Safety Study of Octreotide Injection to Prevent GI Bleeding in Patients With Left Ventricular Assist Device (LVAD)

The primary specific aim is to determine the safety of octreotide LAR in patients with a LVAD.

Patient experience of the following will be assessed throughout the study (list obtained from up-to-date.com)

Cardiovascular:

Sinus bradycardia (19% to 25%) Hypertension (≤13%) conduction abnormalities (9% to 10%)

Central nervous system:

Fatigue (1% to 32%) headache (6% to 30%) malaise (16% to 20%) fever (16% to 20%) dizziness (5% to 20%) Pain (4% to 15%)

Dermatologic:

Pruritus (≤18%) Rash (15%; depot formulation) alopecia (≤13%)

Endocrine \& metabolic:

Hyperglycemia (2% to 27%)

Gastrointestinal:

Abdominal pain (5% to 61%) loose stools (5% to 61%) nausea (5% to 61%) diarrhea (34% to 58%) flatulence (≤38%) cholelithiasis (13% to 38%; length of therapy dependent) constipation (9% to 21%) vomiting (4% to 21%)

Hematologic Anemia (5-15%)

Local:

Injection site pain (2% to 50%; dose and formulation related)

Neuromuscular \& skeletal:

Back pain (1% to 27%) arthropathy (8% to 19%) myalgia (≤18%)

Renal Kidney Stones (5-15%)

Respiratory:

Upper respiratory infection (10% to 23%)

Miscellaneous:

flu symptoms (1% to 20%)

Our key secondary outcomes will focus on study drug efficacy. Patient experience of the following will be assessed:

Need for Blood Transfusion Hospital Admission for GI Bleed

Heart disease is a leading cause of death and disability, according to the American Heart Association. Current therapies include lifestyle modification, medical management and revascularization via Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Surgery (CABG). However, a large portion of patients develop cardiomyopathy which is refractory to the above interventions. They are treated with chronic inotropes, resynchronization and other forms of medical management.

Many of these patients eventually worsen and need consideration for cardiac transplantation. The Thoratec Heartmate II, which is the primary left ventricular assist device (LVAD) implanted at our institution, has been used as a bridge-to-transplantation. More recently it has been approved as destination therapy for patients who are not candidates for transplantation. Over 6000 of these devices have been implanted worldwide since their introduction. We have implanted over 70 here at the VCU Health System and the McGuire VA Medical Center.

The early LVAD devices provided physiologic pulsatility, but were large in size and required large catheters for external venting. The newer continuous flow LVAD devices, such as the Heartmate II, offer the benefit of being smaller and easier to implant as well as improving mobility and thus quality of life. However, this benefit comes with a complication of an increased incidence of GI bleeding, thought to be related to the loss of pulsatility and the nature of these smaller devices.

Approximately 10-30% of patients experience at least one episode GI bleeding which is likely multifactorial. It has already been demonstrated that an acquired von Willebrand Syndrome (vWS) develops due to destruction of multimeric vWF. Additionally, it has been shown that these patients have a higher than normal percentage of gastrointestinal angiodysplasia. Whether these are preexisting or develop as a result of de novo angiogenesis from the gut mucosa is unknown. It is thought that the loss of pulsatility and potential hypoxia result in secretion of angiogenic mediators and contribute to the development of angiodysplasia.

Current treatment for LVAD associated GI bleeding is aimed at identifying the location of bleeding and treatment with blood product transfusion, cryoprecipitate for vWS, Desmopressin for platelet dysfunction, and interventions through Interventional Radiology (IR) and surgery. In addition to the obvious costs and increase in morbidity and mortality associated with the above therapies, patients who receive multiple transfusions develop antibodies and thus become more difficult to transplant. Thus a vicious cycle develops.

We need to strive for a proactive stance in these patients and attack the problem at the source. There is a considerable amount of experience using octreotide in idiopathic chronic GI bleeding. This is likely due to its ability to decrease splanchnic blood flow and its potential ability to inhibit angiogenesis. Octreotide has been thoroughly studied and has a known safety profile. Off label use of octreotide LAR for the purpose of attenuating LVAD associated GI bleeding is currently practiced by some physicians at VCU with no adverse side effects encountered. It is time to formally study the safety and efficacy of octreotide LAR for this purpose. We propose an open-label safety study for 10 subjects to be followed for a total of 24 weeks. Should the safety study be favorably completed, a multi-center trial with randomization to octreotide LAR or placebo with endpoints of GI bleeding and transfusion will be pursued.