Octreotide for gastrointestinal bleeding in hereditary hemorrhagic telangiectasia: A prospective case series
Authors: Steven Kroon, Repke J. Snijder, Johannes J. Mager, Martijn C. Post, Jacco Tenthof van Noorden, Erwin J. M. van Geenen, Joost P. H. Drenth, Karina V. Grooteman
Journal: American Journal of Hematology (2019)

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant-inherited disease, with disease-causing mutations in the genes encoding for endoglin (ENG), or activin A receptor like type 1 (ACVRL1) in most cases. The affected genes play an important role in signaling of the transforming growth factor β pathway, and are expressed in endothelial cells of blood vessels. Disturbance of this pathway results in the formation of the characteristic mucocutaneous telangiectases. Gastrointestinal telangiectases can pose a difficult problem in HHT patients due severe recurrent bleeding, and lack of effective treatment options. Therapy for symptomatic anemia due to chronic gastrointestinal bleeding consists of iron supplementation or red blood cell (RBC) transfusion. Endoscopic treatment with argon plasma coagulation (APC) has reduced transfusion needs, although repeated attempts are discouraged due to increased complication risks.1 The prevalence of the gastrointestinal thin-walled mucosal telangiectases in HHT patients is high. In up to 25% of HHT patients with gastrointestinal bleeding above 60 years of age, frequent RBC transfusions and iron infusions are required.2 Octreotide is an octapeptide that mimics the endogenous hormone somatostatin, which has a vascular endothelial growth factor (VEGF) inhibiting effect and modifies splanchnic blood flow.3 In HHT patients, it is believed that elevated levels of VEGF play an important role in the pathological mechanism of HHT.4 In non-HHT patients with gastrointestinal angiodysplasia bleeding, octreotide treatment has shown to reduce gastrointestinal blood loss, and significantly decrease the need for iron infusions and RBC transfusions.5 Since limited treatment options exist for HHT patients with iron infusion or RBC transfusion dependent gastrointestinal bleeding and the potentially beneficial effects of octreotide, we designed this prospective, non-randomized clinical trial to assess the safety and efficacy of octreotide in these patients. This multicenter study (ClinicalTrials.gov identifier NCT 02874326) was performed in the Radboud University Medical Center (Radboudumc) and the St. Antonius Hospital in the Netherlands. This study was designed as a pragmatic trial with most assessments according to daily clinical practice. The study was approved by the ethics committee of the Radboudumc (commissie mensgebonden onderzoek (CMO) 366), and the local committee of the St Antonius hospital (V16.018). All patients signed informed consent before enrollment. Patients received a monthly intramuscular injection of 20 mg octreotide long-acting release (LAR) for six months. The primary outcome was the change in number of RBC units required during the study period compared to six months prior to inclusion. Secondary outcomes included the change in iron infusions, APC, daycare visits, fatigue symptoms measured with the Multidimensional Fatigue Inventory 20 (MFI-20), quality of life (QoL) measured with the Short Form Health Survey 36 (SF-36), epistaxis severity score (ESS), hemoglobin and ferritin levels, and adverse events.6, 7 Eleven patients (55% female), with a median age of 61.3 years (interquartile range [IQR] 53.9-65.2) were enrolled. Ten patients (91%) possessed an ENG gene mutation, while one patient (9%) carried an ACVRL1 gene mutation. In the six months leading up to enrollment, eight patients (73%) received RBC units and eight patients (73%) received one or more iron infusions. None of the patients used anticoagulant drugs. All baseline characteristics are shown in Table S1. The median number of RBC units needed decreased significantly from 13.5 (IQR 8.0-26.5) units prior to treatment to 8.0 (IQR 4.5-13.8) during six months treatment (Wilcoxon signed-rank test: P = .049). There was neither a significant change in iron infusions (median 4.0 (IQR 2.0-8.5) vs 3.0 (IQR 2.0-9.3), P = .66) nor in the number of APC treatments (median 0 (range 0-3) vs 0 (range 0-1), P = .29) during the treatment compared to prior to treatment. We found that the number of daycare visits (for iron infusions, RBC transfusions, and endoscopic APC treatments) decreased from a median of 9.0 visits (IQR 5.0-14.0) to 5.0 visits (IQR 2.0-11.0), (P = .08). Two fatigue dimensions of the MFI-20 significantly improved during treatment: the physical fatigue (16.0 (15.0-20.0) vs 13.0 (9.5-15.3), P = .01) and reduced activity (18.0 (IQR 14.0-20.0) vs 12.0 (10.0-17.0), P = .02). Physical fatigue covers the physical sensation related to fatigue. The improvement in activity covers both physical and psychological factors that affect the level of activity during a day. The improvement in QoL on the physical component summary (PSC) and mental component summary (MCS) was not statistically significant PSC: 34.4 (29.2-44.3) vs 44.7 (29.0-49.5), P = .06; MSC: 43.5 (29.6-56.1) vs 51.0 (38.4-60.6), P = .39). Likewise, the decrease in ESS was similar prior to the trial (5.5 [3.7-6.2]) compared to during the trial (3.5 [3.1-4.6, P = .14]). Hemoglobin and ferritin levels did not significantly change during the study (hemoglobin: 5.6 mmol/L (5.1-6.9 mmol/L) vs 6.4 mmol/L (5.0-7.3 mmol/L), P = .24; ferritin: 104 μg/L (9.8-291 μg/L) vs 30.0 μg/L (6.8-303 μg/L), P = .86). The outcomes are depicted in Figure 1 and described in Table S2. All side-effects and reported complaints were mild and transient. The most frequently observed side-effects were discolored stool (n = 6) and stomach and abdominal cramps (n = 5). Both lasted only for a couple of days following injection. One patient decided to terminate the study after four months (four octreotide injections) due to palpitations without abnormalities on the electrocardiogram. After the trial had ended, stomach cramps and discolored stool were still present for a couple of days following the last study injection in three patients, but not in the other seven patients. After the trial, the 10 patients decided to continue octreotide treatment. Our most important finding is the decrease in needs of transfusion in HHT patients with gastrointestinal bleeding due digestive tract telangiectases. Our study, however, does have some limitations. Most importantly, the sample size was small, and we had neither a control group nor included randomization. This could have introduced selection and performance bias. Another limitation was that the threshold to administer iron infusions or blood transfusions had not been defined, but left to the discretion of the attending physician who was aware of the patient's study participation. This may have introduced observer bias. A post-hoc analysis performed for the primary outcome showed that our study was underpowered (beta of 0.5), which increases the chance of type two errors. The small sample size may have caused the fact that we did not found significant changes in several of the secondary outcomes such as QoL. Another important limitation was the different number in HHT mutation carriers (91% of our sample had an ENG mutation), which makes generalization to ACVRL1 mutation carriers difficult. The ENG mutation carriers possess more gastrointestinal lesions, in comparison to ACVRL1 mutation carriers.8 Furthermore, we did not assess the cost-effectiveness of octreotide LAR. The costs of somatostatin analogues are relatively high. A formal cost-effectiveness study taking the reduction in RBC transfusions, iron infusions and day care visits is needed prior to widespread use. A large, randomized, placebo-controlled trial designed to further assess the efficacy, safety and cost-effectiveness of octreotide would avoid these limitations. In conclusion, octreotide could be a promising new therapy with a good safety profile for patients with HHT and severe gastrointestinal bleeding. Since limited other treatment options are available for patients with severe gastrointestinal blood loss and HHT, octreotide can be considered as therapeutic option. We thank Drs. L. Bernts for his assistance in collecting data. There are no conflicts of interest. Study concept and design: J.P.H.D., E.J.M.G., K.V.G., J.T.N., J.J.M. Acquisition of the data: S.K., K.V.G., R.S., J.J.M., J.T.N. Analysis and Interpretation of data: S.K., R.S., J.J.M., M.C.P., J.T.N., E.J.M.G., J.P.H.D., K.V.G. Critical writing of the manuscript: S.K., K.V.G. Revising the intellectual content: R.S., J.J.M., M.C.P., J.T.N., E.J.M.G., J.P.H.D., K.V.G. Final approval of the version to be published: S.K., R.S., J.J.M., M.C.P., J.T.N., E.J.M.G., J.P.H.D., K.V.G. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.