Mark D. Johnson

BACKGROUND: Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. METHODS: We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. RESULTS: Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. CONCLUSIONS: In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.).

Captopril, an inhibitor of angiotensin converting enzyme, is widely used clinically to manage hypertension and congestive heart failure. Here captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their chemotaxis with a biphasic dose-response curve showing an initial decrease at clinically achievable doses under 10 microM and a further slow decline in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition, but was suppressed by zinc. Direct inhibition by captopril of zinc-dependent endothelial cell-derived 72-and 92-kD metalloproteinases known to be essential for angiogenesis was also seen. When used systemically on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decreasing the number of mitoses present in carcinogen-induced foci of preneoplastic liver cells and slowing the growth rate of an experimental fibrosarcoma whose cells were resistant to captopril in vitro. These data define this widely used drug as a new inhibitor of neovascularization and raise the possibility that patients on long term captopril therapy may derive unexpected benefits from its antiangiogenic activities.