Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent.
BACKGROUND
In-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model.


METHODS
Randomized, blinded, prospective animal study.


METHODS
Bilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n = 8); polymer control stents (n = 10); low-dose sirolimus-eluting stents (n = 9); and high-dose sirolimus-eluting stents (n = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week.


RESULTS
Treatment with low-dose sirolimus was associated with a 23% (P = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days.


CONCLUSIONS
Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.
Laboratory for Experimental Cardiology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
Bruce D
BD
Klugherz
Gerard
G
Llanos
Warren
W
Lieuallen
Gregory A
GA
Kopia
George
G
Papandreou
Pallassana
P
Narayan
Brett
B
Sasseen
Steven J
SJ
Adelman
Robert
R
Falotico
Robert L
RL
Wilensky
D000818:Animals; D019917:Blood Vessel Prosthesis Implantation; D020099:Coated Materials, Biocompatible; D003324:Coronary Artery Disease / Q000150:complications / Q000188:drug therapy / Q000601:surgery; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006083:Graft Occlusion, Vascular / Q000209:etiology; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008955:Models, Cardiovascular; D011446:Prospective Studies; D011817:Rabbits; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D020123:Sirolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015607:Stents; D013997:Time Factors; D016896:Treatment Outcome
D020099:Coated Materials, Biocompatible; D007166:Immunosuppressive Agents; D020123:Sirolimus