Gastrointestinal (GI) bleed is the most common cause of readmissions in patients with end stage heart disease treated with continuous flow left ventricular assist devices (CF-LVAD).1 As a result of recurrent GI bleed, antiplatelet, and antithrombotic therapies are withheld acutely or even chronically, increasing the chances of thrombotic complications. Currently, there is no effective treatment to prevent or decrease the frequency of recurrent GI bleed in LVAD supported patients.
In non-LVAD supported patients octreotide, a somatostanin analog, has been used with some positive results in the management of recurrent GI bleed due to vascular malformations2 and other etiologies. Here, we describe our experience in the use of octreotide therapy for the management of recurrent GI bleed unresponsive to conventional therapy in patients supported by CF-LVAD.
One hundred and sixteen patients received CF-LVAD at our institution between March 2006 and September 2012. Of these, seven patients were treated with octreotide due to recurrent GI bleeding. Clinical characteristics are shown in Table 1. All patients were male, received LVAD predominantly as a destination therapy strategy, and had a mean follow-up time of 10.2 ± 13.8 months. These patients had the first episode of GI bleed soon after LVAD implantation and were treated for several months before the initiation of octreotide with endoscopic procedures, proton pump inhibitors and progressive reduction of anticoagulation and antiplatelet therapy. During this period patients were frequently hospitalized due to GI bleed (Table 1) and received a median of 14 units (range, 12–58) of pack red blood cells (PRBC) transfusions during the course of LVAD support, before the initiation of octreotide therapy. Octreotide was initiated as a last resort to control recurrent GI bleed. Two patients received the depot formulation at a dose of 20 mg subcutaneously every month and five patients received the short acting formulation of octreotide at a dose of 50 mcg subcutaneously two times a day. The choice of formulation was based on insurance coverage. Patients continued octreotide injection chronically for the 3-month follow-up period. Side effects included abdominal cramps in one patient and diarrhea in two patients but none of these side effects was serious enough to merit discontinuation of treatment. We analyzed the frequency of blood transfusions, endoscopic procedures and hospitalizations 3 months before and after initiation of octreotide treatment.
Data were analyzed for normality with the Shapiro–Wilk test. Owing to the non-normal distribution of our data, we used a nonparametric test (Wilcoxon-matched rank test) for comparisons. When all patients were included in the analysis (n = 7), there were no differences in the frequency of hospitalizations due to GI bleed (p = 0.18), units of PRBC transfused (p = 0.15), or number of endoscopies (p = 0.2). Review of the data demonstrated that one of the patients behaved differently from the rest regarding the frequency and severity of GI bleed and underlying pathology. This individual received 58 units of PRBC before initiation of octreotide and continued to have multiple GI bleed episodes after treatment due to a severe form of gastric antral vascular ectasia. This patient was considered an outlier or a nonresponder. Excluding this patient, reanalysis of the remaining six patients showed a more uniform trend toward a decrease in frequency in hospitalizations due to gastrointestinal bleeding (GIB), number of units of PRBC transfused, and endoscopic procedures (Table 2).
Recurrent GI bleed represents a serious cause of morbidity for patients supported by CF-LVAD. It is hypothesized that the lack of pulse pressure in CF-LVAD may lead to the development of AV malformations through a similar mechanism to the one described in severe aortic stenosis, known as Heyde’s syndrome, a condition which is also associated with a low pulse pressure.3 This theory is supported by reports which suggest an association between low pulsatility index and frequency of GIB.4 The etiology and pathophysiology in the development of AV malformation is not fully understood but it may be related to tissue hypoperfusion and mucosal ischemia.5 Ischemia in the gastro-intestinal mucosa may lead to the increase in the production of vascular endothelial growth factor (VEGF), which in turn plays an important role in the development of AV malformations.6,7 In addition, patients with CF-LVAD develop a deficiency in von Willebrand Factor (vWF).8 vWF is involved in controlling angiogenesis and a decrease in vWF has been associated with an increase in VEGF-dependent proliferation and vascularization.9
Patients with CF-LVAD need chronic anticoagulation and antiplatelet therapy to prevent thrombotic complications.10 Earlier reports of CF technology suggested that the rate of thrombotic complications was low, allowing a lower intensity anticoagulation strategy in the management of these patients to minimize the frequency of GI bleeding.10 However, more recent reports have shown an increase in LVAD thrombosis,11,12 and as a result implanting centers are now stricter with their anticoagulation protocols. With increased concern over device thrombosis risk, increased anticoagulation, and antiplatelet therapy is being applied. This may increase LVAD patient bleeding diathesis and the cumulative incidence of GI bleeding.
Therapies for patients with GI bleeding include: endoscopic therapy (Argon plasma coagulation, electro and photocoagulation, clipping and ligation), pharmacological therapy including hormone therapy,13 somatostatin analogs,2 and thalidomide.14
Somatostatin is a peptide secreted by the gastric and intestinal mucosa, enteric neurons, and pancreatic cells, which reduces gastric, pancreatic, and bile secretions.15 Octreotide is a somatostatin analog, which appears to be effective in the management of GIB secondary to acquired angiodysplasia.2 The mechanisms involved in this pharmacological effect of octreotide include: decreased splanchnic blood flow, increased vascular resistance, improved platelet aggregation, and inhibition of angiogenesis16 via inhibition of VEGF.17
Reports on the effect of octreotide in the management of GI bleed in CF-LVAD patients are discordant with some case reports showing positive results18,19 and others showing no effect.20 In our report, the majority of patients with recurrent GI bleed had an apparent favorable clinical response to the chronic treatment with octreotide and a trend to decrease in the frequency of hospital admissions, blood transfusions, and endoscopic procedures after 3 months of initiation of therapy. Octreotide was well tolerated and none of the patients discontinued the drug.
This report represents a single center case series and as such its conclusions should be analyzed with caution. The number of patients is small and this may have an impact in the power to detect differences with octreotide treatment. The long-term benefits of octreotide treatment (>3 months after initiation of therapy) or its side effects at this point remain unknown and further research in this area is needed.
In summary, octreotide treatment showed a trend to a favorable response in decreasing blood transfusions, number of endoscopic procedures, and readmissions due to GI bleed. Further prospective research involving a larger number of patients and for longer follow-up periods is needed to clarify the role of octreotide in the management of recurrent GI bleed.
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LVAD; gastrointestinal bleed; octreotide