The Endeavor zotarolimus-eluting stent (ZES; Endeavor) is a second-generation stent based on a stronger cobalt-chromium stent platform, with improved flexibility and decreased stent strut size. In addition, the ZES uses a novel phosphorylcholine polymer coating with stable, lipid membrane analogue designed to maximize biocompatibility and minimize inflammation associated with previous polymers. As well, the polymer is engineered to shorten the drug elution time such that most of the drug is eluted during the initial injury phase. Zotarolimus is a sirolimus analogue with similar immunosuppressant properties but enhanced lipophilic properties. This key difference was featured to enhance vessel wall localization and minimize the dispersion into the circulation [33]. Indeed, preliminary animal models supported the potential benefits of this novel stenting system, resulting in less local inflammation and improved re-endothelialization compared with SESs and PESs [34]. The ENDEAVOR I trial was the first to demonstrate safety and efficacy of ZESs in humans [35]. The ENDEAVOR II trial compared the ZES with the Driver BMS, showing improved major adverse composite events (MACE) at 2 years [36]. The subsequent ENDEAVOR III trial then compared ZES with SES, with the ZES paradoxically showing greater in-stent late lumen loss (ISLL) and IRS (11.7 % vs. 4.3 %) but less MACE (0.6 % vs. 3.5 %) [37]. Long-term follow-up to 5 years displayed a “catch-up” phenomenon whereby rates of in-stent restenosis increased in SES patients to levels comparable with ZESs [38]. Similar in design, the ENDEAVOR IV trial compared ZES with PES and again found higher rates of ISR in the ZES group [39]. These findings persisted for 3 years, but clinical outcomes, mainly because of fewer MIs, were less common with the ZES, thereby suggesting a potential benefit in regard to vascular healing [40]. However, these trials were underpowered to adequately assess differences in ST. The PROTECT trial specifically addressed the incidence of ST in a randomized study of ZESs versus SESs in more than 8,700 patients followed up to 3 years and failed to demonstrate a difference in definite or probable ST rates between Endeavor and Cypher stents [41].

The Resolute represents a refinement of the Endeavor stent, using the same cobalt-chromium (Driver) stent platform and zotarolimus agent but with a novel trilayered polymer. Similarly, the newer Resolute Integrity (sometimes classified as a third-generation DES) uses the same drug and novel trilayered polymer but is based on the new Integrity stent platform providing improved deliverability. This novel trilayered polymer is composed of three main components: a hydrophilic polymer for biocompatibility, a hydrophobic polymer for drug elution control, and a polyvinyl polymer which rapidly releases the drug immediately after implantation. The net effect is the suppression of the initial inflammatory response, followed by most of the drug being eluted over the next 60 days in an attempt to improve the late healing characteristics. The RESOLUTE trial was the first clinical study to evaluate the Endeavor Resolute and enrolled patients with simple de novo lesions in a prospective, single-arm, nonrandomized trial demonstrating clinical outcomes similar to its predecessors with no cases of ST [42]. The RESOLUTE All-Comers trial then compared the Resolute with the Xience V (everolimus-eluting stent [EES]). This study population contained greater lesion complexity and demonstrated non-inferiority of the Resolute system in terms of target lesion failure (cardiac death, target vessel MI, ischemia-driven target lesion revascularization) [9]. In the recent DUTCH PEERS randomized trial, the zotarolimus-eluting stent was non-inferior to the everolimus-eluting stent with respect to the primary endpoints of target vessel failure defined as a composite of safety (cardiac death or target vessel-related MI) and efficacy (target vessel revascularization) at 12 months (absolute risk difference 0.88 %, 95 % CI −1.24–3.01 %; upper limit of one-sided 95 %, CI 2.69 %; non-inferiority p = 0.006). Both stents were similarly efficacious and safe and provided excellent clinical outcomes [43].

Everolimus, a derivative of sirolimus, is a cell cycle inhibitor designed to overcome the physicochemical properties that rendered the oral administration of sirolimus difficult [44]. Similar to its predecessor, everolimus inhibits SMC proliferation in vitro and vascular intimal thickening in animal transplant models [45]. Its cytostatic properties rendered it a potentially valuable addition to the evolving arsenal against ISR, prompting the development of the Xience V/Promus CoCr-EES in parallel to the ZES as another second-generation DES. In 2004, Grube et al. published the prospective, randomized, single center, the FUTURE I feasibility trial, demonstrating safety and improved in-stent late loss (ISLL) (i.e., narrowing of the stented segment) over BMSs at 12 months [46]. This was followed by the SPIRIT FIRST trial demonstrating similar results with EES versus BMS in de novo coronary lesions [47]. Later, the SPIRIT II trial demonstrated improvements in ISLL and neointimal volumes over the Taxus PES [48]. Similarly, the SPIRIT III trial compared the Xience V and Taxus Express demonstrating improvements in late lumen loss and lower MACE rates largely because of a few MIs [49]. The subsequent second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE) trial demonstrated improved stent and clinical outcomes in a “real-world” experience, providing further support for the superiority of second-generation EES over their PES counterparts [7]. Finally, the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) trial demonstrated non-inferiority of EES to SES in inhibiting late loss at 9 months and clinical events at 12 months [50]. The newer Promus Element has the identical drug/polymer profile of the Xience V/Promus but offers improved deliverability with a novel platinum-chromium scaffold, demonstrating non-inferiority to the Xience V/Promus in de novo lesions [51].

In summary, regarding DESs, first-generation SESs and PESs provided major advances in the treatment of obstructive CAD with marked reductions in ISR. Second-generation stents appear to be safe and efficacious and provide a modest improvement in outcomes compared with their first-generation counterparts. This difference in outcomes was recently emphasized in a large (n = 94,384 patients) observational study. Compared with the first-generation DESs and BMSs, second-generation devices are associated with a lower risk of ISR, ST, and mortality [52] Thus, these new stent platforms represent the state of the art in DES design and form the cornerstone of modern PCI.

A large-scale meta-analysis by Navarese et al. so far comparing first-generation versus second-generation DES [53] with 31,379 patients included showed the following findings:

Single and composite safety endpoints did not differ in direction or magnitude of the effect favoring durable polymer EES. The inflammation induced by the durable polymers of first-generation DES may result in delayed healing and incomplete covering of stent struts by new and functional endothelium with uncovered stent struts serving as a source for future episodes of ST. Secondly, other factors such as stent malapposition, mechanical tissue injury caused by stent struts during implantation, and, finally, polymer hypersensitivity or even toxicity, as is the case for PES [54] and in turn associated with persistent fibrin deposition, might also play a potential role. Second-generation DES was introduced to address the concerns raised by first-generation DES by both optimizing their metallic stent platform or polymer and eluted drug. That is, second-generation EES uses thin struts coated with durable, fluorinated polymer, which has been shown to have thromboresistant properties in experimental studies. Similarly, ZES-R combined more rapid elution kinetics than SES in the same time offering thinner, more biocompatible phosphorylcholine polymer placed on a cobalt alloy stent platform. In the meta-analysis, which compared first-generation versus second-generation DES data for most robust evidence of safety endpoints, second-generation EES was found superior to first-generation PES but not to SES. This might have been attributed to the proven overdose and/or accumulation of paclitaxel in the arterial wall due to a coronary uptake, in turn leading to toxicity, inflammation, and late in-stent stenosis, which is not the case with SES [55]. The superiority of thin strut EES and ZES in reducing the incidence of MI in the short clinical follow-up might also come from mechanistic reasons. Indeed, the positive clinical effect might be related to the more frequent side-branch jailing with thick strut devices (SES Cypher 140 μm and PES Taxus Express 134 μm vs. ZES Endeavor/Resolute 91 μm and Abbott Xience V 81 μm), resulting in turn in higher rates of periprocedural MI [56–58]. Although ST should be considered a surrogate safety endpoint, which must be interpreted in the perspectives of MI and mortality, it remains a devastating complication and is often associated with high rates of mortality and morbidity. Second-generation EES was associated with significantly lower rates of definite and definite or probable ST in short-term analysis compared with first-generation DES; this finding is in line with other meta-analyses [53, 59] showing the superiority of EES over BMS and first-generation and second-generation DES in reducing early (0–30 days) and late (31 days–12 months) ST. This analysis integrated the most updated data and enriches the previous findings of longer follow-up clinical data for particular devices, demonstrating for the first time that EES reduces definite and definite or probable ST also beyond these time frames (very late ST) compared with first-generation DES. Notably, data on EES do not reflect the performance of second-generation ZES-E in terms of stent thrombosis; indeed, Endeavor was found to even increase the incidence of definite ST as compared with SES at ≤1 year, mainly driven by the results of the SORT OUT III [60–62] and ZEST [63] trials. As zotarolimus is a synthetic analogue of sirolimus, the disparities between stents are attributed to different kinetics of drug release from the polymers used for drug elution (1 week with ZES and 3 months with SES). It is postulated that quick zotarolimus release and high initial concentrations not only affect the healing of the plaque and arterial wall but may also allow for exposure of the atheromatous debris to the bloodstream. Thus, increasing the risk of early ST, which is of particular importance in high-risk patients with acute coronary syndrome or multivessel disease. Design-related factors such as strut thickness, type of antiproliferative agent, drug elution kinetics, elution time, and type of polymer are all factors that may as well impact efficacy outcomes [64]. Although not a new finding, all limus-eluting DESs, with the exception of ZES-E, were associated with significantly lower rates of target lesion revascularization (TLR)/target vessel revascularization (TVR) than the first-generation PES. Taken together, inflammation-causing properties of paclitaxel along with the short-release curve of ZES-E preclude optimal suppression of procedure-related injury responses, in turn resulting in subsequent intimal hyperplasia and increased need for repeat revascularization [34]. Unlike ZES-E, the more recently introduced ZES-R, which has a much longer (up to 180 days) release curve than of the same antiproliferative agent, zotarolimus, is associated with a significant reduction in TVR/TLR compared with ZES-E [65]. Not surprisingly, MACE analysis confirmed the single-outcome findings with second-generation EES outperforming first-generation PES at ≤1 year and beyond. Remarkably, the initial short-term benefit of SES over ZES-E, attributable mainly to higher rates of repeat revascularization with the latter, becomes less pronounced at long-term follow-up when drug elution is over.