Pentoxifylline as an Adjunct Therapy for Patients With Eisenmenger Syndrome

Study Overview
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Brief Summary
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The Eisenmenger syndrome corresponds to the most advanced form of pulmonary arterial hypertension associated with congenital heart disease. The syndrome causes chronic hypoxemia, with an increase in erythrocyte mass, which predisposes to thrombotic complications. Pentoxifylline is a xanthine derivative and it is considered as a hemorrheological agent with described effects of reduction in erythrocyte and platelet aggregation, adhesion and activation of leukocytes, and endothelial damage. The main objective of this study is to verify if the chronic oral administration of pentoxifylline to Eisenmenger patients induces an increase in the circulating levels of thrombomodulin, a naturally occurring proteoglycan with anticoagulant, anti thrombotic and anti-inflammatory properties.

Detailed Description
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The Eisenmenger syndrome corresponds to the most advanced form of pulmonary arterial hypertension associated with congenital heart disease. The syndrome causes chronic hypoxemia, with an increase in erythrocyte mass, which predisposes to thrombotic complications. It also involves endothelial dysfunction characterized by increase in the circulating levels of von Willebrand factor, tissue-type plasminogen activator and P-selectin, with a reduction in the plasma concentration of thrombomodulin. The usual drug treatment is represented by the use of prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors and, eventually, anticoagulation with warfarin. However, the difficulty of controlling the chronic use of warfarin and the few studies with other oral anticoagulants, brings the possibility of using drugs not specifically designated as coagulation inhibitors, such as pentoxifylline. This drug is a xanthine derivative and it is considered as a hemorrheological agent with described effects of reduction in erythrocyte and platelet aggregation, adhesion and activation of leukocytes, and endothelial damage. It is, therefore, considered as an agent capable of reducing blood viscosity and improving erythrocyte deformability probably due to an increase in intracellular adenosine triphosphate (ATP), with a reduction in Ca++ and phosphorylation of membrane proteins. The objective of this study is to verify if the chronic oral administration of pentoxifylline: 1) induces an increase in the circulating levels of thrombomodulin, a naturally occurring proteoglycan with anticoagulant, anti thrombotic and anti-inflammatory properties; 2) stabilizes or induces a reduction in circulating tissue factor and thrombin-antithrombin complexes; 3) changes the expression of thrombomodulin and tissue factor in circulating monocytes; 4) offers protection against the occurrence of predefined clinical events; 5) provides improvement in physical capacity, peripheral oxygen saturation, hematocrit level and right ventricular function. The main study outcome is biochemical: change from baseline (increase) in circulating levels of thrombomodulin at 3 months and 6 months of oral use of pentoxifylline. It will be a prospective, single-center, randomized study. Forty-eight adult patients with Eisenmenger syndrome who are already using specific therapies for pulmonary arterial hypertension will be included and these will be randomized to receive pentoxifylline as an adjunctive treatment or remain under routine therapeutic measures for pulmonary arterial hypertension. Oral pentoxifylline will be started at the dose of 400 mg/day for 30 days, followed by 800 mg/day for 5 months, completing the 6-month period of the study. The routine treatment for pulmonary arterial hypertension will be maintained for all patients.

Official Title
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Pentoxifylline as an Adjunct Therapy for Patients With Eisenmenger Syndrome: a Randomized Study

Conditions
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Eisenmenger Syndrome

Intervention / Treatment
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* Drug: Pentoxifylline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eisenmenger syndrome in functional class II, III or IV (World Health Organization for Pulmonary Hypertension). Using or not oral anticoagulation with warfarin. Exclusion Criteria: Hospitalized. History of relevant and/or repetitive bleeding. Relevant comorbidities with specific treatments. Systemic syndromes, except Down syndrome. Candidates for surgical treatment of any nature, except dental. Clinically manifest systemic infectious or inflammatory disease. Thrombocytopenia (<80x10*9 platelets/L). Patients in chronic anticoagulation regimen other than warfarin. Diabetics individuals. Pregnancy in progress, interruption of contraception or amenorrhea. History of intolerance of pentoxifylline or other xanthine derivatives. Creatinine clearance less than or equal to 30 mL/minute.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No treatment group<br>24 patients that will continue receiving routine treatment for PAH | |
| Other: Pentoxifylline<br>24 patients that will receive pentoxifylline and the routine treatment for PAH | Drug: Pentoxifylline<br>* Oral Pentoxifylline 400 mg/day for 30 days, followed by 800 mg/day for 150 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of Thrombomodulin | Change in plasma concentration of thrombomoduin at 3 months and 6 months of pentoxifylline therapy compared to baseline. | 3 months and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of tissue factor | Change in plasma concentration of tissue factor at 3 months and 6 months of pentoxifylline therapy compared to baseline. | 3 months and 6 months | 
| Monocyte thrombomodulin content | Change in mean fluorescence intensity (MFI) for thrombomodulin in circulating (blood) monocytes measured by flow cytometry 3 months and 6 months of pentoxifylline therapy compared to baseline. | 3 months and 6 months | 
| Monocyte tissue factor content | Change in mean fluorescence intensity (MFI) for tissue factor in circulating (blood) monocytes measured by flow cytometry 3 months and 6 months of pentoxifylline therapy compared to baseline. | 3 months and 6 months | 
| Plasma concentration of other markers of thrombosis | Change in plasma concentration of D-dimer and thrombin-antithrombin complexes at 3 months and 6 months of pentoxifylline therapy compared to baseline. | 3 months and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thrombosis, Pulmonary Hypertension, Congenital Heart Disease, Pentoxifylline, Thrombomodulin, Tissue Factor