terutroban and Brain-Ischemia

One of the leading causes of mortality worldwide is ischemic stroke, which is a major contributor to neurological disability and dementia. Terutroban is a specific thromboxane A2 receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which make it a promising tool for secondary prevention of ischemic stroke.. The Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) Study is an international, multicenter, randomized, double-blind, parallel-group study in patients aged > or =55 years who have suffered ischemic strokes (<3 months) or transient ischemic attacks (<8 days), and who are stable at inclusion with no intracranial hemorrhage or nonischemic neurological diseases. Patients are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy end point is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is evaluated by assessing hemorrhagic events. The first patient was randomized in February 2006 and more than 19,000 patients will be included.. The PERFORM Study will explore the benefits of terutroban in secondary prevention of ischemic stroke. The study results are expected in 2011.

Topics: Brain Ischemia; Humans; Ischemic Attack, Transient; Multicenter Studies as Topic; Naphthalenes; Propionates; Randomized Controlled Trials as Topic; Stroke

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.. 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.. 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).. 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%.. http://www.controlled-trials.com. Unique identifier: ISRCTN66157730.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Brain Ischemia; Carotid Artery Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Disease Progression; Female; Humans; Male; Middle Aged; Naphthalenes; Propionates; Receptors, Thromboxane; Treatment Outcome

The PERFORM MRI Project was an ancillary study of the PERFORM trial. Its aim was to investigate the potential effects of terutroban in patients with atherothrombotic disorders, in comparison to aspirin, on the evolution of magnetic resonance imaging (MRI) lesions after a recent ischemic stroke or transient ischemic attack (TIA). The change in both hypointense and hyperintense lesions on the fluid attenuated inversion recovery (FLAIR) sequence, in the total brain volume and in the hippocampal volume from baseline (M1) to the final visit (M24) was assessed as well as the number of emergent microbleeds. A total of 748 patients had their MRI examination validated both at M1 and M24 during the study. At baseline, the volume of hypointense and hyperintense lesions on FLAIR images, the total brain volume, the hippocampal volume and the number of patients with microbleeds did not differ between the two groups. During follow-up, the mean volumetric increase of lesions hypointense or hyperintense on FLAIR images (from 5 to 8 %), the mean reduction of total brain volume (−0.4 %) and of hippocampal volume (−4 %), did not differ between the two treatment arms. The same parameters analysed ipsilateral to the ischaemic lesion did not differ either between the two groups. In the terutroban group, 16.3 % of patients presented with emergent microbleeds, 10.7 % in the aspirin group; this difference was not significant. In the PERFORM study, the progression of FLAIR lesions, of cerebral or hippocampal atrophy and of microbleeds did not differ between patients treated by terutroban and those treated by aspirin.

Topics: Aged; Aged, 80 and over; Aspirin; Brain; Brain Ischemia; Female; Fibrinolytic Agents; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Naphthalenes; Propionates; Secondary Prevention; Stroke

The antithrombotic, antiplatelet and endothelial activity of terutroban, a specific thromboxane prostaglandin receptor antagonist, was assessed in patients previously treated with aspirin for the prevention of ischemic stroke.. This double-blind, parallel-group, 10-day study included 48 patients (age = 70.5 +/- 9.5 years) with cerebral ischemic event and/or carotid stenosis in 4 groups: terutroban 10 mg/day (n = 13), aspirin 300 mg/day (n = 12), terutroban 10 mg/day + aspirin 300 mg/day (n = 11) or clopidogrel 75 mg/day + aspirin 300 mg/day (n = 12). The measurements included parameters from an ex vivo model of thrombosis, platelet aggregation in platelet-rich plasma and plasma biomarkers of endothelial/platelet activation.. Between days 0 and 10, the mean cross-sectional surface of dense thrombus significantly decreased with terutroban (58%, p = 0.001), terutroban + aspirin (63%, p = 0.005) and clopidogrel + aspirin (61%, p < 0.05). On day 10, the value for terutroban was significantly lower than that for aspirin (p < 0.01) and was comparable to the dual therapy terutroban + aspirin or clopidogrel + aspirin. Similar results were found for total thrombus surface and platelet adhesion. Platelet aggregation induced by the specific thromboxane prostaglandin receptor agonist U46619 was almost completely inhibited on day 10 in both terutroban groups but not in the others. As regards markers of endothelial/platelet activation or lesions, thrombomodulin significantly increased and plasma soluble P selectin significantly decreased by day 10 in both terutroban groups, whereas the von Willebrand factor did not change significantly. Terutroban was found to be safe and well TOLERATED.. Terutroban has demonstrated an antithrombotic activity that is superior to aspirin and similar to clopidogrel + aspirin; it induces a significant in vivo reduction in endothelial/platelet activation.

Topics: Aged; Aged, 80 and over; Aspirin; Biomarkers; Brain Ischemia; Clopidogrel; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Naphthalenes; Platelet Aggregation; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Stroke; Ticlopidine