Gastrointestinal Bleeding in Recipients of the HeartWare Ventricular Assist System

JACC: HEART FAILURE

VOL. 3, NO. 4, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

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Gastrointestinal Bleeding in Recipients of the HeartWare Ventricular Assist System Daniel J. Goldstein, MD,* Keith D. Aaronson, MD,y Antone J. Tatooles, MD,z Scott C. Silvestry, MD,x Valluvan Jeevanandam, MD,k Robert Gordon, MD,{ David R. Hathaway, MD,# Kevin B. Najarian, MS,# Mark S. Slaughter, MD,** for the ADVANCE Investigators

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Otsuka, Astellas, and Roche Diagnostics. Tariq Ahmad, MD, MPH, has received a travel scholarship from Thoratec. Robert Mentz, MD, has

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received a travel scholarship from Thoratec; research grants from Gilead; research support from ResMed, Otsuka, Bristol-Myers Squibb, AstraZeneca, Novartis, and GlaxoSmithKline; and travel related to investigator meetings from ResMed, Bristol-Myers Squibb, AstraZeneca, Novartis, and GlaxoSmithKline. Adam DeVore, MD, has received research support from

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commensurate with the extent of their participation in the activity. Author Disclosures: Dr. Goldstein is a surgical proctor for and is on the Method of Participation and Receipt of CME Certificate To obtain credit for JACC: Heart Failure CME, you must: 1. Be an ACC member or JACC subscriber. 2. Carefully read the CME-designated article available online and in this issue of the journal. 3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME credit.

advisory board of HeartWare Inc.; and is on the medical advisory board of Thoratec Inc. Dr. Aaronson has received grant and research support from HeartWare Inc. and Thoratec; and serves on the advisory board (without remuneration) for HeartWare Inc. and Thoratec. Dr. Tatooles has served as an investigator for HeartWare Inc. and Thoratec. Dr. Silvestry has served as a consultant for HeartWare Inc. and Thoratec. Dr. Jeevanandam has served as a consultant for HeartWare Inc. Dr. Hathaway was formerly an employee of and has served as a consultant for HeartWare Inc. Mr.

4. Complete a brief evaluation.

Najarian is an employee of and owns stock in HeartWare Inc. Dr.

5. Claim your CME credit and receive your certificate electronically by

Slaughter has received research grant support from HeartWare Inc. Dr.

following the instructions given at the conclusion of the activity.

Gordon has reported that he has no relationships relevant to the contents of this paper to disclose.

CME Objective for This Article: After reading this article, the reader should understand: 1) the epidemiology of gastrointestinal bleeding in recipients

Medium of Participation: Print (article only); online (article and quiz).

of left ventricular assist device therapy; and 2) the implications of these data related to clinical practice and future research. CME Term of Approval CME Editor Disclosure: Deputy Managing Editor Mona Fiuzat, PharmD,

Issue date: April 2015

FACC, reports that she has equity interest or stock options in ARCA

Expiration date: March 31, 2016

From *Cardiovascular and Thoracic Surgery, Montefiore Medical Center, Bronx, New York; yDivision of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan; zDivision of Cardiovascular Surgery, Christ Advocate Medical Center, Oak Lawn, Illinois; xDivision of Cardiothoracic Surgery, Washington University Hospital, St. Louis, Missouri; kDepartment of Cardiac and Thoracic Surgery, University of Chicago, Chicago, Illinois; {Division of Cardiology, Department of Medicine, Northwestern Memorial Hospital, Chicago, Illinois; #Clinical Affairs and Biostatistics, HeartWare Inc., Boston, Massachusetts; and the **Thoracic and Cardiovascular Surgery Division, Department of Surgery, University of Louisville, Louisville, Kentucky. HeartWare Inc. (Framingham, Massachusetts) was the sponsor of the study. Dr. Goldstein is a surgical proctor for and is on the advisory board of HeartWare Inc.; and is on the medical advisory board of Thoratec Inc. Dr. Aaronson has received grant and research support from HeartWare Inc. and Thoratec; and serves on the advisory board (without remuneration) for HeartWare Inc. and Thoratec. Dr. Tatooles has served as an investigator for HeartWare Inc. and Thoratec. Dr. Silvestry has served as a consultant for HeartWare Inc. and Thoratec. Dr. Jeevanandam has served as a consultant for HeartWare Inc. Dr. Hathaway was formerly an employee of and has served as a consultant for HeartWare Inc. Mr. Najarian is an employee of and owns stock in HeartWare Inc. Dr. Slaughter has received research grant support from HeartWare Inc. Dr. Gordon has reported that he has no relationships relevant to the contents of this paper to disclose. Manuscript received July 30, 2014; revised manuscript received October 31, 2014, accepted November 14, 2014.

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GIB in HVAD Recipients

Gastrointestinal Bleeding in Recipients of the HeartWare Ventricular Assist System ABSTRACT OBJECTIVES This study evaluated gastrointestinal bleeding (GIB) in patients receiving the HeartWare HVAD System (HeartWare Inc., Framingham, Massachusetts) in the pivotal BTT (Bridge to Transplant) trial and under the continued access protocol (CAP). BACKGROUND GIB has become a significant problem for recipients of continuous flow device left ventricular assist devices (CF-LVAD). The need for anticoagulation and antiplatelet therapies complicates the management of GIB. METHODS Bleeding events from 382 patients with advanced heart failure (140 patients enrolled in the BTT trial, and an additional 242 CAP patients) were analyzed. Post-implant anticoagulation consisted of heparin followed by warfarin at a target international normalized ratio of 2 to 3. Acetylsalicylic acid was recommended at 81 to 325 mg. RESULTS Overall, 59 of 382 (15.4%) patients experienced 108 GIB events (0.27 events per patient year). Mean time to first bleed was 273.1 days and 86.1% of events occurred beyond 30 days. Freedom from GIB was 84.1% at 1 year. Median international normalized ratio at the time of first bleed was 2.4  1.4. The most common etiology of bleeding identified was arteriovenous malformation and the most common site was the small intestine. Repeat bleeding was infrequent, though GIB patients required more readmissions and developed nondevice infections more frequently. No patients required surgical intervention and no deaths directly related to GIB occurred. CONCLUSIONS Recipients of the HeartWare Ventricular Assist Device System had an incidence of 0.27 GIB/patient year with a freedom from GIB of 84.1% at 1 year. All patients with GIB events were managed with medical and endoscopic therapies, although 31% of patients experienced a recurrence of GIB. No surgical intervention was required. GIB did not impact survival. (Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure [ADVANCE]; NCT00751972) (J Am Coll Cardiol HF 2015;3:303–13) © 2015 by the American College of Cardiology Foundation.

R

emarkable improvement in survival and

California) (1,2) or HeartWare (3) devices (HeartWare

quality of life outcomes has been realized

Inc., Framingham, Massachusetts) were reported in

by the introduction of continuous flow

earlier publications, we now report here the inci-

left ventricular assist devices (CF-LVAD) for the man-

dence and rate of GIB in the multicenter BTT (Bridge

agement of advanced heart failure (1–3). While the

to Transplant) clinical trial of the HeartWare Ventric-

benefits associated with enhanced reliability, drive-

ular Assist (HVAD) System.

line size, elimination of noise, and better battery

The pathogenesis of GIB associated with LVAD

duration are undisputed, the use of this technology

implantation is not fully understood, although puta-

has led to vexing clinical challenges occurring more

tive mechanisms include: 1) need for combined

frequently than with previous pulsatile technologies.

antiplatelet and antithrombotic therapy; 2) develop-

Among these are hemolysis and pump thrombosis (4),

ment of acquired von Willebrand syndrome with loss

de novo aortic insufficiency (5) and gastrointestinal

of

bleeding (GIB) (6), with GIB singled out as the most

3) reduced pulse pressure in the setting of high

high

molecular

weight

multimers

(17);

and

common cause of readmission (7). The reported inci-

shear stress—akin to aortic stenosis in Heyde’s syn-

dence in institutional series varies widely, from 5%

drome (18).

to 30% (6,8–16). Because only bleeding meeting pre-

The HVAD System (HeartWare Inc.) is a minia-

specified criteria such as those requiring transfusions

turized, implantable, continuous-flow blood pump.

of $4 U within 7 days post-implant or those requiring

Two large pivotal trials have documented excellent

reoperation in the landmark clinical trials of the

clinical outcomes for recipients of this technology and

HeartMate II (Thoratec Corporation, Pleasanton,

the pump received Food and Drug Administration

Goldstein et al.

JACC: HEART FAILURE VOL. 3, NO. 4, 2015 APRIL 2015:303–13

305

GIB in HVAD Recipients

approval for the BTT trial indication (3,19). Compara-

The studies were conducted in compliance with Food and Drug Administration

tive destination therapy clinical trials are ongoing. The purpose of this investigation was to fully

regulations for Good Clinical Practice, and

characterize GIB events in the entire cohort of 382

were approved by each site’s Institutional

patients who were implanted with the HeartWare

Review Board. All patients or their autho-

HVAD system as BTT who were part of the pivotal and

rized

continued access protocol (CAP) trials.

consent.

representatives

provided

informed

STATISTICAL ANALYSIS. GIB events were

METHODS

ABBREVIATIONS AND ACRONYMS AVM = arteriovenous malformation

ASA = acetylsalicylic acid CAP = continued access protocol

CF-LVAD = continuous flow

reviewed individually for additional details

left ventricular assist device

through manual review of the narrative re-

GIB = gastrointestinal bleeding

The study design of the HVAD BTT trial and the

ports. Descriptive statistics were used to

HVAD = HeartWare ventricular

associated CAP has been described previously (3,20).

describe source, location, and treatment.

assist device

In brief, the BTT trial was a prospective, 30-center

Survival is reported descriptively through

INR = international normalized

clinical trial conducted in the United States that

Kaplan-Meier analysis, with follow-up cen-

ratio

evaluated the HVAD as BTT trial therapy. The trial

sored at the time of heart transplantation or device

enrolled 140 patients with advanced heart failure who

explant for recovery, or withdrawal of consent or

were eligible for heart transplant. Patients were

loss to follow-up. Overall survival was defined as

compared with a contemporaneous group of patients

freedom from death from any cause, with censoring

enrolled in the INTERMACS registry (The Interagency

at the time of heart transplant or explant for re-

Registry for Mechanically Assisted Circulatory Sup-

covery. Competing outcomes were calculated by

port) who received a commercially available LVAD as

Kaplan-Meier nonparametric product limit actuarial

BTT therapy. Patients were followed until cardiac

method.

transplantation, device explant for recovery, death,

All adverse events, including those meeting the

or for at least 180 days after implantation, and follow-

INTERMACS definitions were evaluated with respect

up would continue through 5 years after implanta-

to severity, expectedness, and device relatedness.

tion. The BTT trial achieved its primary success

Adverse events were reported both as the percentage

endpoint, defined as non-inferiority to the INTER-

of subjects affected and the rate per patient-year of

MACS control in terms of survival to 180 days on the

follow-up.

original device or transplant or explant for recovery,

Statistical comparisons were made between out-

with rates of 91% for the HVAD system and 90% for

comes using log-rank t test, with significance deter-

the INTERMACS registry (noninferiority p < 0.0001).

mined at a p value of #0.05, with no adjustment for

Survival at 180 days was 94% for those with an HVAD

multiple comparisons. Adjustments based on baseline

and 90% for those in the control group. The Food and

differences were made using the Cox proportional

Drug

hazards model.

Administration–approved

CAP

enrolled

an

additional 256 patients after completion of enrollment in the BTT trial. We present here an assessment

RESULTS

of GIB events in the 382 patients (140 from the BTT trial and 242 from the CAP) implanted through

PATIENT DEMOGRAPHICS. A total of 382 patients

November 2012 and followed through database lock

enrolled in the BTT or CAP populations between

in July 2013.

August 2008 and November 2012 are included in this

GIB was defined as any clinically suspected or

report. Overall, patients had a mean age of 53.2  11.7

documented suspicion of bleeding from the GI tract as

years, were predominantly male and Caucasian, and

indicated by a new drop in hemoglobin and/or the

had a mean body surface area of 2.0  0.3 m 2.

appearance of melena, hematochezia, hematemesis,

New York Heart Association functional class IV

or guaiac positive stools. All GIB events were recorded

heart failure classification was recorded for 95.8%

and characterized and are included in this analysis.

of patients and 75.4% were in either INTERMACS

Anticoagulation was individualized and differed

Class 2 or 3. Table 1 compares demographic charac-

among centers. After device implantation, patients

teristics of patients with (n ¼ 59) and without GIB

received bridging intravenous heparin. As patients

events (n ¼ 323). Patients with GIB had higher body

became able to tolerate oral medications they transi-

mass index and creatinine, and more frequently had

tioned from heparin to warfarin and acetylsalicylic

diabetes and an ischemic etiology of heart failure.

acid (ASA), with a recommended target international

Overall, patients who experience a GIB were less sick

normalized ratio (INR) of 2 to 3 and a recommended

(mean INTERMACS profile 2.9  1.3 vs. 3.3  1.2;

ASA dose of 81 to 325 mg.

p ¼ 0.014).

Goldstein et al.

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GIB in HVAD Recipients

occurred more than 30 days after LVAD implantation.

T A B L E 1 Baseline Patient Characteristics

The mean time to first event was 273.1 days. The GIB (n ¼ 59)

No GIB (n ¼ 323)

p Value

Age, yrs

55.7  11.1

52.7  11.7

0.0686

Male, %

76.3%

70.3%

0.4347

Baseline Characteristic

Race

0.9583

event distribution is depicted in Figure 1. Among the 59 patients with at least 1 bleeding event, 39 of 59 (66%) had 1 GIB event and 20 of 59 (34%) had more than 1 GIB event (range 1 to 8). Freedom from a GIB

Caucasian

69.5%

67.8%

event was 84.1% at 1 year (Figure 2). There was no site

Black/African American

27.1%

26.3%

effect noted among the centers participating in this

Other

3.4%

5.9%

Hispanic or Latino ethnicity

5.1%

5.9%

clinical trial (Figure 3). INR values at the time of the GIB episode were

Body mass index, kg/m2

29.9  7.1

27.9  5.8

0.0476

Body surface area, m2

2.1  0.3

2.0  0.3

0.0139

50.8%

35.6%

0.0293

Systolic

103.9  14.0

103.5  15.6

0.8378

were significantly higher in patients who developed

Diastolic

62.8  10.0

63.6  10.7

0.5950

GIB than in those who did not (2.4 vs. 1.6, p # 0.0001).

Mean

78.4  10.1

77.4  11.2

0.5950

Table 2 shows a comparison of the aspirin doses being

Systolic

50.2  15.5

48.6  14.4

0.5233

Diastolic

23.2  7.9

24.2  8.5

0.4770

11.4  5.1

11.6  7.7

0.8745

Ischemic cause of heart failure Arterial blood pressure, mm Hg

Pulmonary artery pressure, mm Hg

Central venous pressure, mm Hg 2

available in 102 of 108 (94.4%) episodes. The mean INR at the time of first bleeding event was 2.2  1.1. Mean INRs following initial post-implant discharge

taken by patients with and without GIB events. At the time of their event, patients with GIB were taking significantly higher doses of aspirin than those without GIB. Also, in patients with GIB taking aspirin,

Cardiac Index, l/min/m

2.3  0.6

2.2  0.6

0.3400

Left ventricular ejection fraction, %

19.2  6.8

16.9  7.3

0.0449

4 patients were on dual antiplatelet therapy at the

Creatinine, mg/dl

1.5  0.6

1.3  0.5

0.0126

onset of their bleeding event (1 patient also on clo-

International normalized ratio

1.3  0.5

1.3  0.4

0.3949

pidogrel, and 3 others also taking dipyridamole).

New York Heart Association functional class II

0.4069 1.7%

suspected or identified. By far the most common lesion was an arteriovenous malformation (AVM)

III

1.7%

3.7%

IV

96.6%

95.7%

0.0%

0.3%

N/A

In 78% of bleeding events, a specific lesion was

0.3%

INTERMACS patient profile

followed by an ulcer (includes gastric and duodenal). 0.0024

In 22% of instances, no active site could be identified (Table 3). The most common lesion site was the small

1

1.7%

6.2%

2

20.3%

37.5%

intestine (Figure 4). The duration of LVAD support

3

47.5%

39.3%

was longer for patients with GIB than those without GIB: 477.2  363 days for the 59 patients with GIB vs.

4–7

30.6%

17.1%

Smoker

62.7%

49.8%

0.0886

Diabetic

50.8%

32.2%

0.0074

Right ventricular function reduction

0.1003

372.6  331.24 days for the 323 with no GIB, p ¼ 0.0159. Among patients with GIB, at 365 days post-implantation, 58.2% of patients were alive on

None/mild

28.1%

33.8%

Moderate

36.8%

31.2%

the original device, 27.4% had received a transplant,

Severe

22.8%

13.1%

5.3% required device exchange, and 9.1% had died.

Not assessed

12.3%

22.0%

Tricuspid regurgitation

Among patients with no GIB, at 365 days post0.4218

implantation, 43.8% of patients were alive on the

None/trivial/mild

50.0%

60.1%

original device, 38.2% had received a transplant, 6.3%

Moderate

26.8%

19.0%

required device exchange, and 11.7% had died.

Severe

12.5%

10.0%

Not assessed

10.7%

10.9%

Values are mean  SD or %. p Values for continuous variables are from a t test; p values for categorical variables are from a Fisher’s exact test. GIB ¼ gastrointestinal bleeding; INTERMACS ¼ The Interagency Registry for Mechanically Assisted Circulatory Support.

Figures 5A and 5B show a competing risk analysis for these outcomes. The management of the 108 bleeding events (the 59 patients who experienced a GIB event) is depicted in Figure 6. Transfusion of blood products was required in the overwhelming majority (94%) of bleeding events and in an 18.5% of bleeding events,

GIB EVENTS. GIB events occurred in 59 of 382 (15.4%)

no further therapy was required. An endoscopic pro-

HVAD recipients over a follow-up ranging from 36 to

cedure was used to manage bleeding in 52 of 108

1,339 days (median 365 days). A total of 108 GIB

(48%) cases. Endoscopic procedures used included

events were reported over 406.6 patient-years of

cautery, clipping, thermal ablation, or argon plasma

HVAD support, representing 0.27 GIB events per pa-

coagulation. No surgical procedures (i.e., laparotomy)

tient year. Most of the events (93 of 108, 86.1%)

were required to control GIB.

Goldstein et al.

JACC: HEART FAILURE VOL. 3, NO. 4, 2015 APRIL 2015:303–13

GIB in HVAD Recipients

SURVIVAL AND ADVERSE EVENTS. There were no

deaths directly related to GIB. One patient died 6 days

F I G U R E 1 Distribution of GI Bleeding Events

following a GIB event. The GIB was attributed to intense anticoagulation to treat a pump thrombus event. The patient then had a pump exchange, developed right heart failure, and later died postexchange due to vasodilatory shock. There was no statistically significant difference in overall survival between patients who experienced GIB and those who did not for either unadjusted survival or for survival adjusted for ischemic etiology and body surface area (Figure 7). The rate and incidence of adverse events for the GIB and non-GIB populations are shown in Tables 4 and 5. Patients who had GIB events had higher rates of bleeding requiring hospitalization (1.17 events/ patient year vs. 0.07 events/patient year, p ¼ 0.0001) and higher rates of non–device-related infections (0.74 events/patient year vs. 0.407 events/patient

A total of 108 events occurred in 59 patients. 323 patients had no gastrointestinal (GI) bleeding events.

year, p ¼ 0.0021). Although rates of sepsis were similar for GIB versus non-GIB, the incidence of sepsis was higher among patients with GIB (28.8% vs.

New York, New York) device—an intraventricular

17.0%, p ¼ 0.0452). The rates and incidence of other

axial flow pump. Several single-institution reports

adverse events were not significantly different be-

began documenting a high incidence of GIB in re-

tween patients with and without GIB.

cipients of these technologies and in fact, several

Of the 59 patients who had a bleeding event, five

have singled out GIB as the most frequent etiology for

had a subsequent thrombotic event (pump throm-

readmission following successful implantation (7,22).

bosis, transient ischemic attack, ischemic cerebro-

The present study is, to our knowledge, the first

vascular accident, or peripheral thrombosis). The

multicenter investigation aimed at fully character-

mean time to first thrombus event following the GIB

izing the vexing problem of GIB in recipients of this

was 155.4 days. The history of each thrombotic event

technology. Among 382 patients who received the

is described briefly in Table 6. In 50% of GIB events,

HVAD System as a BTT, 15.4% developed 108 GIB

therapy with 1 or more anticoagulant drugs was

events over nearly 407 years of support, for a rate of

interrupted within 5 days after the event. Table 7 details the interruptions in anticoagulant therapy

F I G U R E 2 Freedom From GIB Events

after GIB events.

DISCUSSION The clinical introduction of miniaturized continuous flow left ventricular assist devices (CF-LVADs) drastically improved survival and quality of life outcomes for recipients of these technologies. Moreover, it led to a wider acceptance of mechanical support by patients, referring physicians and the heart failure community in general. This success has been tempered by the recognition of new adverse events not encountered with previous pulsatile first-generation technology, namely pump thrombosis, de novo aortic insufficiency, and GIB. The latter was the focus of this investigation. Frazier et al. (21) first described gastrointestinal bleeding

(from

CF-LVAD—the

AVMs) Jarvik

in

2000

patients (Jarvik

receiving Heart,

a

Inc.,

Kaplan-Meier chart of freedom from gastrointestinal bleeding (GIB) events from time of implant to 1 year post-implant.

307

308

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GIB in HVAD Recipients

larger (higher body surface area, body mass index),

F I G U R E 3 Percentage of Patients With GIB Across Enrollment Sites

were more likely to be diabetic, had worse renal function, and were as a group less sick. It is well known that renal dysfunction can alter platelet function by interfering with adhesion and aggregation. Our finding that GIB patients had worse baseline renal function supports this pathophysiology. However, because data regarding renal function at the time of GIB events is not available, it is difficult to attribute renal dysfunction as a definitive contributor as it is possible that in many patients with baseline dysfunction, renal function normalized after implantation of the LVAD, as it frequently occurs with restoration of optimal hemodynamics and end organ perfusion. Our findings in this regard, however, mimic those of

The red line indicates overall incidence (15.4%). The numbers at the base of the histo-

Demirozu et al. (9), who noted a trend for patients with

grams represent the total patient enrollment at the site. The p value is from the chi-square

GIB to have higher baseline creatinine level.

test. NS ¼ not significant; other abbreviation as in Figure 2.

The observation of ischemic etiology as a preoperative risk factor for GIB coincides with the finding

0.27 GIB/PPY. Freedom from GIB events was 84.1% at

by Boyle et al. (23), who found that ischemic etiology

1 year and most events occurred beyond the periop-

was a strong perioperative factor (hazard ratio: 1.35)

erative period. This incidence is lower than that sug-

in an analysis of 900 patients who received the

gested by a recent review of all case reports and case

HeartMate II LVAD.

series in the literature whereby 265 of 1,316 (20.1%)

While our data suggests a statistically significant

CF-LVAD recipients developed a GIB (6). In the few

increased risk of GIB for patients with larger body

case series that have reported annualized GIB event

surface area/body mass index, the actual differences

rates, the reported rates were higher and involved

in these values (2.0 vs. 2.1 m 2 and 29.9 vs. 27.9 kg/m 2,

mostly HeartMate II recipients. Stulak et al. (11)

respectively) is very small and likely clinically un-

documented a rate of 0.45 GIB/patient year among

important. The finding of diabetes as a preoperative

389 recipients of 4 different CF-LVADs while Crow

risk factor for GIB is intriguing and is interesting to

et al. (8) described a rate of 0.63 GIB/patient year

note a recent publication documenting diabetes as an

among their 55 recipients of nonpulsatile devices.

independent risk factor for upper GIB in a large pop-

Time to first GIB event was 273 days, longer

ulation study (24). As described previously (15,16,25),

than the 5 months reported by Stulak et al. (11), or the

GIB events often recur, with 34% of our patients

63  62 days, described by Demirozu et al. (9), among

having at least 1 recurrence. The identification of

the 19% of 172 patients who had GIB after receiving a

AVMs as the most common etiology of GIB is also

HeartMate II device. French et al. (12) described a

consistent with previous reports (9,10,21); this finding

maximal hazard rate of GIB of 2.23 events/patient

has been attributed at least partly to low pulsatility

year at 21 days post-implantation.

and shear stress–induced acquired von Willebrand

We noted several interesting differences in baseline

syndrome resulting from continuous flow assist

parameters of patients with GIB compared with those

physiology. In fact, recipients of CF-LVADs with

without GIB. On univariate analysis, the former were

higher pulsatility have been shown to have a reduced incidence of nonsurgical bleeding events (14). In our series, nearly one-quarter of GIB events could not be

T A B L E 2 Average Overall ASA Dosages

GIB (n ¼ 59)

No GIB (n ¼ 323)

20.3% (12)

81–<162 mg

28.8% (17)

162–324 mg

0.0% (0)

$324 mg

p Value

<0.0001

ASA category 0–<81 mg

localized. Many or all of these are likely due to occult

50.8% (30)

AVMs of the small bowel, which are notoriously difficult to identify and treat.

3.1% (10)

Management of GIB events generally followed

26.3% (85)

common clinical practice, with transfusions, cessation

51.1% (165)

of antithrombotic therapy, antacid therapy, and diag-

19.5% (63)

nostic work-ups at the discretion of the caring

Values are % (n). ASA ¼ acetylsalicylic acid; GIB ¼ gastrointestinal bleeding.

physicians. The issue of timing an intensity of reintroduction of antithrombotic therapy following resolution of a GIB event is of paramount importance.

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GIB in HVAD Recipients

T A B L E 3 Lesions Identified as Source of GIB Event

F I G U R E 4 Localization of GIB Events

First Bleed (n ¼ 59)

All Bleeds (n ¼ 108)

Definite or suspected arteriovenous malformations

19% (11)

27% (29)

Ulcers

17% (10)

10% (11)

Source

Dieulafoy lesions

3% (2)

5% (5)

Gastric angioectasia

5% (3)

4% (4)

Iatrogenic

3% (2)

3% (3)

Crohn’s disease

2% (1)

3% (3)

Other (e.g., erosive gastritis, diverticulosis)

22% (13)

27% (29)

No active site identified

29% (17)

22% (24)

Values are % (n). GIB ¼ gastrointestinal bleeding.

Unfortunately, the present study did not capture this information and recommendations cannot be made. Moreover, although higher ASA doses and higher INR values were observed in persons with GIB, the clinical trial was not designed to determine optimal dosing of antithrombotic therapies. Though no data is available to describe frequency of its use or success, octreotide, either in short- or

GIB sites were identified by various scope methods. Note: Patients could have multiple sources of bleeding. Abbreviation as in Figure 2.

long-acting form, has emerged as an additional tool in

F I G U R E 5 Competing Risks Analysis

Competing risks for death, device exchange, transplant, alive with original device, and transplant or alive with original device. (A) Patients with a gastrointestinal (GI) bleeding event; (B) patients without GI bleeding events.

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APRIL 2015:303–13

F I G U R E 6 Treatment of GIB Events

Flow diagram showing the various treatment strategies used for the management of GIB. Abbreviations: BTT ¼ bridge to transplant; CAP ¼ continued access protocol; GIB ¼ gastrointestinal bleeding; PPIs ¼ proton pump inhibitors; pts ¼ patients.

F I G U R E 7 Adjusted Survival With and Without GI Bleeding Events

Comparison of survival between patients with and without GI bleeding event after adjustment for ischemic etiology and body surface area. GI ¼ gastrointestinal.

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T A B L E 4 Incidence of Adverse Events by GIB Status

Adverse Event (INTERMACS category)

GIB (n ¼ 59)

Non-GIB (n ¼ 323)

T A B L E 5 Annualized Adverse Event Rate by GIB Status

p Value

Bleeding <0.0001

Adverse Event (INTERMACS category)

GIB (n ¼ 59) 77.09 pt-yrs

Non-GIB (n ¼ 323) 329.54 pt-yrs

p Value

Bleeding

Rehospitalization

66.1% (39)

6.5% (21)

Reoperation

16.9% (10)

14.6% (47)

0.6908

Rehospitalization

1.17 (90)

0.07 (22)

0.0001

Requiring transfusions*

23.7% (14)

12.4% (40)

0.0397

Reoperation

0.17 (13)

0.15 (51)

0.7840 0.1270

3.4% (2)

5.3% (17)

0.7499

Requiring transfusions*

0.21 (16)

0.13 (43)

30.5% (18)

36.8% (119)

0.3793

Cardiac tamponade

0.03 (2)

0.05 (17)

0.3145

Ventricular

20.3% (12)

20.1% (65)

1.0000

0.48 (37)

0.51 (168)

0.7895

Supraventricular

Cardiac tamponade Cardiac arrhythmia

Cardiac arrhythmia

22.0% (13)

22.3% (72)

1.0000

Ventricular

0.25 (19)

0.25 (82)

0.9702

Hemolysis

10.2% (6)

4.6% (15)

0.1133

Supraventricular

0.22 (17)

0.27 (89)

0.4654

Hepatic dysfunction

10.2% (6)

4.3% (14)

0.1020

Infection Localized nondevice

50.8% (30)

Sepsis Driveline exit site Myocardial infarction

Hemorrhagic CVA TIA Renal dysfunction Acute Chronic

0.08 (6)

0.05 (18)

0.4664

Hepatic dysfunction

0.08 (6)

0.04 (14)

0.2356

Infection

27.9% (90)

0.0007

28.8% (17)

17.0% (55)

0.0452

Localized nondevice

0.74 (57)

0.40 (133)

0.0021

25.4% (15)

18.6% (60)

0.2175

Sepsis

0.29 (22)

0.21 (70)

0.2394

0.0% (0)

0.6% (2)

1.0000

Driveline exit site

0.29 (22)

0.24 (80)

0.5082

Myocardial infarction

0.00 (0)

0.01 (2)

0.3592

Neurological Ischemic CVA†

Hemolysis

6.8% (4)

5.0% (16)

0.5285

Neurological events

10.2% (6)

8.0% (26)

0.6089

Ischemic CVA†

0.06 (5)

0.06 (19)

0.8169

0.09 (7)

0.08 (27)

0.8103

0.03 (2)

0.08 (27)

0.0634

0.10 (8)

0.12 (38)

0.7841

Acute

0.10 (8)

0.11 (37)

0.8387

Chronic

3.4% (2)

6.5% (21)

0.5521

Hemorrhagic CVA

13.6% (8)

9.6% (31)

0.3523

TIA

13.6% (8)

9.3% (30)

0.3426

0.0% (0)

0.3% (1)

Respiratory dysfunction

32.2% (19)

21.4% (69)

0.0914

0.00 (0)

0.00 (1)

Right heart failure

44.1% (26)

31.9% (103)

0.0740

Respiratory dysfunction

0.32 (25)

0.28 (91)

0.5186

37.3% (22)

28.5% (92)

0.2152

Right heart failure

0.38 (29)

0.36 (120)

0.8905

6.8% (4)

3.4% (11)

0.2644

Inotropic Therapy

0.32 (25)

0.32 (104)

0.9098

RVAD

0.05 (4)

0.03 (11)

0.4664

0.03 (2)

0.12 (38)

0.0094

Venous

0.01 (1)

0.06 (20)

0.0546

Arterial

0.01 (1)

0.03 (10)

0.3629

Inotropic therapy RVAD Thromboembolism

1.0000

Renal dysfunction

3.4% (2)

10.5% (34)

0.0933

Venous

1.7% (1)

6.2% (20)

0.2220

Arterial

1.7% (1)

2.5% (8)

1.0000

Values are % (n). All adverse events were adjudicated by the Clinical Events Committee, and include events censored at the time of transplant, explant for recovery, or device exchange. Fisher’s exact test was used for proportions. *Transfusions include those requiring >4 U within 7 days. †Procedural ischemic cerebrovascular accidents (CVAs) occurring within 2 days post-implant have been excluded. CVA ¼ cerebrovascular accident; GIB ¼ gastrointestinal bleeding; INTERMACS ¼ The Interagency Registry for Mechanically Assisted Circulatory Support; RVAD ¼ right ventricular assist device; TIA ¼ transient ischemic attack (<24 h).

the armamentarium to treat occult GIB that is likely secondary to small bowel AVMs (26,27). While GIB events often required readmissions and incurred costs, no surgical interventions were required and no deaths were directly related to the GIB event. At 12 months, 85.6% of patients were alive with device or transplanted. Comparison of the incidence of adverse event rates between patients who had GIB and those who did not suggests that the former are more likely to be readmitted and transfused and are more prone to develop localized nondevice infections and sepsis. The causal relationship between blood transfusions and subse-

Thromboembolism

0.5167

Values represent events per patient-year (number of events). All adverse events were adjudicated by the Clinical Events Committee, and include events censored at the time of transplant, explant for recovery, or device exchange. Poisson regression was used for event rate. *Transfusions include those requiring >4 U within 7 days. †Procedural ischemic CVAs occurring within 2 days post-implant have been excluded. Abbreviations as in Table 4.

T A B L E 6 Brief Histories of Thrombotic Events Subsequent

to GIB

A VAD thrombus preceded by a 3-month interruption in ASA due to GIB A VAD thrombus with no interruption in anticoagulation despite 3 GIB episodes over 7 months An ischemic CVA 11 days after implantation and 3 days after GIB due to erosive gastritis; the VAD was replaced after medical therapy failed to resolve the thrombus and had 2 peripheral bleeding events shortly after the pump exchange; there was no interruption in anticoagulation A TIA 1 month after a 4-day interruption in aspirin and 3 days after a 1-day interruption in aspirin and warfarin due to bleeding events; the TIA was followed by an ischemic CVA several months later An ischemic CVA 11 months after stoppage of aspirin and 10 months after stoppage of warfarin due to a series of 4 bleeding events

quent infections is well established in cardiac surgical patients (28) thus our findings are not surprising. When these events are annualized to adjust for

ASA ¼ acetylsalicylic acid; VAD ¼ ventricular assist device; other abbreviations as in Table 4.

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While the exact etiology of GIBs has not been

T A B L E 7 Duration of Interruptions in Antiplatelet and

elucidated, low pulsatility and VAD-induced shear

Anticoagulant Therapy Duration of Interruption

stress degradation of high molecular weight von Wil-

Therapy Interrupted (n ¼ 108 GIB Events)

lebrand factor appear to contribute to the genesis.

ASA/clopidogrel

Warfarin

Both

65.7% (71)

66.7% (72)

50.0% (54) (no interruption in either therapy)*

1–2 days

3.7% (4)

5.6% (6)

2.8% (3)

erative endoscopic screening of patients with risk

3–7 days

7.4% (8)

11.1% (12)

5.6% (6)

factors for GIB including advanced age, history of GIB,

8–14 days

5.6% (6)

3.7% (4)

1.9% (2)

>14 days

17.6% (19)

13.0% (14)

5.6% (6)

No interruption (0 days)

AVMs of the small bowel are the most common culprit lesions. The morbidity associated with the development of GIB in LVAD recipients suggests that preop-

occult blood in the stool and/or microcytic anemia should be seriously considered. Conventional diag-

Values are % (n). *A total of 34.3% (37) events had only 1 therapy (either antiplatelet or anticoagulant) interrupted. ASA ¼ acetylsalicylic acid; GIB ¼ gastrointestinal bleeding.

nostic evaluations and therapies are effective in managing these bleeding events, but recurrence is not uncommon. Fortunately, while the GIBs are associated with readmissions and a higher incidence of nondevice

different follow up times however, only the differ-

infections, survival is not affected. It is hoped that the

ences in rehospitalization, localized nondevice infec-

introduction of pulsatility algorithms and wider gaps

tion and thromboembolic rates remain statistically

that reduce shear stress in next generation pumps will

significant. The lower rate of thromboembolic com-

reduce rates of this vexing complication.

plications observed among persons with GIB, perhaps

ACKNOWLEDGEMENTS The

underscores the possibility that certain patients have

Mary V. Jacoski, MS, and Edward K. Baldwin, PhD, of

an inherent propensity to bleed and are thus less likely

HeartWare Inc., for their assistance in the preparation

to develop thrombotic complications.

of the manuscript.

authors

acknowledge

Concern has arisen regarding the potential prothrombotic milieu created by the need to discontinue

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

antithrombotic therapy in recipients of CF-LVADs.

Daniel J. Goldstein, Montefiore Medical Center, 3400

Notwithstanding the differences in devices and man-

Bainbridge Avenue, MAP 5, Bronx, New York 10367.

agement strategies it is interesting to note that a recent

E-mail: dgoldste@montefiore.org.

report by Stulak et al. (11) documented a 0.31 thromboembolic event per patient year rate among persons with GIB with a median interval of 5 months after the GIB event. And while thromboembolic events were 7.4 times more likely to occur in patients with prior GIB, neither the GIB nor the thromboembolic event portended a lower survival (11). In our series, nearly two-thirds of patients had interruption of either antiplatelet or warfarin therapy. Five patients developed a thrombotic complication (range 11 days to 10 months) following a GIB event. In 2 of these instances, antithrombotic therapy had not been interrupted. STUDY

LIMITATIONS. Several

limitations

to

our

analysis should be considered. First, the study was not randomized, and all patients received an HVAD. Any comparisons are only available through historical

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE 1: GIB is a common complication in patients who have received a continuous flow left ventricular assist device. COMPETENCY IN MEDICAL KNOWLEDGE 2: Possible etiologies of gastrointestinal bleeding in CF-LVAD recipients include low pulsatility and ventricular assist device–induced shear stress, which degraded high molecular weight von Willebrand factor. COMPETENCY IN PATIENT CARE: Conventional diagnostic evaluations and therapies are effective in

literature. Also, this was a post-hoc analysis, and the

managing gastrointestinal bleeding in CF-LVAD re-

clinical trial was not powered to analyze GIB events.

cipients. Although GIB increases readmissions and

CONCLUSIONS In summary, GIB has emerged as a significant complication limiting the success of current CF-LVAD technologies. GIB events occurred in 16% of HVAD recipients, for an event rate of 0.27 GIB/patient year, which is lower than rates reported for other devices.

nondevice infections, it does not affect survival. TRANSLATIONAL OUTLOOK: Improvements in pump design and control algorithms to reduce shear stress and increase pulsatility are likely to reduce rates of CF-LVAD-related gastrointestinal bleeding.

Goldstein et al.

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KEY WORDS gastrointestinal bleeding, heart failure, left ventricular assist device, LVAD

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