Morphologic Predictors of Drug-eluting Stent Thrombosis

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Citation
US Cardiology, 2007;4(1):75-6

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Polymer-based sirolimus (Cypher®) and paclitaxel (Taxus®) drug-eluting stents (DES) have reduced rates of restenosis and target lesion revascularization (TLR) compared with bare-metal stents (BMS) and have launched a revolution in the interventional treatment of symptomatic coronary artery disease.1,2 However, this overwhelming enthusiasm has recently been dampened by safety concerns regarding a small but significant increase in the rate of late DES thrombosis compared with BMS.3–5 Clinical studies have identified several patient-related risk factors for late stent thrombosis (LST), such as diabetes, low ejection fraction (EF), renal failure, and discontinuation of anti-platelet therapy.6 Our understanding of the pathophysiology of late DES thrombosis is derived from both preclinical animal and human pathological studies. Little was known about the pathology of DES in humans until a recent study from our laboratory of 40 autopsy cases that demonstrated delayed arterial healing, evidenced by persistence of fibrin, minimal neointimal thickening, and incomplete re-endothelialization compared with 25 matched BMS implants of similar duration.7 This type of detailed morphometric and histological analysis of these specimens has allowed us to understand how the vascular responses of the current generation Cypher and Taxus DES differ from those of BMS, and has also emphasized the importance of assessing healing responses in evaluating the safety of DES.

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.

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