Thromboxane Receptor Antagonist to Improve Endothelial Function

Jeffrey Rade57 enrolled

Overview

This study evaluates whether addition of the thromboxane receptor antagonist to chronic aspirin therapy improves endothelial function and reduces non-platelet thromboxane generation in patients with established cardiovascular disease. Half of participants will receive ifetroban and the other half will receive matching placebo for the 4 week study period.

Thromboxane is a prostaglandin produced in healthy individuals mainly in platelets, where it mediates platelet activation and vasoconstriction via binding to cellular thromboxane-prostanoid (TP) receptors. The cardioprotective effect of aspirin is due to suppression of platelet thromboxane generation and reactivity. Unfortunately 25-50% of patients with cardiovascular disease taking ASA continue to generate thromboxane from non-platelet sources, which significantly increases their risk of atherothrombosis and death. Evidence suggests that oxidative stress is a potent stimulus for thromboxane generation in endothelial cells that involves autocrine/paracrine signaling through the TP receptor. This clinical trial addresses the central hypothesis that vascular endothelial cells under oxidative stress are a major source of non-platelet thromboxane generation in patients with cardiovascular disease and that antagonism of the TP receptor will suppress its formation and improve endothelial function.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Cardiovascular Diseases Vascular Dilation

Interventions

Ifetroban SodiumDRUG

Ifetroban sodium 250 mg capsule once daily for 4 weeks

PlaceboDRUG

Placebo arm to match Ifetroban Sodium once daily for 4 weeks.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Males and females 18-80 years of age with established cardiovascular disease * Take \>=81 mg daily of aspirin as part of their daily medical regimen * Urine thromboxane B2 metabolites \>1145 pg/mg creatinine on screening. * Able to provide written consent and comply with protocol-specific procedures. Exclusion Criteria: * Chronic oral anticoagulation with a non-vitamin K antagonist. * Anticipated change or interruption in aspirin therapy during the study period. * ST segment myocardial infarction within the past 30 days. * Cardiac surgery within the past 30 days. * Stage 4-5 renal failure or on renal replacement therapy. * An ongoing uncontrolled severe inflammatory condition. * Pregnant,intending to become pregnant or breast feeding. * Known ifetroban or aspirin sensitivity Inability to perform vascular testing. * Participation in another investigational drug trial within 30 days of randomization.

Locations (1)

University of Massachusetts Medical School

Worcester, Massachusetts, United States

Outcomes

Primary Outcomes

Change in Reactive Hyperemia Index (RHI)

The change in Reactive Hyperemia Peripheral Index (RHI) as measured by Arterial Tonometry. The Reactive Hyperemia Index (RHI) is calculated as the ratio of post- to pre-occlusion peripheral arterial tone signals on the occluded side, normalized to the control side, and further adjusted for baseline vascular tone. RHI is automatically measured by the EndoPAT 2000 software. According to the manufacturer, an RHI value greater than 1.67 is considered normal, while a lower value indicates endothelial dysfunction and is associated with an increased risk of cardiovascular events.

Time frame: Baseline to 4 weeks

Secondary Outcomes

Change in Percent Flow-mediated Vasodilation (FMD)

The measure is the change in flow-mediated vasodilation (FMD) as measured by Brachial vasoractivity

Time frame: Baseline to 4 weeks

Change in Urinary TXB2-M

Urinary urinary TXB2-M measured by 11-dhTXB2 ELISA

Time frame: Baseline to 4 weeks

Data from ClinicalTrials.gov

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