Lessons from Animal Studies
While it is well recognized that arterial repair after stent placement occurs more rapidly in animals than in man, animal models still hold predictive value since the sequence of biological events associated with arterial repair is remarkably similar.⁸ Initially, Suzuki and Klugherz published their findings in the pig and rabbit models, respectively, using sirolimus-eluting stents.^9,10 Although both showed a significant reduction in neointimal formation, persistence of fibrin was also noted at 28 days. We reported an initial reduction in neointimal formation at 28 days when paclitaxel was delivered on the stent, followed by a loss of benefit at 90 days.¹¹ Moreover, paclitaxel delivery also resulted in persistence of fibrin, increase in inflammation, medial necrosis, and decreased endothelialization compared with BMS at 28 days. These findings were confirmed in a latter study utilizing overlapping, commercially available Taxus and Cypher in the rabbit model.¹² In this study, the assessment of endothelialization was carried out on en face using longitudinally cut arteries for scanning electron microscopy analysis, a far superior technique to light microscopy. Cypher and Taxus stents demonstrated significant delay in endothelialization compared with corresponding BMS at 28 days, and this difference persisted up to 90 days. Furthermore, endothelialization in overlapping segments was further delayed compared with non-overlap segments, probably due to higher doses of the drug and polymer. These data mirrored the findings of delayed healing seen in human DES cases and pointed to the possibility of increased late thrombotic risk with this technology. However, animal models of stenting are limited by their inability to predict the timing of complete healing in man following implantation of DES.

Stent Thrombosis and Arterial Healing in Humans
At autopsy, DES stented arteries are characterized by delayed arterial healing, defined as persistence of fibrin, minimal neointimal thickening, and incomplete re-endothelialization compared with BMS of similar duration (see Figure 1).⁷ From these data, it remains unclear how long DES remain incompletely endothelialized in humans. In this study, LST was observed in 14 of 23 patients receiving Cypher or Taxus DES for >30 days. Compared with patent DES, significantly poorer endothelial cell coverage of the lumen was consistently documented in all cases of late DES thrombosis (see Figure 1). We also found several procedural and/or pathological factors—such as local hypersensitivity reactions to DES, ostial and/or bifurcation stenting, incomplete apposition of struts, and struts penetration into a necrotic core—to be associated with LST. Similar underlying mechanisms of LST were previously reported for late BMS thrombosis (except for hypersensitivity reactions), which indicates that these lesion and plaque factors may themselves provide additional barriers to healing.11 However, the timing of LST in BMS was significantly earlier than those in DES (BMS: 11 median, 70 days; interquartile range, 33-127, versus DES: 7 median, 173 days; interquartile range, 66-433; p=0.04). Endothelialization is complete at three to four months in BMS and therefore the risk of LST is minimal, whereas in DES the neointima remains unhealed for much longer periods. It remains unknown how much time it takes for DES to be fully healed, as the number of autopsy cases are too few to make reasonable assessments. This may have important implications for the duration of anti-platelet therapy. Since some risk factors for thrombosis are related to the procedure or patient factors, conditions such as bifurcation stenting, excessive stent length, overlapping stents, or incomplete apposition due to underdeployment should be avoided (see Figure 2). Other patient factors such as previous history of bleeding and non-compliance with anti-platelet therapy must be ascertained and use of DES in such patients should be avoided.