Guidline DVT Hom

CLINICAL GUIDELINES
American Society of Hematology 2019 guidelines for management of

venous thromboembolism: prevention of venous thromboembolism in
surgical hospitalized patients
David R. Anderson,1 Gian Paolo Morgano,2 Carole Bennett,3 Francesco Dentali,4 Charles W. Francis,5 David A. Garcia,6 Susan R. Kahn,7
Maryam Rahman,8 Anita Rajasekhar,9 Frederick B. Rogers,10 Maureen A. Smythe,11,12 Kari A. O. Tikkinen,13,14 Adolph J. Yates,15
Downloaded from https://ashpublications.org/bloodadvances/article-pdf/3/23/3898/1544272/advancesadv2019000975.pdf by guest on 10 February 2020

Tejan Baldeh,2 Sara Balduzzi,16 Jan L. Brożek,2,17 Itziar Etxeandia-Ikobaltzeta,2 Herman Johal,18 Ignacio Neumann,19 Wojtek Wiercioch,2
Juan José Yepes-Nuñez,20 Holger J. Schünemann,2,17 and Philipp Dahm21,22
1
Department of Medicine, Dalhousie University, Halifax, NS, Canada; 2Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON,
Canada; 3Shreveport, LA; 4Department of Medicine and Surgery, Insubria University, Varese, Italy; 5Wilmot Cancer Center, University of Rochester Medical Center, Rochester,
NY; 6Division of Hematology, Department of Medicine, University of Washington Medical Center, University of Washington School of Medicine, Seattle, WA; 7Department of
Medicine, McGill University and Lady Davis Institute, Montreal, QC, Canada; 8Lillian S. Wells Department of Neurosurgery and 9Division of Hematology and Oncology,
Department of Medicine, University of Florida, Gainesville, FL; 10Trauma and Acute Care Surgery, Penn Medicine Lancaster General Health, Lancaster, PA; 11Department of
Pharmaceutical Services, Beaumont Hospital, Royal Oak, MI; 12Department of Pharmacy Practice, Wayne State University, Detroit, MI; 13Department of Urology and
14
Department of Public Health, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 15Department of Orthopedic Surgery, University of Pittsburgh Medical
Center, Pittsburgh, PA; 16Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy; 17Department of Medicine
and 18Center for Evidence-Based Orthopaedics, Division of Orthopaedic Surgery, McMaster University, Hamilton, ON, Canada; 19Department of Internal Medicine, School of
Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; 20School of Medicine, Universidad de los Andes, Bogotá, Colombia; 21Urology Section, Minneapolis VA
Health Care System, Minneapolis, MN; and 22Department of Urology, University of Minnesota, Minneapolis, MN
Background: Venous thromboembolism (VTE) is a common source of perioperative morbidity and

mortality.
Objective: These evidence-based guidelines from the American Society of Hematology (ASH) intend
to support decision making about preventing VTE in patients undergoing surgery.
Methods: ASH formed a multidisciplinary guideline panel balanced to minimize bias from conflicts
of interest. The McMaster University GRADE Centre supported the guideline-development process,
including performing systematic reviews. The Grading of Recommendations Assessment, Development
and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which
were subject to public comment.
Results: The panel agreed on 30 recommendations, including for major surgery in general (n 5 8),
orthopedic surgery (n 5 7), major general surgery (n 5 3), major neurosurgical procedures (n 5 2),
urological surgery (n 5 4), cardiac surgery and major vascular surgery (n 5 2), major trauma (n 5 2), and
major gynecological surgery (n 5 2).
Conclusions: For patients undergoing major surgery in general, the panel made conditional recommen-
dations for mechanical prophylaxis over no prophylaxis, for pneumatic compression prophylaxis over
graduated compression stockings, and against inferior vena cava filters. In patients undergoing total hip or
total knee arthroplasty, conditional recommendations included using either aspirin or anticoagulants, as well
as for a direct oral anticoagulant over low-molecular-weight heparin (LMWH). For major general surgery, the
panel suggested pharmacological prophylaxis over no prophylaxis, using LMWH or unfractionated heparin.
For major neurosurgery, transurethral resection of the prostate, or radical prostatectomy, the panel
suggested against pharmacological prophylaxis. For major trauma surgery or major gynecological surgery,
the panel suggested pharmacological prophylaxis over no prophylaxis.
Summary of recommendations
These American Society of Hematology (ASH) guidelines are based on updated and original systematic
reviews of evidence conducted by researchers and developed under the direction of the McMaster
Submitted 13 September 2019; accepted 22 October 2019. DOI 10.1182/ The full-text version of this article contains a data supplement.
bloodadvances.2019000975.
3898 10 DECEMBER 2019 x VOLUME 3, NUMBER 23

University GRADE Centre with international collaborators. The c For researchers: this recommendation is likely to be strength-
panel followed best practice for guideline development recom- ened (for future updates or adaptation) by additional research.
mended by the Institute of Medicine (now the National Academy of An evaluation of the conditions and criteria (and the related
Medicine) and the Guidelines International Network.1-4 The panel judgments, research evidence, and additional considerations)
used the Grading of Recommendations Assessment, Development that determined the conditional (rather than strong) recommen-
and Evaluation (GRADE) approach5,6 to assess the certainty in the dation will help to identify possible research gaps.
evidence and formulate recommendations.
The population of postoperative patients is heterogeneous with Recommendations
regard to the degree of risk of venous thromboembolism (VTE), Mechanical vs pharmacological prophylaxis for patients
depending on intrinsic patient factors and those factors that are undergoing major surgery
related to the type of surgery, mobilization, anatomic location of the
RECOMMENDATIONS 1 TO 5. For patients undergoing major surgery,
procedures, and risk of bleeding. Surgeons have a long history of

accepting prophylactic measures against VTE, be they mechanical the ASH guideline panel suggests the following:
or pharmacological. 1. Using pharmacological prophylaxis or mechanical prophylaxis
(conditional recommendation based on low certainty in the
evidence of effects ÅÅ◯◯)
Interpretation of strong and
conditional recommendations 2. For patients who do not receive pharmacologic prophylaxis,
using mechanical prophylaxis over no mechanical prophylaxis
The strength of a recommendation is expressed as strong (“the (conditional recommendation based on very low certainty in the
guideline panel recommends…”) or conditional (“the guideline evidence of effects Å◯◯◯).
panel suggests…”) and has the following interpretation:
3. For patients who receive mechanical prophylaxis, using inter-
Strong recommendation mittent compression devices over graduated compression
stockings (conditional recommendation based on very low
c For patients: most individuals in this situation would want the
certainty in the evidence of effects Å◯◯◯).
recommended course of action, and only a small proportion
would not. 4. For patients who receive pharmacologic prophylaxis, using
combined prophylaxis with mechanical and pharmacological
c For clinicians: most individuals should follow the recommended
methods over prophylaxis with pharmacological agents alone
course of action. Formal decision aids are not likely to be needed
(conditional recommendation based on very low certainty in
to help individual patients make decisions consistent with their
the evidence of effects Å◯◯◯).
values and preferences.
5. Depending on the risk of VTE and bleeding based on the
c For policy makers: the recommendation can be adopted as
individual patient and the type of surgical procedure, using
policy in most situations. Adherence to this recommendation
combined prophylaxis or mechanical prophylaxis alone
according to the guideline could be used as a quality criterion or
(conditional recommendation based on low certainty in the
performance indicator.
evidence of effects ÅÅ ◯◯).
c For researchers: the recommendation is supported by credible
Remarks: For patients considered at high risk of bleeding, the
research or other convincing judgments that make additional
balance of effects may favor mechanical methods over pharmaco-
research unlikely to alter the recommendation. On occasion, a
logical prophylaxis. For patients considered at high risk for VTE,
strong recommendation is based on low or very low certainty in
combined prophylaxis is particularly favored over mechanical or
the evidence. In such instances, further research may provide
pharmacological prophylaxis alone.
important information that alters the recommendation.
Prophylactic insertion of an inferior vena cava filter
Conditional recommendation
RECOMMENDATION 6. For patients undergoing major surgery, the
c For patients: the majority of individuals in this situation would ASH guideline panel suggests against using inferior vena cava
want the suggested course of action, but many would not. De- (IVC) filters for prophylaxis of VTE (conditional recommendation
cision aids may be useful in helping patients to make decisions based on very low certainty in the evidence of effects, Å◯◯◯).
consistent with their individual risks, values, and preferences.
Timing of antithrombotic prophylaxis
c For clinicians: different choices will be appropriate for individ-
RECOMMENDATIONS 7 AND 8. For patients undergoing major
ual patients, and clinicians must help each patient to arrive at a
surgery, the ASH guideline panel suggests using extended
management decision consistent with the patient’s values and
antithrombotic prophylaxis over short-term antithrombotic pro-
preferences. Decision aids may be useful in helping individuals
phylaxis (conditional recommendation based on very low certainty in
to make decisions consistent with their individual risks, values,
the evidence of effects Å◯◯◯). The ASH guideline panel further
and preferences.
suggests using early or delayed antithrombotic prophylaxis (condi-
c For policy makers: policy-making will require substantial debate tional recommendation based on very low certainty in the evidence
and involvement of various stakeholders. Performance mea- of effects Å◯◯◯). Remarks: Extended prophylaxis was generally
sures about the suggested course of action should focus considered as beyond 3 weeks (range, 19-42 days) compared with
on whether an appropriate decision-making process is duly short-term prophylaxis, which was considered as up to 2 weeks
documented. (range, 4-14 days). Twelve hours following surgery was arbitrarily
10 DECEMBER 2019 x VOLUME 3, NUMBER 23 ASH 2019 VTE GUIDELINES: SURGICAL PATIENTS 3899
selected to be the cutoff point between early and late postoperative immobility following surgery. In addition, pharmacological prophylaxis
antithrombotic administration. could be considered for patients undergoing major neurosurgical
procedures that carried a lower risk for major bleeding and in those
Orthopedic surgery patients with persistent mobility restrictions after the bleeding risk
RECOMMENDATIONS 9 TO 13. For patients undergoing total hip declines following surgery.
arthroplasty or total knee arthroplasty, the ASH guideline panel
suggests using aspirin (ASA) or anticoagulants (conditional Urological procedures
recommendation based on very low certainty in the evidence of RECOMMENDATIONS 21 AND 22. For patients undergoing transurethral
effects Å◯◯◯). When anticoagulants are used, the panel suggests resection of the prostate (TURP), the ASH guideline panel suggests
using direct oral anticoagulants (DOACs) over low-molecular- against using pharmacological prophylaxis (conditional recommen-
weight heparin (LMWH) (conditional recommendation based on dation based on very low certainty in the evidence of effects
moderate certainty in the evidence of effects ÅÅÅ◯); the panel Å◯◯◯). For the subset of patients undergoing TURP for whom

suggests using any of the DOACs approved for use (condi- pharmacological prophylaxis is used, the ASH guideline panel
tional recommendation based on low certainty in the evidence of suggests using LMWH or UFH (conditional recommendation
effects ÅÅ ◯◯). If a DOAC is not used, the panel suggests using based on very low certainty in the evidence of effects Å◯◯◯).
LMWH rather than warfarin (conditional recommendation based Remark: Patients with other risk factors for VTE (such as history
on very low certainty in the evidence of effects Å◯◯◯) and of VTE, thrombophilia, or malignancy) may benefit from pharma-
recommends LMWH rather than unfractionated heparin (UFH) cological prophylaxis.
(strong recommendation based on moderate certainty in the evidence RECOMMENDATIONS 23 AND 24. For patients undergoing radical
of effects ÅÅÅ◯). prostatectomy, the ASH guideline panel suggests against using
RECOMMENDATIONS 14 AND 15. For patients undergoing hip fracture pharmacological prophylaxis (conditional recommendation based
repair, the ASH guideline panel suggests using pharmacological on very low certainty in the evidence of effects Å◯◯◯). For patients
prophylaxis over no pharmacological prophylaxis (conditional undergoing radical prostatectomy in whom pharmacological pro-
recommendation based on very low certainty in the evidence of phylaxis is used, the ASH guideline panel suggests using LMWH
effects Å◯◯◯) and suggests using LMWH or UFH (conditional or UFH (conditional recommendation based on very low certainty
recommendation based on very low certainty in the evidence of in the evidence of effects Å◯◯◯). Remark: Patients undergoing
effects Å◯◯◯). an extended node dissection and/or open radical prostatectomy
may have a higher VTE risk and may potentially benefit from
Major general surgery pharmacological prophylaxis.
RECOMMENDATIONS 16 AND 17. For patients undergoing major general Cardiac or major vascular surgery
surgery, the ASH guideline panel suggests using pharmacologi-
RECOMMENDATIONS 25 AND 26. For patients undergoing cardiac or
cal prophylaxis over no pharmacological prophylaxis (conditional
major vascular surgery, the ASH guideline panel suggests using
recommendation based on low certainty in the evidence of effects
pharmacological prophylaxis or no pharmacological prophylaxis (condi-
ÅÅ◯◯) and suggests using LMWH or UFH (conditional recom-
tional recommendation based on very low certainty in the evidence of
mendation based on very low certainty in the evidence of effects
effects Å◯◯◯). When pharmacological prophylaxis is used, the panel
Å◯◯◯).
suggests using LMWH or UFH (conditional recommendation based on
Laparoscopic cholecystectomy very low certainty in the evidence of effects Å◯◯◯).
RECOMMENDATION 18. For patients undergoing laparoscopic chole- Major trauma
cystectomy, the ASH guideline panel suggests against using
RECOMMENDATION 27A. For patients experiencing major trauma and
pharmacological prophylaxis (conditional recommendation based
who are at low to moderate risk for bleeding, the ASH guideline
on very low certainty in the evidence of effects Å◯◯◯). Remark:
panel suggests using pharmacological prophylaxis over no pharma-
Patients with other risk factors for VTE (such as history of VTE,
cological prophylaxis (conditional recommendation based on very low
thrombophilia, or malignancy) may benefit from pharmacological
certainty in the evidence of effects Å◯◯◯).
prophylaxis.
RECOMMENDATION 27B. For patients experiencing major trauma and
Major neurosurgical procedures who are at high risk for bleeding, the ASH guideline panel
RECOMMENDATIONS 19 AND 20. For patients undergoing major suggests against pharmacological prophylaxis (conditional recom-
neurosurgical procedures, the ASH guideline panel suggests mendation based on very low certainty in the evidence of effects
against using pharmacological prophylaxis (conditional recom- Å◯◯◯).
mendation based on very low certainty in the evidence of effects RECOMMENDATION 28. For patients experiencing major trauma in
Å◯◯◯). For the subset of patients undergoing major neurosur- whom pharmacological prophylaxis is used, the ASH guideline
gical procedures for whom pharmacological prophylaxis is used, panel suggests using LMWH or UFH (conditional recommendation
the ASH guideline panel suggests using LMWH over UFH (condi- based on low certainty in the evidence of effects ÅÅ◯◯).
tional recommendation based on very low certainty in the evidence of
effects Å◯◯◯). Remarks: Patients undergoing major neurosurgical Major gynecological surgery
procedures are expected to receive prophylaxis with mechanical RECOMMENDATIONS 29 AND 30. For patients undergoing major
methods. Pharmacological prophylaxis may be warranted in a higher- gynecological surgery, the ASH guideline panel suggests using
risk subgroup of patients, such as those experiencing prolonged pharmacological prophylaxis over no pharmacological prophylaxis
3900 ANDERSON et al 10 DECEMBER 2019 x VOLUME 3, NUMBER 23

(conditional recommendation based on very low certainty in the (conditional recommendation based on very low certainty in the
evidence of effects Å◯◯◯) and suggests using LMWH or UFH evidence of effects Å◯◯◯).
Introduction
Aim of these guidelines and specific objectives prophylaxis. For evaluation of the pharmacological methods for
the prevention of VTE, the panel weighed the benefits and risks
The purpose of these guidelines is to provide evidence-based of the various options for individual surgical procedures or
recommendations about the prevention of VTE for patients un- domains, such as hip or knee arthroplasty, general surgery, or
dergoing major surgical procedures. The target audience includes urological or neurosurgical procedures.
patients, surgeons, intensivists, internists, hematologists, general

practitioners, hospitalists, other clinicians, pharmacists, and deci- For mechanical interventions, such as graduated or mechanical
sion makers. Policy makers interested in these guidelines include compression devices or IVC filters, the effectiveness of these
those involved in developing local, national, or international programs interventions was assessed across all surgical domains. Likewise,
aiming to safely reduce the incidence of VTE and/or to evaluate direct other questions, such as the duration of pharmacological pro-
and indirect harms and costs related to VTE and its prevention. This phylaxis and timing of the initiation of pharmacological prophylaxis,
document may also serve as the basis for adaptation by local, were also assessed across all surgical domains.
regional, or national guideline panels. The target populations included patients who underwent surgery for
Description of the health problem cancer or noncancer-related procedures. Patients hospitalized for
major trauma were included whether they underwent surgery or not.
Deep vein thrombosis (DVT) and pulmonary embolism (PE) (collectively,
VTE) are well-recognized, clinically important, and potentially Methods
devastating complications that may occur following major surgical
procedures, defined as any surgical intervention that carries greater The guideline panel developed and graded the recommendations
than minimal risk, is performed in the operating room, and requires and assessed the certainty in the supporting evidence following the
specialized training. Before the era of the routine use of effective GRADE approach.5,6,12-16 The overall guideline-development pro-
prophylaxis, VTE was a common cause of morbidity and mortality cess, including funding of the work, panel formation, management
following major surgery. It has been estimated to cause .50 000 of conflicts of interest, internal and external review, and organiza-
deaths per annum in the United States alone.7 The importance of tional approval, was guided by ASH policies and procedures
preventative measures to minimize the risk of VTE following major derived from the Guidelines International Network–McMaster
surgery has been recognized for decades; however, even with the Guideline Development Checklist (http://cebgrade.mcmaster.ca/
use of prophylaxis, surgery accounts for ;25% of VTEs observed in guidecheck.html) and was intended to meet recommendations
communities.8 for trustworthy guidelines by the Institute of Medicine and the
Guidelines International Network.1-4
Although most surgical procedures carry some risk for VTE, this risk
varies considerably across surgical procures and among individu- Organization, panel composition, planning,
al patients undergoing surgery. Surgical procedures carrying the and coordination
highest risk of developing postoperative VTE include hip and knee The work of this panel was coordinated with 9 other guideline
arthroplasty, invasive neurosurgical procures, and major vascular panels (addressing other aspects of VTE management) by ASH
procedures.9 and the McMaster GRADE Centre (funded by ASH under a paid
Patient factors that carry greater risks for thrombosis include agreement). Project oversight was provided initially by a coordina-
histories of VTE, particularly if unprovoked or associated with tion panel, which reported to the ASH Committee on Quality, and
cancer, or cancer, even in the absence of previous VTE. Scoring then by the coordination panel chair (Adam Cuker) and vice chair
systems that calculate the risk of postoperative VTE for individual (H.J.S.). ASH vetted and appointed individuals to the guideline
patients, such as the Caprini score, have been developed and panel. The McMaster GRADE Centre vetted and retained re-
validated following some surgical procedures.10 searchers to conduct systematic reviews of evidence and coordi-
nate the guideline-development process, including the use of the
Although postoperative VTE has historically been a complication
GRADE approach. The membership of the panels and the GRADE
primarily occurring in the hospital, with shortened hospital stays,
Centre team is described in Supplement 1.
postoperative VTE often occurs in the days to weeks following
discharge from the hospital.11 The panel included surgeons with subspecialty representa-
tion, hematologists, internists, and a pharmacist, all of whom had
Description of the target populations clinical and research expertise on the guideline topic. The panel
The primary target population of this guideline is patients hospitalized also included methodologists with expertise in evidence appraisal
for major surgical procedures that carry a risk for postoperative VTE. and guideline development and 2 patient representatives. Both
This guideline also addresses patients hospitalized following patient representatives participated in question prioritization,
major trauma; most, but not all, subsequently required major and 1 participated in all remaining steps of the development
surgical procedures. The panel recognized that there are 2 major process. The panel chair was a content expert. The vice chair
modalities applied for the prevention of VTE in the postoperative was a urological surgeon with specialized expertise in guideline
period: pharmacological antithrombotic prophylaxis and mechanical development.
In addition to synthesizing evidence systematically, the McMaster guidelines. Supplement 3 provides the complete “Disclosure of
GRADE Centre supported the guideline-development process, Interest” forms of researchers who contributed to these guidelines.
including determining methods, preparing agendas and meeting
materials, and facilitating panel discussions. The panel’s work
was done using Web-based tools (www.surveymonkey.com and Formulating specific clinical questions and
www.gradepro.org) and face-to-face and online meetings. determining outcomes of interest
The panel used the GRADEpro Guideline Development Tool
Guideline funding and management of conflicts
(www.gradepro.org) and SurveyMonkey (www.surveymonkey.com)
of interest to brainstorm and then prioritize the questions described in Table 1.
Development of these guidelines was wholly funded by ASH, a The panel selected outcomes of interest for each question a priori,
nonprofit medical specialty society that represents hematologists. following an approach described in detail elsewhere.21 The panel
Some members of the guideline panel were members of ASH. ASH

rated the following outcomes as critical for clinical decision making
staff supported panel appointments and coordinated meetings but across all questions: mortality, symptomatic PEs, symptomatic
had no role in choosing the guideline questions or determining the proximal DVTs, symptomatic severe distal DVTs, major bleeding,
recommendations. and reoperation. The panel used an explicit process to rate the
Members of the guideline panel received travel reimbursement for clinical severity of DVTs and PEs. The panel determined that all
attendance at in-person meetings. The patient representative (C.B.) symptomatic proximal DVTs and PEs confirmed by objective
received an honorarium of $200. The panelists received no other diagnostic imaging were considered of moderate severity and
payments. Some researchers who contributed to the system- were clinically important.22 For several outcomes, the studies
atic evidence reviews received salary or grant support through reported outcomes that were different or were in addition to the
the McMaster GRADE Centre. Other researchers participated outcomes that the panel determined to be important for decision
to fulfill requirements of an academic degree or program. making. Typically, included studies reported outcomes as any
Conflicts of interest of all participants were managed according PE, any DVT, or any proximal or distal DVT. Some studies did not
to ASH policies based on recommendations of the Institute of distinguish asymptomatic thromboembolic events that were detected
Medicine17 and the Guidelines International Network.4 At the time by the routine performance of sensitive screening studies for VTEs
of appointment, a majority of the guideline panel, including the chair from symptomatic thromboembolic events where patients devel-
and the vice chair, had no conflicts of interest as defined and judged oped overt symptoms that were subsequently confirmed by objective
by ASH (ie, no current material interest in any commercial entity with a testing to be associated with VTEs. Reporting of symptomatic
product that could be affected by the guidelines). Some panelists thromboembolic events was inconsistent across studies.
disclosed new interests or relationships during the development Where available, questions were addressed with studies that
process, but the majority continued to have no conflicts of interest reported symptomatic outcome events. In the absence of reports of
with commercial entities, as judged by ASH. symptomatic VTE in a clinical question, modeling was performed
Before appointment to the panel, individuals disclosed financial and using estimates of the proportion of asymptomatic DVTs that would
nonfinancial interests. Members of the VTE Guideline Coordination become clinically important symptomatic events (Supplement 4).
Panel reviewed the disclosures and judged which interests were Only “severe” distal DVTs were rated as clinically important distal
conflicts and should be managed. Supplement 2 provides the DVTs, and it was estimated that only ;25% of symptomatic
complete “Disclosure of Interests” forms of all panel members. postoperative distal DVTs would be considered severe.
In Part A of the forms, individuals disclosed material interests Major bleeding definitions varied across clinical studies. For the
for 2 years prior to appointment. In Part B, they disclosed other purposes of this analysis, outcome events that met the definition of
interests that were not mainly financial. Part C summarizes ASH major bleeding for individual studies were applied. The exception
decisions about which interests were judged to be conflicts. was that the need for a blood transfusion itself was not considered
Part D describes new interests disclosed by individuals after major bleeding unless other criteria for major bleeding were met.
appointment. The definition of reoperation was not specific for reoperation
Recusal was used to manage conflicts of interest. During caused by or related to major bleeding.
deliberations, panel members with a current direct financial Studies evaluated included patients with cancer and without cancer.
interest in a commercial entity with any product that could be We tested potential differences in the effects on studies with .50%
affected by the guidelines participated in discussions about the and ,50% of participants with cancer. Subgroup analyses did not
evidence and clinical context but were recused from making demonstrate a difference in the relative effectiveness of interventions
judgments or voting about individual domains (eg, magnitude of whether cancer patients were included or not. As a result, recom-
desirable consequences) and the direction and strength of mendations do not distinguish between cancer and noncancer patients.
relevant recommendations. 4,18-20 The Evidence-to-Decision For the use of pharmacological and mechanical methods of
(EtD) framework for each recommendation describes which prophylaxis, the panel advises to follow manufacturer’s recommen-
individuals were recused from making judgments about each dations regarding patient-specific restrictions in the use of individ-
recommendation. ual products (such as levels of renal function for patients receiving
None of the McMaster-affiliated researchers who contributed to LMWHs or DOACs). The panel also advises periodic monitoring of
the systematic evidence reviews or who supported the guideline- the platelet count for patients receiving LMWH and, in particular,
development process had any current material interest in a com- UFH, as postoperative prophylaxis in consideration of the risk of
mercial entity with any product that could be affected by the heparin-induced thrombocytopenia.

Table 1. Prioritized clinical questions for this guideline. The EtD table addressed effects of interven-
tions, resource utilization (cost-effectiveness), values and prefer-
Perioperative VTE prophylaxis in major surgery in general
ences (relative importance of outcomes), equity, acceptability, and
1. Pharmacological prophylaxis vs mechanical prophylaxis
feasibility. The guideline panel reviewed draft EtD tables before,
2. Mechanical prophylaxis vs no prophylaxis during, or after the guideline panel meeting and made suggestions
3. Pneumatic compression devices vs graduated compression stockings for corrections and identified missing evidence. To ensure that recent
4. Pharmacological prophylaxis combined with mechanical prophylaxis vs studies were not missed, searches (Supplement 5) were updated
pharmacological prophylaxis alone during October and November 2016, and panel members were asked
5. Mechanical prophylaxis combined with pharmacological prophylaxis vs mechanical to suggest any studies that may have been considered missed and
prophylaxis alone fulfilled the inclusion criteria for the individual questions. Monthly search
6. Insertion of an IVC filter vs no IVC filter alerts were created and monitored to capture relevant new studies up
7. Extended antithrombotic prophylaxis vs short-term antithrombotic prophylaxis to 1 July 2019, prior to submission of the manuscript for publication.

8. Early vs delayed antithrombotic prophylaxis Under the direction of the McMaster GRADE Centre, researchers
Orthopedic surgery: total hip and knee arthroplasty followed the general methods outlined in the Cochrane Handbook
9. ASA prophylaxis vs anticoagulants
for Systematic Reviews of Interventions (handbook.cochrane.org)
for conducting updated or new systematic reviews of intervention
10. DOAC prophylaxis vs LMWH prophylaxis
effects. When existing reviews were used, judgments of the original
11. DOAC prophylaxis vs prophylaxis with another DOAC authors about risk of bias were randomly checked for accuracy
12. LMWH prophylaxis vs warfarin prophylaxis and accepted or conducted de novo if they were not available or
13. LMWH prophylaxis vs UFH prophylaxis not reproducible. For new reviews, risk of bias was assessed at
Orthopedic surgery: hip fracture repair the health outcome level using the Cochrane Collaboration’s risk
of bias tool for randomized trials or nonrandomized studies. In
14. Pharmacological prophylaxis vs no pharmacological prophylaxis
addition to conducting systematic reviews of intervention effects,
15. LMWH prophylaxis vs UFH prophylaxis
the researchers searched for evidence related to baseline risks,
Major general surgery values, preferences, and costs and summarized findings within
16. Pharmacological prophylaxis vs no pharmacological prophylaxis the EtD frameworks.12,13,16 Subsequently, the certainty in the
17. LMWH prophylaxis vs UFH prophylaxis body of evidence (also known as quality of the evidence or confidence
Laparoscopic cholecystectomy
in the estimated effects) was assessed for each effect estimate of the
outcomes of interest following the GRADE approach based on the
following domains: risk of bias, precision, consistency and magnitude
Major neurosurgical procedures of the estimates of effects, directness of the evidence, risk of publication
19. Pharmacological prophylaxis vs no pharmacological prophylaxis bias, presence of large effects, dose-response relationship, and an
20. LMWH prophylaxis vs UFH prophylaxis assessment of the effect of residual, opposing confounding. The
TURP certainty was categorized into 4 levels ranging from very low to high.5,6,14
21. Pharmacological prophylaxis vs no pharmacological prophylaxis During a 2-day in-person meeting, followed by online communication
22. LMWH prophylaxis vs UFH prophylaxis and conference calls, the panel developed clinical recommendations
Radical prostatectomy
based on the evidence summarized in the EtD tables. For each recom-
mendation, the panel took a population perspective and came to
consensus on the following: the certainty in the evidence, the balance
24. LMWH prophylaxis vs UFH prophylaxis of benefits and harms of the compared management options, and the
Cardiac or major vascular surgery assumptions about the values and preferences associated with the
25. Pharmacological prophylaxis vs no pharmacological prophylaxis decision. The guideline panel also explicitly took into account the extent
of resource use associated with alternative management options. The
panel agreed on the recommendations (including direction and
Major trauma
strength), remarks, and qualifications by consensus or, in rare instances,
by voting (an 80% majority was required for a strong recommendation),
28. LMWH prophylaxis vs UFH prophylaxis based on the balance of all desirable and undesirable consequences. In
Major gynecological surgery the event that consensus was not reached based on discussion, the
29. Pharmacological prophylaxis vs no pharmacological prophylaxis recommendation was made based on a vote of the panel, with the
results of such votes listed in the text following the recommendation.
The final guidelines, including recommendations, were reviewed and
approved by all members of the panel.
Evidence review and development Interpretation of strong and
of recommendations conditional recommendations
For each guideline question, the McMaster GRADE Centre prepared a The recommendations are labeled as “strong” or “conditional”
GRADE EtD framework, using the GRADEpro Guideline Development according to the GRADE approach. The words “the guideline panel
Tool (www.gradepro.org).12,13,16 The EtD table summarized the results recommends” are used for strong recommendations, and “the
of systematic reviews of the literature that were updated or performed guideline panel suggests” is used for conditional recommendations.
Table 2. Interpretation of strong and conditional recommendations
Implications for: Strong recommendation Conditional recommendation
Patients Most individuals in this situation would want the recommended The majority of individuals in this situation would want the
course of action, and only a small proportion would not. suggested course of action, but many would not. Decision aids
may be useful in helping patients to make decisions consistent
with their individual risks, values, and preferences.
Clinicians Most individuals should follow the recommended course of action. Different choices will be appropriate for individual patients;
Formal decision aids are not likely to be needed to help individual clinicians must help each patient arrive at a management
patients make decisions consistent with their values and decision consistent with the patient’s values and preferences.
preferences. Decision aids may be useful in helping individuals to make
decisions consistent with their individual risks, values, and
preferences.
Policy makers The recommendation can be adopted as policy in most situations. Policy making will require substantial debate and involvement of

Adherence to this recommendation according to the guideline various stakeholders. Performance measures should assess
could be used as a quality criterion or performance indicator. whether decision making is appropriate.
Researchers The recommendation is supported by credible research or other The recommendation is likely to be strengthened (for future
convincing judgments that make additional research unlikely to updates or adaptation) by additional research. An evaluation of
alter the recommendation. On occasion, a strong the conditions and criteria (and the related judgments, research
recommendation is based on low or very low certainty in the evidence, and additional considerations) that determined the
evidence. In such instances, further research may provide conditional (rather than strong) recommendation will help to
important information that alters the recommendations. identify possible research gaps.
Table 2 provides the suggested interpretation of strong and will be facilitated by the related interactive forthcoming decision aids.
conditional recommendations by patients, clinicians, and health The use of these guidelines is also facilitated by the links to the EtD
care policy makers. frameworks and interactive summary-of-findings tables in each section.
Document review
Draft recommendations were reviewed by all members of the panel,
Recommendations
revised, and then made available online on 22 June 2018 for Mechanical vs pharmacological prophylaxis for
external review by stakeholders, including allied organizations, patients undergoing major surgery
other medical professionals, patients, and the public. Sixteen individuals
or organizations submitted comments. The document was revised Question: Should pharmacological prophylaxis vs mechanical
to address pertinent comments, but no changes were made to the prophylaxis be used for patients undergoing major surgery?
recommendations. The guidelines were reviewed by the ASH
Guideline Oversight Subcommittee on 28 August 2019, approved
by the Committee on Quality on 6 September 2019 and by the ASH Recommendation 1
officers on 13 September 2019, and then subjected to peer review. For patients undergoing major surgery, the ASH guideline panel
suggests using pharmacological prophylaxis or mechanical
How to use these guidelines
prophylaxis (conditional recommendation based on low certainty
ASH guidelines are primarily intended to help clinicians make in the evidence of effects ÅÅ◯◯). Remark: For patients
decisions about diagnostic and treatment alternatives. Other considered at high risk for bleeding, the balance of effects may
purposes are to inform policy, education, and advocacy and to favor mechanical methods over pharmacological prophylaxis.
state future research needs. They may also be used by patients.
These guidelines are not intended to serve or be construed as a
standard of care. Clinicians must make decisions on the basis Summary of the evidence. We identified 11 systematic
of the clinical presentation of each individual patient, ideally reviews addressing, in part, this question. 23-33 We identified
through a shared process that considers the patient’s values 38 studies in this review that fulfilled our inclusion criteria and
and preferences with respect to the anticipated outcomes of measured outcomes relevant to this context.34-72 Our system-
the chosen option. Decisions may be constrained by the realities of a atic search of randomized controlled trials (RCTs) identified 2
specific clinical setting and local resources, including, but not limited to, additional studies not included in previous systematic reviews
institutional policies, time limitations, and availability of treatments. These and that fulfilled the inclusion criteria. 70,72
guidelines may not include all appropriate methods of care for the Fifteen studies reported the effect of the pharmacological pro-
clinical scenarios described. As science advances and new evidence
phylaxis compared with mechanical prophylaxis alone on risk of
becomes available, recommendations may become outdated. Following mortality.35,36,40,42,51,54,57,59-61,63-65,68,72 Thirteen studies reported
these guidelines cannot guarantee successful outcomes. ASH does the effect on the development of symptomatic PEs,35,37,39,43,45,62,64,67-72
not warrant or guarantee any products described in these guidelines. and 17 studies reported the effect on the development on any
Statements about the underlying values and preferences, as well PE.34,36,38,40,42,46,47,50,51,53,58,60,61,63,67,71,72 Six studies reported
as qualifying remarks accompanying each recommendation, are its data on symptomatic DVTs,35,67,69-72 and 17 studies reported data
integral parts and serve to facilitate more accurate interpretation. on any proximal DVT.34,35,37,39,41,45,52,53,57,58,64,65,67,69-72 Four studies
They should never be omitted when recommendations from these reported data on symptomatic distal DVTs,35,70-72 and 16 studies
guidelines are quoted or translated. Implementation of the guidelines reported data on any distal DVT.34,35,37,39,40,45,52,53,57,58,63,64,66,67,71,72

Eighteen studies reported the effect of pharmacological prophylaxis The panel recognized that most of the evidence informing this
compared with mechanical prophylaxis alone on the risk of major recommendation came from the orthopedic literature (elective knee
bleeding,35-37,41,42,43,48,51,54,59-61,63-66,68,72 and 6 studies reported and hip arthroplasty).
the effect on the risk of reoperation.37,42,46,48,54,72 Conclusions and research needs for this recommendation.
The EtD framework is available at https://guidelines.gradepro.org/ The guideline panel suggests using pharmacological prophy-
profile/B57A59FE-FCA9-8C9A-8C8D-55089B4E8FB1. laxis or mechanical prophylaxis for patients undergoing major
surgery, based on low certainty in the evidence of effects. For
Benefits. The systematic review found that there may be no patients deemed at high risk for major bleeding (because of the
difference in mortality between pharmacological and mechanical nature of the surgical procedure), there is likely a net benefit in
prophylaxis (relative risk [RR], 0.92; 95% confidence interval [CI], favor of mechanical prophylaxis.
0.46-1.84; low certainty in the evidence of effects); this corresponds
to 1 fewer (5 fewer to 7 more) death per 1000 patients. Similarly, The panel determined that it would be valuable to have further high-

irrespective of the baseline risk chosen, which was derived from a quality studies comparing these interventions outside of the
cohort study of 172 320 patients,73 there may be no difference for orthopedic setting to confirm the generalizability of the results
symptomatic PEs (RR, 1.04; 95% CI, 0.36-2.96; low certainty in the across surgical domains. The panel would also welcome high-
evidence of effects), corresponding to 0 fewer events (2 fewer to quality studies to determine the effectiveness of mechanical
7 more). There is also likely little to no difference in symptomatic prophylaxis administered outside the hospital setting. The panel
proximal DVTs (RR, 0.75; 95% CI, 0.11-5.32; moderate certainty in identified the need for more and better studies on how patients
the evidence of effects); depending on the baseline risk of 1.6% or value the various outcomes in the perioperative setting and to what
2.6%,73 this corresponds to anywhere from 4 fewer (15 fewer to degrees these values vary by patients as a future research priority.
71 more) to 7 fewer (23 fewer to 113 more) events, respectively. Question: Should mechanical prophylaxis vs no prophylaxis be
For symptomatic distal DVTs, pharmacological prophylaxis likely used for patients undergoing major surgery?
results in a reduction in risk (RR, 0.16; 95% CI, 0.05-0.58; moderate
certainty in the evidence of effects); however, this corresponds to a Recommendation 2
possibly small, and likely unimportant, reduction in symptomatic distal
DVTs in absolute terms of 2 fewer (1-2 fewer) per 1000 patients, For patients undergoing major surgery who do not receive
based on a baseline risk of 1.2% from observational data.73 pharmacologic prophylaxis, the ASH guideline panel suggests
using mechanical prophylaxis over no mechanical prophylaxis
Harms and burden. Pharmacological prophylaxis likely leads (conditional recommendation based on very low certainty in the
to more major bleeding (RR, 2.87; 95% CI, 1.68-4.92; moderate evidence of effects Å◯◯◯).
certainty in the evidence of effects). This corresponds to a small
absolute increase of 12 more (4-25 more) major bleeds per 1000
patients. Pharmacological prophylaxis probably results in no Summary of the evidence. We identified 5 systematic
difference in reoperations (RR, 2.01; 95% CI, 0.29-14.05; low reviews addressing, in part, this question. 24,25,27,28,30 We
certainty in the evidence of effects), corresponding to 1 more (1 fewer identified 25 studies in these reviews that fulfilled our inclu-
to 19 more) per 1000 patients. sion criteria and measured outcomes relevant to this
context.37,49,53,66,74-94 Our systematic search of RCTs did not
Certainty in the evidence of effects. We rated the overall identify any additional study that fulfilled the inclusion criteria.
certainty in the evidence of effects as low based on the lowest
certainty in the evidence for the critical outcomes, downgrading Ten studies reported the effect of mechanical prophylaxis compared
twice for very serious imprecision. with no prophylaxis on risk of mortality.49,77,78,81,83-85,88,90,94 Nine
studies reported the effect on the development of symptomatic
Other EtD criteria and considerations. The panel deter- PEs,37,76,78,81,83,84,86,88,92 and 5 studies reported the effect on any
mined that, on balance, neither approach was favored over the PE.53,77,85,86,93 No study reported data on symptomatic proximal or
other for patients undergoing major surgery at low or moderate distal DVT, but 8 studies reported on any proximal DVT,37,78,79,82,84,85,92,93
risk for major bleeding because of the low certainty in the and 7 studies reported on any distal DVT.37,77,79,82,85,92,93
evidence, as well as concerns about compliance with mechan-
ical prophylaxis. For patients at high baseline risk for major The EtD framework is available online at https://guidelines.gradepro.org/
bleeding, mechanical prophylaxis would more clearly be favored profile/61E7ADC1-4C91-8D58-9E3A-56BFEE3EAC20.
because of the incremental risk of bleeding with pharmacolog- Benefits. There may be no difference in mortality between
ical prophylaxis. There was possibly important uncertainty or mechanical prophylaxis and no prophylaxis (RR, 1.33; 95% CI,
variability in how much affected individuals valued the main 0.71-2.51; low certainty in the evidence of effects); this corresponds
outcomes. The panel further judged the costs associated with to 6 more (5 fewer to 28 more) deaths per 1000 patients. There may
pharmacological prophylaxis to be moderate based on very low be a small difference in symptomatic PEs (RR, 0.61; 95% CI, 0.27-
certainty in the evidence about resource requirements. Cost- 1.40; low certainty in the evidence of effects) corresponding to 3
effectiveness probably favors mechanical prophylaxis. The panel fewer (6 fewer to 3 more) symptomatic PEs per 1000 patients based
did not account for potential risks of mechanical prophylaxis, on a baseline risk of 0.8% and 4 fewer (8 fewer to 4 more) per 1000
including fall risk, risk of skin damage, and limitation in mobility. patients based on a baseline risk of 1.1% from observational data.73
There would probably be no impact on health equity, and There may be no difference in symptomatic proximal DVTs (RR, 0.75;
pharmacological and mechanical prophylaxis would be ac- 95% CI, 0.35-1.61; very low certainty in the evidence of effects), but
ceptable to stakeholders and probably feasible to implement. we are uncertain of this. The risk of symptomatic distal DVTs may be
reduced (RR, 0.66; 95% CI, 0.50-0.86; very low certainty in the Summary of the evidence. We identified 6 systematic reviews
evidence of effects), but we are uncertain of this. addressing this question.25-28,31,32 We identified 11 studies in these
reviews that fulfilled our inclusion criteria and measured outcomes
Harms and burden. There were no relevant adverse events
relevant to this context.37,94-103 Our systematic search of RCTs did not
deemed critical for this comparison. The panel was unable to
identify any additional study that fulfilled the inclusion criteria.
assess the relative effect of mechanical prophylaxis on potential
hazards, such as falls or skin complications. Five studies reported the effect of pneumatic compression prophylaxis
compared with graduated compression stockings prophylaxis on
Certainty in the evidence of effects. We rated the overall
risk of mortality.94,96,97,101,102 Eight studies reported the effect on
certainty in the evidence of effects as very low based on the lowest
the development of symptomatic PEs,37,95-99,102,103 and 4 studies
certainty in the evidence for the critical outcomes, downgrading for
reported the effect on any PE.94,100,101,103 One study reported data
study limitations, imprecision, and inconsistency.
on symptomatic proximal and symptomatic distal DVTs,98 whereas
6 studies reported on any proximal DVT,37,94,96,98-100 and 5 studies

Other EtD criteria and considerations. The panel deter-
mined that there was possibly important uncertainty or variability in reported on any distal DVT.37,94,96,98,100
how much affected individuals valued the main outcomes. They The EtD framework is available online at https://guidelines.grade-
further judged that the balance between desirable and undesir- pro.org/profile/1584FD2F-9CC6-9C59-8DF5-48F0045F1BE5.
able effects probably favors mechanical prophylaxis over no
prophylaxis for patients at moderate or high risk for VTE but Benefits. There is no difference in mortality between pneumatic
not patients at low risk for VTE. The panel judged the costs compression and graduated compression stockings prophylaxis
associated with mechanical prophylaxis to be moderate based (RR, 1.04; 95% CI, 0.16-6.63; low certainty in the evidence of
on very low certainty in the evidence about resource requirements, effects); this corresponds to 2 more (41 fewer to 274 more) per
with no available studies explicitly addressing this question. Cost- 1000 patients. There may also be no difference in symptomatic PEs
effectiveness probably favors mechanical prophylaxis. There would (RR, 0.56; 95% CI, 0.17-1.86; low certainty in the evidence of
probably be no impact on health equity; mechanical prophylaxis effects). The risk of symptomatic proximal DVTs may be reduced
would probably be acceptable to stakeholders and probably (RR, 0.48; 95% CI, 0.25-0.93, very low certainty in the evidence of
feasible to implement. The panel recognized that many patients effects), but we are uncertain of this finding. This benefit likely
considered at moderate to high risk for VTE would receive corresponds to 9 fewer (1-12 fewer) symptomatic proximal DVTs in
pharmacological prophylaxis in addition to mechanical methods. 1000 patients with a baseline risk of 1.6% and 14 fewer (2-20
The guideline panel determined that there was very low certainty fewer) symptomatic proximal DVTs per 1000 patients based on a
evidence for a net health benefit/harm for mechanical pro- baseline risk of 2.6% from observational data.73 The risk of distal
phylaxis. Most of the evidence comes from orthopedics (elective DVT (RR, 0.55; 95% CI, 0.25-1.22, very low certainty in the
hip and knee arthroplasty). In settings where intermittent evidence of effects) appears to be similar, but we are uncertain of
pneumatic compression is not available, the use of stockings this finding.
as mechanical prophylaxis is an acceptable and feasible option Harms and burden. There were no relevant adverse events
(see Recommendation 3). deemed critical for this comparison. Potential harms included
Conclusions and research needs for this recommendation. reduced mobility, and pneumatic compression prophylaxis may be
For patients undergoing major surgery and at risk for VTE, the ASH uncomfortable. There is also a small risk for inappropriate use of
guideline panel suggests using mechanical prophylaxis over pneumatic compression prophylaxis for some patients (eg, those with
lower extremity fractures).
no mechanical prophylaxis, recognizing that the certainty in the
evidence is very low for this recommendation. Certainty in the evidence of effects. We rated the overall
The panel recognizes that there is a need for high-quality
clinical trials using clinically relevant end points to improve the
study limitations, imprecision, and inconsistency.
certainty of the evidence supporting this recommendation,
particularly outside the orthopedic setting. However, this is Other EtD criteria and considerations. The panel deter-
likely a lower priority for research than studies evaluating mined that there was possibly important uncertainty or variability in
mechanical prophylaxis in combination with pharmacological how much affected individuals valued the main outcomes. They
prophylaxis. further judged that the balance between desirable and undesirable
effects probably favors pneumatic compression prophylaxis over
Question: Should pneumatic compression devices vs graduated
graduated compression stockings prophylaxis. The panel was
compression stockings be used for patients undergoing major
unable to assess the relative effect of pneumatic compression
surgery?
compared with that of graduated compression stockings on the risk of
other hazards, such as falls or skin complications. These might be
Recommendation 3 considered “unmeasured harms” of mechanical prophylaxis. The panel
For patients undergoing major surgery who receive mechanical judged the costs associated with pneumatic compression prophylaxis
prophylaxis, the ASH guideline panel suggests using in- to be moderate based on very low certainty in the evidence about
termittent compression devices over graduated compression resource requirements, with no available studies explicitly address-
stockings (conditional recommendation based on very low ing this question. Cost-effectiveness probably favors pneumatic
certainty in the evidence of effects Å◯◯◯). compression prophylaxis. There would probably be no impact on
health equity; pneumatic compression prophylaxis would probably

be acceptable to stakeholders and probably feasible to implement. 0.06-1.38; low certainty in the evidence of effects); this
Lack of information regarding out-of-hospital use of pneumatic corresponds to 5 fewer (7 fewer to 3 more) deaths per 1000
compression was a limitation of this technique. The panel recognizes patients. There may be a reduction in symptomatic PEs (RR,
that most of the evidence about the effectiveness comes from 0.40; 95% CI, 0.25-0.65; low certainty in the evidence of effects)
orthopedics (elective hip and knee arthroplasty). favoring combined prophylaxis. Depending on the baseline risk, this
Conclusions and research needs for this recommendation. benefit likely corresponds to 5 fewer (3-6 fewer) per 1000 patients
The panel suggests using pneumatic compression devices over with a baseline risk of 0.8% to up to 7 fewer (4-8 fewer) per 1000
graduated compression stockings for patients undergoing major patients based on a baseline risk of 1.2% from observational data.73
surgery, recognizing that there was very low certainty evidence for a We are very uncertain whether the risks of symptomatic proximal
net health benefit/harm. The recommendation applies to patients DVTs (RR, 0.14; 95% CI, 0.01-2.63; very low certainty in the
undergoing major surgery who are considered at risk for VTE. evidence of effects) and symptomatic distal DVTs (RR, 1.99; 95%
CI, 0.35-11.33; very low certainty in the evidence of effects) differ

In settings where pneumatic compression devices are not avail-
between the 2 groups.
able, the use of graduated compression stockings is reasonable,
because mechanical prophylaxis is an acceptable and feasible Harms and burden. Rates of major bleeding may be similar (RR,
option. Further well-designed studies using clinically relevant end 1.05; 95% CI, 0.32-3.40; low certainty in the evidence of effects),
points are required to improve the quality of evidence related to corresponding to 0 fewer (5 fewer to 17 more) events per 1000
this question. Studies outside the field of orthopedics would be patients. We were unable to estimate the RR of major reoperation
particularly useful. given that there were no events in either group in the 2 included
trials.107,117
Question: Should combined pharmacological and mechanical
prophylaxis vs pharmacological prophylaxis alone be used for Certainty in the evidence of effects. We rated the overall
patients undergoing major surgery? certainty in the evidence of effects as very low based on the lowest
certainty in the evidence for the critical outcomes, downgrading
Recommendation 4 for study limitations and imprecision.
For patients undergoing major surgery who receive pharma- Other EtD criteria and considerations. The panel deter-
cologic prophylaxis, the ASH guideline panel suggests using mined that there was possibly important uncertainty or variability in
combined prophylaxis with mechanical and pharmacological how much affected individuals valued the main outcomes. They
methods over prophylaxis with pharmacological agents alone further judged that the balance between desirable and undesirable
(conditional recommendation based on very low certainty in the effects probably favors combined pharmacological and mechanical
evidence of effects Å◯◯◯). Remark: For patients considered prophylaxis over pharmacological prophylaxis alone. The panel was
at high risk for VTE, combined prophylaxis is particularly favored unable to assess the impact of adding mechanical prophylaxis on
over mechanical or pharmacological prophylaxis alone. the risk of other outcomes, such as falls or skin complications.
These might be considered “unmeasured harms” of mechanical
prophylaxis. The panel judged the costs associated with combined
Summary of the evidence. We identified 7 systematic reviews prophylaxis to be moderate based on very low certainty in the
addressing this question.23-26,28,29,31-33 We identified 19 studies in these evidence about resource requirements. Cost-effectiveness proba-
reviews that fulfilled our inclusion criteria and measured outcomes bly favors combined pharmacological and mechanical prophylaxis.
relevant to this context.36,60,62,68,70,104-117 Our systematic search of There would probably be no impact on health equity; combined
RCTs did not identify any additional study that fulfilled the inclusion pharmacological and mechanical prophylaxis would probably be
criteria. acceptable to stakeholders and probably feasible to implement.
Seven studies reported the effect of the combination of pharma- The panel determined that there was very low certainty evidence
cological and mechanical prophylaxis compared with pharmaco- for a net health benefit/harm for combined pharmacological and
logical prophylaxis alone on the risk of mortality.36,60,62,68,104,105,107 mechanical prophylaxis over pharmacological prophylaxis alone.
Ten studies reported the effect on the development of symptomatic Most of the evidence evaluating this question comes from the
PEs,60,62,68,70,105,107,109-111,117 and 6 studies reported the effect orthopedic (joint arthroplasty) setting.
on any PE.36,104,108,112,116,117 Three studies reported data on Conclusions and research needs for this recommendation.
symptomatic proximal DVTs,62,70,112 and 8 studies reported data on The guideline panel suggests using combined pharmacological
any proximal DVT.62,70,104,108,112-114 Three studies reported data and mechanical prophylaxis over pharmacological prophylaxis
on symptomatic distal DVTs,70,105,112 and 7 studies reported on any alone for patients undergoing major surgery, based on very low
distal DVT.68,105,108,109,112-114 Six studies reported the effect of certainty in the evidence of effects. The panel judged that com-
combination pharmacological and mechanical prophylaxis combined pharmacological and mechanical prophylaxis would be most
pared with pharmacological prophylaxis alone on the risk of major beneficial for patients considered at very high risk for VTE following
bleeding,60,62,68,104,109,112 and 2 studies reported the effect on the major surgery.
risk of reoperation.107,117
Further high-quality research studies using clinically important
The EtD framework is available online at https://guidelines.gradepro.org/ outcomes comparing combination pharmacological and mechani-
profile/9AC669C6-30BB-C8DF-8430-3EDA0D4842C8. cal methods with pharmacological methods alone are required
Benefits. There may be no difference in mortality between to provide greater certainty about this recommendation. Studies
pharmacological prophylaxis combined with mechanical prophy- addressing this question outside the orthopedic setting are most
laxis and pharmacological prophylaxis alone (RR, 0.29; 95% CI, needed.
Question: Should mechanical prophylaxis combined with pharma- major reoperation may be similar (RR, 2.96; 95% CI, 0.73-12.05;
cological prophylaxis vs mechanical prophylaxis alone be used for low certainty in the evidence of effects) between the 2
patients undergoing major surgery? interventions, corresponding to 4 more (1 fewer to 21 more)
per 1000 patients.
Recommendation 5 Certainty in the evidence of effects. We rated the overall
For patients undergoing major surgery, the ASH guideline certainty in the evidence of effects as low based on the lowest
panel suggests using combined mechanical and pharmaco- certainty in the evidence for the critical outcomes, downgrading
logical prophylaxis or mechanical prophylaxis alone, depending for study limitations and imprecision.
on the risk of VTE and bleeding based on the individual patient Other EtD criteria and considerations. The panel judged
and the type of surgical procedure (conditional recommenda- that the balance between desirable and undesirable effects does
tion based on low certainty in the evidence of effects ÅÅ◯◯). not favor combined pharmacological and mechanical prophylaxis

Remark: For patients considered at high risk for VTE, com- vs mechanical prophylaxis alone. Instead, the balance between
bined prophylaxis is particularly favored over mechanical or desirable and undesirable effects will depend upon the risk of
pharmacological prophylaxis alone. VTE and bleeding based on the individual patient and the type of
surgical procedure. The panel judged the costs associated with
Summary of the evidence. We identified 7 systematic reviews combined prophylaxis to be moderate based on very low certainty
addressing, in part, this question.23-26,29,32,33 We identified 19 in the evidence about resource requirements. The panel determined
studies in these reviews that fulfilled our inclusion criteria and that there was possibly important uncertainty or variability in how much
measured outcomes relevant to this context.36,60,62,68,118-132 Our affected individuals valued the main outcomes. Cost-effectiveness
systematic search of RCTs identified 5 additional studies that varies based on the underlying VTE and bleeding risk categories. There
fulfilled the inclusion criteria.70,72,133-136 would probably be no impact on health equity, and combined
prophylaxis and mechanical prophylaxis alone would be acceptable
Fourteen studies reported the effect of combined mechanical and to stakeholders and probably feasible to implement.
pharmacological prophylaxis compared with mechanical prophylaxis
alone on the risk of mortality.36,60,62,68,120,121,124,125,127,128,130,133,134,136 Conclusions and research needs for this recommendation.
Sixteen studies reported the effect on the development of The guideline panel suggests using combined mechanical and
symptomatic PEs,60,62,70,120-131,134 and 11 studies reported on pharmacological prophylaxis or mechanical prophylaxis alone
the effect on any PEs36,118,120,121,126,128,130,131,133,135,136 Six for patients undergoing major surgery (based on low certainty in
studies reported data on symptomatic DVTs,62,70,120,127,128,131 and 10 the evidence of effects). The balance of effects was considered
studies reported data on any proximal DVT.62,70,120-122,124,125,127,128,130 dependent upon the risk of VTE and bleeding. Therefore, it is
Five studies reported data on symptomatic distal DVTs,70,120,127,128,131 important to establish the baseline risk for VTE and major bleeding
and 14 studies reported on any distal DVT.118,120-122,124,125,127,128,130 in surgical patients. For patients considered at high thrombosis risk
Fifteen studies reported the effect of combined mechanical and low bleeding risk, combined mechanical and pharmacological
and pharmacological prophylaxis on the risk of major prophylaxis should be considered. For patients at high bleeding risk,
bleeding,60,62,68,118,119,121,123-125,127,128,130,134-136 and 4 studies mechanical prophylaxis methods alone may be preferred.
reported the effect on the risk of reoperation.118,125,134,135 Further high-quality research studies using clinically important
The EtD framework is available online at https://guidelines.gradepro.org/ outcomes to identify patients with high baseline risk for VTE in whom
profile/75138F44-7AFE-A008-A8BD-10DD1DFD5377. combined pharmacological and mechanical prophylaxis would be of
value, particularly outside the orthopedic setting, are needed.
Benefits. There is likely no difference in mortality between
combined prophylaxis and mechanical prophylaxis alone (RR, 1.24; Prophylactic insertion of an IVC filter. Question: Should
95% CI, 0.67-2.30; moderate certainty in the evidence of effects), insertion of an IVC filter vs no IVC filter be used for VTE prophylaxis
corresponding to 3 more (4 fewer to 17 more) deaths per 1000 for patients undergoing major surgery?
patients. There is likely a reduction in symptomatic PEs (RR, 0.34;
95% CI, 0.13-0.90; moderate certainty in the evidence of effects)
Recommendation 6
favoring combined prophylaxis. Depending on the baseline risk,
assumed to be 0.8% or 1.1% based on a large observational For patients undergoing major surgery, the ASH guideline
study,73 this benefit likely corresponds to 5 fewer (1-7 fewer) per panel suggests against using IVC filters for prophylaxis of VTE
1000 patients in a lower-risk population to 7 fewer (1-10 fewer) per (conditional recommendation based on very low certainty in the
1000 patients in a higher-risk population. The risk of symptomatic evidence of effects Å◯◯◯).
proximal DVT (RR, 0.71; 95% CI, 0.07-6.75; low certainty in the
evidence of effects) and symptomatic distal DVT (RR, 0.38;
Summary of the evidence. We identified 2 systematic reviews
95% CI, 0.06-2.42; low certainty in the evidence of effects) may
of RCTs and observational studies137,138 that addressed this
be similar between the 2 interventions, irrespective of the
research question in bariatric surgery and trauma patients. We
baseline risk group.
identified 14 studies139-152 in these reviews that fulfilled our
Harms and burden. Combined prophylaxis likely results in a inclusion criteria and measured outcomes relevant to this
small increased risk for major bleeding (RR, 2.23; 95% CI, 1.09- context. Our search for RCTs and observational studies
4.57; moderate certainty in the evidence of effects). This likely identified 1 additional study that fulfilled the inclusion criteria.153
corresponds to 14 more (1-42 more) per 1000 patients. Rates of Additionally, we identified 1 systematic review of RCTs and

observational studies that was published after our initial observational studies, that the high rates of DVT and the trend for
literature search, which did not include any new study not higher mortality associated with the use of IVC filters outweighed
already included in our meta-analysis. 154 We also identified 1 the potential reduction in PEs. Furthermore, a recently published
RCT published in July 2019, evaluating the use of IVC filters for high-quality RCT of IVC filters, following major trauma for patients
patients experiencing trauma.155 Although we did not update in whom pharmacological prophylaxis was considered contra-
the meta-analysis, the trial results were assessed by the panel as indicated, did not find that IVC filters reduced symptomatic PE or
consistent with the recommendation. death.155 Given there are serious nonthrombotic risks associated
with IVC filters (eg, IVC perforation and IVC filter embolization) that
Of the 15 studies included in the meta-analysis, 1 was an RCT.150
were not considered in our analysis, this would further strengthen
Twelve of the studies reported the effect of IVC filters on the risk of
our recommendation against IVC filter use.156
mortality.139,143-147,149-153 Five studies assessed the development
of symptomatic PEs,142,149,150,152,153 and 10 studies assessed the The panel also recognized that the cost of IVC filters and resources
development of any PE.139-141,143-148,151 Ten studies assessed the associated with their insertion were large. The panel concluded that

development of DVTs,139,141,143,144,146-148,150,151,153 with 1 study routine use of IVC filters following major surgery or trauma was
assessing the development of symptomatic DVTs specifically141 and probably not cost-effective and favored not placing a filter. Because of
1 study assessing the development of proximal DVTs specifically.153 the increased resources required, high costs, and limited availability of
interventional radiology units, health equity would probably be reduced
The EtD framework is available online at https://guidelines.gradepro.org/
by use of IVC filters. Routine use of IVC filters might also not be
profile/4885EDB9-B445-5554-BD62-CFE2EED6D08E.
acceptable or feasible to implement for some stakeholders.
Benefits. IVC filter use may increase mortality slightly (RR, 1.38;
Conclusions and research needs for this recommendation.
95% CI, 0.81-2.37; very low certainty in the evidence of effects),
The panel suggests against using IVC filters for prophylaxis of
although the confidence interval was wide and included the
VTE for patients undergoing major surgery or trauma patients
possibility of no increase. Overall, we are very uncertain of this
based upon very low certainty in the evidence. The very low quality
finding. Based on the control group event rate of 1.1% in this meta-
evidence underlying this recommendation supports the need for
analysis, this would correspond to 4 more deaths (2 fewer to 15
well-designed RCTs evaluating clinically important outcomes to
more) per 1000 patients receiving an IVC filter following major
better define the role of IVC filters for patients who cannot safely
surgery or trauma. IVC filters may reduce the risk of symptomatic PE
or feasibly receive pharmacological or mechanical prophylaxis
following major surgery and trauma (RR, 0.29; 95% CI, 0.11-0.80;
following major surgery or trauma. Further studies quantifying the
very low in the evidence of effects), but we are very uncertain about
nonthrombotic risks of IVC filters would also be of value.
this finding. Based on a baseline risk of 0.8% from observational
data,73 this corresponds to 6 fewer (2-7 fewer) symptomatic PEs.
Based on a higher baseline risk of 1.1%,73 this could result in 8 Timing of antithrombotic prophylaxis
fewer PEs (2-10 fewer) per 1000 patients receiving an IVC filter; Question: Should extended antithrombotic prophylaxis vs short-
however, this is very uncertain. Rates of symptomatic proximal DVT term antithrombotic prophylaxis be used for patients undergoing
may be increased with use of IVC filters (RR, 2.19; 95% CI, 1.07- major surgery?
4.50; very low certainty in the evidence of effects), but we are
once again very uncertain of this finding. This corresponds to 20
more (1-58 more) or 31 more (2-92 more) per 1000 patients, Recommendation 7
based on baseline risks of 1.6% and 2.6%, respectively, from
observational data.73 We are also uncertain whether rates of For patients undergoing major surgery, the ASH guideline
symptomatic distal DVT are increased (RR, 2.72; 95% CI, 1.41- panel suggests using extended antithrombotic prophylaxis over
5.21; very low certainty in the evidence of effects), corresponding to short-term antithrombotic prophylaxis (conditional recommen-
2 more (1-6 more) to 4 more (1-9 more) per 1000 patients, based dation based on very low certainty in the evidence of effects
on baseline risks of 0.1% and 0.2%, respectively, from observa- Å ◯◯◯). Remark: Extended prophylaxis was generally
tional data.73 considered as beyond 3 weeks (range: 19-42 days), and
Harms and burden. The panel did not consider potential harms short-term prophylaxis was considered as up to 2 weeks
(range: 4-14 days).
of IVC filters beyond VTE. These potential harms would include
potentially severe complications, such as IVC perforation and IVC
filter embolization.
Summary of the evidence. We identified 9 systematic
Certainty in the evidence of effects. We rated the overall reviews addressing this research question.157-165 We identified
certainty in the evidence of effects as very low based on the lowest 14 studies166-179 in these reviews that fulfilled our inclusion criteria
certainty in the evidence for the critical outcomes, downgrading for and measured outcomes relevant to this context. Our systematic
study limitations, inconsistency, and indirectness. search of RCTs identified 6 additional studies180-185 not included in
Other EtD criteria and considerations. The panel deter- previous systematic reviews that fulfilled the inclusion criteria.
mined that there was possibly important uncertainty or variability in Seventeen studies reported the effect of extended vs short-term
how much affected individuals might value the main outcomes. They duration of pharmacological thromboprophylaxis on the develop-
judged that the balance between desirable and undesirable effects ment of mortality,166,167,170-173,175-185 17 studies reported the effect
favored not using IVC filters in the setting of major surgery or on the development of PEs,166,167,170-184 18 studies reported the
trauma. The panel judged from our analysis of data, largely from effect on the development of proximal DVTs, 166-173,175-184
14 studies reported the effect on the development of distal short duration of anticoagulant prophylaxis designed to approxi-
DVTs,166,169,171-173,175,177-184 16 studies reported the effect mate the length of a postoperative hospital stay (;4-14 days) in
on the risk of major bleeding,167-173,177-185 and 6 studies reported the eras in which the studies were performed. Furthermore, the
the effect on the risk of reoperation.166,173,174,179,184,185 In general, panel recognized that these studies were largely limited to 2 high-
these studies compared shorter courses of pharmacological risk surgical scenarios (total hip or knee arthroplasty and major
prophylaxis (4-14 days) with extended courses of pharmacological cancer general surgical procedures).
prophylaxis (19-42 days) and then followed patients for a common Conclusions and research needs for this recommendation.
period (3-9 months) for VTE and bleeding complications. The guideline panel determined that the net benefit favored using
The EtD framework is available online at https://guidelines.gradepro.org/ extended-course antithrombotic prophylaxis over short-term antith-
profile/79bce70d-c689-4fbf-b0e4-c2ec3142bb2c. rombotic prophylaxis for patients undergoing major surgery based
Benefits. There is likely no difference in mortality between on very low certainty evidence. Given the very low certainty in the

extended- and standard-course antithrombotic prophylaxis (RR, evidence of effects this is based upon, there is a critical need for
0.94; 95% CI, 0.64-1.39; moderate certainty in the evidence of higher-quality studies comparing extended vs short-term prophylaxis
effects); this corresponds to 1 fewer death (6 fewer to 6 more) using clinically important outcomes in contemporary surgical practices,
per 1000 patients. There is likely a small reduction in which are marked by early patient mobilization and shorter hospital
symptomatic PEs (RR, 0.44; 95% CI, 0.22-0.85; moderate stays. There is particularly a need for studies outside the general
certainty in the evidence of effects). Depending on baseline risk,73 hip and knee arthroplasty and cancer general surgical settings to
this corresponds to 4 fewer (1-6 fewer) deaths per 1000 patients confirm the benefits of extended prophylaxis in other settings.
with a baseline risk of 0.8% and 6 fewer (2-9 fewer) deaths per There also appears to be a need for further research to determine
1000 patients with a baseline risk of 1.1% receiving extended the optimal duration of extended prophylaxis.
pharmacological prophylaxis. Symptomatic proximal DVTs are
also likely reduced (RR, 0.30; 95% CI, 0.21-0.42; moderate Question: Should early vs delayed antithrombotic prophylaxis be
certainty in the evidence of effects). Depending upon the used for patients undergoing major surgery?
baseline risk, 73 this corresponds to 12 fewer (10-13 fewer)
symptomatic proximal DVTs per 1000 patients in a lower-risk
group of patients with a 1.6% baseline risk or 18 fewer (15-21 Recommendation 8
fewer) per 1000 patients in a higher-risk group with a 2.6%
For patients undergoing major surgery, the ASH guideline panel
baseline risk. Extended pharmacological prophylaxis likely
suggests using early or delayed antithrombotic prophylaxis (con-
reduces distal DVTs (RR, 0.57; 95% CI, 0.37-0.87; moderate
ditional recommendation based on very low certainty in the evi-
certainty in the evidence of effects), which corresponds to 1
dence of effects Å◯◯◯). Remark: Twelve hours following surgery
fewer (0-1 fewer) symptomatic distal DVT per 1000 patients
was arbitrarily selected to be the cutoff point between early and
based on a 0.1% baseline risk from observational data. 73
late postoperative antithrombotic administration.
Harms and burden. Rates of major bleeding may be similar (RR,
1.00; 95% CI, 0.59-1.70; low certainty in the evidence of effects),
corresponding to 0 fewer (3 fewer to 6 more) per 1000 patients. Summary of the evidence. We did not find any systematic
Rates of reoperation may also be similar (RR, 0.82; 95% CI, 0.34- reviews that addressed this question. In our systematic search of the
1.99; very low certainty in the evidence of effects), but we are very literature we found 6 studies that fulfilled our inclusion criteria and
uncertain about this finding. measured outcomes relevant to this context.186-191 We cross-
Certainty in the evidence of effects. We rated the overall referenced the studies found in our search with the references from a
certainty in the evidence of effects as very low based on the recent narrative review192 but did not identify any additional studies
lowest certainty in the evidence for the critical outcomes, that fulfilled our inclusion criteria. All studies included surgical patients.
downgrading for study limitations and very serious imprecision. Twelve hours was selected to be the cutoff point between early and
late postsurgical antithrombotic administration. Six studies186-191
Other EtD criteria and considerations. The panel deter- reported the effect of early vs late postsurgical antithrombotic
mined that there was possibly important uncertainty or variability administration on the risk of mortality and on the risk of development
in how much affected individuals valued the main outcomes. of any PEs. Five studies186,188-191 reported the effect on the risk of any
They further judged that the balance between desirable and proximal and any distal DVTs, and 1 reported the effect on the risk of
undesirable effects probably favors extended-duration vs any DVT.187 Only the 5 studies that specified the location of the DVT
standard-duration prophylaxis. The panel judged the costs were included in the evidence profile. Six studies186-191 reported the
associated with extended-duration prophylaxis to be moderate effect of early vs late postsurgical antithrombotic administration on the
based on very low certainty in the evidence. Cost-effectiveness risk of major bleeding and on the risk of reoperation.
probably favors extended-duration prophylaxis. Health equity is
possibly reduced with extended-duration prophylaxis, with The EtD framework is available online at https://guidelines.gradepro.org/
economically disadvantaged patients potentially being unable profile/E664E38D-FA7C-DBC9-8E77-373D0582050E.
to afford the required medications or medication copayments. Benefits. Early prophylaxis may result in no difference in mortality
Extended-duration prophylaxis would probably be acceptable to (RR, 1.57; 95% CI, 0.77-3.19; very low certainty in the evidence of
stakeholders and probably feasible to implement. The panel effects), but we are very uncertain about this finding. This
recognized that most of the trials compared a prolonged pro- corresponds to 1 more (1 fewer to 6 more) per 1000 patients.
phylaxis (up to 42 days, or ;6 weeks following surgery) with a We are uncertain about the effect of early prophylaxis on

symptomatic PEs (RR, 0.63; 95% CI, 0.23-1.72; very low certainty Summary of the evidence. We found 7 RCTs that compared
in the evidence of effects); depending on the baseline risk from the use of ASA vs anticoagulants for patients undergoing total hip
observational data,73 this corresponds to 3 fewer (6 fewer to 6 arthroplasty or total knee arthroplasty.193-199 Additionally, we
more) to 4 fewer (8 fewer to 8 more) per 1000 patients with identified 2 trials comparing ASA with LMWH in total hip
baseline risks of 0.8% and 1.1%, respectively. We are also uncertain arthroplasty patients200 and ASA with DOAC in total hip
of the effect of early prophylaxis on symptomatic proximal DVTs (RR, arthroplasty or total knee arthroplasty patients,201 in which all
0.88; 95% CI, 0.40-1.96; very low certainty in the evidence of effects), participants received a 10-day period of LMWH or a 5-day period of
corresponding to 2 fewer (10 fewer to 16 more) to 3 fewer (16 fewer DOACs, respectively, prior to randomization. The trials were reviewed
to 25 more) per 1000 patients when applying baseline risks of 1.6% by the panel but were not included in the main meta-analysis
and 2.6%, respectively.73 Early prophylaxis has an uncertain effect on because of differences in the comparator groups. Of the 7 studies
distal DVTs (RR, 0.68; 95% CI, 0.41-1.12; very low certainty in the included in the analysis, 2 studies compared ASA with UFH,193,195
evidence of effects), with an absolute risk reduction from 0 fewer (0-1 4 studies compared ASA with LMWH,194,196,198,199 and 2 studies

fewer; baseline risk, 0.1%73) to 1 fewer (0-1 fewer; baseline risk, 0.2% compared ASA with oral anticoagulants.197,199 All 7 studies
73
) symptomatic distal DVT per 1000 patients. reported the outcomes of mortality and PE,193-199 6 studies
reported on proximal and distal DVTs,195-199 and 5 studies reported
Harms and burden. The risk of major bleeding may be similar
(RR, 1.63; 95% CI, 0.81-3.29; very low certainty in the evidence of on major bleeding.194-196,198,199 We found no studies addressing
effects), corresponding to 5 fewer (1 fewer to 17 more), although the outcome of reoperation.
we are very uncertain of this finding. Also, the need for reoperation The EtD framework is available online at https://guidelines.gradepro.org/
may be increased (RR, 1.84; 95% CI, 0.89-3.80; very low certainty profile/3532ED1D-6A40-A982-BC3F-6DA318B3B611.
in the evidence of effects) corresponding to 2 more reoperations (0 Benefits. There may be no difference in mortality between ASA and
fewer to 6 more) per 1000 patients. Once again, we are very anticoagulants (RR, 2.32; 95% CI, 0.15-36.90; low certainty in the
uncertain about this finding. evidence of effects). There also may be no difference in the risk of
Certainty in the evidence of effects. We rated the overall symptomatic PEs between ASA and anticoagulants (RR, 1.49; 95% CI,
certainty in the evidence of effects as very low based on the lowest 0.37-6.09; very low certainty in the evidence of effects), corre-
certainty in the evidence for the critical outcomes and downgrading for sponding to 3 more (4 fewer to 29 more) symptomatic PEs per
study limitations, indirectness, and imprecision. 1000 patients based on a baseline risks of 0.6%202,203 from
observational data; however, we are very uncertain of this finding.
Other EtD criteria and considerations. Based on very low
There also may be no difference in the risk of proximal DVTs (RR,
certainty in the evidence of effects, the panel judged that the
1.49; 95% CI, 0.51-4.34; very low certainty in the evidence of
balance of effects did not favor early or delayed institution of
effects), corresponding to 3 more symptomatic (3 fewer to 30
pharmacological antithrombotic prophylaxis in major surgical
more) proximal DVTs per 1000 patients based on a baseline risk of
patients. Costs and saving would likely be negligible, and the panel
0.6%,202,203 or in the risk of distal DVTs (RR, 1.45; 95% CI, 0.86-
saw no particular issues related to equity, acceptability, or feasibility.
2.46; very low certainty in the evidence of effects), corresponding
Conclusions and research needs for this recommendation. to 0 fewer symptomatic distal DVTs (0 fewer to 1 more) per 1000
The guideline panel suggests early administration (postoperative, patients based on a baseline risk of 0.05%,202,203 although we were
within 12 hours) or late administration (postoperative, after 12 hours) very uncertain about both findings.
of antithrombotic prophylaxis in major surgical patients, based on
Harms and burden. ASA may lead to a small increased risk for
very low certainty in the evidence of effects. In light of the very low
major bleeding (RR, 2.63; 95% CI, 0.64-10.79; low certainty in the
certainty in the evidence of effects, further high-quality studies using
evidence of effects). These findings correspond to 6 more (1 fewer
clinically important outcomes are important to provide greater certainty
to 35 more) major bleeding events per 1000 patients. We found no
about the benefits and risks of early pharmacological prophylaxis.
evidence to inform the comparative risk of reoperation.
The panel was particularly interested in seeing future high-quality
studies of early vs late pharmacological prophylaxis studies in Certainty in the evidence of effects. We rated the overall
high-risk bleeding patients, examining the benefits and risks of later certainty in the evidence of effects as very low based on the lowest
intervention (days following surgery) once the bleeding risk had certainty in the evidence for the critical outcomes, downgrading
greatly subsided. for study limitations, indirectness, and imprecision.
Other EtD criteria and considerations. The panel deter-
Orthopedic surgery mined that there was probably important uncertainty or variability
Question: Should ASA vs anticoagulants be used for patients in how much affected individuals value the main outcomes. It
undergoing total hip or knee arthroplasty? further judged that use of ASA saved costs and resources;
however, the results of cost-effectiveness studies varied, with some
favoring ASA and others favoring anticoagulant prophylaxis.
Recommendation 9 Health equity would probably be increased as a consequence of
the use of ASA. Acceptability was thought to also vary depending
For patients undergoing total hip arthroplasty or total knee on the type of stakeholder (patient vs health care provider). There
arthroplasty, the ASH guideline panel suggests using ASA or were no concerns about the feasibility of implementation. A recent
anticoagulants (conditional recommendation based on very low large RCT supports our recommendation that ASA or anticoagu-
certainty in the evidence of effects Å◯◯◯). lants be used for VTE prophylaxis following total hip or knee
arthroplasty. However, this study was not included in our analysis
because all patients received a 5-day course of a DOAC before moderate certainty in the evidence of effects); this corresponds to
being randomized to ASA or to stay on a DOAC for extended 0 fewer deaths (1 fewer to 1 more) per 1000 patients. DOACs
prophylaxis.201 probably slightly reduce the rate of symptomatic PEs (RR, 0.74;
95% CI, 0.50-1.10; moderate certainty in the evidence of effects);
based on a baseline risk of 0.6% from observational data,202,203 this
The guideline panel suggests using ASA or anticoagulants for
corresponds to 1 fewer (3 fewer to 1 more) symptomatic PE per
patients undergoing total hip arthroplasty or total knee arthro-
1000 patients. The use of DOACs reduces symptomatic proximal
plasty (conditional recommendation based on very low certainty
DVTs slightly (RR, 0.56; 95% CI, 0.39-0.79; high certainty in the
in the evidence of effects). They determined that there was very
evidence of effects), which corresponds to 3 fewer (1-4 fewer)
low certainty evidence for any net health benefit/harm from using
symptomatic proximal DVTs per 1000 patients, based on a base-
ASA vs anticoagulants. Of 8 panel members who voted on this
line risk of 0.6% from observational data.202,203 This effect on
recommendation, 5 voted for recommending either interven-
symptomatic distal DVTs is probably not clinically relevant (RR, 0.56;

tion, and 3 voted for a conditional recommendation in favor of
95% CI, 0.39-0.79; high certainty in the evidence of effects), which
anticoagulants.
corresponds to 0 fewer symptomatic distal DVTs per 1000 patients
The panel identified that there is a need for large well-designed based on a baseline risk of 0.049%, from observational data.202,203
clinical trials using clinically important end points comparing ASA Harms and burden. DOACs probably do not increase major
with other pharmacological methods following total hip and knee bleeding compared with LMWH (RR, 1.03; 95% CI, 0.79-1.35;
arthroplasty. The panel noted that such studies are underway. moderate certainty in the evidence of effects), which corresponds
Question: Should DOACs vs LMWH be used for patients to 0 fewer major bleeding events (2 fewer to 4 more) per 1000
undergoing total hip or knee arthroplasty? patients. Similarly, rates of reoperation may not be meaningfully
increased (RR, 1.43; 95% CI, 0.75-2.71; moderate certainty in the
evidence of effects) given the low event rates; this corresponds to
Recommendation 10 0 fewer reoperations (0 fewer to 2 more) per 1000 patients.
For patients undergoing total hip arthroplasty or total knee Certainty in the evidence of effects. We rated the overall
arthroplasty in which anticoagulants are used, the ASH certainty in the evidence of effects as moderate based on the lowest certainty
guideline panel suggests using DOACs over LMWH (con- in the evidence for the critical outcomes, downgrading for imprecision.
ditional recommendation based on moderate certainty in the Other EtD criteria and considerations. The panel judged the
evidence of effects ÅÅÅ◯). desirable and undesirable effects as being small and trivial,
respectively, in magnitude. Cost-effectiveness was judged to
probably favor the use of DOACs. Similarly, equity, acceptability,
Summary of the evidence. We identified 1 systematic re- and feasibility each favored the use of DOACs and contributed to
view204 that addressed this question. Twenty-two studies in this the recommendation in their favor. Use of out-of-hospital pro-
review fulfilled our inclusion criteria. Our update of the systematic phylaxis, which is routine following total hip or knee arthroplasty,
review identified 16 additional studies. All studies included patients particularly favored DOACs over LMWH, given the need for
undergoing elective hip or knee replacement. parenteral administration of the latter agent.
Five studies assessed the effects of dabigatran,191,205-208 15 studies Conclusions and research needs for this recommendation.
assessed the effects of rivaroxaban,180,185,189,190,199,209-218 4 The guideline panel suggests using DOACs rather than LMWH for
studies assessed the effects of apixaban,219-222 5 studies patients undergoing total hip or knee arthroplasty. Based on an
assessed the effects of darexaban223-226 and edoxaban,227-231 overall moderate certainty in the evidence of effects, the panel
and 4 studies assessed the effects of other DOACs.232-235 judged the balance of effects to probably favor the use of
Thirty-four studies reported mortality,180,185,189-191,199,205-215,218-222, DOACs over LMWH. The ultimate judgment of a conditional
224-231,233-235
whereas 33 studies reported nonfatal PEs.180,185,189-191, recommendation for DOACs was based on anonymous voting by
199,205-212,214-216,219-222,224-231,233-235
We estimated proximal and panel members without direct financial conflicts, with a majority of 5
distal DVTs using the pooled estimate from symptomatic DVTs, which voting for this recommendation (vs 4 in favor of a recommendation
was reported in 30 studies.185,189-191,199,205-212,214-216,219-222,224-230, for using either). The panel recommended a need for large clinical
234,235
Thirty-two studies reported major bleeding,180,185,189-191,205-212, trials using clinically relevant end points comparing different
214,215,219-222,224-235
whereas only 15 studies reported bleeding DOACs. Further studies regarding the optimal timing of the
leading to reoperation.180,185,189-191,205-207,209-212,215,220,221 initiation of postoperative dosing of DOACs are warranted.
We tested potential differences in the effects with specific drugs Question: Should 1 DOAC vs another DOAC be used for patients
and between classes (anti–factor IIa vs anti–factor Xa). We found undergoing total hip or knee arthroplasty?
no interaction for any of the outcomes. Additionally, we conducted a
sensitivity analysis excluding dose-finding studies. The results did
Recommendation 11
not change appreciably.
The EtD framework is available online at https://guidelines.gradepro. For patients undergoing surgery, the ASH guideline panel
org/profile/9160FAA2-4F98-A3AA-9816-64DF796ABBC7. suggests using any of the DOACs approved for use (condi-
tional recommendation based on low certainty in the evidence
Benefits. DOACs probably do not reduce mortality compared of effects ÅÅ◯◯).
with that associated with LMWH (RR, 0.94; 95% CI, 0.53-1.66;

Summary of the evidence. We found no study that compared both populations.238 Five studies219,237-240 reported the effect of
different classes of DOACs or individual DOACs of the same class LMWH compared with warfarin on mortality, 5 studies reported the
head to head. Therefore, we used the body of evidence effect on the development of symptomatic PEs,39,219,237,238,240 6
comparing DOAC prophylaxis vs LMWH (see recommendation studies reported on any proximal DVT,219,237-241 and 2 studies
10) as the basis for an indirect assessment of their relative reported on any distal DVT.237,241 All 7 studies reported the effect
effectiveness. on the risk of major bleeding,39,219,237-241 and 2 studies reported on
The EtD framework is available online at https://guidelines.gradepro.org/ the risk of reoperation.237,241
profile/16A3927F-FB2D-C278-9FE5-D4535020FE27. The EtD framework is available online at https://guidelines.gradepro.org/
Benefits. In the absence of comparative trials of different classes profile/BC1783C1-D62B-AECB-B9F7-87A9D474A834.
of DOACs (anti–factor IIa vs anti–factor Xa) or individual DOACs of Benefits. LMWH may result in little or no difference in mortality
the same class, we tested potential differences by analyzing potential compared with warfarin (RR, 0.51; 95% CI, 0.14-1.88; low certainty

subgroup effects. Based on the tests for interaction, we did not in the evidence of effects). LMWH likely does not reduce
demonstrate any evidence for a clinically relevant subgroup effect for symptomatic PEs (RR, 0.83; 0.27-2.54; moderate certainty in the
any of the potentially desirable outcomes. Based on this finding, the evidence of effects). LMWH may reduce symptomatic proximal
panel assumed that the beneficial effects were likely similar for different DVTs (RR, 0.61; 95% CI, 0.36-1.02; very low certainty in the
DOACs. evidence of effects) and symptomatic distal DVTs (RR, 0.61;
Harms and burden. Similarly, based on tests for interaction, we 95% CI, 0.42-0.88; low certainty in the evidence of effects).
did not find any evidence for a clinically relevant subgroup effect for This corresponds to 2 fewer (0-4 fewer) symptomatic proximal
any of the potentially undesirable outcomes. Based on this finding, DVTs and 0 fewer symptomatic distal DVTs with the use of
the panel assumed that the undesirable effects were likely similar for LMWH than with warfarin for 1000 patients treated, based on
baseline risks of 0.6% and 0.049%, respectively, from observational
different DOACs.
data.202,203
certainty in the evidence of effects as low based on the lowest Harms and burden. LMWH use likely results in increased
major bleeding compared with the use of warfarin (RR, 1.81;
for indirectness and imprecision. 95% CI, 1.31-2.50; moderate certainty in the evidence of
effects). This corresponded to 16 more (5-22 more) major
Other EtD criteria and considerations. Based on these bleeds per 1000 patients. There was no difference with regard to
findings, the panel judged that the balance of effects did not favor any reoperation rates between those receiving LMWH or warfarin (RR,
particular DOAC over another. The panel also judged that issues 3.09; 95% CI, 0.13-75.48; moderate certainty in the evidence of
surrounding cost-effectiveness, equity, acceptability, and feasibility also effects), which corresponded to 0 more events per 1000 patients.
did not weigh in sufficiently to favor 1 DOAC over another.
Conclusions and research needs for this recommendation. certainty in the evidence of effects as very low based on the
Based on overall low certainty in the evidence of effects, the panel lowest certainty in the evidence for the critical outcomes,
judged that there were no net benefits in favor of any DOAC vs downgrading for study limitations and very serious imprecision.
another. Given the lack of direct comparative evidence, the panel
Other EtD criteria and considerations. The panel judged
identified an important need for high-quality head-to-head studies
that there was possibly important uncertainty or variability in
comparing different DOACs for the prevention of VTEs following
how much people value the main outcomes. The balance
total hip or knee arthroplasty.
between desirable und undesirable effects probably favored
Question: Should LMWH vs warfarin be used for patients LMWH. Resources requirements of warfarin were deemed
undergoing total hip or knee arthroplasty? moderate, particularly with regard to the need for, and the
complexity of, anticoagulant monitoring, but cost-effectiveness
data probably did not favor warfarin or LMWH. There probably
Recommendation 12 would be no impact on health equity; both agents appear
For patients undergoing total hip arthroplasty or total knee acceptable to stakeholders and are feasible to implement.
arthroplasty, if a DOAC is not used, the ASH guideline panel Conclusions and research needs for this recommendation.
suggests using LMWH rather than warfarin (conditional rec- The guideline panel suggests using LMWH rather than warfarin for
ommendation based on very low certainty in the evidence of patients undergoing total hip arthroplasty or total knee arthroplasty.
effects Å◯◯◯). The guideline panel determined that there was very low certainty
evidence for a net health benefit/harm from using LMWH rather
than warfarin. Based on the body of available evidence, it is likely
Summary of the evidence. We identified 1 systematic review
that warfarin reduces the risk of major bleeding based on evidence
that addressed this question.236 We identified 7 trials in this review
of moderate certainty. However, it may also increase the risk of
that fulfilled our inclusion criteria and measured outcomes relevant
to this context.39,219,237-241 Our systematic search of RCTs did not proximal DVTs, based on very low quality evidence.
identify any additional study that fulfilled the inclusion criteria. Three Further high-quality studies using clinically important outcomes
studies were conducted with patients undergoing total hip would be of value to improve the certainty in the recommendation.
arthroplasty,39,239,241 3 studies were conducted with patients However, given the availability of DOACs as oral agents that do
undergoing total knee arthroplasty,219,237,240 and 1 study addressed not require anticoagulant monitoring or dose adjustment, further
clinical trials using warfarin are not regarded as a high priority at Other EtD criteria and considerations. The panel deter-
this time. mined that there was probably important uncertainty or variabil-
ity in how much affected individuals value the main outcomes.
Question: Should LMWH vs UFH be used for patients undergoing
Cost-effectiveness likely differs by country but probably favors
total hip or knee arthroplasty?
LMWH. The panel assessed that this recommendation probably
would have no impact on health equity and would be acceptable
Recommendation 13 to stakeholders. LMWH is already widely used, and the panel
had no concern about the feasibility of implementation.
For patients undergoing total hip arthroplasty or total knee
arthroplasty, if a DOAC is not used, the ASH guideline panel Conclusions and research needs for this recommendation.
suggests using LMWH rather than UFH (strong recommenda- The guideline panel recommends LMWH rather than UFH for patients
tion based on moderate certainty in the evidence of effects undergoing total hip arthroplasty or total knee arthroplasty.
ÅÅÅ◯).

The guideline panel determined that there is moderate certainty
evidence for a net health benefit/harm from using LMWH over UFH.
Future large studies using clinically relevant end points would help
Summary of the evidence. We identified 1 systematic review
to better inform this recommendation, although this research
that addressed this question.236 We identified 12 trials in this question would not be regarded as high priority.
review that fulfilled our inclusion criteria and measured outcomes
relevant to this context.242-253 Our systematic search of RCTs did Question: Should pharmacological prophylaxis vs no pharmaco-
not identify any additional study that fulfilled the inclusion criteria. logical prophylaxis be used for patients undergoing hip fracture
Ten trials were performed on patients undergoing total hip repair?
arthroplasty,242-244,246,247,249-253 and 2 trials were conducted on
patients undergoing total knee arthroplasty. 245,248 Five trials
reported the effect of LMWH compared with UFH on Recommendation 14
mortality,244,247,249,251,252 10 studies reported the effect on the
For patients undergoing hip fracture repair, the ASH guideline
development of symptomatic PEs,242-245,247-249,251-253 8 studies
panel suggests using pharmacological prophylaxis over no
reported the effect on any proximal DVT,242,244-249,251 and 6 studies
pharmacological prophylaxis (conditional recommendation
reported the effect on any distal DVT.242,244-249,251 Six studies reported
based on very low certainty in the evidence of effects Å◯◯◯).
the effect on the risk of major bleeding,244,245,249-251,253 and 2 studies
reported the effect on the risk of reoperation.247,248
The EtD framework is available online at https://guidelines.gradepro.org/ Summary of the evidence. We identified 1 systematic
profile/06FDBFB0-4D4E-E0D0-AEAD-C8B371DFA939. review254 that addressed, in part, this question. We identified
Benefits. LMWH results in little or no difference in mortality 5 studies in this review that fulfilled our inclusion criteria and
compared with UFH (RR, 0.26; 95% CI, 0.03-2.36; high certainty measured outcomes relevant to this context.255-259 Our system-
in the evidence of effects), which corresponded to 3 fewer (4 atic search of RCTs identified 7 additional studies that fulfilled
fewer to 5 more) deaths per 1000 patients. LMWH probably the inclusion criteria.260-266 Nine studies reported the effect of
reduces the risk of symptomatic PEs slightly (RR, 0.37; 95% CI, pharmacological prophylaxis compared with no intervention on
0.19-0.71; moderate certainty in the evidence of effects). This risk of mortality.255,256,258,259,261-265 Nine studies reported the
corresponds to 4 fewer (2-5 fewer) symptomatic PEs per 1000 effect on development of any PEs,255-259,261,264-266 and 5
patients, based on a baseline risk of 0.6% from observational studies reported the effect of any proximal DVT and any distal
data.202,203 LMWH also likely reduces the risk of symptomatic DVT.257,260,261,263,265 Eleven studies reported the effect of pharma-
proximal DVTs (RR, 0.48; 95% CI, 0.34-0.69; moderate certainty cological prophylaxis compared with no intervention on risk of major
in the evidence of effects), corresponding to 3 fewer (2-4 fewer) bleeding,255,256,258-266 and 3 studies reported the effect on risk of
per 1000 patients, based on a baseline risk of 0.6% from reoperation.258,261,266
observational data.202,203 LMWH appears to result in little or no We tested potential differences in the effects with ASA and anti-
difference in symptomatic distal DVTs (RR, 1.18; 95% CI, 0.81- coagulant prophylaxis and performed a subgroup analysis. The
1.72; low certainty in the evidence of effects), with very small analysis indicated no subgroup effect with regard to desirable and
corresponding absolute effect size estimates based on a baseline undesirable effects comparing ASA with anticoagulant prophylaxis.
risk of 0.049% from observational data.202,203 As a result, in this analysis, studies with ASA are pooled with those
Harms and burden. LMWH likely results in a small decrease in of anticoagulant prophylaxis compared with no pharmacological
the risk of major bleeding (RR, 0.55; 95% CI, 0.27-1.13; moderate prophylaxis.
certainty in the evidence of effects); this corresponds to 19 fewer The EtD framework is available online at https://guidelines.gradepro.org/
(30 fewer to 5 more) major bleeds per 1000 patients. We were profile/A10CDC06-B411-D572-959A-A8405E1373A1.
unable to estimate an effect on the risk of reoperation given that the Benefits. Pharmacological prophylaxis appears to result in little
included studies reported no events for this outcome. or no difference in mortality (RR, 0.95; 95% CI, 0.84-1.07; very low
Certainty in the evidence of effects. We rated the overall certainty in the evidence of effects), although we are very uncertain
certainty in the evidence of effects as moderate based on the lowest about this finding. This would correspond to 4 fewer deaths
certainty in the evidence for the critical outcomes, downgrading for (11 fewer to 5 more) per 1000 patients based on a baseline risk of
imprecision. 7.1% from the control group event rate in the meta-analysis.

Pharmacological prophylaxis may reduce symptomatic PEs (RR, Summary of the evidence. We identified 1 systematic re-
0.49; 95% CI, 0.33-0.72; very low certainty in the evidence of view254 that addressed this question. We identified 3 studies in this
effects), but we are very uncertain of this finding. This corresponds review that fulfilled our inclusion criteria and measured outcomes
to 6 fewer (3-7 fewer) events per 1000 patients based on a baseline relevant to this context.268-270 Our update of the systematic review
risk of 1.1% from the control group event rate in the meta-analysis. did not identify any additional study that fulfilled the inclusion
Based on lower baseline risk of 0.3% from observational data,267 criteria. Two studies reported the effect of LMWH prophylaxis
this would correspond to 2 fewer (1-2 fewer) symptomatic PEs per compared with UFH prophylaxis on risk of mortality, as well as any
1000 patients. Pharmacological prophylaxis may reduce symptom- proximal and distal DVTs,268,269 and 3 studies reported the effect
atic proximal DVTs (RR, 0.51; 95% CI, 0.38-0.69; very low certainty on any PEs and major bleeding.268-270 No information on
in the evidence of effects), but we are very uncertain of this finding. reoperation rates was available in any of the included studies.
In a moderate-risk population with a baseline risk of 2.5%,267 this The EtD framework is available online at https://guidelines.gradepro.org/
corresponds to 12 fewer (8-16 fewer) per 1000 patients. Pharmaco- profile/80C377E5-E3C0-36CD-B646-C2532AB4D4B9.

logical prophylaxis likely has little or no effect on symptomatic distal
DVTs (RR, 0.85; 95% CI, 0.56-1.29; very low certainty in the evidence Benefits. LMWH appears to result in little or no difference in
of effects), but once again we are very uncertain of this finding. mortality compared with UFH prophylaxis following hip fracture
repair (RR, 0.47; 95% CI, 0.10-2.12; very low certainty in the
Harms and burden. Pharmacological prophylaxis may increase evidence of effects), although we are very uncertain about the
major bleeding (RR, 1.24; 95% CI, 1.12-1.37; low certainty in the effect. Assuming a baseline risk of 7.4% for UFH-treated patients,
evidence of effects). Depending on baseline risk, this corresponds this would correspond to 39 fewer (66 fewer to 88 more) deaths per
to 1 more (1-2 more) major bleed per 1000 patients in a lower-risk 1000 patients. We are very uncertain about the effect of LMWH on
population (baseline risk of 0.5% from observational data)267 or symptomatic PEs (RR, 2.13; 95% CI, 0.06-81.3; very low certainty in the
as many as 20 more (10-31 more) per 1000 patients in a higher- evidence of effect). LMWH may result in a small, possibly unimportant,
risk population (baseline risk of 8% from the control group event increase in symptomatic proximal DVTs (RR, 2.24; 95% CI, 0.92-5.43;
rate in the meta-analysis). Pharmacological prophylaxis appears to low certainty in the evidence of effect) corresponding to 31 more (2
have little or no effect on the need for reoperation (RR, 1.05; 95% fewer to 111 more) per 1000 patients based on a baseline risk of
CI, 0.82-1.35; very low certainty in the evidence of effects); 2.5% from observational data. 267 LMWH appears to result in
however, we are very uncertain of this finding. little or no difference in symptomatic distal DVTs (RR, 0.66; 95%
Certainty in the evidence of effects. We rated the overall CI, 0.21-2.17; very low certainty in the evidence of effects).
certainty in the evidence of effects as very low based on the lowest Harms and burden. LMWH appears to result in little or no
certainty in the evidence for the critical outcomes, downgrading for difference in major bleeding compared with UFH after hip fracture
study limitations, indirectness, and very serious imprecision. surgery (RR, 0.85; 95% CI, 0.19-3.79; very low certainty in the
Other EtD criteria and considerations. The panel judged the evidence of effects). This corresponds to 9 fewer (50 fewer to
magnitude of the desirable effects as moderate in size and the 173 more) major bleeds per 1000 moderate-risk patients with a
undesirable effects as small in size. There was possibly important baseline risk of 6.2% based on a lower baseline risk of 0.5%
uncertainty or variability about how patients may value these outcomes. from observational data267 ; the corresponding absolute risk
There would probably be no impact on equity, and the panel foresaw reduction would be 1 fewer (4 fewer to 14 more) per 1000
no issues with regard to acceptability and feasibility of using patients. No comparative information is available regarding the risks
pharmacological prophylaxis in this patient population. of reoperation following hip fracture with the use of LMWH or UFH.
Conclusions and research needs for this recommendation. Certainty in the evidence of effects. We rated the overall
Although the overall certainty in the evidence of effects was very certainty in the evidence of effects as very low based on the lowest
low, the panel judged that the balance of effects probably favored certainty in the evidence for the critical outcomes, downgrading for
study limitations, indirectness, and very serious imprecision.
the use of pharmacological prophylaxis for VTE prophylaxis following
hip fracture repair. Given the overall very low certainty in the evidence, Other EtD criteria and considerations. The panel determined
the panel indicated that there remains an important need for large that there was possibly important uncertainty or variability in how
much affected individuals valued the main outcomes. They further
high-quality RCTs using clinically important end points to determine
judged that the balance between desirable and undesirable effects
the optimal role of ASA or anticoagulant pharmacological pro-
did not favor LMWH or UFH following hip fracture repair. The panel
phylaxis in this patient population. However, higher priority would be recognized the very low certainty in comparative evidence, which
comparative studies of different antithrombotic regimens for the was based on three small RCTs that did not report symptomatic DVT
prevention of VTEs in these patients requiring repair of hip fracture. outcomes. The panel recognized that the comparative resources
Question: Should LMWH prophylaxis vs UFH prophylaxis be used associated with LMWH and UFH prophylaxis were probably
for patients undergoing hip fracture repair? negligible. Cost-effectiveness was considered to favor LMWH
based upon results of a single study.271 Using LMWH or UFH
would probably not impact health equity, and either drug was
Recommendation 15 deemed to be probably acceptable to stakeholders and feasible to
implement.
For patients undergoing hip fracture repair, the ASH guideline
panel suggests using LMWH or UFH (conditional recommenda- Conclusions and research needs for this recommendation.
tion based on very low certainty in the evidence of effects Å◯◯◯). Taking into consideration the very low certainty in the evidence,
the panel judged that LMWH or UFH prophylaxis could be
recommended following hip fracture repair. Large RCTs using Harms and burden. Pharmacological prophylaxis probably
clinically important outcomes are needed to better define the increases major bleeding (RR, 1.37; 95% CI, 0.89-2.13; moderate
relative benefits and risks of LMWH compared with UFH following certainty in the evidence of effects). This corresponds to 10 more (3
hip fracture surgery. fewer to 29 more) major bleeding events per 1000 patients
undergoing major general surgery. Pharmacological prophylaxis
Major general surgery results in little or no difference in reoperation (RR, 0.75; 95% CI,
0.21-2.77; low certainty in the evidence of effects).
Question: Should pharmacological prophylaxis vs no pharmaco-
logical prophylaxis be used for patients undergoing major general Certainty in the evidence of effects. The overall certainty of
surgery? the estimates of effects was based on the low certainty outcomes
and was not based on the lowest certainty of evidence for the
critical outcomes. In this case, the recommendation was sufficiently
supported by the favorable impact on desirable effects for which

Recommendation 16 there was higher quality evidence.
For patients undergoing major general surgery, the ASH guideline Other EtD criteria and considerations. The panel judged the
panel suggests using pharmacological prophylaxis over no phar- desirable effects to be of moderate magnitude and the undesirable
macological prophylaxis (conditional recommendation based effects to be of small magnitude. They assumed that there was
on low certainty in the evidence of effects ÅÅ◯◯). possibly important uncertainty or variability in patients’ values.
Pharmacological prophylaxis probably would incur moderate
additional costs but was judged to be probably cost-effective.
Summary of the evidence. We identified a systematic review Pharmacological prophylaxis would probably have no impact on
of RCTs 272 addressing this research question. We identified 3 equity, was probably acceptable, and was likely feasible.
studies 273-275 in this review that fulfilled our inclusion criteria
and measured outcomes relevant to this context. Our
The panel judged that the overall balance of effects favored
systematic search for RCTs identified 3249,122,125,131,274,276-302
pharmacological prophylaxis over no pharmacological prophylaxis
additional studies that fulfilled the inclusion criteria, in-
for patients undergoing major general surgery based on low
cluding patients undergoing major general surgery. Sixteen
studies 122,125,274-278,284,285,291,293,296,297,299,300,302 reported certainty in the evidence of effects. Further high-quality comparative
the effect of pharmacological prophylaxis vs no pharma- studies, using appropriate clinical outcomes, would be of value to
cological prophylaxis on the risk of mortality, and 11 add more certainty to these recommendations. However, such
studies 125,273,276-279,285,286,289,293,295 reported the effect on studies would not be considered as high priority by the panel.
the development of symptomatic PEs. Six studies49,125,278,285,287,290 Question: Should LMWH prophylaxis vs UFH prophylaxis be used
reported the effect on development of screening-detected proximal for patients undergoing major general surgery?
DVTs, and 6 studies124,277,283,284,286,289 reported the effect on
development of screening-detected distal DVTs.
Twelve studies125,273-276,282,285,287,293,295,297,298 reported the effect Recommendation 17
of pharmacological prophylaxis vs no pharmacological prophylaxis on
For patients undergoing major general surgery, the ASH guideline
risk of major bleeding, and 3 studies275,282,295 reported the effect on
panel suggests using LMWH or UFH (conditional recommenda-
risk of reoperation.
tion based on very low certainty in the evidence of effects Å◯◯◯).
profile/3B5A5678-B1D9-4D60-8E1F-F3AD700132F8.
Benefits. Pharmacological prophylaxis compared with no Summary of the evidence. We identified 2 systematic
pharmacological prophylaxis probably reduces mortality (RR, reviews of RCTs272,303 addressing this research question. We
0.76; 95% CI, 0.61-0.93; moderate certainty in the evidence of identified 40 studies304-343 in these reviews that fulfilled our
effects). This finding corresponds to 4 fewer deaths (1-7 fewer) per inclusion criteria and measured outcomes relevant to this context.
1000 patients undergoing major general surgery. Pharmacological Our systematic search for RCTs identified 6 additional
prophylaxis probably also reduces symptomatic PEs (RR, 0.45; 95% studies 295,344-348 that fulfilled the inclusion criteria. Thirty
CI, 0.23-0.88; moderate certainty in the evidence of effects). This studies reported the effect of LMWH vs UFH on risk of
corresponds to 4 fewer (1-6 fewer) pulmonary embolic events per mortality.305,307,308,310-312,314,317-319,321,322,325-327,329-339,341,342,346,347
1000 patients undergoing major general surgery. Pharmacological Thirty-one studies reported the effect of LMWH vs UFH on development
of symptomatic PEs,295,305-306,310-312,314-319,321,322,324,326-335,337,339,344-346
prophylaxis may also reduce symptomatic proximal DVTs (RR, 0.38;
95% CI, 0.14-1.00; very low certainty in the evidence of effects), but 5 studies reported the effect on symptomatic proximal
we are very uncertain of this finding. This corresponds to 10 fewer (0- DVTs,306,316,326,334,336 and 7 reported the effect on symptom-
14 fewer) symptomatic proximal DVTs per 1000 patients based on a atic distal DVTs. 306,316,326,329,334,336,341 Thirty-four studies
baseline risk of 1.6% from observational data.73 It may reduce reported the effect of LMWH vs UFH on risk of major
symptomatic distal DVTs (RR, 0.57; 95% CI, 0.36-0.90; low certainty bleeding,295,305-307,311,313,315-319,321-339,341,344-346 and 16 studies reported
in the evidence of effects), which corresponds to 1 fewer (0-1 fewer) the effect on risk of reoperation.305,307,309,317,319,322,323,326,329,330,333-337,341
symptomatic distal DVT per 1000 patients undergoing major general The EtD framework is available online at https://guidelines.gradepro.org/
surgery based on a baseline risk of 1.6% from observational data.73 profile/EF7ADEA0-49F1-7E89-A0DB-DE7A9E854A2B.

Benefits. Prophylaxis with LMWH vs UFH probably does not Summary of the evidence. We identified 1 systematic review of
reduce mortality following major general surgery (RR, 1.03; 95% RCTs addressing this research question.30 We identified 2
CI, 0.89-1.18; moderate certainty in the evidence of effects). studies118,349 in that review that fulfilled our inclusion criteria and
We are very uncertain about the effect of LMWH on measured outcomes relevant to this context. Because of the relative
symptomatic PEs compared with that of UFH (RR, 0.83; 95% paucity of studies on patients undergoing laparoscopic cholecys-
CI, 0.58-1.19; very low certainty in the evidence of effects), which tectomy, data across major general, major gynecological, and
corresponds to 1 fewer (3 fewer to 2 more) symptomatic PE per 1000 major urological procedures were pooled, and laparoscopic
patients undergoing major general surgery based on a baseline cholecystectomy-specific baseline risk estimates were ap-
risk of 0.8% from observational data.73 It also appears to result in little or plied. 350 Five studies66,294,301,351,352 were conducted on
no difference in symptomatic proximal DVTs (RR, 1.01; 95% CI, 0.20- patients undergoing major gynecological surgery. Thirty-
5.00; very low certainty in the evidence of effects) or a reduction in one 49,122,125,131,275-279,281-293,295-300,302 studies were con-
symptomatic distal DVTs (RR, 1.01; 95% CI, 0.30-3.44; very low certainty ducted on patients undergoing major general surgery. Two

in the evidence of effects). We are very uncertain about the last 2 findings. studies 118,349 were conducted on patients undergoing laparo-
Harms and burden. Prophylaxis with LMWH vs UFH probably scopic cholecystectomy. Six studies 38,280,353-356 were con-
ducted on patients undergoing urological surgery. Eighteen
does not affect major bleeding (RR, 0.97; 95% CI, 0.78-1.20;
moderate certainty in the evidence of effects). This corresponds to studies122,125,274-278,284,285,291,293,296,297,299,300,302,353,354 reported the
0 fewer (3 fewer to 3 more) major bleeding events per 1000 effect of pharmacological prophylaxis vs no pharmacological prophylaxis
patients undergoing major general surgery. LMWH probably results on risk of mortality, 16 studies38,118,125,273,276-279,285,286,289,293,295,354-356
in little or no difference in reoperations (RR, 0.79; 95% CI, 0.57- reported the effect on risk of symptomatic PEs, 6 studies49,125,278,285,287,290
1.08; moderate certainty in the evidence of effects), which reported the effect on risk of screening-detected proximal
corresponds to 3 fewer (6 fewer to 1 more) reoperations per DVTs, and 7 studies 66,125,278,284,285,287,290 reported the
1000 patients undergoing major general surgery. effect on risk of screening-detected distal DVTs. Fifteen
studies118,125,273-275,277,282,285,287,293,295,297,298,349,354 reported
Certainty in the evidence of effects. We rated the overall the effect of pharmacological prophylaxis vs no pharmacological
certainty in the evidence of effects as very low based on the lowest prophylaxis on risk of major bleeding, and 6 studies38,118,275,282,295,354
certainty in the evidence for the critical outcomes, downgrading reported the effect on risk of reoperation.
for study limitations and very serious inconsistency.
The EtD framework is available online at https://guidelines.grade-
Other EtD criteria and considerations. There was possibly pro.org/profile/E753AE97-D04A-D35F-ABE1-F9CAB9461DD1.
important uncertainty or variability in how patients valued the
outcomes. Potential costs and savings were deemed of Benefits. Pharmacological prophylaxis probably results in a small
negligible relevance, assuming only in-hospital short-term pro- unimportant reduction in overall mortality (RR, 0.75; 95% CI, 0.61-
phylaxis. There was probably no impact on equity, because both 0.93; low certainty in the evidence of effects). This corresponds
LMWH and UFH were thought to be acceptable and feasible to to 2 fewer (0-2 fewer) deaths per 1000 patients based on a
implement. If extended prophylaxis beyond hospital discharge is baseline risk of 0.6% from observational data.357 It may not reduce
planned, LMWH may be preferable given its once-daily dosing. The symptomatic PEs following laparoscopic cholecystectomy (RR,
panel thought that both treatment options are already widely used 0.48; 95% CI, 0.26-0.88; very low in the evidence of effects), but
and there should be few issues with implementation. we are very uncertain of this finding. Given the very low baseline risk
of VTE events in this specific patient population,350 this would be
Conclusions and research needs for this recommendation. expected to result in 0 fewer (0 fewer to 0 more) symptomatic
The guideline panel judged that the net benefit did not favor LMWH PEs per 1000 patients. Similarly, pharmacological prophylaxis
or UFH prophylaxis for patients undergoing major general surgery. may not reduce symptomatic proximal DVTs (RR, 0.38; 95% CI,
Based on a very low overall certainty in the evidence, the panel 0.14-1.00; very low certainty in the evidence of effects) or
determined that the balance of effects did not favor LMWH or UFH. symptomatic distal DVTs (RR, 0.52; 95% CI, 0.31-0.87; very low
In light of the very low certainty in the evidence, further high-quality certainty in the evidence of effects). Again, given the very low
comparative studies, using appropriate clinical outcomes, would be baseline risks, this would correspond to 0 fewer (0 fewer to
of value to add more certainty to this recommendation. However, such 0 more) events per 1000 patients for both outcomes. We are
comparative studies are not regarded as high priority at this time. very uncertain about the effects on symptomatic proximal DVTs
and symptomatic distal DVTs.
logical prophylaxis be used for patients undergoing laparoscopic Harms and burden. Pharmacological prophylaxis may result in a
cholecystectomy? small increase in major bleeding (RR, 1.24; 95% CI, 0.87-1.77; low
certainty in the evidence of effects). This would be expected to
Recommendation 18 result in 6 more (3 fewer to 20 more) major bleeds per 1000
patients. We are very uncertain whether pharmacological pro-
For patients undergoing laparoscopic cholecystectomy, the phylaxis results in little or no difference in reoperation (RR, 0.93;
ASH guideline panel suggests against using pharmacological 95% CI, 0.35-2.50; very low certainty in the evidence of effects);
prophylaxis (conditional recommendation based on very low cer- this corresponds to 1 fewer (8 fewer to 18 more) reoperation per
tainty in the evidence of effects Å◯◯◯). Remark: Patients with 1000 patients.
other risk factors for VTEs (eg, history of VTE, thrombophilia, or
malignancy) may benefit from pharmacological prophylaxis. Certainty in the evidence of effects. We rated the overall
certainty in the evidence for the critical outcomes, downgrading for the effect of warfarin,124 and 1 study assessed the effect of
study limitations, indirectness, and imprecision. heparin-dihydroergotamine.360 Additionally, across the 10 studies,
Other EtD criteria and considerations. The panel based this mechanical prophylaxis was used as a cointervention in 6 of the
recommendation on the trivial incremental benefits and the small randomized studies68,123,128,130,135,359 and in all 3 of the non-
increased risk of major bleeding associated with pharmacological randomized studies.361-363 Supplement 6 presents the character-
prophylaxis. The panel judged that the potential benefits of pharmaco- istics of all included studies.
logical prophylaxis were outweighed by the small increased risk of major Five RCTs68,104,128,130,359,362 and 2 nonrandomized studies361,363
bleeding in average-risk patients undergoing laparoscopic cholecys- reported the effect of any pharmacological thromboprophylaxis vs
tectomy. This relates to the very low baseline risk of VTE for patients no pharmacological intervention on mortality, 3 RCTs123,128,360 and
undergoing laparoscopic cholecystectomy. The panel discounted the 2 nonrandomized studies reported on development of PEs,361,363 2
mortality difference observed in this analysis as unlikely to relate to RCTs reported on screening-detected proximal DVTs,128,130 and 1
pharmacological prophylaxis, given the very low baseline risk of VTE. study reported on development of screening-detected distal

Patients with other risk factors for VTE (eg, history of VTE, thrombophilia, DVTs.128 Seven RCTs68,123,128,130,135,359,360 and 3 nonrandom-
or malignancy) may benefit from pharmacological prophylaxis. ized studies361-363 reported risk of major bleeding, and 2 RCTs
Conclusions and research needs for this recommendation. reported on risk of reoperation.135,359
The guideline panel determined that potential undesirable effects The EtD framework is available online at https://guidelines.grade-
of pharmacological prophylaxis, in particular major bleeding, out- pro.org/profile/C5A1B92D-0E70-50BA-847C-0497617938F5.
weighed its potential benefit for patients undergoing laparoscopic
Benefits. Pharmacological prophylaxis does not appear to
cholecystectomy. The panel acknowledges that the overall certainty
reduce mortality (RR, 1.27; 95% CI, 0.57-2.69; low certainty in
in the evidence was low, in particular as a result of indirectness, with
the evidence of effects) when considering the body of evidence
most of the trial data included in the analysis involving patients
from RCTs, in which we have more confidence than the non-
undergoing major surgical procedures. Further research into
randomized data. This corresponds to 9 more deaths (15 fewer to 65
pharmacological prophylaxis following laparoscopic cholecystec-
more) per 1000 patients. Based on RCT evidence, pharmacological
tomy was not regarded as high priority given the low baseline
prophylaxis may result in little or no difference in symptomatic PEs
incidence of VTE complications in this patient population.
(RR, 0.84; 95% CI, 0.03-27.42; very low certainty in the evidence of
effects), but we are very uncertain of this finding. This corresponds to
Major neurosurgical procedures 0 fewer events (2 fewer to 53 more) per 1000 patients based on a
Question: Should pharmacological prophylaxis vs no pharmaco- baseline risk of 0.2% from observational data.364 The absolute effect
logical prophylaxis be used for patients undergoing major size is similarly small when considering the body of evidence from
neurosurgical procedures? nonrandomized trials. Pharmacological prophylaxis may result in a
small, possibly unimportant, effect on symptomatic proximal DVTs (RR,
0.50; 95% CI, 0.30 to 0.84; low certainty in the evidence of effects)
Recommendation 19 and symptomatic distal DVTs (RR, 0.60; 95% CI, 0.33-1.08; very
low certainty in the evidence of effects). This would correspond
For patients undergoing major neurosurgical procedures, the to 6 fewer (2-8 fewer) symptomatic proximal DVTs and 0 fewer
ASH guideline panel suggests against using pharmacological (0-1 fewer) symptomatic distal DVTs per 1000 patients un-
prophylaxis (conditional recommendation based on very low dergoing major neurosurgical procedures, based on baseline risks
certainty in the evidence of effects Å◯◯◯). Remarks: Patients from observational data of 1.2% and 0.1%, respectively.364
undergoing major neurosurgical procedures are expected to
receive prophylaxis with mechanical methods. Pharmacological Harms and burden. From RCTs, pharmacological prophylaxis
prophylaxis may be warranted in a higher-risk subgroup of pa- may increase major bleeding (RR, 1.57; 95% CI, 0.70-3.50; low
tients, such as those experiencing prolonged immobility fol- certainty in the evidence of effects), corresponding to 10 more (5
lowing surgery. In addition, pharmacological prophylaxis could fewer to 43 more) events per 1000 patients undergoing major
be considered for patients undergoing major neurosurgical neurosurgical procedures. We are very uncertain of the effect of
procedures that carried a lower risk for major bleeding and in pharmacological prophylaxis on reoperation (RR, 0.43; 95% CI,
those patients with persistent mobility restrictions after the 0.06-2.84; very low certainty in the evidence of effects), which
bleeding risk declines following surgery. would correspond to 18 fewer (29 fewer to 57 more)
reoperations per 1000 patients.
Summary of the evidence. We identified 1 systematic re-
view358 that addressed this question. We identified 6 studies in this
study limitations and very serious imprecision.
relevant to this context.68,123,128,359-361 Our update of the
systematic review identified 1 additional study that fulfilled the Other EtD criteria and considerations. The panel noted that
inclusion criteria.135 We additionally searched for and identified 3 observed RR ratios from observational studies tended to view
nonrandomized studies that informed this question.362-364 All pharmacological prophylaxis more favorably than RCTs. The panel
studies included patients undergoing neurosurgical procedures. based its recommendation on RR ratios from meta-analysis of RCTs
Five studies assessed the effect of LMWH,68,128,130,135,362 4 rather than observational studies, given the greater risk of bias with
studies assessed the effect of UFH,359,361-363 1 study assessed the latter studies. The panel noted that the small benefit of

pharmacological prophylaxis for the prevention of DVT was based The EtD framework is available online at https://guidelines.gradepro.org/
upon randomized controlled studies using screening venography to profile/E9D1EF22-EEC9-560E-A0CC-9FD435188BBE.
detect rates of asymptomatic DVTs. The panel rated the harms of Benefits. Pharmacological prophylaxis with LMWH may result in
major bleeding associated with pharmacological prophylaxis as little to no difference in mortality compared with UFH (RR, 0.34;
moderate because of the potential for greater morbidity associated 95% CI, 0.04-3.21; low certainty in the evidence of effects)
with surgical site bleeding following these procedures. The panel following major neurosurgical procedures; this corresponds to 3
recognized that patients undergoing major neurosurgical proce- fewer (5 fewer to 11 more) deaths per 1000 patients. LMWH may
dures would routinely receive prophylaxis with mechanical result in little or no difference in symptomatic PEs (RR, 0.20; 95%
methods. The panel acknowledged that pharmacological pro- CI, 0.01-4.03; low certainty in the evidence of effects) compared
phylaxis might still be warranted in a higher-risk subgroup of with UFH following major neurosurgical procedures. Based on a
patients, such as those experiencing prolonged immobility baseline risk of 0.2% from observational data,364 this corresponds
following surgery. In addition, the panel acknowledged that to 2 fewer (2 fewer to 6 more) symptomatic PEs in a cohort of 1000

pharmacological prophylaxis could be considered for patients patients following major neurosurgical procedures. We are un-
undergoing neurosurgical procedures that carried a lower risk for certain whether LMWH affects proximal DVTs (RR, 1.00; 95% CI,
major bleeding. It may also be considered for patients with
0.14-6.91; very low certainty in the evidence of effects). Similarly,
persistent mobility restrictions after the bleeding risk subsides the impact of LMWH on symptomatic distal DVTs is very uncertain
following surgery. (RR, 0.33; 95% CI, 0.01-7.93; very low certainty in the evidence of
Conclusions and research needs for this recommendation. effects). In absolute terms, this corresponds to 1 fewer (1 fewer to 7
The panel judged, based on the available very low certainty evidence, more) symptomatic distal DVT per 1000 patients, based on a
that the expected net benefit favored no prophylaxis following major baseline risk of 0.2% from observational data.364
neurosurgical procures, because the potential small benefit of reducing Harms and burden. LMWH may result in little or no difference
VTE events was outweighed by the potential moderate increased risk in major bleeding (RR, 0.76; 95% CI, 0.20-2.95; low certainty in the
of major bleeding. The panel also recognized that mechanical evidence of effects) compared with UFH, which corresponds
methods of thromboprophylaxis are commonly used in this patient to 5 fewer (18 fewer to 43 more) major bleeding events per
population. There is a great need for the performance of large 1000 patients. We were unable to assess the effect on
RCTs evaluating pharmacological prophylaxis following major reoperations.
neurosurgical procedures, and using clinically important end points,
to add certainty to this recommendation. The panel acknowledges
that the current recommendation may not reflect standard practice in
some centers.
study limitations and very serious imprecision.
Question: If pharmacological prophylaxis is indicated, should
Other EtD criteria and considerations. In formulating this
LMWH vs UFH be used for patients undergoing major neurosur-
recommendation, the panel formally acknowledges its prior
gical procedures?
conditional recommendation against pharmacological prophy-
laxis (Recommendation 19) for patients undergoing neurosurgi-
cal procedures. Nevertheless, if pharmacological prophylaxis is
Recommendation 20 considered, the panel judged the desirable effects of LMWH
For the subset of patients undergoing major neurosurgical over UFH as small and the undesirable effects as trivial.
procedures for whom pharmacological prophylaxis is used, the Considering the very low certainty in the evidence, and possibly
ASH guideline panel suggests using LMWH over UFH (con- important uncertainty about or variability in how much people
ditional recommendation based on very low certainty in the value the main outcomes, the balance of effects favored LMWH.
evidence of effects Å◯◯◯). Equity, acceptability, and feasibility were not considered major
factors.
Summary of the evidence. We identified 1 systematic re-
In the subset of high-risk patients following major neurosurgi-
view358 that addressed this question. We identified 4 studies in this
cal procedures for whom pharmacological prophylaxis is being
considered, the ASH guideline panel judged the net benefit to
relevant to this context.348,365-367 Our update of the systematic
favor LMWH over UFH. The panel recognizes this as being
review identified 1 additional study that fulfilled the inclusion
criteria.368 All studies included patients undergoing neurosurgical based upon very low certainty in the evidence.
procedures. Five studies reported the effect of LMWH compared The research priorities following major neurosurgical procedures
with that of UFH on development of mortality,348,365-368 2 studies are to better establish the benefits and risks of any pharmacological
reported on the development of PEs,365,366 1 study reported on the prophylaxis compared with no pharmacological prophylaxis. For
development of screening-detected proximal DVTs,348 and 1 study patients considered at very high risk of postoperative VTE and at low
reported on screening-detected distal DVTs.366 Four studies bleeding risk, high-quality comparative studies of LMWH vs UFH using
reported risk of major bleeding348,365-367 and 1 study reported clinically important outcome measures would be of value.
on risk of reoperation. 366 Urological procedures. Question: Should pharmacological
All participants wore compression stockings, with the exception of prophylaxis vs no pharmacological prophylaxis be used for patients
1 study in which their use was not reported.368 undergoing TURP?
undergoing TURP as trivial and the undesirable effects as small in
Recommendation 21 magnitude. It further judged that there was possibly important
For patients undergoing TURP, the ASH guideline panel sug- uncertainty or variability in how much people value the main
gests against using pharmacological prophylaxis (conditional outcomes. Based primarily on the very low baseline risk of VTE
recommendation based on very low certainty in the evidence of following TURP, the panel judged that the balance of effects
effects Å◯◯◯). Remark: Patients with other risk factors for ultimately favored not using pharmacological prophylaxis. Pharma-
VTE (eg, history of VTE, thrombophilia, or malignancy) may cological prophylaxis would also incur moderate costs and not be
benefit from pharmacological prophylaxis. cost-effective.
The guideline panel suggests against pharmacological prophylaxis
Summary of the evidence. We did not identify any systematic for patients undergoing TURP. Based on overall very low certainty
reviews of RCTs addressing this research question. Because of in the evidence, the panel judged that the desirable effects of

the paucity of studies related to TURP, data across all major pharmacological prophylaxis were outweighed by the undesirable
general, urological, and gynecological surgical procedures were effects, specifically the increased risk of bleeding in this setting.
pooled, and TURP-specific baseline risk estimates were applied, Given the very low baseline risks of VTE following this procedure
where available. The evidence base to inform the relative and the increasing use of alternative modalities to treat lower
effectiveness of pharmacological prophylaxis vs no pharmacolog- urinary tract symptoms attributed to benign prostatic hyperplasia,373
ical prophylaxis was comparable to that used to inform this further RCTs conducted on patients undergoing TURP do not
question for patients undergoing laparoscopic cholecystectomy appear to be a major priority.
(see Recommendation 18). To determine the desirable and
undesirable effects of prophylaxis in absolute terms, the Question: If pharmacological prophylaxis is indicated, should
baseline risks specific for TURP outcomes were drawn from a LMWH vs UFH be used for patients undergoing TURP?
systematic review by Tikkinen et al 369 and from observational
studies.370-372
Recommendation 22
profile/05201A35-BCDA-9EFA-98CB-892C0AB72944. For the subset of patients undergoing TURP for whom phar-
macological prophylaxis is used, the ASH guideline panel sug-
Benefits. Pharmacological prophylaxis may not reduce overall
gests using LMWH or UFH (conditional recommendation based
mortality compared with no pharmacological prophylaxis (RR, 0.75;
on very low certainty in the evidence of effects Å◯◯◯).
95% CI, 0.61 to 0.93; low certainty in the evidence of effects). This
corresponds to 1 fewer (0-1 fewer) death per 1000 patients
undergoing TURP. Pharmacological prophylaxis may not reduce
Summary of the evidence. We did not identify any system-
symptomatic PEs (RR, 0.48; 95% CI, 0.26 to 0.88; low certainty in atic reviews of RCTs addressing this research question.
the evidence of effects), which corresponds to 0 fewer events in Because of the paucity of studies related to TURP,
lower-risk patients and 0 fewer (0-1 fewer) events in higher-risk data across all major general, urological, and gynecologi-
patients undergoing TURP. We are very uncertain of its effect on cal surgical procedures were pooled. Thirty-one stud-
symptomatic proximal DVTs (RR, 0.38; 95% CI, 0.14-1.00; very ies reported the effect of LMWH vs UFH on risk of
low certainty in the evidence of effects), which would mortality,305,307,308,310-312,314,317-319,321,322,325-327,329-339,341,342,346,347,374
correspond to 1 fewer (0-1 fewer) symptomatic event in 1000 and 36 studies reported on development of symptomatic
lower-risk patients or 3 fewer (0-5 fewer) events per 1000 higher-risk PEs.295,305-307,310-312,314-319,321,322,324,326-335,337,339,344-346,374-378 Six
patients. We are very uncertain about its effect on symptomatic distal studies reported the effect of LMWH vs UFH on development of
DVTs (RR, 0.52; 95% CI, 0.31-0.87; very low certainty in the
symptomatic proximal DVTs,306,316,326,334,336,375 8 studies
evidence of effects). Based upon the very low baseline risk for reported the effect on development of symptomatic distal
patients undergoing TURP, this would correspond to 0 fewer DVTs,306,316,326,329,334,336,341,375 31 studies reported on risk of
symptomatic events per 1000 higher-risk patients.
major bleeding,295,305-307,311,313,315-319,321-339,341,344-346,374-377,379
Harms and burden. The risk of major bleeding is probably and 19 studies reported on risk of reoperation.305,307,309,317,319,
322,323,326,329,330,333-337,341,375-377
slightly increased (RR, 1.24; 95% CI, 0.87-1.77; moderate certainty To determine the desirable and
in the evidence of effects) with the use of pharmacological undesirable effects of prophylaxis in absolute terms, the baseline
prophylaxis. This corresponds to 6 more (3 fewer to 20 more) risks specific for TURP outcomes obtained from a systematic
major bleeding events per 1000 patients. We are very uncertain review by Tikkinen et al369 were applied to the corresponding
about reoperations (RR, 0.93; 95% CI, 0.35-2.50; very low pooled RRs.
certainty in the evidence of effects) related to pharmacological The EtD framework is available online at https://guidelines.gradepro.org/
prophylaxis. profile/59BDE78B-362E-9573-980D-41A280D79D9E.
Certainty in the evidence of effects. We rated the overall Benefits. The risks of mortality may be similar for patients treated
certainty in the evidence of effects as very low based on the with LMWH and UFH (RR, 1.03; 95% CI, 0.89-1.18; very low
lowest certainty in the evidence for the critical outcomes, down- certainty in the evidence of effects), but we are very uncertain of this
grading for study limitations, indirectness, and imprecision. finding. Given an assumed baseline risk of 0.2%,370-372 this
Other EtD criteria and considerations. The panel judged the corresponds to 0 fewer (0 fewer to 0 more) deaths per 1000
desirable effects of pharmacological prophylaxis for patients patients. Similarly, there may be little difference for other outcomes,

such as symptomatic PEs (RR, 0.84; 95% CI, 0.59-1.20; very low prophylaxis was comparable to that used to inform this question for
certainty in the evidence of effects), corresponding to 0 fewer (0 fewer patients undergoing TURP (see Recommendation 21); we pooled
to 0 more) events per 1000 patients. We are equally uncertain about data across all surgical procedures and applied surgery-specific
the risk of symptomatic proximal DVTs (RR, 1.01; 95% CI, 0.20-5.0; baseline risk estimates for radical prostatectomy drawn from a
very low certainty in the evidence of effects) and symptomatic severe systematic review by Tikkinen et al.380
distal DVTs (RR, 1.01; 95% CI, 0.30-3.44; very low certainty in the The EtD framework is available online at https://guidelines.gradepro.org/
evidence of effects). Corresponding absolute effect size estimates are profile/F99386B2-4C08-3F36-8029-61B51278B574.
very small.
Benefits. Pharmacological prophylaxis vs no prophylaxis may
Harms and burden. The risks of bleeding may be similar with not reduce mortality (RR, 0.75; 95% CI, 0.61 to 0.93; low
LMWH and UFH (RR, 0.97; 95% CI, 0.78-1.20; low certainty in the certainty in the evidence of effects), corresponding to 0 fewer
evidence of effects), corresponding to 0 fewer (4 fewer to 3 more) deaths per 1000 patients. Pharmacological prophylaxis proba-
major bleeding events per 1000 patients undergoing TURP. The

bly does not reduce symptomatic PEs (RR, 0.48; 95% CI, 0.26-
use of LMWH does not appear to decrease the risk of reoperation 0.88; moderate certainty in the evidence of effects). Depending on
(RR, 0.79; 95% CI, 0.57-1.08; low certainty in the evidence of patient risk, this corresponds to 0 fewer symptomatic PEs in lower-
effects) for patients undergoing TURP. When applying a TURP- risk patients to 0 fewer (0-1 fewer) symptomatic PEs per 1000
specific baseline risk of 0.2%, this corresponded to 0 fewer (0-1 higher-risk patients undergoing radical prostatectomy. We are
fewer) reoperations per 1000 patients undergoing TURP. very uncertain about the effect on symptomatic proximal DVTs
Certainty in the evidence of effects. We rated the overall (RR, 0.38; 95% CI, 0.14-1.00; very low certainty in the evidence
certainty in the evidence of effects as very low based on the lowest of effects). This corresponds to 1 fewer (0-1 fewer) symptomatic
certainty in the evidence for the critical outcomes, downgrading for proximal DVT per 1000 lower-risk patients to 4 fewer (0-5 fewer)
study limitations, indirectness, and very serious imprecision. per 1000 higher-risk patients. Distal DVTs may be reduced (RR,
Other EtD criteria and considerations. The panel rated the 0.52; 95% CI, 0.31-0.87; low certainty in the evidence of
magnitude of the desirable effects and undesirable effects of using effects), but this also corresponds to a negligible effect of
LMWH or UFH as trivial. They further determined that there was 0 fewer symptomatic distal DVT events, irrespective of baseline
possibly important uncertainty and/or variability in how much risk category.
patients value the main outcomes. Overall, the balance of effects Harms and burden. Pharmacological prophylaxis compared
did not favor LMWH or UFH, nor did cost-effectiveness or issues with no prophylaxis may increase major bleeding (RR, 1.24;
surrounding equity, acceptability, and feasibility, at least for inpatient 95% CI, 0.87-1.77; low certainty in the evidence of effects).
prophylaxis. The panel recognized that this particular comparison This corresponds to 6 more (3 fewer to 20 more) major bleeding
applied only to patients undergoing TURP considered at very high events per 1000 patients undergoing radical prostatectomy.
risk for VTE (eg, patients with a history of VTE) in whom We are uncertain about the effect of pharmacological prophylaxis
pharmacological prophylaxis might be considered. compared with no prophylaxis on reoperations (RR, 0.93; 95% CI,
Conclusions and research needs for this recommendation. 0.35-2.50; very low certainty in the evidence of effects); this
corresponds to 0 fewer (3 fewer to 6 more) reoperations per 1000
Based on very low certainty in the evidence for effects, the guideline
men based on a baseline risk of 0.4%.380
panel did not find a net benefit for using LMWH or UFH for patients
undergoing TURP in whom pharmacological prophylaxis is indi- Certainty in the evidence of effects. We rated the overall
cated and suggests that either can be used. For most patients certainty in the evidence of effects as very low based on
undergoing TURP, the panel recommended against the use of the lowest certainty in the evidence for the critical out-
pharmacological prophylaxis (see Recommendation 21). No comes, downgrading for study limitations, indirectness, and
high-priority research needs were identified. imprecision.
Question: Should pharmacological prophylaxis vs no pharmaco- Other EtD criteria and considerations. The panel recog-
logical prophylaxis be used for patients undergoing radical nized during its deliberations that the practice of radical
prostatectomy? prostatectomy varies greatly, ranging from robotically assisted
laparoscopic radical prostatectomy with no or a limited pelvic
lymph node dissection to open radical prostatectomy with
Recommendation 23 extended pelvic lymph node dissection. Based on a systematic
For patients undergoing radical prostatectomy, the ASH review by Tikkinen et al,380 this results in substantially different
guideline panel suggests against using pharmacological pro- baseline risks for VTEs, which are important considerations for
phylaxis (conditional recommendation based on very low cer- these recommendations. The majority of radical prostatectomies
tainty in the evidence of effects Å◯◯◯). Remark: Patients performed by urologists in the United States are performed robotically,
undergoing an extended node dissection and/or open radical typically with no or only a limited lymph node dissection. In this group,
prostatectomy may have a higher VTE risk and may potentially the panel judged the desirable effects of pharmacological
benefit from pharmacological prophylaxis. prophylaxis as trivial and undesirable effects as small. Patients
undergoing open radical prostatectomy with lymph node
dissection were considered at higher risk for VTEs and bleeding.
Summary of the evidence. Because of the paucity of RCTs Cost-effectiveness probably favored no pharmacological prophy-
specific to this setting, the evidence base to inform the relative laxis, whereas issues of equity, acceptability, and feasibility were not
effectiveness of pharmacological prophylaxis vs no pharmacological deemed important in this setting.
Conclusions and research needs for this recommendation. evidence of effects), corresponding to 1 fewer (0-2 fewer) event
The guideline panel judged that the net benefit favors no based on a baseline risk of 0.4%.380
pharmacological prophylaxis for patients undergoing radical Certainty in the evidence of effects. We rated the overall
prostatectomy, based on very low certainty in the evidence of certainty in the evidence of effects as very low based on the lowest
effects. The panel perceived it as important to emphasize that certainty in the evidence for the critical outcomes, downgrading for
this recommendation was based on the panel’s assessment of study limitations, indirectness, and very serious imprecision.
average patients undergoing radical prostatectomy in the form
Other EtD criteria and considerations. The panel rated the
of robotically assisted laparoscopic prostatectomy with no or magnitude of the desirable and undesirable effects of using LMWH
limited lymph node dissection. Patients undergoing an extended over UFH as trivial. They further determined that there was possibly
node dissection and/or open radical prostatectomy may have a important uncertainty and/or variability in how much people value
higher VTE risk and may potentially benefit from pharmacological the main outcomes. Overall, the balance of effects did not favor

prophylaxis. Further high-quality comparative studies, using appro- LMWH or UFH, nor did cost-effectiveness or issues surrounding
priate clinical outcomes, would be of value to add more certainty equity, acceptability, and feasibility, at least for inpatient pro-
to these recommendations. Further studies on patient values phylaxis. The panel recognized that this particular comparison
regarding prevention of VTEs and bleeding would allow for optimal applied only to select patients undergoing radical prostatectomy
shared decision making regarding thromboprophylaxis for radical considered at high risk for VTEs (eg, patients with prior VTEs). For
prostatectomy. most patients undergoing radical prostatectomy, the panel
recommended against the use of pharmacological prophylaxis
Question: If pharmacological prophylaxis is indicated, should (see Recommendation 23).
LMWH vs UFH be used for patients undergoing radical
prostatectomy? Conclusions and research needs for this recommendation.
The guideline panel judged that, for patients undergoing radical
prostatectomy requiring pharmacological prophylaxis, based upon
Recommendation 24 very low certainty in the evidence, LMWH or UFH can be used.
There is a need for high-quality randomized trials specific to patients
For patients undergoing radical prostatectomy in whom
undergoing radical prostatectomy, particularly those treated with
pharmacological prophylaxis is used, the ASH guideline
robotically assisted laparoscopic prostatectomy, the most widely
panel suggests using either LMWH or UFH (conditional rec-
ommendation based on very low certainty in the evidence of used surgical approach for clinically localized prostate cancer.
effects, (Å◯◯◯).
Cardiac or major vascular surgery
Summary of the evidence. In the absence of RCTs specific to logical prophylaxis be used for patients undergoing cardiac or
this setting, the evidence base to inform the relative effectiveness of major vascular surgery?
LMWH prophylaxis vs UFH prophylaxis was comparable to that
used to inform this question for patients undergoing TURP (see
Recommendation 22); we pooled data across all surgical Recommendation 25
procedures and applied surgery-specific baseline risk estimates
For patients undergoing cardiac or major vascular surgery,
for radical prostatectomy drawn from a systematic review by
the ASH guideline panel suggests using pharmacological
Tikkinen et al.380
prophylaxis or no pharmacological prophylaxis (conditional
The EtD framework is available online at https://guidelines.gradepro.org/ recommendation based on very low certainty in the evidence
profile/AEF71CF4-AB9F-1DDF-A08B-1F5E2484EA5F. of effects Å◯◯◯).
Benefits. The risks of mortality may be similar for patients treated
with LMWH and UFH (RR, 1.03; 95% CI, 0.89-1.18; low
certainty in the evidence of effects); this corresponds to 0 fewer Summary of the evidence. Our systematic search for RCTs
deaths per 1000 men. Similarly, there may be little difference for identified 3 studies70,381,382 that fulfilled our inclusion criteria and
the other outcomes of symptomatic PEs (RR, 0.84; 95% CI, measured outcomes relevant to this context. Because of the paucity
0.59-1.20; very low certainty in the evidence of effects), of RCTs, we also systematically searched for observational studies
symptomatic proximal DVTs (RR, 1.01; 95% CI, 0.20-5.0; very low and identified 1 additional study that fulfilled our inclusion criteria.383
certainty in the evidence of effects), and symptomatic distal DVTs (RR, One trial reported the effect of pharmacological prophylaxis vs
1.01; 95% CI, 0.30-3.44; very low certainty in the evidence of effects), no intervention on risk of mortality.381 Two trials reported the effect
with all 95% CIs crossing the line of no effect and very small absolute on the risk of symptomatic PEs and on the risk of any proximal and
effect sizes. distal DVTs.70,381,382 The effect on the risk of major bleeding was
Harms and burden. The risks of bleeding may be similar with reported from an RCT381 and a nonrandomized controlled study.383
LMWH and UFH (RR, 0.97; 95% CI, 0.78-1.20; low certainty in the Surgery-specific baseline risk estimates were obtained from a
evidence of effects), corresponding to 0 fewer (4 fewer to 3 more) systematic review and meta-analysis of risk of VTE after cardiac
major bleeding events per 1000 patients undergoing radical surgery.384
prostatectomy. The risks of reoperation may be similar with LMWH The EtD framework is available online at https://guidelines.gradepro.org/
and UFH (RR, 0.79; 95% CI, 0.57-1.08; low certainty in the profile/D5319730-F947-FFB7-B1F7-D4E9E4697079.

Benefits. We were unable to assess the effect of pharmacolog- very low certainty in the evidence. For subgroup considerations, the
ical prophylaxis on mortality (RR, not estimable because no deaths panel judged that, for patients at higher baseline risk for VTE (eg,
were observed, low certainty in the evidence of effects). Pharma- those with a history of VTE), pharmacological prophylaxis might be
cological prophylaxis appears to result in little or no difference in considered over no prophylaxis.
symptomatic PEs (RR, 2.40; 95% CI, 0.10-55.7; low certainty in the
The panel supported that further research, in the form of well-
evidence of effects); this corresponds to 5 more (3 fewer to 198
designed RCTs using clinically important end points, is needed
more) PEs per 1000 patients receiving pharmacological prophylaxis
to determine the role of pharmacological prophylaxis in the preven-
based on a baseline risk of 0.4%.384 We are very uncertain whether
tion of VTEs following cardiac and major vascular surgery. Further
pharmacological prophylaxis results in little or no difference in
research on the incremental impact of postoperative UFH and
proximal DVTs (RR, 2.85; 95% CI, 0.12-67.83; low certainty in the
LMWH exposure on the development of HIT in this patient
evidence of effects). This finding corresponds to 45 more (21 fewer
population is also warranted.
to 1631 more) symptomatic proximal DVTs per 1000 patients,

based on a baseline risk of 2.4%.384 We are also very uncertain Question: Should LMWH prophylaxis vs UFH prophylaxis be used
about the effect of pharmacological prophylaxis on distal DVTs (RR, for patients undergoing cardiac or major vascular surgery?
0.32; 95% CI, 0.01-7.54; very low certainty in the evidence of
effects). This corresponds to 1 fewer (2 fewer to 13 more)
Recommendation 26
symptomatic distal DVT per 1000 high-risk patients, based on a
baseline risk of 0.2%.384 When pharmacological prophylaxis is used for patients undergoing
383 cardiac or major vascular surgery, the ASH guideline panel
Harms and burdens. Based on 1 large observational study
suggests using LMWH or UFH (conditional recommendation
and supported by a single relevant RCT,381 the rates of major
based on very low certainty in the evidence of effects Å◯◯◯).
bleeding may be increased with pharmacological prophylaxis (RR,
1.26; 95% CI, 1.07-1.47; low certainty in the evidence of effects). This
corresponds to 4 more (1-6 more) major bleeds per 1000 patients. Summary of the evidence. We identified 1 systematic review385
Certainty in the evidence of effects. We rated the overall of RCTs and observational studies that addressed this research
certainty in the evidence of effects as very low based on the lowest question. We identified 3 studies386-388 in these reviews that fulfilled our
certainty in the evidence for the critical outcomes informed by inclusion criteria and measured outcomes relevant to this context. Our
observational studies. update of the systematic review did not identify any additional
studies that fulfilled the inclusion criteria. One study reported the
Other EtD criteria and considerations. The panel recog-
effect of LMWH vs UFH on the risk of mortality, PE, and major
nized that very high doses of UFH are routinely administered to
bleeding.387 Three studies reported the effect of LMWH vs UFH on
most patients undergoing cardiac and major vascular surgery.
the risk of any DVT, including 1 study reporting data for proximal and
Thus, for this recommendation, the benefits and harms of
distal DVTs separately.386-398
postoperative pharmacological prophylaxis are being considered
in an incremental context. The panel recognized there was a paucity Surgery-specific baseline risk estimates were obtained from a system-
of high-quality evidence addressing this particular question, and this atic review and meta-analysis of risk of VTEs after cardiac surgery.384
recommendation was made in the face of very uncertain evidence. The EtD framework is available online at https://guidelines.gradepro.org/
Based upon available evidence, the panel judged that the incremental profile/D32EF371-AE1E-1ACF-82CD-E11528E7B8E0.
desirable and undesirable effects of pharmacological prophylaxis
were trivial and, therefore, balanced. Benefits. We are very uncertain whether LMWH vs UFH affects
mortality following cardiac or major vascular surgery (RR, 4.55; 95%
The panel recognized that cardiac surgery itself is associated with CI, 0.22-93.81; low certainty in the evidence of effects). This
a risk for the development of heparin-induced thrombocytopenia corresponds to 0 fewer deaths per 1000 patients. We were unable
(HIT). The panel reviewed the available literature and found that the to estimate an effect on symptomatic PEs (RR, not estimable). We are
risk of HIT among heparin preparations was higher with the use of also very uncertain about the effect of LMWH on symptomatic proximal
UFH than with LMWH. Available evidence from RCTs did not allow DVTs (RR, 1.33; 95% CI, 0.30-6.01; very low certainty in the evidence
the panel to quantitate whether there was an incremental risk for of effects) and symptomatic distal DVTs (RR, 1.20; 95% CI, 0.45-3.22;
HIT associated with the use of pharmacological heparin prophylaxis very low certainty in the evidence of effects). This would correspond to 8
beyond that of UFH administered during the procedure itself. more (17 fewer to 122 more) symptomatic proximal DVTs per 1000
However, the panel acknowledged that concerns about HIT would patients and 0 more (1 fewer to 4 more) symptomatic distal DVTs per
lead some panelists to be less likely to routinely use postoperative 1000 patients based on baseline risks of 2.4% and 0.2%, respectively.
pharmacological prophylaxis with a heparin preparation, particularly
UFH. The panel did not believe that there were important implementa- Harms and burden. LMWH vs UFH appears to result in little or no
tion considerations with the use of postoperative pharmacological difference in major bleeding (RR, 0.91; 95% CI, 0.19-4.42; low
prophylaxis in this patient population. Should LMWH or UFH be given, certainty in the evidence of effects). We found no data on reoperation.
the panel recommended periodic monitoring of platelet counts Certainty in the evidence of effects. We rated the overall
because of the concern for postoperative HIT. certainty in the evidence of effects as very low based on the lowest
Conclusions and research needs for this recommendation. certainty in the evidence for the critical outcomes, downgrading for
The panel found that the overall net benefit did not favor pharmaco- indirectness and very serious imprecision.
logical prophylaxis or no pharmacological prophylaxis for patients Other EtD criteria and considerations. The panel recog-
undergoing cardiac and major vascular surgery; this was based on nizes that they have judged that evidence was insufficient and of
very low quality to recommend for or against pharmacological Summary of the evidence. We identified 1 systematic review
prophylaxis following cardiac surgery. Nevertheless, particularly for that addressed this question.389 We identified 2 studies47,390 in this
patients considered at high risk for VTE (eg, those with history of review that fulfilled our inclusion criteria and measured outcomes
VTEs), postoperative pharmacological prophylaxis would be consid- relevant to this context. Our update of the systematic review did
ered for use in the cardiac and major vascular surgery settings by not identify any additional studies that fulfilled the inclusion criteria.
some panelists. This recommendation is relevant for patients Two small studies reported the effect of pharmacological pro-
considered at high risk for VTEs. phylaxis compared with no intervention on risk of mortality, on
As discussed in the previous recommendation, HIT is a recognized development of symptomatic PEs, and on any DVT.47,390 No study
complication in the cardiac and vascular surgery settings. Furthermore, reported the effect of pharmacological prophylaxis compared with no
it is recognized that the risk of HIT in other settings has been shown to intervention on risk of major bleeding or on risk of reoperation. The
be higher with the use of UFH vs LMWH. Available evidence from small amount of direct evidence, with a lack of information on
RCTs did not allow the panel to quantitate whether there was an undesirable outcomes, together with the very low certainty on the

incremental risk for HIT associated with the use of pharmacological treatment effect, led the panel to consider the indirect data from hip
UFH or LMWH prophylaxis beyond that of heparin administered fracture repair studies for treatment RR estimates255-266 and
applying baseline VTE and bleeding risks from studies on trauma
during the procedure itself or whether there was a relatively greater
incremental risk for HIT in the cardiac surgery setting with post- patients.391,392
operative UFH prophylaxis than with LMWH. Nevertheless, given the The EtD framework is available online at https://guidelines.gradepro.org/
above factors, if pharmacological prophylaxis is chosen for use, profile/434A9C2D-3417-F3ED-B7C1-4A0BA3EC6699.
panelists concurred that an anticoagulant with a lower risk for HIT
Benefits. We are uncertain about the effect of pharmacological
(eg, LMWH over UFH) should be considered.
prophylaxis on mortality following major trauma (RR, 0.95; 95% CI,
The panel did not believe that there were important implementation 0.84-1.07; very low certainty in the evidence of effects).
considerations with use of postoperative LMWH or UFH pharmacological Pharmacological prophylaxis may reduce symptomatic PEs, but
prophylaxis in this patient population. Should either agent be given, the we are very uncertain of this finding (RR, 0.49; 95% CI, 0.33-0.72;
panel recommended the periodic monitoring of platelet counts. very low certainty in the evidence of effects). Depending upon
Conclusions and research needs for this recommendation. baseline risk, this benefit corresponds to 3 fewer (2-5 fewer)
The panel judged that, based upon available evidence, LMWH or UFH patients with symptomatic PEs per 1000 moderate-risk patients
could be selected for VTE prophylaxis following cardiac surgery based on and 2 fewer (1-2 fewer) patients per 1000 low-risk patients.
very low quality evidence. The panel judged that this question was only Pharmacological prophylaxis may also reduce the risk of proximal
of relevance for patients considered at very high risk for postoperative DVTs (RR, 0.51; 95% CI, 0.38-0.69; very low certainty in the
VTEs following cardiac or major vascular surgery in whom pharmaco- evidence of effects), which corresponds to 7 fewer (4-9 fewer)
logical prophylaxis would be considered over no prophylaxis. in 1000 higher-risk patients and 3 fewer (2-4 fewer) in 1000 lower-
risk patients. We are uncertain of the effect of pharmacological
The panel supported that the more important research question for
prophylaxis on distal DVTs (RR, 0.85; 95% CI, 0.5-1.29, very low
this patient population is the role of pharmacological prophylaxis vs
certainty in the evidence of effects). This would correspond to
no pharmacological prophylaxis for the prevention of VTEs following
1 fewer (3 fewer to 2 more) symptomatic distal DVT in 1000 higher-
cardiac and major vascular surgery. Further research on the incremental
risk patients and 0 fewer in 1000 lower-risk patients.
impact of postoperative UFH and LMWH exposure on the development
of HIT in this patient population would also be of value. Harms and burden. Pharmacological prophylaxis may result in
more major bleeding than no prophylaxis (RR, 1.24; 95% CI, 1.12-
Major trauma 1.37; very low certainty in the evidence of effects), but this finding is
uncertain. Depending upon baseline risk, the risk of major bleeding
Question: Should pharmacological prophylaxis vs no pharmaco- corresponds to 3 more (2-5 more) major bleeds per 1000 lower-
logical prophylaxis be used for patients experiencing major trauma? bleeding-risk patients and to 14 more (7-21 more) major bleeds per
1000 patients with higher bleeding risk.
Recommendation 27a We are very uncertain about the effect of pharmacological prophylaxis
on the need for reoperation (RR, 1.05; 95% CI, 0.82-1.35; very low
For patients experiencing major trauma at low to moderate risk
certainty in the evidence of effects).
for bleeding, the ASH guideline panel suggests using pharma-
cological prophylaxis (conditional recommendation based on Certainty in the evidence of effects. We rated the overall
very low certainty in the evidence of effects Å◯◯◯). certainty in the evidence of effects as very low based on the
lowest certainty in the evidence for the critical outcomes,
downgrading for study limitations, indirectness, and imprecision.
Recommendation 27b Other EtD criteria and considerations. The overall certainty
in the evidence was rated as very low for this question, given the
For patients experiencing major trauma at high risk for bleeding, absence of RCTs comparing pharmacological prophylaxis vs no
the ASH guideline panel suggests against pharmacological prophylaxis for patients experiencing major trauma. The benefits
prophylaxis (conditional recommendation based on very low and harm/burden data were extrapolated from the closest
certainty in the evidence of effects Å◯◯◯). surgical indication for which we had adequate comparative
evidence (ie, hip fracture repair). It is recognized that these hip

fracture studies are dated and that rates of patient-important DVT data.391 LMWH vs UFH likely results in no important effect on
events were derived from modeling of asymptomatic events detected proximal DVTs (RR, 0.57; 95% CI, 0.25-1.31; moderate certainty in
by routine screening studies. The panel presumed that, in the absence the evidence of effects). This corresponds to 3 fewer (5 fewer to 2
of specific contraindications (eg, lower limb injuries), patients more) symptomatic proximal DVTs per 1000 patients based on a
experiencing major trauma would receive mechanical prophylaxis. baseline risk of 0.7% from observational data.391
The panel emphasized the need to periodically reevaluate bleeding risk LMWH probably also results in little or no difference in symptomatic
as patients recover from major trauma. Once bleeding is stabilized and distal DVTs (RR, 0.74; 95% CI, 0.46-1.20; moderate certainty in the
the patient is no longer considered at high risk for major bleeding, the evidence of effects). This corresponds to 0 fewer symptomatic
use of pharmacological prophylaxis should be reconsidered. distal DVTs per 1000 patients based on a baseline risk of 0.1% from
Conclusions and research needs for this recommendation. observational data.391
Based upon the totality of the evidence, the panel judged that Harms and burden. LMWH may result in a small increase in
the moderate overall benefits of pharmacological prophylaxis

major bleeding (RR, 2.4; 95% CI, 0.53-10.78; low certainty in the
outweighed the increased risk of major bleeding for patients at evidence of effects). This corresponds to 20 more (7 fewer to 138
low or moderate risk for bleeding. In contrast, for patients at high more) major bleeding events per 1000 patients receiving LMWH vs
risk for major bleeding, the large undesirable consequences of UFH. There were no comparative data about rates of reoperation of
major bleeding led to a balance that favors no pharmacological LMWH vs UFH following major trauma.
prophylaxis. The very low certainty in the evidence justifies conditional
recommendations for both scenarios.
certainty in the evidence of effects as low based on the lowest
Well-designed trials using clinically important VTE end points are certainty in the evidence for the critical outcomes, downgrading for
required for patients at low to moderate risk for bleeding following very serious imprecision.
trauma to determine the incremental benefits of pharmacological
Other EtD criteria and considerations. The panel judged that
prophylaxis beyond mechanical methods alone. Well-designed studies
the minor differences in the effects of the interventions on benefits and
are also needed to determine the benefits and risks of introducing
undesirable outcomes led to an overall balance that did not favor either
delayed pharmacological prophylaxis for patients experiencing major
intervention. The benefits observed with LMWH were limited to a minor
bleeding, including intracranial hemorrhage as a consequence of
reduction in the rates of symptomatic proximal DVTs, which was
major trauma, as the bleeding risk subsides.
negated by the small observed increased risk of major bleeding. It was
Question: Should LMWH vs UFH be used for patients experienc- recognized that patients at high risk for major bleeding were excluded
ing major trauma? from the studies that formed the basis of this recommendation.
Because LMWH and UFH are in widespread use for this indication, the
panel did not judge there to be major implementation considerations
Recommendation 28 with either intervention. The panel presumed that, in the absence of
For patients experiencing major trauma in whom pharmaco- specific contraindications (eg, lower limb injuries), patients experi-
logical prophylaxis is used, the ASH guideline panel suggests encing major trauma would receive mechanical prophylaxis.
using LMWH or UFH (conditional recommendation based on Conclusions and research needs for this recommendation.
low certainty in the evidence of effects ÅÅ◯◯). The panel suggested that, for patients experiencing major trauma
who are judged to be at low to moderate risk for bleeding, LMWH or
UFH may be used for pharmacological VTE prophylaxis based on
Summary of the evidence. We identified 1 systematic review low certainty in the evidence.
that addressed this question.389 Our update of the systematic
review identified 1 additional study that fulfilled the inclusion The panel judged that the research priorities in major trauma related
criteria,394 and our systematic search of RCTs identified 2 studies to establishing the effectiveness and the timing of intervention
that fulfilled the inclusion criteria394,395 and were not included in the with pharmacological prophylaxis for patients receiving mechan-
review. Three studies reported the effect of LMWH prophylaxis vs ical prophylaxis following major trauma, rather than comparative
UFH prophylaxis on risk of mortality, on development of any PEs, studies of LMWH vs UFH.
and on major bleeding,393-395 whereas 2 studies informed on the
risk of development of proximal and distal DVTs.393,394 Major gynecological surgery
The EtD framework is available online at https://guidelines.gradepro.org/ Question: Should pharmacological prophylaxis vs no pharmacolog-
profile/96D5A309-8606-4469-B732-E1844465CC75. ical prophylaxis be used for patients undergoing major gynecological
surgery?
Benefits. LMWH vs UFH appears to result in little or no
difference in mortality for patients experiencing major trauma (RR, Recommendation 29
1.32; 95% CI, 0.14-12.39; low certainty in the evidence of effects).
This corresponds to 2 more (4 fewer to 54 more) deaths per 1000 For patients undergoing major gynecological surgery, the ASH
trauma patients receiving LMWH vs UFH. Similarly, LMWH may guideline panel suggests using pharmacological prophylaxis
result in little or no difference in symptomatic PEs (RR, 1.04; 95% over no pharmacological prophylaxis (conditional recommen-
CI, 0.11-9.92; low certainty in the evidence of effects). This dation based on very low certainty in the evidence of effects
corresponds to 0 fewer (6 fewer to 61 more) symptomatic PEs per Å◯◯◯).
1000 patients based on a baseline risk of 0.7% from observational
Summary of the evidence. We identified 1 systematic review procedures. The panel considered that patients at increased risk for
of RCTs addressing this research question.29 We identified only 5 VTE would receive mechanical prophylaxis in addition to pharma-
studies118,273-275,349 in this review that fulfilled our inclusion criteria cological prophylaxis. There were no major implementation
and measured outcomes relevant to this context. Because of the considerations.
paucity of studies on patients undergoing major gynecological Conclusions and research needs for this recommendation.
procedures, data across major general, laparoscopic cholecys- The panel judged that pharmacological prophylaxis should be
tectomy, and major gynecological and urological procedures
administered to patients undergoing major gynecological sur-
were pooled. The evidence base to inform the relative
gery, and this recommendation was conditional given the very low
effectiveness of pharmacological prophylaxis vs no pharmaco-
certainty in the evidence. There is a need for large high-quality
logical prophylaxis was comparable to that used to inform this
question for patients undergoing laparoscopic cholecystectomy (see clinical trials using clinically relevant end points to determine the
Recommendation 18). Baseline risk estimates specific to gyneco- benefit of pharmacological prophylaxis following gynecologi-

logical procedures396,397 were applied to determine the desirable cal procedures. These studies should include detailed clinical
and undesirable effects of prophylaxis in absolute terms. characteristics of the patient populations.
The EtD framework is available online at https://guidelines.gradepro.org/ Question: Should LMWH vs UFH prophylaxis be used for patients
profile/B2FDFE66-5A79-4E46-875E-9BB7F3FAFF9F. undergoing major gynecological surgery?
Benefits. Pharmacological prophylaxis probably reduces mor- Recommendation 30

tality slightly following major gynecological surgery (RR, 0.75;
95% CI, 0.61-0.93; low certainty in the evidence of effects). For patients undergoing major gynecological surgery, the ASH
This corresponds to a benefit of 4 fewer (1-7 fewer) deaths per guideline panel suggests using LMWH or UFH (conditional
1000 patients. Pharmacological prophylaxis probably reduces the recommendation based on very low certainty in the evidence
risk of symptomatic PEs (RR, 0.48; 95% CI, 0.26-0.88; low certainty of effects Å◯◯◯).
in the evidence of effects), corresponding to a benefit of 2 fewer
(0-3 fewer) symptomatic PEs per 1000 higher-risk patients
and 0 fewer (0-1 fewer) per 1000 lower-risk patients, based Summary of the evidence. We identified 1 systematic review
on baseline risks from observation data of 0.1% and 0.4%, of RCTs addressing this research question.30 We identified only 4
respectively.396,397 studies374,376,377,379 overall that were conducted with patients
undergoing major gynecological surgery. Because of the paucity
We are uncertain whether pharmacological prophylaxis reduces the of studies on patients undergoing major gynecological proce-
rates of proximal DVTs (RR, 0.38; 95% CI, 0.14-1.00; very low dures, data across major general, laparoscopic cholecystectomy,
certainty in the evidence of effects), corresponding to reduction of and major gynecological and urological procedures were pooled.
4 fewer (0-6 fewer) symptomatic proximal DVTs per 1000 lower-risk The evidence base to inform the relative effectiveness of LMWH
patients and 17 fewer (0-23 fewer) per 1000 higher-risk patients prophylaxis vs UFH prophylaxis was comparable to that used to
based on baseline risks from observation data of 0.7% and 2.7%, inform this question for patients undergoing TURP (see Recom-
respectively.396,397 We are uncertain about the effect of pharma- mendation 22).
cological prophylaxis on distal DVTs (RR, 0.52; 95% CI, 0.31-0.87;
low certainty in the evidence of effects), corresponding to no Baseline risk estimates specific to gynecological procedures396,397
reduction per 1000 patients treated based on a lower baseline risk were applied to determine the desirable and undesirable effects of
of 0.1%. prophylaxis in absolute terms.
Harms and burden. Pharmacological prophylaxis may slightly The EtD framework is available online at https://guidelines.gradepro.org/
increase the risk of major bleeding (RR, 1.24; 95% CI, 0.87-1.77; profile/F213C6D1-F2D9-221A-B8EE-92B6F94F5BB3.
low certainty in the evidence of effects). This corresponds to 6 more Benefits. LMWH prophylaxis appears to result in little or no
(3 fewer to 20 more) major bleeding events per 1000 patients difference in mortality compared with UFH prophylaxis (RR,
receiving pharmacological prophylaxis. Pharmacological pro- 1.03; 95% CI, 0.89-1.18; low certainty in the evidence of
phylaxis does not appear to increase the risk of reoperation (RR, effects), corresponding to 1 more (2 fewer to 3 more) deaths
0.93; 95% CI, 0.35-2.50; very low certainty in the evidence of per 1000 patients. Likewise, use of LMWH prophylaxis vs UFH
effects) following major gynecological procedures. prophylaxis appears to result in little or no difference in
symptomatic PEs (RR, 0.91; 95% CI, 0.63-1.3; low certainty
in the evidence of effects). For a higher baseline risk of 0.4%
from observational data,396 this corresponds to 1 fewer (2 fewer
to 1 more) symptomatic PE per 1000 participants. For
for study limitations, indirectness, and imprecision.
symptomatic proximal DVTs (RR, 1.01; 95% CI, 0.20-5.00;
Other EtD criteria and considerations. The panel based its low certainty in the evidence of effects), the absolute risk
recommendation on the judgment that the desirable benefits of reduction is 0 per 1000 patients, with the 95% CI varying by
pharmacological prophylaxis outweighed the likely small in- baseline risk from 5 fewer to 27 more397 to 22 fewer to 108 more
creased risk of major bleeding following major gynecological (baseline risks of 0.7% and 2.7%, respectively).396 We are very
procedures. The panel acknowledges that the overall certainty in uncertain about the effect on symptomatic distal DVTs (RR,
the evidence was very low given the issue of indirectness, with 1.01; 95% CI, 0.30-3.44; very low certainty in the evidence of
most of the available trial data not being specific to gynecological effects) following major gynecological surgical procedures.

Harms and burden. LMWH appears to confer little or no also acknowledges that modeling was required to determine
difference in major bleeding compared with UFH prophylaxis rates of symptomatic DVTs when only asymptomatic DVT events
following major gynecological procedures (RR, 0.97; 95% CI, were reported, based on the best available estimates drawn from
0.78-1.20; low certainty in the evidence of effects); this the literature.
corresponds to 0 fewer (4 fewer to 3 more) major bleeds per The panel recognized that most of the evidence on mechanical
1000 patients. LMWH prophylaxis may result in a small, possibly methods of VTE prophylaxis comes from the orthopedic literature.
unimportant, reduction in reoperations compared with UFH (RR, Studies of the benefits of mechanical prophylaxis for other surgical
0.79; 95% CI, 0.57-1.08; low certainty in the evidence of effects). settings are needed. Finally, the panel acknowledges that, for some
This corresponds to 4 fewer (8 fewer to 1 more) reoperation questions, limited direct data were available (eg, VTE prophylaxis
procedures per 1000 patients receiving LMWH prophylaxis. following urological and gynecological procedures and for major
Certainty in the evidence of effects. We rated the overall trauma). In these settings, estimates of the benefits of prophylaxis
certainty in the evidence of effects as very low based on the lowest were based upon related surgical settings, such as general surgical

certainty in the evidence for the critical outcomes, downgrading for procedures and hip fracture surgery, respectively.
study limitations and indirectness.
Other EtD considerations. The panel based its recommenda- What are others saying and what is new in
tion on the judgment that the desirable benefits and the risk of these ASH guidelines?
complications were balanced between use of LMWH and UFH These ASH guidelines stand out by their scope, which includes
pharmacological prophylaxis. The panel acknowledges that the general issues relevant to any surgical procedure and those related
overall certainty in the evidence was very low, given the issue of to surgical subspecialties. They make consistent use of high-quality
indirectness, with most of the available trial data not being specific systematic reviews and provide a formal EtD framework for every
to gynecological procedures. There was not deemed to be any recommendation, thereby enhancing transparency about the
major implementation consideration. judgments that were made.
Conclusions and research needs for this recommendation. A widely used high-quality guideline is the 2012 Guideline of the
The panel suggests using LMWH or UFH for patients undergo- American College of Chest Physicians (ACCP), which places a
ing major gynecological surgery procedures based upon very low strong emphasis on patients’ VTE risk scores.398 In the guideline
certainty in the evidence of effects. There is a need for large high- recommendations for VTE prevention in nonorthopedic surgical
quality clinical trials using clinically relevant end points to determine patients, patient-oriented VTE risk calculators, such as the Caprini
the relative benefits of LMWH vs UFH pharmacological prophylaxis score10 and Rogers score,399 were adopted. When the risk for VTE
following gynecological procedures. These studies should include is very low, it was recommended not to use pharmacological or
detailed clinical characteristics of the patient populations. mechanical prophylaxis. For patients at low risk for VTE, mechanical
prophylaxis was suggested over no prophylaxis, preferably with
Limitations of these guidelines intermittent pneumatic compression. For patients at moderate risk
The panel recognized that many studies of pharmacological and for VTE who are not at high risk for major bleeding complications,
mechanical prophylaxis for VTE prevention following major surgery it was suggested to use LMWH, low-dose UFH, or mechanical
date back decades, thereby raising questions about the applicabil- prophylaxis with intermittent pneumatic compression over no
ity of this evidence. This includes largely outdated means (eg, prophylaxis. For patients at high risk for VTE who are not at high
venography) to assess for VTEs postoperatively. Surgical practice risk for major bleeding complications, it was recommended to use
has changed considerably over the decades, aimed at improving pharmacological prophylaxis with LMWH or low-dose UFH over
the patient experience. In most circumstances, these innovations no prophylaxis, and it was suggested to add mechanical prophylaxis
would be expected to reduce the overall risk of postoperative VTEs. with graduated compression stockings or intermittent pneumatic
Examples of such innovations include use of minimally invasive compression to pharmacological prophylaxis. Guidelines by the
surgical procedures, early and increased postoperative patient Scottish Intercollegiate Guidelines Network (SIGN) and the
mobilization, and use of regional anesthesia; however, it is National Institute for Clinical Excellence (NICE) also emphasize
uncertain whether such changes in surgical practice impact the the importance of risk stratification. 400,401
relative effectiveness of various thromboembolic interventions. Mechanical methods of perioperative VTE prophylaxis have been
Therefore, for the purpose of this guideline, this type of evidence addressed by a number of guidelines.398,400-404 The 2012 ACCP
informing the relative effectiveness of these interventions was guidelines did not provide a detailed comparison of the effective-
included when obtained in the setting of RCTs. For determining ness of graduated compression stockings and pneumatic com-
baseline risk of VTEs and major bleeding, we used data, where pression stockings, but they generally favor pneumatic compression
available, from contemporary large cohort studies that were
stockings on the basis of indirect evidence, from the Clots in Legs
deemed representative of contemporary patients. or Stockings after Stroke trial for patients with stroke, that elastic
Although the panel rated symptomatic VTE end points as those stockings increased the risk of skin complications without reducing
upon which recommendations should be based, the panel recog- the risk of VTEs.405 Other guidelines presented by SIGN,400 NICE,401
nized that most studies of VTE prophylaxis following surgery used the American Academy of Orthopedic Surgeons (AAOS),402 the
asymptomatic DVTs detected by the routine performance of Neurocritical Society,404 and the International Union of Angiology403
sensitive screening tests (eg, venography) as the primary study discuss the use of pneumatic compression and graduated compres-
outcome. Reporting of symptomatic DVTs in some studies could sion stockings in various surgical settings but generally consider these
have been influenced by diagnostic suspicion bias. The panel modalities together as “mechanical devices” and do not offer a
direct comparison of their effectiveness or safety other than noting than early ambulation. At low risk, mechanical prophylaxis (prefer-
that graduated compression stockings cannot be used for patients ably with intermittent pneumatic compression) is suggested over no
with certain lower extremity pathologies. prophylaxis. For moderate-risk patients, assuming there is no high
Guidelines addressing the prophylactic placement of IVC filters risk for major bleeding, LMWH, low-dose UFH, and mechanical
include the 2012 ACCP guidelines,398 the 2011 AAOS guideline prophylaxis, preferably with intermittent pneumatic compression
for orthopedic patients,402 the 2013 European Venous Forum,403 devices, are all options. If patients are at high risk for major bleeding
the 2013 guidelines by the Neurocritical Care Society,404 the 2013 complications or if consequences of bleeding are thought to be
British Committee for Standards in Hematology guidelines, and the particularly severe, mechanical prophylaxis (preferably with in-
“appropriateness criteria” by the American College of Radiology.406 termittent pneumatic compression devices) is suggested over no
The recommendation made by these ASH guidelines corresponds prophylaxis.398
with many of these existing recommendations that are mostly critical For patients undergoing neurosurgical procedures, there are a total
of prophylactic IVC filter placement for patients requiring major

of 6 guidelines that offer somewhat conflicting recommendations
surgery or who have experienced trauma. on pharmacological VTE prophylaxis. These guidelines include the
Several recent guidelines comment on VTE prophylaxis after 2012 ACCP guideline, the 2014 Korean Society of Thrombosis and
total hip or knee arthroplasty. The 2012 ACCP guideline for Hemostasis Evidence-Based Clinical Practice Guidelines, the 2018
orthopedic surgery patients407 recommended LMWH, fondapar- NICE guideline, the 2010 SIGN guideline, the 2017 European
inux, apixaban, dabigatran, rivaroxaban, low-dose UFH, adjusted- Society of Anesthesiology guideline, and the 2016 Neurocritical
dose vitamin K antagonists (VKAs), ASA, and/or intermittent Care Society guidelines.398,400,401,404,409,410 The recommenda-
pneumatic compression, with the proviso that they are portable, tions provided by these current ASH guidelines are similar to the
out of concerns regarding compliance. They further indicate 2010 SIGN guidelines, the 2019 Congress of Neurological
a preference for LMWH over the other listed agents, with the Surgeons Guidelines for Spine Trauma, and the 2012 ACCP
exception of ASA. The 2011 AAOS guideline 402 recommends guidelines. Overall, mechanical prophylaxis is recommended for
some form of chemoprophylaxis (including ASA) along with most neurosurgical patients. The benefit of pharmacological
intermittent pneumatic compression after total hip or knee arthro- prophylaxis should be considered for patients at high risk or very
plasty. The 2012 Asian Venous Thromboembolism Guideline408 high risk for VTE, but the overall risk/benefit profile is question-
recommends LMWH, fondaparinux, rivaroxaban, apixaban, edox- able, given an increase in bleeding events, particularly because
aban, dabigatran, warfarin, or ASA with intermittent pneumatic neurosurgical bleeding events can be more serious. Similar to
compression, referencing and effectively accepting the 2012 the 2010 SIGN recommendations, our ASH guidelines suggest
ACCP and 2011 AAOS guidelines. The 2013 International that, for patients who do receive pharmacological prophylaxis,
Angiology guideline favors LMWH, fondaparinux, VKAs, rivaroxaban, LMWH be used over UFH, whereas the 2012 ACCP guidelines
apixaban, or dabigatran, along with use of intermittent pneumatic do not give preference to any specific drug.
compression after total hip arthroplasty.403 The most current Urology is covered within the scope of guidelines by the ACCP, the
NICE guideline recommends LMWH or rivaroxaban after total hip Australian National Health and Medical Research Council, and the
arthroplasty and the same after total knee arthroplasty, with the National Institute for Health and Care Excellence, among others.411
additional option of ASA.401 Urology-specific guidelines are available from the American
For VTE prophylaxis after surgery for hip fractures, the 2012 ACCP Urological Association, the German Association of Scientific
guideline recommends LMWH for VTE prophylaxis vs fondaparinux Medical Societies, and, most recently, the European Associa-
and low-dose UFH over adjusted-dose VKAs or ASA.407 Concur- tion of Urology.412-414 In the absence of direct evidence for
rent use of an intermittent pneumatic compression device was also urology, the European Association of Urology guideline makes
recommended. The 2011 AAOS guideline does not specifically the assumption of a 50% risk reduction for “any serious VTE
address hip fractures; however, in the face of hip arthroplasty as a event” as well as a 50% increase in the risk of major bleeding
treatment for hip fracture, their recommendations of some form of requiring reoperation. When assessing the net benefit in making
chemoprophylaxis (including ASA), along with intermittent pneu- the recommendation, the major bleeding was given twice the
matic compression for total hip arthroplasty, would be applica- weight of the outcome of VTE prevention. The resulting recommen-
ble.402 The 2012 Asian Venous Thromboembolism Guideline dations were supported by a systematic review of the procedure-
recommended LMWH, fondaparinux, rivaroxaban, apixaban, edox- specific VTE risk and the bleeding risk.369,380 For patients undergoing
aban, dabigatran, warfarin, or ASA with intermittent pneumatic TURP, this resulted in a conditional recommendation against
compression.408 The Agency for Healthcare Research and pharmacological prophylaxis across risk groups. For radical prosta-
Quality 2017 guideline favors chemoprophylaxis but is neutral tectomy, the guideline provides a more nuanced set of recommen-
on specific agents because of a lack of evidence.236 The 2013 dations that differ by surgical approach (open, laparoscopic, or
International Angiology Guideline favors LMWH, fondaparinux, robotically assisted laparoscopic) and extent of the node dissection
VKAs, or low-dose UFH. 403 The most current NICE guideline (without, standard, or extended). For patients undergoing robotically
recommends LMWH or fondaparinux. 401 assisted laparoscopic prostatectomy with a standard lymph node
dissection, which was considered the index case for these ASH
For general and abdominal surgery, which includes gastrointestinal,
urological, gynecological, bariatric, vascular, plastic, or recon- guidelines, there is a conditional recommendation against pharma-
structive surgery in its scope, the 2012 ACCP guidelines are once cological prophylaxis.
again the best known. In the very low risk setting, no specific For cardiac surgery patients with an uncomplicated postopera-
pharmacological or mechanical prophylaxis is recommended other tive course, the 2012 ACCP guideline suggested the use of

mechanical prophylaxis, preferably with optimally applied intermit- A guidance document from the American College of Gynecology dates
tent pneumatic compression, over no prophylaxis or pharmacolog- back to 2007415; as a result, the 2012 ACCP guidelines provide the
ical prophylaxis.398 For cardiac surgery patients whose hospital timeliest guidance for gynecological surgery. One set of recommenda-
course is prolonged by $1 nonhemorrhagic surgical complication, tions is made across gastrointestinal, urological, gynecological, bariatric,
the guideline suggested adding pharmacological prophylaxis with vascular, plastic, and reconstructive surgery (see above).
UFH or LMWH to mechanical prophylaxis. They considered that the
risk of VTE following cardiac surgery is uncertain but judged that Revision or adaptation of the guidelines
most patients were at moderate risk for VTEs and at high risk Plans for updating these guidelines
for anticoagulant prophylaxis-related bleeding. Based on these
considerations, it was concluded that, in cardiac patients at usual After publication of these guidelines, ASH will maintain them through
risk for VTE, the harms of anticoagulant prophylaxis outweighed the surveillance for new evidence, ongoing review by experts, and regular
benefits, whereas anticoagulation may be of net benefit for patients revisions.

with high-risk characteristics. The ACCP guidelines did not provide
Updating or adapting recommendations locally
recommendations specific to major vascular surgery. The Interna-
tional Consensus Statement on Prevention and Treatment of Adaptation of these guidelines will be necessary in many circum-
Venous Thromboembolism published by the European Venous stances. These adaptations should be based on the associated EtD
Forum, in cooperation with several other organizations, offers framework.416 The Agency for Healthcare Research and Quality in
guidelines for general, vascular, bariatric, and plastic surgical the United States provides a guide for implementing effective
patients.403 Major vascular surgery was considered with other quality improvement in this patient population.417
“major surgery,” and patients were judged to generally be at
moderate risk in the absence of specific high-risk characteristics, Acknowledgments
such as age older than 60 years or prior VTE. Pharmacological The authors thank Joyce Kirkman and Tracy Minichiello for participa-
prophylaxis was recommended in the absence of unusual bleeding tion on the panel during the initial stages of the guideline-development
risks. Recommendations specific to cardiac surgery patients were process, including to prioritize questions and health outcomes. The
not presented. An update of NICE guidelines published in 2018 authors acknowledge Angela Barbara, Housne Begum, Samantha
offers guidelines regarding VTE prophylaxis for patients undergoing Craigie, Andrea Darzi, Farid Foroutan, Nora Ibargoyen Roteta, Rana
cardiac or major vascular surgery.401 This guideline recommends Qadeer, Yasir Rehman, Mansoor Radwi, Matthew Ventresca, and
considering mechanical VTE prophylaxis on admission for patients Robby Nieuwlaat for supporting the systematic reviews and Wojtek
who are undergoing cardiac surgery and are at increased risk for Wiercioch, Robby Nieuwlaat, and Holger Schünemann for co-
VTE and continuing this until the patient no longer has significantly ordination of the systematic review team. Holger Schünemann
reduced mobility relative to their normal or anticipated mobility. They prepared a template of these guidelines for all panels that was
recommend considering pharmacological VTE prophylaxis for a critically reviewed by Adam Cuker, Rob Kunkle, the ASH Guideline
minimum of 7 days for patients who are undergoing open vascular Oversight Subcommittee, the Methods Group supporting the
surgery or major endovascular procedures, including endovascular guidelines, and Blood Advances editors.
aneurysm repair, and whose risk of VTE outweighs their risk of
bleeding. Further, they recommend considering mechanical Authorship
prophylaxis on admission for people who are undergoing open Contribution: D.R.A. and P.D. wrote the first draft of the manuscript
vascular surgery or major endovascular procedures, including and revised the manuscript based on the authors’ suggestions; C.B.,
endovascular aneurysm repair, if pharmacological prophylaxis is F.D., C.W.F., D.A.G., S.R.K., M.R., A.R., F.B.R., M.A.S., K.A.O.T., and
contraindicated. SIGN published a relevant updated guideline A.J.Y. critically reviewed the manuscript and provided suggestions
in 2014.400 The guideline notes that cardiac surgery patients for improvement; members of the knowledge synthesis team
often receive anticoagulants and antiplatelet agents for reasons (G.P.M., T.B., S.B., J.L.B., I.E.-I., H.J., I.N., W.W., J.J.Y.-N., and H.J.S.)
independent of VTE and that this may impact their VTE risk. contributed evidence summaries to the guidelines; D.R.A. and P.D.
Despite this, these guidelines recommend that patients undergoing were the chair and vice chair of the panel and led the panel
coronary artery bypass grafting surgery should be offered mechanical meeting; and all authors approved the content.
thromboprophylaxis where feasible and that patients undergoing
coronary artery bypass grafting surgery who are not at high risk for Conflict-of-interest disclosure: All authors were members of the
guideline panel or of the systematic review team. As such, they
bleeding can also be offered pharmacological thromboprophylaxis.
completed a disclosure of interest form, which was reviewed by ASH
The most relevant guideline on the perioperative management of and is available as Supplements 2 and 3.
trauma patients is that by the ACCP in 2012.398 For major trauma,
ORCID profiles: G.P.M., 0000-0001-7577-7963; S.B., 0000-
including traumatic brain injury, acute spinal injury, and traumatic
spine injury, VTE prophylaxis is suggested (over no prophylaxis) with 0003-1205-1895; J.L.B., 0000-0002-3122-0773; H.J., 0000-
LMWH, low-dose UFH, or mechanical prophylaxis, preferably with 0003-0643-534X; W.W., 0000-0001-6576-1650; J.J.Y.-N., 0000-
intermittent pneumatic compression. For patients at high risk for 0002-9912-0031; H.J.S., 0000-0003-3211-8479; P.D., 0000-
VTE, addition of mechanical prophylaxis to pharmacological pro- 0003-2819-2553.
phylaxis is suggested when not contraindicated by lower extremity Correspondence: David R. Anderson, Faculty of Medicine,
injury. It further suggests against placement of an IVC filter for primary Dalhousie University, Clinical Research Centre, Room C-205,
VTE prevention, as well as against periodic surveillance with venous 5849 University Ave, PO Box 15000, Halifax, NS B3H 4R2,
compression ultrasound. Canada; e-mail: [email protected].
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CLINICAL GUIDELINES

American Society of Hematology 2019 guidelines for management of

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Background: Venous thromboembolism (VTE) is a common source of perioperative morbidity and

3898 10 DECEMBER 2019 x VOLUME 3, NUMBER 23

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Benefits. Pharmacological prophylaxis probably reduces mor- Recommendation 30

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