Thromboxane Receptor Antagonist to Improve Endothelial Function

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.

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.