Thromboxane Prostaglandin Receptor Antagonist and Carotid Atherosclerosis Progression in Patients With Cerebrovascular Disease of Ischemic Origin

Thromboxane prostaglandin receptors (TPRs) are deeply involved in the atherosclerotic process whether they are located on platelets, immune cells (monocytes/macrophages or lymphocytes), or vascular cells (smooth muscle cells, endothelial cells). Animal experiments suggested that the inhibition of TPRs has a broad action on atherosclerosis, that is, decrease in atherosclerotic plaque formation and induction of a regression of atherosclerotic plaque. Terutroban is a specific TPR antagonist, of which antiplatelet properties have been established. In addition, Terutroban potentially has antiatherosclerotic properties. Extent and progression of atherosclerosis can be noninvasively measured in large groups of patients repeatedly in a valid and reproducible manner. Using ultrasound, such measurements include common carotid intima-media thickness (CIMT) and presence of atherosclerotic plaques. The rate of change in CIMT over time has been used as a primary outcome measure in a Background and Purpose—Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques. Methods—A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period. Results—Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, –0.004 to 0.016) and –0.005 mm per year (95% confidence interval, –0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, −0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77–1.07). Conclusions—Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%. Clinical Trial Registration—URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66157730. (Stroke. 2014;45:2348-2353.)