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Thrombosis, anticoagulation and outcomes in malignant superior vena cava

syndrome

Article  in  Journal of Thrombosis and Thrombolysis · January 2019

DOI: 10.1007/s11239-018-1747-6

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Journal of Thrombosis and Thrombolysis
https://doi.org/10.1007/s11239-018-1747-6

Thrombosis, anticoagulation and outcomes in malignant superior

vena cava syndrome
Roy Ratzon1,2   · Shlomit Tamir2,3 · Tal Friehmann2,3 · Nir Livneh1,2 · Elizabeth Dudnik4,5 · Alon Rozental1,2 ·
Orly Hamburger‑Avnery2,6 · David Pereg2,7 · Estela Derazne2 · Baruch Brenner2,5 · Pia Raanani1,2 · Hugo ten Cate8,9 ·
Galia Spectre1,2 · Avi Leader1,2,8

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Anticoagulation is often used in superior vena cava syndrome (SVCS) associated with cancer (i.e malignant SVCS), even
without thrombosis, but its effect on outcomes has not been reported. We aimed to determine factors and outcomes associ-
ated with thrombosis and anticoagulation in malignant SVCS. Patients with malignant SVCS diagnosed on computerized
tomography (CT) were retrospectively included, indexed at diagnosis and followed for 6 months using medical records. The
cohort included 183 patients with malignant SVCS of which 153 (84%) were symptomatic. Thirty of the 127 patients (24%)
with a reviewable baseline CT had thrombosis of the SVC or tributaries at diagnosis. Patients with baseline thrombosis
more often had symptomatic SVCS (p < 0.01). 70% (21/30) of patients with thrombosis and 52% (49/97) of those without
thrombosis at baseline received anticoagulation, most often at therapeutic doses. Thrombosis occurred in 5/39 patients with
anticoagulation (13%) compared to 2/18 (11%) of those without, during follow-up (p = 0.85). Anticoagulation was associated
with a reduction in risk of SVC stent placement during follow-up that did not reach statistical significance (HR 0.47, 95%
CI 0.2–1.13, p = 0.09). Major bleeding occurred in 7 (4%) patients, six of whom received anticoagulation (four therapeutic
and two intermediate dose). Neither thrombosis nor anticoagulation affected survival. Anticoagulation is commonly used
as primary prevention but its benefit remains to be proven. The role of reduced-dose anticoagulation in non-thrombotic
malignant SVCS should be prospectively assessed.

Keywords  Superior vena cava syndrome · Malignancy · Thrombosis · Anticoagulation

Highlights

• Thrombosis of the superior vena cava (SVC) and tribu-

Galia Spectre and Avi Leader contributed equally to this work.
taries is prevalent at malignant SVC syndrome (SVCS)
Electronic supplementary material  The online version of this diagnosis
article (https​://doi.org/10.1007/s1123​9-018-1747-6) contains
supplementary material, which is available to authorized users.

5
* Avi Leader Institute of Oncology, Davidoff Cancer Center, Rabin
avileader@yahoo.com Medical Center, Petah Tikva, Israel
6
1 Institute of Hematology, Meir Medical Center, Kfar Saba,
Institute of Hematology, Davidoff Cancer Center, Rabin
Israel
Medical Center, 39 Jabotinsky, Petah Tikva 4941492, Israel
7
2 Cardiology Department, Meir Medical Center, Kfar Saba,
Sackler School of Medicine, Tel Aviv University, Tel Aviv,
Israel
Israel
8
3 Cardiovascular Research Institute Maastricht (CARIM),
Radiology Department, Rabin Medical Center, Petah Tikva,
Maastricht University, Maastricht, The Netherlands
Israel
9
4 Thrombosis Expert Center, Maastricht University Medical
Thoracic Oncology Unit, Rabin Medical Center, Petah Tikva,
Center (MUMC+), Maastricht, The Netherlands
Israel

13
Vol.:(0123456789)

• Anticoagulation is commonly used as primary prevention
of SVC thrombosis, especially in patients with high grade
occlusions
• Thrombosis rates were similar with and without antico-
agulation, and major bleeding (4%) occurred mainly with
therapeutic dose anticoagulation
• This analysis was also weakly suggestive of a protective
effect for anticoagulation on salvage SVC stenting; how-
ever, the significance threshold was not reached
• The role of reduced dose anticoagulation for primary pre-
vention of SVCS thrombosis in high risk patients with
malignant SVCS should be prospectively assessed
Introduction
Superior vena cava (SVC) syndrome is caused by a reduc-
tion in the blood flow through the SVC or its tributary veins.
In 60–80% of cases, the SVC syndrome (SVCS) is a result
of external compression by a mediastinal tumor [1–4]. The
most common etiology of malignant SVCS is lung cancer
(75%) followed by non-Hodgkin lymphoma (20%) and meta-
static cancer (usually breast cancer) [1, 4, 5]. Surprisingly,
little is known regarding the coexistence of both external
compression and thrombosis in malignant SVCS.
In most patients the initial management includes diag-
nosing and then treating the underlying malignancy, while
relieving any symptoms. Endovascular stent implantation
is recommended in life threatening cases or refractory dis-
ease [6–8]. Anticoagulation is recommended for patients
undergoing SVC stenting and uniformly used in those with
an intravascular device-associated thrombus [9]. In addi-
tion, some physicians prescribe anticoagulation for primary
and secondary prevention of SVC thrombosis in malignant
SVCS (1,14). However, data on the efficacy and safety of
anticoagulation in this setting is lacking [10].
In this study of patients with malignant SVCS we aimed
to: (1) assess the prevalence of thrombosis at diagnosis; (2)
determine current practice regarding anticoagulation; (3)
evaluate the effect of anticoagulation on clinical outcomes.
Materials and methods
Design, sample and setting
A retrospective cohort study was performed by review-
ing inpatient and outpatient medical records at Rabin and
Meir Medical Centers in Israel. The study was approved
by the institutional ethics committees in accordance with
the Declaration of Helsinki, and informed consent was
waived. Since there is no specific code for SVCS according
to the International Classification of Diseases-9th revision
13
R. Ratzon et al.
(ICD-9), initial screening was done using the following
codes: 4592 (‘compression of vein’ at any site, which
includes, but isn’t restricted to, SVCS) and 45387 (‘acute
venous embolism and thrombosis of other thoracic veins’).
Patients were included in this study if they were aged
18 years or older and diagnosed with malignant SVCS
between January 1st 2007 and December 31st 2016. A
diagnosis of malignant SVCS had to fulfill all the follow-
ing criteria: (1) Diagnosis of SVCS on chest computed
tomography (CT) performed with intravenous (IV) con-
trast media, as well as presence of a thoracic mass; (2) His-
tological evidence of active cancer from the mass or from
another site considered to be the same disease. Patients
whose diagnostic CT was not available for review, but had
a written radiology report confirming the above findings
were also eligible. Subjects with no clinical follow-up data
after diagnosis were excluded. Patients were indexed at the
time of SVCS diagnosis, defined as the date of the imaging
study leading to SVCS diagnosis. Records were followed
from the index date for 6 months or until death.
Variables and measurement
Table 1 presents an overview of baseline variables.
Endovascular stenting
“Baseline SVC stent” was defined as endovascular SVC
stent placement within the first week after SVCS diagno-
sis. These stents were most probably placed as a result of
the initial clinical (or radiological) presentation. Stents
placed beyond the first week were classified as “salvage
stent” and are usually placed due to progression of SVCS
symptoms [11]. Therefore they were considered to be sur-
rogates for failure of initial management.
Radiological review procedures and definitions
CT imaging studies performed at other institutions were
not available for review. Therefore, only a subgroup had
CT imaging available for review. Chest CT studies were
reviewed separately by two board-certified radiologists
(ST, TF) to confirm the diagnosis, identify thrombosis
and classify the degree of venous occlusion using the
definitions in Online Resource 1. The definition of throm-
bosis aimed to exclude tumor thrombi in which the can-
cer invades the intravascular space and is unlikely to be
affected by anticoagulation. In cases of disagreement a
third radiologist was consulted.
Thrombosis, anticoagulation and outcomes in malignant superior vena cava syndrome

Table 1  Baseline characteristics Variables All, N (%) Thrombosis of the SVC and

overall and stratified by ­tributariesa,b (N = 127)
thrombosis status at SVC
syndrome diagnosis Yes, N (%) No, N (%) p value *

Number of subjects, N (% of all subjects) 183 (100) 30 (24) 97 (76)

Male sex 106 (58) 16 (53) 53 (55) 1
Median age, years [IQR] 59 [49;68] 59 [48;66] 59 [43;68] 0.679
Cancer-related factors
Malignancy classification
 Solid malignancy 141 (78) 24 (80) 72 (76) 0.805
 Haematological malignancy 42 (22) 6 (20) 23 (24)
Cancer histology
 Small cell lung cancer 45 (24) 5 (16) 27 (28) 0.639
 Non-small cell lung cancer 64 (35) 11 (37) 33 (33)
 Diffuse large B cell lymphoma 12 (7) 1 (3) 6 (6)
 Primary mediastinal B cell lymphoma 14 (8) 2 (7) 7 (7)
 Other 48 (26) 11 (37) 25 (26)
Malignancy stage
 IV 110 (64) 22 (76) 59 (66) 0.364
 III 33 (19) 3 (10) 15 (17)
 II 23 (13) 3 (10) 13 (14)
 I 6 (4) 1 (4) 3 (3)
Malignancy status
 Newly diagnosed 119 (65) 16 (53) 64 (66) 0.06
 Recurrent 8 (4) 0 (0) 7 (7)
 Refractory disease 56 (31) 14 (47) 26 (27)
Median time since cancer diagnosis, days [IQR] 2 [− 4;188] 37 [− 1;302] 5 [− 3;211] 0.243
Factors related to SVC syndrome
SVC syndrome clinical grade (Yu et al. 2008)
 0 (asymptomatic) 29 (16) 0 (0) 20 (21) 0.004
 1–2 (mild to moderate) 146 (80) 25 (83) 74 (77)
 3–4 (severe) 7 (4) 5 (17) 2 (2)
 5 (death) 0 (0) 0 (0) 0 (0)
Degree of occlusion (SVC or tributaries)b
Data available 127
 Partial 26 (20) 2 (7) 24 (25) 0.038
 Near complete or complete 101 (80) 28 (93) 73 (75)
Degree of occlusion (SVC only)b
Data available 127
 None 5 (4) 3 (10) 2 (2) 0.032
 Partial 55 (43) 11 (37) 44 (45)
 Near complete 56 (44) 10 (33) 46 (47)
 Complete 11 (9) 6 (20) 5 (5)
Anticoagulationc 92 (51) 21 (70) 49 (52) 0.093
Dose of ­anticoagulationc,d
 Data available 171 29 92
 Therapeutic dose 53 (31) 16 (55) 27 (30) 0.040
 Intermediate dose 5 (3) 1 (4) 4 (4)
 Prophylactic dose 27 (16) 3 (10) 15 (16)
 None 86 (50) 9 (31) 46 (50)
Anticoagulation prior to SVC syndrome diagnosis 3 (2) 0 (0) 3 (3) 1
Baseline SVC s­ tente 28 (15) 6 (20) 15 (16) 0.579
Median time to stent, days [IQR] 6 [2;24] 2 [0;4] 0 [2;22] 0.073

13
 R. Ratzon et al.

Table 1  (continued) Variables All, N (%) Thrombosis of the SVC and

­tributariesa,b (N = 127)
Yes, N (%) No, N (%) p value *

Thrombosis-related factors
 Intravascular device 34 (19) 9 (30) 16 (17) 0.119
 Hormonal therapy 6 (3) 2 (7) 3 (3) 0.338
 Prior venous thromboembolism 11 (6) 4 (13) 5 (5) 0.214
Khorana score (Khorana et al. 2008)f
 Data available 150 26 80
 Intermediate risk (1–2) 116 (77) 18 (69) 65 (81) 0.045
 High (≥ 3) 34 (23) 8 (31) 15 (19)
Thrombosis ­statusa,b
 Data available 127
 Thrombosis of SVC or t­ributariesa,b 30 (24)
 Thrombosis of ­SVCa,b 7 (5)

This table shows the baseline characteristics overall and stratified by thrombosis status at SVC syndrome
diagnosis. Univariate analysis was performed, comparing baseline characteristics among patients with
thrombosis vs. without thrombosis at SVC syndrome diagnosis
CT computerized tomography; IQR inter-quartile range; SVC superior vena cava
*This column shows p values from a univariate analysis comparing the “yes” and “no” thrombosis sub-
groups. Each analysis considered the variable in the same row as the p value vs. all other variables in that
group
a
 Thrombosis was defined as a thrombus in a reviewable contrast enhanced CT performed at SVC syndrome
diagnosis. Tributaries were defined as the brachiocephalic, jugular or subclavian veins
b
 This subgroup analysis only includes the 127 patients with a reviewable CT at SVC syndrome diagnosis
c
 Anticoagulation prescribed within 21 days of SVC syndrome diagnosis. The date of anticoagulation was
not known for two patients
d
 The dose of anticoagulation was not known for 12 patients
e
 Baseline SVC stent was defined as stent placement within the 1st week (< 7 days) after the diagnosis of
SVC syndrome (vs. none or ≥ 7days)
f
 The data needed to calculate the Khorana score were missing in 33 patients. The statistical analysis was
performed for increasing Khorana scores. No patient had a score of 0

Interventions Statistical analysis

The intervention, “anticoagulation”, was defined as any
class, dose or duration of anticoagulation prescribed within
the first 21 days after SVCS diagnosis. This period (and not
less) was selected to account for delays in anticoagulation
which may occur when invasive diagnostic or therapeutic
procedures are indicated or when the CT is performed on an
outpatient basis. Data on anticoagulation started later dur-
ing follow-up (≥ 21 days after diagnosis) were collected but
were not considered in the analyses.
Outcomes
Efficacy outcomes included new or recurrent thrombosis of
the SVC or tributaries, salvage stent placement and death
from any cause. The safety outcome was ISTH-defined
major bleeding [12].
Baseline variables were compared according to the status
of anticoagulation and thrombosis at diagnosis (yes vs.
no), using t-test for continuous variables and Chi square for
categorical variables or Fisher’s exact test in case of 2*2
tables. Multivariable general linear models, including vari-
ables with p < 0.1 in univariate analysis, were performed
to identify baseline factors associated with thrombosis and
anticoagulation (in separate models) at SVCS diagnosis.
Multivariable Cox regression models (including variables
with p < 0.1 in univariate Kaplan–Meier survival analysis
of all baseline variables) were performed for salvage stent
placement and death. Hazard ratio (HR), 95% confidence
interval (CI) and p-value were presented. When time to
salvage stent was analyzed, death was added to the model
as a competing risk. Anticoagulation was treated as a fixed
variable.

13
Thrombosis, anticoagulation and outcomes in malignant superior vena cava syndrome
All analyses were performed with IBM SPSS Statistics
for Windows, Version 24.0 (Armonk, NY: IBM Corp.),
except for competing risk models that were performed using
PROC PHREG with SAS 9.4 for windows (SAS Institute
Inc., Cary, NC, USA).
Results
Initial screening using ICD-9 codes identified 278 poten-
tial subjects, of whom 95 were excluded on medical record
review mainly because of extrathoracic venous compression
or absence of malignancy (details in Online Resource 1).
Thus, the study cohort included 183 patients with malignant
SVCS.
Sample characteristics
Baseline patient characteristics are detailed in full in Table 1.
The majority of patients (80%, N = 146) presented with mild
to moderate symptoms, while 29 (16%) were asymptomatic
and only 7 (4%) had severe symptoms. Endovascular SVC
stents were placed in 28 (15%) at baseline (i.e. < 7 days
after the diagnosis) at a median of 2 days (IQR 0–4) from
diagnosis.
Thrombosis prevalence at SVCS diagnosis
Thrombosis and the degree of venous occlusion at diagnosis
were evaluated in the 127 patients (69%) with a reviewable
baseline CT. Patients with and without a reviewable diag-
nostic CT had comparable baseline clinical characteristics
(data not shown).
Thrombosis of SVC tributaries is prevalent, especially
in symptomatic patients
Baseline thrombosis of the SVC or tributaries was found
in 30/127 (24%), while only 7/127 (5%) had a thrombus in
the SVC. High grade venous occlusion of the SVC or its
tributaries was present in 101/127 (80%). Table 1 shows the
characteristics of patients with and without baseline throm-
bosis, as well as univariate analysis of variables associated
with thrombosis. Patients with baseline thrombosis more
often had symptomatic SVCS (vs. asymptomatic; p < 0.01)
and higher Khorana scores (p < 0.05) than patients without
thrombosis, based on multivariate analysis (Online Resource
2).
Current anticoagulation practice in malignant SVCS
Half of patients without thrombosis received
anticoagulation
Anticoagulation was used in 92 (51%) of all patients for a
median duration of 68 days (range: 14–179). Seventy per
cent (21/30) of patients with thrombosis and 52% (49/97) of
those without thrombosis at baseline received anticoagula-
tion. The anticoagulant prescribed was low molecular weight
heparin (LMWH) in 89/92 (97%) and LMWH followed by a
vitamin K antagonist in 3/92 (3%).
Anticoagulation for higher grade venous occlusions
The characteristics of patients with and without anticoag-
ulation, as well as univariate analysis of variables associ-
ated with anticoagulation are shown in Online Resource 3.
Patients receiving anticoagulation had higher grade venous
occlusion more often than patients without anticoagulation
(p < 0.05), based on multivariate analysis (Online Resource
2).
Therapeutic anticoagulation doses were frequently used
for primary prophylaxis
Full dose anticoagulation was used in 80% (16/20) of anti-
coagulated patients with baseline thrombosis and in 59%
(27/46) of anticoagulated patients without thrombosis,
while the remainder received reduced doses (Table 1). An
additional 26 patients (14%) started anticoagulation 3 or
more weeks after SVCS diagnosis, and were not classified
in the anticoagulation group. The median time from SVCS
diagnosis to starting anticoagulation was 0 days (IQR 0–4)
in patients who started anticoagulation within 3 weeks of
SVCS diagnosis compared to 46 days (IQR 29–78) in those
who received anticoagulation later. The indication for early
anticoagulation was the malignant SVCS itself (with or with-
out thrombosis), while the indication varied in patients with
anticoagulation later during follow-up (including pulmonary
embolism, atrial fibrillation).
The effect of anticoagulation on clinical outcomes
Thrombosis rates were similar
with and without anticoagulation
A follow-up CT was performed in 57 of the 127 patients
(45%) with a reviewable baseline CT, at a median of 138
days (IQR 71–182) from diagnosis. The main reason for
not performing a follow-up CT was early death (N = 43).
Thrombosis of the SVC or tributaries during follow-up
was identified in 7/57 (12%) at a median of 73 days (IQR
13
 R. Ratzon et al.

66–139) after SVCS diagnosis. Thrombosis occurred in 5/39
patients with anticoagulation (13%) compared to 2/18 (11%)
of those without anticoagulation (p = 0.85). Table 2 depicts
selected patient variables according to thrombosis status
during follow-up.
Salvage stenting was more likely in solid cancers
included solid malignancy and anticoagulation in the final
model. Patients with solid malignancy (vs. hematological)
had an increased risk of salvage stenting (HR 7.16, 95% CI
1.36–37.68, p < 0.05). Anticoagulation prescribed within 21
days of diagnosis (vs. none) was associated with a reduction
in risk that did not reach statistical significance (HR 0.47,
95% CI 0.2–1.13, p = 0.09).

The 151 patients alive at 7 days with no baseline stent were

included in this analysis (28 had baseline stent, three died
within 1 week, one had missing data). Within this subgroup,
24 (16%) had a salvage stent placed in the SVC of whom
only one had hematological malignancy, while the rest had
solid malignancy. Salvage stents were inserted at a median
of 26 days from SVCS diagnosis (IQR 17–56). A multivaria-
ble Cox regression analysis using death as a competing risk,
Major bleeding occurred mainly with therapeutic dose
anticoagulation
Major bleeding was reported in 7 (4%) patients, all with
solid malignancy, six of whom received anticoagulation
(four therapeutic and two intermediate dose). One patient
with therapeutic dose anticoagulation had fatal bleeding.

Table 2  Characteristics of Stratification based on patient characteristics All patients with a New thrombo-
patients with or without a new follow-up ­CTa,b, N (%) sis of SVC &
SVC thrombosis during follow- ­tributariesa,b, N (%)
upa,b
No Yes

Number of patients, N (% of patients with follow-up CT) 57 (100) 50 (88) 7 (12)

Malignancy classification
 Solid 37 (65) 32 (64) 5 (71)
 Haematological 20 (35) 18 (36) 2 (29)
Malignancy status at SVC syndrome diagnosis [N = 53]
 Newly diagnosed 43 (81) 37 (79) 6 (100)
 Recurrent/refractory 10 (19) 10 (21) 0 (0)
Thrombosis at SVC syndrome diagnosis
 Yes 11 (19) 8 (16) 3 (43)
 No 46 (81) 42 (84) 4 (57)
Endovascular SVC stent
 Baseline SVC s­ tentc 7 (12) 7 (14) 0 (0)
 No baseline SVC stent 50 (88) 43 (86) 7 (100)
  Salvage ­stentd 8 (16) 6 (14) 2 (29)
  None 42 (84) 37 (86) 5 (71)
Anticoagulation
 No ­anticoagulatione 18 (32) 16 (32) 2 (29)
 Anticoagulatione 39 (68) 34 (68) 5 (71)
  Full therapeutic dose 28 (72) 24 (70) 4 (80)
  Reduced dose 9 (23) 8 (24) 1 (20)
  Missing dose data 2 (5) 2 (6) 0 (0)

This table shows selected baseline characteristics overall in patients who underwent follow-up CT. The
characteristics are stratified by thrombosis status in the follow-up CT
CT computerized tomography; SVC superior vena cava
a
 Thrombosis of the SVC or tributaries during follow-up was defined as a thrombus in a reviewable contrast
enhanced CT performed after the diagnosis of SVC syndrome, provided there was no thrombus in this ves-
sel at diagnosis. Tributaries were defined as the brachiocephalic, jugular or subclavian veins
b
 This analysis only includes patients the 57 patients with a reviewable post-diagnosis CT
c
 SVC stent placement within the first week after the diagnosis of SVC syndrome (< 7 days)
d
 Endovascular SVC stent placement ≥ 7 days after the diagnosis of SVC syndrome
e
 Anticoagulation prescribed within 21 days of SVC syndrome diagnosis

13
Thrombosis, anticoagulation and outcomes in malignant superior vena cava syndrome
Neither anticoagulation nor thrombosis affected survival
Over a median follow-up of 44 (IQR 22–93) days, 90 (49%)
patients died. Cancer-related factors were the main prog-
nostic determinants as shown in Online Resource 4 which
depicts the multivariate analysis of factors associated with
death from any cause. Neither thrombosis at diagnosis nor
anticoagulation was associated with death in univariate (data
not shown) or multivariate analysis. The cause of death was
not reliably documented.
Discussion
To the best of our knowledge, this is the largest cohort
reporting patterns of thrombosis (N = 127) and anticoagu-
lation (N = 183) in malignant SVCS. We found that throm-
bosis of the SVC or tributaries was prevalent at diagnosis
(24%) especially in patients with symptoms of the syndrome.
This suggests that the thrombosis was clinically relevant and
not just an incidental finding. As shown in our study, radi-
ologists and clinicians should be aware that the thrombosis
occurs most often in the SVC tributaries (i.e. brachioce-
phalic, jugular and/or subclavian veins) and not necessarily
in the SVC. The prevalence of thrombosis is not surprising
and similar to smaller prior cohorts showing thrombosis in
26–57% [13, 14].
Several anticoagulation practice patterns were apparent
in this study. First, anticoagulation was used after SVCS
diagnosis in half of all patients. Second, anticoagulation
was commonly prescribed in the absence of thrombosis
(52%), while it was not universally used (70%) in patients
with thrombosis. Third, the degree of venous occlusion of
the SVC or tributaries at diagnosis was the only clinical
or radiological variable associated with use of anticoagu-
lation, whereby patients with higher grade occlusion (vs.
occlusions < 90%) were more likely to receive anticoagula-
tion. There is however no evidence to suggest whether the
degree of venous occlusion affects the rate of subsequent
thrombosis and justifies anticoagulation. Fourth, the anti-
coagulation doses used were mostly full therapeutic doses,
even in patients without thrombosis. Reduced doses were
more frequent in patients without thrombosis than those with
thrombosis.
Conflicting estimates of anticoagulation use (13% vs.
94%) have been reported in two retrospective cohorts of
malignant SVCS (N ≤ 50) with very different study popula-
tions [1, 14]. The 94% rate of anticoagulation was in a study
of 50 critically ill cancer patients with malignant SVCS in
the intensive care unit (26% with thrombosis), while the 13%
was in 47 patients with unselected malignant SVCS.
These data suggest that anticoagulation is commonly used
in malignant SVCS but that treatment is not standardized.
Accordingly, the effect of anticoagulation on outcomes is
of interest, but had not been previously reported. New or
recurrent cases of thrombosis during follow-up occurred in
12% of the 57 patients with a reviewable follow-up CT. Of
note, thrombosis rates were similar with and without antico-
agulation. This comparison may have been confounded by
a higher prevalence of high grade occlusions in the antico-
agulated group, which may theoretically confer a higher risk
of thrombosis. However, the number of events and sample
size in this subgroup did not allow us to adjust for baseline
variables or the competing risk of death. We also had no
data on anticoagulation status at the time of the follow-up
CT. Therefore, this analysis does not allow for definitive
conclusions on the role of anticoagulation in prevention of
thrombosis of the SVC or tributaries.
Salvage SVC stenting, performed in 16% of patients,
was far more common in solid malignancies than hemato-
logical. This possibly reflects the usually swift reduction in
tumor mass with steroids and chemotherapy in aggressive
non-Hodgkin lymphoma resulting in a rapid resolution of
SVCS symptoms. This analysis was also weakly suggestive
of a protective effect for anticoagulation on salvage SVC
stenting; however, the significance threshold was not reached
(HR 0.47, 95% CI 0.2–1.13, p = 0.09) making this finding
hypothesis-generating at best.
The overall incidence of major bleeding was high (4% at
6 months). Major bleeding occurred mainly in patients with
therapeutic dose anticoagulation, suggesting that therapeu-
tic dose anticoagulation may be harmful in patients without
thrombosis in this setting, in the absence of evidence clearly
supporting efficacy.
This study also confirmed that the overall prognosis in
malignant SVCS is dismal (51% alive at 6 months). Neither
thrombosis nor anticoagulation affected mortality. Cancer-
related factors were the main prognostic determinants, simi-
lar to prior studies [11], and are unlikely to be overcome by
supportive management strategies (such as anticoagulation
or stenting).
One of the major strengths of this study is the review
of radiological data in a significant proportion of patients
(69%), unlike prior cohorts which didn’t review any imag-
ing studies [13, 14]. Another strong point is that the patient
characteristics are in line with previous malignant SVCS
cohorts, strengthening the external validity of these findings.
There are several limitations which warrant discussion.
First, confounding by indication of anticoagulation is pos-
sible, along with other limitations inherent to any retrospec-
tive study. The factors influencing use of anticoagulation
may differ between physicians, centers and clinical settings
[1, 14]. Second, the diagnosis of malignant SVCS relied
upon the original radiology report in the 56 (31%) patients
whose diagnostic CTs were performed at another center and
were not available for review. Nevertheless, none of the 127
13

diagnostic CTs which were reviewed overturned the diag-
nosis in the written radiology report. Furthermore, patients
with and without a reviewable diagnostic CT had similar
baseline clinical characteristics. Third, the lack of follow-up
CTs in 53% of patients (mainly due to early death) reduces
the internal validity of the data on thrombosis during follow-
up. Patients with a follow-up CT had less refractory disease
and were more likely to have hematological malignancy and
baseline anticoagulation than the overall cohort. Fourth,
patients with asymptomatic venous compression may have
been missed during the screening process which relied upon
ICD-9 diagnoses of venous compression. Last, we used non-
validated definitions to classify timing of anticoagulation
and stent placement. The appropriateness of these pre-study
classifications is supported by the actual indications for anti-
coagulation and salvage stenting documented in the medical
records of the study subjects, as well as the median times to
these treatments.
In summary, thrombosis of the SVC and tributaries is
prevalent at malignant SVCS diagnosis and is associated
with symptoms but not an increased risk of death. Antico-
agulation is commonly used as primary prevention of SVC
thrombosis, especially in patients with high grade occlu-
sions. The role of reduced dose anticoagulation for primary
prevention of SVCS thrombosis in high risk patients with
malignant SVCS should be prospectively assessed while
therapeutic prophylactic doses may be harmful.
Acknowledgements  The authors express their gratitude to Vincent ten
Cate for his critical review of the manuscript.
Funding  This work was supported by the Paul Davidoff Foundation
for the Ofek Program in collaboration with the Tel-Aviv University.
Compliance with Ethical Standards  nal products in surgical patients. J Thromb Haemost 8:202–204.
Conflict of interest  The authors declare that they have no conflict of
interest.
Ethical Approval  All procedures performed in studies involving human
participants were in accordance with the ethical standards of the insti-
tutional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
13
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R. Ratzon et al.
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