The previous discussions have established the clear clinical benefits of DES compared to BMS, however which anti-proliferative drug should be eluted? The role of this agent is ultimately to limit neointimal proliferation, and consequently its ideal properties should include the following: a wide therapeutic window, a low inflammatory potential, a select ability to suppress smooth muscle cell proliferation without being toxic to the medial and adventitial cell layers and an ability to promote re-endothelialization.

Throughout the DES era two main classess of drugs have been used (Fig. 21.1): (1) immuosupressant limus analogues which function by inhibiting the mammalian target of rapamycin (mTOR), thereby reversibly inhibiting growth factor and cytokine stimulated cell proliferation in the G₁ phase of the cell cycle, and (2) anti-proliferative paclitaxel which inhibits cell replication predominantly in the G₀/G₁ and G₂/M phases of the cell cycle. The demonstrated superiority of limus-eluting DES compared to paclitaxel in randomized studies and subsequent meta-analyses in terms of significantly lower late lumen loss, repeat revascularizations, and ST [11, 12, 26] has largely led to paclitaxel losing its role in contemporary DES. However, its properties have resulted in it being the anti-proliferative agent of choice to be released from drug-coated balloons [27].

It follows that contemporary DES elute macrocyclic lactones, which are similar to sirolimus. However, modifications on the carbon atom 40 of the macrocyclic ring have lead to the development of zotarolimus, everolimus, and biolimus. Other agents such as novolimus have been produced through removal of a methyl group from carbon atom 16, and myolimus through replacement of the oxygen on carbon atom 32 of the macrocyclic ring. These agents all offer subtle differences in degrees of immunosuppression and liphophilicity, with the latter influencing the rate of drug absorption into the arterial wall. The direct influence of these different agents on stent performance is impossible to evaluate in isolation, as concurrent modifications to other aspects of stent design have also been made. Pre-clinical data comparing stents with identical platforms, polymers, drug loads and drug release kinetics but releasing everolimus, sirolimus, or zotarolimus—demonstrate that all three limus drugs have comparable effects on neointimal suppression [28]. Clinical data are available from numerous randomized studies and their subsequent meta-analyses, comparing sirolimus-, everolimus-, zotarolimus- and biolimus- eluting stents individually with either BMS or other DES, with additional data obtained from indirect comparisons between these DES from network meta-analyses [10–12, 14, 16].

Conclusions from the largest network meta-analysis by Bangalore et al. [12] which included data from 126 trials and 258,544 patient years of follow-up suggest that the thin-strut, fluoro-polymer coated everolimus-eluting stent (EES, Table 21.1) has the best combination of efficacy and safety as evidenced by:

The cobalt chromium EES stent has a strut thickness of 81 μm, and is coated with a 7.6 μm thick, non-erodable, co-polymer of poly vinylidene fluoride co-hexafluoropropylene (PVDF-HFP), and poly n-butyl methacrylate (PBMA), which facilitates elution of everolimus over 120-days. Everolimus (C₅₃H₈₃NO₁₄, molecular weight 958 Da) is a sirolimus derivative, in which the hydroxyl group at position C40 of sirolimus has been alkylated with a 2-hydroxy-ethyl group. It is slightly more lipophilic than sirolimus, and therefore, it is more rapidly absorbed into the arterial wall. Although binding of everolimus to the FKBP-12 domain is three-fold and immunosuppressive activity in vitro two to five-fold lower than with sirolimus, oral everolimus proved at least as potent as sirolimus in models of autoimmune disease and heart transplantation. The EES platform is potentially associated with less inflammation than SES and PES [29]. The thin-strut structure of the stent platform, the thromboresistant properties of the fluoro-polymer, and the reduced polymer and drug load may contribute to the low rate of ST with EES [30]. The notion of a DES being safer than a BMS represents a paradigm shift in the evolution of PCI.

The role of the stent polymer is to facilitate controlled elution of anti-proliferative drugs over a specified period of time, with their presence obsolete once drug elution has been completed. This latter fact, together with evidence identifying polymers, particularly the non-biocompatible polymers found on first generation DES as a nidus for chronic inflammation within the arterial wall leading to hypersensitivity reactions, endothelial dysfunction and subsequent delayed healing, has led to accusations that they are central to triggering late and very late ST [29, 31–33]. Valid questions have therefore been raised regarding whether the polymer should be permanent or biodegradable, (i.e. biodegrade once drug elution has been completed), or whether they are needed at all.