Research

JAMA Cardiology | Original Investigation

Clinical Presentation and Short- and Long-term Outcomes in Patients

With Isolated Distal Deep Vein Thrombosis vs Proximal Deep Vein
Thrombosis in the RIETE Registry
Behnood Bikdeli, MD, MS; César Caraballo, MD; Javier Trujillo-Santos, MD, PhD; Jean Philippe Galanaud, MD, PhD;
Pierpaolo di Micco, MD, PhD; Vladimir Rosa, MD, PhD; Gemma Vidal Cusidó, MD; Sebastian Schellong, MD, PhD;
Meritxell Mellado, MD, PhD; María del Valle Morales, MD; Olga Gavín-Sebastián, MD, PhD;
Lucia Mazzolai, MD, PhD; Harlan M. Krumholz, MD, SM; Manuel Monreal, MD, PhD; for the RIETE Investigators

Supplemental content
IMPORTANCE Insufficient data exist about the clinical presentation, short-term, and
long-term outcomes of patients with isolated distal deep vein thrombosis (IDDVT), that is,
thrombosis in infrapopliteal veins without proximal extension or pulmonary embolism (PE).

OBJECTIVE To determine the clinical characteristics, short-term, and 1-year outcomes in

patients with IDDVT and to compare the outcomes in unadjusted and multivariable adjusted
analyses with patients who had proximal DVT.

DESIGN, SETTING, AND PARTICIPANTS This was a multicenter, international cohort study in
participating sites of the Registro Informatizado Enfermedad Tromboembólica (RIETE)
registry conducted from March 1, 2001, through February 28, 2021. Patients included in this
study had IDDVT. Patients with proximal DVT were identified for comparison. Patients were
excluded if they had a history of asymptomatic DVT, upper-extremity DVT, coexisting PE, or
COVID-19 infection.

MAIN OUTCOMES AND MEASURES Primary outcomes were 90-day and 1-year mortality, 1-year
major bleeding, and 1-year venous thromboembolism (VTE) deterioration, which was defined
as subsequent development of proximal DVT or PE.

RESULTS A total of 33 897 patients were identified with isolated DVT (without concomitant
PE); 5938 (17.5%) had IDDVT (mean [SD] age, 61 [17] years; 2975 male patients [50.1%]), and
27 959 (82.5%) had proximal DVT (mean [SD] age, 65 [18] years; 14 315 male patients
[51.2%]). Compared with individuals with proximal DVT, those with IDDVT had a lower
comorbidity burden but were more likely to have had recent surgery or to have received
hormonal therapy. Patients with IDDVT had lower risk of 90-day mortality compared with
those with proximal DVT (odds ratio [OR], 0.47; 95% CI, 0.40-0.55). Findings were similar in
1-year unadjusted analyses (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59) and adjusted
analyses (HR, 0.72; 95% CI, 0.64-0.82). Patients with IDDVT had a lower 1-year hazard of VTE
deterioration (HR, 0.83; 95% CI, 0.69-0.99). In 1-year adjusted analyses of patients without
an adverse event within the first 3 months, IDDVT was associated with lower risk of VTE
deterioration (adjusted HR, 0.48; 95% CI, 0.24-0.97). By 1-year follow-up, symptoms or signs
of postthrombotic syndrome were less common in patients with IDDVT (47.6% vs 60.5%).

CONCLUSIONS AND RELEVANCE Results of this cohort study suggest that patients with IDDVT
had a less ominous prognosis compared with patients with proximal DVT. Such differences
were likely multifactorial, including the differences in demographics, risk factors,
comorbidities, particularly for all-cause mortality, and a potential association of thrombus Author Affiliations: Author
affiliations are listed at the end of this
location with VTE deterioration and postthrombotic syndrome. Randomized clinical trials are article.
needed to assess the optimal long-term management of IDDVT.
Group Information: The RIETE
Investigators appear in
Supplement 2.
Corresponding Author: Behnood
Bikdeli, MD, MS, Cardiovascular
Medicine Division and the
Thrombosis Research Group,
Brigham and Women’s Hospital,
Harvard Medical School, 75 Francis
St, Boston, MA 02115 (behnood.
JAMA Cardiol. doi:10.1001/jamacardio.2022.1988 bikdeli@yale.edu; bbikdeli@
Published online July 13, 2022. bwh.harvard.edu).

(Reprinted) E1
© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022

 Research Original Investigation
I
solated distal deep vein thrombosis (IDDVT), ie, thrombo-
sis in the infrapopliteal veins without coexisting proximal
DVT or pulmonary embolism (PE), accounts for 20% to 50%
of all DVTs.1,2 The data related to clinical presentation and out-
comes of patients with IDDVT are limited. Some studies sug-
gest less ominous outcomes with IDDVT compared with proxi-
mal DVT. However, prior studies were from single institutions
or included a small number of patients, were underpowered
to differentiate the clinical presentation of patients with IDDVT
and those with proximal DVT, and focused only on short-
term outcomes.2-6 Limitations with our understanding of out-
comes for IDDVT is also discussed in the practice guidelines.7,8
It remains uncertain whether there are true differences in mor-
tality, venous thromboembolism (VTE) recurrences, and bleed-
ing events among patients with IDDVT compared with proxi-
mal DVT and whether the potential differences attenuate after
consideration of the demographics, comorbidities, and VTE risk
factors.2,3,9-11 Addressing these gaps in knowledge has impli-
cations for prognostication, and may affect the downstream
treatment or follow-up decisions.
The Registro Informatizado Enfermedad Tromboem-
bólica (RIETE) is an ongoing prospective registry of patients
with VTE. Using the data from RIETE, we sought to deter-
mine the clinical presentation and 90-day and 1-year out-
comes in patients with IDDVT. We compared those findings
against patients with proximal DVT in unadjusted and multi-
variable adjusted analyses.
Methods
Data Source and Patients
Details about the methodology of the RIETE registry have been
described previously (eAppendix in Supplement 1).12,13 Currently,
the RIETE registry includes over 200 enrolling centers from Africa,
North and South America, Asia, and Europe. The RIETE registry
enrolls consecutive patients with objectively confirmed VTE (DVT,
PE, or both) with a minimum follow-up of 3 months. Many pa-
tients complete 1-year and 2-year follow-up. All patients provided
written or verbal informed consent in line with institutional re-
view board requirements from each participating center. Previ-
ous studies have shown that the RIETE population closely rep-
resents that of large administrative databases.14 This study ad-
hered to the Strengthening the Reporting of Observational Studies
in Epidemiology (STROBE) reporting guidelines.
For the current investigation, we focused on patients with
IDDVT (ie, those with infrapopliteal DVT in the absence of co-
existing proximal DVT or coexisting PE) enrolled in the RIETE
registry between March 1, 2001, through February 28, 2021.
We compared patients with IDDVT with patients with proxi-
mal DVT. We excluded patients with asymptomatic DVT or up-
per-extremity DVT and patients who had coexisting PE. In ad-
dition, we excluded patients with DVT in the setting of
COVID-19 infection because the clinical characteristics and out-
comes of those patients may be different from other patient
groups.15-17 We determined the demographics, comorbidi-
ties, and treatments in patients with IDDVT. We compared them
against patients with proximal DVT.
E2 JAMA Cardiology Published online July 13, 2022 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022
Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis
Key Points
Question What are the clinical characteristics and outcomes of
patients with isolated distal deep vein thrombosis (DVT)
compared with those with proximal DVT?
Findings Among 33 897 participants in this cohort study, patients
with isolated distal DVT had a lower comorbidity burden and a
lower risk of 90-day mortality (odds ratio, 0.47) and 1-year
composite of pulmonary embolism or new venous
thromboembolism (hazard ratio, 0.83).
Meaning Isolated distal DVT compared with proximal DVT was
associated with lower risk of adverse events; this association was
likely multifactorial with contribution from comorbidity burden on
all-cause mortality and a potential association of thrombus
location with venous thrombosis outcomes.
Outcomes
Short-term outcomes included 30-day and 90-day all-cause
mortality, PE-related mortality, and major bleeding. Bleeding
was considered as major if it was overt and required a trans-
fusion of 2 or more units of blood, involved a critical site (ret-
roperitoneal, spinal, or intracranial), or was fatal.12 This defi-
nition closely resembles that of the International Society on
Thrombosis and Haemostasis for major bleeding.18 Long-
term outcomes included mortality, VTE deterioration (de-
fined as subsequent development of proximal DVT, or PE, in-
cluding fatal PE), and major bleeding. We assessed for signs
or symptoms of postthrombotic syndrome according to the Vil-
lalta score in patients with available follow-up. This outcome
has been available in the RIETE registry since 2009.
Statistical Analysis
Comparison of categorical variables between those with IDDVT
and proximal DVT was done via χ2 tests. We used the t test or
its nonparametric counterparts for comparison of continu-
ous variables between the 2 groups. One-year outcomes were
assessed via survival analysis to account for censored infor-
mation. For each specific outcome, censoring occurred only
by the end of 1-year follow-up, by reaching the outcome of in-
terest, or on loss to follow-up.
It was prespecified to run multivariable models to deter-
mine if differences existed in the outcomes of patients with
IDDVT compared with proximal DVT; if differences did exist,
we prespecified to determine they were driven by the demo-
graphics, comorbidities, and VTE risk factors. For that pur-
pose, we used multivariable logistic regression analysis for
short-term (90-day) outcomes and adjusted hazard models for
1-year outcomes. Variables were preselected by clinical con-
sensus for multivariable adjustment and included age, sex, his-
tory of diabetes, anemia, chronic lung disease, active cancer,
recent surgery (defined as surgery within 2 months before the
index VTE event), immobility (defined as bed rest for at least
4 days within the prior 2 months), creatinine clearance, and
use of anticoagulation.
RIETE is not an interventional study. The duration of an-
ticoagulation may be variable based on patients’ clinical sta-
tus and decisions by the treating clinicians. In the absence of
jamacardiology.com
 Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis Original Investigation Research

contraindications, patients with acute VTE are routinely treated

Table. Demographic and Clinical Characteristics
at least for 90 days. For short-term (90-day) outcomes, ad-
justment in multivariable analyses for use of anticoagulation No./total No. (%)a
was operationalized by a dichotomous variable, indicating IDDVT Proximal DVT
Characteristic (n = 5938) (n = 27 959)
whether anticoagulation was interrupted for 2 or more con- Female sex 2963 (49.9) 13 644 (48.8)
secutive days until the end of the 90-day follow-up period or
Male sex 2975 (50.1) 14 315 (51.2)
reaching the end point in each patient. For adjustment for mul-
Age, mean (SD), y 61 65 (18)
tivariable analyses of 1-year outcomes, a different variable was (17)
operationalized. By 1-year follow-up, patients may have con- BMI, mean (SD)b 27.6 27.8 (5.2)
(5.2)
tinued the anticoagulation indefinitely without any interrup-
Underlying conditions
tions, they may have received at least 3 months of anticoagu-
Chronic lung disease 410 2432 (8.7)
lation and stopped anticoagulation permanently thereafter, or (6.9)
they may have had a more complex sequence of events (eg, Chronic heart failure 238 1146 (4.1)
intermittent initiation and discontinuation). Therefore, for mul- (4.0)
tivariable adjustment, a 3-category categorical variable was Diabetes (n = 21 358) 438/3655 2761/17 703 (15.6)
(12.0)
used.
Hypertension (n = 21 703) 1476/3701 8205/18 002 (45.6)
Because reaching the end point was distinct for mortality (39.9)
and nonmortality outcomes, one such variable was created per Prior myocardial infarction 225/3641 1059/17 593 (6.0)
(n = 21 234) (6.2)
each outcome. For 1-year all-cause mortality, Cox propor-
Prior ischemic stroke 153/3633 1038/17 583 (5.9)
tional hazards models were used. For 1-year PE-related mor- (n = 21 216) (4.2)
tality, VTE deterioration, and major bleeding, Fine-Gray mod- Recent major bleeding 107 531(1.9)
els were implemented to account for the competing risk of (1.8)
event other than the outcomes of interest. A 2-sided P value < Anemia 1692 9897 (35.4)
(28.5)
.05 was considered significant. Data analyses were per- Platelet count, mean (SD), 247 234 (94)
formed using SPSS for SP Release, version 20 (SPSS Inc) and cells per mL (91)
Stata, version 15.1 (StataCorp). Creatinine clearance, mean 85 79 (39)
(SD), mL/min/1.73 m2 (39)
Recent surgery 1692 (15.6) 2572 (9.2)
Recent immobility 1384 (23.3) 6794 (24.3)
Results Active cancer 724 (12.2) 4697 (16.8)
Prior VTE 843 (14.2) 4697 (16.8)
We identified a total of 33 897 patients with isolated DVT, of
Pregnancy/puerperium 58/2963 (2.0) 536/13 644 (4.0)
whom 5938 (17.5%) had IDDVT (mean [SD] age, 61 [17] years; (n = 16 462)
2975 male patients [50.1%]; 2963 female patients [49.9%]), Hormonal use among women 395/2926 1400/14 443 (9.7)
and 27 959 (82.5%) had proximal DVT (mean [SD] age, 65 (n = 17 369) (13.5)
[18] years; 14 315 male patients [51.2%]; 13 644 female Symptoms
patients [48.8%]) (eFigure 1 in Supplement 1). Patients with Pain (n = 33 297) 5261/5807 24 142/27 490 (87.8)
(90.6)
IDDVT were less likely to have chronic lung disease (410
Swelling (n = 33 260) 4958/5765 26 033/27 495 (94.7)
[6.9%] vs 2432 [8.7%]), prior stroke (153 of 3633 [4.2%] vs (86.0)
1038 of 17 583 [5.9%]), prior VTE (843 [14.2%] vs 4697 Vital signs
[18.8%]), or cancer (724 [12.2%] vs 4697 [16.8%]) than those SBP <90 mm Hg (n = 30 752) 90/5057 (1.8) 800/25 695 (3.1)
with proximal DVT but more likely to have had recent sur- Heart rate >100 bpm 380/4827 (5.7) 2996/25 047 (8.7)
gery (1692 [15.6%] vs 2572 [9.2%]) or estrogen/hormone (n = 29 874)
therapy use (395 of 2926 [13.5%] vs 1400 of 14 433 [9.7%]) SaO2 < 90% (n = 2837) 26/330 (7.9) 174/2507 (6.9)

(Table; eTable 1 in Supplement 1).
Treatment Patterns
Most patients with IDDVT or proximal DVT were given anti-
coagulation treatment (33 843 of 33 897 [99.8%]), most com-
monly with low-molecular-weight heparins. No patients with
IDDVT received fibrinolytic therapy. An inferior vena cava fil-
ter was used in 33 patients (0.6%) with IDDVT. Albeit used
rarely, both therapies were more commonly used for patients
with proximal DVT.
By 90-day follow-up, 90.9% of patients (5036 of 5541) with
IDDVT and 97.0% of patients (25 027 of 25 792) with proximal
DVT remained on anticoagulation. By 6-month and 1-year follow-
up, the proportion of patients with IDDVT and proximal DVT who
remained on anticoagulation were 69.1% (2215 of 3207) vs 83.4%
Abbreviations: BMI, body mass index; bpm, beats per minute; DVT, deep vein
thrombosis; IDDVT, isolated distal DVT; SaO2, oxygen saturation; SBP, systolic
blood pressure; VTE, venous thromboembolism.
SI conversion factor: To convert creatinine clearance to milliliter per second per
meter squared, multiply by 0.0167.
a
Values listed as No. (%) unless otherwise specified.
b
Calculated as weight in kilograms divided by height in meters squared.
(14 778 of 17 720) and 49.1% (817 of 1665) vs 64.2% (6453 of
10 047), respectively (Figure 1). Additional details are summa-
rized in eTable 2 in Supplement 1.
Short-term Mortality and Bleeding
At 30 days from enrollment, 64 patients (1.1%) with IDDVT died
(95% CI, 0.9%-1.4%) compared with 760 patients (2.8%) with

jamacardiology.com (Reprinted) JAMA Cardiology Published online July 13, 2022 E3

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022

 Research Original Investigation
Figure 1. Use of Anticoagulation in Patients With Isolated Distal Deep
Vein Thrombosis (IDDVT) and Patients With Proximal DVT
P =.99 IDDVT
P <.001
100
P <.001
80
Proportion of patients, %
60
40
20
0 (Figure 3B). Findings were similar in multivariable analysis
Baseline 3 6
Follow-up period, mo
proximal DVT (95% CI, 2.6%-3.0%). Patients with IDDVT had
a lower risk of 30-day all-cause mortality compared with those
with proximal DVT (odds ratio [OR], 0.39; 95% CI, 0.30-0.51;
P < .001). Results attenuated after multivariable adjustment
(OR, 0.71; 95% CI, 0.51-0.97). Among patients with IDDVT, there
were only 3 deaths (0.05%) from PE at 30-day follow-up
(95% CI, 0.01%-0.1%).
By 90-day follow-up, 168 patients (2.9%) with IDDVT and
1642 patients (6.0%) with proximal DVT died. Therefore, pa-
tients with IDDVT had a lower risk of 90-day mortality com-
pared with those with proximal DVT (OR, 0.47; 95% CI, 0.40-
0.55; P < .001). Results were similar after multivariable
adjustment (OR, 0.65; 95% CI, 0.55-0.73; P < .001). Among pa-
tients with IDDVT, the total number of PE deaths at 90 days
was only 3 (0.05%). No significant difference in PE-related mor-
tality was detected in patients with IDDVT compared with
proximal DVT (OR, 0.49; 95% CI, 0.15-1.61; P = .23).
At 30-day follow-up, major bleeding was less frequent in
patients with IDDVT compared with proximal DVT (0.6% vs
1.2%; OR, 0.51; 95% CI, 0.36-0.72; P < .001). The difference was
attenuated but persisted after multivariable adjustment (OR,
0.60; 95% CI, 0.41-0.88; P = .009). Results were consistent at
90-day follow-up in bivariate (OR, 0.53; 95% CI, 0.40-0.71;
P < .001) and multivariable analysis (OR, 0.64; 95% CI, 0.48-
0.86; P = .01) (Figure 2).
One-Year Mortality, VTE Recurrence, and Bleeding
By 1-year follow-up, patients with IDDVT had a lower hazard
for all-cause mortality (hazard ratio [HR], 0.52; 95% CI, 0.46-
0.59; P < .001) (Figure 3A). After adjustment for demograph-
ics, comorbidities, and VTE risk factors, the association at-
tenuated but persisted (adjusted HR [aHR], 0.72; 95% CI, 0.64-
0.82). By 1-year follow-up, there were only 3 PE-related deaths
(0.05%) in patients with IDDVT.
There were 246 VTE deterioration events (4.5%) (PE, PE-
related mortality, or new proximal DVT) at 1-year follow-up in
patients with IDDVT and 1688 events in patients with proxi-
mal DVT (6.8%; HR, 0.83; 95% CI, 0.69-0.99; P = .04)
E4 JAMA Cardiology Published online July 13, 2022 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022
Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis
Figure 2. All-Cause Death and Major Bleeding Outcomes at 90 Days
90-d Outcome aOR (95% CI)
All-cause death
Proximal DVT
Unadjusted 0.47 (0.40-0.55)
Adjusted 0.65 (0.55-0.73)
Major bleeding
Unadjusted 0.53 (0.40-0.71)
P <.001 Adjusted 0.64 (0.48-0.86)
0 0.5 1.0 1.5
aOR (95% CI)
Reference group (dotted vertical line) is proximal deep vein thrombosis. Point
estimates are adjusted odds ratios (aORs), with 95% CIs shown in error bars.
12 (aHR, 0.83; 95% CI, 0.69-1.00; P = .05).
In a prespecified multivariable 1-year analysis among pa-
tients without an adverse event within first 90 days, after ad-
justment for demographics, comorbidities, VTE risk factors,
and use of anticoagulation, IDDVT compared with proximal
DVT was associated with lower hazard for VTE deterioration
(HR, 0.42; 95% CI, 0.21-0.84) (eFigure 2 in Supplement 1). Re-
sults remained consistent in multivariable analysis (aHR, 0.48;
95% CI, 0.24-0.97).
By 1-year follow-up, patients with IDDVT, compared with
those with proximal DVT, were at lower risk for major bleed-
ing (HR, 0.69; 95% CI, 0.50-0.94; P < .02). Results were no lon-
ger significant in multivariable analysis (aHR, 0.86; 95% CI,
0.64-1.16) (Figure 4).
Symptoms and Signs of Postthrombotic Syndrome
Symptoms or signs of postthrombotic syndrome were avail-
able among 2133 patients at 1-year follow-up. Patients with
IDDVT were less likely to have a composite of postthrombotic
syndrome signs or symptoms than those with proximal DVT
(47.5% vs 59.5%; OR, 0.59; 95% CI, 0.43-0.82; P = .001). Eight
patients with IDDVT and 61 patients with proximal DVT had
venous ulcers at 1-year follow-up. At 2-year follow-up, signs
and symptoms for postthrombotic syndrome were less fre-
quent in patients with IDDVT compared with those who had
proximal DVT (36.8% vs 62.5%; HR, 0.34; 95% CI, 0.20-0.59;
P < .001).
Outcomes in Patients With IDDVT
Who Did Not Receive Anticoagulation
We identified 47 patients with IDDVT who did not receive an-
ticoagulation. Compared with patients who received antico-
agulation, those who did not receive anticoagulation for IDDVT
had a higher relative frequency of history of recent major bleed-
ing (11.0% vs 1.7%). In patients who did not receive anticoagu-
lation, 90-day all-cause and PE-related mortality rates were
4.25% (95% CI, 0.79%-13.36%) and 0% (95% CI, 0%-7.56%).
The rate of 90-day VTE deterioration was 4.25% (95% CI,
0.79%-13.36%). These rates were not significantly different
from those with IDDVT who were anticoagulated. No major
bleeding events occurred in patients who did not receive
anticoagulation.
jamacardiology.com
 Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis Original Investigation Research

Figure 3. Cumulative Incidence Rate for All-Cause Mortality and Venous Thromboembolism (VTE)
Deterioration

Isolated distal DVT Proximal DVT

A All-cause mortality

1.0
0.15

HR, 0.52; 95% CI, 0.46-0.59

Cumulative death rate

0.8
0.10
Cumulative death rate

0.6
0.05

0.4

0
0 30 90 180 270 365
Follow-up, d
0.2

0
0 30 90 180 270 365
Follow-up, d
No. at risk
Isolated distal DVT 5938 5876 5541 3207 2144 1665
Proximal DVT 27 959 27 208 25 792 17 720 12 762 10 047

B VTE deterioration

1.0
0.15
Cumulative VTE deterioration rate

HR, 0.83; 95% CI, 0.69-0.99

0.8
0.10
Cumulative VTE deterioration rate

0.6
0.05

0.4

0
0 30 90 180 270 365
Follow-up, d
0.2

0
0 30 90 180 270 365
Follow-up, d
No. at risk
Isolated distal DVT 5938 5876 5541 3207 2144 1665 A, All-cause mortality. B, VTE
Proximal DVT 27 959 27 208 25 792 17 720 12 762 10 047 deterioration. DVT indicates deep
vein thrombosis; HR, hazard ratio.

One-Year and 2-Year Outcomes in Patients With IDDVT low-up, symptoms or signs of postthrombotic syndrome were
Who Discontinued Anticoagulation After the First 3 Months less common in patients with IDDVT (47.6% vs 60.5%).
Of 33 897 patients with DVT who survived the first 90 days af- Results were similar at 2-year follow-up (eTable 3 in
ter acute VTE, there were 1067 patients with IDDVT and 3486 Supplement 1).
patients with proximal DVT who permanently discontinued an-
ticoagulation between days 91 and 180. Among such pa-
tients, those with IDDVT compared with those with proximal
DVT had a lower hazard for all-cause mortality (HR, 0.26; 95%
Discussion
CI, 0.16-0.39; P < .001) and for VTE deterioration (HR, 0.38; In this large cohort study of patients with IDDVT treated with
95% CI, 0.19-0.75; P = .005) at 1-year follow-up. By 1-year fol- initial anticoagulation, PE-related mortality was rare in short-

jamacardiology.com (Reprinted) JAMA Cardiology Published online July 13, 2022 E5

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022

 Research Original Investigation
Figure 4. All-Cause Death, Venous Thromboembolism (VTE),
and Major Bleeding Outcomes at 1 Year
1-y Outcome aHR (95% CI)
All-cause death
Unadjusted 0.52 (0.46-0.59)
Adjusted 0.72 (0.64-0.82)
VTE deterioration
Unadjusted 0.83 (0.69-0.99)
Adjusteda 0.83 (0.69-1.00)
Major bleeding
Unadjusted 0.69 (0.50-0.94)
Adjusted 0.86 (0.64-1.16)
0 0.5 1.0 1.5
aHR (95% CI)
Reference group (dotted vertical line) is proximal deep vein thrombosis. Point
estimates are adjusted hazard ratios (aHRs), with 95% CIs shown in error bars.
term and 1-year follow-up. All-cause mortality, VTE deterio-
ration, and major bleeding events were less frequent in pa-
tients with IDDVT than in those who had proximal DVT. In
addition, IDDVT was less likely to be associated with signs or
symptoms of postthrombotic syndrome at 1-year follow-up.
Nevertheless, 1 in every 22 patients with IDDVT had recur-
rent VTE at 1-year follow-up, and more than 45% had some form
of signs or symptoms of postthrombotic syndrome.
We urge caution for appropriate interpretation of the study
results. Patients with IDDVT had a lower burden of comorbidi-
ties and were more likely to have postoperative DVT than those
with proximal DVT. Differences in outcomes for patients with
IDDVT compared with proximal DVT may be related to inher-
ent differences in the risk profile and characteristics in each group
(ie, confounding), or a true difference as a result of the location
of the DVT (IDDVT vs proximal DVT). For example, the differ-
ence in 1-year bleeding events in the 2 groups is implausible to
be causal, and in fact, was no longer present after multivariable
adjustment. This indicates the differences in patient profiles (con-
founding). In turn, the lower rate of VTE deterioration (compos-
ite of new PE, death from PE, or new proximal DVT) is plausible
to be related to both patient profile (confounding) and the loca-
tion of the DVT. For this outcome, the results remained consis-
tent after multivariable analysis for demographics and comor-
bidities. In addition, among the small subgroup of patients with
IDDVT who did not receive initial anticoagulation, no cases of
PE-related mortality were identified. Adequately powered ran-
domized clinical trials are required to understand if long-term
management of IDDVT should be different from proximal DVT.19
With respect to mortality outcomes, considering that
PE-related mortality was relatively infrequent, confounding is
an important possibility. Although the results were significant
in multivariable analyses, the association between location of
DVT and mortality may arise from residual (unmeasured) con-
founding. Therefore, the differences in mortality rates should
not be considered as causal, but rather, related to differences in
patient characteristics for those who developed IDDVT com-
pared with proximal DVT.
To our knowledge, very few other large-scale studies have
assessed the risk factors and comorbidities in patients with
E6 JAMA Cardiology Published online July 13, 2022 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022
Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis
IDDVT vs proximal DVT. In our study, patients with IDDVT had
fewer comorbidities but were more likely to have had recent sur-
gery, immobility, or use of hormonal therapy. Hormonal therapy,
particularly estrogen-containing formulations, may be associ-
ated with increased risk of thrombotic events, such as VTE, and
their indiscriminate use should be cautioned. Lower comorbid-
ity burden in patients with IDDVT in RIETE is consistent with
findings from the Global Anticoagulant Registry in the FIELD–
Venous Thromboembolism (GARFIELD-VTE) registry9 and analy-
ses from the RE-COVER trial participants.20 Nearly all patients
in the current study underwent initial anticoagulant therapy,
similar to the findings from the GARFIELD-VTE registry.9
Similarly, lower rate of short-term adverse events with
IDDVT compared with proximal DVT is consistent with the re-
sults from GARFIELD-VTE.9 That study, similar to the cur-
rent investigation, also showed a lower 1-year hazard for mor-
tality (HR, 0.61; 95% CI, 0.48-0.77), recurrent VTE (HR, 0.76;
95% CI, 0.60-0.97), and bleeding (HR, 0.69; 95% CI, 0.57-
0.84) in patients with IDDVT compared with those who had
proximal DVT. The current investigation builds on prior stud-
ies in several ways. The current study had a larger patient popu-
lation, making it possible to provide more reliable estimates.
Further, unlike prior investigations, we were able to assess the
association between IDDVT (vs proximal DVT) and outcomes
in multivariable analyses. Some outcomes are implausible to
have a causal association with IDDVT. For example, our re-
sults suggested the long-term lower risk of bleeding in pa-
tients with IDDVT compared with patients who had proximal
DVT. This difference, however, was no longer significant af-
ter multivariable adjustment for demographics, comorbidi-
ties, and anticoagulant treatment.
With respect to subsequent VTE events, our findings are
in agreement with the Xarelto for Long-term and Initial
Anticoagulation in Venous Thromboembolism (XALIA) study,
which included 1004 patients with IDDVT and 3098 with proxi-
mal DVT and the Optimisation de l’Interrogatoire pour la
Maladie Thromboembolique Veineuse (OPTIMEV) study, in-
cluding 259 patients with proximal DVT and 490 patients with
IDDVT, both of which showed a lower risk of recurrent VTE in
patients with IDDVT compared with proximal DVT.21,22 As a
novel addition, in this study, we demonstrated that the lower
hazard of VTE deterioration by 1-year follow-up persisted in
multivariable analyses. We confirmed these findings with ad-
ditional analyses among patients with IDDVT who discontin-
ued anticoagulation after the first 3 months compared with pa-
tients with proximal DVT.
In additional prespecified analyses, this study showed that
signs and symptoms of postthrombotic syndrome were less fre-
quently observed in those with IDDVT compared with proxi-
mal DVT at 1-year and 2-year follow-up. These results are con-
sistent with a recent analysis from the Compression vs
Anticoagulant Treatment and Compression in Symptomatic
Calf Thrombosis Diagnosed by Ultrasound (CACTUS) trial. That
study of 178 participants showed that the risk of postthrom-
botic syndrome is substantial after IDDVT but much lower than
that reported in patients with proximal DVT.23 Similarly, in a
study of 135 patients with DVT, at 3-year follow-up, IDDVT was
associated with lower risk of postthrombotic syndrome.24
jamacardiology.com
 Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis Original Investigation Research

Collectively, findings from this study have important impli-
cations. We found less ominous outcomes with IDDVT com-
pared with proximal DVT. Further, we demonstrated that some
of these differences stem from a lower burden of comorbidi-
ties, with outcomes such as long-term risk of major bleeding not
having a significant difference once accounting for demograph-
ics and comorbidities. However, we also demonstrated a lower
risk of long-term outcomes, such as signs or symptoms of post-
thrombotic syndrome, and a lower risk of VTE deterioration in
patients with IDDVT compared with proximal DVT; this differ-
ence persisted in multivariable analyses. To our knowledge, these
findings have not been reported in prior studies and are aligned
with the judgment of clinicians who consider IDDVT as a lower-
risk entity than proximal DVT. Results related to all-cause mor-
tality, in contrast, are likely driven by the differences in patient
characteristics (ie, residual confounding).
Nevertheless, the study also confirms that IDDVT is not en-
tirely benign. Even in this population who received initial an-
ticoagulation in more than 99% of participants, signs or symp-
toms of postthrombotic syndrome were present in more than
45% of patients. This is particularly concerning given that other
than anticoagulation, no treatment has been proven to re-
duce the incidence of durable symptoms or the development
of postthrombotic syndrome.25 In addition, although the rates
of VTE deterioration were low in patients with IDDVT, com-
pared with those who had proximal DVT, such events were not
trivial. The annual incidence of VTE in the general popula-
tion is estimated around 104 to 183 per 100 000 person-
years, which is much lower than the 4.5% rate of VTE deterio-
ration observed in our study. Although PE was rarely the cause
of death in patients with IDDVT, it is still proportionally a more
common cause of death in these patients compared with the
average population.26
Strengths and Limitations
The current study should be considered in the context of its
strengths and limitations. The strengths of this study in-
cluded patient enrollment from a multinational registry rep-
resenting small and large referral centers. The large pool of par-
ticipants allowed for robust comparisons between those who
had IDDVT and patients who had proximal DVT, without con-
cern for type II error. Accounting for the competing risk of other
events reduces the likelihood of biased estimates for nonmor-
tality outcomes.
This study had several limitations. First, fewer patients had
1-year and 2-year follow-up data on postthrombotic syn-
drome, which is consistent with dropout in other long-term
follow-up studies. However, there is no reason to suspect the
follow-up duration was differential in those with IDDVT vs
proximal DVT. As for other clinical outcomes, 90-day fol-
low-up was available in all patients, whereas longer
follow-up was encouraged but not mandatory in the RIETE reg-
istry. As a result of losses to follow-up for 1-year clinical out-
comes, dedicated large-scale studies with long-term fol-
low-up are needed to improve the certainty of the long-term
findings that we reported. Second, the RIETE registry did not
distinguish the subtype of distal DVTs (ie, muscular calf veins
[soleus, gastrocnemius] compared with tibial and peroneal
veins).8 Some prior studies failed to show a distinct pattern of
subsequent outcomes based on the subtype of IDDVT.21 Third,
the differences in some outcomes were implausible to be
causal. For example, the difference in 1-year bleeding events
was driven by the differences in patient characteristics and was
no longer significant after multivariable adjustment. For all-
cause mortality, considering that PE-related mortality was rela-
tively infrequent in both groups, the difference is most likely
attributable to differences in patient profile (ie, confound-
ing). Fourth, this study was not designed as a comparative ef-
fectiveness analysis of various treatment strategies among pa-
tients with IDDVT.27,28 In our analyses, similar to those from
the GARFIELD-VTE trial, the vast majority of patients with
IDDVT received initial anticoagulation.9 Considering the find-
ings of this study, future studies should determine whether for-
mal incorporation of IDDVT in risk stratification models can
affect patient outcomes. In addition, future trials are needed
to better understand the optimal intensity and duration of an-
ticoagulation in patients with IDDVT. Of note, no adequately
powered randomized clinical studies have yet determined the
role of direct oral anticoagulants in patients with IDDVT.29 Fi-
nally, routine screening was not a part of case ascertainment
or identification of patients with VTE deterioration. Rather,
such designations were based on signs and symptoms fol-
lowed by objective testing at the discretion of treating clini-
cians. There are no large randomized clinical trials that have
shown a net benefit for routine screening for DVT.30 As such,
routine screening is not advised in most practice guidelines.31-33
Conclusions
In this large, longitudinal, multicenter cohort study, patients
with IDDVT had less ominous short-term and 1-year adverse
events, including mortality and signs or symptoms, for post-
thrombotic syndrome compared with those who had proxi-
mal DVT. These differences were multifactorial; some, such as
VTE deterioration, were only partially related to lower bur-
den of comorbidities in patients with IDDVT, persisted in mul-
tivariable analyses, and may be relevant for risk stratification
and treatment decisions. Other differences, such as lower mor-
tality rates in patients with IDDVT compared with proximal
DVT, are most likely related to differences in measured and un-
measured patient characteristics.

ARTICLE INFORMATION
Accepted for Publication: May 19, 2022.
Published Online: July 13, 2022.
doi:10.1001/jamacardio.2022.1988
Author Affiliations: Cardiovascular Medicine
Division and the Thrombosis Research Group,
Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts (Bikdeli); Center for
Outcomes Research and Evaluation, Yale New
Haven Hospital, New Haven, Connecticut (Bikdeli,
Caraballo, Krumholz); Cardiovascular Research
Foundation, New York, New York (Bikdeli);
Department of Internal Medicine, Hospital General
Universitario Santa Lucía, Cartagena, Murcia, Spain
Universidad Católica San Antonio de Murcia,
Murcia, Spain (Trujillo-Santos); Department of

jamacardiology.com (Reprinted) JAMA Cardiology Published online July 13, 2022 E7

© 2022 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022

 Research Original Investigation
Medicine, Sunnybrook Health Sciences Centre and
University of Toronto, Toronto, Ontario, Canada
(Galanaud); Department of Internal Medicine and
Emergency Room, Ospedale Buon Consiglio
Fatebenefratelli, Naples, Italy (di Micco);
Department of Internal Medicine, Hospital
Universitario Virgen de Arrixaca, Murcia, Spain
(Rosa); Department of Internal Medicine,
Corporación Sanitaria Parc Taulí, Barcelona, Spain
(Cusidó); Department of Medical Clinic, Municipal
Hospital of Dresden Friedrichstadt, Dresden,
Germany (Schellong); Department of Angiology
and Vascular Surgery, Hospital del Mar, Barcelona,
Spain (Mellado); Department of Internal Medicine,
Hospital del Tajo, Madrid, Spain (del Valle Morales);
Department of Haematology, Hospital Clínico
Universitario Lozano Blesa, Zaragoza, Spain
(Gavín-Sebastián); Division of Angiology, Heart and
Vessel Department, Centre Hospitalier Universitaire
Vaudois, University of Lausanne, Lausanne,
Switzerland (Mazzolai); Section of Cardiovascular
Medicine, Department of Internal Medicine,
Yale School of Medicine, New Haven, Connecticut
(Krumholz); Department of Health Policy and
Management, Yale School of Public Health, New
Haven, Connecticut (Krumholz); Department of
Internal Medicine, Hospital Germans Trias i Pujol,
Badalona, Barcelona (Monreal); Universidad
Autónoma de Barcelona, Barcelona, Spain
(Monreal); Chair for the Study of Thromboembolic
Disease, Faculty of Health Sciences, Universidad
Católica San Antonio de Murcia, Spain (Monreal).
Author Contributions: Drs Trujillo-Santos and
Monreal had full access to all of the data in the
study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Drs Bikdeli, Caraballo, and Trujillo-Santos
contributed equally to this study.
Concept and design: Bikdeli, Caraballo,
Trujillo-Santos, Galanaud, Di Micco, Rosa, Mellado,
Morales, Gavín, Monreal.
Acquisition, analysis, or interpretation of data:
Bikdeli, Caraballo, Trujillo-Santos, Rosa, Vidal
Cusidó, Schellong, Mazzolai, Krumholz, Monreal.
Drafting of the manuscript: Bikdeli, Caraballo,
Trujillo-Santos, Schellong, Morales.
Critical revision of the manuscript for important
intellectual content: Bikdeli, Caraballo,
Trujillo-Santos, Galanaud, Di Micco, Rosa, Vidal
Cusidó, Mellado, Morales, Gavín, Mazzolai,
Krumholz, Monreal.
Statistical analysis: Trujillo-Santos, Morales.
Obtained funding: Rosa, Monreal.
Administrative, technical, or material support:
Trujillo-Santos, Galanaud, Rosa, Mellado, Morales.
Supervision: Bikdeli, Rosa, Gavín, Monreal.
Conflict of Interest Disclosures: The RIETE
registry has been supported by Sanofi Spain, Leo
Pharma, and Rovi with an unrestricted educational
grant. Dr Bikdeli reported receiving consulting fees
serving as an expert on behalf of the plaintiff for
litigation related to 2 specific brand models of
inferior vena cava filters. Dr Krumholz reported
receiving personal fees from UnitedHealth,
Element Science, Aetna, Reality Labs, F-Prime,
Tesseract/4Catalyst, Martin/Baughman Law Firm,
Arnold and Porter Law Firm, and Siegfried and
Jensen Law Firm; being a cofounder of HugoHealth,
a personal health information platform; being a
cofounder of Refactor Health, an Enterprise Health
Care artificial intelligence–augmented data
management company; having contracts with the
Centers for Medicare & Medicaid Services
E8 JAMA Cardiology Published online July 13, 2022 (Reprinted)
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022
Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis
Association through Yale New Haven Hospital, to
develop and maintain performance measures that
are publicly reported; and receiving grants from
Johnson & Johnson outside the submitted work.
Dr Monreal reported receiving grants from Sanofi
and Rovi sponsorship of the RIETE registry outside
the submitted work. No other disclosures were
reported.
Funding/Support: This work was supported by an
unrestricted educational grant from Sanofi Spain,
Leo Pharma, and Rovi; the Scott Schoen and Nancy
Adams IGNITE Award from the Mary Horrigan
Connors Center for Women’s Health and Gender
Biology at Brigham and Women’s Hospital (Dr
Bikdeli); and a Career Development Award
(938814) from the American Heart Association (Dr
Bikdeli).
Role of the Funder/Sponsor: The funders had no
role in the design of the current study, statistical
analysis, drafting the manuscript, or the decision to
submit.
Group Information: The RIETE Investigators are
listed in Supplement 2.
Additional Contributions: We thank the RIETE
Registry Coordinating Center, S&H Medical Science
Service, for their quality control data and logistic
and administrative support.
REFERENCES
1. Robert-Ebadi H, Righini M. Management of distal
deep vein thrombosis. Thromb Res. 2017;149:48-55.
doi:10.1016/j.thromres.2016.11.009
2. Galanaud JP, Sevestre-Pietri MA, Bosson JL,
et al; OPTIMEV-SFMV Investigators. Comparative
study on risk factors and early outcome of
symptomatic distal versus proximal deep vein
thrombosis: results from the OPTIMEV study.
Thromb Haemost. 2009;102(3):493-500. doi:10.
1160/TH09-01-0053
3. Galanaud JP, Quenet S, Rivron-Guillot K, et al;
RIETE Investigators. Comparison of the clinical
history of symptomatic isolated distal deep vein
thrombosis vs proximal deep vein thrombosis in
11 086 patients. J Thromb Haemost. 2009;7(12):
2028-2034. doi:10.1111/j.1538-7836.2009.03629.x
4. Spencer FA, Kroll A, Lessard D, et al. Isolated calf
deep vein thrombosis in the community setting: the
Worcester Venous Thromboembolism study.
J Thromb Thrombolysis. 2012;33(3):211-217. doi:10.
1007/s11239-011-0670-x
5. Brateanu A, Patel K, Chagin K, et al. Probability
of developing proximal deep-vein thrombosis
and/or pulmonary embolism after distal deep vein
thrombosis. Thromb Haemost. 2016;115(3):608-614.
doi:10.1160/th15-06-0503
6. Porfidia A, Carnicelli A, Bonadia N, Pola R,
Landolfi R. Controversies in venous
thromboembolism: the unique case of isolated
distal deep vein thrombosis. Intern Emerg Med.
2016;11(6):775-779. doi:10.1007/s11739-016-1453-3
7. Mazzolai L, Aboyans V, Ageno W, et al. Diagnosis
and management of acute deep vein thrombosis:
a joint consensus document from the European
Society of Cardiology working groups of aorta and
peripheral circulation and pulmonary circulation
and right ventricular function. Eur Heart J. 2018;39
(47):4208-4218. doi:10.1093/eurheartj/ehx003
8. Kearon C, Akl EA, Ornelas J, et al.
Antithrombotic therapy for VTE disease: CHEST
guideline and expert panel report. Chest. 2016;149
(2):315-352. doi:10.1016/j.chest.2015.11.026
9. Schellong SM, Goldhaber SZ, Weitz JI, et al.
Isolated distal deep vein thrombosis: perspectives
from the GARFIELD-VTE registry. Thromb Haemost.
2019;119(10):1675-1685. doi:10.1055/s-0039-1693461
10. Barco S, Corti M, Trinchero A, et al. Survival and
recurrent venous thromboembolism in patients
with first proximal or isolated distal deep vein
thrombosis and no pulmonary embolism. J Thromb
Haemost. 2017;15(7):1436-1442. doi:10.1111/jth.13713
11. Krutman M, Kuzniec S, Ramacciotti E, et al.
Rediscussing anticoagulation in distal deep venous
thrombosis. Clin Appl Thromb Hemost. 2016;22(8):
772-778. doi:10.1177/1076029615627343
12. Bikdeli B, Jimenez D, Hawkins M, et al; RIETE
Investigators. Rationale, design, and methodology
of the Computerized Registry of Patients with
Venous Thromboembolism (RIETE). Thromb
Haemost. 2018;118(1):214-224. doi:10.1160/TH17-07-
0511
13. Tzoran I, Brenner B, Papadakis M, Di Micco P,
Monreal M. VTE Registry: what can be learned from
RIETE? Rambam Maimonides Med J. 2014;5(4):
e0037. doi:10.5041/RMMJ.10171
14. Guijarro R, Montes J, Sanromán C, Monreal M;
RIETE Investigators. Venous thromboembolism in
Spain: comparison between an administrative
database and the RIETE registry. Eur J Intern Med.
2008;19(6):443-446. doi:10.1016/j.ejim.2007.06.
026
15. Bikdeli B, Madhavan MV, Jimenez D, et al;
Global COVID-19 Thrombosis Collaborative Group;
Endorsed by the ISTH, NATF, ESVM, and the IUA;
Supported by the ESC Working Group on
Pulmonary Circulation and Right Ventricular
Function. COVID-19 and thrombotic or
thromboembolic disease: implications for
prevention, antithrombotic therapy, and follow-up:
JACC state-of-the-art review. J Am Coll Cardiol.
2020;75(23):2950-2973. doi:10.1016/j.jacc.2020.04.
031
16. Bikdeli B, Madhavan MV, Gupta A, et al; Global
COVID-19 Thrombosis Collaborative Group.
Pharmacological agents targeting
thromboinflammation in COVID-19: review and
implications for future research. Thromb Haemost.
2020;120(7):1004-1024. doi:10.1055/s-0040-1713152
17. Fernández-Capitán C, Barba R, Díaz-Pedroche
MDC, et al. Presenting characteristics, treatment
patterns, and outcomes among patients with
venous thromboembolism during hospitalization
for COVID-19. Semin Thromb Hemost. 2021;47(4):
351-361. doi:10.1055/s-0040-1718402
18. Schulman S, Angerås U, Bergqvist D, Eriksson B,
Lassen MR, Fisher W; Subcommittee on Control of
Anticoagulation of the Scientific and
Standardization Committee of the International
Society on Thrombosis and Haemostasis. Definition
of major bleeding in clinical investigations of
antihemostatic medicinal products in surgical
patients. J Thromb Haemost. 2010;8(1):202-204.
doi:10.1111/j.1538-7836.2009.03678.x
19. Bikdeli B, Tajrishi FZ, Sadeghipour P, et al.
Efficacy and safety considerations with
dose-reduced direct oral anticoagulants: a review.
JAMA Cardiol. Published online June 1, 2022. doi:10.
1001/jamacardio.2022.1292
jamacardiology.com
 Characteristics and Outcomes in Isolated Distal vs Proximal Deep Vein Thrombosis
20. Schellong S, Ageno W, Casella IB, et al. Profile
of patients with isolated distal deep vein
thrombosis vs proximal deep vein thrombosis or
pulmonary embolism: RE-COVERY DVT/PE study.
Semin Thromb Hemost. 2021. doi:10.1055/s-0041-
1729169
21. Galanaud JP, Sevestre MA, Genty C, et al;
OPTIMEV-SFMV investigators. Incidence and
predictors of venous thromboembolism recurrence
after a first isolated distal deep vein thrombosis.
J Thromb Haemost. 2014;12(4):436-443. doi:10.1111/
jth.12512
22. Ageno W, Mantovani LG, Haas S, et al. Patient
management strategies and long-term outcomes in
isolated distal deep vein thrombosis vs proximal
deep vein thrombosis: findings from XALIA. TH Open.
2019;3(1):e85-e93. doi:10.1055/s-0039-1683968
23. Galanaud JP, Righini M, Le Collen L, et al.
Long-term risk of postthrombotic syndrome after
symptomatic distal deep vein thrombosis: the
CACTUS-PTS study. J Thromb Haemost. 2020;18(4):
857-864. doi:10.1111/jth.14728
24. Hach-Wunderle V, Bauersachs R, Gerlach HE,
et al. Postthrombotic syndrome 3 years after deep
venous thrombosis in the Thrombosis and
Pulmonary Embolism in Out-Patients (TULIPA)
PLUS registry. J Vasc Surg Venous Lymphat Disord.
2013;1(1):5-12. doi:10.1016/j.jvsv.2012.07.003
jamacardiology.com
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Harvard University User on 07/13/2022
25. Kahn SR, Comerota AJ, Cushman M, et al;
American Heart Association Council on Peripheral
Vascular Disease, Council on Clinical Cardiology, and
Council on Cardiovascular and Stroke Nursing. The
postthrombotic syndrome: evidence-based
prevention, diagnosis, and treatment strategies:
a scientific statement from the American Heart
Association. Circulation. 2014;130(18):1636-1661.
doi:10.1161/CIR.0000000000000130
26. Barco S, Mahmoudpour SH, Valerio L, et al.
Trends in mortality related to pulmonary embolism
in the European Region, 2000-15: analysis of vital
registration data from the WHO mortality database.
Lancet Respir Med. 2020;8(3):277-287. doi:10.
1016/S2213-2600(19)30354-6
27. Chopard R, Albertsen IE, Piazza G. Diagnosis
and treatment of lower extremity venous
thromboembolism: a review. JAMA. 2020;324(17):
1765-1776. doi:10.1001/jama.2020.17272
28. Righini M, Galanaud JP, Guenneguez H, et al.
Anticoagulant therapy for symptomatic calf deep
vein thrombosis (CACTUS): a randomised,
double-blind, placebo-controlled trial. Lancet
Haematol. 2016;3(12):e556-e562. doi:10.1016/S2352-
3026(16)30131-4
29. Galanaud JP, Trujillo-Santos J, Bikdeli B, et al;
RIETE Investigators. Management of isolated distal
deep vein thrombosis with direct oral
anticoagulants in the RIETE registry. J Thromb
(Reprinted) JAMA Cardiology Published online July 13, 2022
Original Investigation Research
Haemost. 2021;52(2):532-541. doi:10.1007/s11239-
020-02347-6
30. Schmidt B, Michler R, Klein M, Faulmann G,
Weber C, Schellong S. Ultrasound screening for
distal vein thrombosis is not beneficial after major
orthopedic surgery: a randomized controlled trial.
Thromb Haemost. 2003;90(5):949-954.
31. Falck-Ytter Y, Francis CW, Johanson NA, et al.
Prevention of VTE in orthopedic surgery patients:
Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2):e278S-e325S. doi:10.
1378/chest.11-2404
32. Gould MK, Garcia DA, Wren SM, et al.
Prevention of VTE in nonorthopedic surgical
patients: Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2):e227S-e277S. doi:10.
1378/chest.11-2297
33. Anderson DR, Morgano GP, Bennett C, et al.
American Society of Hematology 2019 guidelines
for management of venous thromboembolism:
prevention of venous thromboembolism in surgical
hospitalized patients. Blood Adv. 2019;3(23):
3898-3944. doi:10.1182/bloodadvances.
2019000975
E9