random-effects model.
c
This outcome was not presented in a forest plot in the original meta-analysis. Data were reextracted from the original publication for this outcome and pooled using a fi xed-effects model (same method as
presented in the original publication).
d
Not downgraded for imprecision because CI around absolute events is narrow.
e
All events were drop in hemoglobin level of 2 g/dL.
f
Deaths placebo: two from VTE and one from other causes. Deaths LMWH: death from other causes (pneumonia).
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Prevention of VTE in Orthopedic Surgery Patients
Table 6—[Section 2.1.2] Summary of Findings: LDUH vs No Thromboprophylaxis for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
3
Outcomes No. of Participants (Studies)
Quality of the
Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No LDUH
Risk Difference With
LDUH (95% CI)
PE 3,424 (20 studies) Moderate
a,b
due to imprecision RR 0.69 (0.49-0.99) Study population
60 per 1,000
Contemporary population (initial prophylaxis)
c
10 per 1,000 3 fewer per 1,000
(from 0 fewer to 5 fewer)
Symptomatic DVT (as inferred from
asymptomatic DVT)
6,987 (57 studies) Moderate
d-f
due to indirectness RR 0.42 (0.36-0.5) Study population
289 per 1000
Contemporary population (initial prophylaxis)
c
18 per 1,000 10 fewer per 1,000
(from 9 fewer to 12 fewer)
Bleeding requiring re-operation 0 (0
g
)
Major bleeding 6,669 (49 studies) Moderate
h,i
due to imprecision RR 1.26 (0.99-1.6) Study population
31 per 1,000
Contemporary population (initial prophylaxis)
j
15 per 1,000 4 more per 1,000
(from 0 fewer to 9 more)
Total mortality 12,682 (10 studies) Moderate
i,k
due to imprecision RR 0.91 (0.8-1.04) 66 per 1,000
l
6 fewer per 1,000
(from 13 fewer to 3 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Only one-third of the events from studies in orthopedic surgery. Not downgraded for indirectness because effect similar to effect observed.
b
CI includes zero fewer event in 1,000.
c
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
d
Majority of trials used fi brinogen uptake to detect DVT. Not downgraded to avoid duplicate downgrading with indirectness due to asymptomatic events based on fi brinogen uptake.
e
I
2
. 50%; however, there are consistent large effects across many conditions. Not downgraded.
f
Majority of events were asymptomatic; not a patient-important outcome,
g
This outcome was not reported in the systematic review. Studies were not reextracted to obtain this information.
h
Assessment and reporting of bleeding differs substantially between studies. Not downgraded.
i
CI includes harms and benefi t.
j
Alternate control group bleeding rate to refl ect contemporary surgical technique.
k
The majority of events occurred in medical patients. Not downgraded for indirectness because effect was similar.
l
Only from HFS studies.
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Table 7—[Section 2.1.3] Summary of Findings: VKA vs No VKA for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
3
Outcomes
No. of Participants
(Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No VKA Risk Difference With VKA (95% CI)
PE 610 (5 studies) Moderate
a
due to imprecision RR 0.21 (0.08-0.53) Study population
92 per 1,000
Contemporary population (initial prophylaxis)
b
10 per 1,000 8 fewer per 1,000
(from 5 fewer to 9 fewer)
Symptomatic DVT (as inferred from
asymptomatic DVT)
703 (8 studies) Moderate
c
due to indirectness RR 0.45 (0.32-0.62) Study population
463 per 1,000
Contemporary population (initial prophylaxis)
b
18 per 1,000 10 fewer per 1,000
(from 7 fewer to 12 fewer)
Bleeding requiring reoperation 0 (0
d
)
Major bleeding 840 (8 studies) Moderate
e,f
due to imprecision RR 1.5 (0.92-2.43) Study population
55 per 1,000
Contemporary population (initial prophylaxis)
g
15 per 1,000 7 more per 1,000
(from 1 fewer to 21 more)
Total mortality 727 (6 studies) Moderate
f
due to imprecision RR 0.76 (0.54-1.07) 170 per 1,000 41 fewer per 1,000
(from 78 fewer to 12 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Few events in the study, with a sample size of , 700.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
c
Almost all asymptomatic events. Not a patient-important outcome.
d
This outcome was not reported in the systematic review. Studies were not reextracted to obtain this information.
e
Adjudication of bleeding events not blinded. Assessment and reporting differed between studies. However, likely little effect on the estimate of effect. Not downgraded.
f
CI includes harms and benefi ts.
g
Alternate control group bleeding rate to refl ect contemporary surgical technique.
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2.1.6 Mechanical Interventions vs No Prophylaxis—
Initial Prophylaxis: There are few data regarding the
use of GCS compared with no prophylaxis in major
orthopedic surgery, although they are used frequently
in conjunction with other thromboprophylaxis. A sys-
tematic review identifi ed nine trials in a variety of
patient populations,
3
but only one small trial included
orthopedic surgery patients.
73
The pooled results from
all trials failed to demonstrate or to exclude a benefi -
cial or detrimental effect of GCS on PE (RR, 0.63;
95% CI, 0.32-1.25). Although GCS showed a ben-
efi cial effect on asymptomatic, venographically con-
rmed DVT overall (RR, 0.51; 95% CI, 0.36-0.73),
evidence from a higher-quality large trial in patients
with stroke
74,75
only showed a trend toward reduced
symptomatic DVT (RR, 0.92; 95% CI, 0.77-1.09),
and this was offset by a fourfold increase in skin com-
plications ( Table 10 , Table S7).
Mechanical approaches to perioperative thrombo-
prophylaxis with pneumatic compression devices have
the potential advantage of reducing the incidence of
VTE but without the risk for increased bleeding.
In addition, an intermittent pneumatic device (IPCD)
can be used in the contralateral leg even during sur-
gery and the immediate postoperative period.
Seven RCTs that included . 900 patients under-
going arthroplasty or HFS compared mechanical com-
pression to no thromboprophylaxis.
31,66,76-79
Six used an
IPCD, and one a venous foot pump (VFP).
77
The risk
of bias varied. For instance, in most trials, it was
unclear whether allocation was concealed. Blinding of
patients and caregivers is not possible in such studies,
and not all provided blinded VTE adjudication. In
addition, a systematic review indicated funnel plot
asymmetry, raising the possibility of publication bias.
80
Variation in design and performance of the devices
as well as information about compliance, which was
rarely reported in older trials, introduce uncertainty
in how to apply the evidence.
Taken together, the evidence is of low quality.
Nevertheless, a relative risk reduction of . 50% was
observed for both DVT and PE in THA, TKA, and
HFS (PE RR, 0.4; 95% CI, 0.17-0.92; DVT RR, 0.46;
95% CI, 0.35-0.61). The corresponding estimated
absolute risk difference is 16 fewer symptomatic VTE
per 1,000. The results failed to demonstrate or to
exclude a benefi cial effect on mortality ( Table 11 ,
Figs S21-S23, Table S8).
Compliance remains the biggest challenge associ-
ated with the use of IPCDs. Most devices currently in
use require an external power source, and they often
are found not functioning when patients are getting
out of bed or being transported. Properly functioning
IPCDs were encountered in , 50% in one study
81
and
as low as 19% in another.
82
In addition, those studies
reported no signifi cant improvement in compliance
group, the RR for overall mortality was 0.96 (95% CI,
0.85-1.09). There was a trend toward more major non-
fatal bleeding associated with aspirin (RR, 1.12;
95% CI, 0.94-1.34), but there were no difference in
bleeding requiring reoperation or bleed ing deaths.
In addition, the investigators reported no difference
in major bleeding in the subgroup that did not receive
additional heparin (aspirin alone, 95 of 3,711; placebo
alone, 94 of 3,789). Perioperative aspirin use was
associated with a trend toward more nonfatal myo-
cardial infarctions (RR, 1.59; 95% CI, 0.98-2.57).
In summary, given the moderate-quality evidence,
it appears that low-dose aspirin given before major
orthopedic surgery and continued for 35 days will
result in seven fewer symptomatic VTEs per 1,000
but at the expense of a possible three more major
bleeding episodes and two additional nonfatal myo-
cardial infarctions per 1,000, thus resulting in a close
balance between desirable and undesirable effects
( Table 8 , Figs S9-S14, Table S5).
When considering aspirin vs anticoagulants, the
impact of anticoagulants on myocardial infarction has
not been studied. The relative effects of aspirin are
likely similar whether other additional thrombopro-
phylaxis, including heparins or mechanical interven-
tions, are used. The absolute reduction in thrombosis,
however, will be greater in the absence of antico-
agulants than in their presence, and the absolute
increase in bleeding, if present, is likely to be less in
the absence of anticoagulants than in their presence.
2.1.5 Fondaparinux vs No Prophylaxis—Extended
Prophylaxis Period: We did not identify trials exam-
ining fondaparinux vs placebo for the initial prophy-
laxis period. However, one trial that used fondaparinux
for 6 to 8 days in HFS randomized 656 patients on
postoperative days 6 to 8 to either extended fonda-
parinux for an additional 19 to 23 days or placebo.
28
No PE was observed in the fondaparinux group com-
pared with two of 330 in the placebo group. The
results for symptomatic DVT failed to demonstrate
or to exclude a benefi cial effect (RR, 0.17; 95% CI,
0.02-1.39). Six major bleeding events occurred in the
fondaparinux group compared with none in the pla-
cebo group (RR, 13; 95% CI, 0.74-231), and results
failed to exclude a benefi cial or detrimental effect of
fondaparinux on total mortality (RR, 0.76; 95% CI,
0.27-2.16) ( Table 9 , Figs S15-S20; Table S6).
Based on moderate-quality evidence, 12 fewer symp-
tomatic VTE per 1,000 would be expected with the
use of fondaparinux, but this benefi cial effect would
be offset by an increase of at least 12 major bleeds
per 1,000. The close balance between desirable and
undesirable effects makes the use of fondaparinux for
extended thromboprophylaxis less appealing, partic-
ularly compared with LMWH.
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Table 8—[Section 2.1.4] Summary of Findings: Aspirin vs Placebo for Major Orthopedic Surgery (Both Initial and Extended Prophylaxis)
30
Outcomes
No. of Participants
(Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With Placebo Risk Difference With ASA 160 mg (95% CI)
Nonfatal PE 17,444 (1 study) Moderate
a
due
to imprecision
RR 0.78 (0.51-1.21) Study population
5 per 1,000
Contemporary population (initial prophylaxis)
b
10 per 1,000 2 fewer per 1,000 (from 5 fewer to 2 more)
Contemporary population (full 35-d prophylaxis)
b
15 per 1,000 3 fewer per 1,000 (from 7 fewer to 3 more)
Symptomatic DVT 17,444 (1 study) Moderate
c
due
to imprecision
RR 0.72 (0.53-0.96) Study population
12 per 1,000
Contemporary population (initial prophylaxis)
b
18 per 1,000 5 fewer per 1,000 (from 1 fewer to 8 fewer)
Contemporary population (full 35-d prophylaxis)
b
28 per 1,000 8 fewer per 1,000 (from 1 fewer to 13 fewer)
Bleeding requiring reoperation 17,444 (1 study) High
d-f
RR 0.97 (0.63-1.51) 5 per 1,000 0 fewer per 1,000 (from 2 fewer to 2 more)
Major nonfatal bleeding 17,444 (1 study) Moderate
a,e
due to imprecision RR 1.12 (0.94-1.34) 27 per 1,000 3 more per 1,000 (from 2 fewer to 9 more)
Nonfatal myocardial infarction 17,444 (1 study) Moderate
a
due to imprecision RR 1.59 (0.98-2.57) 3 per 1,000 2 more per 1,000 (from 0 fewer to 5 more)
Total mortality
g
17,444 (1 study) Moderate
a
due to imprecision RR 0.96 (0.85-1.09) 56 per 1,000 2 fewer per 1,000 (from 8 fewer to 5 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
CI includes benefi ts and harms.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]). The event rate from the PEP (Pulmonary Embolism Prevention) trial is likely too low because 43% of patients taking placebo received either unfractionated heparin or
LMWH. The lower baseline risk represents an estimate for the initial prophylaxis period (up to 14 d) and the higher for the up to 35 d extended-prophylaxis period.
c
The entire CI does not lie above the threshold (relative risk reduction of 10%) for minimally important benefi t.
d
This outcome was adjudicated as evacuation of hematoma. Unclear about how many patients required reoperation vs simple drainage.
e
I
2
. 70%; however, when all bleeding events are combined, this value falls to , 10%. Not downgraded.
f
Not downgraded for imprecision because CI around absolute effect was narrow.
g
Deaths placebo: 45 from VTE, 13 from unexplained causes, 15 from bleeding, and 414 from other causes. Deaths ASA: 19 from VTE, 14 from unexplained causes, 13 from bleeding, and 423 from other
causes.
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Prevention of VTE in Orthopedic Surgery Patients
Table 9—[Section 2.1.5] Summary of Findings: Fondaparinux for Extended Prophylaxis vs Placebo After Major Orthopedic Surgery (Additional 21 Days After
Initial Prophylaxis)
28
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With Placebo
Risk Difference With Fondaparinux Extended
Prophylaxis (95% CI)
Nonfatal PE 656 (1 study) Moderate
a
due to imprecision RR 0.2 (0.01-4.2) Study population
6 per 1,000
Contemporary population (extended prophylaxis)
b
5 per 1,000 4 fewer per 1,000 (from 5 fewer to 16 more)
Symptomatic DVT 656 (1 study) Moderate
a
due to imprecision RR 0.17 (0.02-1.39) Study population
18 per 1,000
Contemporary population (extended prophylaxis)
b
10 per 1,000 8 fewer per 1,000 (from 10 fewer to 4 more)
Bleeding requiring reoperation 657 (1 study) Moderate
a
due to imprecision RR 1.01 (0.14-7.12) 6 per 1,000 0 more per 1,000 (from 5 fewer to 37 more)
Major nonfatal bleeding
c
657 (1 study) Moderate
a
due to imprecision RR 13.12 (0.74-231) Study population
0 per 1,000
Contemporary population (extended prophylaxis)
d
1 per 1,000 12 more per 1,000 (from 1 fewer to 17 more)
Total mortality
e
657 (1 study) Moderate
a
due to imprecision RR 0.76 (0.27-2.16) 24 per 1,000 6 fewer per 1,000 (from 18 fewer to 28 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
CI includes both benefi t and harm.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
c
All major bleeding events were in the fondaparinux group, reported at the surgical site, required 2 units blood transfused, or were associated with a drop in hemoglobin level of 2 g/dL.
d
To illustrate increase in absolute risk, a 1/1,000 major bleeding event rate is assumed in the placebo group.
e
Deaths placebo: one from VTE, none from bleeding, and seven from other causes. Deaths fondaparinux: none from VTE, none from bleeding, and six from other causes.
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Table 10—[Section 2.1.6] Summary of Findings: GCS vs No GCS for Major Orthopedic Surgery (Both Initial and Extended Prophylaxis)
3,74,75
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No GCS
Risk Difference
With GCS (95% CI)
PE 2,777 (3 studies) Low
a,b
due to indirectness
and imprecision
RR 0.63 (0.32-1.25) Study population
15 per 1,000
Contemporary population (initial prophylaxis)
c
10 per 1,000 4 fewer per 1,000 (from 7
fewer to 2 more)
Contemporary population (full 35-d prophylaxis)
c
15 per 1,000 6 fewer per 1,000 (from 10
fewer to 4 more)
Symptomatic DVT (as inferred from
symptomatic and asymptomatic DVT)
3,797 (9 studies) Low
a,d
due to inconsistency
and indirectness
RR 0.51 (0.36-0.73) Study population
204 per 1,000
Contemporary population (initial prophylaxis)
c
18 per 1,000 9 fewer per 1,000 (from 5
fewer to 12 fewer)
Contemporary population (full 35-d prophylaxis)
c
28 per 1,000 14 fewer per 1,000 (from 8
fewer to 18 fewer)
Mortality 2,679 (2 studies) Low
a,b
due to indirectness
and imprecision
RR 1.21 (0.87-1.69) 89 per 1,000 19 more per 1,000 (from
12 fewer to 62 more)
Skin complications of elastic compression
stockings
2,512 (1 study) Moderate
e,f
due to risk of bias RR 4.02 (2.34-6.91) 3 per 1,000 10 more per 1,000 (from 4
more to 19 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Results mainly from nonorthopedic surgery trials.
b
CI includes both negligible effect and appreciable benefi t or appreciable harm.
c
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
d
I
2
. 60% with effects seen in older surgical trials and little effect seen in a newer study in patients with stroke.
e
Assessment of outcomes was based on case note review and was not blinded to treatment allocation.
f
Although CI excludes no effect, the number of events is low. This along with study limitations warranted rating down of the quality of evidence by one level.
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Prevention of VTE in Orthopedic Surgery Patients
Table 11—[Section 2.1.6] Summary of Findings: IPCD or FID (VFP) Alone vs No Thromboprophylaxis for Major Orthopedic Surgery (Initial Prophylaxis Period
Up to 14 Days)
31,66,76-79
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No Prophylaxis
Risk Difference With IPCD or FID
Alone (95% CI)
Nonfatal PE 896 (6 studies) Low
a,b
due to risk of bias,
imprecision
RR 0.40 (0.17-0.92) Study population
41 per 1,000
Contemporary population (initial prophylaxis)
c
10 per 1,000 6 fewer per 1,000 (from 1 fewer to 8 fewer)
Symptomatic DVT (as inferred from
asymptomatic DVT)
936 (7 studies) Low
a,d
due to risk of bias,
indirectness
RR 0.46 (0.35-0.61) Study population
349 per 1,000
Contemporary population (initial prophylaxis)
c
18 per 1,000 10 fewer per 1,000 (from 7 fewer to 12 fewer)
Total mortality
f
541 (2 studies) Low
a,e
due to risk of bias,
imprecision
RR 3.12 (0.13-75.94) 18 per 1,000 4 more per 1,000 (from 4 fewer to 11 more)
FID 5 foot impulse device; IPCD 5 intermittent pneumatic compression device; VFP 5 venous foot pump. See Table 1 and 3 legends for expansion of other abbreviations.
a
Quality issues were seen in a number of categories of which each were of borderline magnitude to justify downgrading. For example, not all studies provided blinded VTE adjudication, and not a single
study indicated major bleeding events, raising concern for reporting bias. In addition, the meta-analysis from Urbankova et al
80
indicated funnel plot asymmetry and possible publication bias. Taken together,
these issues limit our confi dence in the estimate of effect, and a judgment was made to downgrade once and not to upgrade for large effect.
b
CI includes as few as one less PE in 1,000.
c
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
d
Asymptomatic DVT not a patient-important outcome.
e
Fewer than 10 events in a sample size of , 400.
f
Deaths IPCD: one from VTE.
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tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. One panel member
believed strongly that aspirin alone should not be
included as an option.
2.2 Timing of Commencement of Anticoagulants
Risk of bleeding complications is closely linked to
the timing of thromboprophylaxis around surgery.
For instance, many trials started LMWH before sur-
gery, sometimes as close to surgery as 2 h. Trials in
which LMWH was started 2 h before surgery showed
a larger increase in major bleeding.
85
A systematic
review compared preoperative (at least 12 h, usually
defi ned as the evening before surgery), postopera-
tive (12-24 h after surgery), and perioperative (2 h
before to 4 h after) initiation of LMWH.
86
Peri-
operative initiation of LMWH resulted in major bleed-
ing rates of 5% to 7%, whereas rates were in the 1%
to 3% range with preoperative and postoperative
administration. The authors concluded that starting
prophylaxis 12 h before surgery is no more effec-
tive in preventing DVT than starting 12 h postoper-
atively and that despite a trend of lower VTE rates
associated with perioperative initiation, the increased
risk of major bleeding outweighed any potential ben-
efit. These findings were based on venographically
confi rmed, but mostly asymptomatic DVT, and the
comparisons were indirect. It is unknown whether
this would be equally true for symptomatic events or
would be confi rmed with direct comparisons.
Recommendation
2.2. For patients undergoing major orthopedic
surgery (THA, TKA, HFS) and receiving LMWH
as thromboprophylaxis, we recommend starting
either 12 h or more preoperatively or 12 h or
more postoperatively rather than within 4 h or
less preoperatively or 4 h or less postoperatively
(Grade 1B) .
2.3 Choice of Thromboprophylaxis
2.3.1 LMWH vs LDUH—Initial Prophylaxis: A
systematic review of comparisons between LMWH
and LDUH included . 23,000 patients from 64 trials
across surgical and nonsurgical patient groups;
2,800 patients were included in arthroplasty or HFS
trials.
3
Pooled estimates showed a 20% relative risk
reduction of primarily asymptomatic DVT in favor
of LMWH (RR, 0.80; 95% CI, 0.73-0.88), with sim-
ilar effects seen in the subgroups of THA, TKA, and
HFS. LMWH was associated with a trend toward
reduced PE in THA, although the pooled results
from all groups failed to demonstrate or exclude a
benefi cial effect of LMWH on PE (RR, 0.78; 95% CI,
0.49-1.24). There was a trend toward less major
rates with systematic education and training of nursing
and other staff. However, because the low compliance
is presumably largely due to the IPCD requir ing a
power outlet, newer battery-powered portable devices
are now available, and a recent study reported increased
compliance with those devices (77.7% vs 58.9%).
83
Other disadvantages of IPCDs are logistical and
include having enough units available and keeping
them in good working condition. Additionally, there
are multiple devices available that have differing prop-
erties, and this makes comparison of benefi ts diffi cult.
In summary, use of an IPCD for thromboprophylaxis
is attractive because of its possible effectiveness and
likelihood of no increase in bleeding events. However,
suboptimal compliance with the use of an IPCD while
in the hospital and the inability to continue this treat-
ment at home for most patients may limit their use.
Newer battery-powered IPCDs that monitor compli-
ance might be successfully used after discharge.
2.1.7 Other Modalities vs No Thromboprophylaxis:
Few recent orthopedic trials have compared other
thromboprophylaxis agents against placebo.
84
How-
ever, large, well-done trials with direct comparisons
against LMWH are available for newer antithrom-
botic agents, and their similar effects attest to their
benefi ts compared with no prophylaxis. Examples
include fondaparinux, apixaban, dabigatran, and rivar-
oxaban. The latter three have been evaluated in THA
and TKA but not in HFS.
Recommendations
2.1.1. In patients undergoing THA or TKA, we
recommend use of one of the following for a
minimum of 10 to 14 days rather than no anti-
thrombotic prophylaxis: LMWH, fondaparinux,
apixaban, dabigatran, rivaroxaban, LDUH,
adjusted-dose VKA, aspirin (all Grade 1B) , or an
IPCD (Grade 1C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpa-
tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. One panel member
believed strongly that aspirin alone should not be
included as an option.
2.1.2. In patients undergoing HFS, we recom-
mend use of one of the following rather than
no antithrombotic prophylaxis for a minimum
of 10 to 14 days: LMWH, fondaparinux, LDUH,
adjusted-dose VKA, aspirin (all Grade 1B) , or an
IPCD (Grade 1C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpa-
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Prevention of VTE in Orthopedic Surgery Patients
Extended Prophylaxis With LMWH vs VKA One
large trial enrolling . 1,200 patients scheduled for
THA compared LMWH vs adjusted-dose VKA (inter-
national normalized ratio [INR] 2-3) given for an
extended 6-week period.
96
No PE was observed in
the LMWH group compared with four of 636 in
the VKA arm. The results failed to demonstrate or to
exclude a benefi cial effect of VKA compared with
LMWH for asymptomatic DVT (RR, 1.35; 95% CI,
0.70-2.6). However, almost four times as many major
nonfatal bleeds were observed with VKA compared
with LMWH (RR, 3.9; 95 % CI, 1.9-8.1). One of the
two deaths in the study (both in the VKA group) was
related to a fatal GI bleed ( Table 14 , Figs S29-S32,
Table S11). In summary, there is moderate-quality
evidence of a substantial increase in major bleeding
with the use of VKA compared with LMWH for
extended prophylaxis.
2.3.3 LMWH vs Aspirin—Initial and Extended
Prophylaxis: Two trials compared LMWH against
aspirin, with one trial using aspirin 325 mg bid
97
and
the other 650 mg bid (only the abstract was avail-
able).
98
The pooled results showed more asymptom-
atic DVT in the aspirin group (RR, 1.87; 95% CI,
1.3-2.7), but PEs were too few to provide a mean-
ingful estimate. No major bleeding events or deaths
were reported. Overall, the evidence from a head-to-
head comparison of LMWH compared with aspirin
is sparse and of low quality. However, indirect evi-
dence from trials of LMWH and aspirin against pla-
cebo also shows greater relative effi cacy of LMWH
( Table 15 , Figs S33, S34, Table S12).
2.3.4 LMWH vs Fondaparinux—Initial Prophylaxis:
Several large trials compared fondaparinux 2.5 mg
started 6 to 8 h after wound closure with LMWH
(started either 12 h before or after surgery) in THA,
99,100
TKA,
101
and HFS.
102
Because the relative effects across
outcomes were similar, we included a trial in abdominal
surgery patients,
103
thus including . 10,000 patients.
In addition, we included all trials, whether GCS were
used in all or only in a portion of patients, as long as it
was used equally in both arms.
The pooled results failed to demonstrate or exclude
a benefi cial or detrimental effect of fondaparinux
on symptomatic DVT and PE despite a substantial
reduction in asymptomatic DVT. There was a sub-
stantial increase in bleeding requiring reoperation
associated with the use of fondaparinux (RR, 1.85;
95 % CI, 1.1-3.11), but the results failed to demon-
strate a difference in nonfatal major bleeding (RR,
1.35; 95 % CI, 0.89-2.05). VTE deaths were rare and
similar in both groups (fondaparinux 5/5,049 vs LMWH
6/5,046). There were two fatal bleeds with fonda-
parinux and three with LMWH. Caution is advised
bleed ing with LMWH after THA (RR, 0.59; 95% CI,
0.34-1.01) but not across all trials (RR, 0.91; 95% CI,
0.75-1.09). These results suggest that LMWH may
reduce symptomatic VTE from 16 per 1,000 with
LDUH to 13 per 1,000 without an increase in major
bleeding ( Table 12 , Table S9).
There have been no trials directly comparing the
effectiveness of LDUH every 12 h vs LDUH every 8 h.
In 1988, two separate meta-analyses were published
that commented on UFH dosing schedules.
87,88
Collins et al
87
included studies in orthopedic, urologic,
and general surgery. Overall, a 72% odds reduction
was found for the 8-h regimen and a 63% odds reduc-
tion for the 12-h regimen, which was not a signifi -
cant difference. In orthopedic surgery studies only,
the odds reduction was 68% for both regimens. In
contrast, the meta-analysis by Clagett et al
88
was con-
ned to general surgery studies and reported DVT
rates in pooled analysis of 11.8% with the 12-h reg-
imen compared with 7.5% using the 8-h regimen.
The authors concluded that the 8-h regimen was
superior. Neither meta-analysis reported differences
in major bleeding between these regimens. These indi-
rect comparisons provide only low-quality, or perhaps
very-low-quality, evidence for the alternate regimens.
2.3.2 LMWH vs VKAs—Initial and Extended
Prophylaxis: Several RCTs in THA and TKA
85,89-95
but
not HFS have compared LMWH to VKA (mainly
warfarin) in . 9,000 patients for the initial prophylaxis.
The results failed to establish or refute a difference
in PE (RR, 0.68; 95% CI, 0.22-2.1), but LMWH use
was associated with signifi cantly less asymptomatic
DVT (RR, 0.68; 95 % CI, 0.6-0.78) at the cost of an
increase in major bleeding events (RR, 1.56; 95% CI,
1.23-2.0). Most of these trials, however, started
LMWH shortly before surgery, which as we have dis-
cussed, likely increases the risk of bleeding substan-
tially. Our sensitivity analysis, excluding trials that
administered LMWH close to the operation ( , 12 h
perioperatively),
85,89-91
still shows a trend in increased
bleeding events, but the magnitude of the effect is
smaller (RR, 1.36; 95% CI, 0.95-1.96). We used this
RR in our evidence summaries for the initial throm-
boprophylaxis period with VKA vs LMWH.
Based on those considerations, we estimate that
there will be three fewer symptomatic VTE events
per 1,000 with the use of LMWH compared with
warfarin, but this benefi t is closely balanced by a
possible increase of four major bleeding events
per 1,000. However, given the two fatal bleeding
events with the use of VKA (vs none in the LMWH
group), safety concerns with warfarin remain ( Table 13 ,
Figs S24-S28, Table S10). Furthermore, the evi-
dence regarding extended prophylaxis, presented
next, favors LMWH.
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Table 12—[Section 2.3.1] Summary of Findings: LMWH vs UFH for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
3
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With UFH Risk Difference With LMWH (95% CI)
PE 16,448 (37 studies) High RR 0.78 (0.49-1.24) Study population
6 per 1,000
Contemporary population (initial prophylaxis)
a
4 per 1,000 1 fewer per 1,000 (from 2 fewer to 1 more)
Symptomatic DVT (as inferred from
asymptomatic DVT)
23,008 (64 studies) Moderate
b
due to indirectness RR 0.80 (0.73-0.88) Study population
78 per 1,000
Contemporary population (initial prophylaxis)
a
12 per 1,000 2 fewer per 1,000 (from 2 fewer to 3 fewer)
Bleeding requiring reoperation 0 (0
c
)
Major bleeding 23,880 (49 studies) High RR 0.91 (0.75-1.09) Study population
31 per 1,000
Contemporary population (initial prophylaxis)
a
16 per 1,000 1 fewer per 1,000 (from 4 fewer to 1 more)
Total mortality
d
4,407 (9 studies) Moderate
e
due to imprecision RR 1.11 (0.63-1.98) 22 per 1,000 2 more per 1,000 (from 8 fewer to 22 more)
UFH 5 unfractionated heparin. See Table 1 and 3 legends for expansion of other abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
Mostly asymptomatic DVT. Not a patient-important outcome.
c
This outcome was not reported in the systematic review. Studies were not reextracted to obtain this information.
d
The absolute rate of overall mortality observed with LMWH in those older trials was seen in patient groups other than orthopedic surgery and does not refl ect a rate typically associated with major
orthopedic surgery.
e
CI includes benefi cial effects for both interventions.
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Table 13—[Section 2.3.2] Summary of Findings: LMWH vs VKA for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
85,89-95
Outcomes No. of Participants (studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With VKA Risk Difference With LMWH (95% CI)
Nonfatal PE 9,324 (8 studies) High RR 0.68 (0.22-2.1) Study population
2 per 1,000
Contemporary population (initial prophylaxis)
a
2 per 1,000 1 fewer per 1,000 (from 2 fewer to 3 more)
Symptomatic DVT (as inferred from
asymptomatic DVT)
5,162 (8 studies) Low
b,c
due to inconsistency and
indirectness
RR 0.68 (0.6-0.78) Study population
333 per 1,000
Contemporary population (initial prophylaxis)
a
5 per 1,000 2 fewer per 1,000 (from 1 fewer to 2 fewer)
Bleeding requiring reoperation 0 (0
d
)
Major bleeding 4,507 (5 studies) Low
e,f
due to indirectness and
imprecision
RR 1.36 (0.95-1.96) Study population
27 per 1,000
g
Contemporary population (initial prophylaxis)
g
11 per 1,000 4 more per 1,000 (from 1 fewer to 11 more)
Total mortality
h
6,328 (7 studies) High RR 0.5 (0.14-1.82) 2 per 1,000 1 fewer per 1,000 (from 2 fewer to 2 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
I
2
. 50%.
c
Most events were asymptomatic.
d
This outcome was not reported in the studies.
e
Estimate excludes studies that administered enoxaparin close to surgery (, 12 h perioperatively), making the true bleeding risk increase with LMWH less certain.
f
CI includes benefi cial effects for both treatment arms.
g
The average bleeding rate for LMWH in trials enrolling patients since 2003 is 1.5%.
h
Deaths VKA: none from VTE, two from bleeding, one from unexplained causes, and three from other causes. Deaths LMWH: none from VTE, none from bleeding, one from unexplained causes, and two
from other causes.
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Table 14—[Section 2.3.2] Summary of Findings: VKA for Extended Prophylaxis vs LMWH After Major Orthopedic Surgery (Up to 35 Days)
96
Outcomes No. of Participants (Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated absolute effects
Risk With LMWH for Extended
Prophylaxis
Risk Difference With VKA for Extended
Prophylaxis (95% CI)
Nonfatal PE 1,279 (1 study) High RR 9.1 (0.49-169) Study population
0 per 1,000
Contemporary population (extended prophylaxis)
a
6 per 1,000 45 more per 1,000 (from 5 fewer to 96 more)
Symptomatic DVT 1,279 (1 study) Moderate
b
due to
imprecision
RR 1.35 (0.7-2.6) Study population
23 per 1,000
Contemporary population (extended prophylaxis)
a
12 per 1,000 4 more per 1,000 (from 4 fewer to 20 more)
Bleeding requiring re-operation 0 (0
c
)
Major nonfatal bleeding 1,279 (1 study) Moderate
d
due to risk of
bias
RR 3.93 (1.91-8.11) 14 per 1,000 41 more per 1,000 (from 13 more to 100 more)
Total mortality 1,279 (1 study) Moderate
b
due to
imprecision
RR 0.2 (0.01-4.11) 0 per 1,000 3 more per 1,000
e
(from 1 fewer to 7 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
CI includes benefi ts for both groups.
c
Outcome not reported.
d
Bleeding adjudication was likely not blinded. Major bleeding defi nition included bleeding that, according to the (potentially unblinded) investigators’ opinion, led to discontinuation of study drug. It is
unreported how this infl uenced the total number of major bleeding events.
e
Deaths VKA: one from GI bleeding and one from myocardial infarction.
Page 22
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Prevention of VTE in Orthopedic Surgery Patients
Table 15—[Section 2.3.3] Summary of Findings: ASA (With or Without IPCD) vs LMWH (With or Without IPCD) for Major Orthopedic Surgery (Both Initial and
Extended Prophylaxis)
97,98
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH IPCD Risk Difference With ASA IPCD (95% CI)
Nonfatal PE 264 (1 study) Very low
a,b
due to risk of
bias and imprecision
RR 3.1 (0.13-76) Study population
N/A
Contemporary population (initial prophylaxis)
c
4 per 1,000 7 more per 1,000 (from 3 fewer to 81 more)
Contemporary population (full 35-d prophylaxis)
c
6 per 1,000 12 more per 1,000 (from 5 fewer to 127 more)
Symptomatic DVT (as inferred from
asymptomatic DVT)
469 (2 studies) Very low
a,d,e
due to risk of
bias, inconsistency, and
indirectness
RR 1.87 (1.3-2.7) Study population
143 per 1,000
Contemporary population (initial prophylaxis)
c
8 per 1,000 7 more per 1,000 (from 2 more to 14 more)
Contemporary population (full 35-d prophylaxis)
c
12 per 1,000 11 more per 1,000 (from 4 more to 21 more)
Major bleeding 0 (0
f
)
N/A 5 not applicable. See Table 1, 3, and 11 legends for expansion of other abbreviations.
a
LMWH started 48 h postoperatively because of spinal epidural anesthesia compared with ASA at the night of surgery. Because asymptomatic DVTs were screened at day 3 to 5 with Doppler ultrasound,
LMWH may have in some instances been given for only 1 or 2 days.
b
Only one event was observed.
c
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
d
I
2
. 80%.
e
Asymptomatic DVT not a patient-important outcome.
f
No bleeding events were reported.
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venience of subcutaneous administration ( Table 17 ,
Figs S41-S47 , Table S14).
Extended Prophylaxis With Rivaroxaban: The
extended use of rivaroxaban was studied in one trial
enrolling . 2,400 patients after THA.
4
The control
group received short-term LMWH for the fi rst 12 days
followed by placebo for an additional 22 days. Rivar-
oxaban signifi cantly reduced symptomatic VTE (symp-
tomatic DVT: RR, 0.18; 95 % CI, 0.04-0.82; PE: RR,
0.25; 95 % CI, 0.02-2.2). There was only one major
bleeding event in both groups. However, in contrast
to most other studies, the major bleeding defi nition
in this study excluded surgical site bleeding, and the
baseline used for change in hemoglobin level was
postoperative day 1. The result was a major bleeding
rate of only one-10th of comparable studies using the
same control agent.
40
Bleeding requiring reoperation
was recorded.
Based on moderate-quality evidence, 12 fewer symp-
tomatic VTE would be expected. However, because
of the uncertainty about the major bleeding rate, it is
unknown whether some of the benefi t would be off-
set by a higher bleeding rate of rivaroxaban compared
with placebo ( Table 18 , Figs S41-S53, Table S15).
2.3.6 LMWH vs Dabigatran—Initial and Extended
Prophylaxis: Dabigatran, a new oral direct thrombin
inhibitor, has been approved by the US Food and
Drug Administration since 2010 for stroke preven-
tion in atrial fi brillation, and European and Canadian
agencies have granted marketing authorization for
the prevention of VTE after total hip and knee arthro-
plasty. Four RCTs examined the use of dabigatran
in . 10,000 patients undergoing THA
23,24
and TKA
25,26
at doses of 220 and 150 mg taken orally once daily
(usually started within 4 h postoperatively at half the
dose) compared with enoxaparin (mainly at doses of
40 mg once daily started the evening before surgery,
although one study used the 30 mg bid dosing sched-
ule that commenced 12 h postoperatively). Treatment
duration ranged from 10 to 15 days (for TKA) to 28 to
35 days for THA. Again, relative effects were similar
to the shorter-term TKA trials, facilitating pooled
effects across all dabigatran trials.
The studies using the 220 mg dose of dabigatran
failed to demonstrate or exclude a difference in
the number of symptomatic VTEs (PE: RR, 1.22;
95% CI, 0.52-2.85; DVT: RR, 0.7; 95% CI, 0.12-3.91)
or major bleeding events (RR, 1.06; 95% CI,
0.66-1.72). Point estimates of absolute differences
between thrombotic and bleeding events were closely
balanced to within one event per 1,000 ( Table 19 ,
Figs S54-S59, Table S16).
Although dabigatran at the 150-mg dose reduced
asymptomatic DVT less than enoxaparin (RR, 1.2;
with fondaparinux in patients weighing , 50 kg
(110 lbs) and elderly and frail patients because bleed-
ing complications may be increased. In summary,
based on moderate-quality evidence, the use of fonda-
parinux compared with LMWH does not appear to
reduce patient-important VTE events but may increase
major bleeding events by nine per 1,000 ( Table 16 ,
Figs S35-S40, Table S13).
2.3.5 LMWH vs Rivaroxaban—Initial and Extended
Prophylaxis: Rivaroxaban, an oral direct factor Xa
inhibitor, is approved in the United States, Canada,
and Europe for the prevention of VTE after THA and
TKA, but it has not been evaluated in HFS. Seven
RCTs enrolling . 10,000 patients after THA
18,19,104
and TKA
20-22
examined the effi cacy of rivaroxaban
10 mg/d (started 6-8 h postoperatively) against enox-
aparin 40 mg/d. Enoxaparin was usually started the
evening before surgery and continued 6 to 8 h post-
operatively, but two studies used 30 mg bid dosing
rather than 40 mg once daily and started 12 h post-
operation. For TKA patients, rivaroxaban usually was
given for 10 to 15 days, and earlier trials in THA had
similarly short treatment durations, but one later
trial treated patients for 31 to 39 days.
19
Because the
relative effects of extended prophylaxis were similar
to shorter-term trials, we estimated pooled effects
across all rivaroxaban trials to increase precision, as
long as rivaroxaban and control treatment were given
for the same duration.
Rivaroxaban reduced symptomatic DVT by . 50%
(RR, 0.41; 95% CI, 0.20-0.83). There was a trend
toward increased major bleeding and bleeding requir-
ing reoperation (major bleeding: RR, 1.58; 95% CI,
0.84-2.97; bleeding requiring reoperation: RR, 2.0;
95% CI, 0.86-4.83; combined: RR, 1.73; 95% CI,
0.94-3.17). The absolute rates for major bleeding were
low in both arms, and the rates were lower than
one would expect from other large trials using sim-
ilar enoxaparin controls. Unlike other trials, the two
major THA studies (RECORD 1 and 2 ) did not include
surgical site bleeding (other than bleeding requiring
reoperation), and drop in hemoglobin level was cal-
culated compared with the postoperative instead of
the preoperative baseline value.
40
The evidence summaries therefore include the
alternate major bleeding rate of 1.5% to better illus-
trate the trade-offs between VTE and bleeding with
rivaroxaban: The best estimates suggest that fi ve
fewer symptomatic DVT per 1,000 achieved with
rivaroxaban over LMWH will be offset by nine
more major bleeding events. In summary, based on
moderate-quality evidence, both the possibility of
increased major bleeding events and the availability
of long-term safety data for LMWH makes LMWH
more appealing than rivaroxaban in spite of the incon-
Page 24
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Prevention of VTE in Orthopedic Surgery Patients
Table 16—[Section 2.3.4] Summary of Findings: Fondaparinux vs LMWH for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
99-103
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH (Any Dosing) Risk Difference With Fondaparinux (95% CI)
Nonfatal PE 10,069 (5 studies) Moderate
a
due to imprecision RR 1.32 (0.37-4.74) Study population
1 per 1,000
Contemporary population (initial prophylaxis)
b
4 per 1,000 1 more per 1,000 (from 2 fewer to 13 more)
Symptomatic DVT 10,069 (5 studies) Moderate
a,c
due to imprecision RR 1.31 (0.47-3.7) Study population
1 per 1,000
Contemporary population (initial prophylaxis)
b
8 per 1,000 2 more per 1,000 (from 4 fewer to 22 more)
Bleeding requiring re-operation 10,095 (5 studies) Moderate
d
due to imprecision RR 1.85 (1.1-3.11) 4 per 1,000 4 more per 1,000 (from 0 more to 9 more)
Major nonfatal bleeding 10,095 (5 studies) Moderate
a
due to imprecision RR 1.35 (0.89-2.05) Study population
14 per 1,000
Contemporary population (initial prophylaxis)
b
15 per 1000 5 more per 1,000 (from 2 fewer to 16 more)
Total mortality
e
10,095 (5 studies) High
f
RR 0.73 (0.46-1.16) 8 per 1,000 2 fewer per 1,000 (from 4 fewer to 1 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
CI includes favorable effects for both interventions.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
c
I
2
. 50%, likely due to clinical heterogeneity (abdominal surgery vs orthopedics). Not downgraded for decision on orthopedic surgery patients.
d
CI includes as few as zero more bleeding events requiring reoperation per 1,000.
e
Deaths LMWH: six from VTE, three from bleeding, none from unexplained causes, and 33 from other causes. Deaths fondaparinux: fi ve from VTE, two from bleeds, none from unexplained causes, and
23 from other causes.
f
The CI around the absolute effect is narrow. Not downgraded.
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Table 17—[Section 2.3.5] Summary of Findings: Rivaroxaban vs LMWH for Major Orthopedic Surgery (Both Initial and Extended Prophylaxis)
18-20,22,104
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk with LMWH Risk Difference With Rivaroxaban (95% CI)
Nonfatal PE 10,869 (7 studies) High RR 1.34 (0.39-4.6) Study population
2 per 1,000
Contemporary population (initial prophylaxis)
a
4 per 1,000 1 more per 1,000 (from 2 fewer to 13 more)
Contemporary population (full 35-d prophylaxis)
a
6 per 1,000 2 more per 1,000 (from 3 fewer to 20 more)
Symptomatic DVT 10,869 (7 studies) Moderate
b
due to imprecision RR 0.41 (0.2-0.83) Study population
8 per 1,000
Contemporary population (initial prophylaxis)
a
8 per 1,000 5 fewer per 1,000 (from 1 fewer to 6 fewer)
Contemporary population (full 35-d prophylaxis)
a
12 per 1,000 7 fewer per 1,000 (from 2 fewer to 10 fewer)
Bleeding requiring re-operation 10,941 (7 studies) Moderate
c
due to imprecision RR 2.03 (0.86-4.83) 1 per 1,000 1 more per 1,000 (from 0 fewer to 5 more)
Major nonfatal bleeding 10,941 (7 studies) Moderatec due to imprecision RR 1.58 (0.84-2.97) Study population
3 per 1,000
Contemporary population (initial prophylaxis)
a
15 per 1,000 9 more per 1,000 (from 2 fewer to 30 more)
Total mortality
d
10,869 (7 studies) High RR 0.84 (0.31-2.27) 2 per 1,000 0 fewer per 1,000 (from 1 fewer to 2 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
CI includes as few as one less symptomatic DVT per 1,000.
c
CI includes no difference and an up to threefold increase in adverse bleeding outcomes in patients receiving rivaroxaban.
d
Deaths enoxaparin: two from VTE, none from bleeding, fi ve from unexplained causes, and eight from other causes. Deaths rivaroxaban: three from VTE, one from bleeding, none from unexplained causes,
and fi ve from other causes.
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Prevention of VTE in Orthopedic Surgery Patients
Table 18—[Section 2.3.5] Summary of Findings: Rivaroxaban for Extended Prophylaxis vs Placebo After Major Orthopedic Surgery (Up to 35 Days)
4
Outcomes No. of Participants (Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH for
12 d 1 Placebo for 22 d
Risk Difference With Rivaroxaban for Extended
Prophylaxis (34 d) (95% CI)
Nonfatal PE 2,419 (1 study) High
a
RR 0.25 (0.02-2.2) Study population
3 per 1,000
b
Contemporary population (extended prophylaxis)
b
5 per 1,000
b
4 fewer per 1,000 (from 5 fewer to 6 more)
Symptomatic DVT 2,419 (1 study) High RR 0.18 (0.04-0.82) Study population
9 per 1,000
Contemporary population (extended prophylaxis)
b
10 per 1,000 8 fewer per 1,000 (from 2 fewer to 10 fewer)
Bleeding requiring reoperation 2,457 (1 study) High Not estimable, no events
Major nonfatal bleeding
d
2,457 (1 study) Moderate
a,c
due to risk of bias
RR 1 (0.06-16) Study population
1 per 1,000
Contemporary population (extended prophylaxis)
b
15 per 1,000 0 fewer per 1,000 (from 1 fewer to 22 more)
Total mortality
e
2,457 (1 study) High
a
RR 0.33 (0.07-1.65) 5 per 1,000 3 fewer per 1,000 (from 5 fewer to 3 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
The CI around the absolute effect is narrow. Not downgraded.
b
Estimated extended period baseline risk for placebo from day 13 to day 34. Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era
surgical technique, early mobilization, etc [see text for detail how baseline risks were calculated]).
c
Major bleeding defi nition excluded surgical site bleeding and the baseline used for change in hemoglobin level was postoperative day 1, resulting in a major bleeding event rate that is only 1/10th of
comparable studies using the same control intervention (enoxaparin) and making the relative risk estimate unreliable.
d
Enoxaparin: one bleeding into critical organ (had blood in cerebrospinal fl uid during spinal anesthesia). Rivaroxaban: one clinically overt extrasurgical site bleeding leading to a fall in hemoglobin level
of . 2 g/dL and requiring transfusion of 2 units of blood (GI bleed).
e
Deaths enoxaparin: one from VTE, none from bleeding, one from unexplained causes, and four from other causes. Deaths rivaroxaban: none from VTE, none from bleeding, none from unexplained causes,
and two from other causes (cardiovascular).
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major bleeding events (from eight fewer to fi ve more
per 1,000), although results failed to demonstrate
a difference when all nonfatal and fatal VTE were
combined (Fig S72).
In summary, based on moderate-quality evidence,
apixaban is similar to LMWH in terms of effi cacy
based on all symptomatic VTEs (including DVT,
non-fatal and fatal PE) (see Fig S72) and showed a
comparable low risk for major bleeding events. How-
ever, the lack of long-term postmarketing safety data
(eg, the confi rmation of bleeding-related safety) for
apixaban currently makes LMWH still the agent of
choice ( Table 21 , Figs S66-S72, Table S18).
2.3.8 IPCDs vs Pharmacologic Thromboprophylaxis—
Initial Prophylaxis: Compression devices are attrac-
tive because they do not increase bleeding. IPCDs
were compared against VKAs in . 500 patients from
four trials: three in patients undergoing THA
105-107
and one with both THA and TKA.
108
Because of the
small sample sizes, no PE was observed. The results
for asymptomatic DVT failed to demonstrate or to
exclude a benefi cial effect of IPCDs over VKAs (RR,
0.79; 95% CI, 0.5-1.25). All major bleeding events
were reported in one study
106
in which warfarin was
started 1 week prior to the operation and the INR
was kept initially at 1.5 during the operation. In
this trial, eight patients required 4 units of blood
transfusion, and two had higher intraoperative blood
loss. Because the usual practice is to give warfarin the
night before surgery and adequate anticoagulation
levels will not be achieved for several days, those
bleeding events may not be applicable to current prac-
tice. Using a more-precise estimate of 2% (90 major
bleeds observed in 4,547 patients) as seen in the VKA
arm of RCTs vs LMWH, it is likely that 19 more bleeds
will occur per 1,000, offsetting the two fewer DVT
seen with warfarin ( Table 22 , Figs S73-S75, Table S19).
Pneumatic compression devices were compared with
LMWH in . 1,000 patients scheduled for THA
109-111
and TKA
31,112
: ve studies used a VFP, and two used
an IPCD. We included studies in our analysis whether
GCS were used in both treatment arms. A single non-
fatal PE was observed in the IPCD/VFP group. Use
of a compression device was associated with a trend
toward an increase in asymptomatic DVT (RR, 1.38;
95% CI, 0.92-2.06). Less major bleeding occurred
in the IPCD group (RR, 0.32; 95% CI, 0.12-0.89).
In these studies, bleeding event adjudication was
not blinded, and bleeding events were inconsistently
reported (eg, bleeding requiring reoperation remained
unreported despite the sample size of . 1,000). Three
deaths from VTE occurred with the compression
device vs none in the LMWH group.
Overall, 10 fewer symptomatic VTE events per
1,000 can be expected with the use of LMWH
95% CI, 1.05-1.37), one trial that used a 50% higher
dosing schedule (enoxaparin 30 mg bid) contrib-
uted the majority of the excess asymptomatic events.
Symptomatic VTE results, however, failed to dem-
onstrate or to exclude a benefi cial effect of dabigatran
compared with LMWH (PE: RR, 0.31; 95% CI,
0.04-2.48; symptomatic DVT: RR, 1.52; 95% CI,
0.45-5.05). Overall, the additional two symptomatic
VTE events per 1,000 observed with the lower dose
of dabigatran are offset by four additional major
bleeding events per 1,000 in the enoxaparin group,
although this increased bleeding is more likely with
the higher enoxaparin dose of 30 mg bid ( Table 20 ,
Figs S60-S65, Table S17).
In summary, dabigatran is similar to LMWH in
terms of effi cacy and propensity to cause bleeding,
based on moderate-quality evidence. Greater long-
term experience with LMWH still favors its use.
2.3.7 LMWH vs Apixaban—Initial and Extended
Prophylaxis: Apixaban, an oral direct factor Xa inhib-
itor, is approved in Europe for the prevention of VTE
after THA and TKA but similar to the other newer
agents, has not been evaluated in HFS. Four RCTs
enrolling close to 12,000 patients after THA
14
and
TKA
15-17
examined the effi cacy of apixaban 2.5 mg bid
taken orally (started 12-24 h postoperatively) against
enoxaparin. Enoxaparin at the 40-mg dosing sched-
ule was started the evening before surgery and con-
tinued after surgery according to the investigators’
standard of care (usually 12 h postoperatively). Two
studies used 30 mg bid dosing rather than 40 mg
once daily and started 12 h postoperatively. For TKA
patients, apixaban usually was given for 10 to 14 days,
and the single trial in THA used an extended protocol
of 32 to 38 days.
Apixaban reduced symptomatic DVT by 59%
(RR, 0.41; 95% CI, 0.18-0.95) and appeared to
have little or no effect on major nonfatal bleeding
(RR, 0.76; 95% CI, 0.44-1.32) or bleeding requiring
reoperation (RR, 0.82; 95% CI, 0.15-4.58) compared
with enoxaparin. However, similar to the two major
rivaroxaban trials, drop in hemoglobin level was cal-
culated compared with the postoperative instead of
the preoperative baseline value for the ADVANCE
(Apixaban Dosed Orally vs Anticoagulation with Enox-
aparin) 2 and 3 trials, which may underestimate
the true major bleeding event rate.
40
Results failed
to demonstrate a benefi cial or detrimental effect of
apixaban on nonfatal PE (RR, 1.09; 95% CI, 0.31-3.88)
and total mortality (RR, 1.87; 95% CI, 0.61-5.74),
and the only fi ve deaths from VTE were found in the
apixaban group.
Best estimates suggest that seven fewer symptom-
atic DVT per 1,000 could be achieved with apixaban
over LMWH without an appreciable increase in
Page 28
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Prevention of VTE in Orthopedic Surgery Patients
Table 19—[Section 2.3.6] Summary of Findings: Dabigatran 220 mg vs LMWH for Major Orthopedic Surgery (Both Initial and Extended Prophylaxis)
23-26
Outcomes No. of Participants (Studies)
Quality of the evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH
a
Risk Difference With Dabigatran 220 mg
(95% CI)
Nonfatal PE 7,377 (4 studies) High RR 1.22 (0.52-2.85) Study population
3 per 1,000
Contemporary population (initial prophylaxis)
b
4 per 1,000 1 more per 1,000 (from 2 fewer to 6 more)
Contemporary population (full 35-d prophylaxis)
b
6 per 1,000 1 more per 1,000 (from 3 fewer to 10 more)
Symptomatic DVT 7,377 (4 studies) High
c
RR 0.70 (0.12-3.91) Study population
5 per 1,000
Contemporary population (initial prophylaxis)
b
8 per 1,000 2 fewer per 1,000 (from 7 fewer to 23 more)
Contemporary population (full 35-d prophylaxis)
b
12 per 1,000 4 fewer per 1,000 (from 11 fewer to 36 more)
Bleeding requiring reoperation 7,411 (4 studies) High RR 0.98 (0.27-3.54) 1 per 1,000 0 fewer per 1,000 (from 1 fewer to 3 more)
Major nonfatal bleeding
d
7,411 (4 studies) High RR 1.06 (0.66-1.72) Study population
12 per 1,000
Contemporary population (initial prophylaxis)
b
15 per 1,000 1 more per 1,000 (from 5 fewer to 11 more)
Total mortality
e
7,377 (4 studies) High RR 1.67 (0.37-7.53) 1 per 1,000 0 more per 1,000 (from 0 fewer to 4 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
Enoxaparin was dosed 30 mg bid in one study. All others were dosed 40 mg/d.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
c
Although I
2
is high (. 50%), was not downgraded for inconsistency because this was mainly caused by one trial that used enoxaparin 30 mg bid instead of 40 mg/d in the control group.
d
Major bleeding enoxaparin: one melena, one rectal bleeding, and all others either specifi cally mentioned to be surgical site or overt with a drop in hemoglobin level of 2 g/dL, associated with 2 units
blood transfusion requirement, or both. Major bleeding dabigatran: one hemarthrosis, one vitreous, one rectal, and all others either specifi cally mentioned to be surgical site or overt with drop in hemoglobin
level of 2 g/dL, associated with 2 units blood transfusion requirement, or both.
e
Deaths enoxaparin: one from VTE, none from bleeding, one from unexplained causes, and none from other causes. Deaths dabigatran: none from VTE, one from bleeding, two from unexplained causes,
and two from other causes.
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Table 20—[Section 2.3.6] Summary of Findings: Dabigatran 150 mg vs LMWH for Major Orthopedic Surgery (Both Initial and Extended Prophylaxis)
23-26
Outcomes No. of Participants (Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH Risk Difference With Dabigatran 150 mg (95% CI)
Nonfatal PE 5,418 (3 studies) High RR 0.31 (0.04-2.48) Study population
3 per 1,000
Contemporary population (initial prophylaxis)
a
4 per 1,000 2 fewer per 1,000 (from 3 fewer to 5 more)
Contemporary population (full 35-d prophylaxis)
a
6 per 1,000 4 fewer per 1,000 (from 5 fewer to 8 more)
Symptomatic DVT 5,418 (3 studies) Moderate
b,c
due to imprecision RR 1.52 (0.45-5.05)
d
Study population
5 per 1,000
Contemporary population (initial prophylaxis)
a
8 per 1,000 4 more per 1,000 (from 4 fewer to 32 more)
Contemporary population (full 35-d prophylaxis)
a
12 per 1,000 6 more per 1,000 (from 7 fewer to 51 more)
Bleeding requiring reoperation 5,453 (3 studies) High RR 0.83 (0.23-2.97) 2 per 1,000 0 fewer per 1,000 (from 1 fewer to 4 more)
Major nonfatal bleeding
e
5,453 (3 studies) Moderate
c
due to imprecision RR 0.71 (0.42-1.19) Study population
13 per 1,000
Contemporary population (initial prophylaxis)
a
15 per 1,000 4 fewer per 1,000 (from 9 fewer to 3 more)
Total mortality
f
5,425 (3 studies) High RR 2.58 (0.47-14) N/A 1 more per 1,000 (from 0 fewer to 5 more)
See Table 1, 3, and 15 legends for expansion of abbreviations.
a
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
b
Although I
2
is high (. 50%), not downgraded for inconsistency because this was mainly caused by one trial that used enoxaparin 30 mg bid instead of 40 mg/d in the control group.
c
CI interval includes benefi ts for both interventions
d
RR for asymptomatic DVT: 1.2 (95% CI, 1.05-1.37).
e
Major bleeding enoxaparin: all were either specifi cally mentioned to be surgical site or overt with drop in hemoglobin level of 2 g/dL, associated with 2 units blood transfusion requirement, or both.
Major bleeding dabigatran: one in critical organ and all others either specifi cally mentioned to be surgical site or overt with drop in hemoglobin level of 2 g/dL, associated with 2 units blood transfusion
requirement, or both.
f
Deaths enoxaparin: one from VTE, none from bleeding; none from unexplained causes; and none from other causes. Deaths dabigatran: one from VTE, one from bleeding, two from unexplained causes,
and one from other causes.
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Table 21—[Section 2.3.7] Summary of Findings: Apixaban vs LMWH for Major Orthopedic Surgery (Both Initial and Extended Prophylaxis)
14-17
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH Risk Difference With Apixaban (95% CI)
Nonfatal PE 11,964 (4 studies) Moderate
a
due to imprecision RR 1.09 (0.31-3.88) Study population
2 per 1,000
Contemporary population (initial prophylaxis)
b
4 per 1,000 0 more per 1,000 (from 2 fewer to 10 more)
Contemporary population (full 35-d prophylaxis)
b
6 per 1,000 0 more per 1,000 (from 4 fewer to 16 more)
Symptomatic DVT 11,964 (4 studies) Moderate
c
due to imprecision RR 0.41 (0.18-0.95) Study population
3 per 1,000
Contemporary population (initial prophylaxis)
b
8 per 1,000 5 fewer per 1,000 (from 0 fewer to 7 fewer)
Contemporary population (full 35-d prophylaxis)
b
12 per 1,000 7 fewer per 1,000 (from 1 fewer to 10 fewer)
Bleeding requiring reoperation 11,964 (4 studies) High RR 0.82 (0.15-4.58) 1 per 1,000 0 fewer per 1,000 (from 0 fewer to 2 more)
Major nonfatal bleeding 11,964 (4 studies) High RR 0.76 (0.44-1.32) Study population
9 per 1,000
Contemporary population (initial prophylaxis)
b
15 per 1,000 4 fewer per 1,000 (from 8 fewer to 5 more)
Total mortality
d,e
11,964 (4 studies) High RR 1.87 (0.61-5.74) 1 per 1,000 1 more per 1,000 (from 0 fewer to 3 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
CI interval includes two fewer and up to 10 more PEs per 1,000.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
c
CI includes as few as zero to one less symptomatic DVT per 1,000.
d
Deaths enoxaparin: none from VTE, none from bleeding, none from unexplained causes, and four from other causes.
e
Deaths apixaban: fi ve from VTE, none from bleeding, none from unexplained causes, and four from other causes.
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Table 22—[Section 2.3.8] Summary of Findings: IPCD vs VKA for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
105-108
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With VKA Risk Difference With IPCD (95% CI)
Nonfatal PE 534 (4 studies) Low due to imprecision Not estimable
Symptomatic DVT (as inferred from
asymptomatic DVT)
534 (4 studies) Low
a,b
due to indirectness and
imprecision
RR 0.79 (0.5-1.25) Study population
254 per 1,000
c
Contemporary population (initial prophylaxis)
d
8 per 1,000
c
2 fewer per 1,000 (from 4 fewer to 2 more)
Bleeding requiring reoperation 534 (4 studies) Low due to imprecision Not estimable
Major nonfatal bleeding 534 (4 studies) Very low
e-g
due to risk of bias,
indirectness, and imprecision
RR 0.06 (0-1.06) Study population
29 per 1,000
e
Contemporary population (initial prophylaxis)
h
20 per 1,000
e
19 fewer per 1,000 (from 20 fewer to 1 more)
Total mortality
i
301 (2 studies) Moderate
g
due to imprecision RR 0.46 (0.07-3.11) 19 per 1,000 10 fewer per 1,000 (from 18 fewer to 41 more)
See Table 1, 3, and 11 legends for expansion of abbreviations.
a
Asymptomatic DVT is a surrogate outcome.
b
CI includes benefi cial effects for both groups.
c
One trial was stopped early (Francis et al
106
) secondary to more proximal DVTs in device group than anticipated.
d
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]). To determine the baseline risk for VKA, the RR from VKA against placebo was applied (0.44).
e
All events from single study: eight patients required 4 units of bloods transfused, and two had higher intraoperative blood loss recorded. This trial (Francis et al
106
) had a 1-wk warfarin lead-in phase with
a target international normalized ratio of 1.5. Other trials and current practice are to give warfarin the night before, which likely does not increase the bleeding risk during surgery.
f
Adjudication of bleeding events likely not blinded.
g
Very few or zero events from a sample size of , 600.
h
Two-percent alternate bleeding rate from LMWH vs VKA trials meta-analysis.
i
Deaths VKA: one from VTE, none from bleeding, and two from other causes. Deaths IPCD: one from other causes (not VTE or bleeding).
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Prevention of VTE in Orthopedic Surgery Patients
In situations where LMWH is unavailable (eg, for-
mulary restrictions) or the patient has a history of
heparin-induced thrombocytopenia, reasonable alter-
nate choices include apixaban, dabigatran, rivaroxaban,
VKA, fondaparinux, IPCD, or IPCD in combination
with low-dose aspirin. The choice of a second-line
strategy should be guided by its relative effectiveness,
propensity to cause major bleeding (fondaparinux,
rivaroxaban, VKA), and challenges with logistics and
expected compliance (mechanical devices, VKA, and
any drug that requires injections during the out-of-
hospital period). Apixaban 2.5 mg bid taken orally as
well as dabigatran 220 mg (with the availability of an
alternate lower dose of 150 mg) once daily combined
with no monitoring requirement appear to have the
most of these desirable properties. However, long-
term safety data (eg, the absence of clinically relevant
liver toxicity) will be important when using these new
oral antithrombotic agents.
Recommendations
2.3.1. In patients undergoing THA or TKA, irre-
spective of the concomitant use of an IPCD
or length of treatment, we suggest the use of
LMWH in preference to the other agents we
have recommended as alternatives: fondaparinux,
apixaban, dabigatran, rivaroxaban, LDUH (all
Grade 2B) , adjusted-dose VKA, or aspirin (all
Grade 2C) .
Remarks: If started preoperatively, we suggest adminis-
tering LMWH 12 h before surgery. Patients who
place a high value on avoiding the inconvenience of
daily injections with LMWH and a low value on the
limitations of alternative agents are likely to choose
an alternative agent. Limitations of alternative agents
include the possibility of increased bleed ing (which
may occur with fondaparinux, rivaroxaban, and VKA),
possible decreased effi cacy (LDUH, VKA, aspirin,
and IPCD alone), and lack of long-term safety data
(apixaban, dabigatran, and rivaroxaban). Further-
more, patients who place a high value on avoiding
bleeding complications and a low value on its incon-
venience are likely to choose an IPCD over the drug
options.
2.3.2. In patients undergoing HFS, irrespective
of the concomitant use of an IPCD or length of
treatment, we suggest the use of LMWH in
preference to the other agents we have recom-
mended as alternatives: fondaparinux, LDUH
(Grade 2B) , adjusted-dose VKA, or aspirin (all
Grade 2C) .
Remarks: For patients in whom surgery is likely to
be delayed, we suggest that LMWH be initiated
compared with a compression device at the expense of
10 additional major bleeds per 1,000. This closely
balanced estimate is sensitive to the baseline bleed-
ing risk, which was set to 1.5% for LMWH as observed
in trials since 2003. Although the actual observed
bleeding rate was 2.6%, these trials were performed
before our cutoff for contemporary surgical technique
and may not be representative of current practice.
Additionally, there was no blinding, and this could
result in overestimating the number of major bleeds
associated with LMWH ( Table 23 , Figs S76-S79,
Table S20). In summary, low-quality evidence, mostly
because of imprecision and risk of bias, reduces our
confi dence in the estimate of the true effect of an
IPCD against LMWH and tilts our judgment in favor
of LMWH.
Newer-generation IPCDs have the advantage of
being portable and able to record effective use time.
Two trials compared these IPCDs in combination with
low-dose aspirin (81-100 mg) to LMWH in THA
113
and both THA and TKA
114
enrolling . 500 patients.
Results failed to demonstrate or to exclude a benefi -
cial effect of the IPCD on PE due to the low number
of events observed, but fewer asymptomatic DVT
were seen in one of the two trials (pooled RR, 0.47;
95% CI, 0.24-0.91). Fewer major bleeding events
occurred with IPCD in one of the trials with LMWH
but not in the other (pooled estimate RR, 0.04; 95%
CI, 0-0.7). However, all results were imprecise because
of low numbers of events (total of 42 VTE and
11 bleeding events), and the defi nition of bleeding
differed from other trials, making a direct compar-
ison diffi cult ( Table 24 , Figs S80-S82, Table S21).
Overall, there are signifi cant methodologic limita-
tions in the trials of new- and prior-generation IPCD
vs LMWH, which include lack of concealment of
allocation, an unblinded adjudication process for
bleeding, the uncertainty generated by the lack of a
standard defi nition of major bleeding, and a gener-
ally small sample size and variation in the properties
of pneumatic compression devices. These limitations
make it diffi cult to accept the apparent benefi t of
new-generation IPCD in combination with aspirin
over LMWH based on a simple trade-off of throm-
botic events against patient-important bleeding.
2.3.9 Summary—Choice of Thromboprophylaxis:
Selecting from the range of pharmacologic and
mechan ical interventions in major orthopedic sur-
gery, the agent that has similar or superior properties
of effective thromboprophylaxis combined with little
risk of bleed ing and extensive clinical experience is
LMWH; extending thromboprophylaxis up to 35 days
compared with 10 to 14 days results in an additional
reduction of symptomatic VTE with a similar safety
profi le.
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Table 23—[Section 2.3.8] Summary of Findings: IPCD or FID (VFP)
a
vs LMWH for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
31,109-112
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH Risk Difference With IPCD or FID (95% CI)
Nonfatal PE 890 (5 studies) Low
b
due to imprecision RR 2.92 (0.12-71) Study population
0 per 1,000
Contemporary population (initial prophylaxis)
c
4 per 1,000 7 more per 1,000 (from 3 fewer to 80 more)
Symptomatic DVT (as inferred
from asymptomatic DVT)
1,084 (7 studies) Very low
d-f
due to inconsistency,
indirectness, and imprecision
RR 1.38 (0.92-2.06) Study population
172 per 1,000
Contemporary population (initial prophylaxis)
c
8 per 1,000 3 more per 1,000 (from 1 fewer to 8 more)
Bleeding requiring reoperation 908 (4 studies) Low due to imprecision Not estimable
Major bleeding 1,078 (6 studies) Low
g,h
due to risk of bias and
imprecision
RR 0.32 (0.12-0.89) Study population
26 per 1,000
Contemporary population (initial prophylaxis)
c
15 per 1,000 10 fewer per 1,000 (from 2 fewer to 13 fewer)
Total mortality
i
689 (4 studies) Moderate
3
due to imprecision RR 2.82 (0.45-17.57) 3 per 1,000 9 more per 1,000 (from 4 fewer to 21 more)
See Table 1, 3, and 11 legends for expansion of abbreviations.
a
Five of seven trials used a foot pump.
b
Fewer than fi ve events in a sample size of , 900.
c
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for detail how baseline
risks were calculated]).
d
I
2
. 48%.
e
Asymptomatic DVT not a patient-important outcome.
f
CI includes benefi cial effects for both interventions.
g
Adjudication of bleeding events likely not blinded.
h
CI includes zero fewer bleeding events.
i
Deaths LMWH: none from VTE and one from other causes. Deaths IPCD or FID: three from VTE and one from other causes.
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Prevention of VTE in Orthopedic Surgery Patients
Table 24—[Section 2.3.8] Summary of Findings: IPCD Plus ASA vs LMWH for Major Orthopedic Surgery (Initial Prophylaxis Period Up to 14 Days)
113,114
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With LMWH Risk Difference With IPCD 1 ASA (95% CI)
Nonfatal PE 521 (2 studies) Moderate
a
due to imprecision RR 0.73 (0.14-3.7) Study population
11 per 1,000
Contemporary population (initial prophylaxis)
b
4 per 1,000 1 fewer per 1,000 (from 3 fewer to 9 more)
Symptomatic DVT (as inferred from
asymptomatic DVT)
507 (2 studies) Very low
c-e
due to inconsistency,
indirectness, and imprecision
RR 0.47 (0.24-0.91) Study population
100 per 1,000
Contemporary population (initial prophylaxis)
b
8 per 1,000 4 fewer per 1,000 (from 1 fewer to 6 fewer)
Bleeding requiring reoperation 528 (2 studies) Moderate
a
due to imprecision Not estimable
Major nonfatal bleeding 528 (2 studies) Low
a,f
due to risk of bias and
imprecision
RR 0.04 (0-0.72) Study population
42 per 1,000
g
Contemporary population (initial prophylaxis)
b
15 per 1,000
g
14 fewer per 1,000 (from 4 fewer to 15 fewer)
Total mortality 528 (2 studies) Moderate
a
due to imprecision Not estimable
See Table 1, 3, and 11 legends for expansion of abbreviations.
a
Few events in a sample size of , 600.
b
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
c
I
2
. 50%.
d
Asymptomatic DVT not a patient-important outcome.
e
CI crosses the threshold for minimal important difference of 10%.
f
Adjudication for bleeding events likely not blinded.
g
Major bleeding events LMWH: fi ve anemia (requiring prolonged hospitalization), two anemia with hypotension (requiring intervention to prevent impairment), two hematoma (requiring prolonged
hospitalization or rehospitalization), one urinary bleeding (requiring hospitalization), and one increased wound drainage (requiring rehospitalization).
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during the time between hospital admission and sur-
gery but suggest administering LMWH at least 12 h
before surgery. Patients who place a high value on
avoiding the inconvenience of daily injections with
LMWH and a low value on the limitations of alterna-
tive agents are likely to choose an alternative agent.
Limitations of alternative agents include the possi-
bility of increased bleeding (which may occur with
fondaparinux) or possible decreased effi cacy (LDUH,
VKA, aspirin, and IPCD alone). Furthermore, patients
who place a high value on avoiding bleeding compli-
cations and a low value on its inconvenience are likely
to choose an IPCD over the drug options.
2.4. For patients undergoing major orthopedic
surgery, we suggest extending thromboprophy-
laxis in the outpatient period for up to 35 days
from the day of surgery rather than for only 10 to
14 days (Grade 2B ) .
2.5 Use of Combination Thromboprophylaxis
The combined use of anticoagulant thrombopro-
phylaxis with a compression device may further
reduce the rate of VTE. A Cochrane systematic review
examined the effects of adding compression devices
to anticoagulant prophylaxis in mostly orthopedic
populations, but some trials also included other sur-
gical groups.
115
Four trials were included
116-119
; we
identifi ed another study that was published more
recently.
120
We reanalyzed the original data by adding
this additional study without reextracting the data in
the Cochrane review, bringing the total number of
patients included to . 2,400. Some older trials used
LDUH or VKA for thromboprophylaxis, but other-
wise, LMWH was the agent used in both arms.
Adding a compression device reduced the inci-
dence of asymptomatic DVT by . 70% (RR, 0.26;
95% CI, 0.14-0.48). However, there were a number
of methodologic limitations, such as issues with ran-
domization, lack of allocation concealment, and lack
of blinding of personnel performing the DVT screen-
ing, resulting in low-quality evidence overall. There-
fore, the apparently large effect must be interpreted
with caution. Bleeding events were not reported, but
adding a compression device should have little or no
effect on bleeding outcomes ( Table 25 , Figs S83,
S84, Table S22).
Recommendations
2.5. In patients undergoing major orthopedic
surgery, we suggest using dual prophylaxis with
an antithrombotic agent and an IPCD during
the hospital stay (Grade 2C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
Table 25—[Section 2.5] Summary of Findings: IPCD Plus Anticoagulant
a
vs Anticoagulant for Major Orthopedic Surgery
b
(Initial Prophylaxis Period Up to 14 Days)
115,120
Outcomes
No. of Participants
(Studies) Quality of the Evidence (GRADE)
Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With Anticoagulant
Risk Difference With IPCD 1 Anticoagulant
(95% CI)
Nonfatal PE 667 (4 studies) Low
c,d
due to risk of bias and imprecision RR 0.96 (0.06-15) 3 per 1,000 0 fewer per 1,000 (from 3 fewer to 40 more)
Symptomatic DVT (as inferred
from asymptomatic DVT)
2470 (5 studies) Low
c,e
due to risk of bias and indirectness RR 0.26 (0.14-0.48) Study population
50 per 1,000
Contemporary population (initial prophylaxis)
f
8 per 1,000 6 fewer per 1,000 (from 4 fewer to 7 fewer)
See Table 1, 3, and 11 legends for expansion of abbreviations.
a
Anticoagulants used in both treatment and control groups: Borow et al,
116
UFH or VKA; Bradley et al,
117
UFH; Edwards et al,
120
enoxaparin 30 mg bid; Eisele et al,
118
certoparin 3,000 International Units/d;
and Silbersack et al,
119
enoxaparin 40 mg/d.
b
Borow et al
116
included general surgery, orthopedics, gynecology, and vascular surgery patients; Bradley et al
117
included THA; Edwards et al
120
included THA and TKA patients; Eisele et al
118
included total
joint arthroplasty, knee surgery, tumor resection, open fi xation of traumatic fractures, osteotomies, contusion injuries; and Silbersack
120
included THA and TKA.
c
One study was quasi-randomized (Bradley et al
117
), and one study was classifi ed as nonrandomized controlled clinical trial (Borow et al
116
). Randomization method was not clear in three trials
(Edwards et al
120
; Eisele et al
118
; and Silbersack et al,
119
which also did not provide enough information to judge allocation concealment). The personnel performing the DVT screening was not blinded in
Eisele et al and likely not blinded in Edwards et al.
d
Only two events.
e
Mostly asymptomatic events.
f
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for details on how
baseline risks were calculated]).
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Prevention of VTE in Orthopedic Surgery Patients
effects were noted for DVT. In addition, substantial
harms were documented in 2% to 6% of patients
receiving an IVC fi lter. These harms included DVT at
the insertion site, occlusion of the IVC due to throm-
bosis below the fi lter, and migration of the fi lter
( Table 26 , Table S23).
A recent observational study involving . 9,000
patients reported on the use of IVC fi lters in ortho-
pedic surgery.
123
Ninety (0.96%) patients received
IVC fi lters, 55 (0.6%) for prophylaxis. Of these, most
were arthroplasty or spinal surgery patients. Only 13
were fracture surgery patients. The most commonly
cited indication for IVC fi lter prophylaxis was pre-
vious VTE. Only 23 of the 55 (42%) patients with
prophylactic fi lters had a contraindication to antico-
agulation. Of the 51% who had retrievable fi lters, less
than one-half had been removed at 6 months after
placement. Two patients had complications of fi lter
removal (carotid artery puncture in one and fi lter
limb migration to right atrium and lung in the other).
In summary, given the low-quality evidence for ben-
efi t but documented adverse events during place-
ment, during their clinical course, on retrieval, and
during the long term (postphlebitic syndrome), the
balance tips toward defi nite net harm, even in patients
with high bleeding risk.
Recommendation
2.8. In patients undergoing major orthopedic
surgery, we suggest against using IVC fi lter
placement for primary prevention over no throm-
boprophylaxis in patients with an increased
bleeding risk (Table 4) or contraindications to
both pharmacologic and mechanical thrombo-
prophylaxis (Grade 2C) .
2.9 Screening for DVT Before Hospital Discharge
Screening for asymptomatic DVT before dis-
charge has been studied to examine the question of
whether DVT seen on compression DUS should be
treated to prevent symptomatic DVT and PE occur-
ring after hospital discharge. One study that did not
use extended out-of-hospital prophylaxis randomized
patients to discharge DUS (and, if positive, 3 months
of warfarin treatment) vs sham DUS screening and
only warfarin treatment if the patient returned with
symptomatic VTE within 90 days.
124
Study results
failed to demonstrate or exclude a benefi cial effect:
DUS screening detected symptomatic VTE on out-
of-hospital follow-up in four of 518 patients vs sham
screening in fi ve of 506 (RR, 0.78; 95% CI, 0.21-2.9).
One of the patients who was found to have an asymp-
tomatic DVT on DUS screening and was subse-
quently treated with warfarin for 3 months developed
a major bleeding complication ( Table 27 , Table S24).
reporting proper wear time on a daily basis. Efforts
should be made to achieve 18 h of daily compliance.
Patients who place a high value on avoiding the unde-
sirable consequences associated with prophylaxis
with both a pharmacologic agent and an IPCD are
likely to decline use of dual prophylaxis .
2.6. In patients undergoing major orthopedic
surgery and increased risk of bleeding (Table 4),
we suggest using an IPCD or no prophylaxis
rather than pharmacologic treatment (Grade 2C) .
Remarks: We recommend the use of only portable,
battery-powered IPCDs capable of recording and
reporting proper wear time on a daily basis for inpa-
tients and outpatients. Efforts should be made to
achieve 18 h of daily compliance. Patients who place
a high value on avoiding the discomfort and inconve-
nience of an IPCD and a low value on avoiding a
small absolute increase in bleeding with pharmaco-
logic agents when only one bleeding risk factor is pre-
sent (in particular the continued use of antiplatelet
agents) are likely to choose pharmacologic thrombo-
prophylaxis over IPCD.
2.7 Other Considerations
A systematic review examining nonadherence in
outpatient thromboprophylaxis after major orthope-
dic surgery found a nonadherence rate of 13% to 37%
in patients receiving LMWH or fondaparinux.
121
The
additional burden of self-injection, or in organizing
family members or visiting nurses to come in for daily
visits, is believed to contribute to the noncompliance.
Newer agents such as apixaban, dabigatran, or rivar-
oxaban can be taken orally and do not require INR
monitoring, potentially improving adherence.
Recommendation
2.7. In patients undergoing major orthopedic
surgery and who decline or are uncooperative
with injections or an IPCD, we recommend using
apixaban or dabigatran (alternatively rivaroxa-
ban or adjusted-dose VKA if apixaban or dabig-
atran are unavailable) rather than alternative
forms of prophylaxis (all Grade 1B) .
2.8 Use of IVC Filter for Thromboprophylaxis
There have been no randomized trials of the use of
IVC fi lters in the prevention of PE in patients at high
risk for DVT but who do not yet have a documented
DVT (primary prevention). Rajasekhar et al
122
pub-
lished a systematic review of seven observational
studies in patients with trauma. Although the potential
benefi t is substantial (79% relative risk reduction
in PE), the quality of the evidence is very low. Most
studies used historical controls, and inconsistent
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Table 26—[Section 2.8] Summary of Findings: IVC Filter vs No IVC Filter for Major Orthopedic Surgery (Extended Prophylaxis Up to 35 Days)
122
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No IVC
Filter
Risk Difference With Preventive IVC Filter
(95% CI)
Nonfatal PE 1,900 (7 studies) Very low
a-c
due to risk of bias and
indirectness
OR 0.21 (0.09-0.49) Study population
52 per 1,000
Contemporary population (full 35-d prophylaxis)
d
15 per 1,000 12 fewer per 1,000 (from 8 fewer to 14 fewer)
Symptomatic DVT 232 (2 studies) Very low
a,b,e,f
due to risk of bias,
inconsistency, indirectness, and
imprecision
OR 1.6 (0.76-3.8) Study population
130 per 1,000
Contemporary population (full 35-d prophylaxis)
d
28 per 1,000 16 more per 1,000 (from 7 fewer to 71 more)
Complications: 2%-6% (including
insertion site thromboses, IVC
occlusion, and fi lter migration)
0 (4 studies) Very low
a,b
due to risk of bias and
indirectness
Not estimable N/A
See Table 1, 3, 11, and 15 legends for expansion of abbreviations.
a
Historical control population.
b
Patients with trauma.
c
Large effect present, but quality of evidence was not rated up because residual confounding could not be ruled out.
d
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for detail how baseline
risks were calculated]).
e
I
2
5 77%.
f
CI includes benefi ts as well as harm.
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Prevention of VTE in Orthopedic Surgery Patients
A second trial randomized patients to a combina-
tion of DUS screening on discharge and no extended
thromboprophylaxis vs no screening but extended
prophylaxis until day 35.
125
Similar to the fi rst study,
any asymptomatic DVT detected during discharge
DUS screening (day 7 mean) was treated. Again, the
results failed to demonstrate or exclude a benefi cial
effect of predischarge screening (RR, 0.56; 95% CI,
0.17-1.9), and major bleeding events were seen in
only two patients who had been treated after diagno-
sis of asymptomatic DVT based on screening DUS
( Table 28 , Table S25).
In summary, moderate-quality evidence indicates
that DUS screening before hospital discharge does
not result in fewer symptomatic postdischarge VTE.
However, screening for asymptomatic DVT appears
to cause harm by leading to unnecessary anticoagula-
tion for several months, resulting in a higher risk of
major bleeding.
Recommendation
2.9. For asymptomatic patients following major
orthopedic surgery, we recommend against DUS
screening before hospital discharge (Grade 1B) .
3.0 Isolated Lower-Leg Injuries
Distal to the Knee
Lower-leg injuries are a heterogeneous mix and
include fractures below the knee, tendon ruptures,
and cartilage injuries of the knee and ankle. There is
less evidence about the incidence of patient-important
VTE events associated with these injuries compared
with major orthopedic surgery, but the risk of DVT
increases with proximity of the fracture to the knee.
126
A Cochrane systematic review analyzed data from
six randomized trials involving close to 1,500 patients
who required lower-leg immobilization for at least
1 week and comparing once-daily LMWH vs no throm-
boprophylaxis continued, typically, until the cast or
brace was removed.
127
We identifi ed an additional
multicenter study that has remained published only
in abstract form
128
and updated the meta-analysis by
performing our own analysis. We did not reextract
the data found in the Cochrane review.
PE was diagnosed in two of 585 patients in the pla-
cebo group and one of 576 in the LMWH group.
Results failed to demonstrate or exclude a benefi cial
effect of LMWH on symptomatic DVT (RR, 0.34;
95% CI, 0.09-1.28), and two major bleeding events
were seen with LMWH vs none in the placebo group.
The patient population was quite heterogeneous, and
patients with a higher risk for VTE were excluded.
Detailed information was not provided with regard to
immobility.
Table 27—[Section 2.9] Summary of Findings: DUS Screening Before Discharge vs No Screening After Major Orthopedic Surgery
124
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No Screening
Risk Difference With DUS Screening on
Discharge (95% CI)
All nonfatal symptomatic VTE
b
1,024 (1 study) Moderate
a
due to imprecision RR 0.78 (0.21-2.9) Study population
10 per 1,000
Contemporary population
c
28 per 1,000 6 fewer per 1,000 (from 22 fewer to 53 more)
Major nonfatal bleeding 1,024 (1 study) Moderate
a
due to imprecision RR 2.93 (0.12-72) 0 per 1,000 2 more per 1,000 (from 2 fewer to 6 more)
Total mortality 1,024 (1 study) Moderate
a
due to imprecision Not estimable N/A
DUS 5 Doppler (or duplex) ultrasound. See Table 1, 3, and 15 legends for expansion of abbreviations.
a
Fewer than 10 events total in a sample size of 1,000.
b
Predischarge sham screening group: two nonfatal PE and three symptomatic DVT on follow-up up to 90 d postoperation. Before discharge, sham DUS detected zero asymptomatic DVT. Predischarge
screening group: zero nonfatal PE, four symptomatic DVT on follow-up up to 90 d postoperation. Before discharge, DUS detected 13 asymptomatic DVT, of which all received treatment with warfarin
(international normalized ratio 2-3) causing one major bleed at the surgical site.
c
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for detail how baseline
risks were calculated]).
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Table 28—[Section 2.9] Summary of Findings: DUS Screening Before Discharge Plus No Extended Prophylaxis vs No Screening Plus Extended Prophylaxis After
Major Orthopedic Surgery
125
Outcomes
No. of Participants
(Studies)
Quality of the Evidence
(GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With No
Screening 1 Extended Prophylaxis
Risk Difference With DUS Screening 1 No
Extended Prophylaxis (95% CI)
All nonfatal symptomatic VTE
a
346 (1 study) Moderate
b,c
due to imprecision RR 0.56 (0.17-1.9) Study population
41 per 1,000
Contemporary population
d
28 per 1,000 12 fewer per 1,000 (from 23 fewer to 25 more)
Nonfatal major bleeding 346 (1 study) Moderate
c
due to imprecision RR 4.94 (0.24-102) 0 per 1,000 6 more per 1,000 (from 5 fewer to 17 more)
Total mortality 346 (1 study) Moderate
c
due to imprecision RR 0.33 (0.01-8) 6 per 1,000
e
6 fewer per 1,000 (from 6 fewer to 17 more)
See Table 1, 3, and 27 legends for expansion of abbreviations.
a
No predischarge screening and extended-prophylaxis group: one nonfatal PE, fi ve symptomatic DVT on follow-up up to 90 d postoperation. Predischarge screening group: one nonfatal PE and three
symptomatic DVT on follow-up up to 90 d postoperation. Before discharge, DUS detected 64 asymptomatic DVT, of which all received treatment with LMWH for 10 d and then prophylaxis dose until day
35, causing two major bleeds (hematuria requiring hospital admission).
b
Reporting unclear with regard to blinding of outcome adjudication. Allocation concealment unclear. Assumed to have small effect of confi dence in effect. Not downgraded.
c
Fewer than 10 events in a study of , 400.
d
Contemporary surgical population from which baseline risk of patient-important outcomes has been derived (contemporary era surgical technique, early mobilization, etc [see text for detail how baseline
risks were calculated]).
e
Fatal PE.
The results did not establish the benefi t of throm-
boprophylaxis in the patients enrolled. Results from
higher-risk populations may, however, be reason-
ably extrapolated to patients at higher risk of DVT
(who were excluded from these studies), particu-
larly those with prior VTE ( Table 29 , Figs S85-S87,
Table S26).
Recommendation
3.0. We suggest no prophylaxis rather than phar-
macologic thromboprophylaxis in patients with
isolated lower-leg injuries requiring leg immo-
bilization (Grade 2C) .
4.0 Knee Arthroscopy
Knee arthroscopy and arthroscopic-assisted knee
surgery is performed frequently and most often as
outpatient procedures in a relatively young patient
population. A systematic review
129
that included
four RCTs examined the use of LMWH vs no throm-
boprophylaxis after arthroscopic knee surgery in
527 patients.
130-133
The knee surgeries included were
anterior cruciate ligament reconstruction, meniscecto-
mies, and other diagnostic and therapeutic arthros-
copies. No trial was blinded to patients, outcome
adjudication was blinded in only two trials, and allo-
cation concealment was unclear or not done in
three trials. One trial was stopped early for benefi t.
Although asymptomatic DVTs were signifi cantly
reduced (RR, 0.16; 95% CI, 0.05-0.52), this was based
on a total of only 23 events, and there were only
ve symptomatic DVTs reported (LMWH one of
262 vs four of 265) and one symptomatic PE, which
was seen in the LMWH group.
131
No major bleed ing
events were reported, and there were no bleed ing
events requiring reoperation. Based on the low-quality
evidence from these trials, one would expect nine
fewer symptomatic DVTs and four more nonfatal PE
per 1,000, but the sample size was not large enough
to estimate the possible increase in bleeding compli-
cations ( Table 30 , Table S27).
These ndings are in contrast to a recent trial that
randomized . 1,700 patients to either LMWH or
GCS.
134
This study examined three groups: 14-day
nadroparin, 7-day nadroparin, and GCS. The 14-day
LMWH arm was stopped early because harms poten-
tially outweighed the benefi ts. Although numerically
more major bleeds were reported in the LMWH
group, including one bleeding event requiring reop-
eration, the effect estimate failed to demonstrate or
exclude a detrimental effect on major bleeding events
because of low event rates (RR, 2.1; 95% CI, 0.44-10).
Signifi cantly fewer symptomatic DVT were observed
in the LMWH groups (RR, 0.2; 95% CI, 0.07-0.62),
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Prevention of VTE in Orthopedic Surgery Patients
although this was based on only 16 events. The over-
all quality of evidence from this study was judged
to be moderate because of imprecision ( Table 31 ,
Table S28).
Given the close balance between the potential risk
for major bleeding (three more per 1,000), the occur-
rence of a bleed requiring reoperation in the LMWH
group and the generally low rate of VTE (1.5%-2%,
with 14 fewer symptomatic VTE per 1,000 expected
with LMWH), routine thromboprophylaxis after an
arthroscopic procedure does not appear warranted.
However, evidence of benefi t from higher-risk popu-
lations may be reasonably extrapolated to patients at
higher risk of DVT, particularly those with prior VTE
( Tables 30, 31 , Tables S27, S28).
Recommendation
4.0. For patients undergoing knee arthroscopy
without a history of prior VTE, we suggest no
thromboprophylaxis rather than prophylaxis
(Grade 2B) .
5.0 Direction of Future Studies
Large, practical, RCTs are needed to further study
thromboprophylaxis after orthopedic surgeries. Those
trials should avoid screening for asymptomatic VTE
and ensure that symptomatic VTE is recorded up to
3 months after surgery, regardless of duration of
intervention. To ensure suffi cient methodologic rigor,
independent adjudication of outcomes not only for
VTE but also for major bleeding events are essential,
as is ensuring allocation concealment through cen-
tral randomization, blinding of data collectors (and
optimally patients and caregivers, which may or may
not be possible with mechanical devices), and using
methods to limit losses to follow-up. In addition to
independent adjudication, it is important to provide
more-precise and clinically important operational
defi nitions for postoperative bleeding and drainage
at the surgical site. Surgical site bleeding and drainage
should be routinely reported in clinical trials.
Relative risk differentials for distal vs proximal
DVT and portable devices using wireless tech-
nology for compliance data for inpatients vs outpa-
tients need to be explored . At a minimum, trials
that use mechanical devices for thromboprophylaxis
should be able to accurately record and report proper
use and daily and cumulative wear time to docu-
ment compliance. In summary, trials with patient-
important end points and long follow-up should be
conducted to evaluate the potential benefi ts vs risks
and downsides of antithrombotic regimens in nonse-
lected populations.
135
Table 29—[Section 3.0] Summary of Findings: LMWH vs Usual Care for Lower-Leg Immobilization
127,128
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With Usual Care Risk Difference With LMWH (95% CI)
Nonfatal PE 1,161 (4 studies) Low
a
due to imprecision RR 0.75 (0.05-10) 3 per 1,000 1 fewer per 1,000 (from 3 fewer to
31 more)
Symptomatic DVT 1568 (5 studies) Low
b,c
due to inconsistency and
imprecision
RR 0.34 (0.09-1.28) 24 per 1,000 16 fewer per 1,000 (from 22 fewer to
7 more)
Major nonfatal bleeding
d
1,721 (6 studies) Moderate
a
due to imprecision RR 5.14 (0.25-106) Study population
N/A
Alternate bleeding risk
e
1 per 1,000 4 more per 1,000 (from 1 fewer to
21 more)
See Table 1, 3, and 15 legends for expansion of other abbreviations.
a
Very few events. CI includes benefi ts and harms.
b
Although the overlapping CI do not indicated major inconsistency, the clinical heterogeneity of included patient populations as well as the heterogeneity in absolute risk in the control group that included
zero events in one study (152 control patients) crossed our threshold for downgrading in this category.
c
CI fails to exclude harm.
d
Major bleeding LMWH: one retroperitoneal bleeding and one discontinuation of LMWH because of bleeding.
e
Alternate bleeding risk of one per 1,000 provided to illustrate increase in absolute bleeding rates.
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Table 30—[Section 4.0] Summary of Findings: LMWH vs No Prophylaxis for Knee Condition Requiring Arthroscopic Intervention
129
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With Usual Care Risk Difference With LMWH (95% CI)
Nonfatal PE 529 (4 studies) Low
a,b
due to risk of bias and imprecision Not estimable 0 per 1,000 4 more per 1,000 (from 4 fewer to 11 more)
Symptomatic DVT 527 (4 studies) Low
a,c
due to risk of bias and imprecision RR 0.42 (0.06 to 3.14)
d
15 per 1,000 9 fewer per 1,000 (from 14 fewer to 32 more)
Major nonfatal bleed 527 (4 studies
e
) Low
a,b
due to risk of bias and imprecision Not estimable N/A
See Table 1, 3, 15, and 29 legends for expansion of abbreviations.
a
No trial was blinded to patients, outcome adjudication was only blinded in two trials, allocation concealment was unclear or not done in three of four trials, and one trial was stopped early for benefi t.
b
Very few events.
c
CI includes benefi ts and harms.
d
Asymptomatic events: three of 262 in LMWH vs 20 of 265 with usual care.
e
Minor bleeding events were reported, but no major bleeds and no bleeding requiring reoperation.
Table 31—[Section 4.0] Summary of Findings: LMWH vs GCS for Knee Condition Requiring Arthroscopic Intervention
134
Outcomes No. of Participants (Studies) Quality of the Evidence (GRADE) Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With GCS Risk Difference With LMWH (95% CI)
Nonfatal PE 1,761 (1 study) Moderate
a
due to imprecision RR 1.2 (0.22-6.5) 3 per 1,000 1 more per 1,000 (from 2 fewer to 17 more)
Symptomatic DVT 1,761 (1 study) High RR 0.2 (0.07-0.62) 18 per 1,000 15 fewer per 1,000 (from 7 fewer to 17 fewer)
Bleeding requiring reoperation
b
1,761 (1 study) Moderate
c
due to imprecision Not estimable 0 per 1,000 1 more per 1,000 (from 1 fewer to 3 more)
Nonfatal major bleeding
d
1,761 (1 study) Moderate
e
due to imprecision RR 2.1 (0.44-10) 3 per 1,000 3 more per 1,000 (from 2 fewer to 27 more)
See Table 1 and 3 legends for expansion of abbreviations.
a
CI includes benefi cial effects for both LMWH and GCS.
b
One event observed in the 7-d LMWH arm.
c
Only one event.
d
GCS: one hematoma associated with a drop in hemoglobin level of . 2 g/dL and one hemarthrosis. LMWH for 14-d group: one hemarthrosis, one GI bleed requiring readmission. LMWH for 7-d group:
one hematoma associated with a drop in hemoglobin level of . 2 g/dL and four hemarthrosis.
e
Failed to exclude increased bleeding risk with GCS.
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Prevention of VTE in Orthopedic Surgery Patients
Comparisons where additional data are particularly
needed include the following:
Major orthopedic surgery: IPCD ( aspirin) vs
LMWH
HFS: preoperative IPCD plus LMWH fol-
lowed by postoperative IPCD plus LMWH
vs preoperative IPCD alone followed by post-
operative IPCD plus LMWH
• Major orthopedic surgery: aspirin vs LMWH
Major orthopedic surgery: mechanical device for
35 days vs 10 to 14 days
Lower-leg injury: anticoagulant thrombopro-
phylaxis vs aspirin stratifi ed by type of injury and
procedure and expected degree of immobility
The infl uence of antithrombotic regimens, sepa-
rately and combined, on perioperative and post-
operative venous and arterial thromboembolism.
Conclusions
VTE is an important complication after major
orthopedic surgery, and numerous approaches to its
prevention have been evaluated. This article reviews
the effectiveness and safety of these approaches and
provides guidelines using methods that differ some-
what from prior versions. First, recommendations
have been based on patient-important outcomes that
include symptomatic PE and DVT, bleeding, and
death, whereas asymptomatic venous thrombosis
identifi ed by screening tests are not used as a basis
for the guidelines. After our review, we recommend
that all patients undergoing major orthopedic surgery
receive prophylaxis with a pharmacologic agent or
IPCD for a minimum of 10 to 14 days, and we suggest
extending prophylaxis for up to 35 days. In patients at
an increased risk of bleeding, we suggest the use of
an IPCD or no prophylaxis. We do not recommend
the use of IVC fi lter placement for primary preven-
tion, and we recommend against DUS screening. For
patients with isolated lower-extremity injuries requir-
ing immobilization and for patients undergoing knee
arthroscopy without a history of VTE, we suggest no
thromboprophylaxis. Adherence to these guidelines
will minimize the adverse consequences of VTE
following orthopedic surgery.
Acknowledgments
Author contributions: As Topic Editor, Dr Falck-Ytter oversaw
the development of this article, including the data analysis and sub-
sequent development of the recommendations contained herein.
Dr Falck-Ytter: served as Topic Editor .
Dr Francis: served as Deputy Editor.
Dr Johanson: served as a panelist.
Dr Curley: served as frontline clinician.
Dr Dahl: served as a panelist.
Dr Schulman: served as a panelist.
Dr Ortel: served as a panelist.
Dr Pauker: served as a panelist.
Dr Colwell: served as a panelist.
Financial/nonfi nancial disclosures: The authors of this guide-
line provided detailed confl ict of interest information related to
each individual recommendation made in this article. A grid of these
disclosures is available online at http://chestjournal.chestpubs.org/
content/141/2_suppl/e278S/suppl/DC1. In summary, the authors have
reported to CHEST the following confl icts of interest: Dr Francis
received research grant support from the National Heart, Lung,
and Blood Institute and Eisai Co, Ltd, and served as a steering
committee member for a clinical trial sponsored by Eisai Co,
Ltd. Dr Dahl has participated in scientifi c and speaking activ-
ities directly and indirectly sponsored by Boehringer Ingelheim
GmbH, GlaxoSmithKline plc, Sanofi -Aventis LLC, Bayer Health-
care Pharmaceuticals, and Pfi zer Inc. Dr Ortel received research
grant support from the National Heart, Lung, and Blood Institute;
the Centers for Disease Control and Prevention; Eisai Co, LtD;
GlaxoSmithKline plc; Pfi zer Inc; and Daiichi Sankyo, and has been
a consultant for Sanofi -Aventis LLC and Boehringer Ingelheim
GmbH. Dr Ortel has also received grant funds and speaking fees
from Instrumentation Laboratories, Inc. Dr Colwell has been a
consultant and received research funds from Medical Compres-
sion Systems, Ltd, but recused himself in determination of use of
compression devices for the Antithrombotic Therapy and Preven-
tion of Thrombosis 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Drs Falck-Ytter,
Johanson, Curley, Schulman, and Pauker have reported that no
potential confl icts of interest exist with any companies/organiza-
tions whose products or services may be discussed in this article .
Role of sponsors: The sponsors played no role in the develop-
ment of these guidelines. Sponsoring organizations cannot rec-
ommend panelists or topics, nor are they allowed prepublication
access to the manuscripts and recommendations. Guideline panel
members, including the chair, and members of the Health & Sci-
ence Policy Committee are blinded to the funding sources. Fur-
ther details on the Confl ict of Interest Policy are available online
at http://chestnet.org .
Endorsements: This guideline is endorsed by the American
Association for Clinical Chemistry, the American College of Clin-
ical Pharmacy, the American Society of Health-System Pharmacists,
the American Society of Hematology, and the International Soci-
ety of Thrombosis and Hematosis.
Additional information: The supplement Figures and Tables
can be found in the Online Data Supplement at http://chestjournal.
chestpubs.org/content/141/2_suppl/e278S/suppl/DC1.
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