Original Article

Incidence and Predictors of Venous Thromboembolism (VTE)

Among Ambulatory High-Risk Cancer Patients Undergoing
Chemotherapy in the United States
Alok A. Khorana, MD1; Mehul Dalal, PhD2; Jay Lin, PhD3; and Gregory C. Connolly, MD1

BACKGROUND: Recent studies suggest that thromboprophylaxis is beneficial in preventing venous thromboembolism (VTE) in
cancer outpatients, but this is not widely adopted because of incomplete understanding of the contemporary incidence of VTE and
concerns about bleeding. Therefore, the authors examined the incidence and predictors of VTE in ambulatory patients with bladder,
colorectal, lung, ovary, pancreas, or gastric cancers. METHODS: Data were extracted from a large health care claims database of com-
mercially insured patients in the United States between 2004 and 2009. Demographic and clinical characteristics of the cancer
cohort (N ¼ 17,284) and an age/sex-matched, noncancer control cohort were evaluated. VTE incidence was recorded during a
3-month to 12-month follow-up period after the initiation of chemotherapy. Multivariate analyses were conducted to identify inde-
pendent predictors of VTE and bleeding. RESULTS: The mean age of the study population was 64 years, and 51% of patients were
women. VTE occurred in 12.6% of the cancer cohort (n ¼ 2170) over 12 months after the initiation of chemotherapy versus 1.4% of con-
trols (n ¼ 237; P < .0001); incidence ranged by cancer type from 19.2% (pancreatic cancer) to 8.2% (bladder cancer). Predictors of
VTE included type of cancer, comorbidities (Charlson Comorbidity Index score or obesity), and commonly used specific antineoplas-
tic or supportive care agents (cisplatin, bevacizumab, and erythropoietin). CONCLUSIONS: This large, contemporary, real-world analy-
sis confirmed high rates of VTE in select patients with solid tumors and suggested that the incidence of VTE is high in the real-world
setting. Awareness of the benefits of targeted thromboprophylaxis may result in a clinically significant reduction in the burden of VTE
in this population. Cancer 2013;119:648-55. V C 2012 American Cancer Society.

KEYWORDS: venous thromboembolism, incidence, neoplasms, drug therapy, outpatients, retrospective studies.

INTRODUCTION
The association between cancer and venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pul-
monary embolism (PE), is well established.1-3 Malignancy is characterized by activation of the coagulation system, and
this prothrombotic state is exacerbated further by chemotherapy, hormone therapy, and surgery.4-6 Cancer is 1 of the
most common and important acquired risk factors for VTE,7 and patients with active malignancy have a 4-fold to 7-fold
higher incidence of symptomatic VTE than the general population.8,9
Historically, VTE has been observed most frequently in hospitalized cancer patients admitted for surgery or acute
medical illness.10,11 The risk of cancer-associated VTE varies markedly; however, population-based case-control studies
indicate a 2-year cumulative incidence of 0.6% to 7.8%, depending on the population studied.12-14 This wide variation
reflects the multitude of influences on VTE risk in cancer patients, including disease-related factors (eg, tumor type, dis-
ease stage), patient-related factors (eg, comorbidity), and treatment-related factors (eg, chemotherapy, antiangiogenic
therapy).9,15 Systemic chemotherapy increases the risk of VTE 6-fold to 7-fold,16 and the rise in cancer-associated VTE
over recent decades16,17 may have been caused in part by the introduction of therapies with direct effects on the vascular
endothelium.18 It has been demonstrated that thromboprophylaxis is beneficial in reducing VTE in hospitalized, acutely
ill medical patients, including those with cancer.19 Recent large studies have suggested that outpatient thromboprophy-
laxis also is beneficial in cancer outpatients.20,21 However, outpatient prophylaxis has not been widely adopted clinically
because of an incomplete understanding of contemporary rates of VTE.16,22 In addition, concerns regarding the risk of
bleeding may lead to low compliance with prophylaxis in the cancer population, and little is known about the

Corresponding author: Alok A. Khorana, MD, School of Medicine and Dentistry, University of Rochester, James P. Wilmot Cancer Center, 601 Elmwood Avenue,
Box 704, Rochester, NY 14642; Fax: (585) 273-4150; alok_khorana@urmc.rochester.edu
1
Department of Medicine, University of Rochester and James P. Wilmot Cancer Center, Rochester, New York; 2Sanofi-Aventis US, Bridgewater, New Jersey;
3
Novosys Health, Flemington, New Jersey
All 4 authors were fully responsible for all content and editorial decisions.
Presented in part at the XXIII Congress of the International Society on Thrombosis and Hemostasis; July 23-28, 2011; Kyoto, Japan.
We acknowledge editorial/writing support provided by Paul Lane, PhD of UBC Scientific Solutions and funded by Sanofi-Aventis US.
DOI: 10.1002/cncr.27772, Received: May 17, 2012; Revised: July 12, 2012; Accepted: July 13, 2012, Published online August 14, 2012 in Wiley Online Library
(wileyonlinelibrary.com)

648 Cancer February 1, 2013


contemporary prevalence of bleeding in cancer patients or
the risk factors for bleeding. The primary objective of this
large, retrospective cohort analysis was to examine the
real-world incidence and predictors of VTE in a contem-
porary cohort of ambulatory patients undergoing current
chemotherapy regimens for select advanced or metastatic
solid tumors compared with an age-matched and sex-
matched control population of noncancer patients. We
chose to focus on 6 common solid tumors at high risk of
VTE that were included in recent large studies of throm-
boprophylaxis.20,21 We also examined the incidence and
predictors of all-cause bleeding events in these patients.
MATERIALS AND METHODS
Data Source
This retrospective, observational cohort study was based
on health care data collected from the IMS/PharMetrics
Patient-Centric database (IMS Health, Inc., New York,
NY) for the period from January 2004 through December
2009. This large database provides integrated enrollment,
medical, and prescription claims information from more
than 90 managed care organizations and Medicare, and it
represents the health services of over 58 million patients
across the United States. It includes both inpatient and
outpatient diagnoses (in International Classification of Dis-
eases, Ninth Revision, Clinical Modification [ICD-9-CM]
format) and procedures (in Current Procedural Terminol-
ogy, Fourth Edition [CPT-4] and Health Care Common
Procedure Coding System [HCPCS] formats) and outpa-
tient prescription records. Additional data elements
include patient demographics (age, sex, US Census Bu-
reau geographic region), health plan type, payer type, pro-
vider specialty, and health plan enrollment dates. All
patient records that we used were deidentified in compli-
ance with the Health Insurance Portability and Account-
ability Act of 1996; therefore, the study was exempt from
institutional review board overview.
Cohort Selection
Cancer cohort
Patients aged 18 years who had an inpatient diag-
nosis of malignant neoplasm of the lung (ICD-9-CM
codes 162.0, 162.2-162.5, 162.8, and 162.9), pancreas
(ICD-9-CM codes 157.0-157.4, 157.8, and 157.9), gas-
trointestinal system (ICD-9-CM codes 151.0-151.6,
151.8, and 151.9), colon/rectum (ICD-9-CM codes
153.0-154.3 and 154.8), bladder (ICD-9-CM codes
188.x), or ovary (ICD-9-CM codes 183.0, 183.2-183.5,
183.8, and 183.9) and who received cytotoxic chemother-
apy between January 2005 and December 2008 (the
Cancer February 1, 2013
10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
VTE in Ambulatory US Cancer Patients/Khorana et al
‘‘index event identification period’’) were selected from
the database. Receipt of chemotherapy was indicated by
health care claims with relevant National Drug Code
(NDC) or HCPCS codes. For study inclusion, patients
also were required to have continuous medical and pre-
scription drug coverage for 12 months before and 3 to
12 months after their earliest (index) cycle of chemother-
apy during the index event identification period. Patients
who received biologic agents alone, in the absence of
chemotherapy, were excluded from the study. Patients
who had a diagnosis of VTE (ICD-9-CM codes 415.1,
451.1, 451.2, 451.81, 451.83, 451.84, 451.9, 453.4,
453.8, and 453.9), severe renal impairment, hemorrhagic
stroke, or thrombocytopenia during the 12-month prein-
dex period, or major bleeding (including gastrointestinal
or ulcer-related bleeding) within the 3-month period im-
mediately before the index date were excluded from the
study. In addition, patients who received antithrombotic/
thrombolytic treatment, as indicated by health care claims
with NDC and HCPCS codes for heparin, enoxaparin,
dalteparin, tinzaparin, fondaparinux, bivalirudin, warfa-
rin, alteplase, reteplase, streptokinase, or urokinase <2
weeks before the index date were excluded.
Matched control cohort
Noncancer patients who were selected from the
same database were matched individually (1:1) to cancer
patients on age, sex, geographic region, and medical and
prescription coverage status to form a matched control
cohort. The control cohort served to demonstrate the
magnitude of VTE burden in real-world patients initiat-
ing chemotherapy for solid tumors. Each control patient
was assigned the index date of the corresponding matched
cancer patient. Control patients also were required to
have continuous medical and prescription drug coverage
data for 12 months before and 3 months after the
index date.
Data Collection and Outcome Measures
Patient characteristics and treatment patterns
Information on patient demographics (sex, age,
geographic region, and health plan) and clinical character-
istics (medical conditions/comorbidities, Charlson
Comorbidity Index [CCI] [an overall composite measure
of the severity of illness23]), during the 12-month prein-
dex period was collected for both patient cohorts. Medical
conditions/comorbidities of interest included hyperten-
sion, stroke/transient ischemic attack, type 2 diabetes,
congestive heart failure, pulmonary disease, hepatic dis-
ease, atrial fibrillation/flutter, and obesity (all identified
by ICD-9-CM codes).
649

Original Article
Receipt of anticoagulation and cancer therapy over
the 3-month to 12-month postindex period was deter-
mined for both patient cohorts. Receipt of anticoagulants
was indicated by the presence of an outpatient health care
claim with an NDC or HCPCS code for heparin, warfa-
rin, enoxaparin, dalteparin, tinzaparin, or fondaparinux.
Receipt of cancer therapy was indicated by the corre-
sponding NDC or HCPCS code for cisplatin, doxorubi-
cin, carboplatin, oxaliplatin, bevacizumab, cetuximab,
erythropoietin, or myeloid growth factors.
Clinical outcomes
Incidence rates of VTE and bleeding events over the
postindex follow-up period were determined from docu-
mented outpatient or inpatient claims with relevant ICD-
9CM, CPT-4, and HCPCS codes. VTE events were sepa-
rately classified as any VTE event (DVT or PE), DVT
only (ICD-9-CM codes 451.1, 451.2, 451.8, 451.9,
453.4, 453.8, and 453.9), PE only (ICD-9-CM code
415.1), and DVT þ PE, as previously defined.24 Major
bleeding was defined based on clinical input as the pres-
ence of appropriate ICD-9-CM codes (431, 432, 767,
767.11, 362.81, 376.32, 377.42, 430, or 719.1-719.19)
or CPT-4 codes (36,430 or 36,455). Minor bleeding was
defined as all other bleeding. Patients who had transfusion
codes alone without diagnostic codes for bleeding events
(based on HCPCS codes) were excluded from counts of
bleeding. Predictors of VTE and bleeding in cancer
patients were determined using a multivariate regression
model that included demographic variables (age, sex,
health plan type) and clinical variables (preindex surgery,
comorbidity, CCI score, cancer type, and index cancer
therapy).
Statistical Analysis
Demographic and clinical characteristics for each patient
cohort were summarized with descriptive statistics. Inter-
cohort comparisons of patient demographic, clinical, and
treatment characteristics and clinical outcomes were per-
formed with Student t tests (continuous variables) and
chi-square tests (categorical variables). A P value < .05
was considered statistically significant. Logistic regression
was performed for a predictor analysis. Statistical analyses
were conducted using SAS version 9.2 (SAS Institute Inc.,
Cary, NC).
RESULTS
Patient Demographics and Clinical
Characteristics
In total, 63,453 patients who had a diagnosis of bladder,
colorectal, lung, ovarian, pancreatic, or gastric cancer who
650
10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
were receiving chemotherapy during the index event iden-
tification period were identified from the database. Of
these, 17,284 patients with cancer fulfilled the study
inclusion criteria, with the majority having either lung
(38.9%) or colorectal (26.3%) cancer (Fig. 1). The con-
trol cohort comprised 17,284 noncancer patients who
matched the cancer cohort on age, sex, geographic region,
and enrollment status.
The mean age in both cohorts was 63.7 years, and
51.1% of patients were women (Table 1). The mean pre-
index CCI score was significantly higher in the cancer
cohort than in the control cohort (6.3 vs 0.6; P < .0001),
and the majority of individuals in the cancer cohort had a
CCI score 5 (59.8% vs 1.8% in noncancer controls;
P < .0001). Compared with the noncancer cohort,
patients in the cancer cohort also had a significantly (P <
.0001) higher prevalence of hypertension, stroke, diabetes
mellitus, congestive heart failure, pulmonary disease, he-
patic disease, atrial fibrillation, and obesity (Table 1).
Venous Thromboembolism Incidence and
Predictors
VTE occurred significantly more commonly in the cancer
cohort than in the noncancer cohort over 12 months after
the initiation of chemotherapy (12.6% vs 1.4%; P <
.0001) (Fig. 2). Similarly, the cancer cohort experienced a
significantly higher incidence of DVT only (7.7% vs 1%;
P < .0001), PE only (2.4% vs 0.2%; P < .0001), and
DVT plus PE (2.5% vs 0.2%; P < .0001) compared with
the control cohort. The incidence of VTE differed signifi-
cantly (P < .0001) across cancer types, with the highest
rates observed in patients with pancreatic cancer (19.2%)
and the lowest rates observed in patients with bladder can-
cer (8.2%) (Fig. 3). Although DVT was most frequent in
patients with pancreatic cancer (12.6%), PE was most fre-
quent in those with lung (3.6%) and gastric (3.3%) can-
cer. The majority of VTE events in the cancer cohort
occurred shortly after initiation of chemotherapy: among
the patients with VTE, 18.1% had their first event within
the first month, 47% had their first event within the first
3 months, and 72.5% had their first event within the first
6 months (Fig. 4).
In multivariate analysis, pancreatic cancer (odds ra-
tio [OR], 5.39; 95% confidence interval [CI], 4.26-6.80),
gastric cancer (OR, 4.00; 95% CI, 3.04-5.25), lung can-
cer (OR, 3.15; 95% CI, 2.55-3.89), a CCI score of 3 or 4
(OR, 3.60; 95% CI, 2.72-4.77), a CCI score 5 (OR,
4.38; 95% CI, 3.33-5.78), obesity (OR, 1.49; 95% CI,
1.23-1.82), and the receipt of erythropoietin (OR, 1.56;
95% CI, 1.41-1.73), bevacizumab (OR, 1.43; 95% CI,
Cancer February 1, 2013

Figure 1. Patient identification and recruitment is illustrated. VTE indicates venous thromboembolism.
1.24-1.65), or cisplatin (OR, 1.36; 95% CI, 1.19-1.55)
were associated with the greatest risk of VTE (Fig. 5, top).
Bleeding Incidence and Predictors
All-cause bleeding occurred in a significantly greater
proportion of the cancer cohort compared with the non-
cancer cohort (17.7% vs 7%; P < .0001) during follow-
up. Both major bleeding events (0.9% vs 0.1%; P <
.0001) and minor bleeding events (16.8% vs 6.9%; P <
.0001) were more common in the cancer cohort than in
the control cohort. Predictors of bleeding differed from
predictors of VTE, and bladder cancer (OR, 4.09; 95%
CI, 3.58-4.68; P < .0001), gastric cancer (OR, 2.16; 95%
CI, 1.77-2.65; P < .0001), atrial fibrillation/flutter (OR,
1.46; 95% CI, 1.29-1.65; P < .0001), receipt of erythro-
poietin (OR, 1.60; 95% CI, 1.48-1.74; P < .0001),
receipt of cetuximab (OR, 1.47; 95% CI, 1.15-1.87; P <
.05), and receipt of bevacizumab (OR, 1.39; 95% CI,
1.23-1.57; P < .0001) were associated with the greatest
risk of bleeding (Fig. 5, bottom).
DISCUSSION
The principal finding of the current population-based
study is the high overall incidence of VTE (12.6%) docu-
Cancer February 1, 2013
10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
VTE in Ambulatory US Cancer Patients/Khorana et al
mented in a large, contemporary, nationally representa-
tive, real-world cohort of ambulatory patients who were
initiating conventional chemotherapy for common can-
cers (lung, gastric, pancreas, colon/rectum, bladder, and
ovary). In this cohort, we identified multiple clinical risk
factors, including specific cancer-associated drug treat-
ments, for VTE (erythropoietin, bevacizumab, and cispla-
tin) and bleeding (erythropoietin, bevacizumab, and
cetuximab). The study is important because it provides a
contemporary estimate of VTE and bleeding rates in the
ambulatory setting, which is where the vast majority of
cancer care now occurs.
The incidence of cancer-associated VTE reported in
previous epidemiologic studies varies from 0.6% to
7.8%,3,12,13 reflecting differences in patient population,
clinical setting, duration of follow-up, receipt of chemo-
therapy, method of detecting VTE, and time frame of the
analysis, with a higher incidence reported in more recent
studies. Nevertheless, differences in the time frame do not
fully explain the markedly greater overall incidence of
VTE (12.6%) noted in our study. The PROTECHT
study,21 which enrolled ambulatory cancer patients
between 2003 and 2007, reported an incidence of throm-
boembolic events (a composite of symptomatic venous or
651
 10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Original Article

Table 1. Patient Demographic and Preindex Clinical

Characteristics

No. of Patients (%)

Characteristic Cancer Cohort, Noncancer
N 5 17,284 Cohort,
N 5 17,284
Age: MeanSD, y 63.712.0 63.712.0

Age group, y
<35 163 (0.9) 163 (0.9)
35-54 3559 (20.6) 3559 (20.6)
55-74 10,255 (59.3) 10,255 (59.3)
‡75 3307 (19.1) 3307 (19.1)
Figure 2. Incidence of venous thromboembolism (VTE) is
Sex illustrated for the cancer and noncancer cohorts. An asterisk
Men 8450 (48.9) 8450 (48.9) indicates P < .0001. DVT indicates deep vein thrombosis; PE,
Women 8831 (51.1) 8831 (51.1) pulmonary embolism.
Unknown 3 (0.02) 3 (0.02)

CCI scorea
0 499 (2.9) 11,843 (68.5)
1-2 3085 (17.9) 4288 (24.8)
3-4 3362 (19.5) 841 (4.9)
‡5 10,338 (59.8) 312 (1.8)
Overall score: Mean6SD 6.33.5b 0.61.1

Comorbidities
Hypertension 8969 (51.9)b 6683 (38.7)
Stroke 1136 (6.6)b 670 (3.9)
Diabetes 3558 (20.6)b 2563 (14.8)
Congestive heart failure 1148 (6.6)b 631 (3.7)
Pulmonary diseases 4067 (23.5)b 995 (5.8)
Liver diseases 3142 (18.2)b 285 (1.7)
AF/flutter 1034 (6.0)b 717 (4.2)
Obesity 675 (3.9)b 458 (2.7)

Abbreviations: AF, atrial fibrillation; CCI, Charlson Comorbidity Index; SD, Figure 3. The Incidence of venous thromboembolism is illus-
standard deviation. trated according to cancer type.
a
Cancer was included as a comorbidity in the calculation of CCI scores.
b
P < .0001 compared with the control cohort.

VTE may result in an overestimate of the incidence of

arterial thromboembolic events) of 3.9% in the placebo
arm (n ¼ 381) with a treatment duration of 4 months.
Another, more recent clinical trial (SAVE-ONCO), in
which selection criteria similar to those in the current
study were used, reported a rate of thromboembolic
events (a composite of symptomatic DVT, nonfatal PE,
and VTE-related death) of 3.4% in the placebo arm (n ¼
1604) with a median treatment period of 3.5 months.20
In our real-world study, the incidence of VTE among am-
bulatory patients with cancer over a similar timeframe
(the first 4 months after initiating chemotherapy) was
markedly higher at 7.2%, which may reflect the selection
bias inherent in clinical trials (ie, cancer patients with bet-
ter performance status and fewer comorbidities) or per-
haps geographic differences in surveillance/treatment
(frequency and resolution of scanning, chemotherapeutic
regimens). Alternatively, it is possible that the use of ICD-
9 diagnosis codes for the identification of patients with
clinical disease. It should be noted, however, that our
choice of ICD-9 diagnosis codes for the identification of
VTE was more selective than the methods used in several
previous database studies of VTE epidemiology.25-28 In
addition, the overwhelming majority of DVT events that
we identified in the database were site-specific, and <5%
of events fell into the ‘‘DVT with unspecified site’’ cate-
gory (ICD-9 code 451.9). Furthermore, there is a large
body of published literature to substantiate the use of
ICD-9 codes as surrogate diagnostic markers for clinically
documented VTE27-31 and major bleeding32-35 in retro-
spective claims data analyses.
The SAVE-ONCO and PROTECHT studies also
provided clear evidence that prophylactic pharmacologic
anticoagulation is effective in reducing clinically impor-
tant VTE in selected cancer outpatients who are receiving
chemotherapy. The SAVE-ONCO study, which was a
randomized, placebo-controlled trial of an ultra-low-

652 Cancer February 1, 2013

 10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
VTE in Ambulatory US Cancer Patients/Khorana et al

Figure 4. The distribution of venous thromboembolism

events is illustrated for the cancer cohort after the initiation
of chemotherapy.

molecular-weight heparin (semuloparin) in patients who

were initiating chemotherapy for common solid tumors,
indicated a significant reduction in the thromboembolic
event rate (1.2% vs 3.4%; P < .001) yet similar rates of
major bleeding (1.2% vs 1.1%) with semuloparin com-
pared with placebo.20 In the PROTECHT study, a low-
molecular-weight heparin (nadroparin) significantly
reduced thromboembolic events compared with placebo
in ambulatory cancer patients who were receiving chemo-
therapy (2.0% vs 3.9%; P ¼ .02). Although PROTECHT
was not powered to assess differences in major bleeding
events between the 2 treatment arms, 5 patients (0.7%) in
the nadroparin group and no patients in the placebo
group had major bleeding events.21
Our observations that the risk of VTE depends
heavily on the primary site of cancer and that pancreatic,
gastric, and lung cancers were significant predictive factors
for developing VTE in this patient cohort are consistent
with earlier epidemiologic findings.10,12,13,17 Similarly,
our identification of erythropoietin, bevacizumab, and
cisplatin therapies as significant predictors for the devel-
opment of VTE is in accordance with earlier evidence
Figure 5. (Top) Risk factors for venous thromboembolism
implicating platinum-based therapy,36,37 erythropoiesis- (VTE) are illustrated for the cancer cohort. Open symbols
stimulating agents,38,39 and antiangiogenic agents18,40,41 indicate the reference parameter for each comparison. A
dagger indicates P < .01; double dagger, P<.0001. (Bottom)
in the pathogenesis of VTE. Furthermore, several risk fac- Risk factors for all-cause bleeding are illustrated for the can-
tors, including obesity, type of cancer, and the receipt of cer cohort. An asterisk indicates P < .05; dagger, P < .01; dou-
ble dagger, P < .0001. CCI indicates Charlson Comorbidity
erythropoietin, further validate variables that were Index score; CI, confidence interval; AF, atrial fibrillation; TIA,
included in a previously developed predictive model for transient ischemic attack.
chemotherapy-associated VTE.42
In the case of bevacizumab, the impact on the risk of
VTE remains controversial based on data from clinical fold greater risk of VTE. Bevacizumab was received by
trials and meta-analyses.43-45 In the current study, bevaci- 25% of patients (n ¼ 1135) in the colorectal cancer sub-
zumab was received by 10.6% of patients across all tumor cohort from this study, in whom it was associated with a
types, and it was associated independently with a 1.43- 1.66-fold increase in the risk of VTE.46 In contrast to the

Cancer February 1, 2013 653


Original Article
more controlled environment of clinical trials, our study
addresses the real-world impact of initiating bevacizumab
in ambulatory patients with solid tumors while control-
ling for other risk factors. It is noteworthy that the US
Food and Drug Administration recently amended the pre-
scribing information for bevacizumab to include concerns
regarding an increased risk of VTE.47
Like VTE, bleeding in cancer patients arises through
the complex interplay of disease-related and treatment-
related factors. In the current study, the high incidence of
bleeding noted in the cancer cohort (approximately 3-fold
higher than in the control cohort) suggests causes other
than anticoagulation. Unfortunately, we were not able to
adjust for anticoagulation, because antiplatelet therapy
was not accurately captured. To the best of our
knowledge, this is the first study to provide contemporary,
real-world risk factors for bleeding in cancer patients. Pre-
dictors for bleeding differed from predictors for VTE. For
instance, the type of cancer with the greatest risk of bleed-
ing was bladder cancer, which had the lowest risk of VTE.
The association of bevacizumab with bleeding is well
documented.47,48 The association of erythropoietin with
bleeding has not previously been reported, but it may be
indicative of the receipt of erythropoietin to treat cancer-
associated anemia rather than indicating causality. The
association of cetuximab with bleeding is novel and may
be related to the cancer stage or site (typically, colorectal
or head and neck) for which this agent is used; however,
the association was significant even after adjusting for can-
cer site. In the context of thromboprophylaxis, it is
encouraging to note that major bleeding rates were not
elevated in recent large clinical trials with the use of
anticoagulation.20,21,49,50
Like all studies that use administrative claims data-
bases, the current investigation has several limitations.
The IMS/PharMetrics Patient-Centric database covers
the commercially insured population and may be unrep-
resentative of those with government-funded health care
and the uninsured. Information on clinical risk factors for
bleeding and thrombosis (eg, tumor stage, histologic sub-
type, and leukocyte and platelet counts), duration of
chemotherapy, and anticoagulant/chemotherapy dose was
unavailable. Similarly, the specific details of bleeding
events could not be determined, and it was not possible to
differentiate between symptomatic versus asymptomatic
VTE events. The use of claims data precludes verification
of diagnoses and possibly introduces coding errors.
Despite these limitations, retrospective analyses using
administrative claims data provide valuable information
that reflects contemporary, real-world clinical practice.
654
10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In conclusion, in the current large, contemporary
analysis, we observed high rates of VTE in patients ini-
tiating chemotherapy for solid tumors. The risk of VTE
was 9-fold greater among cancer patients who were
receiving chemotherapy than in noncancer controls. Fur-
thermore, the incidence of VTE (approximately 8%-
19%, depending on cancer type) reported in this real-
world analysis of patients with solid tumors was consid-
erably higher than the incidence reported in recent stud-
ies of thromboprophylaxis. Improved awareness on the
part of oncologists of the risks and clinical consequences
of cancer-associated VTE is an essential first step toward
reducing the clinical burden of this condition. Predictors
of VTE differ from predictors of bleeding. Results from
large, randomized studies suggest that outpatient throm-
boprophylaxis is feasible, safe, and effective. Targeting
cancer patients who have the greatest risk of VTE with
appropriate prophylaxis may reduce the clinical burden
of VTE and its consequences.
FUNDING SOURCES
This study was supported by Sanofi-Aventis US.
CONFLICT OF INTEREST DISCLOSURES
Dr Khorana has received honorararia for consulting and research
funding from Sanofi-Aventis US. Dr. Dalal is an employee of
Sanofi-Aventis US. The other authors made no disclosures of
conflict of interests.
REFERENCES
1. Noble S, Pasi J. Epidemiology and pathophysiology of cancer-asso-
ciated thrombosis. Br J Cancer. 2010;102(suppl 1):S2-S9.
2. Kessler CM. The link between cancer and venous thromboembo-
lism: a review. Am J Clin Oncol. 2009;32(4 suppl):S3-S7.
3. Khorana AA, Connolly GC. Assessing risk of venous thromboembo-
lism in the patient with cancer. J Clin Oncol. 2009;27:4839-4847.
4. Lip GY, Chin BS, Blann AD. Cancer and the prothrombotic state.
Lancet Oncol. 2002;3:27-34.
5. De Cicco M. The prothrombotic state in cancer: pathogenic mecha-
nisms. Crit Rev Oncol Hematol. 2004;50:187-196.
6. Rickles FR, Falanga A. Activation of clotting factors in cancer. Can-
cer Treat Res. 2009;148:31-41.
7. Falanga A, Zacharski L. Deep vein thrombosis in cancer: the scale
of the problem and approaches to management. Ann Oncol.
2005;16:696-701.
8. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous
thromboembolism: American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines (8th edition). Chest. 2008;
133(6 suppl):381S-453S.
9. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM,
Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmo-
nary embolism: a population-based case-control study. Arch Intern
Med. 2000;160:809-815.
10. Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE.
Incidence of venous thromboembolism in patients hospitalized with
cancer. Am J Med. 2006;119:60-68.
11. Dentali F, Malato A, Ageno W, et al. Incidence of venous throm-
boembolism in patients undergoing thoracotomy for lung cancer. J
Thorac Cardiovasc Surg. 2008;135:705-706.
Cancer February 1, 2013

12. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recur-
rent thromboembolic disease among patients with malignancy versus
those without malignancy. Risk analysis using Medicare claims data.
Medicine (Baltimore). 1999;78:285-291.
13. Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with
solid tumors: determination of frequency and characteristics.
Thromb Haemost. 2002;87:575-579.
14. Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM,
Lyman GH. Thromboembolism in hospitalized neutropenic cancer
patients. J Clin Oncol. 2006;24:484-490.
15. Wun T, White RH. Epidemiology of cancer-related venous throm-
boembolism. Best Pract Res Clin Haematol. 2009;22:9-23.
16. Lyman GH, Khorana AA, Falanga A, et al. American Society of
Clinical Oncology guideline: recommendations for venous throm-
boembolism prophylaxis and treatment in patients with cancer. J
Clin Oncol. 2007;25:5490-5505.
17. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH.
Frequency, risk factors, and trends for venous thromboembolism
among hospitalized cancer patients. Cancer. 2007;110:2339-2346.
18. Zangari M, Fink LM, Elice F, Zhan F, Adcock DM, Tricot GJ.
Thrombotic events in patients with cancer receiving antiangiogenesis
agents. J Clin Oncol. 2009;27:4865-4873.
19. Francis CW. Prophylaxis for thromboembolism in hospitalized
medical patients. N Engl J Med. 2007;356:1438-1444.
20. Agnelli G, George DJ, Fisher W, Kakkar AK, Lassen MR, Mismetti
P. The ultra-low molecular weight heparin (ULMWH) semuloparin
for prevention of venous thromboembolism (VTE) in patients with
cancer receiving chemotherapy: SAVE ONCO study [abstract]. J
Clin Oncol. 2011;29(suppl). Abstract LBA9014.
21. Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the pre-
vention of thromboembolic events in ambulatory patients with met-
astatic or locally advanced solid cancer receiving chemotherapy: a
randomised, placebo-controlled, double-blind study. Lancet Oncol.
2009;10:943-949.
22. Lyman GH. Venous thromboembolism in the patient with cancer:
focus on burden of disease and benefits of thromboprophylaxis.
Cancer. 2011;117:1334-1349.
23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method
of classifying prognostic comorbidity in longitudinal studies: devel-
opment and validation. J Chronic Dis. 1987;40:373-383.
24. Amin AN, Lin J, Yang G, Stemkowski S. Are there any differences
in the clinical and economic outcomes between US cancer patients
receiving appropriate or inappropriate venous thromboembolism
prophylaxis? J Oncol Pract. 2009;5:159-164.
25. Spencer FA, Emery C, Lessard D, et al. The Worcester Venous
Thromboembolism study: a population-based study of the clinical
epidemiology of venous thromboembolism. J Gen Intern Med.
2006;21:722-727.
26. Wang L, Sengupta N, Baser O. Risk of venous thromboembolism
and benefits of prophylaxis use in hospitalized medically ill US
patients up to 180 days post-hospital discharge [serial online].
Thromb J. 2011;9:15.
27. Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in
venous thromboembolism in children’s hospitals in the United
States from 2001 to 2007. Pediatrics. 2009;124:1001-1008.
28. Spyropoulos AC, Lin J. Direct medical costs of venous throm-
boembolism and subsequent hospital readmission rates: an adminis-
trative claims analysis from 30 managed care organizations. J Manag
Care Pharm. 2007;13:475-486.
29. Spencer FA, Emery C, Joffe SW, et al. Incidence rates, clinical pro-
file, and outcomes of patients with venous thromboembolism. The
Worcester VTE study. J Thromb Thrombolysis. 2009;28:401-409.
30. Fang MC, Maselli J, Lurie JD, Lindenauer PK, Pekow PS, Auerbach
AD. Use and outcomes of venous thromboembolism prophylaxis after
spinal fusion surgery. J Thromb Haemost. 2011;9:1318-1325.
31. Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA,
Lyman GH. Blood transfusions, thrombosis, and mortality in hospi-
talized patients with cancer. Arch Intern Med. 2008;168:2377-2381.
32. Happe LE, Rao SV, Horblyuk R, Franklin M, Lunacsek OE, Men-
ditto L. Consequences of major bleeding in hospitalized patients
Cancer February 1, 2013
10970142, 2013, 3, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.27772 by Nat Prov Indonesia, Wiley Online Library on [30/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
VTE in Ambulatory US Cancer Patients/Khorana et al
with non-ST segment elevation acute coronary syndromes receiving
injectable anticoagulants. Curr Med Res Opin. 2009;25:413-420.
33. Ghate SR, Biskupiak J, Ye X, Kwong WJ, Brixner DI. All-
cause and bleeding-related health care costs in warfarin-treated
patients with atrial fibrillation. J Manag Care Pharm. 2011;17:
672-684.
34. Kim MH, Lin J, Hussein M, Kreilick C, Battleman D. Cost of
atrial fibrillation in United States managed care organizations. Adv
Ther. 2009;26:847-857.
35. Kim MM, Metlay J, Cohen A, et al. Hospitalization costs associated
with warfarin-related bleeding events among older community-
dwelling adults. Pharmacoepidemiol Drug Saf. 2010;19:731-736.
36. Moore RA, Adel N, Riedel E, et al. High incidence of thromboem-
bolic events in patients treated with cisplatin-based chemotherapy: a
large retrospective analysis. J Clin Oncol. 2011;29:3466-3473.
37. Starling N, Rao S, Cunningham D, et al. Thromboembolism in
patients with advanced gastroesophageal cancer treated with anthra-
cycline, platinum, and fluoropyrimidine combination chemotherapy:
a report from the UK National Cancer Research. Institute Upper
Gastrointestinal Clinical Studies Group. J Clin Oncol.
2009;27:3786-3793.
38. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboemb-
olism and mortality associated with recombinant erythropoietin and
darbepoetin administration for the treatment of cancer-associated
anemia. JAMA. 2008;299:914-924.
39. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human eryth-
ropoietins and cancer patients: updated meta-analysis of 57 studies
including 9353 patients. J Natl Cancer Inst. 2006;98:708-714.
40. Elice F, Jacoub J, Rickles FR, Falanga A, Rodeghiero F. Hemostatic
complications of angiogenesis inhibitors in cancer patients. Am J
Hematol. 2008;83:862-870.
41. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous
thromboembolism with the angiogenesis inhibitor bevacizumab in
cancer patients: a meta-analysis. JAMA. 2008;300:2277-2285.
42. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW.
Development and validation of a predictive model for chemother-
apy-associated thrombosis. Blood. 2008;111:4902-4907.
43. Hurwitz HI, Saltz LB, Van Cutsem E, et al. Venous thromboem-
bolic events with chemotherapy plus bevacizumab: a pooled analysis
of patients in randomized phase II and III studies. J Clin Oncol.
2011;29:1757-1764.
44. Hapani S, Wu S. Controversial role of bevacizumab in the develop-
ment of venous thromboembolic events [letter]. J Clin Oncol.
2011;29:3490.
45. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combi-
nation with chemotherapy as first-line therapy in advanced gastric
cancer: a randomized, double-blind, placebo-controlled phase III
study. J Clin Oncol. 2011;29:3968-3976.
46. Khorana AA, Connolly GC, Dalal M, Lin J. Does bevacizumab
increase the risk of venous thromboembolism? A cohort study
[abstract]. J Clin Oncol. 2011;29(suppl). Abstract e19543.
47. US Food and Drug Administration. Changes in bevacizumab (Avas-
tin, Genentech, Inc.) package insert regarding: risk of ovarian fail-
ure, osteonecrosis of the jaw, risk of venous thromboembolic event
(VTE), and bleeding in patients receiving anticoagulation therapy
after first VTE event. Silver Spring, MD: US Food and Drug
Administration; 2011. Available at: www.fda.gov/AboutFDA/Cen-
tersOffices/OfficeofMedicalProductsandTobacco/CDER/
ucm274394.htm. [Accessed July 26, 2012].
48. Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemor-
rhage with bevacizumab in cancer patients: a meta-analysis. Oncol-
ogy. 2010;79:27-38.
49. Riess H, Pelzer U, Deutschinoff G, et al. A prospective, randomized
trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pan-
creatic cancer (APC): results of the CONKO 004 trial [abstract]. J
Clin Oncol. 2009;27(suppl). Abstract LBA4506.
50. Maraveyas A, Waters J, Roy R, et al. Gemcitabine versus gemcita-
bine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J
Cancer. 2012;48:1283-1292.
655