Features of Patients With Gastrointestinal Bleeding After Implantation of Ventricular Assist Devices

Accepted Manuscript Features of Patients with Gastrointestinal Bleeding Following Implantation of Ventricular Assist Devices Gurshawn Singh , MD Mazen Albeldawi , MD Saminder S. Kalra , MD Paresh P. Mehta , MD Rocio Lopez , John J. Vargo , MD, MPH

PII: DOI: Reference:

S1542-3565(14)00750-2 10.1016/j.cgh.2014.05.012 YJCGH 53828

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 1 May 2014 Please cite this article as: Singh G, Albeldawi M, Kalra SS, Mehta PP, Lopez R, Vargo JJ, Features of Patients with Gastrointestinal Bleeding Following Implantation of Ventricular Assist Devices, Clinical Gastroenterology and Hepatology (2014), doi: 10.1016/j.cgh.2014.05.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

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Features of Patients with Gastrointestinal Bleeding Following Implantation of Ventricular Assist Devices Gurshawn Singh MD1, Mazen Albeldawi MD2, Saminder S. Kalra MD1, Paresh P. Mehta MD2, Rocio Lopez3, John J. Vargo MD, MPH2

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Gurshawn Singh MD – acquistion of data; drafting of manuscript

Mazen Albeldawi MD – study concept; acquistion of data; drafting of manuscript Saminder S. Kalra MD – acquisition of data

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Paresh Mehta – revision of manuscript

Rocio Lopez – statistical analysis; analysis and interpretation of data John J. Vargo MD – revision of manuscript

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All authors report no conflict of interest

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Department of Internal Medicine1, Cleveland Clinic, Cleveland, OH; Department of Gastroenterology and Hepatology2, Cleveland Clinic, Cleveland, OH; Department of Quantitative Sciences3, Cleveland Clinic, Cleveland, OH

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Corresponding Author: John J. Vargo, M.D., M.P.H. Department of Gastroenterology and Hepatology Digestive Disease Institute Cleveland Clinic 9500 Euclid Avenue Cleveland, Ohio 44195 Tel: 216-444-6521 Fax: 216-444-6284 E-mail: [email protected]

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Abstract: Background & Aims: Ventricular assist devices (VADs) are used to treat patients with end-stage heart disease. However, patients with VADs frequently develop gastrointestinal (GI) bleeding. We investigated the incidence, etiology, and outcome of GI bleeding in patients with VADs.

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Methods: In a retrospective study, we analyzed data from 391 consecutive patients (mean age 53.9 ± 14.2 years old, 81% male) who underwent VAD implantation for endstage heart disease from January 2000 through May 2012 at the Cleveland Clinic. Multivariable logistic regression analysis was used to identify factors independently associated with GI bleeding in patients with VADs.

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Results: Sixty-two patients (15.9%) had GI bleeding. The risk of GI bleeding increased by 10% for every 5 year increase in age (P=.006). GI bleeding was also associated with lower body mass index (P=.046), current smoking (P=.007), and lower baseline levels of hemoglobin (P<.001). Bleeding was primarily overt (79%), and most patients presented with hematochezia (43.5%). Causes of bleeding were primarily vascular malformations (26.5%) and ulcers (26.5%). Patients who received VADs as their only therapy, rather than as a bridge to transplantation, were more likely to have GI bleeding (P=.008). Colonoscopy detected GI bleeding with the highest diagnostic yield; most bleeding was associated with colonic lesions (51.4%). Overall mortality was 39.4%, and 2 deaths were directly related to GI bleeding.

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Conclusion: Based on a large case series analysis, GI bleeding is common following implantation of VADs (15.9% of patients have at least 1 episode of bleeding). Episodes were mostly overt and predominantly from the lower GI tract; colonoscopy is the best method of detection.

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Introduction

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KEY WORDS: endoscopy; cardiovascular disease, heart failure, pulsatile and continuous devices

Left ventricular assist devices (LVADs) have emerged as a valuable therapeutic option in the management of advanced systolic heart failure. They are being used to provide longterm mechanical circulatory support to a growing population of patients with end-stage heart disease (ESHD) refractory to medical therapies [1, 2]. ESHD is associated with a high mortality when treated with medical therapy alone, and these patients are

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traditionally referred for cardiac transplantation [3]. Given the large discrepancy between the demand for heart transplants and limited availability of donor organs,

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mechanical circulatory support has become common practice. These devices are primarily being utilized for circulatory failure as a bridge-to-transplant or as destination

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therapy for those deemed ineligible for cardiac transplantation [4, 5].

Currently there are two generations of left ventricular assist devices: (1) Pulsatile

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devices and (2) Continuous devices. The newer, smaller, and more durable continuous devices have been shown to improve survival and functional quality of life as compared to the previous generation of pulsatile flow devices [5].

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Several investigators have reported a higher incidence of GI bleeding after the implantation of a ventricular assist device. However, it is not well understood why there is an increased predilection for GI bleeding. There are several potential mechanisms

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including increased intraluminal pressure and lowered pulse pressure leading to hypoperfusion of the intestines and resultant arteriovenous malformations (AVMs).

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These devices also decrease the high molecular weight von Willebrand factor (vWF) multimer size resulting in an acquired form of vWF disease [6]. It is hypothesized that these mechanisms work synergistically increasing the risk of GI bleeding in this population. Also important to note is that thromboembolism is a known and feared complication in the use of VADs, with a mechanism that is unknown to date [7].

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Therefore most patients with VADs are already on anticoagulation, which also does contribute to the patients’ risk of bleeding.

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There are still many unanswered questions regarding the risk of GIB during VAD support. The aim of our study was to determine the incidence, etiology, and outcome of

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GIB in patients receiving VAD support at a single large tertiary center.

Methods

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Patients

Using our institutional database we identified adult patients who had undergone ventricular assist device implantation for ESHD over a 12-year period between 2000 and 2012. The review of clinical data for the purpose of this study was approved by the

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Institutional Review Board at the Cleveland Clinic.

VAD Implantation

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The indication for VAD therapy was either a bridge-to-transplant or destination therapy

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in patients deemed not to be candidates for cardiac transplant. Patients were categorized based on VAD device: continuous flow vs. pulsatile flow vs. total artificial heart. All patients received anticoagulant therapy after VAD implantation with oral warfarin, with a goal international normalized ratio (INR) of 2 to 3. Aspirin at a dosage of 81 mg was used universally. Clopidogrel, dipyridamole, and a proton pump inhibitor were added at the discretion of the attending cardiologist and cardiac surgeon.

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Data Collection Data collected included variables such as age, sex, race, body mass index, tobacco use,

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alcohol use, medical co-morbidities, etiology of heart failure and concurrent patient medications including non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, clopidogrel, dipyramidole, statins, sucralfate, proton pump inhibitors (PPI), and

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warfarin. Baseline pre- and post- device implantation laboratory studies including

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hemoglobin, platelets, INR and creatinine were also collected.

GI Bleed

The primary end point for this study was a GI bleeding event after implantation of a ventricular assist device. GI bleed was defined as overt or occult bleeding within the

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gastrointestinal tract that occurred during the period from when the VAD was placed, until death, transplant, or explantation of the VAD. An overt bleed was classified as melena, hematochezia, hematemesis, and coffee ground emesis. An occult bleed was

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defined as an acute drop in hemoglobin with positive fecal occult blood test and negative upper and lower endoscopies. Hemodynamic instability was defined as use of

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pharmacologic vasopressor support or red blood cell transfusion, and this was recorded as positive if it occurred secondary to a GI bleed event.

Patients who experienced a bleeding event underwent upper endoscopy, colonoscopy, push enteroscopy, balloon enteroscopy, capsule endoscopy, or a tagged RBC scan. All endoscopic procedures were performed in our endoscopy suite or at the bedside in our

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intensive care unit. All patients received either conscious sedation with fentanyl and

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midazolam, or monitored anesthesia care with propofol and alfentanil.

Statistical Analysis

Continuous variables were expressed as a mean ± standard deviation (SD), median [25th,

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75th percentiles] or N (%). Univariable and multivariable Cox regression analysis was performed to identify factors independently associated with GI bleed in patients

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receiving VAD support. An automated stepwise variable selection method performed on 1000 bootstrap samples was used to choose the final multivariable model; variables with inclusion rates of at least 20% were included in the final model. A p < 0.05 was considered statistically significant. Analyses were performed using SAS (version 9.2

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software, The SAS Institute, Cary, NC) and graphics were generated by R (version 2.15.2, The R Foundation for Statistical Computing, Vienna, Austria).

Patients

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Results

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A total of 391 patients who had end stage heart disease and underwent VAD support at our institution were included in the study. These patients were divided into 3 groups based on the VAD hardware installed: (1) pulsatile flow device [Thoratec HeartMate™ XVE, (Pleasanton, CA) (n = 132)], (2) continuous flow devices [Thoratec HeartMate™ II (Pleasanton, CA), Jarvik Heart Inc., Jarvik 2000® (Manhattan, NY), HeartWare Corp.,

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HVAD™ (Miami Lakes, FL) (n = 236)], and (3) SynCardia Systems, Inc., Total artificial

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heart (Tucson, AZ) (n = 23).

Patient demographics and characteristics are presented in Table 1. In our patient population, the mean age was 53.9 ± 14.2 years, 81.1% were male, and 80% were

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Caucasian. Etiology of heart failure was classified as non-ischemic (53.7%) vs. ischemic (46.3%). Those presenting with gastrointestinal bleeding were significantly older (58.2

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vs. 53.0 years, P=0.006) in comparison to those without bleeding. Patients with total artificial heart implant had a significantly lower BMI in comparison to both pulsatile and continuous device groups (24.0±6.4 vs. 28.7±5.8 vs. 28.3±5.4 kg/m2; p=0.025) respectively. Furthermore, patients with a GIB were more likely to have a history of

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current smoking (P=0.007) (Table 2).

Choice of VAD was determined by standard of care at the time of implant. Between 2000-2007, 157 devices were placed, and the continuous flow devices were the

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preferred choice (79.6% continuous flow vs. 15.3% pulsatile flow vs. 5.1% total artificial heart). Between 2008-2012, 234 devices were placed, and the pulsatile flow devices

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were the preferred choice (3% continuous flow vs. 90.6% pulsatile flow vs. 6.4% total artificial heart).

GI bleeding We identified sixty-two patients (15.9%) with a GI bleeding event. Of these, 49 were overt and 13 were occult GIB. The majority of patients with overt bleeding presented

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with hematochezia (55.1%). Hemodynamic instability was observed in 32.1% of patients presenting with a GIB. The use of aspirin (46.6% vs. 67.7% vs. 65.2%; p=0.003) and

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warfarin (37.1% vs. 71.2% vs. 47.8%; p<0.001) were significantly lower in the pulsatile device group in comparison to both the continuous flow and total artificial heart groups respectively. Patients with GIB were not significantly different with respect to alcohol

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use, or medical co-morbidities such as diabetes, hypertension, hyperlipidemia, coronary artery disease or chronic renal insufficiency. After adjusting for all variables in the

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model, the risk of experiencing a GIB, increased by 10% for every 5-year increase in age (Supplemental Table 1). When comparing different time periods (2000-2007 vs. 20082012) where there was a preference to a specific type of VAD, we found that there was no difference in occult (2% vs. 4%, P=0.2) or overt (9% vs. 15%, P=0.08) bleeding.

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Stratified multivariable analysis comparing pulsatile to continuous flow VAD shows that there is no significant difference in GIB between continuous vs. pulsatile devices in 2000-2007; However in 2008-2012, patients with a continuous device had 84% lower

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hazard of GIB than those with a pulsatile device (HR = 0.16; P=0.002) after adjusting for

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age, hemoglobin, and PPI use (Supplemental Table 2).

Etiology of GI bleed

The most common sources of GI bleeding were vascular malformations (26.5%) and ulcers (26.5%). Other sources included polyps (17.6%), erosions (11.8%), hemorrhoids (11.8%), and diverticuli (8.8%). Bleeding in the 2000-2007 period vs. the 2008-2012 period was more common from polyps and erosions (polyps: 44% vs. 8%; P=0.031 and

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erosions: 33% vs. 4%; P=0.048). Of the patients who had polyps, pathology revealed hyperplastic polyps in one patient and tubular adenoma in another; the rest either had

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no biopsy done given the setting (bedside in the ICU) or no data available regarding any biopsy or surgical pathology.

A source of bleeding was identified in 54.8% (n=34) of patients who underwent upper

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endoscopy and colonoscopy. Identified sources of bleeding were most common in the colon (51.4%), followed by stomach (35.1%), small intestine (18.9%) and esophagus

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(5.4%). For patients with VAD devices presenting with GIB, colonoscopy provided the highest yield in identifying the etiology of bleeding. Overall mortality was 39.4%, with only 2 deaths directly related to GI bleeding.

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Time to GI Bleed

Median time to GIB after VAD implant was 1.1 months. Median follow-up time after VAD implant was 19.0 [5.6, 45.2] months. There was no significant difference in follow-

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up time between subjects with and without a GI bleeding event [15.6 vs. 21.0 months; p=0.13]. The cumulative risk of GIB at 1 and 5-years were 16% and 20% respectively

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(Figure 1). Patients with an indication of VAD placement as destination therapy had a time dependent risk of GIB that was double when compared to patients with an indication of VAD as bridge to transplant (Figure 3).

Ventricular Assist Devices

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The incidence of GIB was 26.1%, 10.6%, and 17.8% in patients with a total artificial heart, pulsatile devices and continuous devices respectively. Additionally, compared to

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subjects with total artificial heart, those with pulsatile and continuous devices had a 69% and 61% lower hazard of developing a GIB, respectively, after adjusting for all variables in the model (Figure 2). Those patients who underwent VAD implantation for

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therapy to cardiac transplant (19.3% vs. 11.5%; P=0.046).

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destination therapy were also more likely to experience a GIB as compared to bridge

Discussion

The evolution of mechanical cardiac support has been fueled by an increasing need to support patients with ESHD. The prognosis in this group of patients is dismal, with a 4-

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year mortality of more than 50%. The option of cardiac transplantation is limited by organ availability and, as wait times have increased, the need for mechanical cardiac support as a bridge-to-transplant has also increased [8, 9]. Weighing against the

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potential for prolonged survival and improved quality of life are the adverse events

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observed with VAD support.

In the largest study to date, we report a 15.9% incidence of GIB after VAD support. Furthermore, we report that GIB episodes are mostly overt, and identified bleeding sources are predominantly from the lower GI tract. Our results indicate that endoscopic evaluation can identify a cause of GI bleeding in over 50% of cases, and colonoscopy provided the highest diagnostic value to investigate and visualize the source of GIB.

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The high rate of GIB observed in our study is consistent with prior case series reporting

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an increased risk of GIB after LVAD support [5, 10-13]. In this study, a source of GIB was identified in 54.8% of patients, which is higher than reported by Stern et al where a definite bleeding source was identified in only 35% of cases [6]. In another study, a

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potential source of GIB was identified in 70% of patients; however, this may be attributed to the high rates of peptic ulcer disease bleeding (32%) reported in their 154,

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patient cohort [8].

Bleeding in patients with VAD support can occur throughout the GI tract. Letsou et al reported 3 patients supported by Jarvik 2000 axial-flow LVADs who experienced GIB

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from the small intestine [14]. Daas et al reports 3 patients who had GIB from the pylorus, mid–small bowel, and fundus of the stomach [15]. Stern et al found the small bowel to be the predominate site of bleeding [11]. These authors ascribed that GIB

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appears to occur more frequently in the upper GI tract.

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The paramount finding of this study was that colonoscopy provided the highest diagnostic yield with colonic lesions (51.4%) dominating the findings (Figure 1). While previous studies have reported that upper endoscopy is the best modality for localizing a GIB, these studies have all been substantially smaller with many of them being case reports and case studies [6,8,15]. Additionally, in many studies a bleeding site was not identified or reported. For example, Stern et al reported during 17 bleeding episodes,

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36 diagnostic studies were performed, but only 10 tests identified a definite bleeding

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site. No definite bleeding source could be identified in 65% of these episodes [6].

The clinical indication for VAD support and risk of GIB were also assessed. Patients with VAD implantation for destination therapy in comparison to bridge-to-transplant were

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more likely to experience a GIB (P=0.008). This is likely attributed to a longer duration of implant in those patients receiving VADs for destination therapy. Risk of bleeding

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was significantly affected by type of VAD hardware. We observed an increased risk of GI bleed in patients receiving a total artificial heart in comparison to both continuous flow (p=0.04) and pulsatile flow devices (p=0.016). Furthermore, compared to subjects with total artificial heart, those with pulsatile and continuous devices had a 69% and 61%

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lower hazard of developing a GIB, respectively. Although, there was a higher incidence of GIB events in those with continuous devices in comparison to pulsatile devices (17.8%

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vs. 10.6%) this was not statistically significant (p=0.074).

There are three proposed mechanistic theories for the pathophysiology of GIB with

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continuous-flow ventricular assist devices: coagulopathy, acquired von Williebrand disease, and lack of pulsatility. Patients with continuous flow VADs have a state physiologically similar to aortic stenosis because of the narrow pulse pressure [16]. Heyde suggested the physiology resulting in distension of the sub-mucosal venous plexus of GI tract eventually lead to angiodysplasia, AVMs, and bleeding [17]. An alternative mechanism that has been suggested describes decreased perfusion of the GI

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and intestinal mucosa due to low pulse pressure, causing mucosal ischemia and the formation of friable new vessels that are likely to bleed [18]. The integrity of vascular

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endothelium, as evidenced by border protein expressions such as von Willebrand Factor (vWF), is partially dependent on the stretch and distension created by the pulsatile flow. This plays an important homeostatic role in areas of high sheer stress such as

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gastrointestinal AVMs [19]. Klovaite et al demonstrated the impact of continuous flow LVADs on vWF dependent platelet aggregation and showed that almost 70% of patients

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had impaired ristocetin-induced platelet aggregation [19].

Our study does have some limitations. The retrospective design of this study may have led to an underestimation of the true incidence of GIB. A single patient with biopsy

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proven H. Pylori in the pulsatile device group experienced a GIB. It is plausible we may have underestimated the incidence of H Pylori in our cohort, as the majority of patients did not undergo evaluation for H Pylori. The advancement of technology in the care of

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ESHD has led to the use of newer VAD devices and therefore the pulsatile- and continuous-flow devices were not balanced. Finally, we did not assess vWF activity and

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can only offer a hypothesis on the pathogenesis of GIB during VAD support.

With an aging population, limited donor heart availability, improved reliability of mechanical cardiac support and improved patient outcomes, VAD options to support patients with end-stage heart disease are rapidly expanding. In the largest study to date, we report a 15.9% incidence of GIB after VAD support. The majority of GIB events, after

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VAD implant were overt and from the lower GI tract; vascular malformations and colonic ulcers dominating the etiology when a bleeding source was identified. Incidence

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of GIB did not differ between pulsatile and non-pulsatile devices; however, those receiving a total artificial heart or destination therapy in comparison to bridge-totransplant were at increased risk for GIB. Bidirectional endoscopy can identify a cause of

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GIB in over 50% of cases, with colonoscopy offering the highest diagnostic yield. Finally, future studies are needed to advance our current understanding of the mechanisms

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leading to GI bleeding.

Table 1. Demographic and Clinical Characteristics Overall (N=391)

Factor Age

53.9±14.2

Female BMI Current Smoker

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Alcohol Use

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Caucasian

74(18.9)

296(80.0) 28.2±5.6 13(3.7)

Never

188(52.7)

Occasional

132(37.0)

Heavy

37(10.4)

Alcohol Use

169(47.3)

Any comorbidities

374(96.6)

Diabetes

123(31.8)

Hypertension

235(60.7)

Hyperlipidemia

211(54.5)

Coronary Artery Disease

201(51.9)

Chronic Kidney Disease

102(26.4)

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Medications PPI

223(57.0)

Sucralfate

1(0.26)

NSAID

12(3.1)

Warfarin

228(58.3)

Clopidogrel Aspirin

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21(5.4) 235(60.4)

Dipyramidole

10(2.6)

Statin

222(56.9)

H Pylori infection

1(0.26)

Non-Ischemic Heart Failure Pulsatile Flow device

132(33.8)

Continuous Flow device

236(60.4)

Total artificial heart

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23(5.9)

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210(53.7)

Device Type

Therapy type Bridge to transplant

281(71.9)

Destination therapy

110(28.1)

Hemoglobin (g/dL)

10.5±5.3 3

Platelet count (x10 /µL)

166.0[120.0,234.0]

INR

1.5±0.61

Serum Creatinine (mg/dL)

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1.3[0.99,1.7]

Table 2. GIB in LVAD: Univariable Cox Regression Analysis Factor Age Female

No GIB (N=329)

GIB (N=62)

Hazard Ratio (95% CI)

p-value

53.0±14.3

58.2±13.1

1.03 (1.01, 1.05)

0.006

14(22.6)

1.2 (0.68, 2.2)

0.5

47(77.0)

0.88 (0.48, 1.6)

0.66

28.4±5.6

26.8±5.3

0.95 (0.90, 1.00)

0.046

8(2.7)

5(8.6)

3.5 (1.4, 8.8)

0.007

Never

161(53.8)

27(46.6)

reference

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Occasional

108(36.1)

24(41.4)

1.3 (0.77, 2.3)

0.31

Heavy

30(10.0)

7(12.1)

1.3 (0.58, 3.1)

0.5

Alcohol use

138(46.2)

31(53.4)

1.3 (0.80, 2.2)

0.28

Any comorbidities

314(96.0)

60(100.0)

4.0 (0.24, 66.1)

0.33

Diabetes

107(32.7)

16(26.7)

0.77 (0.43, 1.4)

0.37

Hypertension

200(61.2)

35(58.3)

0.84 (0.50, 1.4)

0.5

Hyperlipidemia

180(55.0)

31(51.7)

0.85 (0.51, 1.4)

0.52

Coronary artery disease

168(51.4)

33(55.0)

1.2 (0.75, 2.1)

0.39

BMI

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Current Smoker

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60(18.2) 249(80.6)

Caucasian

Alcohol use

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Chronic kidney disease

83(25.4)

19(31.7)

1.3 (0.75, 2.2)

0.37

181(55.0)

42(67.7)

1.5 (0.90, 2.6)

0.11

Sucralfate

1(0.30)

0(0.0)

---

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NSAID

11(3.3)

1(1.6)

0.49 (0.07, 3.5)

0.48

193(58.7)

35(56.5)

0.96 (0.58, 1.6)

0.89

PPI

Warfarin Clopidogrel Aspirin Dipyramidole Statin

16(4.9)

5(8.1)

199(60.9)

36(58.1)

8(2.4)

2(3.2)

181(55.0)

41(67.2)

H. Pylori infection

0(0.0)

1(1.6)

Non-Ischemic CHF

178(54.1)

32(51.6)

Pulsatile flow

118(35.9)

Continuous flow

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Medications

2.1 (0.82, 5.1)

0.12

0.88 (0.53, 1.4)

0.61

1.3 (0.32, 5.3)

0.72

1.3 (0.79, 2.3)

0.28 --0.56

14(22.6)

reference

---

194(59.0)

42(67.7)

1.8 (0.99, 3.4)

0.053

17(5.2)

6(9.7)

2.8 (1.06, 7.2)

0.037

Bridge therapy

243(73.9)

38(61.3)

reference

---

Destination therapy

86(26.1)

24(38.7)

2.0 (1.2, 3.4)

0.008

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---

0.86 (0.52, 1.4)

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Device Type

Total artificial heart Therapy type

Hemoglobin (g/dL) Platelet count (x103/µL)

10.6±5.7

9.6±2.1

0.77 (0.66, 0.90)

<0.001

166.0[120.0,235.0]

163.0[119.0,232.0]

1.00 (1.00, 1.00)

0.88

1.5±0.59

1.7±0.69

1.3 (0.95, 1.9)

0.092

1.3[0.99,1.7]

1.3[0.98,1.7]

0.98 (0.88, 1.1)

0.76

Serum Creatinine (mg/dL)

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INR

Table 3. Clinical and GIB Characteristics based on Ventricular Assist Device

Female Age BMI

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Current smoker

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Factor

Pulsatile Flow (N=132)

Continuous Flow (N=236)

Total artificial heart (N=23)

p-value

30(22.7)

42(17.8)

2(8.7)

0.22

52.8±13.7

55.0±13.9

48.2±18.5

0.05

28.7±5.8

28.3±5.4

24.0±6.4

0.025

6(5.7)

7(3.1)

0(0.0)

0.31

1(0.76)

0(0.0)

0(0.0)

0.40F

Medications

Sucralfate NSAID

Warfarin

Clopidogrel Aspirin

Dipyramidole

2(1.5)

9(3.8)

1(4.3)

0.45

49(37.1)

168(71.2)

11(47.8)

<0.001

8(6.1)

11(4.7)

2(8.7)

0.65

61(46.6)

159(67.7)

15(65.2)

0.002

3(2.3)

6(2.5)

1(4.3)

0.84

75(56.8)

135(57.4)

12(52.2)

0.7

H. Pylori infection

1(0.78)

0(0.0)

0(0.0)

0.39F

GIB

14(10.6)

42(17.8)

6(26.1)

0.074

Statin

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Overt Bleeding Melena

5(41.7)

15(48.4)

1(16.7)

0.35

Hematochezia

5(41.7)

18(58.1)

4(66.7)

0.52

Hemetemesis

3(25.0)

1(3.2)

0(0.0)

0.076F

Coffee ground/NG aspirate

0(0.0)

2(6.5)

1(16.7)

0.45F

Ulcer

3(50.0)

5(21.7)

AVM

1(16.7)

8(34.8)

Polyps

1(16.7)

2(8.7)

Erosions

1(16.7)

1(4.3)

Diverticulosis

0(0.0)

3(13.0)

Hemorrhoids

0(0.0)

4(17.4)

Esophagus

0(0.0)

2(8.0)

Stomach

4(66.7)

6(24.0)

Small Intestine

1(16.7)

Colon

2(33.3)

Any Intervention

2(14.3)

Heater Probe APC

RI PT

Source of Bleeding

0.43F

0(0.0)

0.37F

3(60.0)

0.023F

2(40.0)

0.052F

0(0.0)

0.99F

0(0.0)

0.77F

0(0.0)

0.99F

3(50.0)

0.097F

6(24.0)

0(0.0)

0.59F

14(56.0)

3(50.0)

0.71F

14(33.3)

3(50.0)

0.26F

0(0.0)

3(7.1)

0(0.0)

0.68F

0(0.0)

5(11.9)

0(0.0)

0.45F

Injection

1(7.1)

6(14.3)

2(33.3)

0.31

Clips

0(0.0)

5(11.9)

1(16.7)

0.30F

3(21.4)

6(14.3)

0(0.0)

0.46

6(42.9)

11(26.2)

0(0.0)

0.16F

6(42.9)

13(31.0)

0(0.0)

0.18F

6(54.5)

11(30.6)

0(0.0)

0.061F

M AN U

Location of Lesion

SC

1(20.0)

Short Term Management PRBC FFP Transfusion Requirements

AC C

EP

Hemodynamic instability

TE D

Intervention

TE D

M AN U

SC

RI PT

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References:

3.

4. 5. 6. 7.

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Slaughter, M.S., et al., Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med, 2009. 361(23): p. 2241-51. Frazier, O.H., et al., Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg, 2001. 122(6): p. 1186-95. Rogers, J.G., et al., Chronic mechanical circulatory support for inotropedependent heart failure patients who are not transplant candidates: results of the INTrEPID Trial. J Am Coll Cardiol, 2007. 50(8): p. 741-7. Rose, E.A., et al., Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med, 2001. 345(20): p. 1435-43. Miller, L.W., et al., Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med, 2007. 357(9): p. 885-96. Suarez, J., et al., Mechanisms of bleeding and approach to patients with axialflow left ventricular assist devices. Circ Heart Fail, 2011. 4(6): p. 779-84. Pennington, D.G., et al., Eight years' experience with bridging to cardiac transplantation. J Thorac Cardiovasc Surg, 1994. 107(2): p. 472-80; discussion 480-1.

AC C

1.

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13.

14.

15.

16. 17. 18.

19.

RI PT

SC

12.

M AN U

11.

TE D

10.

EP

9.

Rosamond, W., et al., Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2008. 117(4): p. e25-146. Allen, L.A., et al., High mortality without ESCAPE: the registry of heart failure patients receiving pulmonary artery catheters without randomization. J Card Fail, 2008. 14(8): p. 661-9. Schaffer, J.M., et al., Bleeding complications and blood product utilization with left ventricular assist device implantation. Ann Thorac Surg, 2011. 91(3): p. 740-7; discussion 747-9. Stern, D.R., et al., Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg, 2010. 25(3): p. 352-6. Morgan, J.A., et al., Gastrointestinal bleeding with the HeartMate II left ventricular assist device. J Heart Lung Transplant, 2012. 31(7): p. 715-8. Islam, S., et al., Left ventricular assist devices and gastrointestinal bleeding: a narrative review of case reports and case series. Clin Cardiol, 2013. 36(4): p. 190-200. Letsou, G.V., et al., Gastrointestinal bleeding from arteriovenous malformations in patients supported by the Jarvik 2000 axial-flow left ventricular assist device. J Heart Lung Transplant, 2005. 24(1): p. 105-9. Daas, A.Y., et al., Safety of conventional and wireless capsule endoscopy in patients supported with nonpulsatile axial flow Heart-Mate II left ventricular assist device. Gastrointest Endosc, 2008. 68(2): p. 379-82. Loscalzo, J., From clinical observation to mechanism--Heyde's syndrome. N Engl J Med, 2012. 367(20): p. 1954-6. Gastrointestinal Bleeding in Aortic Stenosis. New England Journal of Medicine, 1958. 259(4): p. 196-196. Demirozu, Z.T., et al., Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant, 2011. 30(8): p. 849-53. Klovaite, J., et al., Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II). J Am Coll Cardiol, 2009. 53(23): p. 2162-7.

AC C

8.

AC C

EP

TE D

M AN U

SC

RI PT

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EP

TE D

M AN U

SC

RI PT

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Supplemental Tables Supplemental Table 1. GIB in LVAD: Multivariable Cox Regression analysis Hazard Ratio (95% CI)

Factor

p-value

0.39 (0.16, 0.96)

0.04

Pulsatile flow vs. Total artificial heart

0.31 (0.12, 0.80)

0.016

Hemoglobin g/dL (1 unit increase)

0.80 (0.68, 0.93)

0.005

Age (5 year increase)

1.1 (1.03, 1.3)

0.012

PPI use

1.5 (0.86, 2.5)

0.16

Destination vs. Bridge therapy

1.5 (0.87, 2.7)

0.14

AC C

EP

TE D

M AN U

SC

RI PT

Continuous flow vs. Total artificial heart

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Supplemental Table 2. LVAD and GIB: Multivariable Stratified Cox Regression analysis between two time periods 2000-2007 HR (95% CI) p-value 0.04 (0.01, 0.32)

0.002

0.06 (0.02, 0.20)

<0.001

8.4 (1.2, 59.1)

0.032

0.59 (0.10, 3.5)

0.56

0.16 (0.05, 0.51)

0.002

0.74 (0.53, 1.02)

0.067

0.82 (0.69, 0.98)

0.031

0.012

1.1 (0.99, 1.3)

0.067

----

2.7 (1.2, 6.0)

0.016

Continuous Flow vs. Total artificial heart Pulsatile Flow vs. Total artificial heart

Hgb (1 unit increase)

1.4 (1.07, 1.7)

Age (5 yr increase)

----

PPI use

M AN U

HR: hazard ratio; CI: confidence interval

SC

Continuous Flow vs. Pulsatile Flow

AC C

EP

TE D

Dashes (-) mean factor was not included in the model.

1.4 (0.26, 7.1)

RI PT

Factor

2008-2012 HR (95% CI) p-value 0.72