Toxic vessel reaction to an absorbable polymer-based paclitaxel-eluting stent in pig coronary arteries.
OBJECTIVE
The goal of this study was to evaluate a new drug-eluting stent (DES) comprising a bioabsorbable polymer eluting a moderate dose of paclitaxel in a clinically relevant animal model.


BACKGROUND
Although DES limit restenosis, adverse vascular pathologies and toxicities continue to be of major concern. Optimization of DES components, especially completely absorbable polymers, may reduce these toxicities.


METHODS
Bare-metal (BM), absorbable polymer coating only (POLY), and polymer-based paclitaxel-eluting (PACL) stents were implanted in porcine coronary arteries using intravascular ultrasound (IVUS) to optimize stent apposition. The dose density of paclitaxel was 0.30-0.35 mcg/mm2, with in vitro elution studies demonstrating a gradual elution over 6-8 weeks. The animals were terminated at 1 week, 1 month and 3 months. Histopathologic and histomorphometric analyses were perform.


RESULTS
The arteries with PACL showed extensive smooth muscle cell necrosis at 1 week and poor apposition of stent struts at 1 month (malapposition measured as gap width between strut and internal elastic lamina), with greater gap width compared to the BM and POLY groups (0.22 mm +/- 0.02 vs. 0.03 mm +/- 0.02 and 0.02 mm +/- 0.01, respectively; p < 0.001). At 3 months, the PACL group showed rebound neointimal thickness and histological percent stenosis compared to the BM group (0.48 mm +/- 0.14 vs. 0.07 mm +/- 0.02, respectively; p < 0.001 and 59% +/- 11 vs. 17% +/- 2, respectively; p < 0.001).


CONCLUSIONS
Despite in vitro data showing slow, sustained release of paclitaxel from a bioabsorbable polymer, the porcine coronary artery model demonstrated a sequence of medial necrosis, stent malapposition and late neointimal thickening. Since the therapeutic window for paclitaxel may be narrower than currently inferred, thorough preclinical testing coupled with the polymer development process for stents eluting paclitaxel is needed.
Jabara
Refat
R
American Cardiovascular Research Institute/Saint Joseph's Hospital of Atlanta, Georgia, USA.
Chronos
Nicolas
N
Tondato
Fernando
F
Conway
Damian
D
Molema
Warner
W
Park
Kenneth
K
Mabin
Tom
T
King
Spencer
S
Robinson
Keith
K
D020341:Absorbable Implants / Q000009:adverse effects*; D000818:Animals; D023921:Coronary Stenosis / Q000209:etiology / Q000473:pathology; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000473:pathology*; D016503:Drug Delivery Systems / Q000009:adverse effects*; D004867:Equipment Design; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009336:Necrosis; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011108:Polymers / Q000009:adverse effects*; D015607:Stents / Q000009:adverse effects*; D013552:Swine; D017539:Tunica Intima / Q000473:pathology; D018084:Ultrasonography, Interventional
D011108:Polymers; D017239:Paclitaxel