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Gastrointestinal Bleeding in Left Ventricular Assist Device: Octreotide and Other Treatment Modalities

Molina, Tara L.; Krisl, Jill C.; Donahue, Kevin R.; Varnado, Sara

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doi: 10.1097/MAT.0000000000000758
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Abstract

Left ventricular assist devices (LVADs) offer a therapeutic strategy for patients with end-stage heart failure as a bridge to transplant (BTT) or as destination therapy. An increasing population of advanced heart failure patients and improvements in device technology have contributed to a continual increase in the number of LVAD implantations today. Historically, primarily pulsatile mechanical ventricular assist devices were implanted; however, these devices were large and susceptible to pump failure because of mechanical wear. Since 2007, nonpulsatile devices or continuous flow LVADs (CF-LVADs) have become the standard of care in advanced heart failure by offering a more compact design and improved durability compared with previous devices. More recently, a device with artificial pulse technology producing intermittent pulsatility has been under clinical investigation in the United States. The impact of this device on the future treatment of advanced, left ventricular heart failure is yet to be seen.

Despite benefits over first-generation devices, the physiologic changes caused by nonpulsatile flow can lead to complications, notably gastrointestinal bleeding (GIB), a leading cause of morbidity and mortality post-LVAD. The incidence of GIB with CF-LVADs ranges from 18% to 40%, a significantly higher rate than pulsatile devices with an incidence of around 10%.1–6 Postimplant infection, history of previous GIB, elevated international normalized ratio, and low platelet count have been described as independent predictors of GIB occurrence with CF-LVADs. Increased bleeding rates have also been observed in patients receiving LVAD as destination therapy as compared with BTT.4,7,8

Multiple mechanisms have been proposed in the pathophysiology of LVAD-associated GIB. The risk directly associated with anticoagulation and antiplatelet therapy represents only a single component of this complex phenomenon. CF-LVADs are noted to mimic the physiologic state of aortic stenosis. As first described by Heyde in the 1950s, factors contributing to GIB in aortic stenosis included increased intraluminal pressure leading to arteriovenous malformations (AVM), low pulse pressure leading to intestinal hypoperfusion and resulting angiodysplasia, and acquired von Willebrand syndrome as a result of shear stress.9–11 Similarly, the development of AVMs, weakened vascular endothelial integrity, capillary destruction, and acquired von Willebrand syndrome have been described in patients presenting with LVAD-associated GIB.1,12–14

In conditions of high shear, such as aortic stenosis and CF-LVAD support, von Willebrand factor (vWF) functional deficiency and depletion can arise by two primary mechanisms—vWF-cleaving metalloprotease (ADAMTS-13) proteolyzes vWF into smaller multimers and increased vWF–platelet interaction leading to vWF degradation and clearance.9,15 The normalization of vWF levels and resolution of GIB after LVAD explantation lend support to this association.3,16,17 More recently, other avenues of LVAD platelet dysfunction have been explored including the role of nitric oxide and cyclic guanosine monophosphate as potent platelet inhibitors.18

The location and characteristics of lesions in LVAD-associated GIB are also important considerations in defining treatment strategies. A pooled analysis of five studies reporting the location of GIB in LVAD patients demonstrated event rates of 48% for upper gastrointestinal (GI), 22% for lower GI, 15% for small bowel, and 19% with unknown location. The most common reported causes of GIB were attributed to gastrointestinal angiodysplastic lesions in 29% of the cases, followed by gastritis, then by peptic ulcer disease. Fifty-six percent of the lesions in the stomach or duodenum were characterized as gastrointestinal angiodysplastic lesions.4 A cohort study of 112 HeartMate II (HMII) patients with GIB identified upper GI angioectasia (25%) and ulcers (20%) as the most common causes of bleeding.13

Letsou et al.19 first described the association between gastrointestinal AVMs and axial CF-LVADs in three patients of whom two had resolution of GIB after restoration of physiologic pulsatility post-heart transplant; in a larger cohort, AVMs were identified as the source of GIB in 10 out of 32 HMII patients.20 Wide pulse pressure and pulsatile wave forms are important for GI tract circulation, and low arterial pulsatility seen with CF-LVADs may weaken gut mucosa contributing to the development of angiodysplasia.21–23 Although Wever-Pinzon et al. described an association of decreased pulsatility index (PI) with an increased risk of nonsurgical bleeding, the majority of which were gastrointestinal angiodysplastic lesions-related GIB, others have found no difference in LVAD pump speed or PI between patients who developed GIB and those who did not.7,14 Still, others have demonstrated a higher pulsatility index and aortic valve opening are associated with lower GIB rates.4,13

Nonpharmacological Approaches to Treatment

When LVAD patients present with GIB, current guidelines recommend a colonoscopy or upper endoscopic exam as part of the diagnostic evaluation, with further consideration to evaluate the small bowel. In patients presenting with recurrent bleeding, repeated endoscopic evaluation may be warranted to identify a potential site for intervention.24

Adjustments to LVAD parameters have included decreasing pump speed under echocardiographic monitoring in an effort to generate pulsatility while maintaining adequate left ventricular unloading.7,14 Guidelines recommend to consider reducing pump speed for continuous flow devices in the setting of recurrent GIB because of AVMs.24 These adjustments require consideration for hemodynamic parameters in addition to balancing the risks of bleeding and increased pump thrombosis with lower device speeds.25

Pharmacologic Approaches to Treatment

In managing acute LVAD GIB, volume resuscitation and establishing hemodynamic stability are first priority. Withholding anticoagulation and antiplatelet agents until hemostasis is achieved in the setting of clinically significant bleeding has been reported.7,24,26 Reversal of anticoagulation remains controversial because of the concurrent risk of potentially fatal thromboembolic events such as stroke or pump thrombosis, but should be considered for patients with life-threatening bleeding and an elevated international normalized ratio. Although guidelines have recommended reintroducing antiplatelet and anticoagulant agents when GIB has resolved, decisions to reinitiate anticoagulation and antiplatelet therapy after GIB have varied across treatment centers.24 Considerations for modifying maintenance anticoagulation may include a stepwise approach to management based on bleeding episode number.27 Discontinuing antiplatelet therapy, lowering international normalized ratio target ranges, and discontinuing all anticoagulation have been described in the literature. The addition of proton pump inhibitors, if not previously prescribed, should also be considered.7

Octreotide

An additional approach for patients with LVAD-associated GIB is octreotide, a somatostatin (SST) analogue. SST is an endogenous hormone with exocrine and endocrine functions. Five unique SST receptors (SSTR) have been identified with varying effects, resulting in inhibition of the secretion of insulin, glucagon, gastrin, secretin, and growth hormone among others.28 Octreotide, a synthesized SST analogue, shows increased binding specificity for SSTR 2, 3, and 5 compared with SST. SSTR 2 inhibits the secretion of glucagon, growth hormone, thyroid stimulating hormone, and gastric acid. SSTR 3 inhibits the activity of endothelial nitric oxide synthase, whereas SSTR 5 inhibits the secretion of insulin, growth hormone, and thyroid stimulating hormone.29 Octreotide has been described in the treatment of acromegaly, carcinoid tumors, sulfonylurea-induced hypoglycemia, and vasoactive intestinal peptide tumors along with other uses.

Splanchnic vasoconstriction is a unique pharmacologic characteristic of octreotide that is beneficial in the treatment of hepatorenal syndrome, variceal bleeding, and has been explored for use in non-variceal GIB. Octreotide induces splanchnic vasoconstriction by inhibiting the release of glucagon (a vasodilator) and through inhibiting production of nitric oxide.28

In variceal hemorrhage, splanchnic vasoconstrictors such as terlipressin, vasopressin, and octreotide have been associated with a lower risk of early rebleeding rates, all-cause mortality, and transfusion requirements.30–34 Further benefit from octreotide may be seen through reduced GI motility, inhibition of acid secretion, and associated gastric cytoprotective effects.35

The effect of octreotide has also been examined in non-variceal, angiodysplastic GIB. Therapeutic endoscopic or surgical approaches are often ineffective for vascular abnormalities of the GI tract as these lesions tend to spread throughout the GI tract and may be inaccessible by endoscopy. In a small cohort study, patients saw a significant increase in hemoglobin, and 82.3% of patients had a decrease in blood units transfused after receiving octreotide as adjunctive therapy for GIB.36 A meta-analysis of octreotide for the treatment of recurrent bleeding from GI vascular malformations also suggested octreotide-reduced transfusion requirements.37 Octreotide was not found to be effective in treatment of GIB from peptic ulcers.38

Adverse effects noted with octreotide include nausea, abdominal cramps, diarrhea, malabsorption of fat, and flatulence. These symptoms are thought to subside in 10 to 14 days with continuation of therapy.39–41 Reduced glucose tolerance and delayed metabolism and absorption of carbohydrates, cholesterol cholelithiasis, and hypertriglyceridemia have also been observed during octreotide therapy.39,40,42 In a recent study utilizing octreotide long-acting release (LAR) in 10 LVAD patients, no adverse effects were noted at 28 weeks.43 Similarly, of seven CF-LVAD patients receiving octreotide twice daily or octreotide LAR monthly, one patient experienced abdominal pain and two patients experienced diarrhea during treatment; none of the side effects were severe enough to warrant discontinuation of therapy.44 Pooled data from two randomized controlled trials of octreotide LAR for diabetic retinopathy evaluated the long-term safety profile over a time period of approximately 3.5 years. Among the most common adverse effects reported in this analysis were diarrhea (52.7%) and cholelithiasis (43%).45

LVAD Octreotide

Therapeutic strategies to minimize the morbidity and mortality of LVAD-associated GIB are needed. Acquired von Willebrand syndrome and the vascular effects of nonpulsatile flow with CF-LVADs including the formation of AVMs become key players in developing a treatment plan for LVAD patients presenting with GIB. Many of the proposed factors that contribute to LVAD-associated GIB may be targeted by the pharmacologic effects of octreotide, including improved platelet aggregation, increased vascular resistance, and decreased splanchnic circulation.38,46–49 Downregulation of vascular endothelial growth factor and subsequent inhibition of angiogenesis may also treat angiodysplastic lesions that develop during CF-LVAD support.13,36 Additional supportive benefits of octreotide therapy may include the inhibition of pepsin, gastrin, and acid secretion.38

Octreotide’s use in LVAD-associated GIB stemmed from successful case reports describing a significant reduction in hospital admissions and amount of blood products in patients with chronically bleeding AVMs.50,51 Octreotide has also demonstrated clinical value in several CF-LVAD-associated GIB cases. Benefits such as decreased GIB-hospital admissions, reduced blood product utilization, fewer endoscopic procedures, and reduced rebleeding episodes after treatment have been described in several publications. In the current literature, many LVAD patients who responded to octreotide suffered from GIB secondary to AVMs. Nonresponders included patients suffering from severe gastric antral vascular ectasia and gastric erosions. Various dosing strategies for octreotide have been described in the literature, including 50 to 100 μg subcutaneous (SQ) twice daily (BID) or octreotide LAR 20 to 30 mg intramuscularly (IM) monthly.49 Octreotide requires multiple daily injections, while octreotide LAR is a long-acting microsphere formulation that slowly releases octreotide and reaches steady state after three injections.52,53 This dosage form may improve medication compliance and subsequently impact therapeutic effectiveness.

Although no large studies are presently published, a number of case series and reports describe the use of octreotide in various formulations for the prevention and treatment of LVAD-associated GIB (Table 1). In the largest population reported to date, the use of octreotide in LVAD-associated GIB was examined in a multicenter study of 51 HMII patients with a previous GIB episode. Patients received SQ or depot LAR octreotide for a median of 34 days after hospital discharge. At 6 months, freedom from GI rebleeding was significantly less in the octreotide group compared with a historical cohort without octreotide treatment.54

Table 1.
Table 1.:
Key Studies Utilizing Octreotide in LVAD-Associated GIB

Another publication reports five patients who had successful resolution of GIB of which four were able to be reinitiated on antiplatelet or anticoagulation therapy. The five CF-LVAD patients with GIB received octreotide by continuous infusion, twice daily SQ injection, or monthly LAR octreotide IM injection for 10 to 69 days. Three patients were diagnosed with AVMs, one with an ulcer, and one with an unknown source of bleeding.51 A female HeartWare BTT patient after multiple hospital readmissions was diagnosed with two bleeding AVMs and a bleeding gastric erosion. She was started on octreotide 100 μg SQ BID and maintained a stable hemoglobin for 8 weeks of follow-up.59

Octreotide use has also been described in conjunction with other medical therapies and interventions such as withholding anticoagulation, endoscopic procedures, and LVAD pump parameter modifications. A case report describes a HMII BTT patient with a diagnosis of GIB with AVMs. A regimen including the use of octreotide SQ BID during hospital admission and LAR octreotide IM before discharge was used for bleeding that persisted despite optimization of LVAD pump settings, the addition of inotropes, and pharmacologic intervention with misoprostol for history of peptic ulcer disease and conjugated estrogens based on presumed benefit in AVM treatment. Although bleeding reoccurred during therapy, the patient ultimately remained free from GIB for 6 months and tolerated 2 months of full anticoagulation while octreotide was continued.60

A case series highlights seven patients who were treated for several months with endoscopic procedures, proton pump inhibitors, and reduction in anticoagulation and antiplatelet therapies before the initiation of octreotide. Two patients received LAR octreotide 20 mg IM monthly and five patients received octreotide 50 μg SQ BID. Although one patient with severe gastric antral vascular ectasia was termed a nonresponder, six patients showed a trend toward a decrease in GIB-related hospitalizations, packed red blood cells transfusions, and endoscopic procedures after treatment with octreotide.44

An additional case details a HMII patient requiring extensive blood product transfusion more than 9 weeks after device implantation. In conjunction with infusions of vWF concentrates for detected vWF dysfunction, the patient received octreotide SQ to prevent further development of angiodysplasia after the diagnosis of two angiodysplastic lesions that were not amenable to cauterization. He was ultimately discharged without further bleeding noted.56

To contrast these findings, Aggarwal et al.7 described a retrospective review of 23 HMII recipients who experienced GIB primarily because of gastric erosions (54%). Ten patients received octreotide, though there was no significant difference seen in length of stay, packed red blood cell units transfused, rebleeding episodes, or mortality when compared with those who did not receive octreotide.7 Notably, only 15% of the GIB cases were attributed to AVMs, which lends further consideration to understanding the perhaps heterogeneous characterization of LVAD-associated GIB before therapy selection.

Three publications have also described the use of octreotide for GIB prevention in CF-LVAD patients. A case report of a Jarvik 2000 destination therapy LVAD patient with previous bleeding episodes secondary to angiodysplasia achieved 23 months free from GIB after monthly IM octreotide administration.58 More recently, a phase I study examined the safety and tolerability of prophylactic LAR octreotide in HMII patients. Beginning within 1 month of LVAD implantation, patients received IM octreotide LAR every 4 weeks for 16 weeks total. During the study period of 28 weeks, no patients experienced GIB.43 This finding is significant given that literature suggests bleeding rates up to 39% within 2 months of LVAD implantation.13 Presenting results of the first known head-to-head comparison of different octreotide dosage forms for LVAD-associated GIB, a published abstract describes the findings of 34 patients receiving octreotide SQ or LAR to prevent recurrence of LVAD-associated GIB. Compared with daily injections, the LAR monthly injection showed a lower rate of bleeding versus short-acting octreotide formulations.43

A cost-effectiveness study examining the use of octreotide LAR in the treatment of vascular malformation-related GIB found treatment with octreotide LAR to be cost-effective in patients with relevant risk factors, such as recurrent bleeding episodes, unsuccessful endoscopic treatment, and high transfusion requirements among others. A significant reduction in total treatment costs, primarily because of decreased hospital admissions, length of stay, and decreased blood transfusions, was noted in this high-risk population.61 Extrapolation of this data to a strategically selected patient population receiving octreotide for LVAD-associated GIB may suggest similar findings; however, studies evaluating this factor are still forthcoming.

Other Pharmacologic Modalities

Other pharmacologic modalities have been used in the management of LVAD-associated GIB. Hormonal therapy consisting of estrogen used alone or in combination with progesterone has been proposed to improve vascular endothelium and potentially reduce bleeding times and has demonstrated potential benefit in AVM GIB.62–64 Thalidomide’s antiangiogenic properties have shown to be effective in treating GIB secondary to angiodysplasia.65,66 Similar benefit has been explored in LVAD patients to reduce recurrent bleeding. However, strict prescribing regulations and serious concerns related to adverse events have limited the use of thalidomide.4,67 An alternative pathway targeting angiogenesis of vascular malformations has been described after the discovery that LVAD patients have increased levels of transforming growth factor-β and higher endothelial expression and serum levels of angiopoetin-2 which stimulate angiogenesis. Angiotensin II signaling promotes transforming growth factor-β and vascular endothelial growth factor pathways along with angiopoietin-2 expression; therefore, blocking angiotensin II formation or binding to its receptor may suppress AVMs. In a cohort of 100 CF-LVAD patients treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs), 24 patients experienced GIB compared with 15 of 31 patients not receiving ACEI or ARB therapy. Further analysis showed that approximately 40% of GIB in the ACEI/ARB group was attributed to AVMs, whereas 60% of GIB in those not treated with ACEI/ARB was secondary to AVMs. Herein, investigators concluded that ACEI/ARB therapy may reduce the risk of AVM-related GIB in CF-LVAD patients, but larger studies are needed to confirm this finding.68 The use of doxycycline to inhibit vWF degradation by ADAMTS-13 has also been described. An in vitro study showed doxycycline therapy decreased vWF degradation and improved vWF function during shear stress.69 However, in six patients receiving oral doxycycline 100 mg twice daily for 7 days, there was no significant difference in ADAMTS-13 activity or vWF multimer density reported.70 Additional investigation to identify potential dose-dependent benefit is needed.

Conclusions

Many steps have been taken to advance LVAD technology along with strategies to optimize the management of patients presenting with GIB in the setting of LVAD support. Understanding the complex pathophysiology proposed to contribute to the development of LVAD-associated GIB is the first step. The use of anticoagulation, often in combination with antiplatelet agents, places patients with CF-LVADs at a higher risk of bleeding; however, this alone does not explain the increased incidence of GIB. Enlisting a multimodal approach to treating LVAD-associated GIB may lead to improved outcomes. An initial strategy can include adjustments to anticoagulant and antiplatelet selection and dosing. Pump flow parameter modifications may aid in addressing the sequelae of nonpulsatile flow. The addition of pharmacologic interventions to target preserving vWF and platelet function and to manage established AVM bleeding and AVM formation can contribute to positive outcomes in LVAD-associated GIB.

Further studies surrounding the use of octreotide in this unique patient population will help guide the selection of treatment options. Current literature suggests that patients with LVAD-associated GIB secondary to AVMs may have better response to octreotide treatment than those with GIB secondary to gastric antral vascular ectasia or ulcerations. Additional work into identifying the patients who have the greatest benefit from octreotide should be considered. Furthermore, determining the optimum dosing, formulation, and timing of initiating octreotide treatment in LVAD patients is needed. As the population of patients with CF-LVADs continues to increase and GI bleeding events remain prevalent, identifying strategies to minimize the morbidity of LVAD-associated GIB will provide substantial impact.

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    Keywords:

    octreotide; somatostatin; left ventricular assist device; continuous flow left ventricular assist device; gastrointestinal; bleeding

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