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.
Curr Cardiol Rep (2014) 16:469
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
Curr Cardiol Rep (2014) 16:469
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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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Curr Cardiol Rep (2014) 16:469
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
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
469, Page 2 of 10
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.
Curr Cardiol Rep (2014) 16:469
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
Curr Cardiol Rep (2014) 16:469
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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
469, Page 4 of 10
Curr Cardiol Rep (2014) 16:469
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
Curr Cardiol Rep (2014) 16:469
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
