Oral Everolimus Inhibits In-Stent Neointimal Growth

Abstract

Background— Rapamycin (sirolimus)-eluting stents are associated with reduced restenosis rates in animal studies and initial human trials. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries. Methods and Results— New Zealand white rabbits were randomized to everolimus 1.5 mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for each group. Drugs were administered by oral gavage. Stents were deployed in both iliac arteries, and arteries were harvested 28 days after stenting. Group 1 everolimus-treated rabbits experienced weight loss and anorexia, which resolved after the everolimus dose was lowered on day 14. Group 2 animals were healthy for the duration of everolimus dosing. Both everolimus treatment groups significantly reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal thickness in groups 1 and 2, respectively). In group 2 everolimus-treated animals, the neointima was healed or healing, characterized by stent struts covered by a thin neointima, overlying endothelial cells, and only small foci of fibrin. Scanning electron microscopy showed >80% stent surface endothelialization in group 2 everolimus-treated rabbits. Conclusions— Oral everolimus suppresses in-stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was well tolerated and was associated with significant neointimal healing.

Long time clinical outcomes of limus-eluting stent versus paclitaxel-eluting stent in patients undergoing percutaneous coronary artery intervention: A meta-analysis of randomized controlled clinical trials

“…LBS and PES are the two most common DES in clinical practice. As mentioned before, the neointimal proliferation pharmacological mechanisms differ significantly between LBS and PES [8][9][10]. Thus, it is reasonable to hypothesize that LBS and PES would have different clinical outcomes, especially over a long period of time.…”

“…Sirolimus is a potent immunosuppressant agent, which induces expression of the cyclin-dependent kinase inhibitor, p27 kip1, blocks the cell cycle at the G1 to S phase [9]. Everolimus can also exert anti-proliferative effect by inhibiting cell proliferation and inducing cell cycle arrest in the late G1 stage [10].…”

Antimonocyte chemoattractant protein-1 gene therapy reduces experimental in-stent restenosis in hypercholesterolemic rabbits and monkeys

“…Small-scale neointimal formation is also reported in normocholesterolemic rabbits (0.1370.03 mm). 29 This difference might be because hypercholesterolemic animals were used in the present study. Although the appropriate animal model for evaluation of experimental in-stent restenosis is uncertain, the hypercholesterolemic non-human primate model might have an advantage over normocholesterolemic nonprimate animal models, because (1) adequate degrees of neointimal hyperplasia develop after stenting and (2) vascular inflammatory and proliferative responses to injury in non-human primates are presumed to be closer to those in humans than other nonprimate models.…”

Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin

“…33 Previous studies of rapamycin-or everolimusimpregnated stents in animal models have shown that, compared to controls, local drug delivery inhibited within-stent stenosis or intimal hyperplasia by approximately 50%, but not much more. [34][35][36] Clinical trials with rapamycin-impregnated coronary stents have found within-stent restenosis to be nearly completely eliminated, indicating that atherosclerotic lesions may be more sensitive to rapamycin than normal animal arteries. 37 Human leukocytes are more sensitive to the antiproliferative effect of rapamycin than porcine leukocytes, 38 and the clearance of systemic rapamycin is slower in humans than in other species.…”