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Historically, “breakthrough” technologies in the field of interventional cardiology have been developed at intervals of approximately 1 decade. Thus, balloon angioplasty was applied in the early 1980s, bare metal stents (BMS) in the early 1990s, and DES were introduced in the early 2000s. Next-generation stents currently being tested and beginning to demonstrate promising outcomes must also target the enhancement of safety profiles. These can be divided into 2 categories: (1) DES with bio-absorbable polymer (which becomes a BMS after drug elution)3 and (2) drug-eluting bioabsorbable “scaffolding” technology (the platform disappears after drug elution).4 Thus, anticipating further advances in developing such promising bio-absorbable polymer technologies, it is now timely to ponder what we have learned from the experience gathered so far with durable polymer-coated DES. The 3 basic components of DES, which together are considered crucially important for determining performance, are the drug, the polymer, and the stent platform. Recalling the first-in-man trial of sirolimus-eluting stents, different drugelution patterns were compared and it was decided to adopt the “slow release” type (Cypher, Cordis, Miami Lake, FL, USA).5 Owing to its clinical success, gradual-elution for up to several months became the “model” for subsequent products. Furthermore, sirolimus-derivatives (ie, everolimus, zotarolimus, and biolimus A-9, the so-called “limus family”) have been extensively used in DES, and have mostly achieved good results. Control of neointimal hyperplasia (NIH) is a primary objective of using DES. Optimal neointimal control not only requires reducing the “average” NIH, but also minimization of its “variations” (ie, lesion-to-lesion variation and distribution along the length of the vessel). If such variations can be minimized, average NIH is theoretically no longer so important, because of the accurate prediction of late lumen dimension at the time of the procedure. However, in practice, we have learned that there is a relationship between these variations and the average degree of NIH. To minimize such variations (to obtain the most consistent clinical outcomes), at the very least we need to equip current DES with a durable polymer that will give them a strong NIH suppressive capacity. The zotarolimus-eluting stent, Endeavor (Medtronic, Santa Rosa, CA, USA), has shown unique performance. Its neointimal suppression capacity is relatively low compared with the other approved DES, thought to be related primarily to a shorter drug-elution period (mostly within 2 weeks) because of the nature of its biocompatible polymer. Accordingly, the polymer was modified to resolve this problem of a short drug-elution period, and the result was designated Endeavor “Resolute” (85% of the drug elutes within 60 days but elution continues up to 180 days). The difference between the original and modified versions resides solely in the polymer applied, whereas drug, drug dose, and the “Driver” stent platform are identical. Therefore, their comparison illustrates how differences in the polymer or drug-elution profile affect stent performance. The study by Waseda et al in this issue of the Journal confirmed the sustained stronger neointimal suppression by the Resolute stent during up to 9 months follow-up.6 An advantage of this study group is that the authors analyzed a series of DES trials conducted over a decade and pooled the data accumulated by consistent intravascular ultrasound methods.7 According to their study, in terms of neointimal control, Resolute is superior to the other zotarolimus-eluting stents, and almost equivalent to Cypher. Modification of drug-elution profiles is thus shown to alter efficacy. Maximizing safety is the other objective of DES. Concerns regarding late or very late stent thrombosis (ST) remain as the biggest unresolved issues of DES use. NIH reduction and optimal coverage of stent struts seem to be essentially contradictory aspects of DES. However, we still do not precisely understand the relationship between the degree of NIH and the probability of ST. Some vascular “over-reactions”, such as late incomplete stent apposition (LISA), are considered likely to be associated with ST. Endeavor is slightly less effective in neointimal control, but guarantees low rates of LISA (0–1%).8 Given the enhanced efficacy, LISA occurred rather more frequently (6.7%) with Resolute, as first reported

Modifying the Drug Elution Profile for Neointimal Control