Prevention of venous thromboembolic disease in surgical patients

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Sep 28, 2017.

INTRODUCTION — Using the 2003 nationwide inpatient sample from the Health Care Cost and
Utilization Project in the United States, there were over 38 million discharges in 2003 [1]. Twenty
percent of those were surgical inpatients and, using the ACCP Guidelines for risk stratification, it was
estimated that 15 percent, 24 percent, and 17 percent were at moderate, high, or very high risk for
venous thromboembolism (VTE, which includes deep vein thrombosis and pulmonary embolism).

Despite significant advances in the prevention and treatment of VTE, pulmonary embolism remains
the most common preventable cause of hospital death [2-6], responsible for approximately 150,000 to
200,000 deaths per year in the United States [7,8]. Thus, it is vital that efforts continue to be made to
find the safest and most effective means of preventing and managing VTE.

Practical approaches to the prevention of VTE in surgical patients will be reviewed here. Prevention
of VTE in medical patients is presented separately. (See "Prevention of venous thromboembolic
disease in acutely ill hospitalized medical adults".)

Detailed discussions about specific pharmacologic agents employed for VTE prevention are
presented separately. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Warfarin
and other VKAs: Dosing and adverse effects" and "Fondaparinux: Dosing and adverse
effects" and "Low molecular weight heparin for venous thromboembolic disease".)

PROBLEM OVERVIEW — In the United States there have been a number of initiatives aimed at
calling attention to the prevalence of VTE and increasing the use of prophylaxis of VTE in the hospital
setting. These initiatives have come from the National Quality Forum [9], the Surgical Care
Improvement Project [10], the Centers for Medicine and Medicinal Services, the Joint Commission on
Accreditation of Health Care Organizations [11], and the Office of the Surgeon General of the United
States [12]. Similar initiatives have been developed in Canada [13], the United Kingdom [14,15], and
Europe.

According to the Agency for Healthcare Research and Quality, the prevention of VTE is the number
one strategy to improve patient safety in hospitals [16]. As an example, as part of the Surgical Care
Improvement Project, the Center for Medicare and Medicaid Services (CMS) now considers
appropriate VTE prophylaxis to be a pay-for-performance quality measure for specific procedures
(table 1) [17-19]. Effective and safe prophylactic measures are now available for most high risk
patients [20-23], and numerous evidence-based guidelines have been published for the prevention of
VTE [24-26].

In spite of the availability of these guidelines and the availability of safe and effective prophylactic
agents, numerous audits have demonstrated that appropriate thromboprophylaxis is not being offered
to large numbers of surgical patients [27-33]. As examples:

●The ENDORSE study evaluated VTE risk and prophylaxis in all hospital inpatients ≥18 years of
age admitted to a surgical ward in 358 hospitals from 32 different countries [28,34]. For the
 30,827 surgical patients in this study, 64.4 percent (range between countries: 44 to 80 percent)
were judged to be at risk for VTE according to the American College of Chest Physicians (ACCP)
Guidelines available at that time. However, only 58.5 percent (range between countries: 0.2 to 92
percent) of the at-risk surgical patients received ACCP-recommended VTE prophylaxis.
●In a Canadian study of 10,744 patients ≥65 years of age who had hip or knee replacement
therapy, only 19 percent received thromboprophylaxis at the time of hospital discharge [30]. Of
importance, the risk of short-term mortality (ie, death within three months of discharge) was
significantly lower among those who received post-discharge thromboprophylaxis (hazard ratio
0.34; 95% CI 0.20-0.57).

Various strategies to improve the use of thromboprophylaxis have been demonstrated to be effective,
including computerized order sets with electronic alerts, or pre-printed orders and quality
improvement in the form of clinician education programs, audit, and feedback, but further efforts are
required at improving the translation of data from clinical trials into clinical practice [35-42].

RISK FACTORS FOR VTE — There are numerous risk factors for the development of VTE in
surgical patients, including the type and extent of surgery or trauma, duration of hospital stay, a
history of previous VTE or cancer, immobility, recent sepsis, presence of a central venous access
device, pregnancy or the postpartum period, and inherited or acquired hypercoagulable states [43-
60]. For surgical patients, prophylaxis has been recommended according to assignment of the patient
to one of the defined surgical risk groups described below [25].

Incidence — In the absence of appropriate prophylaxis, the incidence of asymptomatic DVT

detected by objective diagnostic screening tests has ranged from 10 to 80 percent in various
hospitalized medical and surgical groups [24]. From earlier studies, the incidence of fatal pulmonary
embolism in the absence of prophylaxis was estimated to be 0.1 to 0.8 percent in patients undergoing
elective general surgery, 2 to 3 percent in patients having elective total hip replacement, and 4 to 7
percent of patients undergoing surgery for a fractured hip [24].

These estimates are likely lower today because of the increasing use of early ambulation and shorter
lengths of hospitalization. However, data from audits and registries demonstrate that the incidence of
VTE, and in particular fatal pulmonary embolism, remains excessively high, even after hospital
discharge.

As an example, in a prospective cohort study of 947,454 middle aged women in the UK, an estimated
1 in 140 women undergoing inpatient surgery in the UK will be admitted with venous
thromboembolism during the 12-week period following surgery, 1 in 815 after outpatient surgery, and
only 1 in 6200 women not undergoing surgery [61]. No information was available on the use or non-
use of VTE prophylaxis in this cohort of patients.

Surgical risk groups — The risk of postoperative VTE depends upon a number of factors related to
the surgical procedure itself (eg, degree of invasiveness, type and duration of anaesthesia,
requirement for immobilization) [62,63], as well as a number of patient-related adverse risk factors
[15,24,25,64-66]. (See "Overview of the causes of venous thrombosis", section on 'Acquired risk
factors'.)
 ●Increasing age
●Prior VTE in patient or family members
●Presence of malignancy or obesity
●Presence of an inherited or acquired hypercoagulable state
●One or more significant medical comorbidities (eg, heart disease, infection, inflammatory
conditions, recent stroke, preoperative sepsis)

In addition, certain procedures can be shown to increase thrombin generation, further increasing
thrombotic risk (eg, reaming out of the femur during total hip replacement surgery) [67].

The 2012 ACCP Guidelines have divided patients undergoing surgical procedures into very low, low,
moderate, or high risk groups [68]. Although there have been many attempts to quantitate these risks,
no one method has been found to be universally acceptable. Thus, the caveat is that if a patient has
additional risk factors, consideration should be given to either increasing the intensity or the duration
of the prophylactic agent [25,38].

The most widely tested surgical risk assessment model (the Modified Caprini Risk Assessment
Model, Caprini score) has been slightly modified for use in the 2012 ACCP Guidelines and is
described in the accompanying table (table 2) [64,68-70]. This risk model will be used throughout this
review to determine the surgical risk groups listed below.

Very low risk patients — Very low risk patients have been defined as those undergoing general and
abdominal-pelvic surgery with a Caprini score of zero, and those undergoing plastic and
reconstructive surgery with a Caprini score of zero to two. Their estimated baseline risk of VTE in the
absence of prophylaxis is estimated to be less than 0.5 percent.

A prospective observational cohort study using the American College of Surgeons National Surgical
Quality Improvement Program was used to identify independent predictors of 30-day VTE events
requiring treatment following outpatient or same-day surgery [71]. The 30-day incidence of VTE for
the 173,501 subjects in the derivation cohort was 0.15 percent, and was 0.06 and 1.18 percent
among those in the lowest and highest risk categories, respectively. Results of this study must be
interpreted in context; it was unable to provide details on the use of VTE prophylaxis or common VTE
risk factors, such as personal or family history of VTE. Nine independent risk factors were identified,
including age 40 to 59 years, age ≥60 years, current pregnancy, active cancer, increased body mass
index, operative time ≥120 minutes, arthroscopic surgery, saphenofemoral junction surgery, and
venous surgery not involving the great saphenous vein. Even the highest risk patients using this
outpatient model fit in the “low risk” surgical group, despite the fact that some of the identified risk
factors may place a given patient in the highest Caprini risk group.

Low risk patients — Low risk surgical patients have been defined as those undergoing general and
abdominal-pelvic surgery with a Caprini score of 1 to 2, or those undergoing plastic and
reconstructive surgery with a Caprini score of 3 to 4. Their estimated baseline risk of VTE in the
absence of prophylaxis is estimated to be approximately 1.5 percent.
In most cases, low risk surgical patients are those undergoing minor elective abdominal or thoracic
surgery. However, in some settings the risk of VTE remains uncertain, and there have not been good
randomized clinical trials demonstrating effectiveness of any particular form of VTE prophylaxis.
These include vascular surgery, laparoscopic surgery, knee arthroscopy in the absence of more
complicated surgery, elective spine surgery (eg, spinal fusion [72]), shoulder and elbow surgery [73],
isolated lower extremity fractures, Achilles tendon rupture repair [74], and podiatric surgery [25].

Moderate risk patients — Moderate risk surgical patients have been defined as those undergoing
general and abdominal-pelvic surgery with a Caprini score of 3 to 4, or those undergoing plastic and
reconstructive surgery with a Caprini score of 5 to 6. Their estimated baseline risk of VTE in the
absence of prophylaxis is estimated to be approximately 3 percent.

Patients undergoing general gynecologic, urologic, thoracic, ankle fracture, or neurosurgical

procedures usually fall into the moderate risk category [24,25,75,76].

High risk patients — High risk surgical patients have been defined as those undergoing general and
abdominal-pelvic surgery with a Caprini score of 5 or more, or those undergoing plastic and
reconstructive surgery with a Caprini score of 7 to 8. Their estimated baseline risk of VTE in the
absence of prophylaxis is estimated to be approximately 6 percent. Examples of patients in the high
risk group are those undergoing hip or knee arthroplasty, pelvic or hip fracture surgery, colorectal
surgery, major trauma, spinal cord injury, or cancer surgery [25,77,78].

Orthopedic surgery — A number of factors increase the risk of VTE during major orthopedic surgery
(eg, arthroplasty or hip fracture surgery), including the supine position on the operating table, the
anatomic position of the extremity in a patient undergoing knee arthroplasty, and the use of a thigh
tourniquet. As examples, internal injury may result from positioning of the extremity, and compression
of the femoral vein may occur due to flexion and adduction of the hip during surgery on this joint.

The use of prophylactic anticoagulation in those undergoing major orthopedic surgery substantially
reduces, but does not completely eliminate, the risk of VTE. One meta-analysis of 47 studies in
44,844 patients who underwent either total or partial knee (TPKA) or total or partial hip (TPHA)
arthroplasty and received currently approved VTE prophylaxis found that the rates of symptomatic
VTE prior to hospital discharge were approximately 1.1 and 0.53 percent, respectively [79]. Because
the endpoint was symptomatic VTE during (but not after) hospitalization, the true rate of relevant VTE
events was presumably underestimated.

Whether those undergoing other less extensive lower limb orthopedic surgery require VTE
prophylaxis is less well studied. However, one randomized trial suggested that pharmacologic
prophylaxis with low-molecular-weight (LMW) heparin in this population is not warranted, particularly
when no other risk factors for VTE exist. In an open label trial (POT-CAST) of 1519 patients
undergoing below knee casting of the lower leg (requiring surgical or conservative management), the
rate of symptomatic VTE was similar among those receiving LMW heparin for the full period of
immobilization compared to those not receiving anticoagulant prophylaxis (1.4 versus 1.8 percent)
[80]. Similarly, in 1543 patients (POT-KAST) who underwent arthroscopy (three quarters had
meniscectomy), eight days of LMW heparin did not reduce the rate of symptomatic VTE compared
with those not receiving prophylactic anticoagulation (0.7 versus 0.4 percent) [80]. There were no
differences in major bleeding events in any of the groups (0.1 percent each) in either study. However,
noteworthy is that among those who did develop thrombus, many had risk factors for VTE.  

Obese patients and those undergoing bariatric surgery — The obese surgical patient is
considered to be at moderate to high risk for VTE, with an estimated Caprini score of 4 or more for
those undergoing bariatric surgery [68,81]. However, the preferred anticoagulant (eg, unfractionated
versus LMW heparin) and appropriate prophylactic anticoagulation dosing are both unclear; available
studies on this subject have been considered to be of low quality [68,82,83].

A more complete discussion of this subject is presented separately. (See "Bariatric surgery: Intensive
care unit management of the complicated postoperative patient", section on 'Anticoagulant
dosing' and "Bariatric surgery: Postoperative and long-term management of the uncomplicated
patient", section on 'Venous thromboembolism'.)

PREVENTION OF VTE

Overall approaches — There are two approaches to the prevention of fatal pulmonary embolism:

●Primary prophylaxis — Primary prophylaxis is carried out using either drugs or physical
methods that are effective for preventing DVT.
●Secondary prevention — Secondary prevention involves the early detection and treatment of
subclinical venous thrombosis by screening postoperative patients with objective tests that are
sensitive for the presence of DVT.

However, no single screening method (eg, contrast venography, ultrasonography, MRI venography)
has found universal acceptance for secondary prevention [84,85]. Accordingly, primary prophylaxis is
preferred in most clinical circumstances; it is more cost effective than treatment of complications once
they occur [86]. Secondary prevention with screening is reserved for patients in whom primary
prophylaxis is either contraindicated or shown to be ineffective.

Primary prophylaxis — The characteristics of a preferred primary prophylactic method include a

method that is easy to administer, is safe and effective with limited or no need for laboratory
monitoring, that is cost effective.

Selecting prophylaxis options — Options for primary VTE prophylaxis include

pharmacologic and/or mechanical methods, which have variable efficacy and bleeding risk. In
general, the preferred method of prophylaxis is dependent upon the risk of postoperative VTE which
is, in turn, determined by the type of surgery and the Caprini score (table 2):

●Early and frequent ambulation is preferred in surgical patients at very low risk of VTE (eg,
patients undergoing general and abdominal-pelvic surgery with a Caprini score of zero
OR plastic/reconstructive surgery with a Caprini score of zero to two). (See 'Very low risk
patients' above.)
 ●Mechanical methods are preferred in patients with a contraindication to pharmacologic
prophylaxis and in low-risk surgical patients (eg, patients undergoing general and abdominal-
pelvic surgery with a Caprini score of 1 to 2 OR plastic/reconstructive surgery with a Caprini
score of 3 to 4). (See 'Low risk patients' above and 'Mechanical methods of
thromboprophylaxis' below.)
●Pharmacologic prophylaxis is preferred in surgical patients at moderate and high risk of VTE
(eg, patients undergoing general and abdominal-pelvic surgery with a Caprini score of ≥3
OR plastic/reconstructive surgery with a Caprini score of ≥5). (See 'Moderate risk patients' above
and 'High risk patients' above and 'Pharmacologic agents for VTE prevention' below.)
●Combined pharmacologic and mechanical methods (usually intermittent pneumatic
compression) rather than either method alone can be considered in surgical patients assessed to
be at very high risk of VTE (eg, high risk cancer surgery and multiple additional risk factors).
(See 'Pharmacologic agents for VTE prevention' below and 'Intermittent pneumatic
compression' below.)

Selecting a pharmacologic agent will depend on its efficacy and safety as well as the presence of
comorbidities (eg, renal insufficiency), and patient preferences and values. In general, the following
applies:

●LMW heparins and fondaparinux are preferred rather than UFH or other pharmacologic agents,
particularly in high risk surgical patients (eg, total hip and knee replacement) due to their proven
efficacy and extended experience in this population. (See 'Low molecular weight heparin' below
and 'Fondaparinux' below.)
●Low dose UFH is a reasonable alternative to LMW heparin for surgical patients in whom there
is a contraindication to LMW heparin (eg, renal insufficiency) or for patients in whom cost is an
issue. (See 'Low dose unfractionated heparin' below.)
●Warfarin may be considered as an alternative to LMW heparin and UFH when delayed
prophylaxis is desired in surgical patients after total hip or knee replacement.
(See 'Warfarin' below.)
●Direct thrombin and factor Xa inhibitors have not been studied in the general surgical population
but may be alternatives to LMW heparin in orthopedic patients who have undergone a total hip or
knee replacement. These agents have not been compared with UFH or aspirin. (See 'Direct
thrombin and factor Xa inhibitors' below.)
●Aspirin can be considered for orthopedic patients who have undergone a total hip or knee
replacement and are not candidates for other anticoagulants. (See 'Aspirin' below.)

VTE prophylaxis in special surgical populations is discussed separately in the followings sections:

●Patients undergoing gynecologic surgery (see "Overview of preoperative evaluation and

preparation for gynecologic surgery", section on 'Thromboprophylaxis')
●Patients that are critically ill (see "Prevention of venous thromboembolic disease in acutely ill
hospitalized medical adults", section on 'Selection of method of prophylaxis')
●Patients undergoing bariatric surgery (see "Bariatric surgery: Postoperative and long-term
management of the uncomplicated patient", section on 'Venous thromboembolism' and "Bariatric
 surgery: Intensive care unit management of the complicated postoperative patient", section on
'Prophylaxis for venous thromboembolic events')

Timing of commencement of prophylaxis — Prophylaxis is ideally started during hospitalization,

either before or shortly after surgery, and continued at least until the patient is fully ambulatory
[25,87,88]. The administration of thromboprophylaxis in close proximity to surgery has been shown to
enhance its efficacy in a systematic review that compared prophylaxis with LMW heparin
versus warfarin [89-91].

●A large risk reduction in venographically-detected DVT was observed when the LMW
heparin dalteparin was initiated at half the usual high risk dose in proximity to total hip
replacement (ie, either within two hours before surgery or four to six hours after surgery).
●When LMW heparin was started either 12 hours before surgery or 18 to 24 hours after surgery,
the efficacy advantage of LMW heparin over warfarin was not observed. However, starting LMW
heparin within two hours of surgery was associated with an increased risk of major bleeding.

Values and preferences — The concept of values and preferences was introduced starting with the
2004 ACCP Guidelines [38]. This issue requires considerable thought by both the clinician and the
patient. As examples:

●In the treatment of established pulmonary embolism (PE), a greater value is normally placed on
the prevention of death from recurrent PE than from the relatively low risk of bleeding from the
use of anticoagulation.
●In orthopedic surgery, greater value is placed on the avoidance of bleeding from anticoagulation
over the relatively low frequency of death from pulmonary embolism if thromboprophylaxis is not
used. Thus in North America a common regimen with LMW heparin is to start at 18 to 24 hours
postoperatively [90]. It also explains why the use of warfarin, with its delayed onset of effective
anticoagulation, remains popular, particularly in the United States.
A systematic review and meta-analysis of randomized clinical trials evaluating VTE prophylaxis in
patients undergoing elective cranial neurosurgery has estimated that for every 1000 patients who
receive heparin prophylaxis, 91 VTE events will be prevented [92]. Approximately 35 of these will
be proximal DVT or PE, and only 9 to 18 will be symptomatic. On the other hand, 7 intracerebral
hemorrhages and 28 more minor bleeds were estimated to occur if a heparin preparation is
employed, versus none if a mechanical method of thromboprophylaxis is used. Such analyses
can be employed to better inform clinicians and their patients about DVT prophylaxis options for
cranial neurosurgical procedures. (See 'Mechanical methods of thromboprophylaxis' below.)

Definition of major bleeding — The commonly used traditional classification for major bleeding is
recommended and has been approved by the International Society for Thrombosis and Hemostasis
[93]:

●Fatal bleeding, and/or
●Symptomatic bleeding in a critical area or organ, and/or
●Bleeding causing a fall in hemoglobin of ≥2 g/dL or leading to transfusion of two or more units of
whole blood or red cells
Extended prophylaxis — Extended VTE prophylaxis is offered to patients at high risk for VTE to
accommodate earlier discharge and in recognition that VTE can occur days to weeks post discharge
[94,95]. Evidence is strongest for patients who have undergone major orthopedic surgery (total hip
replacement [THR], total knee replacement [TKR], hip fracture surgery [HFS]), and cancer and major
abdominal surgery. Low-molecular-weight (LMW) heparin is the preferred agent. The optimal duration
of extended prophylaxis is unknown but is usually given beyond 10 days and up to 35 days following
major orthopedic surgery and for a period of three to four weeks for selected high-risk patients who
undergo major abdominal and/or pelvic surgery for cancer.  

For patients with major orthopedic surgery, in particular THR, many randomized trials and meta-
analyses have shown that compared to placebo and other agents (eg, warfarin and aspirin), extended
prophylaxis (28 to 35 days) with LMW heparin reduces the rate of VTE without excess bleeding
[94,96-103].

Although LMW heparin is superior, other agents may be preferred in certain settings. For example,
LMW heparin is costly and some patients cannot tolerate or self-administer LMW heparin injections.
Studies comparing the safety and efficacy of warfarin and aspirin to LMW heparin are described
below:

●One randomized trial of 1279 patients who had undergone THR showed that, compared to
LMW heparin, six weeks of warfarin resulted in a similar rate of VTE (2 versus 3 percent) [104].
However, major bleeding was higher with warfarin (6 versus 1 percent).
●In one multicenter controlled trial (EPCAT), 778 patients who had undergone THR and had
received an initial 10 days of LMW heparin (dalteparin) were randomly assigned to either
extended prophylaxis with LMW heparin or to aspirin [105]. Compared with LMW heparin, aspirin
was associated with a similar rate of VTE (1.3 for aspirin versus 0.3 percent for LMW heparin)
and bleeding events (0.5 versus 1.3 percent) at 28 days. However, this trial was stopped early
due to slow enrollment and the effect size was based on a small number of events, limiting the
quality of the data.

Thus, we and others support the use of LMW heparin as the preferred agent for extended prophylaxis
after THR [68]. Although the evidence is not as strong for patients with TKR and HFS, small trials and
the rationale that these patients are also at high risk for VTE support the use of extended prophylaxis
in this population as well [68,96].

The duration of extended prophylaxis following orthopedic surgery has varied between studies.
However, most trials support prophylaxis beyond 10 days and up to 35 days following surgery [94,96-
99,102,104,106].

Patients undergoing cancer surgery or major abdominal surgery also benefit from extended
prophylaxis, most commonly for a period of four weeks [107-111]. One randomized study of 1113
patients post abdominal or pelvic surgery for cancer reported that, compared to eight days of LMW
heparin, four weeks decreased major VTE (4.6 versus 0.8 percent) without increasing hemorrhagic
complications [110]. In another study of patients who had undergone major abdominal surgery, the
administration of LMW heparin for four weeks significantly reduced the rate of VTE (16.3 versus 7.3
percent), without increasing the risk of bleeding [109]. Extended prophylaxis for cancer surgery
patients has also been recommended in the 2012 guidelines issued by the American College of
Chest Physicians (ACCP), the National Comprehensive Cancer Network (NCCN), and the American
Society of Clinical Oncology (ASCO) [68,111,112]. (See "Risk and prevention of venous
thromboembolism in adults with cancer", section on 'Surgical patients'.)

Comparison of agents — Comparisons of agents across studies of hip or knee surgery have been
difficult, since the drugs under investigation and the dosing schedules have varied from one clinical
trial to another. Even within the same clinical trial there can be considerable intercenter variability. In
addition, bleeding rates have varied quite widely across studies, at least in part because different
definitions for bleeding have been used [113]. (See 'Definition of major bleeding' above
and 'Rivaroxaban' below.)

A number of randomized trials have compared LMW heparin with UFH, warfarin or acenocoumarol,

or fondaparinux in patients undergoing total hip replacement surgery, and to a lesser extent total knee
replacement surgery. A meta-analysis comparing vitamin K antagonists versus LMW heparin for the
prevention of VTE in orthopedic surgery indicated that the vitamin K antagonists are less effective
than LMW heparin, without any significant difference in bleeding risk [114].

In general, LMW heparin has been shown to be superior to UFH or warfarin, but inferior
to fondaparinux in terms of efficacy, with similar bleeding rates in patients undergoing total hip or total
knee replacement surgery.

The use of the LMW heparin enoxaparin differs between regions [22]. Thus:

●In North America, enoxaparin is commonly used in the dose of 30 mg twice daily starting 12 to
24 hours postoperatively.
●In Europe, enoxaparin at a dose of 40 mg is started 12 hours preoperatively and is then given
once daily.
●Other LMW heparin preparations have usually been given in a once daily dosage, starting
postoperatively.

A meta-analysis in patients undergoing cancer surgery concluded that there was no difference
between LMW heparin and UFH in terms of efficacy, DVT location, or bleeding complications [115].

A Cochrane review of the use of LMW heparin to prevent VTE in patients with lower leg
immobilization concluded that LMW heparin in outpatients significantly reduced the incidence of VTE
[116]. A further meta-analysis reviewed the use of intermittent pneumatic compression (IPC) with or
without pharmacologic prophylaxis used in the form of LMW heparin. It was shown that, compared
with IPC alone, combined prophylactic modalities decreased the incidence of VTE [117].

In patients undergoing neurosurgical procedures, LMW heparin was shown to be superior to IPC
[118,119]. In patients suffering major trauma, LMW heparin was superior to UFH in the prevention of
both total and proximal DVTs [120].
PHARMACOLOGIC AGENTS FOR VTE PREVENTION — A number of pharmacologic agents are
now available for VTE prevention in surgical patients, including unfractionated heparin, the LMW
heparins, fondaparinux, the vitamin K antagonists, and the new oral antithrombotic
agents rivaroxaban, dabigatran, and apixaban. These will be discussed below. When available, meta-
analyses of the comparative effectiveness among these various agents will also be discussed [121-
125].

Low dose unfractionated heparin — Low dose subcutaneous unfractionated heparin (UFH) for

prophylaxis of VTE is usually given in a dose of 5000 units two hours preoperatively and then every 8
to 12 hours postoperatively (ie, either twice or three times daily).

An early prospective randomized study of over 4000 patients found that low dose heparin reduced the
incidence of fatal PE in patients undergoing major surgical procedures from 0.7 to 0.1 percent
compared with controls [126]. Pooled data from meta-analyses confirmed that low dose UFH reduced
the incidence of all DVT, proximal DVT, and all PE including fatal PE [20,21,127,128]. Most of the
patients in these trials underwent abdominal or thoracic surgery (particularly for gastrointestinal
disease), but some patients had gynecologic or urologic surgery, mastectomy, or vascular procedures
[20,21].

In addition to the relatively low side effect profile of low dose UFH, its advantages are that it is
relatively inexpensive and easily administered, and anticoagulant monitoring is not required.
However, the platelet count should be monitored regularly in all patients receiving low dose UFH to
detect the development of heparin-induced thrombocytopenia [129,130]. (See "Heparin and LMW
heparin: Dosing and adverse effects", section on 'Platelet count monitoring'.)

Low molecular weight heparin — A number of low molecular weight heparin (LMW heparin)
preparations are available. These drugs have the advantage that they can be given subcutaneously
once or twice daily at a constant dose without laboratory monitoring for therapeutic effect. However,
creatinine clearance should be intermittently monitored during the hospital admission for patients
receiving LMW heparin. In addition, there is a lower incidence of heparin-induced thrombocytopenia
than with UFH. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW
heparin' and "Low molecular weight heparin for venous thromboembolic disease", section on
'Prevention of VTE'.)

As an example, in a randomized double blind study of patients undergoing hip replacement surgery,
heparin-induced thrombocytopenia (HIT) occurred in 9 of 332 patients (2.7 percent) receiving UFH
compared with none of 333 patients receiving LMW heparin [129]. A meta-analysis of all studies
comparing the incidence of HIT occurring after exposure to UFH versus LMW heparin after any
surgical intervention confirmed that the incidence of HIT is significantly less with LMW heparin (RR
0.20, 95% CI 0.04-0.90) [131]. However, this conclusion is limited by a scarcity of high quality studies
including HIT as an outcome. (See "Clinical presentation and diagnosis of heparin-induced
thrombocytopenia".)

The LMW heparins have been extensively studied for the prevention of VTE. Studies in surgical
patients have included those undergoing general surgery, including gynecologic and urologic surgery
[22,23,132,133], orthopedic surgery including total hip and knee replacement surgery [91,96,97,134-
140], hip fracture [106,141], lower leg fractures [116,142-144], arthroscopy [145-147], trauma
including spinal cord injury and neurosurgery [118-120,148-152], and cancer surgery [107-
109,115,153-155]. Meta-analyses of LMW heparin in the prevention of VTE in general surgery have
shown efficacy to be at least as good as with UFH, with equal safety [22,23].

In most countries, LMW heparin is the prophylactic agent of choice for preventing VTE in high risk
patients.

Fondaparinux — The dosing of fondaparinux is discussed elsewhere in UpToDate, but issues

related to its use in surgical patients will be reviewed here. (See "Fondaparinux: Dosing and adverse
effects".)

Fondaparinux has been evaluated in the prevention of VTE in patients undergoing orthopedic surgery
and general surgery:

●Total hip replacement – One phase II [156] and two phase III trials [137,157] have been
completed in which fondaparinux, in doses ranging from 2.5 to 3 mg/day subcutaneously, starting
four to eight hours postoperatively, was compared with 30 mg of enoxaparin subcutaneously
every 12 hours starting 12 to 24 hours postoperatively (PENTATHLON trial) [137,156], or with 40
mg of enoxaparin given 12 hours before surgery, followed by 40 mg 12 to 24 hours after surgery
and daily thereafter (EPHESUS trial) [157]. In all three studies, fondaparinux was more effective
than enoxaparin in preventing postoperative VTE, with relative risk reductions in the phase II and
III trials ranging from 26 to 81 percent. Rates of major bleeding ranged from 1.8 to 4.1 percent for
fondaparinux and 1.0 to 3.5 percent for enoxaparin.
In a 2002 meta-analysis of four available trials, it was concluded that the efficacy
of fondaparinux was superior to that of enoxaparin [158]. In these studies, major bleeding
occurred more frequently in fondaparinux-treated subjects, but there was not an increase in
bleeding leading to death or re-operation or bleeding into a critical organ with fondaparinux
compared with enoxaparin [158]. Most of the patients who bled had their initial fondaparinux
injection less than eight hours postoperatively.
A single center, retrospective cohort study in 5061 consecutive unselected patients undergoing
major orthopedic surgery reported that thromboprophylaxis with rivaroxaban was associated with
significantly fewer episodes of symptomatic VTE and major bleeding events
than fondaparinux [159]. Prospective comparison studies are warranted to confirm these
findings. (See 'Rivaroxaban' below.)
●Hip fracture – In a phase III trial, patients undergoing surgery for fracture of the upper third of
the femur were randomly assigned to treatment with fondaparinux (2.5 mg once daily starting
four to eight hours postoperatively) or enoxaparin (40 mg/day starting 12 hours preoperatively)
[106]. The incidence of VTE by day 11 was significantly lower with fondaparinux (8.3 versus 19.1
percent). There were no significant differences in the incidence of death or major bleeding.
The benefit of thromboprophylaxis with fondaparinux for one month, rather than one week was
studied in a double-blind, multicenter trial [141]. All patients received fondaparinux for the first six
to eight days, following which they were randomly assigned to receive fondaparinux
 (2.5 mg/day) or placebo for an additional 19 to 23 days. Compared with one week of
fondaparinux (followed by three weeks of placebo), one month of fondaparinux resulted in a
highly significant reduction in the incidence of documented VTE from 35 to 1.4 percent (relative
risk reduction 96 percent, 95% CI: 87-100 percent), as well as an 87 percent reduction in the risk
of symptomatic VTE. Although there was a non-significant trend toward more major bleeding in
the group treated with one month of fondaparinux, as judged by the bleeding index, there were
no differences between the two groups in the incidence of bleeding into critical organs, or
bleeding leading to death or reoperation.
●Knee surgery – In a phase III trial, patients undergoing major knee surgery were randomly
assigned to treatment with fondaparinux (2.5 mg once daily starting four to eight hours after
surgery) or enoxaparin (30 mg twice daily starting 12 to 24 hours after surgery) [140]. The
incidence of VTE by day 11 was significantly lower with fondaparinux (12.5 versus 27.8 percent).
Major bleeding occurred more frequently in the fondaparinux group, as judged by the "bleeding
index" (see above), but there were no significant differences between the two groups in the
incidence of clinically relevant bleeding (eg, fatal bleeding, bleeding in a critical organ, or
bleeding requiring reoperation).
●Abdominal surgery – In the double-blind randomized PEGASUS trial, patients scheduled for
major abdominal surgery under general anesthesia were randomly assigned to one of the
following two treatments [133]:
•Fondaparinux (2.5 mg subcutaneously daily for five to nine days, starting six hours after
surgery), or
•Dalteparin (2500 units subcutaneously two hours before surgery and 12 hours after the
preoperative administration, followed by 5000 units subcutaneously daily for five to nine
days)
Among 2048 evaluable patients, the rate of VTE for those treated
with fondaparinux or dalteparin was 4.6 versus 6.1 percent, respectively, for a relative risk
reduction of 25 percent (95% CI -9 to +48), meeting the predetermined criterion for non-inferiority
of fondaparinux. Major bleeding was similar in the two treatment arms (3.4 versus 2.4 percent,
respectively).
In the APOLLO Study, patients age ≥40 undergoing major abdominal surgery of at least 45
minutes duration were randomly assigned to receive postoperative VTE prevention with
intermittent pneumatic compression plus either placebo or fondaparinux (2.5 mg once daily
subcutaneously for five to nine days, starting six to eight hours postoperatively) [160]. The vast
majority (82 percent) of the subjects had at least one VTE risk factor over and above their age
and the abdominal surgery. Fondaparinux significantly reduced the VTE rate versus that seen
after placebo (1.7 versus 5.3 percent; odds ratio reduction 70 percent, 95% CI 28-87).Major
bleeding was more frequent after fondaparinux (1.6 versus 0.2 percent), although none of the
bleeding events were fatal or involved a critical organ.

Warfarin — Oral anticoagulation with vitamin K antagonists (VKA) such

as warfarin or acenocoumarol, can be commenced preoperatively, at the time of surgery, or
postoperatively for the prevention of VTE [161]. However, therapy started at the time of surgery or in
the early postoperative period may not prevent small venous thrombi from forming because the
anticoagulant effect of the VKAs is not achieved until the third or fourth day of treatment with these
agents. (See "Biology of warfarin and modulators of INR control", section on 'Mechanism of action'.)

Nonetheless, warfarin appears to effectively inhibit extension of such thrombi if present, thereby

preventing clinically important VTE. Because of its delayed onset of action along with bleeding rates
similar to those seen with LMW heparin, warfarin has been favored as a thromboprophylactic agent
by orthopedic surgeons in the United States.

Warfarin has been compared with LMW heparin in patients undergoing total hip or knee replacement
surgery [91,162,163]. Most studies have shown superior benefit with LMW heparin without any
increase in bleeding rates. In a comparison of warfarin with intermittent pneumatic compression after
total hip replacement, warfarin was significantly more effective [13]. In one earlier study, warfarin was
superior to aspirin or placebo for the prevention of DVT following surgery for hip fracture [164].

Warfarin reduces the incidence of VTE when used for four weeks following total hip replacement.
When compared with LMW heparin, each given for four weeks postoperatively after total hip
replacement, warfarin showed equal efficacy but a significantly increased incidence of major bleeding
[104].

In patients undergoing hip arthroplasty, genotype-guided warfarin dosing does not appear to offer

conclusive benefit over routine clinical INR-guided dosing, the details of which are discussed
separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Baseline
testing'.)

Direct thrombin and factor Xa inhibitors — Orally active agents that specifically inhibit either
activated factor X or activated factor II (thrombin) have undergone extensive evaluation with favorable
results from a number of phase III studies. Rivaroxaban and apixaban, factor Xa inhibitors,
and dabigatran etexilate, a factor IIa inhibitor (direct thrombin inhibitor), have been approved for use
by regulatory agents in the United States and several other countries. From a practical standpoint,
these agents are appealing because of their ease of administration, as a pill instead of a
subcutaneous injection. While these agents are superior to placebo [165], their benefits compared
with other anticoagulants remain uncertain. The safety and efficacy of individual agents are
summarized below.

Rivaroxaban — Rivaroxaban is a specific inhibitor of activated factor X with excellent oral

bioavailability and a half-life of approximately nine hours. It is primarily excreted renally, although
some is excreted through the gastrointestinal tract. As a result, caution is recommended in patients
with renal insufficiency; its use is contraindicated in patients with a creatinine clearance <30 mL/min.
It is also contraindicated in patients with severe hepatic disease and dosage reduction is
recommended in patients >65 years of age. (See "Direct oral anticoagulants and parenteral direct
thrombin inhibitors: Dosing and adverse effects", section on 'Rivaroxaban'.)

Two studies were carried out in patients undergoing total hip replacement. The first
compared rivaroxaban 10 mg orally once daily with enoxaparin 40 mg once daily subcutaneously
starting 12 hours preoperatively, both for 35 ± 4 days (RECORD 1) [166]. The second (RECORD 2)
compared oral rivaroxaban 10 mg once daily for 35 ± 4 days with enoxaparin 40 mg once daily
starting 12 hours preoperatively for 12 ± 2 days [167].

●In RECORD 1, rivaroxaban showed superiority to enoxaparin for the reduction of total VTE,

major VTE (ie, a composite of proximal DVT, non-fatal PE, or VTE related death), with no
difference in major bleeding events [166].
●RECORD 2 showed superiority of rivaroxaban in the incidence of total VTE, major VTE, and
proximal or distal DVT, and notably in the incidence of symptomatic VTE [167].
●In patients undergoing total knee replacement (RECORD 3), rivaroxaban 10 mg orally once
daily was compared with enoxaparin 40 mg subcutaneously daily starting 12 hours
preoperatively, with either agent continued for 12 ± 2 days [168]. In this study, rivaroxaban was
superior to enoxaparin in the reduction of total VTE, major VTE and distal DVT, and significantly
reduced the incidence of symptomatic VTE.
●In the RECORD 4 study, patients undergoing total knee replacement were randomly assigned
to receive either rivaroxaban 10 mg daily PO or enoxaparin 30 mg twice daily starting 12 to 24
hours postoperatively, with both given for 12 ± 4 days [169]. There was a significant decrease in
total VTE with rivaroxaban, but the difference in the incidence of major VTE and symptomatic
VTE did not reach statistical significance.

A pooled analysis of four phase III studies was performed

comparing rivaroxaban 10 mg/day with enoxaparin (either 40 mg/day or 30 mg twice per day) for
thromboprophylaxis after total hip or knee replacement surgery [170]. The following results were
obtained:

●Compared with enoxaparin, thromboprophylaxis with rivaroxaban was associated with

significantly fewer symptomatic VTE events and all-cause mortality (odds ratio 0.48; 95% CI
0.30-0.76) during the treatment period.
●The composite of major and non-major clinically relevant bleeding during the treatment period
was 2.8 percent with rivaroxaban versus 2.5 percent with enoxaparin (odds ratio 1.17; 95% CI
0.93-1.46).
●In all studies with rivaroxaban there was no significant elevation of liver enzymes or increase in
thrombotic events during the treatment period.

A retrospective cohort study from the ORTHO-TEP registry evaluated the relative efficacy and safety
of rivaroxaban versus fondaparinux thromboprophylaxis in 5061 unselected consecutive patients
undergoing major orthopedic surgery. Results included the following [159]:

●Rates of symptomatic VTE were significantly lower for rivaroxaban (2.1 versus 5.6 percent)
●Rates of severe bleeding were significantly lower for rivaroxaban (2.9 versus 4.9 percent)
●The mean length of hospitalization was significantly shorter in the rivaroxaban group (8.3
versus 9.3 days).

A similar retrospective cohort study from the ORTHO-TEP registry evaluated the relative efficacy and
safety of rivaroxaban versus low molecular weight heparin thromboprophylaxis in 5061 unselected
consecutive patients undergoing hip and knee replacement surgery. Results included the following
[171]:

●Rates of symptomatic VTE were significantly lower for rivaroxaban (2.1 versus 4.1 percent)
●Rates of major bleeding were significantly lower for rivaroxaban (2.9 versus 7.0 percent)
●The mean length of hospitalization was significantly shorter in the rivaroxaban group (8.3
versus 11.1 days).

Prospective studies will be required in order to confirm both of these findings.

Dabigatran etexilate — Dabigatran etexilate is an orally absorbed pro-drug with approximately 5

percent bioavailability. It is converted to the active agent dabigatran, which has a half-life of
approximately eight hours after a single dose and 17 hours after multiple doses. Dabigatran is a direct
thrombin inhibitor that is active against both free and clot-bound thrombin. The activity of dabigatran
is directed against the conversion of fibrinogen to fibrin, but it also inhibits platelet activation by
thrombin and the activation of clotting factors V, VIII, and XI by thrombin. (See "Direct oral
anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects", section on
'Dabigatran'.)

For the prevention of VTE, dabigatran has been studied in patients undergoing total hip or total knee
replacement surgery. Based on a phase II dose-finding study in patients undergoing total hip or knee
replacement surgery, a safe and effective daily dosing of dabigatran etexilate was suggested to be in
the range between 100 and 300 mg/day [172,173]. A meta-analysis of available efficacy and safety
data from three trials has concluded that dabigatran, at the recommended dose of 220 mg once daily,
was non-inferior to enoxaparin (40 mg/day) for VTE prophylaxis after total knee or total hip
arthroplasty, with a similar toxicity profile [174].

In patients undergoing total knee replacement surgery (the REMODEL study) oral dabigatran 150 mg
or 220 mg daily was compared with enoxaparin 40 mg daily starting 12 hours pre-operatively, with
mandatory venography at day 6 to 10 and follow up for 10 to 14 weeks [175]. In the dabigatran
150 mg/day group the first dose was given one to four hours postoperatively at a dose of 75 mg and
thereafter 150 mg once/day, and in the 220 mg/day dabigatran group the initial dose was 110 mg,
followed by 220 mg/day.

This trial was designed as a non-inferiority study and achieved non-inferiority compared
with enoxaparin for the prevention of total VTE and reduction of all-cause mortality. There was no
difference in the incidence of symptomatic VTE. Bleeding rates were low and comparable in both
groups, with 89 percent of major bleeding events being noted at the surgical site.

The RENOVATE trial in patients undergoing total hip replacement surgery compared
oral dabigatran 150 mg/day or 220 mg/day starting within one to four hours postoperatively
with enoxaparin 40 mg once daily starting 12 hours pre-operatively [176]. All treatment continued for
28 to 35 days, at which time venography was done [176]. For the composite endpoint of total VTE
and all-cause mortality, both arms of the dabigatran study showed non-inferiority to enoxaparin, with
similar bleeding rates and with most major bleeding events being at the surgical site.
The REMOBILIZE trial was carried out in patients undergoing total knee replacement surgery. In this
study, dabigatran etexilate 150 mg/day or 220 mg/day starting with a dose of either 75 or 110 mg 6 to
12 hours postoperatively, respectively in the two groups, was compared with enoxaparin 30 mg twice
daily, starting 12 to 24 hours postoperatively [177]. Venography was performed at day 12 to 15.
Dabigatran failed to meet the predefined criteria for non-inferiority against enoxaparin in terms of the
composite endpoint. Rates for major VTE or death were similar and major bleeding events were
comparable. As with fondaparinux and rivaroxaban, dabigatran was not as effective against the North
American regimen of enoxaparin (ie, 30 mg twice daily) as it was against the dosing favored in
Europe (ie, 40 mg once daily).

In all three studies with dabigatran there was no significant elevation of liver enzymes or in thrombotic
events following the treatment period [175-177]. Based on evidence from these trials, dabigatran has
been approved for use in a number of countries in Europe, the United States, and Canada [178,179].

Apixaban — Apixaban is a specific inhibitor of activated factor X with excellent oral bioavailability and
a half-life of approximately eight hours. It is primarily metabolized by the liver. Its use is not
recommended in those with a creatinine clearance <15 mL/minute or in those with severe hepatic
impairment. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and
adverse effects", section on 'Apixaban'.)

In a double-blind randomized study comparing apixaban to enoxaparin for thromboprophylaxis after

knee replacement, apixaban did not meet the prespecified criteria for noninferiority, but its use was
associated with lower rates of clinically relevant bleeding and it had a similar adverse event profile to
enoxaparin [180]. Other phase II and III trials have shown that apixaban compared favorably to both
enoxaparin and warfarin as VTE prophylaxis in total knee replacement surgery [181-183] and that
thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with significantly
lower rates of venous thromboembolism without increased bleeding in patients undergoing total hip
replacement [184]. Dose reduction is not required if the creatinine clearance is ≥30 mL/min [185].

A randomized, dose-ranging study compared three different schedules of apixaban (oral daily doses
of 5 mg twice daily, 10 mg twice daily, or 20 mg once daily) or LMW heparin followed by a vitamin K
antagonist (VKA), all given for a total of 84 to 91 days, in 520 patients with symptomatic DVT. Results
included [186]:

●The primary efficacy end-point, a composite of symptomatic recurrent VTE and asymptomatic
deterioration of bilateral compression ultrasound or perfusion lung scan obtained at the end of
treatment, occurred in 4.7 and 4.2 percent of those treated with apixaban and
LMW heparin/VKA, respectively.
●The primary safety end-point, a composite of major and clinically relevant, non-major bleeding
was noted in 7.3 and 7.9 percent of those treated with apixaban and
LMW heparin/VKA, respectively.
●There was no evidence for a dose-response relationship with apixaban for either the efficacy or
safety end-points. Routine liver function testing revealed no evidence of liver toxicity.
Edoxaban — Data regarding the use of edoxaban, a factor Xa inhibitor, for the prevention of VTE
come from two randomized trials in Japanese patients undergoing total knee replacement or total hip
replacement. These trials (STARS E-3 and STARS J-5) compared edoxaban with the low molecular
weight heparin enoxaparin [187]. A pooled analysis of the results showed that when compared with
enoxaparin, edoxaban was associated with a lower incidence of DVT and PE (5.1 versus 10.7
percent) and a similar safety profile. (See "Direct oral anticoagulants and parenteral direct thrombin
inhibitors: Dosing and adverse effects", section on 'Edoxaban'.)

Comparison with LMW heparin — Numerous randomized trials and meta-analyses have compared
the efficacy and safety of factor Xa and direct thrombin inhibitors to conventional VTE prophylaxis in
patients following total hip and knee replacement [121,123,124,165,188-192]. The most commonly
studied agents are the direct thrombin inhibitor, dabigatran, and the orally active factor Xa
inhibitors rivaroxaban, apixaban, and edoxaban. These agents have been compared to LMW heparin
(enoxaparin, dalteparin). They have not been compared with warfarin, aspirin, or UFH. (See "Direct
oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects", section on
'Dabigatran' and "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and
adverse effects", section on 'Direct factor Xa inhibitors'.)

While data from randomized trials, systematic reviews and meta-analyses report favorable effects on
all outcomes (symptomatic DVT, nonfatal pulmonary embolism and mortality), others report
unchanged or improved rates of symptomatic DVT only [121,123,124,188-191]. Similarly, while some
analyses report no difference in rates of bleeding others report increased bleeding risk with these
agents. Conflicting results may be due to differences among the studies in the agent used, dosing,
timing of initiation, duration of prophylaxis. Despite conflicting data, meta-analyses suggest that, on
balance, the benefits of direct thrombin inhibitors and factor Xa inhibitors for the prevention of VTE
are marginal and may be offset by an increased risk of bleeding [124,191]:

●One 2012 meta-analysis of 22 randomized trials (32,159 patients) compared the factor Xa
inhibitors (rivaroxaban, apixaban, edoxaban) with LMW heparin in adults for VTE prevention
following hip or knee replacement [124]. The efficacy and safety of the direct thrombin inhibitor
was not examined in this analysis. Factor Xa inhibitors were associated with a reduced risk of
symptomatic DVT (4 fewer events per 1000) without an effect on nonfatal pulmonary embolism
or death. However, high doses of factor Xa inhibitors, but not lower doses, increased the risk of
bleeding more than the LMW heparins (2 more bleeding events per 1000). Major limitations of
this analysis were that many included studies reported bleeding as a composite outcome and the
outcomes were missing in 3 to 41 percent of patients. In addition, the enoxaparin dosing in most
of the included studies was the lower dose of 40 mg daily, whereas in North America the usual
dose of enoxaparin is 30 mg twice-daily. Thus, use of a 40 mg dose as a comparator may favor
efficacy while increase bleeding events in this analysis.
●Additional systematic reviews and meta-analyses report no difference between LMW heparin
and the direct thrombin inhibitor, dabigatran, in the rates of VTE prevention (relative risk [RR]
0.71, 95% CI 0.23-2.12) or bleeding (RR 1.12, 95% CI 0.94-1.35) [189,191]. In addition, indirect
comparison of the newer orally active agents with each other suggested that rivaroxaban was
more efficacious at preventing symptomatic DVT (RR 0.50, 95% CI 0.37-0.68) than dabigatran
 or apixaban but was associated with excess bleeding risk (RR 1.14; 95% CI 0.80-1.64)
[190,191].

Additional trials will be required to establish the optimal agent, dosing, overall relative safety, and
efficacy of these new anticoagulants compared to conventional VTE prophylaxis.

Aspirin — While evidence favors aspirin for the prevention of thrombotic events in atherosclerotic

disease, its efficacy for the prevention of VTE in medical and surgical patients is unclear.
(See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults",
section on 'Aspirin'.)

An older meta-analysis suggested that, compared with placebo, aspirin reduced the incidence of VTE
by approximately 20 percent [193]. However, other studies suggest that it is less efficacious when
compared with LMW heparin [194-197]. Renewed interest in aspirin, as a prophylactic agent in at-risk
patients led to a multicenter randomized, controlled trial of aspirin in 778 surgical patients after total
hip replacement (THR) [105]. All patients received 10 days of LMW heparin prior to randomization.
Compared to LMW heparin, aspirin was associated with a lower rate of VTE that did not reach
statistical significance for superiority (0.3 versus 1.3 percent). This trial was stopped early due to slow
enrollment and event numbers were small which may explain why a four-fold difference in event rates
between the groups was not reported as superior.

The 2012 ACCP Guidelines included aspirin among the list of thromboprophylactic agents that can be
considered for use in patients undergoing total hip or total knee arthroplasty or hip fracture surgery
[198]. However, its use was not unanimously supported. We also suggest that it can be considered,
but is not the preferred agent, for extended VTE prophylaxis in this population of surgical patients.  

MECHANICAL METHODS OF THROMBOPROPHYLAXIS — Mechanical methods of

thromboprophylaxis that have been used in surgical patients include intermittent pneumatic
compression (IPC), graduated compression stockings (GCS), and the venous foot pump (VFP).

Mechanical methods for the prevention of VTE are primarily indicated in surgical patients at high risk
of bleeding (eg, following neurosurgery, patients with intracranial hemorrhage) and in whom there is a
contraindication to anticoagulants (eg, bleeding peptic ulcer) [68]. Among these devices IPC is
typically preferred [68,117,199,200]. Devices are typically placed on the patient just prior to the start
of surgery and used continuously until hospital discharge. When used in any of these circumstances,
consideration should be given to the additional use of a pharmacologic agent, such as LMW heparin,
as soon as the bleeding risk becomes acceptably low (eg, 48 to 72 hours following neurosurgery) or
when the bleeding lesion or bleeding risk has been reversed [68].

Intermittent pneumatic compression — Intermittent pneumatic compression (IPC) prevents venous

thrombosis by enhancing blood flow in the deep veins of the legs, thereby preventing venous stasis
[201]. IPC also reduces plasminogen activator inhibitor-1 (PAI-1), thereby increasing endogenous
fibrinolytic activity [202]. (See "Vascular endothelial function and fundamental mechanisms of
fibrinolysis (thrombolysis)", section on 'Plasminogen activator inhibitor-1' and "Thrombotic and
hemorrhagic disorders due to abnormal fibrinolysis", section on 'Plasminogen activator inhibitor-1'.)
IPC is an alternative for VTE prevention in patients with a high risk of bleeding or in whom
anticoagulation is contraindicated (eg, active or intracranial hemorrhage). Data supporting the use of
IPC for the prevention of VTE in surgical patients is limited. However, of the mechanical devices (IPC,
GCS, VFP), efficacy appears best with IPC use [68,117,199,200,203]. Meta-analyses of small
randomized trials agree that IPC use is superior to no prophylaxis and graduated compression
stockings, and may offer additive benefit to surgical patients on LMW heparin [68,203-205]. The
largest meta-analysis, which included data on 16,164 patients enrolled in 70 trials, reported that IPC
was more effective than no prophylaxis in reducing DVT (7.3 versus 16.7 percent; relative risk [RR]
0.43; 95% CI 0.36-0.52) and PE (1.2 versus 2.8 percent, RR 0.48; 95% CI 0.33-0.69) without any
effect on mortality [204]. On further analysis, although the addition of pharmacologic prophylaxis to
IPC further reduced the risk of DVT (RR 0.54; 95% CI 0.32-0.91), it had no effect on the incidence of
PE.

IPC devices may be removed while the patient is ambulating, but should be put back on when the
patient returns to a seated or supine position. Attention must be paid to optimal compliance, as well
as proper fit of the IPC device. However, reflective of practice, one observational study reported
frequent errors in IPC application. This suggests that frequent interference with the device is common
and may potentially interfere with efficacy [206].  

IPC is contraindicated in patients with evidence of leg ischemia due to peripheral vascular disease.
Although there are no data available on skin complications of IPC use, skin breakdown is a known
complication, especially in the frail, older adult population. In addition, practical considerations for
amputees or patients with burns or extensive skin lesions (eg, Stevens Johnson’s syndrome) may
limit its use. In this context, although one device can be applied to any extremity, its efficacy in the
prevention of VTE is not assured and likely limited. There is also a hypothetical concern that patients
who have been immobilized for a period of ≥72 hours without any form of prophylaxis may be at risk
of dislodging recently formed venous clot in the lower extremities. The value of clinical examination or
ultrasound in determining risk of clot dislodgement following the application of IPC in this setting is
unknown.  

Optimal timing of IPC in surgical patients is poorly studied. However, one study suggested that IPC
should be started as soon as possible, preferably in the operating room or recovery room and
continued with few interruptions until discharge [207]. In a study of 957 patients with no history of
prior VTE who had laparoscopic Roux-en-Y gastric bypass, calf-length pneumatic compression
devices were placed before anesthesia induction and mandatory ambulation was begun on the day of
operation without the use of pharmacologic anticoagulation [207]. The incidence of symptomatic
postoperative VTE and bleeding complications were low at 0.42 and 0.73 percent, respectively.

Graduated compression stockings — There is a paucity of high quality randomized trials that have
studied the efficacy of graduated compression stockings (GCS) in the surgical population [200,208-
212]. GCS alone are effective at preventing DVT but may be less effective than pharmacologic
agents. However, GCS when combined with other prophylactic methods appears to improve rates of
DVT prevention.  

As examples:
 ●One meta-analysis of 18 randomized trials in surgical patients reported that the use of GCS
alone was more effective than no prophylaxis in the prevention of DVT (26 versus 13 percent;
odds ratio 0.35 95% CI 0.26-0.47) [210].
●In another meta-analysis of eight studies, the incidence of proximal DVT and PE was lower in
patients treated with GCS compared with patients without GCS (1 versus 5 percent, 2 versus 5
percent, respectively) [212]. However, addition of a second method of prophylaxis in some of the
included trials may have biased the favorable outcome associated with GCS in this analysis.
●In one randomized trial of 1761 patients undergoing knee arthroplasty, a lower rate of DVT and
mortality was reported in those who were treated for seven days with LMW heparin compared
with GCS alone (0.9 versus 3.2 percent) [208]. However, many of the events prevented by LMW
heparin were episodes of asymptomatic distal DVT.  
●Another meta-analysis of 25 randomized trials reported that, compared to either modality alone,
combining GCS with pharmacologic agents halved the rate of postoperative DVT (risk ratio 0.51;
95% CI 0.36-0.73) while the risk of bleeding almost doubled (RR 1·74, 95% CI 1.29-2.34) [211].
Similarly, in another meta-analysis, rates of DVT prevention were greatest in those treated with
compression stockings plus any other prophylactic method compared with compression
stockings alone (4 versus 13 percent) [210].

Inferior vena cava filters — In general, inferior vena cava filters should be avoided as primary
prophylaxis against postoperative DVT [213]. The indications for filter placement as a therapy for DVT
are discussed separately. (See "Placement of vena cava filters and their
complications" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)",
section on 'Inferior vena cava filter'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The
Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10 th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some medical
jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the
Basics)" and "Patient education: Warfarin (Coumadin) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Medical center policies — Every hospital should develop a formal active strategy for the prevention
of VTE in medical and surgical patients. This should be in the form of a written institution-wide
thromboprophylaxis policy endorsed by department heads and medical advisory boards. Strategies
should be developed to increase compliance with thromboprophylaxis recommendations, including
the use of computerized order sets and prompts, pre-printed orders, and periodic audit, including
follow-up with feedback [161]. (See 'Problem overview' above.)

The article "Prevention of Venous Thromboembolism: American College of Chest Physicians

Evidence-based Clinical Practice Guidelines (8th Edition)" is an extensively referenced guideline for
the prevention of VTE, which may be useful in formulating these policies [161]. Their grading system
is identical to that used in UpToDate, and includes both the strength of the recommendation as well
as the quality of the available evidence. The concept of values and preferences has also been
incorporated into a number of these recommendations. (See 'Values and preferences' above.)

Group versus individual recommendations — Numerous attempts have been made to develop

risk assessment models for VTE in individual patients [43,44,47,49,52-55]. At this time, none of the
risk stratification models has been validated in prospective trials, although this subject is under active
study [60,161].

Since clinical trials for the prevention of VTE have been successfully carried out only in specific
surgical groups, the following recommendations are therefore group specific, with important caveats
[38]:

●In patients with additional risk factors (eg, previous VTE, advanced age particularly >75, active
cancer or a history of cancer, a more extensive than usual surgical procedure) consideration
should be given to more aggressive prophylaxis in the form of increased intensity or duration of a
pharmacologic agent, or the addition of a mechanical device such as IPC [161].
●In patients from specific ethnic groups in which the incidence of post-surgical venous
thromboembolism is low (eg, Asian populations), consideration may be given to less aggressive
prophylaxis [214].

Assignment of surgical risk groups — The risk of postoperative VTE depends upon the surgical
procedure (eg, degree of invasiveness, type and duration of anaesthesia, requirement for
immobilization), as well as patient-related variables (eg, increasing age, prior VTE, presence of
malignancy or obesity, presence of an inherited or acquired hypercoagulable state). Patients have
been generally divided into very low, low, moderate, and high risk categories. (See 'Surgical risk
groups' above.)

Group specific recommendations — Group specific recommendations are based upon the surgical
risk group classification noted above, based in part on the use of the modified Caprini risk
assessment model (table 2).

Contraindication to anticoagulation — For surgical patients with risk factors for VTE for whom
there is a contraindication to anticoagulant thromboprophylaxis, we recommend the optimal use of
mechanical methods of thromboprophylaxis (Grade 1B). (See 'Mechanical methods of
thromboprophylaxis' above.)
Consideration should be given to the use of a pharmacologic agent (eg, LMW heparin) as soon as the
bleeding risk becomes acceptably low or when the bleeding lesion or bleeding risk has been
reversed.

Very low risk general and abdominal-pelvic surgery patients — For very low risk general and
abdominal-pelvic surgery (Caprini score zero) we recommend against the use of specific
thromboprophylaxis other than early and frequent ambulation (Grade 1B). (See 'Very low risk
patients' above.)

Low risk general and abdominal-pelvic surgery patients — For low risk general and abdominal-
pelvic surgery (Caprini score 1 to 2) we suggest the use of mechanical prophylaxis, preferably with
intermittent pneumatic compression, over no prophylaxis or prophylactic anticoagulation (Grade 2C).
(See 'Low risk patients' above.)

Moderate risk general and abdominal-pelvic surgery patients — For moderate risk general and
abdominal-pelvic surgery (Caprini score 3 to 4) we recommend the use of prophylactic
anticoagulation over no prophylaxis (Grade 1B). (See 'Moderate risk patients' above.)

Reasonable choices include LMW heparin, low dose unfractionated heparin, or fondaparinux at doses
recommended by the manufacturer.

High risk general and abdominal-pelvic surgery patients — For high risk general and abdominal-
pelvic surgery (Caprini score 5 or more) we recommend the use of prophylactic anticoagulation over
other methods (Grade 1B). (See 'High risk patients' above.)

Reasonable choices include LMW heparin, low dose unfractionated heparin three times daily,
or fondaparinux. Additional guidance in patients undergoing gynecologic surgery can be found
elsewhere. (See "Overview of preoperative evaluation and preparation for gynecologic surgery",
section on 'Thromboprophylaxis'.)

Because surgical patients with multiple VTE risk factors are thought to be at the highest risk for VTE,
we suggest that a pharmacologic method be combined with optimal use of a mechanical method
(Grade 2C). (See 'Surgical risk groups' above.)

Special groups

●For obese patients, including those undergoing inpatient bariatric surgery, pharmacologic
prophylaxis with LMW heparin or low dose unfractionated heparin is preferred. (See "Bariatric
surgery: Postoperative and long-term management of the uncomplicated patient", section on
'Venous thromboembolism' and "Bariatric surgery: Intensive care unit management of the
complicated postoperative patient", section on 'Anticoagulant dosing'.)
●For patients admitted to a critical care unit, burn patients with additional risk factors, acute
spinal cord injury, or those with major trauma, we recommend routine assessment for VTE risk
and routine thromboprophylaxis in most (Grade 1A).
 ●For patients undergoing elective total hip or total knee replacement, we recommend the routine
use of pharmacologic prophylaxis (Grade 1A). Reasonable choices include: LMW heparin at a
usual high-risk dose, fondaparinux, a vitamin K antagonist (target INR 2.5, range: 2.0 to
3.0), dabigatran, or rivaroxaban. All have been approved for this indication. For patients without
risk factors for VTE who undergo less extensive lower limb orthopedic surgery (eg, surgery
requiring immobilization and below knee lower limb casting or arthroscopy), anticoagulant
prophylaxis in not typically warranted. (See 'Orthopedic surgery' above.)  
●For patients undergoing total knee replacement, the optimal use of intermittent pneumatic
compression (IPC) is an alternative option to anticoagulant prophylaxis for patients with a high
bleeding risk, or can be employed in combination with other thromboprophylactic options.
(See 'Intermittent pneumatic compression' above.)

Length of treatment

●For moderate risk patients undergoing major general and abdominal-pelvic surgical procedures,
we recommend that thromboprophylaxis continue until hospital discharge, rather than for a
shorter or longer period (Grade 1A).
●For selected high risk general and abdominal-pelvic surgery patients, including those who have
undergone major cancer surgery or have previously had VTE, we suggest that continuing
thromboprophylaxis after hospitalization with LMW heparin for up to 28 days be considered
(Grade 2A). (See 'Extended prophylaxis' above.)
●For patients undergoing total hip replacement or hip fracture surgery, we recommend that
thromboprophylaxis be extended beyond 10 days and up to 35 days after surgery (Grade 1A).
For patients undergoing total knee replacement, we suggest that thromboprophylaxis be
extended beyond 10 days and up to 35 days after surgery (Grade 2B). Options include LMW
heparin, fondaparinux, or a vitamin K antagonist. (See "Medical consultation for patients with hip
fracture", section on 'Thromboembolic