Low-Molecular-Weight Heparin in Preventing and Treating DVT
ERIC J. RYDBERG, M.D., JOHN M. WESTFALL, M.D.,
M.P.H., and RICHARD A. NICHOLAS, M.D., University of Colorado Health Sciences
Center, Denver, Colorado
Low-molecular-weight heparin is a relatively recent addition to the list
of therapies for prophylaxis and treatment of deep venous thrombosis (DVT). As
a prophylactic, low-molecular-weight heparin is as effective as standard
heparin or warfarin and does not require monitoring of the activated partial
thromboplastin time or the International Normalized Ratio. Traditionally,
treatment for DVT required patients to be hospitalized for administration of
intravenous heparin. With subcutaneous injections of low-molecular-weight
heparin, treatment of DVT can be initiated or completed in the outpatient
setting with no increased risk of recurrent thromboembolism or bleeding
complications. Low-molecular-weight heparin is an attractive option for use in
patients with a first episode of DVT, no risk factors for bleeding and the
ability to administer injections with or without the help of a visiting nurse
or family member
Deep venous thrombosis (DVT) is a relatively common
disease that is often encountered by family physicians. Epidemiologic data
suggest that the annual incidence of a first episode of DVT ranges from 60 to
180 cases per 100,000 people, or more than 300,000 new cases annually in the
United States.1 The
cost burden of this disease is quite high, since most patients with DVT require
one or more diagnostic tests, treatment with intravenous heparin and a three-
to seven-day hospital stay.2 Low-molecular-weight
heparin, which is administered by subcutaneous injection, offers the option of
treatment on an outpatient basis for patients with DVT. Low-molecular-weight
heparin can also be used effectively in patients requiring prophylaxis for DVT
after general or orthopedic surgery.
Advantages of Low-Molecular-Weight
Heparin
The clinical advantages of low-molecular-weight
heparin include predictability, dose-dependent plasma levels, a long half-life
and less bleeding for a given antithrombotic effect.3 Furthermore,
immune-mediated thrombocytopenia is not associated with short-term use of
low-molecular-weight heparin,3 and
the risk of heparin-induced osteoporosis may be lower than the risk with the
use of standard heparin. Low-molecular-weight heparin is administered according
to body weight once or twice daily, both during the high-risk period when
prophylaxis for DVT is recommended and also when waiting for oral
anticoagulation to take effect in the treatment of DVT. The activated partial
thromboplastin time (aPTT) does not need to be monitored, and the dosage does
not need to be adjusted. Since low-molecular-weight heparin is given
subcutaneously, outpatient administration by the patient, with or without the
assistance of a visiting nurse or family member, is both possible and
cost-effective.
Properties of Low-Molecular-Weight
Heparin
Low-molecular-weight heparin is a relatively new
class of anticoagulant that has been used in Europe and is now being used more
often in the United States following reports of randomized, controlled trials
demonstrating its efficacy and safety.
Low-molecular-weight heparin is derived from
standard heparin through either chemical or enzymatic depolymerization. Whereas
standard heparin has a molecular weight of 5,000 to 30,000 daltons,
low-molecular-weight heparin ranges from 1,000 to 10,000 daltons, resulting in
properties that are distinct from those of traditional heparin.
Low-molecular-weight heparin binds less strongly to protein, has enhanced
bioavailability, interacts less with platelets and yields a very predictable
dose response, eliminating the need to monitor the aPPT. Low-molecular-weight
heparin, like standard heparin, binds to antithrombin III; however,
low-molecular-weight heparin inhibits thrombin to a lesser degree (and Factor
Xa to a greater degree) than standard heparin.4
Prophylaxis of DVT
The symptoms, signs, risk factors and diagnosis of
DVT are reviewed elsewhere.5 Low-molecular-weight
heparin helps prevent DVT in a variety of clinical situations, including
patients undergoing general surgery, or hip or knee replacements. Given the high
incidence of DVT after such procedures, prophylaxis is strongly recommended.
Although a surgeon often consults in such cases, family physicians should be
aware of the need for prophylaxis for DVT and should ensure that adequate
therapy is provided, when appropriate. The Fourth American College of Chest
Physicians Consensus Conference on Antithrombotic Therapy has recently
published a review of the complex data on prophylactic treatment for DVT, which
is summarized below.6
PROPHYLAXIS FOR GENERAL
SURGERY
Patients undergoing general surgery have a 16
percent risk of DVT and a 1.6 percent incidence of pulmonary embolus when they
do not receive prophylactic treatment for DVT.6 Low-molecular-weight
heparin is as effective as low-dose subcutaneous heparin, decreasing the
incidence of DVT to 5 to 8 percent following general surgery, and slightly reducing
bleeding complications. Although low-molecular-weight heparin costs
approximately 10 times more per dose than low-dose subcutaneous heparin, it can
be given once daily, which may offset some of the higher cost. While
noninvasive methods of preventing DVT (i.e., use of elastic compression
stockings or intermittent pneumatic stockings) are adequate in low- and
moderate-risk surgical patients, low-molecular-weight heparin is an excellent
therapeutic choice in high-risk patients (i.e., patients over 40 years of age,
patients undergoing major surgery, patients with concurrent risk factors for
DVT).6 Prophylactic
low-molecular-weight heparin should be given subcutaneously once or twice daily
until the patient is ambulating well.
PROPHYLAXIS FOR ORTHOPEDIC
SURGERY
In patients not receiving prophylaxis for DVT who
are undergoing elective hip or knee replacement or hip fracture surgery, the
risk of postoperative DVT is at least 40 percent, and the risk of pulmonary
embolus ranges from 1.8 to 30 percent.6 Low-molecular-weight
heparin is safe and effective following surgery for hip replacement. It has
been shown in a recent meta-analysis7 to
be superior to low-dose subcutaneous heparin, and its use resulted in
significantly fewer hemorrhagic complications.8
Studies comparing low-molecular-weight heparin with
low-dose warfarin (Coumadin) therapy (maintaining an International Normalized
Ratio [INR] between 2.0 and 3.0) showed that low-molecular-weight heparin is
slightly more effective, although the difference is quite small.9,10 Thus,
the decision to use low-molecular-weight heparin or warfarin should be based on
convenience and cost. Low-molecular-weight heparin is given subcutaneously
twice daily, and laboratory monitoring is not required. Treatment with either
warfarin or low-molecular-weight heparin should be continued for a minimum of
seven days postoperatively.
DVT is especially hard to prevent following knee
replacement surgery, and low-dose standard heparin provides marginal benefit.11 Again,
low-molecular-weight heparin is safe and effective. Five studies comparing
low-molecular-weight heparin with low-dose warfarin demonstrate better efficacy
with low-molecular-weight heparin.6 Intermittent
pneumatic compression stockings are also quite effective in preventing DVT
following knee replacement surgery12; however, the number of patients studied in this
trial was small compared with the number of patients in the
low-molecular-weight heparin trials. No trials to date have compared the use of
intermittent pneumatic compression stockings with low-molecular-weight heparin
therapy and, currently, either offers adequate prophylaxis. In high-risk
patients, low-molecular-weight heparin and compression stockings may be used
simultaneously.
Treatment of DVT
Traditionally, a patient diagnosed with DVT has
been hospitalized for treatment, which includes intravenous heparin and
monitoring of the aPTT. The patient remains hospitalized until warfarin is
administered to achieve an INR between 2.0 and 3.0. Such management usually
results in a three- to seven-day hospital stay.2
Recent randomized, controlled trials demonstrate
the efficacy of low-molecular-weight heparin in the treatment of DVT, both in
the hospital13–16 and
in an outpatient setting.17,18
Results of each of these studies demonstrated no advantage to standard intravenous
heparin over low-molecular-weight heparin in terms of recurrent thromboembolism
or major bleeding complications (Table 1).
Patients who received twice-daily injections of low-molecular-weight heparin
spent fewer days in the hospital and, in the studies where low-molecular-weight
heparin was administered in the outpatient setting, many patients did not
require hospitalization at all.17,18 Furthermore,
social functioning and physical activity were better in the group receiving
low-molecular-weight heparin.18 The dosage of low-molecular-weight heparin
depends on the specific agent used (Table 2).
TABLE 1
Controlled Trials Comparing Intravenous Heparin with Subcutaneous LMW Heparin in Proximal DVT
Controlled Trials Comparing Intravenous Heparin with Subcutaneous LMW Heparin in Proximal DVT
Study
|
Number of patients
|
Outcome
|
170
|
No
difference in rates of symptomatic extension, recurrence, pulmonary embolus
or severe bleeding
|
|
432
|
No
difference in rates of recurrence, pulmonary embolus, or major or minor
bleeding
|
|
134
|
Less
enlargement of thrombus in patients Treated with LMW heparin, fewer
thromboembolic events in patients treated with LMW heparin, no difference in
rates of major bleeding
|
|
204
|
No
difference in Marder score (venographic assessment of clot size)
|
|
400
|
No
difference in rates of recurrent thromboembolism or major bleeding
|
|
400
|
No
difference in rates of recurrent thromboembolism or major bleeding
|
LMW = low-molecular-weight; DVT = deep
venous thrombosis.
TABLE 2
Low-Molecular-Weight Heparins
Low-Molecular-Weight Heparins
Heparin
|
Availability
|
Prophylactic dosing
|
Ardeparin
(Normiflo)
|
5,000 U
in 0.5 mL; 10,000 U in 0.5 mL
|
50 U
per kg SC on the evening of the day of surgery or the following morning, then
every 12 hours for 14 days or until ambulatory
|
Dalteparin
(Fragmin)
|
16 mg
per 0.2 mL; 32 mg per 0.2 mL
|
2,500
IU SC 1 to 2 hours before surgery, then 2,500 IU every day for 5 to 10 days
|
High-risk
patients: 5,000 IU SC the evening before surgery, then 5,000 IU every day for
5 to 10 days
|
||
Danaparoid
(Orgaran)
|
750 U
per 0.6 mL
|
750 U
SC 1 to 4 hours before surgery, then 750 U every 12 hours for 7 to 10 days
|
Enoxaparin
(Lovenox)
|
30 mg
per 0.3 mL; 40 mg per 0.4 mL
|
30 mg
SC every 12 hours or 40 mg every day for 7 to 10 days, depending on the type
of surgery (hip, knee, abdomen); therapy should begin postoperatively (see
prescribing information for more details)
|
SC = subcutaneously.
Cost analysis was incomplete in these trials;
however, elimination of even a single hospital day by use of
low-molecular-weight heparin would be likely to yield a savings. In our
community, the cost of low-molecular-weight heparin ranges from approximately
$100 to $150 per day. The average cost of treating a patient with uncomplicated
DVT is reduced by approximately $5,000 to $8,000 when using
low-molecular-weight heparin instead of standard heparin therapy. It is likely
that additional studies will yield important information on the cost savings of
treatment with low-molecular-weight heparin.
Patients with a first episode of proximal DVT and
no risk factors for bleeding complications (e.g., active peptic ulcer disease,
thrombocytopenia, liver disease, other coagulopathy) are good candidates for
initial therapy with low-molecular-weight heparin. The Physicians' Desk Reference19 does not yet list low-molecular-weight
heparin as an indicated use in the treatment of DVT; hence, this suggested
treatment represents an off-label use. Because several subsets of patients were
excluded from the low-molecular-weight heparin trials, treatment with
low-molecular-weight heparin in these patients cannot be recommended at this
time (Table 3).
TABLE 3
Subsets of Patients Excluded from Controlled Trials of LMW Heparin in DVT*
Subsets of Patients Excluded from Controlled Trials of LMW Heparin in DVT*
Previous
history of DVT:
|
|
Other
relative contraindications:
|
|
Thrombocytopenia
|
|
Coagulopathy
|
|
Active
peptic ulcer disease
|
LMW = low-molecular-weight; DVT = deep
venous thrombosis.
*—Currently evidence is insufficient to
support the routine use of low-molecular-weight heparin in the treatment of DVT
in these patients.
Several recent articles have reported the safety
and efficacy of low-molecular-weight heparin in the treatment of pulmonary
embolism.20,21 Because
pulmonary embolism is sometimes suspected in patients with DVT, appropriate
treatment is essential. Treatment with low-molecular-weight heparin may still
be considered in patients with DVT and suspected pulmonary embolus. Physicians
should become familiar with the absolute and relative contraindications of the
specific brand of low-molecular-weight heparin they choose to use.
Appropriate patients may be taught to self-administer
low-molecular-weight heparin or, if needed, a visiting nurse or a family member
can give the injections. Warfarin is started on the first or second day of
therapy with low-molecular-weight heparin and, once the INR is between 2.0 and
3.0, the low-molecular-weight heparin is discontinued
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