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Gastrointestinal Bleeding during Continuous-Flow Left Ventricular Assist Device Support is Associated with Lower Rates of Cardiac Transplantation

Holley, Christopher T.*; Harvey, Laura*; Roy, Samit S.; Cogswell, Rebecca; Eckman, Peter; Liao, Kenneth; John, Ranjit*

doi: 10.1097/MAT.0000000000000279
Adult Circulatory Support
Conference Article

Gastrointestinal bleeding (GIB) remains a significant problem after continuous-flow left ventricular assist device (CF-LVAD) implantation. We hypothesized that the subsequent need for blood transfusions in patients with GIB may reduce rates of cardiac transplantation. We performed a retrospective review of 232 patients implanted with the HeartMate II (HM II) CF-LVAD from June 2005 through May 2013 at our center to determine risk factors for GIB and assess its effect on cardiac transplantation. Over a total LVAD follow-up time of 364 person-years, 62 GIB episodes occurred in 49 patients (27%), for an event rate of 0.45 gastrointestinal bleeds/patient-year of LVAD support. Women made up 15% of our cohort, yet contributed 29% of the GIB (p = 0.06). Survival at 6 month, 1 year, and 2 years was not statistically different in patients who developed GIB and those who did not (77% vs 78%, 74% vs 71%, and 61% vs 54%, respectively). In transplant-eligible patients, GIB was associated with a 27% lower rate of cardiac transplantation (rate ratio 0.73, p < 0.05). Although the mechanism behind this finding is unclear, GIB appears to be linked to higher transfusion rates, which may cause the development of subsequent allosensitization.

From the *Department of Surgery, University of Minnesota, Minneapolis, Minnesota; and Department of Cardiology, University of Minnesota, Minneapolis, Minnesota.

Submitted for consideration September 2014; accepted for publication in revised form August 2015.

Presented at 60th Annual ASAIO Conference, Washington, DC, June 2014.

Disclosure: Peter Eckman has received honoraria from Thoratec and HeartWare, and has had prior research grants from Thoratec and HeartWare. Ranjit John has research grants from Thoratec and HeartWare.

Correspondence: Ranjit John, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, 420 Delaware Street, SE Mayo Mail Code 207, Minneapolis, MN 55455. E-mail: johnx008@umn.edu.

Continuous-flow left ventricular assist devices (CF-LVADs) have become the standard of care for patients with end-stage heart failure who have failed maximal medical therapy and are unable to undergo, or are awaiting, a heart transplant. These devices have demonstrated superior durability compared with first-generation pulsatile LVADs, and have proven effective in providing prolonged circulatory support and improved survival for both bridge-to-transplant (BTT) and destination therapy (DT) patients.1–51–51–51–51–5 However, compared with first-generation LVADs, an increased frequency of gastrointestinal bleeding (GIB) has consistently been demonstrated6,7 in CF-LVAD recipients.

Gastrointestinal bleeding remains a significant clinical concern after CF-LVAD implantation, with retrospective studies showing that it develops in 18–40% of patients implanted with a CF-LVAD.8 Although anticoagulation and antiplatelet therapy are required to minimize the risk of thrombosis, it appears that the pathophysiology of GIB development in these patients is related to acquired von Willebrand syndrome,9,10 arteriovenous malformation from decreased pulsatility,11 and impaired platelet aggregation.12

Diagnosis of GIB often is clinical; patients present with melena or hematochezia and an associated hemoglobin drop. Endoscopic modalities can be performed for diagnosing GIB in a suspected HeartMate II (HM II) (Thoratec Corp., Pleasanton, CA) patient, but the bleeding source is not always identifiable and for uncomplicated GIB that is self-resolving is often not used.13 Nevertheless, GIB is a contributing factor to readmission after HM II implantation in up to 14% of cases.14 Although survival does not appear to be impacted by the development of GIB,15 given the limited and relatively fixed number of heart transplants performed every year combined with an increasing waiting list and the potential risk of sensitization these patients may experience secondary to repeated blood transfusions, we sought to evaluate the impact GIB has on cardiac transplantation rates.

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Methods

Cohort

Patients who underwent placement of the HM II at our institution from June 2005 through May 2013 were identified and data were collected retrospectively. Patients were managed as part of a multidisciplinary team, including the cardiothoracic surgery service and the heart failure cardiology service. Our database and study were approved by the University of Minnesota Institutional Review Board, which waived the need for individual patient consent.

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Patient Care and Device Management

As per our local practice at the University of Minnesota, the speed of the HM II was adjusted to provide adequate cardiac output and achieve optimal left ventricular decompression. When possible, the fixed rate speed of the HM II is adjusted to additionally allow for the aortic valve to open in at least one of every three beats.

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Anticoagulation Therapy

On postoperative day 1 or 2, stable HM II recipients are started on warfarin. In those without bleeding diathesis, the goal international normalized ration (INR) has evolved from a range of 1.5–2.5 to a range of 2.0–2.5. Once surgical bleeding is no longer a concern, we initiate a low-dose heparin infusion in addition to antiplatelet therapy with a low-dose enteric-coated aspirin (81 mg daily).16

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Data Collection

Demographic and clinical characteristics of the cohort at baseline as well as outcomes data were collected. To determine risk factors for GIB, we assessed baseline demographic characteristics (such as age, gender, body mass index [BMI], and smoking status), etiology of heart failure, laboratory values, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, and concomitant surgeries and medication use. We analyzed clinical variables for predictors of GIB—including duration of device support at the time of GIB, laboratory values (such as hematocrit, platelets, and INR) at the time of GIB, and the amount of blood transfusions that patients received at the time of their presentation for GIB. Hospital readmission data and adverse events for all recipients, both GIB patients and those without GIB, were recorded and overall survival and cardiac transplantation rates were calculated for both groups.

We defined GIB according to the INTERMACS definition of major bleeding in a patient whose source of bleeding is clinically suspected to be GIB. Specifically, melena or hematochezia associated with a hemoglobin drop without another identifiable source and requiring transfusion or hospital admission. Endoscopy was not performed in all patients if bleeding subsided and ongoing transfusions were not necessary.

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Statistical Analysis

All analyses were performed using Stata statistical software, release 13 (StataCorp, College Station, TX). For all statistical testing, we used a two-sided significance level of 0.05. For between-group comparisons, we used a two-sample t-test for continuous variables and a χ2 test for categorical variables. For survival analysis and transplantation rates, we used the Kaplan-Meier method and log-rank test to compare and assess unadjusted all-cause mortality for GIB and non-GIB patients. We accounted for competing outcomes by censoring for the competing risk of death when assessing transplants and censoring for transplants when assessing death. When assessing GI bleed, we censored for both competing risks of transplant and death. Transplant rates were calculated as standard incidence rate per person-year, derived by dividing the total number of GI bleeds/transplants/deaths over the course of follow-up by the total time at risk for the population (person-year).

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Results

Patient Characteristics

During our 8 year study period, 232 patients underwent HM II implantation, with 183 of those patients designated as BTT status. The mean age of patients was 57 ± 14 years (standard deviation). One hundred and eighty-nine (82%) patients were male. The etiology of heart failure was ischemic in 135 patients (58%) and nonischemic (including postpartum cardiomyopathy, myocarditis, congenital heart disease, postcardiotomy shock, and idiopathic) in 97 patients (42%). The overall median duration of HM II support was 398 days (interquartile range [IQR] 192–776 days).

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Adverse Events: Gastrointestinal Bleeding

In our 232 HM II recipients, there were 62 bleeding episodes that occurred in 49 (27%) patients. Of these, 34 (69%) were BTT, whereas 15 (31%) were DT patients. Median duration of support at the time of first GIB was 650 days (IQR 220–1,162 days). The overall event rate was 0.45 GIB/patient-year of LVAD support. In DT patients, the event rate was 0.33 GIB/patient-year of LVAD support and in BTT patients, the event rate was 0.55 GIB/patient-year (rate ratio = 1.68; p = 0.09). Freedom from GIB for patients in our cohort is demonstrated in Figure 1. Gastrointestinal bleeding was found to be localized to the stomach in 9 patients, to the small intestine in 3 patients, and to the rectum in 2 patients; in the other 35 patients, the source of GIB was either not identified or not specified. The mean hemoglobin, platelets, and INR at the time of presentation for GI bleeding were 10.9 g/dl, 184 × 109/L, and 2.1, respectively.

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Comparison of Patients with GIB versus No GIB

Baseline demographic and clinical characteristics of patients who developed GIB and those that did not develop GIB are shown in Table 1. Patients who developed GIB were older, more likely to have ischemic etiology heart failure, and had a lower preoperative BMI, a lower preoperative hemoglobin level, and a lower preoperative albumin levels (3.3 vs 3.5 g/dl, p = 0.032). Women made up 15% of the cohort, yet contributed 29% of the GIB (p = 0.06). There was no statistical difference in preoperative INTERMACS profile or platelet count. A comparison of freedom from GIB between DT versus BTT patients is shown in Figure 2.

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Blood Transfusion Rates

The average number of red blood cell transfusions received by patients who presented with a GIB during their hospitalization was just more than 2 units. Patients who developed GIB had approximately twice the number of transfusions in the first year after device implantation, on average, compared with patients who did not develop GIB (18.4 vs 9.3, respectively, p < 0.001).

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Overall Survival

There were no reported mortalities as a result of GIB and no surgical interventions were necessary. There was no statistical difference in 6 month, 1 year, or 2 year survival in patients who developed a GIB and those who did not (82% vs 83%, 79% vs 74%, and 67% vs 59%, respectively; log-rank p = 0.35). Kaplan-Meier survival curves for patients who developed GIB versus for those who did not are demonstrated in Figure 3.

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Rate of Cardiac Transplantation

The cardiac transplantation rate among eligible patients with GIB (194/1,000 patient-years) was 27% lower than the rate of transplantation in patients without GIB (266/1,000 patient-years), resulting in a rate ratio of 0.73 (p < 0.05).

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Discussion

With continued improvement in CF-LVAD technology and increasing experience with postoperative follow-up, outcomes for patients with end-stage heart failure have continued to improve.2,3,17,18 However, GIB actually appears to be increasing in incidence since the introduction of CF-LVADs,7,8,19 and has been reported to be among the most common reasons for readmission after CF-LVAD implantation.14,20,21 The etiology of GIB in CF-LVAD recipients is likely multifactorial; proposed contributing factors include the narrowed pulse pressures and shear forces inherent in CF-LVAD implantation,22,23 acquired von Willebrand syndrome caused by fragmentation of von Willebrand factor multimers,9,10,12,24,25 and impaired platelet aggregation.12,13 Our institutional experience of GIB rate compares favorably with those previously reported,7,15,19,26,27 and similar to previous series,15,28 did not impact survival.

In these patients, a multidisciplinary approach is preferred, with input from cardiology, cardiothoracic surgery, and gastroenterology. Cessation of both anticoagulation and antiplatelet therapy is the primary treatment for uncomplicated GIB in CF-LVAD patients. Durable discontinuation of anticoagulants or antiplatelet agents may even be necessary,29 but this decision must be balanced against the risk of device thrombosis.30 Ongoing studies such as TRACE (NCT01477528) are anticipated to shed further light on the risks of scaling back anticoagulant therapy after bleeding events in the HM II population.

Gastrointestinal bleeding in CF-LVAD recipients appears to be equally common in the upper and lower gastrointestinal tract,7 and can be localized with a combination of upper endoscopy, colonoscopy, tagged red blood cells scan, and mesenteric angiography, although these modalities are reserved for recurrent or complicated GIB, and may fail to localize the source of bleeding. More recently, capsule endoscopy has been shown to be both safe and effective in CF-LVAD recipients for localizing the source of GIB.31

When needed, treatment modalities include proton pump inhibitors and standard endoscopic treatment, such as epinephrine injection and clip placement. Newer treatments that have been described with varying success include systemic epinephrine or octreotide, either by infusion or by subcutaneous injection.32,33 In patients with severe or refractory GIB, long-term cessation of anticoagulation29,34 or surgical therapy35 may be required.

In our study, risk factors predicting the development of GIB included older age, lower preoperative albumin level, and lower preoperative BMI. Surprisingly, females developed GIB at approximately twice the rate of males in our cohort, although the reasons for this association remain unclear. However, this finding is consistent with a recent analysis of preoperative risk factors for postoperative nonsurgical bleeding in CF-LVAD recipients by Boyle et al,36 which demonstrated female gender to be an independent risk factor for both bleeding and stroke.

The main finding of our retrospective analysis was that the development of GIB while on CF-LVAD support negatively impacts rates of cardiac transplantation. Although the association of GIB with increased transplant waiting time is likely multifactorial, it is troubling, as the development of GIB appears to additionally increase the risk for thromboembolic events while on device support as well.28,37 In addition, increased blood transfusion rates, because of repeated bleeding episodes, can predispose to increased allosensitization, thereby decreasing the likelihood of finding a compatible organ. Previous studies have reported that the average number of blood transfusions a patient receives on readmission for a GIB-related complication is 2–4 units.7 Indeed, in our cohort, the average number of red blood cell transfusions in patients who developed a GIB was just more than 2 units. Furthermore, patients who developed GIB had nearly twice the number of transfusions in the first year after device implantation, on average, compared with patients who did not develop GIB. The risk of allosensitization caused by recent blood transfusions in these patients increases the need for prospective cross-matches, thereby limiting the donor pool for LVAD patients with a recent GI bleed. Finally, it is also possible that patients with a recent GI bleed experience delays in being reactivated on the cardiac transplantation list because of concerns of recurrent bleeding in the perioperative period as a result of the heparinization needed to perform cardiac transplantation.

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Limitations

This study was a retrospective chart review and with its inherent limitations that must be acknowledged. Charts were only available for review from our institution and the potential inaccuracy of data not retrievable in our electronic medical record system (e.g., at other institutions) could lead to a falsely low reported number of blood transfusions or of GIB-related episodes. In addition, some patients were not endoscopically evaluated for their GIB episodes, and no definitive, confirmatory site of GIB was found in others. Finally, the reasons why patients who developed GIB experienced longer transplant waiting times has not been definitively established. Further studies are needed to better explain this association.

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Conclusion

In this large, single-center analysis, it was noted that although mortality did not appear to be affected by the presence or absence of GIB episodes, the rates of cardiac transplantation were significantly decreased in patients who developed GIB while on LVAD support. Although the mechanism for this association remains unclear and at best multifactorial, repeat bleeding episodes leading to increased blood transfusion rates can cause an increase in allosensitization, thereby decreasing the likelihood of finding a compatible organ on an ever-growing waiting list. An aggressive preoperative screening program of patients to determine the presence of preexisting angiodysplasias or von Willebrand syndrome (thought to be the main culprits of CF-LVAD-related GIB) could potentially allow for minimizing development of GIB postoperatively;4 however this has not been definitively demonstrated.

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Acknowledgment

The authors thank Mary Knatterud, PhD, for her assistance in editing the manuscript.

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allosensitization; blood transfusion; cardiac transplantation; gastrointestinal bleeding; left ventricular assist device

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