Original Contribution

Is Prophylactic Anticoagulation for Deep Venous Thrombosis

Common Practice After Intracerebral Hemorrhage?
Shyam Prabhakaran, MD, MS; Patricia Herbers, MS; Jane Khoury, PhD; Opeolu Adeoye, MD;
Pooja Khatri, MD; Simona Ferioli, MD; Dawn O. Kleindorfer, MD

Background and PurposeProphylactic anticoagulation for deep venous thrombosis prevention after intracerebral
hemorrhage (ICH) is safe. Current guidelines recommend prophylactic anticoagulation after cessation of hematoma
growth. We aimed to evaluate nationwide trends in deep venous thrombosis prophylaxis after ICH.
MethodsIn an analysis of the Premier database, we identified adult patients with ICH (International Classification of
Diseases Ninth edition code 431) from 2006 to 2010 who survived to day 2 of hospitalization. We excluded those
with trauma or who underwent craniotomy or angiography. We abstracted type of anticoagulant used and date of first
administration. We used univariate statistics and multivariable logistic regression to assess factors associated with
prophylactic anticoagulation after ICH.
ResultsAmong 32690 (mean age, 69.7 years; 50.1% men) patients with spontaneous ICH, 5395 (16.5%) patients received
any prophylactic anticoagulation during the hospital stay. Among these patients, 2416 (44.8%) received prophylactic
anticoagulation by day 2. The most commonly used agents were heparin (71.1%), enoxaparin (27.5%), and dalteparin
(1.4%). The proportion of patients receiving prophylactic anticoagulation increased slightly during the study period
from 14.3% to 18.0% (P<0.01 for trend). Use of prophylactic anticoagulation varied by geographic region (P<0.001)
in the United States: Northeast (23.2%), South (19.0%), Midwest (10.8%), and West (9.8%). In multivariable analysis,
geographic region remained an independent predictor of prophylactic anticoagulation.
ConclusionsLess than 20% of patients with ICH receive anticoagulation for deep venous thrombosis in the
United States. When used, the time to initiation is <2 days in less than half of the patients. Further study should
focus on understanding variations in practice and emphasize guideline-driven care. (Stroke. 2015;46:00-00.
DOI: 10.1161/STROKEAHA.114.008006.)
Key Words: anticoagulants pulmonary embolism thromboembolism

I ntracerebral hemorrhage (ICH) is a major cause of adult

morbidity and mortality. The 30-day mortality associated
with spontaneous ICH is 40% and a majority of survivors are
functionally dependent at long-term follow-up.1 Studies focus-
ing on halting hematoma expansion, hemostatic medications,
and hematoma evacuation surgery have failed to show clinical
benefit.2,3 Besides aggressive blood pressure control, which
showed a tendency toward improved outcome,4 there are no
proven treatment strategies to improve outcome after ICH,
and comprehensive medical management is recommended.5
A mainstay of medical management in ICH is prevention
of venous thromboembolism (VTE), including deep venous
thrombosis (DVT) and pulmonary embolism (PE). Patients
with ICH are at high risk for DVT and PE, with 4-fold
higher rates than in patients with acute ischemic stroke.6,7
Prophylaxis for VTE includes sequential compression
devices (nonpharmacological) and low-dose anticoagulant
medications (pharmacological). American Heart Association/
American Stroke Association guidelines have recommended
low-dose unfractionated heparin or low-molecular weight
heparin use early after ICH since 20078 and currently recom-
mend initiation between 1 and 4 days after ICH onset and after
cessation of active bleeding (class IIb, level of evidence B).5
However, real-world compliance with this recommendation is
unknown. Using the Premier database, we evaluated patient,
hospital, and geographic factors associated with prophylactic
anticoagulation after ICH in the United States.
Methods
Study Population
The Premier Hospital database is a privately owned data set that has
partnered with the Food and Drug Administration to study drug use in

Received November 4, 2014; final revision received December 10, 2014; accepted December 11, 2014.
From the Department of Neurology, Northwestern University, Chicago, IL (S.P.); Division of Biostatistics and Epidemiology, Cincinnati Childrens
Hospital Medical Center, OH (P.H., J.K.); and Department of Neurology, University of Cincinnati, OH (O.A., P.K., S.F., D.O.K.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
114.008006/-/DC1.
Correspondence to Shyam Prabhakaran, MD, MS, Department of Neurology, Northwestern University, 710 North Lake Shore Dr, Suite 1422, Chicago,
IL 60611. E-mail shyam.prabhakaran@northwestern.edu
2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.008006

1
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2StrokeFebruary 2015
hospitalized patients at 506 hospitals across the United States, repre-
senting 15% of hospital discharges annually. All billing and admin-
istrative coding information can be cross-linked to hospital pharmacy
billing records. Previous studies suggest that hospital and patient
characteristics in Premier are representative of the US population,9
although it may over-represent larger, teaching hospitals (Table1).
Unlike other large administrative data sets, such as MedPar, an advan-
tage of Premier is that it includes all payors, has pharmacy drug use
data, and is not limited to the Medicare-eligible patient population.
Using the Premier database, we identified all adult patients (>18
years) with ICH by primary or admitting International Classification
of Diseases Ninth edition (ICD-9) code 431 between January 1,
2006, and December 31, 2010 (Figure I in the online-only Data
Supplement). We included only patients who survived to day 2 of hos-
pitalization. We excluded those patients who underwent craniotomy
(ICD-9 procedure code 01.2x), cerebral angiography (88.41), or had
traumatic brain injury (850.xx to 854.xx); they were deemed more
likely to harbor secondary causes of ICH, have contraindications to
anticoagulation in the acute period, or be subarachnoid hemorrhage
misclassified as ICH. We also excluded those patients given warfa-
rin during the hospital stay because these patients probably required
therapeutic anticoagulation for conditions, such as atrial fibrillation.
Variables
Type of anticoagulant used and date of first administration was
captured if a patient was billed for heparin (in any form besides in-
travenous flush), enoxaparin, dalteparin, ardeparin, tinzaparin, or
fondaparinux (the study period predated the release of any of the
novel anticoagulant medications). Doses were not available but were
assumed to be prophylactic doses. Date of first administration was
transformed into hospital day with day 0 being the day of admission.
Other covariates of interest included hospital characteristics, such as
location (rural versus urban), academic or teaching (versus nonteach-
ing) status as defined by Premier, geographic location in the United
States (Northeast, Midwest, South, and West), number of beds, and
annual ICH case volume; and patient characteristics, such as demo-
graphics (age, sex, race, and ethnicity), type of insurance, baseline
medical risk factors (diabetes mellitus, hypertension, congestive heart
failure, atrial fibrillation, coronary artery disease, previous VTE, and
smoking history as defined by ICD-9 codes), location where patient
Table 1. Comparison of AHA Hospital Survey to Premiere
Database for Hospitalizations in 2012
AHA Community Hospital Premier Research Database,
Inpatient Hospitalizations, %* Inpatient Hospitalizations, %
Bed size
699 9.7 4.4
100199 17.2 13.3
200299 18.3 18.0
300499 28.0 35.3
>500 26.8 29.0
Region
Midwest 22.9 19.5
Northeast 19.7 20.8
South 38.5 42.9
West 18.8 16.8
Teaching status
Teaching 39.8 41.8
Nonteaching 60.2 58.2
AHA indicates American Heart Association.
*Source: AHA Hospital Statistics, 2014 (2012 Data). Chicago: Health Forum
LLC, an American Hospital Association company; 2014.
Premier research database, 2012 data, as of March 25, 2014.
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first received care, and patient location of initial care. Data on day of
week and time of arrival (daytime or not) were not available.
Statistical Analysis
Data are expressed as number (percent), mean (SD), or median (in-
terquartile range) as appropriate. The KolmogorovSmirnov test
was used to assess for normality of continuous data distribution.
Frequency of anticoagulant use overall and by hospital day is re-
ported. We assessed for differences in baseline patient and hospital
characteristics and anticoagulant use after ICH using 2 test for cate-
gorical variables, t test for normally distributed continuous variables,
and MannWhitney U test for ordinal variables and non-normally
distributed continuous variables. Multivariable logistic regression
was used to estimate odds ratios and 95% confidence intervals for
independent predictors of prophylactic anticoagulant use after ICH.
Candidate variables for the initial model were selected based on uni-
variate strength of association and plausibility. However, those with
<5% prevalence in this population were not included. A P<0.05 was
considered statistically significant. Analysis and data management
was performed using SAS, version 9.3 and SAS Enterprise guide,
version 4.3.
Results
There were 32690 inpatient records during the study period
meeting our inclusion/exclusion criteria. The mean age was
69.7 years (SD, 14.7) with 50.1% male and 59.3% white. The
overall frequency of any prophylactic anticoagulant use was
16.5% and increased during the study period (2006, 14.3%;
2007, 15.8%; 2008, 17.4%; 2009, 17.1%; and 2010, 18.0%;
P<0.01 for trend) and modestly following the publication of
the American Heart Association guidelines in 2007 (17.5%
versus 15.0%; P<0.001). The most commonly used agents
were as follows: heparin (71.1%), enoxaparin (27.5%), and
dalteparin (1.4%). Approximately 45% of those receiving pro-
phylactic anticoagulation were initiated before day 2 increas-
ing to 67% by day 4, and 91% by day 11 (Figure1). During
the study period, there was no trend suggesting an increase
in use within 2 days overall (P=0.42); however, among those
receiving prophylactic anticoagulation at any time during hos-
pitalization (n=5395), use within 2 days actually declined over
time (P<0.01 for trend; Figure2).
Using bivariate analysis (Table2), use of prophylactic
anticoagulation varied by geographic region (P<0.01) in the
United States: Northeast (23.2%), South (19.0%), Midwest
(10.8%), and West (9.8%). Among patient characteris-
tics, those who received prophylactic anticoagulation were
younger (median, 67.0 versus 73.0 years; P<0.01), arrived
less commonly through the emergency department (65.3%
versus 69.7%; P<0.01), and were more frequently black
(26.1% versus 14.7%; P<0.01) and had Medicaid or were
self-pay (18.5% versus 12.5%; P<0.01) than those who never
received it.
Those who received prophylactic anticoagulation were
more likely to have diabetes mellitus (33.0% versus 27.2%;
P<0.01), congestive heart failure (15.0% versus 10.2%;
P<0.01), atrial fibrillation (20.3% versus 18.3%; P<0.01), pre-
vious ischemic stroke (3.6% versus 1.9%; P<0.01), and coro-
nary artery disease (24.2% versus 22.2%; P=0.01). Among
hospital characteristics, those who received prophylactic anti-
coagulation were more likely to be treated at urban hospitals
(95.8% versus 91.9%; P<0.01), academic medical centers

(57.6% versus 48.2%; P<0.01), and at larger hospitals (513
[interquartile range, 370649] versus 440 [interquartile range,
325562] beds; P<0.01). Furthermore, they were more likely
to be treated at hospitals in the highest tertile of annual ICH
case volume (P<0.01).
In multivariable analysis (Table3), in addition to several
patient factors (age, race and ethnicity, insurance status, arrival
location, and medical risk factors) and hospital factors (urban
location and bed size), geographic region remained indepen-
dently associated with prophylactic anticoagulation after ICH.
Compared with Western states, patients treated at hospitals
in Northeastern (adjusted odds ratio, 2.30; 95% confidence
intervals, 2.072.56) and Southern (adjusted odds ratio, 1.59;
95% confidence intervals, 1.432.76) states were more likely
to receive prophylactic anticoagulation.
Discussion
We found that prophylactic anticoagulation is used in <20% of
patients with ICH. Early prophylactic anticoagulation (within
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Prabhakaran et al DVT Prophylaxis in ICH 3
Figure 1. Frequency of prophylactic anticoagulation
initiation by hospital day.
2 days) was provided in <10% of patients with ICH overall
and actually declined during the 5-year study period among
the subset of patients who received any prophylactic antico-
agulation. Besides patient and hospital characteristics typical
of urban and academic centers (ie, younger age, minorities,
presence of vascular risk factors, and larger urban hospitals),
we also observed geographic variation such that Northeastern
hospitals were more likely to provide prophylactic anticoagu-
lation than other regions of the United States. Despite guide-
lines supporting the practice, our findings suggest that DVT
prophylaxis after ICH may be suboptimal nationwide.
Multiple studies have observed that hematoma expansion
is infrequently encountered after the first 24 to 48 hours in
spontaneous patients with ICH.10,11 In contrast, clinically evi-
dent VTE occurs in up to 13% of patients with ICH, peaks
between days 2 and 7 of hospitalization, and carries a high
risk of fatality because of PE.1215 However, large randomized
clinical trials of pharmacological DVT prophylaxis in patients
with ICH have not been conducted. Several observational and
Figure 2. Temporal trends in prophylactic antico-
agulation use within 2 days of admission among
patients with intracerebral hemorrhage (ICH) who
received prophylactic anticoagulation during hos-
pital stay (arrow indicates date of publication of
American Heart Association/American Stroke Asso-
ciation (AHA/ASA) ICH guidelines in October 2007).
4StrokeFebruary 2015

Table 2. Baseline Patient and Hospital Characteristics Among Patients Who Received and Did Not
Receive Prophylactic Anticoagulation After ICH
No Prophylactic Anticoagulation Prophylactic Anticoagulation
n=27295 n=5395 P Value
Demographics
Age median (IQR) 73 (60, 82) 67 (55, 78) <0.01
Women 13779 (50.5%) 2525 (46.8%) <0.01
Race

White 16623 (60.9%) 2751 (51.0%) <0.01

Black 4018 (14.7%) 1419 (26.3%)

Hispanic 1547 (5.7%) 328 (6.1%)

Other 5107 (18.7%) 897 (16.6%)
Medicaid/self-pay 3417 (12.5%) 1000 (18.5%) <0.01
Arriving via emergency department 19029 (69.7%) 3521 (65.3%) <0.01
Arriving from nursing home 400 (1.5%) 66 (1.2%) 0.17
Comorbidities
Diabetes mellitus 7415 (27.2%) 1780 (33.0%) <0.01
Hypertension 22288 (81.7%) 4459 (82.6%) 0.08
Congestive heart failure 2783 (10.2%) 812 (15.0%) <0.01
Atrial fibrillation 5004 (18.3%) 1094 (20.3%) <0.01
Coronary artery disease 6063 (22.2%) 1306 (24.2%) 0.01
Previous ischemic stroke 522 (1.9%) 193 (3.6%) <0.01
Smoking 3182 (11.7%) 668 (12.4%) 0.13
Previous VTE 299 (1.1%) 347 (6.4%) <0.01
Hospital characteristics
Rural location 2219 (8.1%) 226 (4.2%) <0.01
Region

Midwest 5527 (20.2%) 669 (12.4%) <0.01

Northeast 5070 (18.6%) 1527 (28.3%)

South 10972 (40.2%) 2577 (47.8%)

West 5726 (21.0%) 622 (11.5%)
Hospital beds median (IQR) 440 (325, 562) 513 (370, 649) <0.01
Academic medical center 13144 (48.2%) 3109 (57.6%) <0.01
ICH case volume

Lowest tertile 732 (2.7%) 100 (1.8%) <0.01

Middle tertile 5189 (19.0%) 795 (14.7%)

Highest tertile 21374 (78.3%) 4500 (83.4%)
ICH indicates intracerebral hemorrhage; IQR, interquartile range; and VTE, venous thromboembolism.

nonrandomized studies have indicated that low-dose anticoag-
ulation does not result in hematoma expansion after ICH.1621
Three small randomized trials have also been completed.2224
In 68 patients with ICH, low-dose heparin starting on day 2
led to a statistically lower rate of PE when compared with
4th or 10th day of initiation.24 The second trial included 46
patients and found that low-dose subcutaneous heparin did not
increase risk of rebleeding or hematoma expansion.23 A more
recent trial of 75 patients using enoxaparin also observed no
increase risk of hematoma expansion.22 A meta-analysis of 4
controlled (2 randomized)17,21,22,24 studies suggested a signifi-
cant reduction in PE with prophylactic anticoagulation with
no effect on DVT occurrence or bleeding.25
Despite previous studies showing modest benefits in reduc-
ing PE balanced partly by risk of bleeding in medically ill
and hospitalized patients with stroke,2628 current American
Heart Association/American Stroke Association guidelines
recommend prophylactic anticoagulation (class I, level of
evidence A) in immobilized patients with acute ischemic
stroke.29 In contrast, guidelines for ICH management con-
vey more uncertainty. Multiple organizations in the United
States (since 2007), Europe (since 2006), and Japan (since
2011) recommend that prophylactic doses of unfractionated
heparin or low-molecular weight heparin be considered for
DVT prevention,5,3032 whereas prophylactic anticoagulation
is not recommended in the United Kingdom or Australia.33,34
Furthermore, current Joint Commission guidelines include
pneumatic compression devices and prophylactic antico-
agulation as acceptable forms of DVT prophylaxis, whereas
excluding compression stockings as clearly inappropriate.35

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 Prabhakaran et al DVT Prophylaxis in ICH 5

Table 3. Multivariable Model of Independent Factors were able to assess temporal and geographic variation with
Associated With Use of Prophylactic Anticoagulation After ICH* large sample sizes. However, because our analysis relies on
Adj. OR 95% CI administrative data compiled by ICD-9 codes, we are sub-
ject to the potential for case ascertainment errors. We cannot
Patient characteristics
be certain that our included cohort contains only patients
Age (per 5 y) 0.92 0.90 0.93
with spontaneous ICH, the population of primary interest
Black (vs white) 1.61 1.49 1.75 because these patients would have few or no contraindica-
Hispanic (vs white) 1.11 0.97 1.27 tions to low-dose anticoagulation. However, the positive
Other race (vs white) 1.03 0.94 1.12 predictive value of ICD-9 coding of ICH (431.x) has been
Medicaid/self-pay 1.15 1.05 1.26 previously shown to be modest (75%77%) with errors
Emergency department arrival 0.80 0.75 0.85 predominantly being because of misclassification with sub-
Diabetes mellitus 1.23 1.15 1.32 arachnoid hemorrhage and ischemic stroke with hemor-
rhagic transformation.36,37 An underestimation of the true
Congestive heart failure 1.52 1.38 1.67
use of prophylactic anticoagulation for ICH would exist in
Atrial fibrillation 1.31 1.20 1.42
the case of misclassification of ischemic stroke with hemor-
Coronary artery disease 1.14 1.06 1.23 rhagic transformation as ICH in our data. We also excluded
Hospital characteristics patients who underwent cerebral angiography, as these may
Urban hospital 1.43 1.24 1.66 include secondary causes of ICH (ie, arteriovenous mal-
Northeast hospital (vs Western) 2.24 2.02 2.50 formation) and also aneurysmal subarachnoid hemorrhage.
Southern hospital (vs Western) 1.58 1.43 2.75 Because clinical and imaging data are not available, we can-
Midwest hospital (vs Western) 0.88 0.78 1.00 not comment on the size, location, intraventricular exten-
Beds (per 50) 1.04 1.04 1.05
sion, presumed cause, or stability of the hematoma or the
clinical severity of the presentation. Stroke or coma scales
Adj. OR indicates adjusted odds ratio; CAD, coronary artery disease; CHF,
and other surrogates of disease severity were not available
congestive heart failure; CI, confidence intervals; ED, emergency department;
and ICH, intracerebral hemorrhage. in the Premiere database; therefore, we are not able to adjust
*Variables entered into the full model: age, sex, race, Medicaid, teaching for or stratify by clinical severity. We did, however, exclude
hospital, ED arrival, diabetes mellitus, hypertension, CHF, atrial fibrillation, CAD, those patients who did not survive to day 2, a group likely
urban/rural, region, and hospital volume (beds). to have been too severe to justify prophylactic anticoagula-
tion. We did not exclude patients with external ventricular
The strength of these recommendations, in addition to the drains or other surgical procedures, besides craniotomy, that
discrepancies, may be deterring more widespread imple- might delay or contraindicate anticoagulant use. Likewise,
mentation in practice. we could not adjust for other clinical risk factors, such as
There have been, to our knowledge, no previous reports on family history of VTE, body mass index or known contra-
nationwide use of prophylactic anticoagulation after ICH. Our indications to prophylactic anticoagulation, such as sys-
results indicate that widespread acceptance of the current US temic bleeding or early ambulatory status. Individualized
guidelines is low, particularly at nonacademic or rural centers. decision-making probably occurs such that factors associ-
Although we cannot explain the geographic or hospital-level ated with increased risk of VTE (ie, prolonged immobility,
variations or overall underuse, we speculate that physician cancer, or hypercoagulable state) or hemorrhagic complica-
lack of awareness of the evidence and guidelines, preferences tion (ie, coagulopathy or active bleeding) are carefully con-
toward nonpharmacological prophylaxis, or safety concerns sidered. We are unable to correlate administration or timing
about pharmacological prophylaxis probably play major roles of prophylactic anticoagulation with measures of efficacy
in decision-making. Indeed, the decline in early prophylactic (occurrence of acute DVT or PE) or with adverse events
anticoagulation suggests increased safety concerns as a poten- (occurrence of hematoma expansion or recurrent bleeding)
tial reason. A lack of specialists with expertise in managing during hospitalization or beyond. Finally, we cannot com-
patients with ICH and lower annual volume of patients with ment on nonpharmacological prophylaxis (ie, sequential
ICH may also contribute to inexperience and unease with this compression devices), which afford some protection from
practice guideline at smaller hospitals. Specialists in stroke VTE. These limitations are unlikely to explain our main
and neurocritical care, who tend to be clustered at larger urban finding of <20% prophylactic anticoagulation use after ICH.
and academic hospitals, may be more familiar with guide-
lines and also have greater experience with safe initiation Conclusions
of prophylactic anticoagulation after ICH. Alternatively, the In a large nationwide registry, we observed that prophylactic
lack of large definitive randomized controlled trials to sup- anticoagulation was provided to less than one-fifth of patients
port stronger recommendations may be driving practice in the with ICH. Our results suggest that current guidelines are not
community. accepted broadly in clinical practice, which may be because
Our study has several strengths and limitations. First, by of the strength of the recommendations, lack of knowledge or
using a large nationwide database with linked pharmacy expertise, or concerns about safety. Further analysis of practi-
records, we were able to estimate anticoagulant use and tioner preferences and perceptions may help guide next steps.
date of first administration with high accuracy. Second, we These may include targeted dissemination and education.

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6StrokeFebruary 2015
However, larger randomized clinical trials may be required to
change current perception of clinical equipoise.
Disclosures
Dr Khatris Department of Neurology receives funds for her research
efforts from Genentech (Lead PRISMS PI), Penumbra (THERAPY
Neuro PI), and Biogen (DSMB member). The other authors report
no conflicts.
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 Is Prophylactic Anticoagulation for Deep Venous Thrombosis Common Practice After
Intracerebral Hemorrhage?
Shyam Prabhakaran, Patricia Herbers, Jane Khoury, Opeolu Adeoye, Pooja Khatri, Simona
Ferioli and Dawn O. Kleindorfer

Stroke. published online January 8, 2015;

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