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Venous thrombosis and pulmonary embolism constitute major
health problems that result in significant morbidity and mortality in
the United States. It is estimated that venous thrombosis and pulmonary
embolism are associated with 300,000 to 600,000 hospitalizations a year
and that as many as 50,000 individuals die each year as a result of
pulmonary embolism.
Both venous thrombosis and pulmonary embolism are often silent and
difficult to detect by clinical examination. The use of a number of
diagnostic tests such as fibrinogen uptake, Doppler ultrasound,
impedance plethysmography, venography, ventilation-perfusion scans, and
pulmonary angiography has resulted in the identification of several
groups of patients at high risk of developing venous thromboembolic
disease. Patients undergoing various types of surgery--general,
orthopedic, gynecological-obstetrical, urological, and neurosurgical--are
at high risk for developing deep venous thrombosis (DVT) and pulmonary
embolism (PE). Of these groups, orthopedic patients appear to be
especially prone to thrombosis, particularly patients with hip fracture.
Patients with various types of medical diseases, usually chronic, are
also at high risk for venous thrombotic events.
Because some groups of patients at high risk for the development of
venous thromboembolism can be identified, it is reasonable and desirable
to consider ways of prevention; prevention is far superior to treatment.
To help resolve questions that relate to various prophylactic
measures in high-risk groups of patients, the National Heart, Lung, and
Blood Institute and the NIH Office of Medical Applications of Research
convened a Consensus Development Conference on Prevention of Venous
Thrombosis and Pulmonary Embolism on March 24-26, 1986. After hearing a
series of expert presentations and discussion from the audience and
reviewing the medical literature, a consensus development panel
representing the professional fields of vascular, orthopedic, urologic,
and trauma surgery, hematology, pulmonary medicine, obstetrics and
gynecology, family practice, epidemiology, biostatistics, and the
general public considered the evidence and agreed on answers to the
following questions:
- What is the level of risk of venous thrombosis and embolism in
various patient groups?
- What is the efficacy and safety of various forms of prophylaxis in
these patient groups?
- What are the recommended forms of prophylaxis in these patient
groups?
- What questions remain to be answered about prophylaxis of venous
thromboembolism?
Inherent in the first three questions is an epidemiologic and
statistical assessment of whether the existing data are sufficient to
warrant recommendations on the prophylaxis of venous thromboembolism.
The most rigorous and definitive test of any method of prophylaxis is
the randomized clinical trial. However, the incidence of clinically
significant PE is low and would thus require trials on the order of
5,000 patients to examine the effect of prophylaxis on all PE or 100,000
patients to examine the effect on all-cause mortality. In contrast, the
incidence of DVT is substantially higher, ranging from 20 to 70 percent.
Thus, prophylactic treatment of DVT can be evaluated with trials of
smaller sample size, but it is first necessary to demonstrate the
clinical relevance of the presence of DVT to the development of
pulmonary embolism.
The use of DVT screening tests as a marker for pulmonary embolism is
justified both by the known pathophysiology of pulmonary embolism and
the association of a reduction in DVT with a reduction in PE. In
particular, the combined data on over 12,000 individuals in randomized
clinical trials of low-dose heparin showed a 68 percent reduction in DVT
as measured by the 125I-fibrinogen uptake test and/or
venography; this was associated with a 49 percent reduction in PE.
Moreover, there was a decrease in overall mortality that was due to the
decrease in fatal pulmonary embolism. The evidence for a benefit of
prophylaxis in preventing pulmonary embolism is compelling using DVT as
a marker. The findings within most specific patient subgroups rely on
this assumption: that DVT is an appropriate marker for PE.
When using DVT as a marker for PE, many clinical trials have had an
inadequate number of patients to detect important therapeutic
differences. Trends that may appear to be a chance finding in any one
trial assume importance when consistently seen in multiple trials. In
evaluating the evidence, the panel has assessed each trial as it stands
alone and has searched for consistency among trials with similar therapy
and patient groups.
The panel has also evaluated the evidence from all clinical trials
presented at the conference and addressed each question as it relates to
specific patient groups at high risk for the development of venous
thromboembolic events.
What Is the Level of Risk
of Venous Thrombosis and Embolism in Various Patient Groups?
Venous thrombosis and PE constitute major causes of morbidity
associated with many common medical conditions and surgical procedures.
Reliable natural history data are available from the control arms of
well over 100 clinical trials published during the past two decades,
generally from patients over the age of 40. European trials document a
higher rate of DVT than has been reported in North America, Asia, or
Africa, but a significant incidence of these complications has been
found in all studies directed at this problem, regardless of the
location of the investigation.
General Surgery
The largest pool of data has been obtained in studies of patients
over the age of 40 undergoing general surgical procedures, where the
average incidence of deep venous thrombosis in control patients is 25
percent by fibrinogen scanning and 19 percent by venography. The pooled
data incidence of DVT in Europe is 30 percent, and in North America it
is 16 percent. DVT extends proximal to the knee joint in 7 percent, and
clinically significant pulmonary embolism occurs in 1.6 percent of the
general surgical population. Finally, the likelihood of a major
pulmonary embolus leading to death approaches 1 percent. Advancing age
and malignancy are associated with even higher rates of both DVT and PE.
Orthopedic Surgery
All elective orthopedic surgical patients undergoing lower extremity
surgery are at risk for deep venous thrombosis. The risk to patients is
greatest for hip surgery and knee reconstruction, where DVT rates range
from 45 to 70 percent.
Clinically significant PE has been reported to be as high as 20
percent in hip surgery patients, with a 1 to 3 percent incidence of
fatal PE. The rates of both clinical PE and fatal PE following knee
reconstruction are lower than following hip surgery but remain a
problem.
Urology
The incidence of DVT in urologic surgery is similar to that in
general surgery, that is, about 25 percent, and ranges from 40 percent
in transvesical prostatectomy to 10 percent in transurethral surgery.
Because increasing age has a high correlation with increased risk of DVT,
urologic patients often have a higher risk than other surgical patients.
Gynecology and Obstetrics
The reported overall risk of DVT in gynecologic surgery ranges from 7
to 45 percent. Fatal PE is estimated to occur in nearly 1 percent of
these patients. Low-risk patients include those up to 40 years of age
undergoing surgical procedures of less than 30 minutes, and in this
group, the incidence of DVT is under 3 percent. Moderate-risk patients,
40 to 70 years of age, undergoing minor or major surgery with no other
risk factors, have a 10 to 40 percent risk of DVT. High-risk patients,
age 40 or over with added risk factors (prior DVT/PE, varicose veins,
infection, malignancy, estrogen therapy, obesity, and prolonged
surgery), have a 40 to 70 percent risk of DVT and a 1 to 5 percent risk
of fatal PE.
The risk of DVT in pregnancy has been reported to be five times
higher than in nonpregnant patients in the same age group and may be
increased post partum. Antenatal risks are increased in patients with
prior DVT or PE, varicose veins, and obesity. It is not known whether
these risks are additive. Postpartum risks are increased by Cesarean
delivery, which carries risks similar to those of gynecologic surgery.
Neurosurgery and Neurology
The risk of DVT and fatal PE in neurosurgical patients is similar to
that of other surgical high-risk groups. The incidence of DVT ranges
from 9 to 50 percent. Fatal PE occurs in from 1.5 to 3 percent. In
stroke, the risk of DVT in the paralyzed leg is as high as 75 percent,
whereas in the nonparalyzed leg it is approximately 7 percent.
Trauma
The risks of thromboembolic diseases and subsequent PE have not been
specifically defined for the general trauma population. This is due in
part to the complex nature and wide variety of systems injured. In
addition, the most prevalent diagnostic test used for DVT, the 125I-fibrinogen
uptake, cannot be used effectively in this population because tissue
trauma itself can produce a positive scan. Although data are lacking, it
is estimated that the incidence of DVT in the young multisystem trauma
patient is about 20 percent. The incidence of fatal PE is not known. Two
subgroups of trauma patients have a much higher risk of thrombosis. The
elderly patient with a hip fracture has a reported incidence of DVT
exceeding 40 percent and an incidence of fatal PE exceeding 4 percent.
The patient with an acute head or spinal cord injury has a reported 40
percent incidence of DVT and a greater than 1 percent incidence of fatal
PE.
Medical Conditions
Two groups of medical conditions exist in which the incidence of
thromboembolism is greatly increased (Table 1). One group consists of
inherited deficiencies of inhibitors and regulators of coagulation or
fibrinolysis. These inherited conditions are associated with a positive
family history for thromboembolism, onset at an early age, and repeated
episodes of thromboembolism, often in the absence of other known
predisposing factors. Although the exact cumulative risk of
thromboembolism is not known in most of these uncommon genetic
disorders, it approaches 80 percent in antithrombin III deficiency.
A much larger group encompasses patients with acquired conditions
predisposing to thromboembolism. The risk of thromboembolism in this
group of patients ranges up to 80 percent in paroxysmal nocturnal
hemoglobinuria, up to 70 percent in congestive heart failure, and up to
40 percent in acute myocardial infarction.
In patients from either category, the risk for thromboembolism is
heightened by the presence of additional risk factors--but by an unknown
amount.
Table 1. Risk Factors
Predisposing to Thromboembolism
- Inherited Risk Factors
- Antithrombin III deficiency
- Protein C deficiency
- Protein S deficiency
- Dysfibrinogenemia
- Disorders of plasminogen and plasminogen activation
- Acquired Risk Factors
- Lupus anticoagulant
- Nephrotic syndrome
- Paroxysmal nocturnal hemoglobinuria
- Cancer
- Stasis--congestive heart failure, myocardial
infarction, cardiomyopathy, constrictive pericarditis,
anasarca
- Advancing age
- Estrogen therapy
- Sepsis
- Immobilization
- Stroke
- Polycythemia rubra vera
- Inflammatory bowel disease
- Obesity
- Prior thromboembolism
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General Surgery
Within the broad scope of general surgery, low-dose heparin
administered subcutaneously every 8 or every 12 hours beginning 2 hours
prior to surgery reduces the rate of DVT by 60 percent, for a net
decrease in incidence from 25 percent to 10 percent. In pooled studies,
the likelihood of a calf thrombus extending proximally is reduced by
approximately one-half, as is the risk of clinically significant PE.
Finally, fatal PE decreases from 0.7 to 0.2 percent. Heparin-associated
thrombocytopenia has been reported rarely in patients receiving low-dose
heparin.
Although fewer data are available, dextran-70 exerts a comparable
protective effect in decreasing PE, but a lesser decrease in DVT.
Dextran-40 appears to have a similar effect. The use of a combination of
dihydroergotamine and heparin, as well as the use of external pneumatic
compression, produce comparable benefits with respect to DVT, but fewer
patients have been studied with these modalities. The use of graduated
compression elastic stockings has also been reported to be of benefit,
but even fewer patients have been studied and stockings must be
carefully fitted if they are to have prophylactic merit. The likelihood
of benefit with any of these methods suggests that the prophylactic
treatment of 200 patients will prevent 1 death from PE, 1.2 episodes of
clinically significant PE, and 20 episodes of DVT. No benefits were
associated with aspirin prophylaxis. Both heparin and dextran increase
the risk of bleeding and hematoma formation, but the risk of serious
complications or death is minimal. The side effects of external
pneumatic compression and elastic stockings are limited to patient
discomfort and subsequent failure of compliance.
Orthopedic Surgery
Despite the effectiveness of low-dose heparin in other situations, it
may be less beneficial in orthopedic patients. Dextran and warfarin have
been shown to reduce the incidence of DVT by a factor of two in
controlled trials in patients undergoing elective hip surgery and knee
reconstruction. Rates of clinical PE are also reduced, but the lowered
death rate from PE, while suggestive, is not statistically significant.
Elevation of the foot of the bed, gradient elastic stockings, and
external pneumatic compression also reduce the incidence of DVT
significantly. The use of these mechanical measures is without known
complications.
Warfarin and dextran in commonly used doses can cause complications
of operative bleeding and wound hematomas. Congestive heart failure,
renal failure, and anaphylaxis are uncommon complications of dextran.
Fatal hemorrhage has been reported with warfarin. The incidence of these
bleeding complications is not well documented in orthopedic surgery.
Wound hematomas can be a significant problem in joint replacement
patients. Small-scale studies suggest that low-dose warfarin may be
safe, but the data are limited.
Urology
The efficacy of prophylaxis for DVT in urologic patients has been
studied most extensively with low-dose heparin. In several studies, the
reduction in incidence following prophylaxis is 75 percent--similar to
data from general surgery. Small-scale studies using external pneumatic
compression suggest a decrease in DVT similar to that in patients
receiving low-dose heparin.
Low-dose heparin appears safe as measured by transfusion requirements
and the postoperative decrease in hemoglobin concentration. External
pneumatic compression also appears to carry no significant risk.
Gynecology and Obstetrics
The evidence suggests that for low-risk patients with little chance
of DVT, early ambulation and graduated compression stockings are
sufficient prophylaxis. Patients at moderate to high risk, with benign
disease, can be managed effectively with low-dose heparin, dextran,
and/or external pneumatic compression with comparable results. Some
evidence suggests that low-dose heparin is ineffective for prophylaxis
in patients with gynecologic malignancy. In this category, dextran,
warfarin, and/or external pneumatic compression can be effective.
Although data are lacking, the panel believes that warfarin also may
provide effective and safe prophylaxis for patients with benign or
malignant disease.
Data from controlled trials are lacking for pregnant and postpartum
patients. However, the panel believes that low-dose heparin may be
effective and safe for prophylaxis when used antenatally in pregnant
patients at risk. There are no data regarding the optimal timing of
therapy. Warfarin prophylaxis is contraindicated in pregnancy, and there
are no data on the use of dextran in pregnancy. The panel believes that
low-dose heparin and/or external pneumatic compression may be effective
and safe in prophylaxis in postpartum patients at risk.
Neurosurgery and Neurology
There is a relative paucity of studies on specific therapies for
special subgroups of neurosurgical patients as compared with general and
orthopedic surgery patients. The efficacy of external calf compression,
low-dose heparin (with or without dihydroergotamine), and warfarin has
been demonstrated for patients with extracranial problems.
Patients with intracranial lesions and spinal lesions for which even
minor bleeding complications could have disastrous effects are generally
not considered candidates for prophylaxis with anticoagulants, although
limited data support the use of low-dose heparin as safe for selected
craniotomy patients. External pneumatic compression is recommended for
patients with this group of problems and has been shown to be both
efficacious and safe.
Trauma
Because hemorrhage is a major complication of traumatic injury,
trauma-induced bleeding must be controlled prior to the use of any agent
that might accentuate the bleeding process. The efficacy and safety of
the various forms of prophylaxis have not been evaluated in the
multisystem trauma patient population, but a number of specific patient
subgroups have been studied. In young patients with musculoskeletal
trauma, low-dose heparin (with or without dihydroergotamine) and
dextrans have been studied. When begun within the first 2 days, these
agents decrease the rate of DVT. Increased bleeding is seen with these
methods, but the incidence is no greater than that encountered with
their use in elective orthopedic surgery patients. A number of
prophylactic measures have been studied in high-risk hip fracture
patients. Aspirin and low-dose heparin have not been shown to be
effective. Dextran has been shown to decrease the incidence of DVT.
Although bleeding complications are increased, the use of dextran-40 in
doses not exceeding 10 ml/kg in the first 24 hours and 5-7 ml/kg every
24 hours after this point decreases this problem. Warfarin in elderly
patients with hip fractures decreases the incidence of both DVT and
pulmonary emboli. Bleeding complications are increased, but the problem
can be minimized if the increase in prothrombin time does not exceed 1.4
times control. External pneumatic compression has also been shown to
decrease the incidence of DVT. There are some data to indicate that
pressure gradient stockings are also effective.
Anticoagulants have not been used in the acute head injury patient
because of the risk of bleeding. External pneumatic compression has been
shown to decrease the incidence of DVT in this group. Both low-dose
heparin and external pneumatic compression are effective in reducing DVT
in trauma-induced paraplegia.
Medical Conditions
Several approaches are available to decrease the risk of
thromboembolism in patient groups listed in Table 1. These treatments
include low-dose heparin, warfarin, and early ambulation and other
physical methods. One study reported that administration of low-dose
heparin decreased all-cause mortality from 10 percent to 5 percent for
patients with a wide variety of medical conditions. Low-dose heparin
reportedly decreases the incidence of DVT in persons hospitalized for
acute myocardial infarction, heart failure, and/or pulmonary infection.
Data are lacking for other prophylactic methods. Because of the
synergistic nature of an underlying thrombotic tendency and the added
risk of an acute condition or a surgical procedure in some medical
patients, low doses of heparin may be inadequate for prophylaxis. The
risk of hemorrhage from prophylactic methods is no higher in medical
than in general surgical patients receiving these treatments and, in
fact, is lower in the absence of a surgical wound.
What Are the Recommended
Forms of Prophylaxis in These Patient Groups?
General Surgery
Available data justify routine prophylaxis of all surgical patients
in high-risk situations. In high-risk patients--those over the age of
40, or obese, or with malignancy, or prior DVT or PE, or undergoing
large or complicated surgical procedures--prophylactic treatment with
low-dose heparin using 5,000 U subcutaneously every 8 or 12 hours is
recommended, at least until the patient is ambulatory. Dextran in
initial doses of 10 ml per kg appears equally effective in decreasing PE
but is more expensive. Most studies have employed dextran-70 but the
fewer studies with dextran-40 suggest it is equally effective.
Both external pneumatic compression and gradient elastic stockings
are also effective modalities in preventing DVT. The addition of
dihydroergotamine to the same dose of heparin may be more efficacious,
but the contraindications and potential risks associated with its
vasoconstrictive effects must be borne in mind by physicians selecting
this modality. The need for prophylaxis in patients under 40 with no
known risk factors undergoing uncomplicated operative procedures lasting
less than 1 hour is unknown.
Orthopedic Surgery
For high-risk orthopedic patients undergoing elective hip surgery or
knee reconstruction, one of the following prophylactic regimens is
recommended for at least 7 days or longer if the patient remains
bedridden: low-dose warfarin, dextran, or adjusted-dose heparin. For
other patients, mechanical measures, including gradient elastic
stockings or external pneumatic compression, may be used if feasible.
Early mobilization and elevation of the foot of the bed or of injured
limbs are also recommended.
Urology
Because the low-dose heparin prophylaxis data document both efficacy
and safety, this therapy should be used in urologic patients over the
age of 40. The use of mechanical modalities such as external pneumatic
compression offers a possible attractive alternative, although more
trials are necessary in urologic patients.
Gynecology and Obstetrics
Evidence indicates that low-risk gynecologic patients are
satisfactorily managed with early ambulation and graduated compression
stockings. Patients at moderate and high risk (exclusive of those with
gynecologic malignancy) should be managed with low-dose heparin and/or
external pneumatic compression. Dextran is an alternate choice. Patients
with gynecologic malignancy should be managed with dextran and/or
external pneumatic compression until fully ambulatory. Some evidence
suggests that patients with gynecologic malignancy can be managed with
low-dose heparin combined with external pneumatic compression. The panel
believes that warfarin may be a useful alternative in patients with
benign or malignant disease.
A reduction of risk factors, such as the discontinuance of
contraceptive pills or estrogen therapy prior to surgery, is recommended
in all elective surgical patients.
Although data regarding prophylaxis of DVT in pregnancy and the
postpartum period are limited, the panel believes that patients with a
prior history of DVT/PE may be treated antenatally with low-dose
heparin. The time of onset of therapy is arbitrary, as no clear
recommendation is supported by the literature. Pregnant patients with
other risk factors should have their prophylactic management
individualized. The panel believes that postpartum patients at risk
should be managed with low-dose heparin and/or external pneumatic
compression according to the level of risk until fully ambulatory.
Neurosurgery and Neurology
Prophylactic regimens must be considered by specific subgroup of
neurosurgical conditions. For patients undergoing craniotomy for tumor,
subarachnoid hemorrhage, AV malformation, aneurysm, arterial bypass,
shunting procedures, and other intracranial problems, external pneumatic
compression is recommended. This modality is effective in reducing the
risk of DVT and avoids those potential hemorrhagic complications of
antithrombotic therapies that, even if minor, may be disastrous in
neurosurgical cases.
For extracranial neurosurgical problems such as elective spinal cord
surgery and laminectomy, external pneumatic compression and low-dose
heparin are equally effective and are recommended, either alone or in
combination.
Stroke patients in whom hemorrhagic stroke has been excluded by CT
scan should receive low-dose heparin. For all other stroke patients,
external pneumatic compression is recommended. Neurosurgical and stroke
patients who remain bedridden for more than 5 days should receive
prophylaxis until ambulatory. No studies provide information regarding
the use of gradient compression stockings, physical therapy, or early
ambulation as modes of prophylaxis either singly or in conjunction with
other recommended modalities.
Trauma
The specific risks of bleeding dictate the manner and type of
prophylaxis to be used in the trauma patient. The elderly patient with a
hip fracture is at high risk for thromboembolic complications and
clearly requires some form of prophylaxis for at least 7 days or until
ambulatory. One can choose from three effective measures: dextran,
external pneumatic compression, or pressure gradient elastic stockings
may be useful. The efficacy of low-dose warfarin in hip fracture
patients is not known. Aspirin and low-dose heparin are of no benefit.
Head injury and acute spinal cord injury patients also require
prophylaxis. To minimize the high risk of bleeding, external pneumatic
compression and pressure gradient elastic stockings are the methods of
choice.
For severe musculoskeletal trauma, prophylaxis is indicated until the
patient is ambulatory. Low-dose heparin or dextran is effective in young
patients if initiated early. External pneumatic compression and gradient
compression stockings are effective alternatives for decreasing lower
leg thrombosis if lower extremity trauma does not preclude their use. In
multisystem trauma, anticoagulants should be used with caution until the
types of injuries present have been assessed and initial bleeding
controlled.
Medical Conditions
Limited clinical trials support the use of low-dose heparin for
patients with heart failure, acute myocardial infarction, or pulmonary
infection to prevent DVT. Although studies do not exist to support
extension of these observations to other medical patients at bed rest
and at risk for thromboembolism, administration of low-dose heparin may
be indicated, especially as long as other conditions predisposing to DVT
coexist. Where long-term prophylaxis is indicated in chronic high-risk
patients, warfarin therapy is appropriate.
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