Keywords venous thromboembolism - pulmonary embolism - prognosis - epidemiology
Introduction
Venous thromboembolism (VTE) is associated with a high risk of recurrence and death.[1 ]
[2 ]
[3 ]
[4 ] Age, sex, hemodynamic status at presentation, and the comorbidities represent key
prognostic factors.[5 ]
[6 ] The location of first VTE also plays a role, as patients diagnosed with isolated
distal deep vein thrombosis (IDDVT) have a lower risk of recurrence and death than
those with symptomatic pulmonary embolism (PE) or proximal DVT.[7 ]
[8 ]
[9 ]
[10 ]
[11 ]
[12 ] This has an impact on therapeutic management: while patients with acute PE or proximal
DVT invariably receive anticoagulation treatment, physicians may opt for serial imaging
of the deep veins after acute IDDVT, provided that these patients do not report severe
symptoms or present with major risk factors for extension.[5 ]
[13 ]
In this perspective, it remains unclear whether the distal location of DVT is independently
associated with a lower risk for recurrence in all patients, or represents a marker
of the presence and severity of provoking (risk) factors.[14 ]
[15 ] Preliminary results from cohort studies suggest that cancer, initial burden of thrombus
and degree of thrombus resolution, bilateral presentation, inpatient setting, and
patient demographics might explain a significant proportion of the individual risk
of recurrence in patients with first acute IDDVT.[8 ]
[10 ]
[16 ]
[17 ]
[18 ]
[19 ] The differential role of DVT location may therefore be less relevant in the presence
of major risk factors for recurrence, which would then play as the main determinants
of patients' prognosis and dictate the duration of anticoagulation; however, this
question has not formally been addressed yet.
In the present analysis, we investigated the impact of distal (vs. proximal) DVT location
on the risk of developing symptomatic, objectively confirmed recurrent DVT or PE in
patients with a first acute symptomatic DVT not associated with PE, who were stratified
by the presence of transient or persistent risk factors.
Patients and Methods
The details of our cohort study, which retrospectively investigated the association
of DVT location (IDDVT vs. proximal DVT) with DVT recurrence or survival, have been
previously described.[19 ] In short, we included consecutive adult patients followed up at a single center
between 2000 and 2012 meeting the following eligibility criteria: objective diagnosis
of first symptomatic IDDVT or proximal DVT with compression ultrasound examination,
no concomitant PE or prior VTE, and at least one follow-up visit.[20 ] In accordance with current recommendations, and upon availability of the clinical
covariates, we have categorized patients according to the presence of the following
risk factors[1 ]: transient (e.g., immobilization, recent surgery or trauma, pregnancy or caesarean
section, long-haul flight)[2 ]; minor persistent (e.g., autoimmune diseases, inherited thrombophilia, familiar
history of VTE, congestive heart failure)[3 ]; no identifiable risk factor (“unprovoked” DVT)[4 ]; and cancer-associated DVT.[5 ]
[21 ] We did not distinguish between major and minor transient risk factors, which are
viewed as a continuum in clinical practice[5 ]
[21 ] and, in our study population, were often concomitant to minor persistent risk factors
(and therefore classified accordingly). The primary outcome was symptomatic, objectively
diagnosed recurrent VTE, including proximal DVT and fatal or nonfatal PE. Recurrent
events had been reviewed by two investigators based on the original reports. The secondary
outcome was all-cause death.
Routine clinical care included patient education with all patients instructed to contact
the center in case of signs or symptoms of recurrence. After the diagnosis of acute
DVT, annual controls were scheduled and patients contacted on the same day if they
missed the visit. Routine ultrasound examination of the whole leg was performed at
the time of DVT diagnosis, upon anticoagulant discontinuation as a baseline reference
allowing future comparisons in case of suspected recurrent events, during follow-up
visits, and on suspicion of recurrence.
We accessed the center database including patient demographics and personal data.
Follow-up data were extracted from source medical charts of the clinic and the institutional
electronic medical record including information on admissions, consults, discharge
letters, outpatient visits, and radiological data. Variable coding has been previously
reported.[19 ] The Web site of the Local Health Authority was used for assessing patients' vital
status on December 2017. Two study protocols had been developed for the primary[19 ] and the present analysis, and received separate approvals by the institutional Ethical
Committee. Patients provided written consent for the use of clinical data at the first
available follow-up visit after the first approval of the study protocol.
Descriptive analyses were performed using counts (n /N ) and percentages for categorical data and mean/median plus adequate measures of dispersion
for continuous variables. Incidence rates of recurrent VTE, expressed as number of
events per 100 patient-years, were calculated for the time elapsing between first
DVT and recurrence: right censoring was applied if the patient died or at the latest
available follow-up visit. Cox regression models were fit to estimate hazard ratios
(HRs), and corresponding 95% confidence intervals (95% CIs), for the risk of recurrent
VTE after first IDDVT (vs. proximal DVT). The covariates used for calculating adjusted
HRs (aHRs) were chosen based on the primary analysis; they included age, sex, recent
hospitalization, and duration of anticoagulation.[19 ] R v.3.4.3 (ggplot2 , survival ) and SPSS v.23 (IBM, US) served for data analysis.
Results
After screening of 4,759 medical records of patients referred to our center,[19 ] a total of 831 patients with first acute symptomatic DVT were included, of whom
202 had IDDVT and 629 had proximal DVT. The median age was 66 years (interquartile
range [IQR], 52–76); 50.5% were women. A total of 205 (24.7%) patients presented with
a transient risk factor, 189 (22.7%) with a minor persistent risk factor, 202 (24.3%)
with unprovoked DVT, and 235 (28.3%) with cancer-associated DVT. Median (IQR) length
of follow-up in the four groups was 4.7 (IQR 2.3–6.1), 4.6 (IQR 2.3–6.3), 4.9 (IQR
1.9–6.9), and 3.7 (IQR 0.6–6.1) years, respectively. The baseline characteristics
of the study population stratified by the presence of risk factors and the location
of first DVT are summarized in [Table 1 ]. The location of cancer in patients with cancer-associated DVT is reported in [Table 2 ]. Additional details have been previously reported.[19 ]
Table 1
Baseline characteristics of the study population, number of recurrent events, and
mortality rate
Transient risk factor (n = 205)
Minor persistent risk factor (n = 189)
Unprovoked DVT (n = 202)
Cancer-associated DVT (n = 235)
Proximal (n = 144)
Distal (n = 61)
Proximal (n = 139)
Distal (n = 50)
Proximal (n = 159)
Distal (n = 43)
Proximal (n = 177)
Distal (n = 58)
Age (y), median (IQR)
59 (43–75)
65 (52–74)
59 (45–73)
59 (42–73)
70 (59–79)
68 (50–75)
70 (59–76)
67 (61–75)
Female sex, n (%)
72 (50.0)
35 (57.4)
74 (49.7)
18 (45.0)
76 (47.8)
27 (62.8)
84 (47.5)
34 (58.6)
In-hospital status at diagnosis, n (%)
43 (29.9)
15 (24.6)
19 (12.8)
5 (12.5)
0
0
51 (28.8)
17 (29.3)
Autoimmune disease, n (%)
0
0
48 (32.2)
15 (37.5)
0
0
11 (6.2)
3 (5.2)
Inherited thrombophilia, n (%)
0
0
50 (33.6)
13 (32.5)
0
0
14 (7.9)
2 (3.4)
Familiar history of VTE, n (%)
0
0
30 (20.1)
5 (12.5)
0
0
1 (0.6)
1 (1.7)
Recent long-distance travel, n (%)
9 (6.3)
2 (3.3)
3 (2.0)
0
0
0
0
0
Pregnancy or cesarean section, n (%)
7 (8.8)
0
4 (4.8)[a ]
1 (5.9)[a ]
0
0
0
0
Recent trauma or fracture, n (%)
42 (29.2)
24 (39.3)
10 (6.7)[a ]
1 (2.5)[a ]
0
0
5 (2.8)
3 (5.2)
Prolonged immobilization, n (%)
49 (34.0)
26 (42.6)
47 (31.5)
14 (35.0)
0
0
9 (5.1)
7 (12.1)
Recent surgery, n (%)
61 (42.4)
25 (41.0)
11 (7.4)[a ]
4 (10.0)[a ]
0
0
30 (16.9)
14 (24.1)
Diabetes mellitus, n (%)
11 (7.6)
7 (11.5)
15 (10.1)
4 (10.0)
22 (13.8)
6 (14.0)
29 (16.4)
9 (15.5)
Vascular disease, n (%)
32 (22.2)
13 (21.3)
29 (19.5)
10 (25.0)
54 (34.0)
13 (30.2)
23 (13.0)
14 (24.1)
Arterial hypertension, n (%)
39 (27.1)
20 (32.8)
47 (31.5)
16 (40.0)
75 (47.2)
18 (41.9)
68 (38.4)
28 (48.3)
Intermediate or therapeutic dosage of anticoagulant, n (%)
138 (98.6)
53 (89.8)
144 (98.8)
37 (94.9)
156 (98.7)
41 (95.3)
167 (96.5)
51 (91.1)
Length of anticoagulation (d), median (IQR)
212 (107–462)
83 (42–120)
302 (175–1155)
101 (43–185)
342 (103–1161)
49 (32–117)
188 (77–451)
67 (43–151)
1-y mortality, n (%)
9 (6.3)
2 (3.3)
2 (1.3)
1 (2.5)
9 (5.7)
1 (2.3)
58 (33.0)
22 (37.9)
10-y mortality, n (%)
26 (18.1)
11 (18.0)
26 (17.4)
3 (7.5)
46 (28.9)
8 (18.6)
121 (68.4)
34 (58.6)
Recurrent VTE events, n (%)[b ]
22 (15.3)
4 (6.6)
26 (17.4)
4 (10.0)
36 (22.6)
2 (4.7)
25 (14.1)
6 (10.3)
PE events associated or not with DVT, n
2
3
3
0
9
2
2
1
Proximal DVT, n
20
1
23
4
27
0
23
5
Abbreviations: DVT, deep vein thrombosis; IQR, interquartile range; VTE, venous thromboembolism.
a Presenting with both a transient and a minor persistent risk factor.
b Incidence rates are provided in [Fig. 1 ].
Table 2
Localization of cancer and ongoing cancer treatment in patients with proximal or distal
deep vein thrombosis
Cancer-associated deep vein thrombosis (n = 235)
Proximal (n = 177)
Distal (n = 58)
Localization
Colon, n (%)
35 (19.8)
5 (8.6)
Lung, n (%)
12 (6.8)
7 (12.1)
Breast, n (%)
12 (6.8)
4 (6.9)
Pancreas, n (%)
5 (2.8)
5 (8.6)
Leukemia, n (%)
33 (18.6)
6 (10.3)
Myeloproliferative, n (%)
6 (3.4)
1 (1.7)
Gynecological, n (%)
20 (11.3)
4 (6.9)
Kidney, n (%)
14 (7.9)
3 (5.2)
Gastric, n (%)
9 (5.1)
8 (13.8)
Central nervous system, n (%)
7 (4.0)
2 (3.4)
Liver, n (%)
7 (4.0)
4 (6.9)
Metastatic cancer, n (%)
58 (32.8)
15 (25.9)
Cancer treatment
Chemotherapy, n (%)
72 (40.7)
21 (36.2)
Radiotherapy, n (%)
12 (6.8)
5 (8.6)
Hormonal treatment, n (%)
12 (6.8)
5 (8.6)
One-hundred twenty-five patients (15.0%) had recurrent symptomatic proximal DVT or
PE, corresponding to overall annualized incidence rates of 2.0% in patients after
IDDVT and 4.5% after proximal DVT. The annualized rates of recurrence in patients
stratified by DVT location and baseline risk factors are presented in [Fig. 1 ]. The largest relative difference between patients with distal and proximal DVT was
observed in the absence of identifiable risk factors (adjusted HR [aHR]: 0.11; 95%
CI: 0.03–0.45) after adjustment for age, sex, and length of anticoagulant treatment.
Similar results were obtained if only events off anticoagulation were considered ([Fig. 1 ]). The impact of DVT location was less prominent in the presence of cancer (aHR:
0.70 for distal vs. proximal DVT [95% CI: 0.28–1.78]). No firm conclusions could be
drawn for patients with transient (0.47 [95% CI: 0.15–1.45]) and minor persistent
(aHR: 0.44; [95% CI: 0.15–1.30]) provoking risk factors, due to the lack of statistical
power. The cumulative recurrence in patients with distal and proximal DVT stratified
according to baseline risk factors is depicted in [Fig. 2 ].
Fig. 1 Prognostic value of distal (vs. proximal) isolated deep vein thrombosis (DVT) according
to baseline provoking risk factors. Rates and hazard ratios (HR) for cancer-associated
DVT patients off anticoagulants were not calculated as the mortality rate was high
and vast majority of them received extended anticoagulant treatment. Adjusted HRs
account for age, sex, length of anticoagulant treatment (only for events on and off
anticoagulant), in-hospital status at the time of DVT diagnosis.[19 ] CI, confidence interval; IDDVT, isolated distal deep vein thrombosis.
Fig. 2 Cumulative rate of recurrent deep vein thrombosis (DVT) or pulmonary embolism in
patients with first distal versus proximal DVT stratified according to baseline risk
factors.
Since cancer patients were characterized by the highest 1-year mortality (33.0% after
proximal DVT and 37.9% after distal DVT) and 10-year mortality (68.4% after proximal
DVT and 58.6% after distal DVT), in this group we used Cox regression models adjusted
for different potential confounders to assess the impact of DVT location also on all-cause
mortality ([Table 3 ]). At univariate analysis, HR (95% CI) for distal (vs. proximal) DVT was 0.67 (95%
CI: 0.26–1.72). In the fully adjusted model accounting for age, sex, in-hospital status
at diagnosis, presence of metastasis, cardiovascular or autoimmune disease, and recent
surgery/trauma, HR for distal (vs. proximal) DVT was 1.02 (95% CI: 0.69–1.50). The
cumulative mortality in patients with distal and proximal DVT is depicted in [Fig. 3 ].
Fig. 3 Cumulative mortality after first distal versus proximal cancer-associated deep vein
thrombosis (DVT).
Table 3
Impact of distal (vs. proximal) deep vein thrombosis location on mortality in cancer
patients
Hazard ratio
(95% confidence interval)
Model 1: univariate
0.67 (0.26–1.72)
Model 2: adjusted for age and sex
0.87 (0.60–1.27)
Model 3: adjusted for age, sex, in-hospital status, metastasis, cardiovascular disease
0.96 (0.67–1.41)
Model 4: adjusted for age, sex, in-hospital status, metastasis, cardiovascular disease,
recent surgery or trauma, autoimmune diseases, immobilization
1.02 (0.69–1.50)
Discussion
The decision to continue anticoagulation for an extended period after DVT depends
on the estimated risk of progression or recurrence after diagnosis and, thereafter,
after discontinuing anticoagulation.[22 ] The results of our analysis confirm that the risk of recurrence is substantial not
only in patients with a first unprovoked proximal DVT event (annualized rate of 10.1% after anticoagulant discontinuation), but also
in those with a proximal DVT caused by transient (4.2%) or minor persistent risk factors
(6.7%).[23 ]
[24 ] These rates are comparable to that described in a post hoc analysis of VTE patients
enrolled in the Einstein CHOICE trial.[23 ] Consistently, a recent population-based study conducted in Denmark showed that patients
with first unprovoked VTE had similar 6-month risk of recurrence compared with those
with non–cancer-provoked VTE.[25 ] These data challenge the notion of tailoring anticoagulation to the individual patient
on the basis of categorization of transient and persistent risk factors other than
cancer, also because a large proportion of patients may present with both transient
and persistent risk factors, or with multiple persistent risk factors.[26 ]
On the other hand, we found that patients with a first episode of IDDVT in the absence
of identifiable risk factors were at truly low risk of developing long-term recurrence
(1.0% per year after anticoagulant discontinuation). This rate is lower than the one
observed in the OPTimisation de l'Interrogatoire pour la Maladie thromboEmbolique
Veineuse (OPTIMEV) study (3.8%),[10 ] but comparable to the results of the Austrian Study on Recurrent Venous Thromboembolism
(AUREC) study (1.7%).[8 ] The differences may be explained, at least in part, by the longer follow-up time
in AUREC (10 years) and in the present analysis (∼4.5 years) compared with OPTIMEV
(3 years), leading to a dilution of the initial peak of recurrence usually observed
after anticoagulant discontinuation.[22 ]
Our results indirectly support the hypothesis that not all patients with IDDVT may
even require initial anticoagulant therapy due to their negligible risk of progression
or recurrence, as suggested by the results of the CACTUS trial, in which low-risk
outpatients with IDDVT were randomized to receive either low-molecular-weight heparin
or placebo.[27 ] In contrast, based on our data only patients with unprovoked IDDVT appeared at a
truly low risk of recurrence after standard course of anticoagulation with an annualized
rate of 1.0%, whereas the presence of additional risk factors for recurrence doubled
this risk. The long-term risk of recurrence and death was comparable between patients
with distal and proximal cancer-associated DVT, with aHR of 0.70 (95% CI: 0.28–1.78)
and 1.02 (95% CI: 0.69–1.50), respectively. Our results confirmed prior reports showing
that the short-term risk of recurrence is substantial in patients with cancer-associated
IDDVT.[17 ]
[28 ] These findings support the view that decisions on anticoagulation should be primarily
based on the assessment of individual risk factors rather than categorization by location,
and that distal versus proximal DVT location appears relevant only in patients at
low risk in whom no provoking factors are identified.[26 ]
Limitations of our analysis include confounding by indication (IDDVT patients were
often treated for shorter periods and with lower anticoagulant doses[19 ]) and wide confidence intervals of the estimates. Moreover, the classification of
patients according to baseline risk factors was done retrospectively. Finally, the
relatively low count of events recorded in this study did not allow us to adjust for
other important variables which may confound the association between DVT location
and outcomes.
Conclusions
The distal (vs. proximal) location of first acute symptomatic DVT represented, in
the absence of any identifiable transient or persistent risk factors, a favorable
prognostic factor for recurrence. This observation supports the decision to abstain
from extended anticoagulant therapy after unprovoked IDDVT. In contrast, the prognostic
impact of DVT location was weaker or absent if persistent provoking factors for VTE
are present, notably cancer. These results should be taken into account when tailoring
the duration of anticoagulant treatment in patients diagnosed with acute symptomatic
DVT.
