Thromboxane Receptor Antagonist to Improve Endothelial Function

Phase 2

Completed

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

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.

Arm && Interventions

Group	Intervention	Description
Ifetroban	Ifetroban Sodium	Ifetroban 250 mg oral capsule administered once daily for a minimum of 4 weeks.
Placebo	Placebo	Matching placebo administered once daily for a minimum of 4 weeks.

Primary Outcome Measures

Name	Time	Method
Change in Reactive Hyperemia Index (RHI)	Baseline to 4 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Change in Percent Flow-mediated Vasodilation (FMD)	Baseline to 4 weeks	The measure is the change in flow-mediated vasodilation (FMD) as measured by Brachial vasoractivity
Change in Urinary TXB2-M	Baseline to 4 weeks	Urinary urinary TXB2-M measured by 11-dhTXB2 ELISA