Memorandum by Professor Ajay Kakkar (VT
13)
1. WHAT IS
VENOUS THROMBOEMBOLISM
(VTE)
Venous thromboembolism is a spectrum of disease
ranging from (small) deep vein thrombosis (DVT), most frequently
occurring in the deep venous system of the lower limbs to pulmonary
embolism (PE), a potentially fatal disease resulting when thrombus
enters the pulmonary arterial circulation and occludes blood flow
to the lungs. Thrombosis in the venous circulation may be asymptomatic
(no clinical symptoms) whether a DVT or a PE, or symptomatic (clinically
apparent). Both asymptomatic and symptomatic VTE may be associated
with acute morbidity or may be fatal.
2. WHAT IS
THE RATIONALE
FOR PREVENTING
VENOUS THROMBOEMBOLIC
DISEASE (THROMBOPROPHYLAXIS)
FOR HOSPITALISED
SURGICAL AND
MEDICAL PATIENTS
2.1 The rationale for providing thromboprophylaxis
is based upon (1) the high prevalence of VTE amongst hospitalised
patients in certain defined risk groups; (2) the adverse consequences
of unprevented VTE; (3) the proven efficacy and cost effectiveness
of thromboprophylaxis.
2.2 Without thromboprophylaxis the reported
frequency of hospital acquired DVT is approximately 10-30% for
medical and general surgical patients and 40-60% for orthopaedic
surgical patients. About ¼ to 1/3 of these thrombi form in
the proximal deep veins. The proximal vein thrombi may be associated
with potentially fatal pulmonary embolism (PE).
2.3 VTE is the most common serious complication
experienced by certain groups of hospitalised patients, with a
reported frequency of PE at autopsy of about 30% for patients
dying within 30 days of operation, in whom about 1/3 it was the
cause of death. 10% of hospital deaths may be attributed to PE.
2.4 Since VTE is often silent when acquired
in hospital, reliance on clinical diagnosis is not appropriate,
since the first manifestation of this disease may be fatal PE.
2.5 If VTE is not prevented, the consequences
include the risk of fatal PE, the morbidity associated with acute
symptomatic VTE, bleeding associated with long-term anticoagulation,
need for monitoring of long-term anticoagulant therapy, increased
risk for future episodes of VTE, need for re-admission/increased
lengths of stay to treat the thrombosis as well as the considerable
healthcare and wider associated costs, and the pain and disability
associated with the post-thrombotic syndrome many years after
the acute thrombosis.
2.6 Thromboprophylaxis has been shown to
be effective in preventing both DVT and PE, for which such strategies
have also been shown to be cost effective in high-risk hospitalised
patients.
3. REPORTED FREQUENCY
OF VTE FOR
SPECIFIC HOSPITALISED
POPULATIONS
3.1 The rate of DVT in hospitalised patients,
not receiving thromboprophylaxis using objective diagnostic methods
for screening both asymptomatic (not clinically overt) and symptomatic
(clinical) disease are:
| general surgical | 15-30%
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| hip and knee | 40-60% |
| medical | 10-20% |
| stroke | 20-50% |
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3.2 Identification of high-risk patient groups (eg above)
is possible but predicting which individual patient will develop
a hospital acquired VTE is not. Fatal PE frequently occurs without
warning, and thus strategies based upon diagnosing VTE once it
occurs and treating it will not be successful. Frequently, (70-80%
of cases) when fatal PE occurs it was not considered as a potential
diagnosis prior to death.
3.3 Numerous clinical trials over the past 30 years have
confirmed that thromboprophylaxis reduces the frequency of both
asymptomatic and symptomatic VTE and fatal PE.
3.4 Pulmonary embolism is the most common preventable
cause of hospital death. In the report "Making healthcare
safer: a critical analysis of patient safety practices" by
the United States Agency for Healthcare research and quality,
a 79 patient safety intervention was reviewed. The highest ranked
safety practice was the "appropriate use of prophylaxis to
prevent VTE in patients at risk". This conclusion was based
upon evidence that thromboprophylaxis reduced adverse patient
outcome and at the same time decreased overall cost.
4. INTERPRETING THE
RESULTS OF
CLINICAL TRIALS
IN THE
FIELD OF
THROMBOPROPHYLAXIS
4.1 Numerous studies have evaluated the efficacy and
safety of various methods for thromboprophylaxis over the past
three decades. These studies have utilised different endpoints
including asymptomatic thrombosis, detected by objective screening
methods, symptomatic DVT and PE, fatal PE and all cause mortality.
4.2 Safety endpoints in such studies have included minor
and major bleeding events associated with pharmacological therapy.
4.3 For both efficacy and safety, well-designed trials
have used independent blinded adjudication of events to maintain
objectively.
4.4 Although the priority of thromboprophylaxis is to
prevent fatal PE, this event is uncommon. Beyond prevention of
fatal PE, avoidance of symptomatic DVT or PE are also very important
objectives, since these events occur more frequently than fatal
PE and are associated with a significant morbidity, increased
consumption of healthcare resources and long-term clinical consequences
as manifest by the post phlebitic syndrome and chronic pulmonary
hypertension.
4.5 There are differing views as to which endpoints are
appropriate for clinical trials assessing thromboprophylaxis.
Some argue that the demonstration that a specific method of prophylaxis
can prevent fatal PE is the only endpoint suitable to validate
its use in specific high-risk populations. Others argue that endpoints
that screen for all thrombosis, even if the disease is asymptomatic
are valid, since although most asymptomatic disease is not clinically
relevant, there is a strong correlation between the surrogate
marker of asymptomatic thrombosis, and symptomatic clinical disease.
4.6 Studies evaluating pharmacological methods of thromboprophylaxis
utilising low dose unfractionated heparin (LDUH) or low molecular
weight heparin (LMWH) have been shown to reduce the frequency
of asymptomatic DVT, symptomatic disease and fatal PE for general
surgical patients.
5. GENERAL SURGICAL
PATIENTS
5.1 The observed rate for DVT in general surgical patients
not receiving thromboprophylaxis is 15-30% with a fatal PE rate
of 0.2% to 0.9%. Many factors may influence the risk of thrombosis
in this patient group including age, previous history of DVT,
obesity, cancer, oestrogen use.
5.2 Some argue that these reported rates are historic
and the frequency of VTE may be falling. This is not possible
to test since it would be unethical to perform trials without
thromboprophylaxis in this population. However, demographic considerations
indicate that there are now more extensive operations being performed
on older patients, more cancer operations and more patients with
obesity than in the past. These would suggest an increasing risk
for thrombosis in contemporary general surgical populations.
5.3 For surgical patients, patients may be allocated
to one of four potential risk groups low, moderate, high and highest
based upon patient age, presence of absence of VTE risk factors,
and type of operation. Not all patients require active pharmacological
prophylaxis. For low risk patients eg under the age of 40 with
no other risk factors and a duration of operation less than 30
minutes, no specific thromboprophylaxis is required apart from
mobilisation. But for highest risk patients, where the VTE risk
is substantial (proximal DVT rate 10-25%; fatal PE rate 0.2-5%),
eg age over 40 years, with other VTE risk factors present, having
an operation for cancer or an orthopaedic procedure, pharmacological
prophylaxis would be indicated.
5.4 The landmark study that heralded the modern era of
thromboprophylaxis was the International Multicentre trial (Lancet
1975) published from the United Kingdom. This study in over 4,000
patients undergoing major surgery, with an endpoint of autopsy
proven fatal PE, demonstrated that the use of perioperative low
dose heparin reduced the frequency of fatal PE from eight per
1,000 to one per 1,000 operated patients—saving seven lives
per 1,000 operated patients.
5.5 In a meta-analysis of 46 studies evaluating low dose
heparin against placebo/control in general surgical patients,
the rate of DVT was reduced from 22% to 9% (OR 0.3, number of
patients needed to treat to avoid one DVT was seven); fatal PE
was reduced from 0.8% to 0.3% (OR 0.4, number of patients needed
to treat to avoid one fatality 182). This was associated with
a small increase in bleeding 3.8% to 5.9% (number needed to harm
47).
5.6 An alternative option for pharmacological thromboprophylaxis
in general surgical patients is low molecular weight heparin (LMWH)
administered once daily subcutaneously. A meta-analysis of randomised
trials in general surgical patients comparing LDUH with LMWH involving
44,000 patients demonstrated LMWH administered once daily to be
as effective as LDUH, which is usually administered twice or three
times daily.
5.7 Mechanical methods of thromboprophylaxis (pneumatic
calf compression, compression stockings) have been evaluated in
general surgical patients. A systematic review of trials using
such methods indicated that mechanical methods did reduce the
frequency of DVT, but these methods have not been as extensively
investigated as pharmacological methods of thromboprophylaxis,
and have not been shown to reduce the frequency of fatal pulmonary
embolism (PE). They may be considered in general surgical patients
at high-risk for bleeding.
5.8 Thromboprophylaxis for moderate to high-risk general
surgical patients is usually recommended for the duration of hospital
stay. The question of extended thromboprophylaxis beyond hospital
discharge has recently been considered, since although the risk
of developing VTE is greatest in the first week or so after surgery,
certain patients including those having undergone operation for
cancer have a persistent VTE risk beyond hospital discharge. There
is no consensus as to whether thromboprophylaxis should be extended
out of hospital for this population.
5.9 Routine thromboprophylaxis appears to be well accepted
among general surgical practitioners in the UK.
6. ORTHOPAEDIC PATIENTS
6.1 Elective joint arthroplasty is a common procedure.
Without thromboprophylaxis the frequency of asymptomatic (non-clinical)
DVT is 40-60%, symptomatic clinical VTE is 2.5% and fatal PE is
about 0.5% in elective hip joint replacements.
6.2 The great fear of orthopaedic surgeons with regard
to the use of pharmacological thromboprophylaxis is the risk of
bleeding complications, which may result in an increased risk
for bleeding around the replaced joint cavity with risk of prosthesis
infection or loosening.
6.3 Mechanical methods of thromboprophylaxis have been
evaluated in orthopaedic patients but have not been as extensively
tested as pharmacological methods. Although they do not increase
bleeding risk, they are not as effective as pharmacological methods
in the prevention of potentially serious proximal vein thrombi,
nor have they been shown to reduce the frequency of fatal PE.
6.4 Pharmacological methods have been extensively studied
in this population. The available recommended options include
LMWH and the oral anticoagulant Vitamin K antagonists. Low dose
heparin is not as effective an agent for thromboprophylaxis in
orthopaedic patients as other methods available, and is not recommended.
Vitamin K antagonists are used in North America, but not Europe.
Rates of DVT are reduced to around 15-20% with LMWH prophylaxis,
with reported rates of bleeding around 5%, compared to bleeding
rates in historic placebo controlled studies of about 4% (ie 1%
increase).
6.5 The recommended thromboprophylaxis for orthopaedic
hip surgical patients in Europe is LMWH. The duration is for at
least the duration of hospital stay. Recent studies indicate that
for hip replacement patients, the duration of risk for VTE extends
into the post discharge period for up to 5 weeks after operation,
where continuing LMWH prophylaxis into the post discharge is associated
with a significant reduction in both asymptomatic and symptomatic
VTE.
6.6 Use of thromboprophylaxis among orthopaedic practitioners
is less well established. This may be driven by concern about
the adverse consequences of bleeding.
7. MEDICAL PATIENTS
7.1 Acutely ill hospitalised medical patients are at
risk for the development of VTE. 50-70% of symptomatic VTE and
70-80% of fatal PEs occur in hospitalised medical patients. The
reported rate of all thrombosis (asymptomatic disease), screened
using venography in hospitalised medical patients, is 15% indicating
these patients have a low to moderate risk for hospital acquired
VTE.
7.2 Patients at particular risk for the development of
VTE in an acute medical illness include those with severe heart
failure, chronic respiratory disease, sepsis and cancer.
7.3 Both LDUH and LMWH have been shown to provide effective
and safe thromboprophylaxis in hospitalised acutely ill medical
patients who are at risk for VTE. These interventions have also
been shown to be cost effective if applied to appropriate populations
with acute illness.
8. RECOMMENDATIONS
8.1 Appropriate use of pharmacological prophylaxis has
the ability to prevent potentially serious VTE. Not all hospitalised
medical or surgical patients require prophylaxis. Specific patient
groups at particular risk for the development of hospital acquired
VTE are recognised. In these specific groups application of validated
methods of thromboprophylaxis are both efficacious, safe, and
cost effective.
8.2 Hospitals should be encouraged to have written policies
for VTE prevention which may be applied to appropriate patient
populations in whom a definite risk for VTE is identified. These
policies may be based on internationally accepted consensus guidelines
which are available.
REFERENCE
Prevention of Venous Thromboembolism
The Seventh ACCP Conference on Antithrombotic and Thrombolytic
Therapy
Geerts W H, Pineo G F, Heit J A, Bergqvist D, Lassen M R,
Colwell C W, Ray J G
Chest 2004;126:338S-4002S
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