Curr Cardiol Rep (2014) 16:469 DOI 10.1007/s11886-014-0469-4

INTERVENTIONAL CARDIOLOGY (S RAO, SECTION EDITOR)

Choosing the Right Coronary Stent in the Modern Era Bora Toklu & Sripal Bangalore

Published online: 7 March 2014 # Springer Science+Business Media New York 2014

Abstract Research and development in the field of coronary stent design is a fast-evolving and fascinating journey. A device that was once introduced to salvage acute closure associated with balloon angioplasty is now the standard of care for many patients with coronary artery disease. Newer generation stents are the product of remarkable progress in technology and innovation, driven by the need to make the stents easier to deliver and to improve their safety and efficacy. As such, the design of these stents has become quite sophisticated and complex. The number of available stents has increased giving patients and physicians more choices on one hand, but also created confusion in selecting the optimal stent for a given patient. Although a ‘one size fits all’ approach may not be reasonable, several randomized trials have attested to the efficacy and safety of newer generation durable polymer drug eluting stents. This article discusses the evidence base to support various stent choices in contemporary practice.

Keywords Bare metal stents . Coronary artery disease . Drug-eluting stents . Coronary stent

Introduction Over the past 3 decades, we have witnessed research and technology driven progress in treatment of coronary artery disease pioneered by the landmark introduction of coronary stents into clinical practice. A basic theory of keeping the stenotic vessel open with a cylindrical metal platform led to a fascinating series of advancements in the design and complexity of stents. This era is marked by development of numerous types of coronary stents with ever-improving safety, efficacy profiles, and deliverability, which have remarkably expanded the application of coronary stents in today’s medicine. Until recently, use of bare metal stents (BMS) for coronary artery disease has been regarded as the benchmark for clinical safety (ie, stent thrombosis, death, and myocardial infarction) whereas drug-eluting stents (DES) have been regarded as the benchmark for clinical efficacy (ie, target lesion and target vessel revascularization—markers of restenosis). However, in an ever-evolving field of stent technology, these standards will likely be replaced by newer and better designs in the years to come. In this article, we will summarize the past experiences that brought us to today’s coronary stent technology and applications, and then review the evidence for choosing one stent over another in contemporary practice.

This article is part of the Topical Collection on Interventional Cardiology B. Toklu Virginia Commonwealth University School of Medicine, Richmond, VA, USA S. Bangalore Cardiac Catheterization Laboratory, Cardiovascular Outcomes Group, Cardiovascular Clinical Research Center, New York University School of Medicine, New York, NY, USA S. Bangalore (*) The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA e-mail: [email protected]

Today’s Coronary Stent in the Making The advancements in medicine are often triggered by the search for safer and more efficacious treatment modalities. Coronary stents were similarly introduced in clinical practice as the need arose when coronary balloon angioplasty was found associated with serious drawbacks. Dilating a stenotic vessel with a balloon, a breakthrough innovation when first introduced in 1977 by Gruntzig [1], was associated with high rates of acute vessel closure due to balloon-induced subintimal

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dissection, acute vessel recoil, and also late restenosis due to constrictive remodeling. This called for a way to keep the vessel open and stable while dilating a stenosis. In 1986, Puel and Sigwart implanted the first balloon-mounted coronary stent, a self-expandable mesh-like stainless-steel platform, opening an era of continuous progress in stent technology ever since [2]. When compared with balloon angioplasty, coronary stenting decreased rates of acute vessel closure as well as the need for repeat revascularization, and became the standard of care [3, 4]. While BMS addressed some of the drawbacks of balloon angioplasty, a significant rate of in-stent restenosis (ISR) was evidenced with BMS use [3]. Neointimal hyperplasia due to arterial injury and inflammation caused by the stent implantation led to ISR and consequently, repeat revascularizations [5]. This paved the way for development and introduction of DES in 2003, stents with antiproliferative drugs deposited at and eluted from polymers coating the metal lining of previous BMS.

First Generation DES The antiproliferative drugs of DES limited smooth muscle proliferation thereby reducing neointimal hyperplasia and the risk of restenosis. As with any new product, DES have gone through the 5 phases of development; unbridled enthusiasm, false sense of security, rude awakening, resetting of expectation, and persistent mistrust. First generation DES, mainly paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES), significantly improved the rate of target lesion restenosis and repeat revascularizations when compared with BMS [6–8]. This led to an unbridled enthusiasm and false sense of security with DES utilization rates rocketed to upward of 90 % between 2003 and 2005. However, as earlier progress has shown us before, the new innovation was later found to have previously unforeseen drawbacks. Initial research suggested that first generation DES had higher rates of late and very-late stent thrombosis (ST) when compared with BMS [9, 10], stemming from delayed endothelial healing [11]. Further concerns were raised about patient compliance to extended course of dual antiplatelet therapy with a number of studies showing a marked increase in the risk of ST when antiplatelet therapy was discontinued. Subsequently, this rude awakening led to the resetting of expectations and the utilization of DES trended down in 2007. Moreover, some evidence suggested a trend toward diminishing benefit in efficacy in late and very-late follow-up with first generation DES (ie, a late catchup phenomenon) [12–14]. Given these safety concerns with DES, BMS have been generally accepted as the benchmark for safety, whereas DES for efficacy.

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Second Generation DES Research proven facts combined with technological advancements built into the innovative designs of second generation DES, mainly cobalt chromium everolimus-eluting stents (CoCr EES), platinum chromium EES (PtCr EES), zotarolimus-eluting stents (ZES), and zotarolimus-eluting Resolute stents (ZES-R). A recent meta-analysis that pooled 76 randomized controlled trials (RCT) comparing all FDA approved stents with more than 117,000 patient-years of follow-up found that each type of DES not only reduced target vessel revascularization (TVR) rates but was also as safe as BMS [15•]. However, the study found that not all DES are created equal, and there were significant differences in efficacy with the CoCr EES, ZES-R, and the SES being the most efficacious stents at reducing restenosis (Fig. 1). Furthermore, when compared with BMS, DES except PES reduced myocardial infarction (MI), and CoCr EES even reduced ST rates [15•, 16]. The analysis found that among all of the FDA approved DES and BMS, CoCr EES was the safety stent with reduction in MI and ST when compared with BMS (Fig. 2). These findings, therefore, question the applicability of safety concerns with first generation DES and whether BMS should still be considered the benchmark for safety in light of evidenced inferiority to CoCr EES.

Anatomy of a Coronary Stent In an ever-evolving field of stent technology, a simple metal strut to keep the stenotic vessel open is not sufficient anymore. The newer designs of stents are quite complex and sophisticated. Therefore, it has become essential to understand the key components of typical DES, and how each component factor into the overall clinical performance. The Scaffold Traditionally, relatively thicker stainless steel struts were the material used for most BMS and first generation DES scaffolds. Stents with thinner struts were found to be more deliverable and to have reduced arterial damage when deployed [17, 18]. Moreover, they elicit less inflammation than a thick strut stent, further reducing the propensity for restenosis and ST [17]. In addition, thinner struts create fewer disturbances of blood flow patterns around a strut leading to less recirculation and stagnation of blood pool and have been shown to be less thrombogenic, thereby, reducing the risk of ST [17]. Cobalt chromium and platinum chromium alloy scaffolds have been introduced into the design of most second generation DES providing thinner struts with better radial strength and deliverability with less inflammation and thrombogenicity, all of which have resulted in better safety and efficacy outcomes

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Fig. 1 Risk of target vessel revascularization for various indications from network metaanalysis of various BMS vs DES studies. Adapted from: Bangalore S, Kumar S, Fusaro M, et al. Circulation. 2012;125:2873–91 [15•]; Bangalore S, Amoroso N, Fusaro M, Kumar S, Feit F. Circ: Cardiovasc Interv. 2013;6:378– 90 [40•]; and Bangalore S, Kumar S, Fusaro M, et al. BMJ. 2012;345:e5170 [50]. TVR Target vessel revascularization

[19, 20]. Most recently, stents with fully biodegradable scaffolds have been developed and are currently being tested in randomized controlled trials. Antiproliferative Drug Anti-proliferative drug content and dosage both contribute to the performance of a stent. Delayed endothelial healing, which stems from factors including dosage of antiproliferative drug and inflammatory reaction to the agent-polymer complex, plays a major role in increased rates of ST associated with first generation DES [11, 21]. Over time, the dosage of the antiproliferative drug was reduced and more biocompatible agents were used in newer stent designs. First generation DES Fig. 2 Risk of stent thrombosis for various indications from network meta-analysis of various BMS vs DES studies. Adapted from: Bangalore S, Kumar S, Fusaro M, et al. Circulation. 2012;125:2873–91 [15•]; Bangalore S, Amoroso N, Fusaro M, Kumar S, Feit F. Circ: Cardiovasc Interv. 2013;6:378– 90 [40•]; and Bangalore S, Kumar S, Fusaro M, et al. BMJ. 2012;345:e5170 [50]

contained paclitaxel and sirolimus, whereas second generation DES contained everolimus and zotarolimus as the antiproliferative agent [22, 23]. Drugs such as everolimus have been shown to have antiplatelet properties, potentially contributing to CoCr EES’ superb clinical performance. Polymer Coating The metallic strut of a stent is coated with polymer that serves to deposit and steadily release the antiproliferative drug. While the polymer serves as a conduit for drug release, it has been shown that hypersensitivity and resultant inflammation to the polymer coating lead to increase in late stent malapposition, which is a risk factor for very late ST and

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restenosis with first generation DES [11, 24]. In addition, the first generation DES’ polymers had more nonuniform coating of the polymer surface, webbing, and bonding of the surfaces and polymer delamination—all of which contribute to surface irregularities and consequently to increased inflammation. Second generation DES have more stable, biocompatible polymers with improved polymer coating technology resulting in less bonding and cracking of the surface. In addition, the fluoropolymer present on the CoCr EES renders the stent surface relatively thromboresistant by a process of fluoropassivation (preferential absorption of albumin when compared with other proteins). The resultant stent has been shown to have less inflammation and less thrombogenicity than even a BMS [17], which probably is the reason for superior results seen with CoCr EES. Similarly, ZES-R were introduced with more biocompatible polymer (BioLinx; Medtronic, Minneapolis, MN) and slower drug release kinetics—all of which have reduced the late lumen loss seen with the prior version of ZES (Endeavor; Medtronic, Minneapolis, MN) [25]. Meanwhile, polymer related drawbacks of first generation DES paved the way for the development of the biodegradable polymer and polymer-free stents, which are currently been tested in clinical trials. Table 1 shows selected features of commonly used coronary stents.

Choosing the Right Coronary Stent in the Modern Era “One size fits all” strategy may not be the right one for every patient characteristics and presentation. Several aspects of the patient’s and the lesion’s characteristics, as well as the clinical indication for percutaneous coronary intervention (PCI) need to be considered when choosing the right stent for the patient.

Dual Antiplatelet Therapy (DAPT) Duration and Compliance When choosing a coronary stent, probably the most important step is to decide whether the patient would tolerate and comply with extended duration of DAPT. Interruption of the long term DAPT poses the greatest safety risk for DES use, since noncompliance with either one of antiplatelet agents, especially the P2Y2 inhibitor, is associated with markedly increased rates of ST [26–28]. Meanwhile, the optimal duration of DAPT after DES implantation is controversial. Evidence based on first generation DES suggests a minimum duration of 6 months [9], guidelines recommend continuation of DAPT for at least 12 months after DES use [29, 30], and some trials, such as the DAPT trial (ClinicalTrials.gov Identifier: NCT00977938), are testing even longer duration of DAPT (12 months vs 30 months). However, there is accumulating evidence suggesting shorter duration of DAPT may be sufficient with second generation DES [31–33]. Consequently, ZES-R now has CE mark for 1 month of DAPT, and the CoCr EES has CE mark for 3 months of DAPT. Nevertheless, randomized controlled trials sufficiently powered to test the safety of a shorter duration of DAPT are needed. Recently published OPTIMIZE trial showed that 3 months of DAPT was noninferior to 12 months of DAPT after ZES implantation, and was associated with a lower risk of major bleeding [34•]. In the bygone first generation DES era, BMS, being the benchmark for safety, were preferred in patients with high bleeding risk, and those who can’t comply with uninterrupted DAPT due to financial, social limitations, or need for DAPT interruption due to noncardiac surgery [29]. However, it is not entirely clear if this general rule is applicable in the current era of second generation DES and especially, in the context of

Table 1 Selected characteristics of commonly used stents Stent

Platform material

Strut thickness

Polymer

Drug eluted

BMS (Liberte) BMS (Bx Velocity) BMS (VeriFLEX) BMS (Vision) BMS (Driver/Integrity) SES (Cypher) PES (Taxus Liberte) CoCr EES (Xience V/Prime) PtCr EES (Promus element) ZES (Endeavor) ZES-R (Resolute) ZES-R (Resolute Integrity)

Stainless steel Stainless steel Stainless steel Cobalt chromium Cobalt chromium Stainless steel Stainless steel Cobalt chromium Platinum chromium Cobalt chromium Cobalt chromium Cobalt chromium

0.096 mm 0.14 mm 0.097 mm 0.081 mm 0.091 mm 0.14 mm 0.097 mm 0.081 mm 0.081 mm 0.091 mm 0.091 mm 0.089 mm

NA NA NA NA NA PEVA/PBMA SIBS PBMA/PVDF-HFP PBMA/PVDF-HFP MPC, LMA, HPMA, and 3-MPMA PBMA, PHMA, PVP, and PVA (BioLinx) PBMA, PHMA, PVP, and PVA (BioLinx)

NA NA NA NA NA Sirolimus Paclitaxel Everolimus Everolimus Zotarolimus Zotarolimus Zotarolimus

3-MPMA 3-(trimethoxysilyl) propyl methacrylate, HPMA Hydroxypropyl methacrylate, LMA Lauryl methacrylate, MPC Methacryloyloxyethyl phosphorylcholine, NA Not applicable, PBMA poly n-butyl methacrylate, PEVA Poly(ethylene-co-vinyl acetate), PHMA Poly(hexyl methacrylate), PVA Polyvinyl acetate, PVDF-HFP poly vinylidene fluoride and hexafluoropropylene, PVP Polyvinylpyrrolidinone, SIBS styrene-b-isobutylene-bstyrene

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CoCr EES showing superior safety profile compared with BMS. Clinical Indication for PCI Patient presentation and the clinical indication for PCI play an important role in stent choice. Acute Coronary Syndrome Coronary stent selection in ST-elevation myocardial infarction (STEMI) is controversial. Earlier studies utilizing first generation DES in STEMI and meta-analysis derived from these studies did not show any difference in death or MI with DES when compared with BMS, except a few trials, such as the DEDICATION trial [35], that suggested a potential increase in risk of cardiac death or MI with DES use. The main benefit of first generation DES appeared to be a slight reduction in TVR rates [36–38], but there has been significant concern about potential increase in very late ST [39]. It has been shown that deployment of a stent in a lesion with high burden of thrombosis results in an increased likelihood of late stent malapposition when the underlying thrombus dissolves, leading to increased risk of ST. Moreover, determining long term DAPT candidacy is challenging in an emergent STEMI situation therefore, traditionally BMS have been preferred in STEMI. Until as recent as 2009 STEMI guidelines, DES use carried a class IIa recommendation as an alternative to BMS for primary PCI in STEMI [39]. Nonetheless, second generation DES, utilizing more biocompatible antiproliferative agents, alloys, thinner struts, and polymers than their predecessor designs, have challenged this traditional thinking. A recent meta-analysis of 28 randomized controlled trials in STEMI patients not only found similar safety and better efficacy of each type of DES over BMS, but also found that the second generation DES, specifically CoCr EES, reduced ST rates when compared with BMS [40•] (Figs. 1 and 2). In the EXAMINATION trial, patients with STEMI were randomized to CoCr EES vs BMS, and a significant reduction in ST was seen with CoCr EES both at 1 year and 2 years of follow-up when compared with BMS [41]. Interestingly, the difference was seen as early as 30 days postrandomization, attesting to the acute safety of CoCr EES. Like patients with STEMI, those with unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI) also benefit from an invasive strategy and revascularization with reduced rates of death and MI when compared with medical management alone. Similar to STEMI, DES, especially second generation DES (and perhaps preferentially CoCr EES), are preferred over BMS in UA/NSTEMI [29]. DES achieve better efficacy and similar/better safety profile compared with BMS, especially when medical comorbidities (eg, DM) and

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lesion features (eg, small vessel, long lesion) place the patient at higher risk for restenosis.

Stable Ischemic Heart Disease (SIHD) In patients with SIHD, the role of PCI to reduce the risk of death or MI is controversial and the benefit appears to be a short-term reduction in angina. Two large scale landmark trials in patients with SIHD compared optimal medical therapy with addition of revascularization vs optimal medical therapy alone, and did not show survival benefit with PCI [42, 43]. These studies used BMS predominantly with only a small proportion of patients receiving first generation DES. Given the considerable progress with second generation DES, especially CoCr EES showing superior safety and efficacy when compared with BMS, the relevance of these trials has to be reconsidered. In addition, there have been remarkable advancements in ancillary technologies to the PCI, such as an ischemia driven revascularization using FFR measurements, a strategy proven to reduce cardiovascular events compared with the anatomy driven revascularization used in the above trials [44]. A recent follow-up trial utilizing these advancements, the FAME 2 trial, although stopped early for significant reduction in primary endpoint driven by reduction in the risk of urgent revascularization, again failed to show any mortality benefit with PCI in SIHD [45]. The on-going ISCHEMIA trial (ClinicalTrials.gov Identifier: NCT01471522) utilizing the best stent and revascularization technology and medications will randomize approximately 8000 patients with moderate to severe ischemia into an invasive strategy of revascularization plus optimal medical therapy vs a conservative strategy of optimal medical therapy alone. This trial, once completed, will shed more light on this controversial area. Nevertheless, PCI with stenting is a Class IA recommendation for patients with SIHD with persistent angina despite optimal medical therapy [29, 46]. Similar to the acute coronary syndrome, DES, especially the second generation DES, outperform BMS in efficacy while providing similar/better safety profile in SIHD patients [10, 15•]. Therefore, most recent European stable angina guidelines recommend second generation DES as the standard of care as long as compliance with extended DAPT is committed [47].

Coronary Anatomy Characteristics Besides clinical presentation, patient’s comorbidities and lesion characteristics also play an important role in the choice of a coronary stent. Certain patient comorbidities and lesion characteristics may deem a coronary lesion high risk for restenosis, and therefore, may benefit most from DES rather than BMS.

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Diabetes Patients with diabetes have rapidly progressive, diffuse, and burdensome atherosclerosis in small coronary vessels—a milieu associated with increased rates of restenosis and worse cardiovascular outcomes when compared with nondiabetic patients in the balloon angioplasty era, BMS era, first generation DES era, and also in the second generation DES era. DES have consistently outperformed BMS in diabetic patients, providing marked decrease in restenosis rates while achieving similar safety outcomes [48–50]. Guidelines reflect this evidence and DES are preferred over BMS in this patient population [29]. However, choosing one DES type over another is controversial. A recent meta-analysis of 42 RCTs in diabetics including 22,844 patient years of follow-up compared individual DES types, and showed that CoCr EES is the most efficacious and the safest stent even when compared with a BMS [50] (Figs. 1 and 2). Interestingly, the only DES that has an FDA indication for treatment of patients with diabetes is the ZES-R, although head-to-head randomized trials proving its superiority over other second generation DES is lacking. Small Vessels and Long Lesions Small vessel coronary artery disease (diameter <3 mm) are associated with high rates of restenosis following stent placement. Similarly, long lesions are associated with increased rates of periprocedural complications and restenosis [51]. Therefore, DES are favored over BMS in these challenging lesions [29, 52]. Chronic Total Coronary Occlusion (CTO) CTO constitutes yet another challenging lesion subset. The benefit of PCI with stenting of CTO is controversial. Many observational studies have shown a mortality benefit of successful CTO recanalization when compared with failed interventions [53]. However, it is not clear if this benefit is a mere indication of disease severity (lesser severity in those with successful intervention and greater severity in those with failed intervention) rather than benefits from an open artery. Stent selection is similar with the current general PCI practice, and DES show better efficacy and similar safety profile compared with BMS [29, 54] second generation DES with thinner strut and polymer may therefore be preferable and more deliverable in a CTO setting.

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restenosis. Evidence is scarce and observational at best, as these lesion subsets are often excluded from randomized stent comparison trials. Nonetheless, DES are favored over BMS given the propensity for restenosis [29]. Moreover, the thinner and more deliverable second generation DES may be preferable both for acute success and for superior efficacy and safety. Saphenous Vein Grafts (SVG) PCI of SVG is associated with high rates of periprocedural MI due to distal embolization of atherosclerotic debris. DES outperform BMS in restenosis rates without compromising safety, and are favored per guidelines for SVG revascularization [29, 55]. However, the data are driven by small randomized trials and larger trials are currently underway to evaluate the efficacy and safety of DES. Cost-Effectiveness Although DES are more expensive than BMS, first generation DES are cost-effective for lesions with high restenosis risk due to reduced rates of repeat revascularization when compared with BMS therapy [56]. Guidelines recommend BMS as a reasonable option when restenosis risk is low and benefit with DES does not significantly surpass that with BMS [29]. However, the cost-effectiveness of second generation DES compared with first generation DES or BMS has not been studied sufficiently. A substudy of SPIRIT-IV trial reported medical expense reduction of $273/patient with CoCr EES use compared with PES use over 2 years of follow-up [57]. It is likely that cost-effectiveness will shift more in favor of second generation DES, especially that of CoCr EES, due to reduced rates of repeat revascularization, ST, and potentially death or MI when compared with BMS [15•]. A potential future reduction in duration of DAPT recommendations by guidelines may also help shift cost-effectiveness in favor of second generation DES.

New Innovations and Future of PCI It’s the golden age for newer and better stent designs driven by evidence based technological advancements. There is a search for better designs for potential short-comings of the current stent technology, and the field is fast evolving. Biodegradable Polymer Stents

Calcified Lesions Severely calcified lesions are challenging as they are often resistant to balloon angioplasty leading to suboptimal stent expansion, poor procedural outcomes, and increased risk of

Polymer component of first generation DES is found to be associated with hypersensitivity and inflammatory reactions leading to increased ST and restenosis [11, 24]. Therefore, biodegradable polymers were introduced in newer stent

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designs to overcome these issues. In theory, biodegradable polymer stents (BP-DES) initially function as DES potentially providing favorable early efficacy of traditional DES; and once the drug-carrying polymer is degraded, they essentially function as BMS potentially providing favorable late safety. The BP-DES stents hold promise in the traditional paradigm of stent efficacy (DES) and safety (BMS). However, the shifting paradigm of stent safety to CoCr EES has questioned the very hypothesis of BP-DES stents. We have recently completed a network meta-analysis of all FDA approved durable polymer stents and BP-DES, pooling 258,544 patient-years follow-up from 126 randomized controlled comparison trials, showing that BP-DES are more efficacious and safer compared with first generation DES; and as efficacious but less safe compared with second generation DES [58•]. The current trials of BP-DES have not been designed to either show superiority in efficacy and safety over second generation DES nor have they been designed to show reduced DAPT duration requirements. As such, the utility of BP-DES in the current era of high bar set by second generation durable polymer DES needs to be defined. If the data suggesting a possible beneficial effect of the fluoropolymer (ie, thromboresistance and anti-inflammatory) holds true, BPDES with the conversion of stent to a BMS maybe a step in the wrong direction.

short-term following stent implantation to prevent acute recoil, abrupt closure, and restenosis. However, a permanent stent has many disadvantages including persistent inflammation due to a foreign body reaction, impairment of endothelial function, and vasomotion of the coronary artery due to splinting of the artery by the metallic stents, and potentially making the coronary artery segment unfavorable for coronary artery bypass grafting in the setting of restenosis. Therefore, a stent that’s fully biodegradable can ideally provide the shortterm scaffolding needed to prevent acute closures while preserving vasomotion and other revascularization options when the scaffold fully resorbs. Clinical performance of this stent (ABSORB BVS) is currently being tested against the durable CoCr EES in 3 on-going randomized trials (ClinicalTrials.gov Identifiers: NCT01425281, NCT01751906, NCT01923740). Another disadvantage of currently available durable scaffolds is the scaffold thickness and reduced deliverability. It remains to be seen if biodegradable scaffolds can show superiority in clinical outcomes against the high bar set by the second generation durable polymer DES. Nevertheless, even if the biodegradable scaffolds prove to be noninferior to the best in class durable polymer DES, the potential advantages of restoring endothelial function and vasomotion in addition to preserving options in the setting of restenosis makes biodegradable scaffolds an appealing option.

Polymer-Free Stents

Drug-Eluting Balloons

Another route to overcome shortcomings associated with the polymer component of DES was to design polymer-free drugcoated stents (PF-DES)—stents with a microporous surface functioning as a reservoir for polymer-free antiproliferative drug elution. In the ISAR-TEST trial, PF-SES achieved similar safety and efficacy up to 5 years of follow-up compared with PES [59]. More recently, when compared with ZES, PFDES again achieved similar safety and efficacy up to 2 years of follow-up [60, 61]. Larger scale clinical trials are needed to show superiority of PF-DES to the best performer CoCr EES before PF-DES make it into clinical practice. Also, PF-DES elute most of their antiproliferative agent within a month, hence, a shorter duration of DAPT may be sufficient. Therefore, PF-DES can challenge BMS for patients who have high risk of bleeding or have social or financial limitations to continue DAPT for extended period. Therefore, on-going large scale LEADERS FREE trial is currently testing BMS against BioFreedom PF-DES in patients at high risk for bleeding using a month course of DAPT (ClinicalTrials.gov Identifier: NCT01623180).

It’s a twist to the old-school balloon angioplasty. Drug-eluting balloons (DEB) dilate the stenotic lesion and simultaneously deliver antiproliferative agent free of potentially inflammatory polymer and metallic scaffold. Although based on small RCTs and registries, DEB achieved comparable outcomes in lesions with high risk of restenosis such as small vessel disease, bifurcation lesions, and ISR of BMS and DES [62–64]. However, although promising for the treatment of restenosis, especially since avoiding a second layer of metal, the risk of restenosis with DEB is still unacceptably higher when compared with restenting with a second generation DES. Large scale studies with longer follow-up are needed to further assess the potential future clinical application of DEB.

Fully Biodegradable Scaffolds It has long been known that the benefits of scaffolding provided by metallic stents are important in the acute phase and

Conclusions Since their first clinical use in 1986 there has been a remarkable progress in coronary stent technology with introduction of more deliverable stents, stents with thinner struts, biocompatible and potentially thromboresistant polymers with consequent improvement in efficacy and safety outcomes. Although, initial experience with first generation DES had some setbacks owing to very-late ST and the late catch-up phenomenon, second generation DES have overcome many of these

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shortcomings. The incidence of ST is at an all-time low with the cumulative incidence being half of that of early generation stents. The traditional paradigm of stent benchmark—DES for efficacy and BMS for safety—has been questioned with more recent data showing superior safety with second generation DES (especially CoCr EES) even when compared with BMS. Moreover, the need for extended DAPT with DES has also been questioned with data suggesting that a shorter course (3 or 6 months) may be reasonable with newer generation DES. Several other advances such as biodegradable polymer stents and polymer free stents were developed based on the traditional paradigm of stent benchmarks (ie, BMS for safety) and the extended DAPT requirements with first generation DES use. However, given the shift in paradigm one is left to wonder if the above advances are a step in the wrong direction and the logical next step should rather be a biodegradable scaffold! Compliance with Ethics Guidelines

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Conflict of Interest Bora Toklu declares that he has no conflict of interest. Sripal Bangalore has received grant support and honoraria from Abbott Vascular, and has received travel/accommodations expenses covered or reimbursed from Medtronic. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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