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Duration of Anticoagulant Therapy After Venous Thromboembolism
tinzaparin (104,105), bemiparin (106)). In these studies, the daily LMWH dose was as low as 4,000 IU
(29,97) to as high as 200 IU/kg (96,103); approximately a 3.5-fold difference. Two meta-analyses of
studies that compared LMWH with VKA, each given for 3
months after initial heparin therapy, have
been performed
(107,108). In the analysis by Iorio and colleagues, which includes seven studies
(29,94,97,98,102–104) and a total of 1,379 patients, there were trends towards less recurrent VTE
(odds ratio 0.66; 95% CI 0.41–1.07) and less major bleeding (odds ratio 0.45; 95% CI 0.18–1.11) with
3
months of LMWH compared with VKA (108). Compared with outcomes in patients who received
VKA therapy, between study differences of mean daily dose of LMWH had little effect on efficacy
but did appear to influence the risk of major bleeding (odds ratio of about 0.2 with ~4,000
IU/day to
about 0.7 with 12,000
IU/day, relative to the VKA groups [p = 0.03]) (108). Three subsequent studies
that selectively enrolled a total of 1,019 patients with VTE in association with active cancer found
that, compared to VKA therapy, 3
(99,109) or 6 (96) months of therapeutic-dose LMWH was associ-
ated with less recurrent VTE in one study
(96) and less bleeding in another (99) (Table 4) (RR for the
three studies: recurrent VTE 0.56 [95% CI 0.38–0.82]; major bleeding 1.01 [95% CI 0.62–1.64];
mortality 0.92 [95% CI 0.78–1.10] Table 4) (99,108,109). Randomized trials have not evaluated
approaches to anticoagulant therapy after the first 6
months of VKA or LMWH therapy in patients
with VTE and cancer, either to assess the duration of therapy or to compare VKA with LMWH for
extended therapy. Observational studies suggest that the risk of recurrent VTE is unacceptably high
in patients with active cancer who terminate anticoagulant therapy
(24–26,38).
New Anticoagulants
Ximelagatran, an oral direct thrombin inhibitor, has been shown to be effective for the initial and
long-term treatment of VTE but has been withdrawn because of hepatic toxicity (39,110). Idraparinux,
the synthetic long-acting pentasaccharide, was recently reported to be as effective (recurrent VTE at
3 months: 2.9% vs. 3.0%) and as safe as VKA for the first 3 or 6 months of treatment of DVT but less
effective than VKA (recurrent VTE at 3
months: 3.4% vs. 1.6%; p < 0.05) in patients with PE (111).
After 6
months of treatment of VTE with idraparinux or VKA, compared with placebo, 6 months of
further treatment with idraparinux reduced their recurrence (1.0% vs. 3.7%; p
= 0.002) but was associ-
ated with increased major bleeding (1.9% vs. 0%; p
< 0.001) (112). New Anticoagulants including
dabigatran etexilate, rivaroxaban and apizaban, are at an advanced of development.
ANTIPLATELET THERAPY FOR TREATMENT OF VTE
Antiplatelet therapy, usually with aspirin, reduces the risk of postoperative VTE by about 40% (i.e.,
primary prophylaxis) (113,114). This has led to the hypothesis that aspirin may also reduce the risk of
recurrent VTE if it is started after anticoagulant therapy, which is being tested in two ongoing placebo-
controlled trials in patients with unprovoked VTE (114). If patients were on long-term antiplatelet
therapy before starting treatment for VTE, it is usually appropriate to restart this therapy if anticoagu-
lants are stopped. Currently, there is insufficient evidence to support use of aspirin in patients with
unprovoked VTE who are not candidates for indefinite anticoagulant therapy.
RECOMMENDED DURATION OF ANTICOAGULATION IN INDIVIDUAL
PATIENTS
Based largely on the preceding analysis of risk factors for recurrent thrombosis and bleeding, and
on the findings of studies that compared different durations and intensities of anticoagulation, an
approach to selection of duration of anticoagulation for individual patients with VTE is outlined in
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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 4
LMWH vs. VKA for long-term treatment of VTE in patients with active cancer
First author
(acronym) Interventions Blinding
# pts
analyzed
Length of
follow-up
Recurrent
DVT or PE
Major
bleeding
Total mortal-
ity Comments
Meyer 2002
(99)
VKA (INR 2.0–3.0)
for 3 months
after
Initial enoxaparin
Enoxaparin 1.5 mg/
kg OD for
3 months
Allocation: likely
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
unlikely
75/75
71/71
3 month
3 month
3/75 (4%)
2/71 (3%)
RR 0.7 (0.1,
4.1)
12/75 (16%)
5/71 (7%)
RR 0.4 (0.2,
1.2)
17/75 (23%)
8/71 (11%)
RR 0.5 (0.2,
1.1)
Population: DVT
(proportion with
calf DVT not
known) or PE
and active cancer.
All fatal bleeding
(n = 6) were in
VKA group.
Lee 2003 (96)
(CLOT)
VKA (INR 2.0–3.0)
for 6 months
after initial
dalteparin-
Dalteparin
200
U/kg OD
for 1 month fol-
lowed by 150 U/
kg for 5 months
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
likely
336/338
336/338
6
month
6 month
53/336
(16%)
27/336 (8%)
RR 0.5 (0.3,
0.8)
12/335 (4%)
19/338 (6%)
RR 1.6 (0.8,
3.2)
136/336
(40%)
130/336
(37%)
RR 1.0 (0.8,
1.2)
Population: proxi-
mal DVT or PE
and active cancer
Difference in effi-
cacy mainly due
to recurrent DVT
(14 vs. 37 epi-
sodes)
Hull 2006
(109)
(Main LITE-
cancer)
VKA (INR 2.0–3.0)
for 3 months
after initial IV
UFH
Tinzaparin 175 mg/
kg OD for
3 months.
Allocation: likely
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
likely
100/100
100/100
3 month
3 month
10/100
(10%)
6/100 (6%)
RR 0.6 (0.2,
1.6)
7/100 (7%)
7/100 (7%)
RR 1.0 (0.4,
2.8)
19/100
(19%)
20/100
(20%)
RR 1.0 (0.6,
1.9)
Population: proxi-
mal DVT and
active cancer
Pre-specified, strati-
fication, sub-
group within a
larger trial.
Outcomes at
12 months were
also reported.
Summary 1019 RR 0.7 (0.4,
0.8)v
RR 1.0 (0.6,
1.6)
RR 0.9 (0.8,
1.1)
Heterogeneity
p < 0.1 for all
estimates
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Duration of Anticoagulant Therapy After Venous Thromboembolism
Table 5. Because the presence of a reversible risk factor for VTE, lack of a provoking factor, or cancer,
at the time of thrombosis has the greatest prognostic influence on the risk of recurrence, this assess-
ment carries most weight.
For patients whose VTE is associated with a major reversible risk factor, such as recent surgery,
stopping anticoagulant therapy after 3 months of treatment is expected to be associated with a subse-
quent risk of recurrent VTE of about 3% in the first year and about 10% over 5
years
(4,5,18,24,26,29,30,34,39). For patients whose VTE is associated with a lesser reversible risk factor,
such as a soft tissue injury to the leg or a prolonged flight, stopping anticoagulant therapy after
3 months of treatment is expected to be associated with a subsequent risk of recurrent VTE of about
5% in the first year and about 15% over 5 years (31). These rates of VTE are not high enough to
justify treatment for longer than 3 months.
For patients with unprovoked VTE, stopping anticoagulant therapy after 3 or more months of treat-
ment is expected to be associated with a subsequent risk of recurrent VTE of about 10% in the first
year and about 30% over 5 years (26,28,30,33). This rate is high enough to justify long-term antico-
agulation in the majority of patients. The argument favoring long-term therapy is stronger if the
unprovoked episode of VTE was a second or subsequent episode of unprovoked VTE, a PE, occurred
in a male, or was associated with an antiphospholipid antibody or a hereditary thrombophilia. A low
D-dimer level (e.g., corresponding to a “negative test” result using a D-dimer assay that has a high
sensitivity for diagnosing acute VTE) 1 month after stopping anticoagulant therapy may identify
patients with unprovoked proximal but or be who have a low risk of recurrence, and do not require
long-term anticoagulant therapy (35,52,54,115). However, this author suggests that the use of D-dimer
testing to identify patients with unprovoked proximal DVT or PE who can safely discontinue anticoagulant
Table 5
Recommendations for duration of anticoagulant therapy for VTE
Risk factor for VTE
Durations of treatment (Target INR 2.5,
range 2.0–3.0)
Transient risk factor
a
3 months
UnprovokedIf also:
isolated distal DVT; or a first proximal DVT or PE
and a moderate or higher risk of bleeding
c
; or an
informed patient’s preference to stop therapy
Indefinite
b
3 months
Uncontrolled malignancyIf also:
a very high risk of bleeding
c
; isolated distal DVT; or an
additional major reversible provoking risk factor for
VTE
a
Indefinite(preferably with LMWH for at least
the first 3 months)
consider stopping therapy at 3 or when can-
cer becomes inactive
a
Transient risk factors include: major factors, such as surgery with general anesthesia, plaster cast immobilization of a
leg, or hospitalization, all within the past month; and minor factors, such as estrogen therapy, pregnancy, prolonged travel
(e.g., longer than 8 h), less marked leg injury, or the previously noted “major factors” when they occur 1–3 months before
diagnosis of VTE
b
Decision should be reviewed annually to consider if the patient’s risk of bleeding has increased, or if patient preference
has changed. Additional factors favoring indefinite therapy include: more than one episode of unprovoked VTE; PE vs.
proximal DVT at presentation; male sex; antiphospholipid antibodies; hereditary thrombophilia
c
Risk factors for bleeding include: age 65 years or older, particularly after 75 years; previous non-cardioembolic stroke;
previous bleeding (e.g., gastrointestinal), particularly if there was not a reversible cause; active peptic ulcer disease; renal
impairment; anemia; thrombocytopenia; liver disease; diabetes mellitus; use of antiplatelet therapy (to be avoided); poor
patient compliance; poor control of anticoagulation; structural lesion (including tumor) expected to be associated with
bleeding. One or two risk factors suggests moderate risk, and three or more risk factors suggests high risk, of bleeding
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Antithrombotic Drug Therapy in Cardiovascular Disease
therapy requires further prospective validation before this can be recommended in usual clinical practice
(the author is currently involved in such a study).
Patients with active cancer should generally remain on long-term anticoagulant therapy (LMWH
or VKA) because the risk of recurrent VTE is expected to be higher than 10% within a year of stop-
ping treatment.
If anticoagulant therapy is expected to be associated with a high risk of bleeding because of risk
factors for bleeding or lack of access to appropriate anticoagulant monitoring, longer than 3
months
of treatment generally should be avoided in patients with a first unprovoked VTE. Annual review is
recommended for patients on long-term therapy to ensure that the benefits of continuing therapy are
likely to exceed the risks (e.g., that contraindications have not developed).
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Part VII
Clinical Consideration
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