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Vascular Medicine
http://vmj.sagepub.com/content/3/1/57
The online version of this article can be found at:
DOI: 10.1177/1358836X9800300112
1998 3: 57Vasc Med
Paolo Prandoni, Anthonie WA Lensing and Martin R Prins
Long-term outcomes after deep venous thrombosis of the lower extremities
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Vascular Medicine 1998; 3: 57–60
Long-term outcomes after deep venous thrombosis of the
lower extremities
Paolo Prandoni
a
, Anthonie WA Lensing
b
and Martin R Prins
b
Abstract: Few natural history studies are available which describe long-term outcomes after
venous thromboembolism. However, symptomatic deep-vein thrombosis (DVT) of the lower
extremities carries a high risk for recurrent venous thromboembolism that persists for many
years. This risk is higher among patients with permanent risk factors including inherited
abnormalities of hemostasis than among patients who have suffered trauma or who are post-
operative. The development of recurrent ipsilateral DVT carries a high risk for severe post-
thrombotic syndrome, an otherwise rare problem in patients with a first episode of DVT
adequately treated with anticoagulant drugs and wearing vascular compression stockings.
Long-term survival following DVT is generally good in the absence of malignancy. Carefully
designed randomized trials are needed to determine whether chronic anticoagulation can
reduce further the risks of recurrent DVT and symptoms of post-thrombotic syndrome.
Key words: anticoagulation; factor V Leiden; post-thrombotic syndrome; thrombophilia;
venous thrombosis
Introduction
While abundant information is available describing short-
term prognosis following deep-vein thrombosis (DVT),
limited and conflicting results are available regarding the
long-term clinical course of this disease. Recurrent throm-
boembolism and post-thrombotic syndrome (PTS) are the
most important long-term complications of DVT. Throm-
boembolic complications are reported to occur with a fre-
quency of approximately 5% during the first 3 months of
anticoagulant treatment and are related to the intensity and
duration of initial heparinization. The clinical signs and
symptoms of PTS become manifest in the months and years
that follow. Unfortunately, data are limited concerning the
true frequency of PTS since most evidence is based on
small retrospective studies.
This paper reviews those studies that describe the natural
history of DVT. The only studies included were those in
which patients with confirmed DVT were prospectively fol-
lowed to document recurrent thromboembolic events or
PTS. Efforts were made to identify all trials, both published
and unpublished, addressing the long-term clinical history
of DVT in symptomatic patients. This included a Medline
search, reviewing bibliographies of appropriate publi-
cations, and searching recent journals using Current Con-
tents to find reports that may not have been included in
Medline data bases. Studies that were duplicate reports or
preliminary reports which were later presented in full were
excluded. The clinical outcome variables reviewed here are
recurrent thromboembolism, prevalence of PTS and all-
cause mortality.
a
The Institute of Medical Semeiotics, University Hospital of Padua, Italy
and
b
The Academic Medical Centre, Amsterdam, The Netherlands
Address for correspondence: Paolo Prandoni, Instituto di Demeiotica Med-
ica, Via Ospedale Civile, 105, 35128 – Padova, Italy.
Arnold 1998 1358-863X(98)VM216MP
Recurrent thromboembolism
Patients with DVT are usually treated with an initial course
of heparin (5–10 days) followed by 3–6 months of oral
anticoagulant therapy. This treatment regimen reduces the
risk for short-term thromboembolic complications to
approximately 5%. Schulman et al performed a multicenter
trial comparing 6 weeks versus 6 months of oral anticoagu-
lant therapy in 897 patients who had suffered a first episode
of venous thromboembolism (VTE).
1
After 2 years of fol-
low-up, there were 80 recurrences among the 443 patients
randomized to the 6-week group (18.1%) and 43 among
the 454 randomized to the 6-month group (9.5%). The odds
ratios for recurrence in the 6-week group was 2.1 (95% CI,
1.4–3.1). This trial showed, therefore, a substantial
reduction in the risk for recurrent thromboembolism among
patients receiving 6 months of anticoagulation. However,
there was no difference in the incidence of recurrent events
in the two groups from 6–24 months after the initial episode
in both groups of patients. Indeed, in both groups, there was
a linear increase in risk after cessation of anticoagulation,
corresponding to a 5–6% incidence annually. Furthermore,
although there was a trend towards a higher rate of recur-
rence among patients with temporary risk factors in the 6-
week group than in the 6-month group (8.6% versus 4.8%),
the overall rate of recurrence after 2 years was much lower
among patients with temporary risk factors than among
those with permanent risk factors (6.6% versus 18%).
In a small prospective 12-year follow-up study of Swiss
patients with symptomatic DVT, venous thromboembolic
recurrent events were observed in 14 (24%) of 58 patients.
2
None of these patients had malignancy or well-recognized
risk factors for venous thrombosis. Further, in a prospective
randomized study addressing the effect of elastic stockings
for prevention of PTS, recurrence of VTE was recorded in
14 (14.6%) of the 96 patients in the stocking group, and in
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58 P Prandoni et al
13 (13.3%) of the 98 patients in the control group over a
5-year follow-up period.
3
The long-term incidence of recurrent venous thromboem-
bolism was additionally determined in 355 consecutive
patients with a first episode of DVT confirmed by venogra-
phy.
4
Patients were followed over a period of 8 years and
were treated with an initial course of full-dose heparin, fol-
lowed by at least 3 months of oral anticoagulants. Follow-
up assessments were scheduled at 3 and 6 months, and then
every 6 months until 8 years. Diagnosis of recurrent VTE
was adjudicated according to standard criteria. After cess-
ation of anticoagulation, a high risk of recurrent venous
thromboembolic disease was found, resulting in a cumulat-
ive incidence of 30% after 8 years of follow-up (Figure
1). One of every five recurrent episodes was pulmonary
embolism (which was fatal in more than half), and approxi-
mately one-third of the recurrent leg vein thromboses were
in the previously asymptomatic leg.
Patients with underlying malignancy, or defects that
impaired coagulation inhibition (antithrombin, protein C
and S defects, lupus-like anticoagulants) were at a statisti-
cally significant higher risk for recurrences than patients
without these features (risk ratio (RR), 1.7 and 1.4,
respectively). As expected, a considerable number of
patients suffered DVT following surgery or trauma. The
findings that these patients were at a significantly lower risk
for recurrent VTE (RR, 0.4 and 0.5, respectively) indicates
that these conditions are transient risk factors for DVT.
The presence of factor V Leiden was subsequently
determined in 251 surviving patients of the previous cohort
free from malignancies or other confirmed abnormalities in
the coagulation or fibrinolytic system.
5
This mutation was
detected in 41 patients (16.3%). The cumulative incidence
of recurrent thromboembolism in carriers of factor V
Leiden mutation after 8 years was 39.7% versus 18.3% in
patients free from this abnormality (RR, 2.4; 95% CI, 1.3
to 4.5; p⬍0.01). These data confirm prior findings from
the Physicians’ Health Study
6
in which a group of 77 men
with a history of venous thromboembolism not associated
with surgery, cancer or trauma, was followed prospectively
over a period of 5 years. In that study, the overall rate of
recurrence was 2.5 events per 100 person years of follow-
up. However, the recurrence rate was significantly higher
among those with factor V Leiden compared with those
without this mutation (7.46 versus 1.82 events per 100 per-
son years of follow-up, p=0.04). Thus, in this study, those
Figure 1 The cumulative incidence (with 95% confidence
intervals) of recurrent venous thromboembolism after a first
episode of symptomatic deep-vein thrombosis. (Adapted from
ref. 4 with permission.)
Vascular Medicine 1998; 3: 57–60
with factor V Leiden had a fourfold increase in risk of
recurrent events. In contrast, recurrent VTE was extremely
uncommon in the Physicians’ Health Study among patients
who had DVT in association with surgery or trauma.
Indeed, among such patients, the association between factor
V Leiden and VTE was no longer statistically significant.
7
What do these findings imply for the management of
patients with DVT? The observed difference in recurrence
rates between patients with and without reversible risk fac-
tors is relevant to the issue of optimal duration of oral anti-
coagulant therapy.
8,9
The long-term prognosis of patients in
whom DVT occurs following exposure to temporary risk
factors (i.e. recent surgery, trauma or fracture) is excellent.
Accordingly, these patients may not require further anti-
coagulation following the initial 3-month period.
In contrast, in patients with malignancy and in those with
either hereditary or acquired thrombophilia, the incidence
of long-term recurrent thromboembolism is high. Accord-
ingly, longer-term anticoagulation may be considered in
these patients, particularly when there is a history of recur-
rent episodes of VTE.
There is insufficient evidence to support a life-long treat-
ment for patients suffering a first idiopathic venous throm-
bosis, since the risks of full dose warfarin over long periods
of time can be substantial. Randomized trials are therefore
needed to explore the benefit to risk ratio of prolonged
anticoagulation beyond the currently recommended 3–6-
month period in patients presenting with a first episode of
spontaneous DVT.
Post-thrombotic syndrome
Post-thrombotic syndrome (PTS) is probably caused by a
combination of venous hypertension, resulting from per-
sisting venous obstruction and venous valve damage, and
abnormal microcirculation.
10
The incidence of PTS follow-
ing confirmed DVT is unknown, but has been reported to
be between 20% and 100%. To date, studies of PTS have
been small or retrospective, and the lack of objective diag-
nostic criteria for PTS makes comparison of these studies
difficult. Further, in all studies, the potential for bias was
high due to either the selection of patients with extensive
thrombotic disease or to failure to distinguish post-
thrombotic sequelae from recurrent venous thrombosis.
Recently, the results of a prospective randomized study
on the prevention of PTS in patients with DVT have
become available. In this study, 194 consecutive patients
with confirmed proximal-vein thrombosis were allocated to
usual care or to elastic commercial stockings.
3
The study
was designed to have at least 5 years of follow-up. A pre-
defined scoring system was used to classify two categories
of patients: mild-to-moderate PTS and severe PTS. Median
follow-up was 76 months in both groups. Mild-to-moderate
PTS occurred in 19 (20%) of the 96 patients with stockings,
and in 46 (47%) of the 98 patients without stockings (p
⬍0.001). Eleven (11.5%) patients in the stocking group
developed severe PTS, while this occurred in 23 (23.5%)
patients without stockings (p⬍0.001). In both groups, the
majority of PTS cases was documented within the first 24
months after the thrombotic event. Extent of initial throm-
bus on venography was not related to the development of
PTS.
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Long-term outcomes after DVT of the lower extremities 59
The long-term incidence of PTS was determined in a
large cohort of consecutive symptomatic patients with a
first episode of venographically proven DVT.
4
All patients
were treated with full-dose heparin followed by at least 3
months of oral anticoagulation, and were instructed to wear
compression elastic stockings as soon as possible after hos-
pital discharge. At each follow-up visit over a 2-year per-
iod, the severity of post-thrombotic signs and symptoms
was scored using a standardized scale. Five subjective
symptoms (heaviness, cramps, pruritis, paresthesia, pain)
and six objective signs (induration of the skin, edema, hyp-
erpigmentation, redness, pain during calf compression, new
venous ectasia) were assessed using a score between 0 and
3. In addition, the presence of ulceration of the leg was
evaluated. A patient was defined as having severe PTS if
ulceration of the leg was observed or if a score higher than
15 was obtained on a single occasion. Mild-to-moderate
PTS was defined if, on two consecutive follow-up visits, a
score from 5 to 14 was reached. All other patients were
considered not to have PTS. The score was determined in
all patients by a single trained physician who was unaware
of the results of the previous evaluations. The validity of
this standardized scale, its reproducibility and its correspon-
dence with a patient’s quality of life have been demon-
strated in a prospective study.
11
Of the 344 patients, 84 developed PTS. Of these, 25
(30%) had severe post-thrombotic manifestations. The
cumulative incidence of the PTS was 18% after 1 year and
24.5% after 2 years of follow-up. Thereafter, the incidence
of the PTS increased gradually until reaching a plateau at
about 30% after 5 years. Considering only severe post-
thrombotic manifestations, a slightly different pattern was
seen: the cumulative incidence increased gradually from
2.7% after 1 year to 8.1% after 5 years (Figure 2). Post-
thrombotic manifestations usually became apparent within
the first 2 years following an acute episode of DVT. These
findings challenge the general view that PTS requires a long
time period to become manifest and are in agreement with
those of the Dutch study.
3
Severe PTS was relatively rare following an episode of
venous thrombosis in patients wearing elastic compression
stockings and adequately treated with anticoagulants. This
low incidence of post-thrombotic manifestations is in clear
contrast with the results of most available studies on PTS,
reporting a risk of severe long-term sequelae in as many
Figure 2 The cumulative incidence (with 95% confidence
intervals) of post-thrombotic syndrome (PTS) after a first
episode of symptomatic deep-vein thrombosis. Data are
shown for all cases of PTS and for the subgroup of cases
considered severe. (Adapted from ref. 4 with permission.)
Vascular Medicine 1998; 3: 57–60
as 50–70% of patients with an acute episode of DVT.
12–22
These conclusions are supported by the findings of another
recent study in which a cohort of 58 consecutive patients
with DVT was prospectively followed for 12 years.
2
During
this long follow-up period, only one patient developed
severe PTS, while 37 patients had both clinical and hemo-
dynamic normal findings. In view of the low absolute inci-
dence of severe PTS found in the recent studies, surgical
thrombectomy or thrombolysis should be reserved for spe-
cial circumstances.
Although it was expected that the extent of the initial
thrombosis and the degree of thrombus occlusiveness
would be related with the risk of developing PTS, this has
not been demonstrated consisently.
3,4
Thus, patients with
minor proximal DVT and those with isolated calf-vein
thrombosis were as likely to develop late sequelae as
patients with extensive thrombosis involving the entire
venous system of the thigh and pelvis. The explanation for
this observation is uncertain. However, the development of
ipsilateral recurrent DVT was associated with increased risk
for PTS. Prevention of recurrent thrombosis with long-term
anticoagulation might thus represent a method to prevent
severe PTS.
Mortality
Short-term mortality (3–6 months) for patients suffering an
episode of DVT is reported to range between 7% and
15%.
23–29
Causes of death include cancer, pulmonary
embolism and major bleeding. However, cancer accounts
for the large majority of patients who die within the first
months after DVT, indicating that patients free of oncologic
disease generally have good prognosis.
23–29
Recently, the long-term mortality of patients with DVT
was documented.
3
In a Dutch study of 355 patients, 90 died
during follow-up. Causes of death in this study included
malignancy (n=52), pulmonary embolism (n=9), acute
myocardial infarction or heart failure (n=5), ischemic
stroke (n=10), anticoagulant related hemorrhage (n=2)
and other miscellaneous etiologies (n=6). In six patients
who died suddenly, a definitive diagnosis could not be
made.
Overall, survival was 83.3% after 1 year and 80.1% after
2 years of follow-up. After 5 and 8 years, the survival was
74.6% and 70.2%, respectively (Figure 3). The presence of
Figure 3 The proportion of patients surviving (with 95%
confidence intervals) after a first episode of symptomatic
deep-vein thrombosis. (Adapted from ref. 4 with permission.)
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60 P Prandoni et al
malignancy increased the risk of death remarkably (RR =
8.1). Other clinical features showed no association with
mortality.
Mortality occurred mainly during the first year in patients
with underlying malignancy. In fact, most patients who
died did so because of a neoplastic disorder already known
at the time of a patient’s presentation or which became
manifest soon after. In patients without malignant dis-
orders, total mortality was low, supporting the view that
current therapeutic approaches to patients with venous
thrombosis are effective and safe. These results also con-
firm previous observations of a strong relationship between
cancer and thrombosis.
30,31
However, whether extensive
diagnostic evaluation for occult malignancy is justified at
the time of referral for idiopathic DVT, remains uncertain.
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