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Gastrointestinal Bleeding in Recipients ofthe HeartWare Ventricular Assist System
Daniel J. Goldstein, MD,* Keith D. Aaronson, MD,y Antone J. Tatooles, MD,z Scott C. Silvestry, MD,xValluvan Jeevanandam, MD,k Robert Gordon, MD,{ David R. Hathaway, MD,# Kevin B. Najarian, MS,#Mark S. Slaughter, MD,** for the ADVANCE InvestigatorsJACC: HEART FAILURE CME
This article has been selected as the month’s JACC: Heart Failure CME
activity, available online at http://www.acc.org/jacc-journals-cme by
selecting the CME tab on the top navigation bar.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by
the Accreditation Council for Continuing Medical Education (ACCME) to
provide continuing medical education for physicians.
The ACCF designates this Journal-based CME activity for a maximum
of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit
commensurate with the extent of their participation in the activity.
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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
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3. Answer the post-test questions. At least 2 out of the 3 questions
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5. Claim your CME credit and receive your certificate electronically by
following the instructions given at the conclusion of the activity.
CME Objective for This Article: After reading this article, the reader should
understand: 1) the epidemiology of gastrointestinal bleeding in recipients
of left ventricular assist device therapy; and 2) the implications of these
data related to clinical practice and future research.
CME Editor Disclosure: Deputy Managing Editor Mona Fiuzat, PharmD,
FACC, reports that she has equity interest or stock options in ARCA
From *Cardiovascular and Thoracic Surgery, Montefiore Medical Center, Bro
University of Michigan, Ann Arbor, Michigan; zDivision of Cardiovascular S
Illinois; xDivision of Cardiothoracic Surgery, Washington University Hospit
Thoracic Surgery, University of Chicago, Chicago, Illinois; {Division of Card
morial Hospital, Chicago, Illinois; #Clinical Affairs and Biostatistics, HeartW
and Cardiovascular Surgery Division, Department of Surgery, University
(Framingham, Massachusetts) was the sponsor of the study. Dr. Goldstein is
HeartWare Inc.; and is on the medical advisory board of Thoratec Inc. Dr. Aar
HeartWare Inc. and Thoratec; and serves on the advisory board (without r
Tatooles has served as an investigator for HeartWare Inc. and Thoratec. Dr. Si
and Thoratec. Dr. Jeevanandam has served as a consultant for HeartWare Inc
served as a consultant for HeartWare Inc. Mr. Najarian is an employee of a
received research grant support from HeartWare Inc. Dr. Gordon has reported
of this paper to disclose.
Manuscript received July 30, 2014; revised manuscript received October 31,
Biopharma, consults for CCA, and receives research support from
ResMed, GE Healthcare, Gilead, Critical Diagnostics, BG Medicine,
Otsuka, Astellas, and Roche Diagnostics. Tariq Ahmad, MD, MPH, has
received a travel scholarship from Thoratec. Robert Mentz, MD, has
received a travel scholarship from Thoratec; research grants from Gilead;
research support from ResMed, Otsuka, Bristol-Myers Squibb, Astra-
Zeneca, 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
the American Heart Association, Novartis Pharmaceuticals, Thoratec,
and Amgen.
Author Disclosures: 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.
Medium of Participation: Print (article only); online (article and quiz).
CME Term of Approval
Issue date: April 2015
Expiration date: March 31, 2016
nx, New York; yDivision of Cardiovascular Medicine,
urgery, Christ Advocate Medical Center, Oak Lawn,
al, St. Louis, Missouri; kDepartment of Cardiac and
iology, Department of Medicine, Northwestern Me-
are Inc., Boston, Massachusetts; and the **Thoracic
of Louisville, Louisville, Kentucky. HeartWare Inc.
a surgical proctor for and is on the advisory board of
onson has received grant and research support from
emuneration) for HeartWare Inc. and Thoratec. Dr.
lvestry has served as a consultant for HeartWare Inc.
. Dr. Hathaway was formerly an employee of and has
nd owns stock in HeartWare Inc. Dr. Slaughter has
that he has no relationships relevant to the contents
2014, accepted November 14, 2014.
Goldstein et al. J A C C : H E A R T F A I L U R E V O L . 3 , N O . 4 , 2 0 1 5
GIB in HVAD Recipients A P R I L 2 0 1 5 : 3 0 3 – 1 3
304
Gastrointestinal Bleeding in
Recipients of theHeartWare Ventricular Assist SystemABSTRACT
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 andquality of life outcomes has been realizedby the introduction of continuous flow
left ventricular assist devices (CF-LVAD) for the man-agement of advanced heart failure (1–3). While thebenefits associated with enhanced reliability, drive-line size, elimination of noise, and better batteryduration are undisputed, the use of this technologyhas led to vexing clinical challenges occurring morefrequently than with previous pulsatile technologies.Among these are hemolysis and pump thrombosis (4),de novo aortic insufficiency (5) and gastrointestinalbleeding (GIB) (6), with GIB singled out as the mostcommon cause of readmission (7). The reported inci-dence in institutional series varies widely, from 5%to 30% (6,8–16). Because only bleeding meeting pre-specified criteria such as those requiring transfusionsof $4 U within 7 days post-implant or those requiringreoperation in the landmark clinical trials of theHeartMate II (Thoratec Corporation, Pleasanton,
California) (1,2) or HeartWare (3) devices (HeartWareInc., Framingham, Massachusetts) were reported inearlier publications, we now report here the inci-dence and rate of GIB in the multicenter BTT (Bridgeto Transplant) clinical trial of the HeartWare Ventric-ular Assist (HVAD) System.
The pathogenesis of GIB associated with LVADimplantation is not fully understood, although puta-tive mechanisms include: 1) need for combinedantiplatelet and antithrombotic therapy; 2) develop-ment of acquired von Willebrand syndrome with lossof high molecular weight multimers (17); and3) reduced pulse pressure in the setting of highshear stress—akin to aortic stenosis in Heyde’s syn-drome (18).
The HVAD System (HeartWare Inc.) is a minia-turized, implantable, continuous-flow blood pump.Two large pivotal trials have documented excellentclinical outcomes for recipients of this technology andthe pump received Food and Drug Administration
AB BR E V I A T I O N S
AND ACRONYM S
AVM = arteriovenous
malformation
ASA = acetylsalicylic acid
CAP = continued access
protocol
CF-LVAD = continuous flow
left ventricular assist device
GIB = gastrointestinal bleeding
HVAD = HeartWare ventricular
assist device
INR = international normalized
ratio
J A C C : H E A R T F A I L U R E V O L . 3 , N O . 4 , 2 0 1 5 Goldstein et al.A P R I L 2 0 1 5 : 3 0 3 – 1 3 GIB in HVAD Recipients
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approval for the BTT trial indication (3,19). Compara-tive destination therapy clinical trials are ongoing.
The purpose of this investigation was to fullycharacterize GIB events in the entire cohort of 382patients who were implanted with the HeartWareHVAD system as BTT who were part of the pivotal andcontinued access protocol (CAP) trials.
METHODS
The study design of the HVAD BTT trial and theassociated CAP has been described previously (3,20).In brief, the BTT trial was a prospective, 30-centerclinical trial conducted in the United States thatevaluated the HVAD as BTT trial therapy. The trialenrolled 140 patients with advanced heart failure whowere eligible for heart transplant. Patients werecompared with a contemporaneous group of patientsenrolled in the INTERMACS registry (The InteragencyRegistry for Mechanically Assisted Circulatory Sup-port) who received a commercially available LVAD asBTT therapy. Patients were followed until cardiactransplantation, device explant for recovery, death,or for at least 180 days after implantation, and follow-up would continue through 5 years after implanta-tion. The BTT trial achieved its primary successendpoint, defined as non-inferiority to the INTER-MACS control in terms of survival to 180 days on theoriginal device or transplant or explant for recovery,with rates of 91% for the HVAD system and 90% forthe INTERMACS registry (noninferiority p < 0.0001).Survival at 180 days was 94% for those with an HVADand 90% for those in the control group. The Food andDrug Administration–approved CAP enrolled anadditional 256 patients after completion of enroll-ment in the BTT trial. We present here an assessmentof GIB events in the 382 patients (140 from the BTTtrial and 242 from the CAP) implanted throughNovember 2012 and followed through database lockin July 2013.
GIB was defined as any clinically suspected ordocumented suspicion of bleeding from the GI tract asindicated by a new drop in hemoglobin and/or theappearance of melena, hematochezia, hematemesis,or guaiac positive stools. All GIB events were recordedand characterized and are included in this analysis.
Anticoagulation was individualized and differedamong centers. After device implantation, patientsreceived bridging intravenous heparin. As patientsbecame able to tolerate oral medications they transi-tioned from heparin to warfarin and acetylsalicylicacid (ASA), with a recommended target internationalnormalized ratio (INR) of 2 to 3 and a recommendedASA dose of 81 to 325 mg.
The studies were conducted in compli-ance with Food and Drug Administrationregulations for Good Clinical Practice, andwere approved by each site’s InstitutionalReview Board. All patients or their autho-rized representatives provided informedconsent.STATISTICAL ANALYSIS. GIB events werereviewed individually for additional detailsthrough manual review of the narrative re-ports. Descriptive statistics were used todescribe source, location, and treatment.Survival is reported descriptively throughKaplan-Meier analysis, with follow-up cen-
sored at the time of heart transplantation or deviceexplant for recovery, or withdrawal of consent orloss to follow-up. Overall survival was defined asfreedom from death from any cause, with censoringat the time of heart transplant or explant for re-covery. Competing outcomes were calculated byKaplan-Meier nonparametric product limit actuarialmethod.All adverse events, including those meeting theINTERMACS definitions were evaluated with respectto severity, expectedness, and device relatedness.Adverse events were reported both as the percentageof subjects affected and the rate per patient-year offollow-up.
Statistical comparisons were made between out-comes using log-rank t test, with significance deter-mined at a p value of #0.05, with no adjustment formultiple comparisons. Adjustments based on baselinedifferences were made using the Cox proportionalhazards model.
RESULTS
PATIENT DEMOGRAPHICS. A total of 382 patientsenrolled in the BTT or CAP populations betweenAugust 2008 and November 2012 are included in thisreport. Overall, patients had a mean age of 53.2 � 11.7years, were predominantly male and Caucasian, andhad a mean body surface area of 2.0 � 0.3 m2.New York Heart Association functional class IVheart failure classification was recorded for 95.8%of patients and 75.4% were in either INTERMACSClass 2 or 3. Table 1 compares demographic charac-teristics of patients with (n ¼ 59) and without GIBevents (n ¼ 323). Patients with GIB had higher bodymass index and creatinine, and more frequently haddiabetes and an ischemic etiology of heart failure.Overall, patients who experience a GIB were less sick(mean INTERMACS profile 2.9 � 1.3 vs. 3.3 � 1.2;p ¼ 0.014).
TABLE 1 Baseline Patient Characteristics
Baseline CharacteristicGIB
(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
Race 0.9583
Caucasian 69.5% 67.8%
Black/African American 27.1% 26.3%
Other 3.4% 5.9%
Hispanic or Latino ethnicity 5.1% 5.9%
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
Ischemic cause of heart failure 50.8% 35.6% 0.0293
Arterial blood pressure, mm Hg
Systolic 103.9 � 14.0 103.5 � 15.6 0.8378
Diastolic 62.8 � 10.0 63.6 � 10.7 0.5950
Mean 78.4 � 10.1 77.4 � 11.2 0.5950
Pulmonary artery pressure, mm Hg
Systolic 50.2 � 15.5 48.6 � 14.4 0.5233
Diastolic 23.2 � 7.9 24.2 � 8.5 0.4770
Central venous pressure, mm Hg 11.4 � 5.1 11.6 � 7.7 0.8745
Cardiac Index, l/min/m2 2.3 � 0.6 2.2 � 0.6 0.3400
Left ventricular ejection fraction, % 19.2 � 6.8 16.9 � 7.3 0.0449
Creatinine, mg/dl 1.5 � 0.6 1.3 � 0.5 0.0126
International normalized ratio 1.3 � 0.5 1.3 � 0.4 0.3949
New York Heart Association functional class 0.4069
II 1.7% 0.3%
III 1.7% 3.7%
IV 96.6% 95.7%
N/A 0.0% 0.3%
INTERMACS patient profile 0.0024
1 1.7% 6.2%
2 20.3% 37.5%
3 47.5% 39.3%
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
None/mild 28.1% 33.8%
Moderate 36.8% 31.2%
Severe 22.8% 13.1%
Not assessed 12.3% 22.0%
Tricuspid regurgitation 0.4218
None/trivial/mild 50.0% 60.1%
Moderate 26.8% 19.0%
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 variablesare from a Fisher’s exact test.
GIB ¼ gastrointestinal bleeding; INTERMACS ¼ The Interagency Registry for Mechanically Assisted CirculatorySupport.
Goldstein et al. J A C C : H E A R T F A I L U R E V O L . 3 , N O . 4 , 2 0 1 5
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GIB EVENTS. GIB events occurred in 59 of 382 (15.4%)HVAD recipients over a follow-up ranging from 36 to1,339 days (median 365 days). A total of 108 GIBevents were reported over 406.6 patient-years ofHVAD support, representing 0.27 GIB events per pa-tient year. Most of the events (93 of 108, 86.1%)
occurred more than 30 days after LVAD implantation.The mean time to first event was 273.1 days. Theevent distribution is depicted in Figure 1. Among the59 patients with at least 1 bleeding event, 39 of 59(66%) had 1 GIB event and 20 of 59 (34%) had morethan 1 GIB event (range 1 to 8). Freedom from a GIBevent was 84.1% at 1 year (Figure 2). There was no siteeffect noted among the centers participating in thisclinical trial (Figure 3).
INR values at the time of the GIB episode wereavailable in 102 of 108 (94.4%) episodes. The meanINR at the time of first bleeding event was 2.2 � 1.1.Mean INRs following initial post-implant dischargewere significantly higher in patients who developedGIB than in those who did not (2.4 vs. 1.6, p # 0.0001).Table 2 shows a comparison of the aspirin doses beingtaken by patients with and without GIB events. At thetime of their event, patients with GIB were takingsignificantly higher doses of aspirin than thosewithout GIB. Also, in patients with GIB taking aspirin,4 patients were on dual antiplatelet therapy at theonset of their bleeding event (1 patient also on clo-pidogrel, and 3 others also taking dipyridamole).
In 78% of bleeding events, a specific lesion wassuspected or identified. By far the most commonlesion was an arteriovenous malformation (AVM)followed by an ulcer (includes gastric and duodenal).In 22% of instances, no active site could be identified(Table 3). The most common lesion site was the smallintestine (Figure 4). The duration of LVAD supportwas longer for patients with GIB than those withoutGIB: 477.2 � 363 days for the 59 patients with GIB vs.372.6 � 331.24 days for the 323 with no GIB,p ¼ 0.0159. Among patients with GIB, at 365 dayspost-implantation, 58.2% of patients were alive onthe original device, 27.4% had received a transplant,5.3% required device exchange, and 9.1% had died.Among patients with no GIB, at 365 days post-implantation, 43.8% of patients were alive on theoriginal device, 38.2% had received a transplant, 6.3%required device exchange, and 11.7% had died.Figures 5A and 5B show a competing risk analysis forthese outcomes.
The management of the 108 bleeding events(the 59 patients who experienced a GIB event) isdepicted in Figure 6. Transfusion of blood productswas required in the overwhelming majority (94%) ofbleeding events and in an 18.5% of bleeding events,no further therapy was required. An endoscopic pro-cedure was used to manage bleeding in 52 of 108(48%) cases. Endoscopic procedures used includedcautery, clipping, thermal ablation, or argon plasmacoagulation. No surgical procedures (i.e., laparotomy)were required to control GIB.
FIGURE 2 Freedom From GIB Events
Kaplan-Meier chart of freedom from gastrointestinal bleeding (GIB) events from time of
implant to 1 year post-implant.
FIGURE 1 Distribution of GI Bleeding Events
A total of 108 events occurred in 59 patients. 323 patients had no gastrointestinal (GI)
bleeding events.
J A C C : H E A R T F A I L U R E V O L . 3 , N O . 4 , 2 0 1 5 Goldstein et al.A P R I L 2 0 1 5 : 3 0 3 – 1 3 GIB in HVAD Recipients
307
SURVIVAL AND ADVERSE EVENTS. There were nodeaths directly related to GIB. One patient died 6 daysfollowing a GIB event. The GIB was attributed tointense anticoagulation to treat a pump thrombusevent. The patient then had a pump exchange,developed right heart failure, and later died post-exchange due to vasodilatory shock. There was nostatistically significant difference in overall survivalbetween patients who experienced GIB and thosewho did not for either unadjusted survival or forsurvival adjusted for ischemic etiology and bodysurface area (Figure 7).
The rate and incidence of adverse events for theGIB and non-GIB populations are shown in Tables 4and 5. Patients who had GIB events had higher ratesof 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/patientyear, p ¼ 0.0021). Although rates of sepsis weresimilar for GIB versus non-GIB, the incidence ofsepsis was higher among patients with GIB (28.8% vs.17.0%, p ¼ 0.0452). The rates and incidence of otheradverse events were not significantly different be-tween patients with and without GIB.
Of the 59 patients who had a bleeding event, fivehad a subsequent thrombotic event (pump throm-bosis, transient ischemic attack, ischemic cerebro-vascular accident, or peripheral thrombosis). Themean time to first thrombus event following the GIBwas 155.4 days. The history of each thrombotic eventis described briefly in Table 6. In 50% of GIB events,therapy with 1 or more anticoagulant drugs wasinterrupted within 5 days after the event. Table 7details the interruptions in anticoagulant therapyafter GIB events.
DISCUSSION
The clinical introduction of miniaturized continuousflow left ventricular assist devices (CF-LVADs) dras-tically improved survival and quality of life outcomesfor recipients of these technologies. Moreover, it ledto a wider acceptance of mechanical support bypatients, referring physicians and the heart failurecommunity in general. This success has been temperedby the recognition of new adverse events not encoun-tered with previous pulsatile first-generation tech-nology, namely pump thrombosis, de novo aorticinsufficiency, and GIB. The latter was the focus of thisinvestigation.
Frazier et al. (21) first described gastrointestinalbleeding (from AVMs) in patients receiving aCF-LVAD—the Jarvik 2000 (Jarvik Heart, Inc.,
New York, New York) device—an intraventricularaxial flow pump. Several single-institution reportsbegan documenting a high incidence of GIB in re-cipients of these technologies and in fact, severalhave singled out GIB as the most frequent etiology forreadmission following successful implantation (7,22).
The present study is, to our knowledge, the firstmulticenter investigation aimed at fully character-izing the vexing problem of GIB in recipients of thistechnology. Among 382 patients who received theHVAD System as a BTT, 15.4% developed 108 GIBevents over nearly 407 years of support, for a rate of
FIGURE 3 Percentage of Patients With GIB Across Enrollment Sites
The red line indicates overall incidence (15.4%). The numbers at the base of the histo-
grams represent the total patient enrollment at the site. The p value is from the chi-square
test. NS ¼ not significant; other abbreviation as in Figure 2.
Goldstein et al. J A C C : H E A R T F A I L U R E V O L . 3 , N O . 4 , 2 0 1 5
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308
0.27 GIB/PPY. Freedom from GIB events was 84.1% at1 year and most events occurred beyond the periop-erative period. This incidence is lower than that sug-gested by a recent review of all case reports and caseseries in the literature whereby 265 of 1,316 (20.1%)CF-LVAD recipients developed a GIB (6). In the fewcase series that have reported annualized GIB eventrates, the reported rates were higher and involvedmostly HeartMate II recipients. Stulak et al. (11)documented a rate of 0.45 GIB/patient year among389 recipients of 4 different CF-LVADs while Crowet al. (8) described a rate of 0.63 GIB/patient yearamong their 55 recipients of nonpulsatile devices.
Time to first GIB event was 273 days, longerthan the 5 months reported by Stulak et al. (11), or the63 � 62 days, described by Demirozu et al. (9), amongthe 19% of 172 patients who had GIB after receiving aHeartMate II device. French et al. (12) described amaximal hazard rate of GIB of 2.23 events/patientyear at 21 days post-implantation.
We noted several interesting differences in baselineparameters of patients with GIB compared with thosewithout GIB. On univariate analysis, the former were
TABLE 2 Average Overall ASA Dosages
GIB(n ¼ 59)
No GIB(n ¼ 323) p Value
ASA category <0.0001
0–<81 mg 20.3% (12) 3.1% (10)
81–<162 mg 28.8% (17) 26.3% (85)
162–324 mg 0.0% (0) 51.1% (165)
$324 mg 50.8% (30) 19.5% (63)
Values are % (n).
ASA ¼ acetylsalicylic acid; GIB ¼ gastrointestinal bleeding.
larger (higher body surface area, body mass index),were more likely to be diabetic, had worse renalfunction, andwere as a group less sick. It is well knownthat renal dysfunction can alter platelet functionby interfering with adhesion and aggregation. Ourfinding that GIB patients had worse baseline renalfunction supports this pathophysiology. However,because data regarding renal function at the time ofGIB events is not available, it is difficult to attributerenal dysfunction as a definitive contributor as it ispossible that in many patients with baseline dysfunc-tion, renal function normalized after implantation ofthe LVAD, as it frequently occurs with restoration ofoptimal hemodynamics and end organ perfusion. Ourfindings in this regard, however, mimic those ofDemirozu et al. (9), who noted a trend for patients withGIB to have higher baseline creatinine level.
The observation of ischemic etiology as a preop-erative risk factor for GIB coincides with the findingby Boyle et al. (23), who found that ischemic etiologywas a strong perioperative factor (hazard ratio: 1.35)in an analysis of 900 patients who received theHeartMate II LVAD.
While our data suggests a statistically significantincreased risk of GIB for patients with larger bodysurface area/body mass index, the actual differencesin these values (2.0 vs. 2.1 m2 and 29.9 vs. 27.9 kg/m2,respectively) is very small and likely clinically un-important. The finding of diabetes as a preoperativerisk factor for GIB is intriguing and is interesting tonote a recent publication documenting diabetes as anindependent risk factor for upper GIB in a large pop-ulation study (24). As described previously (15,16,25),GIB events often recur, with 34% of our patientshaving at least 1 recurrence. The identification ofAVMs as the most common etiology of GIB is alsoconsistent with previous reports (9,10,21); this findinghas been attributed at least partly to low pulsatilityand shear stress–induced acquired von Willebrandsyndrome resulting from continuous flow assistphysiology. In fact, recipients of CF-LVADs withhigher pulsatility have been shown to have a reducedincidence of nonsurgical bleeding events (14). In ourseries, nearly one-quarter of GIB events could not belocalized. Many or all of these are likely due to occultAVMs of the small bowel, which are notoriouslydifficult to identify and treat.
Management of GIB events generally followedcommon clinical practice, with transfusions, cessationof antithrombotic therapy, antacid therapy, and diag-nostic work-ups at the discretion of the caringphysicians. The issue of timing an intensity of rein-troduction of antithrombotic therapy following reso-lution of a GIB event is of paramount importance.
FIGURE 4 Localization of GIB Events
GIB sites were identified by various scope methods. Note:
Patients could have multiple sources of bleeding. Abbreviation as
in Figure 2.
TABLE 3 Lesions Identified as Source of GIB Event
SourceFirst Bleed(n ¼ 59)
All Bleeds(n ¼ 108)
Definite or suspected arteriovenousmalformations
19% (11) 27% (29)
Ulcers 17% (10) 10% (11)
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.
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Unfortunately, the present study did not capture thisinformation and recommendations cannot be made.Moreover, although higher ASA doses and higher INRvalues were observed in persons with GIB, the clinicaltrial was not designed to determine optimal dosing ofantithrombotic therapies.
Though no data is available to describe frequencyof its use or success, octreotide, either in short- orlong-acting form, has emerged as an additional tool in
FIGURE 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.
FIGURE 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.
FIGURE 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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TABLE 5 Annualized Adverse Event Rate by GIB Status
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 1.17 (90) 0.07 (22) 0.0001
Reoperation 0.17 (13) 0.15 (51) 0.7840
Requiring transfusions* 0.21 (16) 0.13 (43) 0.1270
Cardiac tamponade 0.03 (2) 0.05 (17) 0.3145
Cardiac arrhythmia 0.48 (37) 0.51 (168) 0.7895
Ventricular 0.25 (19) 0.25 (82) 0.9702
Supraventricular 0.22 (17) 0.27 (89) 0.4654
Hemolysis 0.08 (6) 0.05 (18) 0.4664
Hepatic dysfunction 0.08 (6) 0.04 (14) 0.2356
Infection
Localized nondevice 0.74 (57) 0.40 (133) 0.0021
Sepsis 0.29 (22) 0.21 (70) 0.2394
Driveline exit site 0.29 (22) 0.24 (80) 0.5082
Myocardial infarction 0.00 (0) 0.01 (2) 0.3592
Neurological events
Ischemic CVA† 0.06 (5) 0.06 (19) 0.8169
Hemorrhagic CVA 0.09 (7) 0.08 (27) 0.8103
TIA 0.03 (2) 0.08 (27) 0.0634
Renal dysfunction 0.10 (8) 0.12 (38) 0.7841
Acute 0.10 (8) 0.11 (37) 0.8387
Chronic 0.00 (0) 0.00 (1) 0.5167
Respiratory dysfunction 0.32 (25) 0.28 (91) 0.5186
Right heart failure 0.38 (29) 0.36 (120) 0.8905
Inotropic Therapy 0.32 (25) 0.32 (104) 0.9098
RVAD 0.05 (4) 0.03 (11) 0.4664
Thromboembolism 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
Values represent events per patient-year (number of events). All adverse eventswere adjudicated by the Clinical Events Committee, and include events censored atthe time of transplant, explant for recovery, or device exchange. Poisson regres-sion was used for event rate. *Transfusions include those requiring >4 U within7 days. †Procedural ischemic CVAs occurring within 2 days post-implant havebeen excluded.
Abbreviations as in Table 4.
TABLE 4 Incidence of Adverse Events by GIB Status
Adverse Event(INTERMACS category)
GIB(n ¼ 59)
Non-GIB(n ¼ 323) p Value
Bleeding
Rehospitalization 66.1% (39) 6.5% (21) <0.0001
Reoperation 16.9% (10) 14.6% (47) 0.6908
Requiring transfusions* 23.7% (14) 12.4% (40) 0.0397
Cardiac tamponade 3.4% (2) 5.3% (17) 0.7499
Cardiac arrhythmia 30.5% (18) 36.8% (119) 0.3793
Ventricular 20.3% (12) 20.1% (65) 1.0000
Supraventricular 22.0% (13) 22.3% (72) 1.0000
Hemolysis 10.2% (6) 4.6% (15) 0.1133
Hepatic dysfunction 10.2% (6) 4.3% (14) 0.1020
Infection
Localized nondevice 50.8% (30) 27.9% (90) 0.0007
Sepsis 28.8% (17) 17.0% (55) 0.0452
Driveline exit site 25.4% (15) 18.6% (60) 0.2175
Myocardial infarction 0.0% (0) 0.6% (2) 1.0000
Neurological
Ischemic CVA† 6.8% (4) 5.0% (16) 0.5285
Hemorrhagic CVA 10.2% (6) 8.0% (26) 0.6089
TIA 3.4% (2) 6.5% (21) 0.5521
Renal dysfunction 13.6% (8) 9.6% (31) 0.3523
Acute 13.6% (8) 9.3% (30) 0.3426
Chronic 0.0% (0) 0.3% (1) 1.0000
Respiratory dysfunction 32.2% (19) 21.4% (69) 0.0914
Right heart failure 44.1% (26) 31.9% (103) 0.0740
Inotropic therapy 37.3% (22) 28.5% (92) 0.2152
RVAD 6.8% (4) 3.4% (11) 0.2644
Thromboembolism 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 Com-mittee, and include events censored at the time of transplant, explant for recovery,or device exchange. Fisher’s exact test was used for proportions. *Transfusionsinclude those requiring >4 U within 7 days. †Procedural ischemic cerebrovascularaccidents (CVAs) occurring within 2 days post-implant have been excluded.
CVA ¼ cerebrovascular accident; GIB ¼ gastrointestinal bleeding; INTERMACS ¼The Interagency Registry for Mechanically Assisted Circulatory Support;RVAD ¼ right ventricular assist device; TIA ¼ transient ischemic attack (<24 h).
TABLE 6 Brief Histories of Thrombotic Events Subsequent
to GIB
A VAD thrombus preceded by a 3-month interruption in ASA due toGIB
A VAD thrombus with no interruption in anticoagulation despite 3 GIBepisodes over 7 months
An ischemic CVA 11 days after implantation and 3 days after GIB due toerosive gastritis; the VAD was replaced after medical therapy failedto resolve the thrombus and had 2 peripheral bleeding eventsshortly after the pump exchange; there was no interruption inanticoagulation
A TIA 1 month after a 4-day interruption in aspirin and 3 days after a1-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 monthsafter stoppage of warfarin due to a series of 4 bleeding events
ASA ¼ acetylsalicylic acid; VAD ¼ ventricular assist device; other abbreviations asin Table 4.
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the armamentarium to treat occult GIB that is likelysecondary to small bowel AVMs (26,27). While GIBevents often required readmissions and incurredcosts, no surgical interventions were required and nodeaths were directly related to the GIB event. At 12months, 85.6% of patients were alive with device ortransplanted.
Comparison of the incidence of adverse event ratesbetween patients who had GIB and those who did notsuggests that the former are more likely to be read-mitted and transfused and are more prone to developlocalized nondevice infections and sepsis. The causalrelationship between blood transfusions and subse-quent infections is well established in cardiac surgicalpatients (28) thus our findings are not surprising.When these events are annualized to adjust for
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 highmolecularweight vonWillebrand factor.
COMPETENCY IN PATIENT CARE: Conventional
diagnostic evaluations and therapies are effective in
managing gastrointestinal bleeding in CF-LVAD re-
cipients. Although GIB increases readmissions and
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.
TABLE 7 Duration of Interruptions in Antiplatelet and
Anticoagulant Therapy
Duration ofInterruption
Therapy Interrupted (n ¼ 108 GIB Events)
ASA/clopidogrel Warfarin Both
No interruption(0 days)
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)
3–7 days 7.4% (8) 11.1% (12) 5.6% (6)
8–14 days 5.6% (6) 3.7% (4) 1.9% (2)
>14 days 17.6% (19) 13.0% (14) 5.6% (6)
Values are % (n). *A total of 34.3% (37) events had only 1 therapy (either anti-platelet or anticoagulant) interrupted.
ASA ¼ acetylsalicylic acid; GIB ¼ gastrointestinal bleeding.
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different follow up times however, only the differ-ences in rehospitalization, localized nondevice infec-tion and thromboembolic rates remain statisticallysignificant. The lower rate of thromboembolic com-plications observed among persons with GIB, perhapsunderscores the possibility that certain patients havean inherent propensity to bleed and are thus less likelyto develop thrombotic complications.
Concern has arisen regarding the potential pro-thrombotic milieu created by the need to discontinueantithrombotic therapy in recipients of CF-LVADs.Notwithstanding the differences in devices and man-agement strategies it is interesting to note that a recentreport by Stulak et al. (11) documented a 0.31 throm-boembolic event per patient year rate among personswith GIB with a median interval of 5 months after theGIB event. And while thromboembolic events were7.4 times more likely to occur in patients with priorGIB, neither the GIB nor the thromboembolic eventportended a lower survival (11). In our series, nearlytwo-thirds of patients had interruption of either anti-platelet or warfarin therapy. Five patients developed athrombotic complication (range 11 days to 10 months)following a GIB event. In 2 of these instances, antith-rombotic therapy had not been interrupted.
STUDY LIMITATIONS. Several limitations to ouranalysis should be considered. First, the study wasnot randomized, and all patients received an HVAD.Any comparisons are only available through historicalliterature. Also, this was a post-hoc analysis, and theclinical trial was not powered to analyze GIB events.
CONCLUSIONS
In summary, GIB has emerged as a significant compli-cation limiting the success of current CF-LVAD tech-nologies. GIB events occurred in 16% of HVADrecipients, for an event rate of 0.27 GIB/patient year,which is lower than rates reported for other devices.
While the exact etiology of GIBs has not beenelucidated, low pulsatility and VAD-induced shearstress degradation of high molecular weight von Wil-lebrand factor appear to contribute to the genesis.AVMs of the small bowel are the most common culpritlesions. The morbidity associated with the develop-ment of GIB in LVAD recipients suggests that preop-erative endoscopic screening of patients with riskfactors for GIB including advanced age, history of GIB,occult blood in the stool and/or microcytic anemiashould be seriously considered. Conventional diag-nostic evaluations and therapies are effective in man-aging these bleeding events, but recurrence is notuncommon. Fortunately, while the GIBs are associatedwith readmissions and a higher incidence of nondeviceinfections, survival is not affected. It is hoped that theintroduction of pulsatility algorithms and wider gapsthat reduce shear stress in next generation pumps willreduce rates of this vexing complication.
ACKNOWLEDGEMENTS The authors acknowledgeMary V. Jacoski, MS, and Edward K. Baldwin, PhD, ofHeartWare Inc., for their assistance in the preparationof the manuscript.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.Daniel J. Goldstein, Montefiore Medical Center, 3400Bainbridge Avenue, MAP 5, Bronx, New York 10367.E-mail: [email protected].
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KEY WORDS gastrointestinal bleeding,heart failure, left ventricular assist device,LVAD
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