An intricate interplay between stent drug dose and release rate dictates arterial restenosis

Abstract

Since the introduction of percutaneous coronary intervention (PCI) for the treatment of obstructive coronary artery disease (CAD), patient outcomes have progressively improved. Drug eluting stents (DES) that employ anti-proliferative drugs to limit excess tissue growth following stent deployment have proved revolutionary. However, restenosis and a need for repeat revascularisation still occurs after DES use. Over the last few years, computational models have emerged that detail restenosis following the deployment of a bare metal stent (BMS), focusing primarily on contributions from mechanics and fluid dynamics. However, none of the existing models adequately account for spatiotemporal delivery of drug and the influence of this on the cellular processes that drive restenosis. In an attempt to fill this void, a novel continuum restenosis model coupled with spatiotemporal drug delivery is presented. Our results indicate that the severity and time-course of restenosis is critically dependent on the drug delivery strategy. Specifically, we uncover an intricate interplay between initial drug loading, drug release rate and restenosis, indicating that it is not sufficient to simply ramp-up the drug dose or prolong the time course of drug release to improve stent efficacy. Our model also shows that the level of stent over-expansion and stent design features, such as inter-strut spacing and strut thickness, influence restenosis development, in agreement with trends observed in experimental and clinical studies. Moreover, other critical aspects of the model which dictate restenosis, including the drug binding site density are investigated, where comparisons are made between approaches which assume this to be either constant or proportional to the number of smooth muscle cells (SMCs). Taken together, our results highlight the necessity of incorporating these aspects of drug delivery in the pursuit of optimal DES design.

Keywords: Drug-eluting stents; In-stent restenosis; Modelling and simulation; Pharmacodynamics; Tissue growth.