We conducted a controlled multicenter trial with central randomization and evaluation of events under blind conditions involving 652 patients with unstable angina. Patients were treated either with conventional therapy alone (group C) (n = 338) or with conventional therapy combined with an inhibitor of platelet aggregation, ticlopidine 250 mg b.i.d. (group C + T) (n = 314). Patients were assigned randomly within 48 hours of admission and followed up for 6 months. With the "intention-to-treat" approach, the primary end points, vascular death and nonfatal myocardial infarction, were observed in 13.6% of the patients in group C and in 7.3% of the patients in group C + T, which is a reduction in risk of 46.3% (p = 0.009). Vascular mortality was 4.7% in patients in group C and 2.5% in patients in group C + T, which is a reduction in risk of 46.8% (p = 0.139). The risk of nonfatal myocardial infarction was reduced by 46.1% (p = 0.039), with a frequency of 8.9% in patients in group C and 4.8% in patients in group C + T. New Q wave myocardial infarction occurred with a frequency of 6.8% in patients in group C and 3.8% in patients in group C + T, which is a reduction in risk of 44.1% (p = 0.091). Fatal and nonfatal myocardial infarction was 10.9% in patients in group C and 5.1% in patients in group C + T, which is a reduction in risk of 53.2% (p = 0.006). These findings confirm the importance of platelets in the pathogenesis of unstable angina and the usefulness of antiplatelet treatment for the prevention of cardiovascular events.

F2-Isoprostanes are prostaglandin (PG) isomers formed in situ in cell membranes by peroxidation of arachidonic acid. 8-epi PGF2alpha and IPF2alpha-I are F2-isoprostanes produced in humans which circulate in plasma and are excreted in urine. Measurement of F2-isoprostanes may offer a sensitive, specific, and noninvasive method for measuring oxidant stress in clinical settings where reactive oxygen species are putatively involved. We determined whether isoprostanes were present in human atherosclerotic lesions, where lipid peroxidation is thought to occur in vivo. 8-epi PGF2alpha ranged from 1.310-3.450 pmol/micromol phospholipid in atherectomy specimens compared with 0.045-0.115 pmol/micromol phospholipid (P < 0.001) in vascular tissue devoid of atherosclerosis. Corresponding values of IPF2alpha-I were 5.6-13.8 vs. 0.16-0.44 pmol/micromol phospholipid (P < 0.001). Levels of the two isoprostanes in vascular tissue were highly correlated (r = 0.80, P < 0.0001). Immunohistochemical studies confirmed that foam cells adjacent to the lipid necrotic core of the plaque were markedly positive for 8-epi PGF2alpha. These cells were also reactive with anti-CD68, an epitope specific for human monocyte/macrophages. 8-epi PGF2alpha immunoreactivity was also detected in cells positive for anti-alpha-smooth muscle actin antibody, which specifically recognizes vascular smooth muscle cells. Our results indicate that 8-epi PGF2alpha and IPF2alpha-I, two distinct F2-isoprostanes and markers of oxidative stress in vivo, are present in human atherosclerotic plaque. Quantitation of these chemically stable products of lipid peroxidation in target tissues, as well as in biological fluids, may aid in the rational development of antioxidant drugs in humans.