**3. Somatostatin analogues**

In 1993, octreotide was first reported for the treatment of bleeding small bowel angiodysplasias, in a small series of three patients successfully treated for 10 to 40 months.7 The rationale for the use of somatostatin analogues is based on its effects on splanchnic circulation, as they induce a marked reduction of portal and mesenteric blood flow mediated through inhibition of vasodilator peptides. Additionally, experimental studies have shown that octreotide has antiangiogenic effects, by downregulation of vascular

Pharmacological Therapy for Recurrent Obscure Gastrointestinal Bleeding 265

related to diffuse small bowel angiodysplasias.13-18 LAR octreotide is administered intramuscularly monthly, which makes it an attractive and comfortable therapy on an

Two small prospective uncontrolled series have been published using LAR octreotide. In the first study, 13 patients with chronic GI bleeding due to angiodysplasias were treated with octreotide LAR 10 mg per month and followed for at least 1 year.19 Nine out of the thirteen patients (69%) did not require further blood or iron supplementation, and partial improvement was also observed in another patient. The second study addressed the response to octreotide LAR 20 mg per month in a cohort of 11 elderly patients with multiple comorbidities and severe OGIB, mostly related to small-bowel diffuse angiodysplasia (72%).20 Median follow-up was 15 months (5-48). Only 2 out of 11 patients (18%) remained free of transfusions. However, a significant decrease in the need of red cell packets (14 (9-49) vs 4 (0-9), p 0.002) and in hospital stay due to GI bleeding (27 days (10-99) vs 7 days (0-23), p<0.001) during the first year of treatment was observed. These less promising results were perhaps due to a higher proportion of patients on anticoagulation or antiplatelet therapy, which was not withdrawn at study inclusion. Furthermore, the patients included in this

study had more severe GI bleeding as shown by higher transfusional requirements.

transfusional requirements and repeat admissions.

usually during a 3-month course due to adverse effects.

The main disadvantage of this drug formulation is its high cost, ranging from 785 euros (10mg) to 1300 euros (30 mg) monthly. However, it may be cost-effective in very specific difficult to treat patients, only tributary to conservative management, with higher

The main advantage of lanreotide over LAR octreotide is its subcutaneous administration, avoiding painful intramuscular injections and their inherent risk for complication in anticoagulated or cirrhotic patients. Up to date, there is only a case report on the successful use of lanreotide in a patient with severe OGIB due to universal portal hypertension stigmata in stomach, small bowel and colon.21 After a successful response to octreotide at a dose of 100 µg twice a day, the patient was given lanreotide, administered at dose of 60 mg, subcutaneously, on a monthly basis. This drug achieved complete remission of bleeding

Thalidomide is a drug with powerful immunomodulatory, anti-inflammatory and antiangiogenic effects, banned in the 1960s because of its teragenocity. However, it has been recently reintroduced for the treatment of leprosy, multiple myeloma and a variety of tumors. Over the last decade, thalidomide has gained interest as a therapeutic tool for OGIB. The rationale for its use in bleeding GI angiodysplasias is based on the inhibition of VEGFdependent angiogenesis. It is administered orally at a variable dose of 100-300 mg per day,

Thalidomide has been reported to be effective in controlling refractory severe bleeding from small bowel angiodysplasia, bleeding portal hypertensive gastropathy and enteropathy, radiation-induced proctitis and Crohn´s disease.22-29 Thalidomide, at a dose of 100 mg per day for three months, controlled OGIB in a case series of 3 patients with chronic bleeding from small-bowel angiodysplasia evidenced by capsule endoscopy.30 Repeat capsule

outpatient basis.

**3.3 Lanreotide** 

during 15 months of follow-up.

**4. Antiangiogenic drugs** 

**4.1 Thalidomide** 

endothelial growth factor (VEGF).8 In fact, a study reported endoscopic resolution of angiodysplastic lesions after treatment with octreotide, albeit the effect was not quantified.9 Interestingly, a more recent study showed that a 3-month-treatment of long-acting release (LAR) octreotide 20 mg once a month in cirrhotic patients decreased significantly both the hepatic venous pressure gradient and VEGF in hepatic venous blood.10 Other potential mechanisms of action of somatostatin analogues in OGIB, although more controversial, are by increasing vascular resistance and improving platelet aggregation.

Octreotide is, by far, the most studied somatostatin analogue in OGIB. However, recent studies are focusing on long-acting intramuscular (LAR octreotide) or subcutaneous (lanreotide) formulations, which have the great advantage of a once monthly administration. A recent meta-analysis, which included three prospective studies, aimed at evaluating the effectiveness of conventional and depot somatostatin analogues for bleeding vascular malformations, showed an average clinical response rate of 76%.11 Despite the small sample size of the studies included and the heterogeneity in the dose and molecular forms of the medication, these results are encouraging and a trial of somatostatin analogues is warranted, especially in patients in whom endoscopic therapy has failed, with unaccessible lesions or unknown source of bleeding. Its good safety profile, when compared with other pharmacological agents such as hormonal therapy or thalidomide, is another meaningful advantage. Nonetheless, randomized controlled trials are needed to confirm this data.

#### **3.1 Octreotide**

Octreotide can be administered intravenously (50 µg per hour) or subcutaneously (50-100 µg b.i.d or t.i.d). Its main disadvantage for long-term therapy is the need of parenteral administration several times a day, owing to its short half-life (90-120 minutes). Octreotide has been reported successful in stopping GI bleeding from angiodysplasia in multiple case reports and small series, both in acute and chronic bleeding.

To date, the most solid evidence is obtained in two prospective cohort studies, the latter comparing the results to historical controls. The former included 17 patients, (of whom 6 were cirrhotic), with chronic bleeding from angiodysplasias. 7 patients had isolated angiodysplasias, whereas other 7 had diffuse lesions in upper and lower segments of the GI tract and 3 watermelon stomach.9 Octreotide was given subcutaneously (100 µg t.i.d) for 6 months. More than half of the patients (10/17) achieved complete remission without further iron or transfusion requirements, whereas a transient improvement was observed in another 4 patients. Of note, octreotide lead subjectively to disappearance or reduction of the number, size and colour of the vascular malformations on follow-up endoscopy. The second study included 32 patients with acute or chronic bleeding due to GI angiodysplasias, which were treated with octreotide 50 µg b.i.d for a 1-2 yr period.12 Cirrhotic patients were excluded. Treatment failure (rebleeding or iron deficiency anemia during follow-up) was significantly higher in the controls cohort (48%) in comparison with the octreotide cohort (23%). A significant decrease in iron requirements, but not in hemoglobin or transfusion requirements, was also observed in the octreotide arm. Adverse effects in both studies were uncommon and mild, including diarrhea, constipation, hyperglycemia or gallbladder stones.

#### **3.2 Long-acting release (LAR) octreotide**

Several case reports and small series have recently revealed the efficacy of a depot formulation of octreotide (LAR octreotide) for severe OGIB, either of unknown origin or related to diffuse small bowel angiodysplasias.13-18 LAR octreotide is administered intramuscularly monthly, which makes it an attractive and comfortable therapy on an outpatient basis.

Two small prospective uncontrolled series have been published using LAR octreotide. In the first study, 13 patients with chronic GI bleeding due to angiodysplasias were treated with octreotide LAR 10 mg per month and followed for at least 1 year.19 Nine out of the thirteen patients (69%) did not require further blood or iron supplementation, and partial improvement was also observed in another patient. The second study addressed the response to octreotide LAR 20 mg per month in a cohort of 11 elderly patients with multiple comorbidities and severe OGIB, mostly related to small-bowel diffuse angiodysplasia (72%).20 Median follow-up was 15 months (5-48). Only 2 out of 11 patients (18%) remained free of transfusions. However, a significant decrease in the need of red cell packets (14 (9-49) vs 4 (0-9), p 0.002) and in hospital stay due to GI bleeding (27 days (10-99) vs 7 days (0-23), p<0.001) during the first year of treatment was observed. These less promising results were perhaps due to a higher proportion of patients on anticoagulation or antiplatelet therapy, which was not withdrawn at study inclusion. Furthermore, the patients included in this study had more severe GI bleeding as shown by higher transfusional requirements.

The main disadvantage of this drug formulation is its high cost, ranging from 785 euros (10mg) to 1300 euros (30 mg) monthly. However, it may be cost-effective in very specific difficult to treat patients, only tributary to conservative management, with higher transfusional requirements and repeat admissions.

#### **3.3 Lanreotide**

264 Gastrointestinal Endoscopy

endothelial growth factor (VEGF).8 In fact, a study reported endoscopic resolution of angiodysplastic lesions after treatment with octreotide, albeit the effect was not quantified.9 Interestingly, a more recent study showed that a 3-month-treatment of long-acting release (LAR) octreotide 20 mg once a month in cirrhotic patients decreased significantly both the hepatic venous pressure gradient and VEGF in hepatic venous blood.10 Other potential mechanisms of action of somatostatin analogues in OGIB, although more controversial, are

Octreotide is, by far, the most studied somatostatin analogue in OGIB. However, recent studies are focusing on long-acting intramuscular (LAR octreotide) or subcutaneous (lanreotide) formulations, which have the great advantage of a once monthly administration. A recent meta-analysis, which included three prospective studies, aimed at evaluating the effectiveness of conventional and depot somatostatin analogues for bleeding vascular malformations, showed an average clinical response rate of 76%.11 Despite the small sample size of the studies included and the heterogeneity in the dose and molecular forms of the medication, these results are encouraging and a trial of somatostatin analogues is warranted, especially in patients in whom endoscopic therapy has failed, with unaccessible lesions or unknown source of bleeding. Its good safety profile, when compared with other pharmacological agents such as hormonal therapy or thalidomide, is another meaningful advantage. Nonetheless, randomized controlled trials are needed to confirm this data.

Octreotide can be administered intravenously (50 µg per hour) or subcutaneously (50-100 µg b.i.d or t.i.d). Its main disadvantage for long-term therapy is the need of parenteral administration several times a day, owing to its short half-life (90-120 minutes). Octreotide has been reported successful in stopping GI bleeding from angiodysplasia in multiple case

To date, the most solid evidence is obtained in two prospective cohort studies, the latter comparing the results to historical controls. The former included 17 patients, (of whom 6 were cirrhotic), with chronic bleeding from angiodysplasias. 7 patients had isolated angiodysplasias, whereas other 7 had diffuse lesions in upper and lower segments of the GI tract and 3 watermelon stomach.9 Octreotide was given subcutaneously (100 µg t.i.d) for 6 months. More than half of the patients (10/17) achieved complete remission without further iron or transfusion requirements, whereas a transient improvement was observed in another 4 patients. Of note, octreotide lead subjectively to disappearance or reduction of the number, size and colour of the vascular malformations on follow-up endoscopy. The second study included 32 patients with acute or chronic bleeding due to GI angiodysplasias, which were treated with octreotide 50 µg b.i.d for a 1-2 yr period.12 Cirrhotic patients were excluded. Treatment failure (rebleeding or iron deficiency anemia during follow-up) was significantly higher in the controls cohort (48%) in comparison with the octreotide cohort (23%). A significant decrease in iron requirements, but not in hemoglobin or transfusion requirements, was also observed in the octreotide arm. Adverse effects in both studies were uncommon

and mild, including diarrhea, constipation, hyperglycemia or gallbladder stones.

Several case reports and small series have recently revealed the efficacy of a depot formulation of octreotide (LAR octreotide) for severe OGIB, either of unknown origin or

by increasing vascular resistance and improving platelet aggregation.

reports and small series, both in acute and chronic bleeding.

**3.2 Long-acting release (LAR) octreotide** 

**3.1 Octreotide** 

The main advantage of lanreotide over LAR octreotide is its subcutaneous administration, avoiding painful intramuscular injections and their inherent risk for complication in anticoagulated or cirrhotic patients. Up to date, there is only a case report on the successful use of lanreotide in a patient with severe OGIB due to universal portal hypertension stigmata in stomach, small bowel and colon.21 After a successful response to octreotide at a dose of 100 µg twice a day, the patient was given lanreotide, administered at dose of 60 mg, subcutaneously, on a monthly basis. This drug achieved complete remission of bleeding during 15 months of follow-up.
