Endothelialization of drug eluting stents and its impact on dual anti-platelet therapy duration

Abstract

Coronary artery disease is a leading cause of death and disability worldwide with contemporary treatment strategies employing both optimal medical therapy and catheter based percutaneous coronary intervention (PCI) with drug eluting stents (DES). While DES have dramatically reduced restenosis rates, their use has been associated with an increased risk of late stent thrombosis and accelerated neointimal atherosclerosis (i.e. “neoatherosclerosis”) both major contributors to late stent failure. The underlying substrate of late DES failure is likely related to vascular endothelial dysfunction such as poor endothelial regrowth and barrier function (i.e. “endothelial healing”). Initial concerns with 1st generation DES have lead to improvements in mechanical and biologic properties of current 2nd generation DES, which inhibit endothelial regrowth to a lesser extent, lessening late stent failure and resulting in an overall improved safety profile. Current guidelines recommend duration of at least one year of dual anti-platelet therapy with aspirin and a thienopyridine agent such as clopidogrel or prasugrel as sufficient to prevent late thrombotic complications. Recent studies, however, suggest a shorter duration of dual anti-platelet therapy may be equally as safe and efficacious in preventing stent thrombosis with newer generation DES. However, higher risk populations such as patients receiving 1st generation DES or those with increased risk for future ischemic events may benefit from a longer duration (i.e. 30 months) of DAPT to prevent major cardiovascular events with the caveat that such an approach may be associated with an increased risk for bleeding. This review examines the vascular responses to 1st and second generation DES and recent clinical trials examining DAPT duration.

Duration of dual antiplatelet therapy after various drug-eluting stent implantation

“…However, these pharmacological agents locally released from DES also impair arterial healing which leads to delay and sometimes-incomplete endothelization in the stented portion of the vessel and thus increasing the risk of late ST when compared to BMS [20]. DAPT can reduce the risk of ST [20].…”

Endothelial repair in stented arteries is accelerated by inhibition of Rho-associated protein kinase

“…Given the essential role of EC in suppressing inflammation and thrombosis, the restoration of functional vascular endothelium is an important therapeutic goal to avoid the lethal consequences of in-stent restenosis and thrombosis 1 , 2 . There are several factors that can potentially influence re-endothelialization in stented arteries, one of which is the presence of the stent itself that provides a non-physiological surface for cell adhesion and alters blood flow 3–5 .…”

“…They are coated with sirolimus (Cypher) that targets the mammalian target of rapamycin pathway or paclitaxel (Taxus) that targets microtubules to suppress cell motility and mitosis. Although drug-eluting stents have effectively reduced rates of restenosis, they have also been associated with a higher incidence of late and very late thrombosis 1 , 2 , 6 . These deleterious effects have been attributed, in part, to the effects of cytostatic compounds on vascular endothelium leading to delayed healing and subsequent exposure of stent struts for thrombus initiation 6–8 .…”

Analytical modeling of drug dynamics induced by eluting stents in the coronary multi-layered curved domain

“…In order to contribute to a better understanding and characterization of dominant effects related to the previously-mentioned factors, many in-vivo and in-vitro experimental studies, as well as (pre-)clinical trials and follow-up analyses have been recently carried out (e.g., [7][8][9][10][11][12][13][14][15][16][17]). Furthermore, in the last few years many theoretical and computational models have been also developed, aiming to provide insights into the drug-release mechanisms, as well as to establish analysis tools and parametric indications for conception and design of effective DESs and therapeutic strategies.…”

“…Other model parameters are set as inTable 1.by considering different sets of values for model parameters within typical physiological and clinical ranges-reveal the model capable to properly describe well-established evidence from in-vivo and invitro experimental analyses, as well as from (pre-)clinical trials and follow-up studies (e.g.,[7][8][9][10][11][12][13][14][15][16][17]31,32,55]). Further quantitative comparisons among present results and available experimental data have not been performed, due to the wide patient-dependent variability of many model parameters.…”