Sirolimus-eluting stents in the canine cerebral vasculature: a prospective, randomized, blinded assessment of safety and vessel response.

Object: Use of the sirolimus-eluting stent has led to a reduction of in-stent stenosis following treatment of coronary atherosclerosis, whereas treatment of intracranial atherosclerosis with bare-metal stents results in excessive restenosis rates of approximately 40%. Neurotoxicity effects and vessel injury are unknown in the cerebral vasculature. To assess the safety profile and vascular effects of sirolimus-coated stents, the authors conducted a prospective comparative study in which drug-eluting and bare-metal stents were implanted in the canine basilar artery (BA).

Methods: Sixteen mongrel dogs were randomized (eight animals per group) to receive either bare-metal 1.5 x 8-mm (six-cell) stents or sirolimus-eluting stents of the same dimensions. Interventionists, histopathologists, and histopathology technicians who participated in the study were blinded to the stent characteristics. Stents were implanted in the canine BA. Serial peripheral blood samples were obtained during the 1st week after implantation to determine the time-dependent serum concentration of sirolimus. Follow-up angiographic studies were performed 30 days after stent implantation to assess the effects of stent placement on the BA and brainstem perforating vessels. Explantation of the stent and BA was performed immediately after angiography by using a pressurized formalin fixation procedure. Histological and computer-assisted morphometric analyses of specimens obtained in each animal were performed. Sirolimus could not be detected in peripheral blood samples obtained later than 24 hours posttreatment. On follow-up angiography, all perforating vessels observed on initial angiograms remained patent, and no evidence of parent vessel damage or pseudoaneurysm formation was observed. Explanted vessels and brainstem sections did not demonstrate evidence of histological neurotoxicity, such as gliosis or infarction. No significant differences were found in the time to endothelialization of bare-metal and sirolimus-coated stents. Smooth-muscle cell (SMC) proliferation, the putative agent for restenosis, was lower in animals receiving sirolimus-coated stents (p = 0.003). Additionally, intimal fibrin density was increased in the dogs treated with sirolimus-coated stents (p < 0.0001). Histological evidence of an inflammatory response demonstrated a trend toward a reduced response in the sirolimus group (mean 0.58) compared with the bare-metal group (mean 0.83, p = 0.33).

Conclusions: No neurotoxic effects were observed in the intracranial vessel walls or brainstem tissue in which sirolimus-coated stents were implanted. Compared with bare-metal stents, the sirolimus-coated devices did not impair endothelialization and, furthermore, tended to reduce the proliferation of SMCs. These findings indicate that sirolimus-coated devices may inhibit in-stent stenosis. Further studies with longer-term follow up are required to assess the restenosis rates of sirolimus-coated stents implanted in the intracranial vasculature.