Pentoxifylline as an Adjunct Therapy for Patients With Eisenmenger Syndrome

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

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.

Study Overview

• Status: Recruiting
• Conditions: Eisenmenger Syndrome
• Intervention / Treatment: Drug: Pentoxifylline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Antonio Augusto Barbosa Lopes, MD; Phone Number: +55 11 2661-5409; Email: aablopes@usp.br
• Study Contact Backup: Name: Mariana Cappelletti Galante, PharmD; Phone Number: +55112661-5709; Email: Mariana.galante@hc.fm.usp.br

Study Locations

• Brazil
  • São Paulo, Brazil
    • Recruiting
    • Antonio Augusto Barbosa Lopes
    • Contact: MarianaCappelletti Galante, PharmD; Phone Number: PharmD +55 11 2661-5709; Email: Mariana.galante@hc.fm.usp.br
    • Sub-Investigator: Nair Maeda, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 78 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Eisenmenger syndrome in functional class II, III or IV (World Health Organization for Pulmonary Hypertension).
2. Using or not oral anticoagulation with warfarin.

Exclusion Criteria:

1. Hospitalized.
2. History of relevant and/or repetitive bleeding.
3. Relevant comorbidities with specific treatments.
4. Systemic syndromes, except Down syndrome.
5. Candidates for surgical treatment of any nature, except dental.
6. Clinically manifest systemic infectious or inflammatory disease.
7. Thrombocytopenia (<80x10*9 platelets/L).
8. Patients in chronic anticoagulation regimen other than warfarin.
9. Diabetics individuals.
10. Pregnancy in progress, interruption of contraception or amenorrhea.
11. History of intolerance of pentoxifylline or other xanthine derivatives.
12. "Creatinine clearance" less than or equal to 30 mL/minute.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Sao Paulo General Hospital
• Collaborators: InCor Heart Institute
• Investigators: Principal Investigator: Antonio Augusto Barbosa Lopes, MD, InCor Heart Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2022
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: August 24, 2022
• First Submitted That Met QC Criteria: November 3, 2022
• First Posted (Actual): November 10, 2022

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Congenital Heart Disease; Thrombosis; Pentoxifylline; Tissue Factor; Thrombomodulin
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Syndrome; Eisenmenger Complex; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: CAAE 57562322.5.0000.0068

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No