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Duration of Anticoagulant Therapy After Venous Thromboembolism
with VTE that was provoked by a reversible risk factor and compared shorter durations of therapy
(36) (Table 3).
Isolated Calf DVT Vs. Proximal DVT
Patients with DVT that is confined to the distal veins (often called “isolated calf” DVT) have about
half the risk of recurrence than patients with DVT that involves the proximal veins (i.e., popliteal or
more proximal veins)
(28,30,37). If ultrasound rather than venography is used to diagnose distal DVT,
the risk of recurrence after distal DVT may be even lower as a higher proportion of such patients may
have false-positive findings or may have thrombosis of the muscular rather than of the deep veins.
Many studies that compared durations of anticoagulation excluded patients with isolated distal DVT
(4,20,34,35).
Second Vs. First Episode of VTE
After a second or subsequent episode of VTE, the risk of recurrence appears to be about 1.5-fold
higher than that after a first episode (18,38,39). Many studies that compared durations of anticoagula-
tion excluded patients if their VTE was not a first episode (28,30,33–35).
Pulmonary Embolism Vs. Deep Vein Thrombosis
Patients with pulmonary embolism (PE) appear to have the same risk of recurrent VTE as those
with proximal DVT (25,28,38,40). However, after a PE, about 60% of recurrent episodes of VTE are
Table 2
Risk factors for recurrent VTE after stopping anticoagulant therapy
Variable Relative risk
Transient risk factor (4,5,24,26,28,29,31,42,58) £0.5
Persistent risk factor (4,5,24,26,28,29,42) ³2
Unprovoked VTE (4,5,16,26,28,31) ³2
Protein C, protein S and antithrombin deficiencies (24,31,52,58) ~1.5
Heterozygous for factor V Leiden or the G20210A prothrombin gene (16,18,42,55) ~1.5
Homozygous for factor V Leiden (42,56–58) 1.5–2
Heterozygous for both factor V Leiden and G20210A prothrombin gene (56,58,121–123) 1.5–2
FactorVIIIlevel>150IU/dL(54,58,65) ~1.4
Antiphospholipid antibodies (16,36,42,59) 1.5–2
Mild hyperhomocysteinemia (69,124) 1.5–2.5
D-dimer elevation after stopping therapy (35,52–54) ~2.5
Family history of VTE (28,56,73) ~1
Cancer (23–26) ~3
Metastatic vs. non-metastatic (23) ~3
Chemotherapy (25) ~2
Discontinuation of estrogen (25,58,125–131) ~0.5
Proximal DVT vs. PE (16,28,38) ~1
Distal DVT vs. proximal DVT or PE (28,30) ~0.5
Residual thrombosis (4,16,22,28,34,62,132) 1–2
Vena caval filter (38,63,64,132) 1–1.5
Second vs. first episode of VTE (3,18,38,39) 1.5–2
Age (16,25,38,56) ~1
Gender (60) ~1.5
Asian (38) ~0.8
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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 3
Comparisons of Durations and Intensities of Anticoagulant Therapy for DVT and PE
First author/
year (acro-
nym) Intervention Blinding
# pts
analyzed
Length fol-
low-up
Recurrent
DVT or PE
Major bleed-
ing
Total
mortality Comments
Short (4 or 6 weeks) vs. Intermediate (3 or 6 months) durations of anticoagulation
Kearon 2004
(36)
(SOFAST)
VKA stopped
(Placebo)
VKA (INR
2.0–3.0)
For 2 more
month
Allocation: yes
Patients: yes
Caregivers: yes
Adjudications:
yes
Data analysts:
yes
84/84
81/81
11
month
11 month
5/84 (6%)
3/81 (4%)
RR 0.6 (0.1,
2.5)
0/84
0/81
RR 1.0 (0.0,
51.6)
0/84
1/81 (1%)
RR 3.1
(0.1, )
Population: first DVT
or PE. Treated for
1 month VTE was
asymptomatic in 9%,
and isolated calf DVT
in 18%. One VTE
occurred while on
warfarin.
Pinede 2001
(30)
(DOT AVK)
VKA (INR
2.0–3.0) for
1.5 month
VKA (INR
2.0–3.0) for
3
month
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
unlikely
105/105
92/92
15
month 2/105 (2%)
3/92
RR 1.7 (0.3,
10.0)
1/105 (1%)
3/92
RR 3.4 (0.4,
33.4)
Not spec-
ified
Population: first isolated
calf DVT.
Schulman
1995
(28)
(DURAC 1)
VKA (INR
2.0–2.85) for
1.5 month
VKA (INR
2.0–2.85) for
6 month
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
VTE, yes
Other, unlikely
Data analysts:
unlikely
443/443
454/454
2 years 80/443 (18%)
43/454 (9%)
RR 0.5 (0.4,
0.7)
1/443
5/454 (1%)
RR 4.9 (0.6,
41.6)
22/443
(5%)
17/454
(4%)
RR (0.7,
1.4)
First VTE: DVT (distal
or proximal) or PE.
Only asked about
bleeding while on
VKAs.
Levine 1995
(4)
VKA stopped
(Placebo)
VKA (INR 2.0
–3.0) for 2
more month
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
VTE, yes
Data analysts:
unlikely
105/107
109/113
9 month 12/105 (11%)
7/109 (6%)
RR 0.6 (0.2,
1.4)
0/105
1/109 (1%)
RR 2.9 (0.1,
70.2)
(within 2
month of
randomiza-
tion)
9/105
(9%)
9/109
(8%)
RR 1.0
(0.4,
2.5)
Proximal DVT (first epi-
sode in 91%). Cancer
in 21%
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Duration of Anticoagulant Therapy After Venous Thromboembolism
British
Thoracic
Society
(5)
VKA (INR
2.0–3.0)
For 1 month
VKA (INR
2.0–3.0) for
3 months
Allocation: yes
Patients: no
Caregivers: no
Adjudications: no
Data analysts:
unlikely
358/358
354/354
1 year
1 year
28/358 (11%)
14/354 (4%)
RR 0.5 (0.3,
0.9)
5/358 (1%)
4/354 (1%)
RR 0.8 (0.2,
3.0)
26/358
(7%)
28/354
(8%)
RR 1.1
(0.6,
1.8)
Population: DVT or PE;
only 71% objectively
diagnosed; proportion
with a previous VTE
not known.
All bleeds were on
VKA. Only 1 recur-
rent VTE among 116
pts with post opera-
tive VTE.
Summary 2,198 RR 0.53
(0.40,
0.70)
RR 1.84
(0.76,
4.50)
RR 1.04
(0.74,
1.48)
For all analyses, p ³ 0.1
for heterogeneity.
SOFAST (36) not
included in estimate
for major bleeding
as no events in either
group.
Different intermediate durations (6 or 12
months vs. 3 months) of anticoagulation
Campbell
2004 (75)
VKA (INR
2.0–3.5) for
3 months
VKA (INR
2.0–3.5)
for 6 months
Allocation: yes
Patients: no
Caregivers: no
Adjudications: no
Data analysts:
unlikely
369/396
380/414
1 year
1 year
31/369 (8%)
29/380 (8%)
RR0.9 (0.6,
1.5)
0/369
(during
3 month
treatment)
8/380 (2%)
(during
6 month
treatment)
RR 16.5 (1.0,
285)
15/369
(4%)
19/369
(5%)
RR 1.3
(0.6,
2.5)
Population:
DVT or PE; proportion
with calf DVT not
known;
Only bleeding during
treatment is reported.
20% of VTE outcomes
were not objectively
verified.
(continued)
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Antithrombotic Drug Therapy in Cardiovascular Disease
Table 3
(continued)
First author/
year (acro-
nym) Intervention Blinding
# pts ana-
lyzed
Length follow-
up
Recurrent DVT
or PE Major bleeding
Total mor-
tality Comments
Agnelli 2003
(34)
(WODIT-PE)
VKA stopped
VKA (INR
2.0–3.0) for 9
more month
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
unlikely
91/91
90/90
2.6
years
(mean)
2.9 years
(mean)
11/91 (12%)
11.90 (12%)
RR 1.0 (0.5,
2.2)
1/91 (1%)
2/90 (2%)
RR 2.0 (0.5,
21.9)
7/91 (8%)
8/90 (9%)
RR 1.16
(0.4,
3.0)
Population: first unpro-
voked PE. Treated
for ³3 month Among
the 4 groups, only 1
recurrent VTE while
on VKA.
VKA stopped
VKA (INR
2.0–3.0) for 3
more month
70/70
75/75
2.8 years
(mean)
2.9 years
(mean)
7/70 (10%)
4/75 (5%)
RR 0.5 (0.2,
1.7)
0/70 (0%)
1/75 (1%)
RR 1.9 (0.1,
56)
0/70 (0%)
4/75 (5%)
RR 8.4
(0.5,
153)
Population: first pro-
voked PE. Treated for
³3 month (see above)
Agnelli 2001
(33)
(WODIT-
DVT)
VKA stopped
VKA (INR
2.0–3.0) for
9 month
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
unlikely
133/133
134/134
3.2 years
(mean)
3.1 years
(mean)
21/133 (16%)
21/134 (16%)
RR 1.0 (0.6,
1.7)
2/133 (2%)
4/134 (3%)
RR 2.0 (0.4,
10.7)
7/133
(5%)
7/134
(5%)
RR 1.0
(0.4,
2.8)
Population: first unpro-
voked proximal DVT
treated for 3 month.
One patient had
recurrent VTE on
VKA. Bleeding in the
intervention group
was while on VKA.
Pinede 2001
(30)(DOT
AVK)
VKA (INR
2.0–3.0) for
3 month &
VKA (INR
1.0–3.0) for
6 month
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
unlikely
270/270
269/269
15 month 21/270 (8%)
23/269 (9%)
RR 1.1 (0.6,
1.9)
5/270 (2%)
7/269 (3%)
RR 1.4 (0.4,
4.4)
not speci-
fied
Population: first proxi-
mal DVT or PE.
Recurrent VTE
occurred after VKA
in 26/28 of the short
duration groups and
21/27 of the long
duration groups.
Summary 1881 RR 0.95
(0.72,
1.26)
RR 2.53
(1.18,
5.46)
RR 1.3
(0.82,
2.08)
For all analyses, p ³ 0.1
for heterogeneity.
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Duration of Anticoagulant Therapy After Venous Thromboembolism
Indefinite vs. intermediate durations of anticoagulation (INR ~20–3.0)
Palereti 2006
(35)
(PROLONG)
Remain aff
(stop)
VKA
Restart
Indefinitely
VKA (INR
2.0-3.0)
(not blinded)
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
yes
Data analysts:
unlikely
103/105
120/122
1.4 years
(mean)
(max
1.5 years)
18/103 (17%)
2/120 (2%)
RR 0.1 (0.0,
0.4)
0/103
1/120 (1%)
RR 2.6 (0.1,
62.6)
1/103
(1%)
1/120
(1%)
RR 0.9
(0.1,
13.6)
Population: first
unprovoked proximal
DVT or PE. Treated
for ³3 month. VKA
stopped & D-dimer
positive 1 month later.
Eight control pts.
Restarted VKA, some
after superficial phle-
bitis. 1 recurrent VTE
in VKA group after
VKA stopped.
Kearon 1999
(16)
(LAFIT)
VKA stopped
(Placebo)
VKA (INR
2.0–3.0) for 2
more years
Allocation: yes
Patients: yes
Caregivers: yes
Adjudications:
yes
Data analysts:
yes
83/83
79/79
10 month
(mean)
(max
2 years)
17/83
(20%)1/79
(1%)
RR 0.1 (0.0,
0.5)
0/83
3/79 (4%)
RR 7.4 (0.4,
140)
3/83 (4%)
1/79 (1%)
RR 0.3
(0.0,
3.3)
Population: first unpro-
voked proximal DVT
or PE (5%) had previ-
ous provoked VTE).
The recurrent VTE in
the VKA patient was
after stopping VKA.
Schulman
1997
(3)
(DURAC 2)
VKA (INR
2.0–2.85) for
6 month
VKA (INR 2.0-
2.85) indefi-
nitely.
Allocation: yes
Patients: no
Caregivers: no
Adjudications:
VTE, yes
Other, unlikely
Data analysts:
unlikely
111/111
116/116
4 years 23/111 (2%)
3/116 (3%)
RR 0.1 (0.0,
0.4)
3/111 (3%)
10/116 (9%)
RR 3.2 (0.9,
11.3)
16/111
(14%)
10/116
(9%)
RR 0.6
(0.3,
1.3)
Second VTE: DVT
(distal or proximal)
or PE. All recurrent
VTE in the indefinite
VKA group were
after stopping VKAs.
Bleeding during the
first 6 month of VKA
in 1 of 6 month group
and 6 of indefinite
group. (Only asked
about bleeding while
on VKAs.
Summary RR 0.1 (0.04,
0.22)
RR 3.61
(1.22,
10.7)
RR 0.58
(0.29,
1.14)
For all analyses, p ³ 0.1
for heterogeneity.
(continued)
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Antithrombotic Drug Therapy in Cardiovascular Disease
Indefinite vs. intermediate durations of anticoagulation (INR ~1.5–2.0 after initial INR 2.0–3.0 in both groups)
Ridker 2003
(18)
(PREVENT)
VKA stopped or
not restarted
(Placebo)
VKA INR
1.5–2.0
Allocation: yes
Patients: yes
Caregivers: yes
Adjudications:
yes
Data analysts:
yes
253/253
255/255
2.1 years
(mean)
(max
4.3 years)
37/253 (15%)
14/255 (5%)
RR 0.4 (0.2,
0.7)
2/253 (1%)
5/255 (2%)
RR 2.5 (0.5,
12.7)
8/253
(3%)
4/255
(2%)
RR 0.5
(0.1,
1.6)
Population: unpro-
voked DVT (distal
or proximal) or PE
(first episode in 38%)
8 recurrent VTE in
the VKA group after
stopping VKAs.
Low intensity (INR 1.5–1.9) vs. conventional intensity (INR 2.0–3.0)
Kearon 2003
(17)
(ELATE)
VKA INR
1.5–1.9
VKA INR
2.0–3.0
(blinded)
Allocation: yes
Patients: yes
Caregivers: yes
Adjudications:
yes
Data analysts:
yes
369/369
369/369
2.4
years
(mean)
16/369 (4%)
6/369 (2%)
RR 0.4 (0.1,
0.9)
9/369 (2%)
8/369 (2%)
RR 0.9 (0.3,
2.3)
16/369
(4%)
8/369
(2%)
RR 0.5
(0.2,
1.2)
Population: unprovoked
proximal DVT or PE
(first episode in 31%).
Treated for ³3
month
VKA (INR 2.0–3.0)
(mean 12 month) 5
recurrent VTE in INR
1.5–1.9 and 3 in the
INR 2.0–3.0 group
after stopping VKAs.
Table 3
(continued)
First author/
year (acro-
nym) Intervention Blinding
# pts ana-
lyzed
Length follow-
up
Recurrent DVT
or PE Major bleeding
Total mor-
tality Comments
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Duration of Anticoagulant Therapy After Venous Thromboembolism
also PE, whereas only about 20% of recurrent episodes of VTE are a PE after an initial DVT
(33,34,38,40–42). This pattern of recurrence, with about a three-fold higher risk of PE after an initial
PE than after an initial DVT, appears to persist long-term
(38,41,42). About 10% of symptomatic PE
are considered to be rapidly fatal
(43–45) and another 5% of patients whose PE is diagnosed and
treated also die from PE
(38,41,46–50). Thus, after 3 or more months of treatment for DVT or PE,
recurrent VTE that presents as PE probably has a case-fatality of about 15%. The risk of dying from
acute DVT, because of early subsequent PE or other complications (e.g., bleeding, precipitation of
myocardial infarction), appears to be 2% or less
(24,38,41,47,50,51). Based on these estimates, the
case-fatality associated with late recurrent VTE after a preceding PE is expected to be about 10%,
whereas that after a preceding DVT is expected to be about 5%. Consistent with the latter estimate,
an overview of randomized trials calculated a 5.1% case-fatality for recurrent VTE in patients with
DVT who had completed 3 months of treatment (40). Therefore, although the risk of a recurrence is
the same after PE and proximal DVT, the case-fatality for a recurrence is expected to be two-fold
higher after PE than after DVT.
D-Dimer Level After Withdrawal of Treatment
A negative D-dimer test 1
month after withdrawal of VKA appears to identify patients with a
substantially reduced risk of recurrent VTE (relative risk ~0.4)
(35,52–54).
Hereditary Thrombophilias
A recent meta-analysis estimated that the risk of recurrent VTE associated with heterozygous factor
V Leiden was 1.4 (95% CI 1.1–1.8) and that associated with prothrombin G20210A was 1.7 (1.3–2.3),
with heterogeneity of these estimates among studies
(55). Among the five large prospective studies
that included a total of 2,691 patients with a first episode of VTE (provoked and unprovoked), and of
whom 117 (4.3%) had homozygous factor V Leiden, homozygous prothrombin gene G20210A, dou-
ble heterozygous states for these two mutations, or deficiency of protein C, protein S or antithrombin,
the overall odds ratio for recurrent VTE associated with these major thrombophilias was 1.5 (95% CI
0.9–2.4)
(31,52,56–58).
Antiphospholipid Antibodies
Schulman et
al. found that an anticardiolipin antibody was associated with recurrent VTE in the
first 4
years after the first VTE (59), but at the end of 10 years of follow-up it was no longer predictive
(42). Kearon found that an anticardiolipin antibody or lupus anticoagulant was associated with recur-
rent VTE after an unprovoked VTE (hazard ratio 4.0, 95% CI 1.2–13) (16), but not after a provoked
VTE (hazard ratio 1.3, 95% CI 0.2–11) (36).
Sex
A recent meta-analysis estimated that the risk of recurrent VTE is higher in males than in females
(RR 1.6, 95% CI 1.2–2.0), with heterogeneity of this association among studies (60).
Residual Deep Vein Thrombosis
A relation between the presence of residual DVT on ultrasound and the risk of recurrent VTE has
been reported (22,61). However, a number of other studies have not found the residual DVT to be an
independent predictor of recurrence (16,34,36,62), and why residual DVT would be associated with
DVT in the contralateral leg remains unexplained (61).
Vena Caval Filter
In patients who have had a vena caval filter inserted, followed by standard anticoagulant therapy, a
trend to a higher risk of a new episode of DVT (RR 1.3; 95% CI 0.9–1.8), a lower risk of PE (RR 0.4; 95%
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Antithrombotic Drug Therapy in Cardiovascular Disease
CI 0.2–0.9), and no difference in the risk of VTE (DVT and/or PE; RR 1.0; 95% CI 0.7–1.4) was
observed after 8
years of follow-up (63,64).
Other Markers for Recurrence
Factor VIII
(54,58,65,66), factor IX (58), factor XI (58,67), homocysteine (58,68,69), thrombin
generation
(70), activated partial thromboplastin time (71), family history of VTE (72), and age at
diagnosis
(25,38) have been evaluated, but the evidence that they are clinically important risk factors
for recurrent VTE is generally weak.
Comparisons of Different Durations of Anticoagulation Therapy for Venous
Thromboembolism
Trials that have evaluated different durations of anticoagulant therapy in patients with VTE can be
divided into three categories, according to the durations of the therapy that were compared: (1) short
vs. intermediate durations, (2) different intermediate durations, and (3) indefinite therapy vs. intermediate
durations. Within each of these categories, studies that included heterogeneous (i.e., less selected)
patients with VTE will be considered first, followed by studies that enrolled subgroups of (i.e.,
selected) patients who were expected to have either a lower (e.g., associated with reversible risk fac-
tors) or a higher (e.g., unprovoked, or second episodes of VTE) risk of recurrence.
Short (4 or 6 Weeks) Vs. Intermediate (3 or 6 Months) Durations of Therapy
Five trials have evaluated shortening the duration of oral anticoagulant therapy from 3 or 6 months
to 4 or 6
weeks in patients with mostly first episodes of VTE (Table 3) (4,5,28,30). The first three stud-
ies (British Thoracic Society, Levine, DURAC 1; Table
3), which mainly enrolled unselected patients
with proximal DVT or PE, found that shortening the duration of anticoagulation was associated with
about double the frequency of recurrent VTE during follow-up of 1 to 2 years (an absolute risk increase
of ~5%)
(4,5,28). Major bleeding was uncommon during the incremental period of anticoagulation in
these three studies (estimated as seven episodes among 1,009 patients during 259-patient years of
additional treatment [2.7% per year])
(4,5,28). Therefore, the main finding of these studies was that
anticoagulant therapy should not be shortened to 4 or 6
weeks in patients with VTE.
Subgroup analyses of one of the above studies (DURAC 1) suggest that isolated distal DVT
provoked by a major transient risk factor can safely be treated with only 6 weeks of therapy (28).
A subsequent study (component of DOTVAK), which compared 6 vs. 12
weeks of therapy in
patients with isolated calf DVT (unprovoked or provoked; mostly diagnosed by ultrasound), found
no evidence to suggest that shortening therapy increased the risk of recurrence (RR 0.6; 95%
CI 0.01–3.4) and, in general, observed a low frequency of recurrent VTE with isolated calf DVT
(~2% in the first year) compared to proximal DVT or PE (~6% in the first year) (30). These findings
suggest that if anticoagulants need to be stopped after 6 weeks of therapy in patients with isolated
distal DVT, the subsequent risk of recurrence is not expected to be excessive. The fifth of these
studies enrolled only patients with VTE that was associated with a major reversible risk factor
(SOFAST; Table 3); however, because only 165 patients were enrolled, its findings were not defini-
tive (36). A meta-analysis of five studies (retrospective identification of the patient’s subgroup in
four studies (4,5,28,73); prospective enrollment of patients in one study (36)) that compared 4 or
6 weeks with 3 or 6 months of treatment among 725 patients with VTE provoked by a reversible
risk factor found that the shorter durations of therapy were associated with more than double the
risk of recurrent VTE during the subsequent year (odds ratio 2.9; 95% CI 1.2–6.9; absolute increase
of ~3.4%) (36).
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Duration of Anticoagulant Therapy After Venous Thromboembolism
Different Intermediate Durations of Therapy (6 or 12 Months Vs. 3 Months)
Two studies have compared 6 vs. 3 months of anticoagulant therapy in patients with predominantly
first episodes of DVT or PE (unprovoked, or provoked by a reversible risk factor) (DOTAVK, Campbell;
Table
3) (30,74). There was no difference in the risk of recurrence during follow-up in both studies, and
one study
(74) reported a lower risk of bleeding in the 3-month group (Campbell; Table 3).
Agnelli and colleagues compared stopping anticoagulant therapy at 3
months with continuing it for
another 9
months after a first episode of unprovoked proximal DVT (WODIT-DVT; Table 3) (33). At
the end of the first year, recurrent VTE was less frequent in the group that continued on anticoagulant
therapy (3.0% vs. 8.3%) but this benefit was no longer present after 2
years of follow-up (RR 1.0; 95%
CI 0.6–1.7). The same investigators obtained similar results in a comparable study of patients with
unprovoked PE (WODIT PE and Table
3) (34).
Based on the findings of these five studies (including the two components of WODIT-PE)
(30,33,34,74), anticoagulants are found to be very effective in preventing recurrence when patients
are receiving therapy but, at the end of extended follow-up after stopping treatment, a similar risk of
recurrence is expected if anticoagulants are stopped at 6 or 12 months compared to at 3 months (RR
for the five studies 0.95; 95% CI 0.72–1.26; Table
3) (30,33,34,74), including among patients with
unprovoked proximal DVT or PE.
Indefinite Therapy Vs. Intermediate Durations of Anticoagulant Therapy
Four trials have compared indefinite (i.e., extended therapy without scheduled stopping of
treatment and subsequent follow-up) anticoagulation (target INR of 2.0–2.85
(3), 2.0–3.0
(16,35), 1.5–2.0 (18)) with stopping therapy in patients with VTE who were believed to have a
high risk of recurrence because thrombosis was a second episode
(3), unprovoked (16,18), or
was unprovoked and had a positive D-dimer result 1
month after stopping therapy (35) (DURAC
2, LAFIT, PREVENT, PROLONG; Table
3). The results indicate that randomization to indefi-
nite treatment with conventional-intensity VKA (target INR 2.5) reduces recurrent VTE by
about 90% (RR for the three studies 0.10; 95% CI 0.04–0.22; Table 3) (3,16,35), and randomi-
zation to low-intensity therapy (target INR 1.75) reduces VTE by 64% (95% CI for HR,
23–81%) (18) (Table 3; both risk reductions are appreciably greater among patients who remain
on VKA therapy).
Bleeding During Long-Term Anticoagulant Therapy
A meta-analysis of seven studies (4,16,18,33,39,75,76) that compared durations of conventional-
intensity anticoagulant therapy for VTE (not all patients had unprovoked VTE) estimated the rate of
major bleeding to be 1.1% per patient-year (18 episodes in 1,571 years) during the extended phase
of anticoagulation compared with 0.6% per patient-year (9 episodes during 1,497 years) without
anticoagulation (RR of 1.80; 95% CI 0.72–4.51) (77). Similar low rates on major bleeding were
observed during long-term treatment of unprovoked VTE in the more recent ELATE and PROLONG
studies (Table 3) (17,74).
Of factors that have been evaluated as risk factors for major bleeding during anticoagulant therapy,
the following appear to have the greatest potential to be clinically useful markers of increased risk:
old age, particularly after 75 years; previous gastrointestinal bleeding, particularly if not associated
with a reversible cause; previous non-cardioembolic stroke; chronic renal or hepatic disease; con-
comitant antiplatelet therapy (to be avoided if possible); other serious acute or chronic illness; poor
anticoagulant control; and suboptimal monitoring of anticoagulant therapy (17,78–85).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Balancing Reduction of VTE with Increase of Bleeding During Long-Term Therapy
As noted previously, the likelihood of dying from recurrent VTE depends on whether the recurrence
is a PE or a DVT, with PE being much more common after an initial PE than after an initial DVT. After
completing 3 or more months of initial anticoagulant therapy, case-fatality for recurrent VTE is expected
to be about 10% after an initial PE and 5% after an initial DVT (see above). Case-fatality with major
bleeding during long-term anticoagulant therapy for VTE is about 10% (86). Comparison of associated
case-fatalities suggests that the consequence of major bleeding during long-term anticoagulation is similar
to that of a recurrent episode of VTE that occurs after a PE, and is about twice as severe as the conse-
quences of a recurrent episode of VTE that occurs after a DVT. Therefore, given a relative risk reduction
for recurrent VTE of over 90%, and a relative risk for bleeding of 2.5, with long-term anticoagulation, if
the annual rate of major bleeding on anticoagulant therapy is 2%, the annual risk of recurrent VTE needs
to exceed 1.2% after a PE, and 2.4% after a DVT just to offset the increased fatal bleeding.
As the average rate of recurrence is about 6% per year in the first 5 years after stopping anticoagulant
therapy in patients with a first episode of unprovoked proximal DVT or PE
(4,5,16,18,27,28,30,31,33,34),
indefinite anticoagulant therapy is expected to be beneficial in a majority of such patients (see also Table
3). Consistent with this risk:benefit analysis, the combined results of the five randomized trials that have
compared long-term conventional-intensity
(3,16,35) or low-intensity (18) therapy with stopping ther-
apy, and conventional-intensity with low-intensity therapy
(17), in patients with mostly unprovoked
VTE suggests that long-term therapy reduces all-cause mortality (risk ratio 0.53; 95% CI 0.33–0.87
(87)
[see Baglin
(88) for the argument against long-term anticoagulation for a first unprovoked VTE]).
Patient Preferences and the Burden of Anticoagulation
The perceived burden associated with being on VKA therapy differs markedly among patients. For
example, Locadia and colleagues identified that being on VKA was associated with a median utility
of 0.92 (where 0 is equivalent to death and 1.0 is equivalent to perfect health) by 124 patients who
had a recent or remote VTE; however, the associated utility was 0.77 or lower for a quarter of patients,
and was 0.98 or higher for another quarter of patients (i.e., rated more highly that the median utility
of 0.96 associated with not being on VKA). Consistent with these large differences in patients’ per-
ception of the burden of VKA therapy, irrespective of whether the risk of recurrence was assumed to
be high or low after stopping therapy, 25% of surveyed patients always opted to stop therapy and 23%
always opted to continue with the therapy. There were also marked difference in how negatively (i.e.,
“bad”) patients consider it would be to have an episode of bleeding or VTE
(90).
Alternatives to Vitamin K Antagonists
Subcutaneous Unfractionated Heparin
Adjusted-dose subcutaneous UFH is an effective approach for the long-term treatment of DVT
(91), whereas low-dose UFH (5,000 U twice daily) is inadequate for this purpose (2,92). In a study
of 80 patients with DVT, contraindications to VKA therapy that compared 10,000 U UFH with
5,000 IU dalteparin, each administered subcutaneously twice daily for 3 months, there was a similar
low frequency of recurrent VTE and bleeding in both groups, and a less frequent spinal fracture in the
LMWH group (93).
Subcutaneous Low-Molecular-Weight-Heparin
Fourteen randomized trials have compared VKA (INR of 2.0–3.0) with widely differing regimens
of five LMWH preparations (dalteparin (94–96), enoxaparin (29,97–101), nadroparin (102,103),
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