Risk Factors and Outcomes of Gastrointestinal Bleeding in

Left Ventricular Assist Device Recipients

Parijat Saurav Joy, MD, MPHa,*, Gagan Kumar, MDb, Achuta Kumar Guddati, MD, PhDc,
Jay Kumar Bhama, MDd, and Linda Marie Cadaret, MDa

Increasing use of left ventricular assist devices (LVADs) has been accompanied by rising
incidence of gastrointestinal bleeding (GIB). Objectives of this study were to determine the
yearly incidence of GIB in LVAD recipients, compare outcomes of continuous-flow (CF) and
pulsatile-flow LVAD eras, and investigate for risk factors. The Healthcare Cost and Utili-
zation ProjecteNationwide Inpatient Sample database from 2005 to 2010 was analyzed.
Primary outcome of interest was incidence of GIB in LVAD recipients. Multivariate logistic
regression model was used to examine independent associations of GIB with risk factors and
outcomes. An estimated 8,879 LVAD index admissions and 8,722 readmissions in LVAD
recipients over 6 years were analyzed. The yearly incidence of GIB after LVAD implantation
increased from 5% in 2005 to 10% in 2010. On multivariate regression analysis, the odds of
GIB was 3.24 times greater (95% confidence interval 1.53 to 6.89) in the era of CF LVADs
than in the era of pulsatile-flow LVADs. Compared to their younger counterparts, in LVAD
recipients aged >65 years, the adjusted odds of GIB was 20.5 times greater (95% confidence
interval 2.24 to 188). GIB did not significantly increase the inhospital mortality but increased
the inpatient length of stay. In conclusion, the incidence of GIB in LVAD recipients has
increased since the use of CF LVADs has increased, leading to greater inpatient lengths of
stay and hospital charges. Older recipients of CF LVADs appear to be at a greater risk of
GIB. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:240e244)

A growing population of patients with end-stage heart
disease are being considered for left ventricular assist device
(LVAD) implantation because of organ shortage. First-
generation LVADs were pulsatile volume-displacement
devices. Second-generation continuous-flow (CF) systems,
such as the HeartMate-II (Thoratec, Pleasanton, California)
and HeartWare (HeartWare, Massachusetts), based on
rotary-pump technology offer improved reliability and allow
implantation in smaller sized patients.1 The increasing use
of LVADs has led to a significant rate of gastrointestinal
bleeding (GIB) in their recipients. For patients with CF
LVADs, reported incidence of GIB is 17.6% to 40%2e5
which is more than that for pulsatile-flow devices.6 Our
aim was to evaluate outcomes and investigate for significant
risk factors for GIB in these patients. After the Food and
Drug Administration approved CF LVADs such as the
HeartMate-II in April 20087 for use as “bridge to trans-
plant,” a much wider patient population became eligible for
CF devices and so, pulsatile-flow LVADs fell out of use in
the United States. To best compare pulsatile-flow versus CF
LVADs, we performed our analysis in 2 temporal
Departments of aInternal Medicine and dCardiothoracic Surgery, Uni-
versity of Iowa, Iowa City, Iowa; bDepartment of Critical Care, Phoebe
Putney Memorial Hospital, Albany, Georgia; and cDepartment of Hema-
tology and Oncology, SUNY Downstate Medical Center, New York, New
York. Manuscript received July 22, 2015; revised manuscript received and
accepted October 17, 2015.
See page 244 for disclosure information.
*Corresponding author: Tel: (267) 979-8293; fax: (319) 356-3086.
E-mail address: joymedicine2@gmail.com (P.S. Joy).
subgroups: 2005 to 2007 representing the pulsatile LVAD
era and 2008 to 2010 representing the CF LVAD era.
Methods
The Healthcare Cost and Utilization ProjecteNationwide
Inpatient Sample (NIS) database from the year 2005 to 2010
was used for this study.8 NIS was created by the Agency for
Healthcare Research and Quality as part of the Healthcare
Cost and Utilization Project and contains data on hospital stays
from about 1,000 hospitals sampled to approximate a 20%
stratified sample of US community hospitals. Each hospitali-
zation is treated as an individual entry in the database and
is coded with 1 principal diagnosis, up to 14 secondary
diagnoses, and 15 procedural diagnoses associated with that
stay. NIS includes information on all hospitalizations,
regardless of the payer. To facilitate the production of national
estimates, both hospital and discharge weights are provided.
As the NIS database is publicly available and without patient
identifiers, this study is deemed exempt from review by the
institutional review board. Adults aged
18 years were
considered for the study. The International Classification of
Diseases, Ninth Revision, clinical modification code 37.66
(ICD-9-CM) was used to identify admissions during which
LVAD was placed, which will be referred to as index
admission in this study. During index admissions, upper and
lower GI bleed, if they occurred after LVAD placement,
were identified using procedure codes for esophagogas-
troduodenoscopy and colonoscopy. Readmissions were
identified using ICD-9-CM code V43.21. During read-
missions, GIB was identified using primary diagnosis of upper
or lower GI bleed. The ICD-9-CM codes to identify upper and
lower GI bleed are provided in Supplementary Table 1.

0002-9149/15/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. www.ajconline.org
http://dx.doi.org/10.1016/j.amjcard.2015.10.041
 Heart Failure/GI Bleeding in LVAD Recipients 241

Table 1 Table 2
Characteristics of Left Ventricular Assist Device recipients for index Characteristics of Left Ventricular Assist Device recipients needing
admission readmission
Variable 2005-2007 2008-2010 P-value Variable 2005-2007 2008-2010 P value

Total LVADs 2672 6207 Total admissions 1180 7542

GI Bleed after 7.7% 8.6% 0.67 GI bleed 2.9% 10% <0.001*
LVAD placement Age 0.39
Age (years) 0.025* 18-34 8.5% 8.6%
18-34 10.7% 10.4% 35-49 21.6% 15.2%
35-49 25.3% 19.1% 50-64 41.9% 48.1%
50-64 46.7% 46.7%
65 28.0% 28.2%

65 17.3% 23.8% Males 68.2% 74.8% 0.17
Males 73% 78% 0.025* Race 0.88
Race 0.58 White 51.2% 53.7%
White 58.1% 54.5% Black 23.4% 18.2%
Black 14.4% 16.7% Hispanic 5.5% 5.2%
Hispanic 6.5% 6.0% Asian 0% 0.9%
Asian 1.7% 2.4% Others 1.0% 2.3%
Others 2.4% 3.8% Unknown 18.5% 19.6%
Unknown 16.8% 16.7% Insurance 0.65
Insurance <0.001* Medicare 44.1% 51.2%
Medicare 26.1% 41.0% Medicaid 14.0% 10.7%
Medicaid 12.7% 11.9% Private 39.4% 35.4%
Private 52.2% 42.7% Uninsured 1.3% 0.9%
Uninsured 3.3% 2.1% Others 1.2% 1.7%
Others 5.6% 2.3% Teaching hospital 85.7% 93.1% 0.22
Teaching hospital 91.3% 94.8% 0.40 Urban hospital 96.8% 99.7% <0.001*
Urban hospital 98.9% 99.6% 0.025* Hospital bed size 0.006*
Hospital bed size 0.006* Small 5.8% 0.6%
Small 2.2% 0.8% Medium 16.7% 4.5%
Medium 19.3% 3.7% Large 77.5% 94.9%
Large 78.5% 95.5% Hospital region 0.81
Hospital region 0.69 Northeast 18.2% 28.0%
Northeast 27.8% 20.6% Midwest 36.0% 36.2%
Midwest 23.2% 34.4% South 27.0% 19.5%
South 27.4% 23.8% West 18.8% 16.4%
West 21.7% 21.1% Co-morbidities
Co-morbidities Atrial Fibrillation 20.3% 23.8% 0.34
Atrial Fibrillation 26.8% 22.6% 0.13 Hypertension 42.0% 43.7% 0.76
Hypertension 25.9% 31.6% 0.10 Coronary artery disease 42.8% 54.6% 0.02*
Coronary artery disease 50.2% 46.2% 0.25 Peripheral vascular disease 3.3% 5.3% 0.23
Peripheral vascular disease 3.2% 4.3% 0.29 Diabetes 24.2% 33.2% 0.048*
Diabetes 17.2% 15.9% 0.6 Body Mass Index >40 2.2% 4.5% 0.18
Body Mass Index >40 1.0% 4.0% <0.001* Chronic obstructive 6.7% 11.6% 0.025*
Chronic obstructive 8.7% 7.0% 0.25 pulmonary disease
pulmonary disease Venous thromboembolism 1.1% 1.7% 0.54
Venous thromboembolism 6.9% 7.5% 0.79 Stroke 7.5% 5.3% 0.16
Stroke 6.1% 6.9% 0.56 Cirrhosis 0% 1.8% 0.14
Cirrhosis 2.6% 1.7% 0.13 Chronic anemia 5.6% 6.9% 0.49
Chronic anemia 1.5% 3.5% 0.039* Cancer 3.7% 2.6% 0.44
Cancer 1.8% 2.2% 0.75 End stage renal disease 2.8% 2.6% 0.93
End stage renal disease 2.2% 0.5% 0.001* Malnutrition 4.5% 6.1% 0.37
Malnutrition 9.8% 21.1% 0.003* Peptic ulcer disease 0% 1.3% 0.21
Peptic ulcer disease 0.6% 0.8% 0.69 Smoker 6.4% 13.3% 0.16
Smoker 6.2% 7.4% 0.41
GI ¼ gastro-intestinal; LVAD ¼ Left Ventricular Assist Device.
GI ¼ gastrointestinal; LVAD ¼ Left Ventricular Assist Device. *p <0.05.
*p <0.05.

missing in 20% to 25% of records, and these are reported

Known risk factors for GIB were identified using ICD-9-CM
codes as presented in Supplementary Table 2. NIS variables
were used to identify patient age, gender, race, and primary
payer. Age groups were divided into 4 categories: 18 to 34, 35
to 49, 50 to 64, and
65 years. Information on race was
under “unknown” category. NIS classifications for a hospital’s
teaching characteristics were also used.
Primary outcomes of interest were the frequency of GIB
and all cause inhospital mortality. Secondary outcomes
included length of hospital stay and hospital charges. The
variables and outcomes related to GIB were examined in
242 The American Journal of Cardiology (www.ajconline.org)
Figure 1. Trends of GIB in LVAD recipients. Overall trends of GIB are
shown for LVAD implantations (during index admission and readmission).
LVAD recipients in 2 groups: during index admission for
LVAD implantation and readmissions. The 2 groups were
further subdivided into 2 temporal subgroups: 2005 to 2007
and 2008 to 2010, respectively, representing the eras when
pulsatile LVADs and CF LVADs were placed. Statistical
analysis was performed in STATA IC 11.0 (STATA-Corp,
College Station, Texas) using the strata weights and survey
commands to generate national estimates of patients with
LVADs during index admissions and readmissions. Pearson
chi-square test and Wilcoxon rank test were used to compare
categorical and continuous variables, respectively. Multi-
variate logistic regression model was used to examine
independent associations of GIB with the 2 eras. Univariate
model was initially used to identify clinically plausible risk
factors associated with GIB. Variables that were significant
in the univariate analysis at p <0.10 were included in the
final multivariate model. Those variables, which have been
shown to be associated with GIB in the literature, were kept
in the model even if they did not meet the statistical sig-
nificance. These independent variables were then checked
for multicollinearity using variance inflation factor. Inter-
action between the 2 eras and the variables were checked
and kept in the model if p value was <0.10. Similarly,
multivariate logistic regression was used to examine if GIB
was independently associated with an increase in hospital
mortality in patients receiving LVADs.
Results
In the era of pulsatile-flow LVADs, 2,672 devices were
implanted with 1,180 readmissions, whereas in the era of
CF LVADs, 6,207 devices were implanted with 7,542 read-
missions (Tables 1 and 2). Demographic information
of LVAD recipients in the 2 eras is provided in Table 1 (LVAD
index admissions) and Table 2 (LVAD readmissions). Device
recipients in the CF LVAD era were older, predominantly
male, and had more co-morbidities such as obesity, malnu-
trition, and chronic anemia, compared to pulsatile-flow LVAD
recipients (Table 1). The trend of the yearly incidence of all
episodes of GIB in LVAD recipients requiring inpatient care
increased from 5% in 2005 to 10% in 2010 (Figure 1). Inci-
dence of GIB during LVAD index admissions was not
significantly different in the 2 eras (7.7% vs 8.6%; Table 1).
However, among the patients readmitted after LVAD
implantation, the proportion of recipients admitted for GIB
was more than 3 times greater in the CF LVAD era than the
pulsatile-flow LVAD era (10% vs 2.9%, p <0.001; Table 2).
After adjusting for other clinically plausible risk factors using
multivariate regression analysis, the odds of GIB was 3.24
times greater (95% confidence interval [CI] 1.53 to 6.89) in the
CF LVAD era compared to the era of pulsatile-flow LVAD
implantation (Figure 2). Age was the strongest independent
risk factor associated with increased incidence of GIB in
LVAD recipients. For readmissions after LVAD placement,
compared to 18- to 34-year-old recipients, the adjusted odds of
having GIB was 20.5 times greater (95% CI 2.24 to 188) for
patients aged >65 years and 13.5 times greater (95% CI 1.47
to 124) for recipients aged 50 to 64 years (Figure 2). Among
other co-morbidities, history of peptic ulcer disease was
independently associated with 20.5 times greater odds of GIB
in LVAD recipients. The inhospital mortality in patients
receiving LVADs has decreased in CF LVAD era compared to
pulsatile-flow LVAD era. Presence of GIB did not signifi-
cantly increase the inhospital mortality in either of the 2 eras;
both during index admission and readmissions (Table 3).
Readmissions for GIB after LVAD placement had higher
mortality in the CF LVAD era compared to pulsatile-flow
LVAD era (2.1% vs 0%) though not reaching statistical sig-
nificance. In the era of CF LVADs, presence of GIB during
index admission was significantly associated with increased
median inpatient length of stay (LOS; 44.5 vs 29 days,
p <0.001). However, in the era of pulsatile-flow LVADs,
presence of GIB during index admission did not significantly
increase the median LOS (36 vs 31 days). In the absence of
GIB, median LOS in the CF LVAD era was similar to the
pulsatile-flow LVAD era (29 vs 31 days). When the index
admission was complicated by GIB, the hospital charges were
significantly greater for both pulsatile-flow LVADs
($714,567) and CF LVADs ($674,038) compared to implan-
tations that were not complicated by GIB (p <0.05).
Discussion
This is the first study based on a pooled countrywide
sample to show the trend of yearly incidence of GIB in
LVAD recipients observed across the country and also
compare the prevalence and risk factors for GIB in CF
versus pulsatile-flow LVADs. Advanced age, particularly
>65 years and a history of peptic ulcer disease in LVAD
recipients, emerged as strong independent risk factors
associated with GIB (Figure 2). Previous single-center
studies with smaller samples have also reported increased
age as a significant risk for GIB in LVAD recipients.5,9,10
Other LVAD recipient characteristics such as smoking sta-
tus9 and elevated creatinine10 that have been earlier reported
as risk factors for GIB were not significant in this analysis.
On multivariate analysis adjusting for other clinically rele-
vant variables, device recipients in the era of CF LVADs
had more than 3 times greater odds of GIB compared to the
era when pulsatile-flow LVADs were implanted (Figure 2).
An inverse association between GIB and mechanical
ventilation was noted likely from confounding because of
specific therapeutic measures at the intensive level of care,
such as use of stress ulcer prophylaxis and/or vasopressors
leading to vasoconstriction in the gastrointestinal tract,
reducing the chances of bleeding from arteriovenous
 Heart Failure/GI Bleeding in LVAD Recipients 243

Figure 2. Adjusted OR of factors associated with GIB in LVAD recipients. Adjusted OR are shown for GIB events in LVAD recipients requiring readmission.
p <0.05 for the 3 age groups compared to the reference age group of 18 to 34 years. p <0.05 for LVAD implant era of 2008 to 2010 compared to 2005 to 2007.
p <0.05 for history of peptic ulcer disease.

Table 3 commonly identified lesion.9,10 The prevalence of angio-

Outcomes of Left Ventricular Assist Device recipients with gastro-intestinal
dysplasia in the general population is higher in older
bleeding during index admissions and re-admissions
subjects12,13 and in patients with certain predisposing con-
Variable LVAD Index admissions ditions, such as end-stage renal disease,14 von Willebrand
2005-2007 2008-2010 disease,15 and aortic stenosis.16 In severe aortic stenosis,
reduction in pulsatility of blood flow is proposed to cause
No GI GI Bleed No GI GI Bleed gut hypoperfusion possibly leading to growth of AVMs.
bleed bleed Additionally, while passing through a stenotic aortic valve,
Mortality 39.2% 43.7% 16.2% 20.9% mechanical disruption of the von Willebrand factor multi-
Length of 31(13-54) 36(24-68) 29(18-47) 44.5(29-64)* mers, measurable in vitro as impairment of shear
Stay† (days) stresseinduced platelet aggregation leads to the develop-
Hospital charges $475,460 $714,567* $608,359 $674,038* ment of acquired von Willebrand syndrome. This mecha-
(median USD) nism has been proposed for defective hemostasis and
consequent further increase in the risk of GIB in patients
LVAD Re-admissions
with aortic stenosis.17 Most recipients of CF LVADs also
2005-2007 2008-2010 develop acquired von Willebrand syndrome after LVAD
No GI GI Bleed No GI GI Bleed
placement as demonstrated by reduced high-molecular-
bleed bleed weight von Willebrand factor multimer levels, although all
recipients do not experience bleeding complications.18
Mortality 6.3% 0% 4.8% 2.1% Notably, LVAD recipients of younger ages do not have
Length of 5(2-10) 6(3-14) 6(3-13) 5(4-11) GIB complications as frequently as the older recipients.
Stay† (days) However, in the general population, AVMs have higher
Hospital charges $26,590 $23,702 $41,659 $39,976
prevalence in the elderly. Therefore, it is possible that the
(median USD)
lack of pulsatile blood flow after implantation of CF LVADs
GI ¼ gastrointestinal; LVAD ¼ Left Ventricular Assist Device. may have further accentuated the development and/or pro-
*p <0.05. gression of intestinal AVMs in the elderly who have a
†
Median (inter quartile range). higher prevalence of AVMs to begin with, further increasing
the likelihood of GIB. Despite endoscopic interventions,
malformations (AVMs). Unfortunately, the NIS database GIB in CF LVAD recipients is often recurrent with no long-
does not provide details of administered medications. term cure. Indeed, recurrent GIB when considered as a
For CF LVADs, lack of pulsatility, coagulopathy, and complication of LVAD implantation could upgrade an
acquired von Willebrand disease are the proposed leading LVAD recipient on the United Network for Organ Sharing
mechanisms for GIB.11 In LVAD recipients with GIB, listing from status 1B to status 1A, thus expediting a heart
angiodysplastic lesions in the intestine are the most transplant. However, the concern for worsening of GIB and
244 The American Journal of Cardiology (www.ajconline.org)
consequent hemodynamic compromise intraoperatively,
after administration of high-dose heparin during cardiopul-
monary bypass at heart transplant surgery, often leads to
downlisting of such patients to status 7 on the United
Network for Organ Sharing list, further delaying a trans-
plant. With recurrent episodes of GIB, multiple blood
transfusions in these LVAD recipients lead to the develop-
ment of circulating antibodies, reducing the probability of
an organ donor match and simultaneously raises the risk of
cellular rejection after heart transplantation.19
As the NIS is an observational database with a cumula-
tive sample over multiple years, multiple regression
modeling in this case is not a predictive model.20 However,
because of the large size of the NIS data set encompassing
countrywide academic and community hospitals, it provides
the best sample for analyzing independent associations for
GIB in LVAD recipients. For the best comparability, we
chose the 2 groups (2005 to 2007 and 2008 to 2010) to be
temporally the closest. However, the continuous blood flow
pattern generated by LVADs being used in 2008 to 2010
and 2015 remains unchanged.
A recent single-institution estimate of 22.8% incidence of
GIB in LVAD recipients is greater than our nationwide
estimation of 10% from 2009. This is likely because
compared to 2009, LVADs are now being used more widely
to include destination therapy patients who are more prone
to GIB.5 This group of LVAD recipients were ineligible for
cardiac transplantation, likely due to greater age and/or
co-morbidities, similar to the risk factors for GIB in LVAD
recipients elucidated here. NIS data set does not provide
data on severity of GIB. However, GIB significantly
increased LOS in the CF LVAD era relative to the pulsatile-
flow LVAD era. This may suggest increased severity of the
GIB episodes in recipients of CF LVADs compared to
pulsatile-flow LVADs.
Increased pump speed in CF LVADs has recently been
shown to be associated with increased chances of GIB.21 A
lower pump speed increases the preload for the left ventricle
allowing some degree of effective pumping function by the
heart likely translating to a more pulsatile blood flow and the
observation of reduced incidence of GIB. To reduce this
complication, prospective studies to evaluate the effect of
reducing or varying pump speed on occurrence of GIB are
needed. Judicious recipient selection by avoiding patients
having high risk characteristics for GIB after CF LVAD
placement will also help. As shown here and in previous
studies, higher incidence of GIB in CF LVAD recipients has
led to significantly increased LOS and resource utilization.22
Therefore, practice guidelines from professional organiza-
tions should include suggestions to carefully consider the
risk of such serious complications, when selecting patients
for resource intensive advanced therapies.
Disclosures
The authors have no conflicts of interest to disclose.
Supplementary Data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
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