Dig Dis Sci DOI 10.1007/s10620-015-3538-7

CASE REPORT

Characteristics of Gastrointestinal Bleeding After Placement of Continuous-Flow Left Ventricular Assist Device: A Case Series Joseph Marsano • Jay Desai • Shannon Chang • Michelle Chau • Mark Pochapin • Grigoriy E. Gurvits

Received: 25 October 2014 / Accepted: 12 January 2015 Ó Springer Science+Business Media New York 2015

Abstract Background Medical management of patients with continuous-flow left ventricular assist devices (LVADs) remains challenging for the gastroenterologist given their high risk of gastrointestinal bleeding (GIB) and need for continuous anticoagulation. Aims Our aim was to better characterize LVAD patients who presented with a GIB at our facility and delineate the prevalence, presentation, time to diagnosis, management, and therapeutic endoscopic interventions, including small bowel tools that may offer additional benefit. Methods We retrospectively reviewed adult patients ([18 years) who underwent LVAD implantation at our tertiary care facility between October 2011 and October 2013. Electronic medical records were reviewed for presenting symptoms, average days to initial and repeat GIB, hospital course, and techniques that led to diagnosis and hemostasis. Results Eighteen patients underwent LVAD implantation, of which 61 % presented with a GIB for a total of 20 presentations (1.8 per patient). Mean time to initial GIB was 154 days. Patients required an average of 1.8 endoscopic procedures per admission. Esophagogastroduodenoscopy

J. Marsano Department of Medicine, New York University School of Medicine, New York, NY, USA J. Desai
S. Chang
M. Pochapin
G. E. Gurvits (&) Division of Gastroenterology, Langone Medical Center, New York University School of Medicine, 240 East 38th Street, 23rd Floor, New York, NY 10016, USA e-mail: [email protected] M. Chau Population Council, New York, NY, USA

(EGD) and push enteroscopy (PE) were more likely to lead to a diagnosis, and EGD was the most commonly used diagnostic tool at initial presentation. Sixty percent of patients who initially received EGD presented with a recurrent GIB and required PE, which was diagnostic and therapeutic for small bowel angiodysplasias in 80 % of cases. Conclusion We found a higher GIB rate compared with prior studies. Bleeding events were associated with multiple procedures and interventions. We recommend an algorithmic approach to LVAD patients who bleed. Our experience suggests that PE is warranted at initial presentation in order to achieve hemostasis, prevent recurrent GIB, and decrease subsequent readmission rates. Keywords Gastrointestinal bleeding
LVAD
Small bowel
Push enteroscopy

Introduction Left ventricular assist devices (LVADs) are increasingly being utilized in patients with heart failure refractory to medical management who require long-term mechanical circulatory support. Originally used as a bridge to heart transplantation, LVADs are gaining acceptance as a destination therapy in patients who cannot receive transplantation. In the USA, the incidence of LVAD implantations is rising. In fact, from 2006 to 2010, the number of procedures increased from 206 to 1,451, while the number of heart transplants remained unchanged [1]. Increased integration of LVADs in today’s medical practice has led to a surge in observed complications related to device use and highlights present challenges in postoperative medical management. Repeat hospitalizations, augmented costs to the health care system, and

123

Dig Dis Sci

increased morbidity remain important factors in health care delivery. Complications of LVAD placement include postoperative bleeding, infection, device malfunction, arrhythmias, right ventricular failure, non-surgical bleeding, thromboembolic disease, and, perhaps most commonly, gastrointestinal bleeding (GIB) [2]. Postimplantation, LVAD patients routinely require anticoagulation therapy with warfarin (INR goal 1.5–2.5) and antiplatelet therapy with aspirin for the duration of support [2]. Management of GIB in LVAD patients can be challenging and requires a multidisciplinary team approach of gastroenterologists, cardiologists, and anesthesiologists trained in managing LVAD patients. Community hospitals with little or no exposure to LVAD patients may be presented with the difficult task of emergency management in the acute setting. Increased awareness and institutional experience are important components of recognizing disease processes and delivering appropriate care to affected patients. To date, gastrointestinal complications following LVAD implantation have received limited attention in the gastroenterological literature, but with a growing number of LVAD implantations, more information is needed regarding resulting GIB. The aim of this case series was to evaluate the prevalence, individual predisposition, etiology, location, management, and outcome in LVAD patients who presented with gastrointestinal hemorrhage at our tertiary care institution. We also aim to propose an interventional algorithm for such patients who present to the hospital with gastrointestinal hemorrhage.

Methods Consecutive adult patients who underwent HeartMate II (HMII) LVAD placement (Thoratec, Pleasanton, CA) at our institution between October 2011 and July 2013 were selected for this study. Their electronic medical records were retrospectively reviewed from October 2011 to October 2013 for presentation of anemia and gastrointestinal hemorrhage. All patients had LVAD placed for either bridge-to-transplant or destination therapy. Patients were maintained on dual, single, or no anticoagulation therapy with warfarin [maintaining an international normalized ratio (INR) of 1.5–2.5] and anti-platelet therapy with aspirin (81 mg/day). The retrospective review of these clinical data was approved through the Institutional Review Board at New York University School of Medicine on October 17, 2013 (Study No. S14-00113). Gastrointestinal Bleeding Gastrointestinal bleeding was classified as: patient or health care provider reports of melena, hematochezia,

123

hematemesis, stigmata of gastrointestinal hemorrhage detected during endoscopic procedure, or unexplained anemia defined as a hemoglobin drop [2 mg/dl from prior levels. History of GIB before LVAD placement was included if documented in medical record or prior endoscopy reports. Average time (days) to initial bleeding was defined as the number of days from LVAD placement to initial clinical presentation for presumed GIB at either clinical office or emergency room of a hospital. Average time (days) to repeat GIB was defined as the date of hospital discharge from first GIB to the date of subsequent presentation for suspected GIB. Hemodynamic instability was defined as the necessity of vasopressors in patients with suspected or established GIB. The use of anticoagulant and anti-platelet agents was recorded for each patient. Procedures Type of endoscopic procedure that led to diagnosis was defined as any procedure which had documented visual evidence of active intraluminal hemorrhage, stigmata of recent bleeding, clotted blood without source, or lesion known to cause GIB such as gastrointestinal ulcer, friable mucosa, tumor, angiodysplasia, or visible vessel. Location of bleeding source was categorized at the time of endoscopic procedure. All endoscopic procedures were performed in the intensive care unit (ICU) or operating room under conscious sedation, monitored anesthesia care (MAC), or general anesthesia. All procedures were carried out with anesthesiologists trained in cardiac anesthesia and in the presence of the LVAD cardiac team. Endoscopic interventions included hemostatic resolution clip placement, cautery (gold-probe or bipolar cautery), submucosal injection (epinephrine 1:10,000), or argon plasma coagulation (APC). Number, type, and combined use of various applications were recorded. Interventions defined as having achieved hemostasis were those that required no further endoscopic investigation for persistent GIB for each hospital admission. Data Collection and Analysis Age, gender, concomitant use aspirin, warfarin, or both, admission to ICU, hemoglobin and INR at initial presentation, number of packed red blood cell transfusions, necessity of vasopressors, the use of octreotide, number and type of endoscopic procedures, location of the lesion responsible for hemorrhage, time from LVAD placement to first GIB, history of GIB prior to LVAD placement, number of admissions to the hospital, and mortality rate were obtained from the electronic medical record. Normally distributed data were reported as means and percentages. The Chi-square test was used for intergroup

Dig Dis Sci

comparison with respect to gender and history of GIB, and two-tailed Student’s t test was used to compare differences in age in bleeders and non-bleeders. A p value \0.05 was considered statistically significant. All analyses were performed using Stata (version 12.1; StataCorp, College Station, TX).

Results

Table 2 Time course of initial GI bleed post-LVAD and recurrent GI bleeds Mean time to first bleed (days) (range)

154 (9, 395)

Mean time to second bleed (days) (range)

95 (27, 214)

Mean time to third bleed (days) (range)

68.5 (17, 120)

Mean bleeding admissions per patient (range)

1.8 (1, 3)

Total number of hospitalizations for GI bleeding

20

Mean length of hospitalization (days) (range)

8.6 (1, 43)

Includes mean (range)

Between October 2011 and October 2013, 18 patients (60.2 years old) underwent LVAD implantation at our institution. All patients were implanted with HMII devices. Of these patients, 11 (61 %) developed 20 episodes of GIB, with males and females comprising 64 and 36 %, respectively. Patients who bled tended to be older (60.2 vs. 57 years; p = 0.477) and had a history of GIB prior to LVAD placement (4 vs. 0; p = 0.07) (Table 1). No patients died during the study period. The average time to first GIB occurred 154 days (range 9–395 days) after LVAD implantation. Of the 11 patients presenting with initial GIB, seven patients (63.6 %) presented for a second GIB with an average time of 95 days (range 27–214 days) from the date of hospital discharge from first GIB. Moreover, two patients (18.1 %) presented for a third GIB that occurred on average of 68.5 days (range 17–120) from previous hospital discharge date. Overall, there was an average of 1.8 admissions per patient who presented for GIB (Table 2). Fifty percent of patients presented with melena, while unexplained anemia, hematochezia, and hematemesis accounted for 25, 15, and 10 % of symptoms, respectively (Table 3). Besides GIB, other sources of bleeding in the post-implantation period included mediastinal hemorrhage (5 %), cardiac tamponade (20 %), hemorrhagic stroke (10 %), and hematuria (5 %). The mean INR upon presentation was supratherapeutic at 3.35, and the average hemoglobin was 7.53 mg/dl Table 1 Demographics of patients with LVAD placement

(Table 4). The majority of patients were on aspirin 81 mg and warfarin, but 17 % of patients were on warfarin alone (Table 1). It should be noted that one patient was not on aspirin or warfarin for a 3-week period after thromboembolic stroke with subsequent hemorrhagic conversion. This patient did not develop any episode of GIB at any point in our study period. The mean number of packed red blood cell transfusions each patient received per bleeding event was 4.1 (range of 1–12 units) (Table 4). None of the patients were hemodynamically unstable to the point of requiring vasopressors, but 80 % required admission to the ICU. No patients received subcutaneous or intravenous octreotide therapy. Of the 20 admissions for GIB, there were a total of 36 procedures performed, resulting in an average of 1.8 procedures per admission. Eighty-five percent of patients received esophagogastroduodenoscopy (EGD), while 40, 35, 10, 5, and 5 % of admissions required colonoscopy, push enteroscopy, double-balloon enteroscopy, flexible sigmoidoscopy, and video capsule endoscopy, respectively (Table 5). In three GIB episodes, there was more than one location and one type of bleed diagnosed with endoscopy. This resulted in a total of 23 locations and bleeding types for the 20 GIB admissions. Anatomical locations of bleeding included the stomach (40 %), followed by duodenum (25 %), jejunum (15 %), esophagus (10 %), ileum

All (%)

GI bleeds (%)

Non-GI bleeds (%)

p value

Number

18

11 (61)

7 (39)

–

Mean age (range)

60.2 (25, 76)

62.2 (25, 76)

57.1 (37, 72)

0.477

Ischemic cardiomyopathy

9 (50)

6 (55)

3 (43)

–

Non-ischemic cardiomyopathy

9 (50)

5 (45)

4 (57)

Gender Male Female

– 0.783

11 (61) 7 (39)

7 (64) 4 (36)

4 (57) 3 (43)

4 (22)

4 (36)

0 (0)

0.07

Aspirin/warfarin

14 (78)

8 (73)

6 (86)

–

Warfarin

3 (17)

3 (27)

0 (0)

–

None

1 (5)

0 (0)

1 (14)

–

History of GI bleeding Anticoagulation

Includes total number (%) and mean (range)

123

Dig Dis Sci Table 3 Frequency of symptoms, location, and type of GI bleed Patients (%) Presenting symptom Melena

10 (50)

Hematochezia

3 (15)

Hematemesis

2 (10)

Anemia/Hg drop

5 (25) Total (%)

Location of bleed Esophagus

Table 4 Presenting INR, hemoglobin, and transfusion requirement Mean INR on admission (range)

3.35 (1.2, 8)

Mean Hemoglobin on admission (range)

7.53 (6.6, 10)

Mean number PRBC transfusion units (range) Requiring vasopressors (%) Requiring octreotide (%) Requiring ICU admission (%)

8 (40)

Duodenum

5 (25)

Jejunum

3 (15)

Ileum

1 (5)

0 (0) 16 (80)

Total number (%) and mean (range) INR international normalized ratio, ICU intensive care unit

Table 5 Procedures and interventions Mean procedures per admission (range)

Total (%)

1 (5)

Rectum

1 (5)

Esophagogastroduodenoscopy

2 (10)

Colonoscopy

Total (%) Type of bleed 11 (55)

1.8 (1, 4)

Types of procedures

Colon

Angiodysplasia

0 (0)

2 (10)

Stomach

Unknown

4.1 (1, 12)

17 (85) 8 (40)

Push enteroscopy

7 (35)

DBE

2 (10)

Flexible sigmoidoscopy

1 (5)

Video capsule endoscopy

1 (5)

Dieulafoy

4 (20)

Procedures leading to diagnosis

Friable mucosa

3 (15)

Esophagogastroduodenoscopy

Ulcer

2 (10)

Push enteroscopy

6 (30)

Unknown

2 (10)

DBE

2 (10)

Clot (not removed)

1 (5)

Colonoscopy

2 (10)

0 (0)

None Flexible sigmoidoscopy

1 (5) 0 (0)

Video capsule endoscopy

0 (0)

Hemorrhoidal

Total number of location and type of bleed was divided by the total GIB admissions (20) resulting in percentages that do not add to 100 %. This is reflected because three patients presented with more than one type of bleed and location at each admission

Mean interventions per admission (range)

9 (45)

1.3 (0, 3) Total (%)

(5 %), colon (5 %), and rectum (5 %). In 10 % of cases, the location of bleeding could not be localized. The most common source of bleeding was angiodysplasias (55 %). These lesions occurred in the stomach (27 %), duodenum (37 %), jejunum (27 %), and rectum (9 %). Other sources included dieulafoy lesions (20 %), friable mucosa (15 %), and peptic ulcer (10 %). The procedure with the highest rate of diagnosis was EGD (45 %) followed by push enteroscopy (30 %). Of the initial 11 cases of GIB, ten (91 %) underwent EGD, while two (18 %) received push enteroscopy (one patient received both EGD and push enteroscopy at initial presentation, while another patient just received push enteroscopy without EGD). A majority (5/7) underwent push enteroscopy at the second visit, and this led to diagnosis in 80 % (4/5) cases. In the only case where push enteroscopy was not diagnostic, bleeding was indentified, but the scope could not reach and required double balloon for definitive

123

Type of intervention APC

10 (50)

Clip

8 (40)

Injection with epinephrine

5 (25)

None

5 (25)

Cautery

3 (15)

Percentage determined from total number divided by 20 GIB admissions. Percentages for procedures and interventions do not add to one hundred as multiple procedures performed per each admission DBE double-balloon enteroscopy, APC argon plasma coagulation

diagnosis and treatment. All sources of bleeding were small bowel angiodysplasias. Eighty percent of patients who had push enteroscopy performed at their second visit were not admitted for an additional GIB during the study period.

Dig Dis Sci

When intervening, hemostatic clips, electrocautery, APC, and epinephrine injections were used with varying frequency, depending on operator preference. There were a total of 31 interventions for each of the 20 GIB presentations, an average of 1.3 interventions per presentation. The most frequent was APC (50 %), while hemostatic clips, epinephrine injections, and electrocautery were utilized 40, 25, and 15 % of the time at each presentation, respectively. There was no intervention done in 5 (25 %) of the bleeding episodes because there was no identifiable source of bleeding or there were low-risk stigmata of recent bleeding that did not require intervention.

Discussion The use of LVADs is an established treatment for advanced heart failure. First developed in the early 1980s for longterm hemodynamic support, early-generation devices were large and externalized [3]. They relied upon pneumatic pressure to pump blood in a pulsatile fashion similar to a filling ventricle and ejection. Over time, technologic advances have allowed LVADs to become more compact, transition to electrical power and internalization—which all play an important role in improving quality of life. Early pulsatile LVADs raised significant concern for the increased incidence of thromboembolic disease and hemolysis that spurned the evolution to continuous axialflow rotary-based model (CF-LVAD). Several continuousflow models have been developed, including the Heartmate II (HMII) Left Ventricular Assist System (Thoratec) [4], the MicroMedDeBakey Ventricular Assist Device (MicroMed) [5], the Jarvik 2000 Heart (Jarvik Heart) [6], and the VentrAssist Left Ventricular Assist System (Ventracor) [7]. In the HMII, blood is directed via an outflow catheter that is implanted in the apex of the left ventricle into a continuously running turbine and directed through an inflow catheter implanted into the aorta. Adjustments can be made to the rotary speed to modify hemodynamics and to control the amount of blood passing through the aortic valve. These devices have shown excellent efficacy in providing hemodynamic support as a bridge to transplant as well as increasing use as destination therapy for selected patients with advanced heart failure [8]. As with any implanted device that has constant contact with the blood stream, there is a risk of activation of the coagulation and fibrinolysis pathways. In early pulsatile flow devices, pump thrombosis was a major clinical issue with early trials showing a rate of cerebral vascular accidents as high as 16 % [9]. Through the incorporation of biomaterials such as titanium, polytetrafluoroethylene, and acrylics, newer continuous-flow devices were designed to minimize this risk of pump thrombosis. However, it is clear

that these materials are not biologically inert. Recent studies have shown that the risk of pump thrombosis remains a concern and the use of concomitant anti-platelet agents and vitamin K antagonists can reduce this risk [10]. Though the risk of thrombosis is reduced, there is a subsequent increased in the risk of bleeding, which often involves the GI tract. In early studies that looked at continuous-flow HMII, the risk of bleeding was reported as negligible to as high as 15.6 % [11]. In a review of patients receiving high-dose aspirin and warfarin for the prevention of stroke in atrial fibrillation, the 2-year cumulative rate of any bleeding event was 24.4 % [12]. Based on this information, an argument could be made that the high prevalence of GIB observed in early HMII studies may have been attributed to the anticoagulation therapy rather than the device itself. However, two recent retrospective reviews in the surgery and cardiology literature have reported a bleeding rate of approximately 40 % in HMII patients [13, 14]. A separate review by Crow et al. [15] reported that bleeding rates from continuous-flow LVADs were ten times higher per 100 person years than previous-generation pulsatile flow devices. These recent data suggest that the continuous-flow devices likely play a larger role than concurrent anticoagulation therapy in the increased bleeding rate. We performed a single-center retrospective case series of all patients post-implantation of the HMII to assess the rate of GIB and to better characterize the locations, types, and interventions done on these lesions. In our study, 61 % patients (11/18) developed a GIB, which is higher than reported in any other previous series. There was also a trend toward increased risk of GIB in older patients and those who had a GIB at any point prior to LVAD implantation. Patients tended to have multiple presentations for GIB (mean 1.8 bleeding episodes per patient) and bleeding events were associated with longer hospital stays (mean 8.6 days), multiple endoscopic procedures (1.8 per visit), considerable blood products (mean 4.1 units packed red blood cells), and 80 % required admission to the medical ICU. The high rate of ICU admissions and considerable amount of blood products highlights the high-risk nature of these patients and the intensive hemodynamic monitoring required to effectively care for LVAD patients. Unless contraindicated, an overwhelming majority of patients were receiving concomitant aspirin 81 mg daily and warfarin with an INR target of 1.5–2.5 during our study period. We found that the average INR of LVAD patients admitted for GIB was supratherapeutic at 3.32, which likely reflected consumptive coagulopathy during bleeding episodes and could have further contributed to increased bleeding rates. Of those who presented with a GIB, a large number of patients were receiving aspirin and warfarin, while a small minority was only receiving

123

Dig Dis Sci

warfarin. Given the small number of patients only receiving warfarin, it was difficult to analyze whether dual therapy increases the risk of GIB. In this case series, there was a wide variety of culprit bleeding lesions identified, but the most common were angiodysplasias (55 %). Previous studies have suggested a similar mechanism of angiodysplasia development in LVAD patients to what Heyde described in 1958 in patients with severe aortic stenosis [13, 16–19]. In continuous-flow LVADs, blood is directed out of the left ventricle directly into the aorta bypassing the aortic valve [8]. This results in less frequent opening of the valve causing a reduced aortic pulse pressure similar to aortic stenosis. By reducing the aortic pulse pressure, arteriole smooth muscle tone is reduced resulting in dilated mucosal veins and angiodysplasia formation [20]. We found that an overwhelming majority (91 %) of angiodysplasias occurred in the upper gastrointestinal tract with over a quarter occurring in the jejunum. Given the high propensity of angiodysplasia development in LVAD patients and their high prevalence in the small bowel, there are important management implications as it suggests that a large number of lesions may be missed with standard EGD. In previous series, the culprit lesion went undiagnosed as high as 65 % of the time [13], while in our series only 10 % of bleeding sources were unidentified. We attribute this to the aggressive use of small bowel diagnostic tools, specifically push enteroscopy, followed by double-balloon enteroscopy and video capsule endoscopy. Of all the presentations for GIB, 50 % (10/20) of encounters required small bowel studies (Table 5). Of these, push enteroscopy was the most used (7/10) and led to diagnosis 85 % (6/7) of the time. Double balloon was used twice and led to diagnosis in both instances while video capsule failed to lead to diagnosis. Moreover, we found that a large number of patients who underwent EGD without push enteroscopy returned for additional GIB. This suggests that despite initial positive findings on EGD, further small bowel investigation may be warranted given the high rate of small bowel angiodysplasias. This may help to detect additional sources of bleeding, potentially reduce GIB readmission rates, and, by a direct result, decrease cost. We recommend these tools be available to any center that frequently treats GIB associated with LVADs. Not only do LVAD patients have a higher propensity to develop angiodysplasias, there is higher risk of bleeding with the inherent coagulopathy that exists in these patients. Slaughter et al. [21] found that older patients with endstage heart failure had an activated fibrinolytic system prior to receiving an LVAD, peaked 30 days after implantation and eventually normalized a year after implantation. A majority of our patients sustained a GIB within the first year of implantation with an average time to presentation

123

of 5 months and may reflect the altered fibrinolytic pathway seen in LVAD patients within the first year of implantation. Adding to this, platelet aggregation is also impaired in HMII patients and normalizes after heart transplant and removal of the LVAD [22]. This suggests that through early activation of the fibrinolytic pathway, LVAD patients are prone to bleeding prior to and initially after implantation. As the fibrinolytic system normalizes, the risk of bleeding may be sustained from impaired platelet aggregation from the device and compounded by anti-platelet and anticoagulation therapy. Another cause of coagulopathy may be due to the decreased functionality of von Willebrand factor (vWF), which is a large multimer complexed with factor VIII. As these multimers move through the LVAD turbine, they become sheared and non-functional, similar to what has been observed as blood passes through a severely stenotic aortic valve. This leads to an acquired von Willebrand deficiency (AVWD) (type 2a) resulting in decreased platelet functionality and a subsequent coagulopathy. In a review by Uriel et al. [14], 31 post-HMIII patients were evaluated for the presence of vWF multimers and all had reduced levels, with 58 % developing GIB. Meyer et al. [23] measured vWF multimers and platelet aggregation and found reduced levels in all LVAD patients which corrected after removal of the LVAD, and persisted in patients whose LVADs were not removed. Adding to the causal relationship between AVWD and GIB have been numerous case reports of recurrent bleeding from angiodysplasias which also stopped after aortic valve replacement or removal of the LVAD [13, 24, 25]. Overall, hematologic evaluation for vWF and platelet function and aggregation should be considered and requirements for anticoagulation agents should be evaluated over time and continually readdressed. Management of active bleeding in patients with LVADs remains a challenge. We demonstrate that every part of the gastrointestinal tract may be affected. A majority of our GIBs were located in the stomach, duodenum, and jejunum, but other sites such as the esophagus, distal ileum, colon, and rectum were also present (Table 3). If a bleeding lesion is identified and deemed amenable to endoscopic intervention, the decision on what therapy to use is made by the gastroenterologist as per standard practices. The most common endoscopic intervention used in this series was APC (50 % of interventions) for the treatment of angiodysplasias. The use of APC has been shown in prior studies to reduce the incidence of recurrent bleeding in non-LVAD patients with gastric, small bowel, and colonic angiodysplasias as well as improve overall hemoglobin and reduce the amount of blood transfusions [26, 27]. Of the instances where APC was used to treat angiodysplasias, it led to effective hemostasis in all cases. Similar results were

Dig Dis Sci

also observed when APC was combined with hemostatic clips. However, half of these patients did have recurrent GIB that occurred approximately 100 days after their previous admissions. This failure rate could be explained by the high propensity for angiodysplasia development in LVAD patients and that many of the additional angiodysplasias were small and subtle which may have made it difficult to assess additional lesions with initial endoscopy. Moreover, detection of angiodysplasias is dependent upon splanchnic blood flow which may be vulnerable to changes in patients’ blood pressure, volume status, and level of sedation during endoscopy [28]. In those patients who have had bleeding after LVAD placement, there need to be strategies for secondary prevention. This will depend on the nature of the offending lesion. In the setting of peptic ulcer disease, Helicobacter pylori should be tested for and eradicated. If the ulcer is thought to be due to the use of aspirin, anticoagulation should be closely monitored and concomitant use of a proton pump inhibitors can be administered to decrease the risk of recurrent bleeding [29]. Finally, the use of concurrent nonsteroidal anti-inflammatory medications should be avoided. If bleeding is from angiodysplasias, further episodes of bleeding may occur given the high incidence of these lesions in patients with LVADs. The main mechanisms of LVAD bleeding as has already been described include the continuous-flow devices resulting in angiodysplasia development in the small bowel, dual use of aspirin and warfarin, non-functional von Willebrand multimers, impaired platelet aggregation, and an over-activated fibrinolytic system. The multifactorial nature of gastrointestinal hemorrhage makes it particularly challenging to develop adequate secondary prophylaxis against bleeding angiodysplasias. One area of interest is octreotide, a somatostatin analog, which acts as a splanchnic vasoconstrictor. Much of the experience derived from octreotide exists in the management of variceal hemorrhage. Not only does it decrease splanchnic blood flow, octreotide can decrease platelet aggregation and angiogenesis, making it a potential pharmacologic intervention to reduce small bowel angiodysplasias [30]. Several case reports have shown that octreotide (0.2–0.75 mg SC divided two to three times daily) may be effective in achieving hemostasis in refractory bleeding from angiodysplasias in patients with congenital or acquired von Willebrand disease from continuous LVADs [30–33]. In our series, no patients were treated with octreotide in the acute setting of a GIB or for secondary prophylaxis. Likely limiting its use are the high cost of the medication and limited outpatient use. Overall, the use of octreotide in cases of angiodysplasias is promising and its benefit in LVAD patients deserves investigation from prospective, randomized studies.

As previously noted, patients with continuous-flow LVADs have lower levels of vWF multimers in the serum due to the shearing from the device’s turbine [14]. Replacement of these factors has been discussed as way to prevent further bleeding. The closest model we have for studying this disease are patients with severe aortic stenosis or those with congenital von Willebrand disease phenotype 2a. The major mechanism in both is defective platelet function due to lack of intact vWF multimers. Treatment with Factor VIII–vWF concentrate or desmopressin is recommended in von Willebrand disease phenotype 2a, but has shown poor results in patients with severe aortic stenosis [34]. To our knowledge, there have been no trials to assess whether LVAD patients with refractory GIB who are deficient in vWF respond well to replacement therapy. Regardless, in severe cases of GIB, a consultation with a hematologist for vWF replacement should be considered. The risk of future GI bleeding should be assessed and factored into the selection process for patients who receive LVADs. Unfortunately, many of the risk factors associated with GIB such as increased age, the presence of valvular disease, concomitant use of anti-platelet, and vitamin K antagonists are also frequently present in patients requiring LVADs. Recent data showing an increased rate of pump thrombosis than previously reported are likely to result in recommendations for even more aggressive anti-platelet and anticoagulant therapy [10]. Finally, the increasing use of these devices as destination therapy, as opposed to a bridge to transplant, will further increase the incidence of GIB. Previous GIB has been shown to be a strong risk factor for bleeding after LVAD implantation. In our study, four patients had documented previous GIB before implantation, and they all developed GIB during the postimplantation period. Tools that incorporate known risk factors to predict the risk of bleeding, such as the HASBLED score for atrial fibrillation, may be helpful in improving patient selection and adjusting anticoagulation strategies for these devices ultimately leading to decreased morbidity and aggregated cost [35]. There are limitations to this study. As a retrospective case series, we are dependent on the accuracy and completeness of the recorded events. Furthermore, the approach to management was not standardized across multiple physicians managing GI bleeding. Creating a prospective study with an algorithmic endoscopic approach with standardized data recording forms would limit these weaknesses. Finally, the size of this case series is small. Future studies could be prospective, include multicenter data, and have standardized protocols, as well as longer observation periods. In conclusion, our case series identified a higher rate of GIB with the continuous-flow HMII LVAD than previously reported in the literature. Bleeding events are

123

Dig Dis Sci

Fig. 1 Diagnostic and interventional algorithm in managing LVAD patients who present with clinical signs of gastrointestinal bleed

associated with a significant length of stay and a need for multiple interventions. Overall, we recommend that a trained, specialized, and multi-disciplinary team involving gastroenterology, cardiology, anesthesia, critical care, and hematology services is necessary for optimal treatment of LVAD patients who present with GIB. We outline (Fig. 1) a possible diagnostic and interventional algorithm based on our experience in managing LVAD patients who present with clinical signs of GIB. As the number of patients with LVADs is on the rise, further research is needed to analyze the causes for higher rates of bleeding, management of active bleeding, and strategies for prevention of recurrent bleeding. Acknowledgments We thank Dr. Alex Reyentovich and Dr. Leora Balsam for their expertise in providing cardiac care to our LVAD patients at NYU. Conflict of interest

123

None.

References 1. Birks EJ. A changing trend toward destination therapy: are we treating the same patients differently? Tex Heart Inst J. 2011;38:552–554. 2. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant. 2010;29:S1–S39. 3. Szycher M, Clay W, Gernes D, et al. Thermedics’ approach to ventricular support systems. J Biomater Appl. 1986;1:39–105. 4. Griffith BP, Kormos RL, Borovetz HS et al. HeartMate II left ventricular assist system: from concept to first clinical use. Ann Thorac Surg. 2001;71:S116–S120; discussion S114–S116. 5. Goldstein DJ. Worldwide experience with the MicroMed DeBakey Ventricular Assist Device as a bridge to transplantation. Circulation. 2003;108:II272–II277. 6. Frazier OH, Myers TJ, Westaby S, et al. Clinical experience with an implantable, intracardiac, continuous flow circulatory support device: physiologic implications and their relationship to patient selection. Ann Thorac Surg. 2004;77:133–142. 7. Esmore DS, Kaye D, Salamonsen R, et al. First clinical implant of the VentrAssist left ventricular assist system as destination

Dig Dis Sci

8.

9.

10.

11.

12.

13.

14.

15.

16.

17. 18.

19.

20.

21.

therapy for end-stage heart failure. J Heart Lung Transplant. 2005;24:1150–1154. Miller LW, Pagani FD, Russell SD, et al. Use of a continuousflow device in patients awaiting heart transplantation. N Engl J Med. 2007;357:885–896. John R, Lee S. The biological basis of thrombosis and bleeding in patients with ventricular assist devices. J Cardiovasc Transl Res. 2009;2:63–70. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med. 2014;370:33–40. John R, Kamdar F, Liao K et al. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg. 2008;86:1227–1234; discussion 1234–1225. Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. Arch Intern Med. 1999;159:1322–1328. Stern DR, Kazam J, Edwards P, et al. Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg. 2010;25:352–356. Uriel N, Pak SW, Jorde SP, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol. 2010;56:1207–1213. Crow S, John R, Boyle A, et al. Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg. 2009;137:208–215. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant. 2011;30:849–853. Heyde E. Gastrointestinal bleeding in aortic stenosis. N Engl J Med. 1958;259:196–200. Massyn MW, Khan SA. Heyde syndrome: a common diagnosis in older patients with severe aortic stenosis. Age Ageing. 2009;38:267–270. Warkentin TE, Moore JC, Anand SS, et al. Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev. 2003;17:272–286. Suarez J, Patel CB, Felker GM, et al. Mechanisms of bleeding and approach to patients with axial-flow left ventricular assist devices. Circ Heart Fail. 2011;4:779–784. Slaughter MS, Sobieski MA, Gallagher C, et al. Fibrinolytic activation during long-term support with the HeartMate II left ventricular assist device. ASAIO J. 2008;54:115–119.

22. Klovaite J, Gustafsson F, Mortensen SA, 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;53:2162–2167. 23. Meyer AL, Malehsa D, Bara C, et al. Acquired von Willebrand syndrome in patients with an axial flow left ventricular assist device. Circ Heart Fail. 2010;3:675–681. 24. Morishima A, Marui A, Shimamoto T, et al. Successful aortic valve replacement for Heyde syndrome with confirmed hematologic recovery. Ann Thorac Surg. 2007;83:287–288. 25. Goda M, Jacobs S, Rega F, et al. Time course of acquired von Willebrand disease associated with two types of continuous-flow left ventricular assist devices: HeartMate II and CircuLite Synergy Pocket Micro-pump. J Heart Lung Transplant. 2013;32:539–545. 26. Olmos JA, Marcolongo M, Pogorelsky V, et al. Argon plasma coagulation for prevention of recurrent bleeding from GI angiodysplasias. Gastrointest Endosc. 2004;60:881–886. 27. Kwan V, Bourke MJ, Williams SJ, et al. Argon plasma coagulation in the management of symptomatic gastrointestinal vascular lesions: experience in 100 consecutive patients with longterm follow-up. Am J Gastroenterol. 2006;101:58–63. 28. Boley SJ, Brandt LJ. Vascular ectasias of the colon—1986. Dig Dis Sci. 1986;31:26S–42S. 29. Masso Gonzalez EL, Garcia Rodriguez LA. Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study. Aliment Pharmacol Ther. 2008;28:629–637. 30. Rennyson SL, Shah KB, Tang DG, et al. Octreotide for left ventricular assist device-related gastrointestinal hemorrhage: can we stop the bleeding? ASAIO J. 2013;59:450–451. 31. Bowers M, McNulty O, Mayne E. Octreotide in the treatment of gastrointestinal bleeding caused by angiodysplasia in two patients with von Willebrand’s disease. Br J Haematol. 2008;108:524–527. 32. Rossini FP, Arrigoni A, Pennazio M. Octreotide in the treatment of bleeding due to angiodysplasia of the small intestine. Am J Gastroenterol. 1993;88:1424–1427. 33. Boesby L, Christensen NJ, Kristensen LO. Somatostatin analogues in the treatment of bleeding GI-angiodysplasias. Ugeskr Laeger. 2008;170:958. 34. Mannucci PM. Treatment of von Willebrand disease. Thromb Haemost. 2001;86:149–153. 35. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093–1100.

123