**4. Antiangiogenic drugs**

#### **4.1 Thalidomide**

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

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

Pharmacological Therapy for Recurrent Obscure Gastrointestinal Bleeding 267

been proven useful for chronic bleeding from angiodysplasias in patients with end-stage renal failure and bleeding gastric antral vascular ectasia in cirrhosis.40-42 A systematic review on the use of tranexamic acid for upper GI bleeding was recently published.43 Although it seemed to reduce overall mortality, there were no significant differences regarding bleeding, surgery or transfusion requirements. Of note, tranexamic acid did not increase thromboembolic risk. Therefore, the current evidence does not support routine use of tranexamic acid in clinical practice. The main risk derived from the use of antifibrinolytics is thrombosis, so thrombophilia should be ruled out before prescribing them. Adverse events associated to ACA and tranexamic acid may be frequent, and the use of these drugs is not supported by randomized controlled trials, which makes antifibrinolytics a last option for

Danazol is an anti-gonadotropin drug with weak androgenic activity that blocks pituitary secretion of FSH and LH, leading to ectopic and normal endometrial tissue atrophy. It has been widely used for endometriosis and uterine bleeding disorders. Anecdotal reports suggest a partial improvement with danazol in patients with gastrointestinal bleeding and HHT,44-46 although cosmetic stigmata (acne, hair loss, mild hirsutism) and uncommon but severe adverse effects (intracranial hypertension, peliosis hepatitis, thrombosis, seizures)

Desmopressin is a synthetic analog of the antidiuretic hormone vasopressin that lacks vasopressor activity. It increases vW factor and factor VIII levels, and also enhances hemostasis in patients with defective platelet function. It is indicated as a hemostatic therapy for patients with hemophilia A and von Willebrand's disease, and can be administered intravenously, subcutaneously, or by intranasal spray. An isolated report showed a benefit of intravenous desmopressin for life-threatening gastrointestinal bleeding in a patient with HHT and vW factor deficiency, allowing elective colectomy and bleeding

Recombinant activated human factor VII (rFVIIa) is a drug that strongly promotes hemostasis, and is currently indicated for hemophiliac A and B patients with antibody inhibitors to coagulation factors VIII or IX, congenital deficiency of factor VII, and Glanzmann's thromboasthenia. This drug has been used anecdoctically for stopping hemorrhage, with or without hematological disorders, in massive or uncontrollable bleeding at multiple GI and non GI locations. Its short half-life of 2 hours requires frequent boluses or continuous infusion to achieve hemostasis, and it can induce definite control of bleeding or be a bridge until a causal therapy can be provided. It has been mainly used in cirrhotic patients with acquired coagulation factor deficiencies, especially in variceal and nonvariceal upper GI hemorrhage related to cirrhosis or acute liver failure.48,49 Albeit preliminary results showed that it might have a beneficial effect for advanced cirrhotic patients with variceal bleeding, a randomized placebo controlled trial failed to demonstrate a significant benefit of rFVIIa for controlling variceal bleeding or preventing rebleeding in these patients.50 Thus, the use of rFVIIa should be carefully individualized in cirrhotic

leave danazol to a secondary role in OGIH, when other therapies have failed.

patients and it is not recommended in the routine clinical practice.

OGIH.

**5.2 Danazol** 

**5.3 Desmopressin** 

resolution47.

**5.4 Recombinant activated factor VIIa** 

endoscopy after therapy revealed a substantial reduction in lesion number, size and colour intensity. Of note, the response was sustained for a median of 34 months despite discontinuation of the drug. Due to its antiangiogenic property, thalidomide may not only lead to cessation of bleeding but also to prevention of further angiodysplasia formation. More recently, two small prospective series, involving 3 and 7 patients, respectively, have confirmed the utility of thalidomide for bleeding small-bowel angiodysplasia.31,32 However, a high rate of discontinuation was observed in these series (1/3 and 4/7, respectively), owing to intolerable side effects (fatigue, peripheral neuropathy, dizziness, urticarial rash). The main drawback of thalidomide is it frequent side effects, although these are mostly minor (fatigue, somnolence, constipation, dizziness, peripheral neuropathy). Nonetheless, fatal complications such as acute liver failure have been reported.33 In addition, the risk of thromboembolic events associated with thalidomide should be considered in OGIB patients. Overall, thalidomide is an effective drug for refractory bleeding GI angiodysplasia. Taking into account its numerous side effects, it seems cautious to save thalidomide for OGIB refractory to both endoscopic therapy and a trial of somatostatin analogues, albeit a head-tohead comparison is required to validate this algorithm.

#### **4.2 Lenalidomide**

Lenalidomide is an antiangiogenic drug commonly used for multiple myeloma. It has two mayor advantages over thalidomide: a more powerful antiangiogenic effect and a lower toxicity profile. Its use in the context of life-threatening bleeding due to gastrointestinal angiodysplasia in a patient suffering from HHT, in whom thalidomide was effective but had to be stopped because of severe neuropathy has been recently reported34. Lenalidomide successfully controlled bleeding and the patient remained free of either gastrointestinal bleeding or drug symptoms. However, although lenalidomide is more effective and better tolerated than thalidomide, further studies are warranted to evaluate its role in refractory OGIB. On the other hand, lenalidomide is 10 times more expensive than thalidomide and dosing should be carefully titrated owing to severe bone marrow suppression, much higher than that described for thalidomide.

#### **4.3 Bevacizumab**

Recently, a growing number of reports on the use of VEGF antagonist bevacizumab in HHT have lead to outstanding improvement in GI bleeding episodes, reductions in cardiac output and liver size, even obviating the need for liver transplantation in a single patient.35,36 This benefit has been also proven for recurrent epistaxis, administering bevacizumab intravenously, injected locally or sprayed topically to the nasal mucosa.37,38

#### **5. Miscellaneous drugs**

#### **5.1 Antifibrinolytics**

Aminocaproic acid is a powerful inhibitor of the fibrinolytic system that blocks conversion of plasminogen to plasmin when used at low doses. There is only one isolated report in which it was effective in the management of epistaxis from arteriovenous malformations in two patients with HHT at a dose of 1.5 g twice a day, although it was not clear whether concomitant gastrointestinal bleeding was present.39

Tranexamic acid is a synthetic lysine analog that inhibits the conversion of plasmin to fibrinogen, with less antifibrinolytic power than aminocaproic acid. Tranexamic acid has been proven useful for chronic bleeding from angiodysplasias in patients with end-stage renal failure and bleeding gastric antral vascular ectasia in cirrhosis.40-42 A systematic review on the use of tranexamic acid for upper GI bleeding was recently published.43 Although it seemed to reduce overall mortality, there were no significant differences regarding bleeding, surgery or transfusion requirements. Of note, tranexamic acid did not increase thromboembolic risk. Therefore, the current evidence does not support routine use of tranexamic acid in clinical practice. The main risk derived from the use of antifibrinolytics is thrombosis, so thrombophilia should be ruled out before prescribing them. Adverse events associated to ACA and tranexamic acid may be frequent, and the use of these drugs is not supported by randomized controlled trials, which makes antifibrinolytics a last option for OGIH.

#### **5.2 Danazol**

266 Gastrointestinal Endoscopy

endoscopy after therapy revealed a substantial reduction in lesion number, size and colour intensity. Of note, the response was sustained for a median of 34 months despite discontinuation of the drug. Due to its antiangiogenic property, thalidomide may not only lead to cessation of bleeding but also to prevention of further angiodysplasia formation. More recently, two small prospective series, involving 3 and 7 patients, respectively, have confirmed the utility of thalidomide for bleeding small-bowel angiodysplasia.31,32 However, a high rate of discontinuation was observed in these series (1/3 and 4/7, respectively), owing to intolerable side effects (fatigue, peripheral neuropathy, dizziness, urticarial rash). The main drawback of thalidomide is it frequent side effects, although these are mostly minor (fatigue, somnolence, constipation, dizziness, peripheral neuropathy). Nonetheless, fatal complications such as acute liver failure have been reported.33 In addition, the risk of thromboembolic events associated with thalidomide should be considered in OGIB patients. Overall, thalidomide is an effective drug for refractory bleeding GI angiodysplasia. Taking into account its numerous side effects, it seems cautious to save thalidomide for OGIB refractory to both endoscopic therapy and a trial of somatostatin analogues, albeit a head-to-

Lenalidomide is an antiangiogenic drug commonly used for multiple myeloma. It has two mayor advantages over thalidomide: a more powerful antiangiogenic effect and a lower toxicity profile. Its use in the context of life-threatening bleeding due to gastrointestinal angiodysplasia in a patient suffering from HHT, in whom thalidomide was effective but had to be stopped because of severe neuropathy has been recently reported34. Lenalidomide successfully controlled bleeding and the patient remained free of either gastrointestinal bleeding or drug symptoms. However, although lenalidomide is more effective and better tolerated than thalidomide, further studies are warranted to evaluate its role in refractory OGIB. On the other hand, lenalidomide is 10 times more expensive than thalidomide and dosing should be carefully titrated owing to severe bone marrow suppression, much higher

Recently, a growing number of reports on the use of VEGF antagonist bevacizumab in HHT have lead to outstanding improvement in GI bleeding episodes, reductions in cardiac output and liver size, even obviating the need for liver transplantation in a single patient.35,36 This benefit has been also proven for recurrent epistaxis, administering bevacizumab

Aminocaproic acid is a powerful inhibitor of the fibrinolytic system that blocks conversion of plasminogen to plasmin when used at low doses. There is only one isolated report in which it was effective in the management of epistaxis from arteriovenous malformations in two patients with HHT at a dose of 1.5 g twice a day, although it was not clear whether

Tranexamic acid is a synthetic lysine analog that inhibits the conversion of plasmin to fibrinogen, with less antifibrinolytic power than aminocaproic acid. Tranexamic acid has

intravenously, injected locally or sprayed topically to the nasal mucosa.37,38

head comparison is required to validate this algorithm.

**4.2 Lenalidomide** 

**4.3 Bevacizumab** 

**5. Miscellaneous drugs** 

concomitant gastrointestinal bleeding was present.39

**5.1 Antifibrinolytics** 

than that described for thalidomide.

Danazol is an anti-gonadotropin drug with weak androgenic activity that blocks pituitary secretion of FSH and LH, leading to ectopic and normal endometrial tissue atrophy. It has been widely used for endometriosis and uterine bleeding disorders. Anecdotal reports suggest a partial improvement with danazol in patients with gastrointestinal bleeding and HHT,44-46 although cosmetic stigmata (acne, hair loss, mild hirsutism) and uncommon but severe adverse effects (intracranial hypertension, peliosis hepatitis, thrombosis, seizures) leave danazol to a secondary role in OGIH, when other therapies have failed.

#### **5.3 Desmopressin**

Desmopressin is a synthetic analog of the antidiuretic hormone vasopressin that lacks vasopressor activity. It increases vW factor and factor VIII levels, and also enhances hemostasis in patients with defective platelet function. It is indicated as a hemostatic therapy for patients with hemophilia A and von Willebrand's disease, and can be administered intravenously, subcutaneously, or by intranasal spray. An isolated report showed a benefit of intravenous desmopressin for life-threatening gastrointestinal bleeding in a patient with HHT and vW factor deficiency, allowing elective colectomy and bleeding resolution47.

### **5.4 Recombinant activated factor VIIa**

Recombinant activated human factor VII (rFVIIa) is a drug that strongly promotes hemostasis, and is currently indicated for hemophiliac A and B patients with antibody inhibitors to coagulation factors VIII or IX, congenital deficiency of factor VII, and Glanzmann's thromboasthenia. This drug has been used anecdoctically for stopping hemorrhage, with or without hematological disorders, in massive or uncontrollable bleeding at multiple GI and non GI locations. Its short half-life of 2 hours requires frequent boluses or continuous infusion to achieve hemostasis, and it can induce definite control of bleeding or be a bridge until a causal therapy can be provided. It has been mainly used in cirrhotic patients with acquired coagulation factor deficiencies, especially in variceal and nonvariceal upper GI hemorrhage related to cirrhosis or acute liver failure.48,49 Albeit preliminary results showed that it might have a beneficial effect for advanced cirrhotic patients with variceal bleeding, a randomized placebo controlled trial failed to demonstrate a significant benefit of rFVIIa for controlling variceal bleeding or preventing rebleeding in these patients.50 Thus, the use of rFVIIa should be carefully individualized in cirrhotic patients and it is not recommended in the routine clinical practice.

Pharmacological Therapy for Recurrent Obscure Gastrointestinal Bleeding 269

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This drug has been proven useful in other settings as well. In a series of 11 unselected patients with upper GI haemorrhage, half of them related to liver disease, rFVIIa stopped the bleeding in 7 patients and markedly reduced it in other 2 patients.51 Other successful indications relating severe GI bleeding have been refractory bleeding after endoscopic sphincterotomy in patients with preexisting coagulopathy,52 severe recurrent GI bleeding due to multiple GI angiodysplasias in a patient with vW disease,53 massive colonic bleeding54 or exsanguinating bleeding due to Mallory-Weiss tear.55 Of note, no thromboembolic events were reported in the aforementioned trials or series. However, secondary myocardial and cerebrovascular infarctions have been described while using factor VIIa.56,57 As such, it is important to stress once more that the use of this drug should always be carefully individualized.

#### **5.5 Tamoxifen**

In a recent randomized, double-blind placebo controlled trial, the efficacy of antiestrogen therapy (Tamoxifen) was evaluated in patients with epistaxis due to HHT.58 There was a significant reduction in the frequency of epistaxis in the tamoxifen-treated group, frequently associated to a rise in haemoglobin or a reduction in transfusion requirements. As previously mentioned in the case of bevacizumab, a potential therapeutic role for GI bleeding in HHT patients warrants further research.

#### **5.6 Non-selective beta-blockers**

These drugs aim to control hemorrhage by reducing gastrointestinal blood flow due to splanchnic vasoconstriction and reduction of cardiac output in cirrhotic patients with portal hypertension. Its proven benefit for secondary prophylaxis of bleeding portal hypertensive gastropathy in two randomized controlled trials led to the consensus recommendation that beta-blockers should be used for chronic bleeding once the acute episode of bleeding is controlled.59,60

#### **6. References**


This drug has been proven useful in other settings as well. In a series of 11 unselected patients with upper GI haemorrhage, half of them related to liver disease, rFVIIa stopped the bleeding in 7 patients and markedly reduced it in other 2 patients.51 Other successful indications relating severe GI bleeding have been refractory bleeding after endoscopic sphincterotomy in patients with preexisting coagulopathy,52 severe recurrent GI bleeding due to multiple GI angiodysplasias in a patient with vW disease,53 massive colonic bleeding54 or exsanguinating bleeding due to Mallory-Weiss tear.55 Of note, no thromboembolic events were reported in the aforementioned trials or series. However, secondary myocardial and cerebrovascular infarctions have been described while using factor VIIa.56,57 As such, it is important to stress once more that the use of this drug should

In a recent randomized, double-blind placebo controlled trial, the efficacy of antiestrogen therapy (Tamoxifen) was evaluated in patients with epistaxis due to HHT.58 There was a significant reduction in the frequency of epistaxis in the tamoxifen-treated group, frequently associated to a rise in haemoglobin or a reduction in transfusion requirements. As previously mentioned in the case of bevacizumab, a potential therapeutic role for GI

These drugs aim to control hemorrhage by reducing gastrointestinal blood flow due to splanchnic vasoconstriction and reduction of cardiac output in cirrhotic patients with portal hypertension. Its proven benefit for secondary prophylaxis of bleeding portal hypertensive gastropathy in two randomized controlled trials led to the consensus recommendation that beta-blockers should be used for chronic bleeding once the acute episode of bleeding is

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