New-generation metallic DES

Despite the lack of a consensus definition, representatives of early-generation DES can be assumed the Cypher sirolimus-eluting stents (SES; Cordis, Miami Lakes, Florida, USA) and the Taxus paclitaxel-eluting stents (PES; Boston Scientific, Natick, Massachusetts, USA). Despite highly effective in reducing the need for repeat revascularisation compared with bare-metal stents (BMS), early-generation DES were associated with an increased risk of late (>1 year) thrombotic events due to an excess of very late stent thrombosis.7–9 The transition from early-generation to new-generation DES entailed a broad range of refinements affecting all the three domains of a prototypical device: the metallic stent platform, the polymer carrier substance and the antiproliferative drug.

Antiproliferative drugs

Antiproliferative drugs are lipophilic molecules that distribute into the arterial vessel wall, inhibit smooth muscle cells and reduce neointimal hyperplasia and restenosis. While the antiproliferative drug paclitaxel has been widely used in the past, it has been largely replaced by analogues of rapamycin (‘limus family’) that inhibit the mammalian target of rapamycin (mTOR) and its two related complexes (mTORC1 and mTORC2), are associated with a broader therapeutic window and induce a reversible arrest of cell cycle at the G₁ to S transition phase (figure 1).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Mechanism of action of rapamycin analogues. Sirolimus, everolimus, biolimus A9, novolimus and zotarolimus are analogues of rapamycin that exert antiproliferative effects on smooth muscle cells by inhibiting the mammalian target of rapamycin (mTOR) that regulates the transition from G1 to S-phase of the cell cycle. mTOR can be found in two complexes with distinctive functions and dissimilar sensitivity to the action of rapamycin: mTORC1 is acutely sensitive to inhibition by rapamycin, whereas mTORC2 becomes typically disrupted during chronic exposure.

Durable polymer DES (DP-DES)

Although polymer coatings in DP-DES reside permanently on the stent surface after drug release, they allow for a more complete and rapid re-endothelialisation as well as a more functionally and biologically active endothelium compared with early-generation DES.13

Currently, the Xience everolimus-eluting stents (EES; Abbott Vascular, Santa Clara, California, USA) represent the new-generation DES with the most extensive investigation in a randomised clinical trial setting and has served as control arm in numerous non-inferiority trials. Direct and indirect comparisons attest to the efficacy and safety profile of the Xience EES, which has emerged as the coronary device with the lowest propensity for stent thrombosis at any time point after PCI.14 Despite identical antiproliferative drug and polymer coating, the Xience and Promus EES (Boston Scientific) differ in terms of the metallic platform, which consists of cobalt chromium and platinum chromium, respectively. While reduced strut thickness, increased radiopacity and preserved radial strength are advantages of platinum-enriched platforms, the issue of longitudinal stent shortening related to the stent design required the addition of two additional connectors in the proximal stent hoops in the Promus Premier EES. The Resolute zotarolimus-eluting stent (ZES; Medtronic, Minneapolis, Minnesota, USA) at variance with its predecessor (Endeavor ZES) features more delayed drug release, which significantly improves its antirestenotic properties and has undergone extensive clinical investigation. Several randomised, non-inferiority trials demonstrated similar safety and efficacy outcomes of the Promus EES and Resolute ZES when compared against the Xience EES, with data extending up to 5-year follow-up.15 16

Biodegradable polymer DES

Biodegradable polymers constitute temporary surface coatings that, after drug release, are eliminated from the stent surface. Polyacidic acid copolymers, such as polylactic acid or polyglycolic acid, are commonly used in BP-DES and biodegradation occurs through a hydrolytic process (table 1). Polymer degradation is a complex process that requires a variable period of time between 3 to more than 12 months according to the type and composition of BP-DES (figure 2). Therefore, the completion of drug release does not necessarily correspond to the elimination of the polymer coating from stent surface.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Structure and composition of new-generation biodegradable polymer drug-eluting stents. BES, biolimus-eluting stent; EES, everolimus-eluting stent; NES, novolimus-eluting stent; SES, sirolimus-eluting stent. Adapted from Piccolo et al.4

Collectively, data from randomised trials comparing BP-DES with new-generation DP-DES reveal similar safety and efficacy profile at 1-year follow-up (figure 3).17–25 However, a direct comparison between different BP-DES suggests that devices with thinner struts are associated with a lower risk of stent thrombosis in the early period after PCI.26 This finding has been confirmed in a network meta-analysis also accounting for available indirect evidence.27 BP-DES were originally conceived to overcome the concerns related to chronic inflammatory properties of permanent polymer coatings of early-generation DES. Along this line, long-term outcome data revealed a decreased risk of very late stent thrombosis associated with BP-DES compared with the early generation Cypher SES.28 29 However, the safety profile of BP-DES and new-generation DP-DES appears largely comparable without relevant differences in terms of very late stent thrombosis.30–32 Table 2 shows data from large randomised trials at longest available follow-up.

• Download figure
• Open in new tab
• Download powerpoint

Figure 3

Forest plot showing summary results from large randomised trials (≥500 patients per arm) comparing BP-DES versus new-generation DP-DES. Unweighted squares depict HRs or rate ratios (RR) at 12-month follow-up for target lesion failure, target lesion revascularisation (or if not available target vessel revascularisation) and definite or probable stent thrombosis. BP-DES, biodegradable polymer drug-eluting stents; DP-DES, durable polymer drug-eluting stents. Other abbreviations as in figure 2.

Polymer-free DES

Conceptually, PF-DES represent a further iteration in stent technology because they eliminate the risk of chronic tissue responses to polymers and avoid any potential issue related to polymer webbing, delamination or cracking that have been described with both durable and biodegradable polymers. Nevertheless, clinical data on PF-DES remain limited to few randomised trials, and more data regarding long-term clinical outcomes vis-à-vis polymer-based DES are needed. PF-DES are developed through both physical and chemical methods, mainly consisting of creating pores and reservoirs or coating the stent with a porous inorganic material. These technical aspects have an influence on the kinetic of drug release. For instance, the Biofreedom biolimus-eluting stents (Biosensors International, Singapore) use a stainless steel platform with a microstructured abluminal surface from which the drug is rapidly released with 98% of biolimus eliminated at 28 days.33 Conversely, the drug-filled stent (Medtronic, Santa Rosa, California, USA) features a trilayer wire design, with the inner layer being removed to create a lumen coated with sirolimus, which is released over an extended period through multiple laser-drilled holes on the abluminal side of the stent.34 Finally, in the case of the Cre8 (Alvimedica, Istanbul, Turkey), it is the conjunction between the abluminal reservoirs and a mixture between sirolimus and amphilimus, a long-chain fatty acid, to allow for a controlled drug release (70% released within 30 days with a complete elution by 90 days).35

Indications for new-generation DES

New-generation DES are indicated in all patient and lesion subsets, and there is no formal restriction to their use in clinical practice.5 In patients with stable coronary artery disease, PCI with the use of new-generation DES has been associated with improved prognosis compared with medical therapy in a large network meta-analysis of randomised trials.36 Moreover, new-generation DES have been shown to reduce by approximately one-third the risk of stent thrombosis compared with BMS in one particular trial.37 Although one may envisage a dilution of the treatment effect as the complexity of coronary disease increases, a pooled analysis of randomised trials shows that the efficacy and safety of new-generation over early-generation DES is not only maintained across the spectrum of disease but is more pronounced in more challenging anatomies.38 Along this line, a recent randomised trial comparing PCI with EES against CABG for the treatment of left main disease reported similar outcomes for both revascularisation techniques at 3-year follow-up, with very low rates of stent thrombosis (0.7%).39 The superiority of limus-based, new-generation DES for parameters of both efficacy and safety has been also established in patients with diabetes, for whom a benefit of PES was initially postulated.40 Moreover, new-generation DES represent the most effective therapy for the treatment of in-stent restenosis with a difference in diameter stenosis of about 10% at angiographic follow-up when compared against drug-coated balloons.41 Of note, stent implantation for in-stent restenosis inevitably introduces an additional metallic layer in the coronary vessel.

New-generation DES have superseded BMS also for the treatment of patients with acute coronary syndromes, including those patients undergoing primary PCI as the benefit in terms of prevention of repeat revascularisation and reinfarction during the first year after PCI is not offset by a late increase in thrombotic events, as previously described for early-generation DES.8 9 42 43 Finally, there is recent evidence supporting the use of PF-DES for patients at high risk of bleeding. After a short course of dual antiplatelet therapy for 1 month, PF-DES compared with BMS reduced the risk of repeat revascularisation and the composite of cardiac death, myocardial infarction or stent thrombosis, with a clinical benefit documented up to 2 years.44

Other metallic coronary stents

Bifurcation lesions are common among patients undergoing PCI and represent approximately 15%–20% of the treated coronary lesions. Although new-generation DES improve the treatment of bifurcation lesions by facilitating side branch access and improving angiographic outcomes in both main and side branches, bifurcation PCI is still associated with a higher risk of recurrence during follow-up.45 Therefore, several dedicated devices have been developed for the treatment of bifurcation lesions, and they can be broadly divided in stents requiring or not side branch stenting. However, these devices for bifurcation PCI have not been embraced in routine clinical practice due to the absence of clinical superiority reported so far.46 47

While balloon-expandable stents remain the standard of care among patients undergoing PCI, self-expanding DES have been developed and may be useful in specific setting such as primary PCI, in which the thrombotic milieu and vasoconstriction may predispose to early or late malapposition. Few studies with relatively smallsample size have shown procedural feasibility and encouraging surrogate outcome by using nitinol, self-expanding DES.48

In less challenging coronary lesions, amenable for direct stenting, implantation of BP-DES with a stent-on-a-wire system has been shown feasible and associated with similar angiographic outcomes compared with new-generation DP-DES.49

Bioresorbable vascular scaffolds

BRS were conceived to overcome the limitations of permanent metallic stent platforms by providing transient vessel support and local drug delivery followed by complete resorption in a variable time period (ranging from 3 to 42 months). Prototypical devices can have polymeric or metallic platform. Poly-L-lactic acid is the most commonly used polymer, and its degradation occurs through hydrolysis and depolymerisation and provides substrates for the Krebs cycle. Metal-based scaffolds are usually made of alloy combining magnesium or iron and rare earth metals to increase radial strength. Magnesium degradation occurs by corrosion and produces soft amorphous hydrohyapatite. Other materials for BRS include tyrosine polycarbonate or polylactic anhydride. Polymer or metal act as backbone for drug elution. Main features of BRS that have obtained the Conformité Européenne mark are presented in figure 4.

• Download figure
• Open in new tab
• Download powerpoint

Figure 4

Structure and composition of drug-eluting bioresorbable vascular scaffolds with Conformité Européenne (CE) mark approval. Abbreviations as in figure 2. PDLLA, poly-D-L-lactic acid; PLLA, poly-L-lactic acid.

The Absorb BVS (Abbott Vascular) represents the most extensively investigated BRS with seven randomised trials reported to date, including overall more than 5000 patients and follow-up data available beyond 1 year. In contrast to the expectations, meta-analyses of randomised trials consistently showed that the use of the Absorb BVS is associated with a higher risk of target lesion failure and myocardial infarction compared with the Xience EES.50 Although there is no difference in mortality, the risk of scaffold thrombosis is increased and particularly of concern during the very late period.51 Based on the 2-year data from the ABSORB III trial, the Food and the Drug Administration released a safety alert and recommended adherence to the prescribed dual antiplatelet therapy. It is likely that scaffold thrombosis is the result of several mechanisms that may ensue at different time points and include acute disruption, malapposition, incomplete lesion coverage, late discontinuity, late recoil, restenosis and neoatherosclerosis.52 53 Moreover, local flow disturbances in the presence of thick struts (150 µm) may precipitate scaffold thrombosis—a mechanism that may be of particular relevance in small vessels.54 At the present time, it is speculated whether adherence to dedicated implantation protocols may overcome some of the adverse events, and it seems reasonable to extend dual antiplatelet therapy in patients who have received the Absorb BVS and are at low risk of bleeding, potentially until the time of complete resorption.55

Clinical data on other BRS are limited to single-arm registries powered for angiographic surrogate endpoints. The Magmaris (Biotronik AG, Bülach, Switzerland) is a magnesium-based BRS that features a fast bioresorption process, which is completed within 1 year. Angiographic data reported a stable lumen loss between 6 and 12 months.56

Clinical perspectives on coronary stenting

Numerous clinical trials, investigating very different coronary devices, have accumulated over the past years. Available evidence suggests that new-generation DP-DES are safe and effective, with data supporting their use at long-term follow-up. Although BP-DES are non-inferior to new-generation DP-DES in terms of both safety and efficacy, available data do not suggest a clinically detectable benefit after polymer biodegradation. Metallic DES without surface polymer coatings remain promising and a realistic option for clinical application in the near future. However, the assumption of a class effect for PF-DES cannot be assumed given the substantial heterogeneity among different devices. It remains to be shown whether the mode of drug release will ensure comparable efficacy outcomes as observed with other new-generation DES. Improvements in stent structure and design remain of paramount importance irrespective of type of metallic DES and, in this context, the development of devices with very low strut thickness but maintained mechanical properties should be encouraged.

Despite the very low rates of adverse outcomes, several unmet needs remain with metallic DES. About 50% of adverse events following PCI are indeed attributable to stent-related events rather than a progression of the underlying disease.57 Moreover, patients with multivessel coronary artery disease, diabetes or diffuse disease remain challenging to treat with PCI in view of a relatively high rate of adverse cardiac events. Therefore, bioresorbable scaffolds remain a valid concept in the future. As the greater risk of scaffold-related failures emerged only in direct randomised comparisons, it is important to underscore the need for dedicated randomised trials powered for clinical outcomes. An important prerequisite of BRS remains the demonstration of non-inferiority compared with contemporary metallic DES before the assessment of the long-term benefits related to the restoration of coronary anatomy and physiology is pursued. New iterations in BRS technology are expected, and two points have to be addressed. First, the reduction of strut thickness is indispensable as already observed in the transition from early to new-generation DES. Second, the process of bioresorption has to be more predictable in vivo and free from adverse events. At the present time, new-generation metallic DES, with durable or biodegradable polymers, remain the standard of care among patients undergoing PCI in view of their excellent performance, predictable results and accumulated level of clinical evidence.