Continuing Cardiology Education

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1 Continuing Cardiology Education Stent selection for percutaneous coronary intervention P. D. Williams* & M. Awan James Cook University Hospital, Middlesbrough, United Kingdom Keywords Coronary artery disease, percutaneous coronary intervention, stent Correspondence P. D. Williams, Consultant Cardiologist, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, United Kingdom. Tel: ; Fax: ; Funding Information None. Abstract Percutaneous coronary intervention (PCI) with stent deployment is the dominant form of myocardial revascularization, with millions of procedures performed worldwide each year. Stent design has evolved substantially over time and there are now a wide range of options available to the interventional cardiologist. This review will cover the development of intracoronary stents and the patient and vessel factors which are important in stent selection. Answer questions and earn CME: /Activity.aspx Continuing Cardiology Education, 2017; 3(2), Introduction Endovascular treatment of coronary artery disease was initially performed using balloon angioplasty alone but this technique was limited by a high rate of acute vessel closure and late restenosis. The introduction of coronary stents more than 20 years ago revolutionized practice and percutaneous coronary intervention (PCI) with stent deployment is now the dominant form of myocardial revascularization, with millions of procedures performed worldwide each year. Stent design has evolved substantially over time and there are now a wide range of options available to the interventional cardiologist. This review will cover the development of intracoronary stents and the patient and vessel factors which are important in stent selection. Early Developments in Percutaneous Coronary Intervention The first human percutaneous coronary intervention (PCI) procedure was performed by Andreas Gruentzig in Although a huge step forward in the treatment of obstructive coronary artery disease, the original procedure of balloon angioplasty alone had important limitations. In the short-term there was a risk of acute vessel closure due to vessel wall dissection or thrombus formation, which would often require emergency bypass surgery. In the longer term, there was a high rate of vessel restenosis which occurred in 20 50% patients within 12 months, often necessitating a repeat procedure. The major contributors to restenosis were identified as acute vessel recoil (within 6 24 h of angioplasty), the contraction of the external elastic lamina of the vessel (constrictive remodeling) and neointimal hyperplasia secondary to local trauma inflicted by balloon inflation. The bare metal stent era The introduction of coronary stents, facilitated by improvements in antiplatelet therapy, was the next major evolution in the percutaneous management of coronary disease. In 1994, two randomized control trials demonstrated the superiority of uncoated stainless steel balloonexpandable stents for the treatment of de novo coronary artery lesions in native coronary vessels. The use of these bare metal stents (BMS) reduced angiographic restenosis, and hence the need for repeat procedures, by about onethird compared with balloon angioplasty only [1, 2]. As a result, stent use rapidly proliferated and stent deployment became routine practice during PCI procedures. Coronary stents solved many of the problems of balloon angioplasty. By scaffolding the vessel and tacking down vessel dissections they reduced the risk of acute Continuing Cardiology Education, doi: /cce2.54 (64 of 69) ª 2017 Hellenic College of Cardiology

2 P. D Williams & M. Awan Stent Selection for PCI vessel closure. They also reduced the risk of restenosis by combating vessel recoil, thereby improving acute lumen gain, and constrictive remodeling. However, early stents had significant limitations. Restenosis due to neointimal hyperplasia within the stented segment remained an important clinical problem, and repeat revascularization was required to treat in-stent restenosis (ISR) in approximately 15% of patients treated with a BMS [3]. Initial stent designs such as the Palmaz- Schatz stent were also stiff and bulky and were difficult to deliver in tortuous, calcified anatomy. First generation drug eluting stents Drug-eluting stents (DES) were developed to specifically address the issue of ISR encountered with BMS. They typically consist of a metallic stent coated with a layer of polymer which gradually releases an anti-mitotic drug to inhibit the cell proliferation that causes restenosis. The first two DES to reach market were Taxus (Boston Scientific) and Cypher (Cordis). Cypher consisted of a 140 mcm stainless steel stent coated with a permanent polymer containing the drug sirolimus. The Taxus Express DES consisted of a 132 mcm stainless steel stent coated with a permanent polymer containing paclitaxel. The later iteration Taxus Liberte stent possessed the same polymer and drug as the Taxus Express but with a thinner strut platform (97 mcm). Clinical trials with these DES platforms demonstrated dramatic reductions in ISR compared to BMS and a consequent reduction in the need for repeat revascularization [4 6]. However, first generation DES did not prove to be a panacea for coronary artery disease and were associated with an increased risk of late stent thrombosis related to delayed endothelialization of the stented segment [7]. Later generations of drug eluting stents were designed to improve on these late outcomes. Components of a Drug Eluting Stent Platform A modern drug eluting stent platform typically has three elements: the stent backbone, the antiproliferative drug, and a mechanism for bonding the drug to the backbone to allow controlled elution, which is usually a biocompatible polymer coating. Modern DES have seen significant developments in all three of these elements compared to the first generation devices. The stent backbone Arguably the most important component of a coronary stent platform is the stent backbone itself. An ideal coronary stent has several desirable characteristics: it should have a low profile, low strut thickness, a good conformational profile and flexibility, acceptable radial and longitudinal strength, allow easy side branch access and have adequate radio-opacity. Stent design is a delicate balancing act, however, and improving some of these characteristics may have a deleterious effect on others. Thin strut stents reduce the profile and make the stent more flexible and hence improve deliverability. Thin strut BMS have also been shown to result in a reduction in restenosis, possibly related to reduced flow disturbance within the vessel [8]. Development of thin strut stents has therefore been a major design focus for stent manufacturers. Early stents were mostly manufactured from 316L stainless steel with relatively thick struts. Alloys such as cobalt chromium and platinum chromium are increasingly used which have allowed the construction of thinner strut backbones while maintaining strength and radioopacity. Strut thickness has fallen dramatically over the last 15 years. For instance the original Cypher stent (Cordis) had a strut thickness of 140 mcm, while the Orsiro stent (Biotronik) has a strut thickness of 61 mcm. Innovative stent designs have been required to maintain radial and longitudinal strength. The Cypher stent had a closed cell configuration and was relatively inflexible and prone to stent fracture [9]. Most modern DES are constructed with an open cell configuration which results in increased flexibility, as well as improving ease of access to side branches. The drug Paclitaxel has a narrow therapeutic index with an increased risk of arterial toxicity compared to sirolimus [10]. Evidence from multiple comparative trials of the first generation DES showed that sirolimus-coated stents were superior to those coated with paclitaxel, with reduced rates of both restenosis and late stent thrombosis [11]. Subsequently all mainstream contemporary DES are coated with a limus analogue, although paclitaxel is still utilized on many drug-eluting balloons because of its tissue retention characteristics. Bonding of drug to stent Most DES are coated with a layer of polymer to allow controlled release of the antimitotic drug, typically over the period of 3 9 months in which vessel healing occurs. Polymers have been shown to cause persistent local inflammation and delayed endothelialization in animal models, which represents one possible mechanism for late stent thrombosis [12]. Therefore modern DES have been ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: /cce2.54 (65 of 69)

3 Stent Selection for PCI P. D Williams & M. Awan designed with thin layer polymer coatings. Stents coated with bioabsorbable polymer and/or polymer solely on the abluminal surface have been developed in an attempt to further improve long term safety, although this theoretical benefit has not been shown to improve clinical outcomes compared to modern permanent polymer DES in studies to date [13]. The novel polymer-free BioFreedom DES has been roughened on the abluminal surface to increase the surface area allowing direct application of the drug. Newer Generation DES There are now several commercially available newer generation DES (see Table 1). The increased risk of late events with first generation DES compared with BMS has not been shown with these later generation DES and numerous studies have shown the superiority of modern DES over first generation DES for both efficacy and safety, including at longterm follow-up [14 16]. As a result, the 2014 ESC guidelines on myocardial revascularization recommend unrestricted use of new-generation DES in all patients undergoing PCI including patients with diabetes, multivessel and left main disease, STEMI, vein grafts, restenosis, and chronic total occlusions [17]. Factors to Consider in Stent Selection Duration of dual antiplatelet therapy The optimal duration of dual antiplatelet therapy following stent deployment remains uncertain and depends on the balance between bleeding risk and ischemic risk in the individual patient. Concerns about late stent thrombosis with first generation DES initially lead to expert consensus recommendations for 1 year of oral dual antiplatelet therapy following DES implantation, despite limited evidence that this was effective [17]. The improved long term safety profile of modern DES means that this recommendation may no longer be appropriate and there is increasing evidence that shorter durations of dual antiplatelet therapy may be safe. Several modern DES have received CE mark approval for durations of dual antiplatelet therapy shorter than 6 months, but this is based on observational registry data rather than randomized trial evidence. Current ESC guidelines recommend in patients undergoing PCI with modern DES a minimum duration of dual antiplatelet therapy of 6 months in stable coronary disease and 12 months in acute coronary syndromes [17]. A course of dual antiplatelet therapy of less than 6 months in high-bleeding risk patients is endorsed, but this is based on limited evidence (Class IIb, Level A). For patients at high-bleeding risk bare metal stents are therefore frequently still used as a minimum duration of 1 month of dual antiplatelet therapy is considered sufficient. The recent LEADERS FREE trial investigating the polymer-free BioFreedom stent (BioSensors Europe) is an important addition to the literature on this issue. LEA- DERS FREE was a randomized, double-blind trial comparing BioFreedom with a bare metal stent in almost 2500 high-bleeding risk patients [18]. The most common criteria for high bleeding risk in the study were age 75 years, need for oral anticoagulation, a hemoglobin Table 1. Comparison of selected commercially available current generation DES with first generation DES. Stent Manufacturer Drug Backbone Strut thickness (mcm) Polymer Polymer thickness (mcm) Xience Prime Abbott Vascular Everolimus CoCr 81 Permanent, circumferential 8 Promus Premier Boston Scientific Everolimus PtCr 81 Permanent, circuferential 8 Synergy Boston Scientific Everolimus PtCr 74 Bioabsorbable, abluminal 4 Resolute Integrity Medtronic Zotarolimus CoCr 89 Permanent, circumferential 6 Resolute Onyx Medtronic Zotarolimus CoCr with 81 Permanent, circumferential 6 PtCr corewire Biomatrix Biosensors Biolimus A9 SS 112 Bioabsorbable, abluminal 10 BioFreedom Biosensors Biolimus A9 SS 112 Polymer-free N/A Ultimaster Terumo Sirolimus CoCr 80 Bioabsorbable, abluminal 15 Orsiro Biotronik Sirolimus CoCr 61 Bioabsorbable, circumferential 3.5 (7.5 on abluminal surface) ABSORB Abbott Everolimus PLLA 150 Bioabsorbable, circumferential 3 Taxus Express Boston Scientific Paclitaxel SS 132 Permanent, circumferential 18 Taxus Liberte Boston Scientific Paclitaxel SS 97 Permanent, circumferential 18 Cypher Cordis Sirolimus SS 140 Permanent, circumferential 7 (14 on abluminal surface) SS, stainless steel; CoCr, cobalt chromium; PtCr, platinum chromium; PLLA, polylactic acid. Continuing Cardiology Education, doi: /cce2.54 (66 of 69) ª 2017 Hellenic College of Cardiology

4 P. D Williams & M. Awan Stent Selection for PCI <11 g/l or transfusion within the previous 4 weeks. All patients received only 1 month of dual antiplatelet therapy. There was a significant reduction in both the primary safety end-point (cardiac death, myocardial infarction, or definite or probable stent thrombosis at 390 days) and primary efficacy endpoint (clinically driven target lesion revascularization at 390 days) with the use of the BioFreedom stent. The results of this study indicate that BMS should no longer be the recommended therapy for patients felt unable to tolerate dual antiplatelet therapy for longer than 1 month. However, it is not known whether BioFreedom stents are as effective as modern polymer-coated DES in patients able to tolerate dual antiplatelet therapy and future studies, such as the SORT OUT IX trial ( linicaltrials.gov/ct2/show/nct ) are planned to investigate this. Size matrix Each stent platform has several different models with different expansion capacities. It is crucially important for the interventional cardiologist to know these limits when selecting stents. This is of particular importance where there is a large size mismatch between the proximal and distal vessel, for instance in left main stem bifurcation interventions. In these cases, if the incorrect stent model is selected, post-dilatation can overcome the maximum expansion capacity in the proximal vessel resulting in incomplete strut apposition. Foin and colleagues conducted an independent bench test comparing the maximum expansion capacity of several contemporary DES, which offers a useful reference on this issue [19]. Stent deliverability As the indications for PCI have expanded, the severity of coronary disease being tackled has become more complex and lesions with significant calcification and/or tortuosity are frequently encountered by the interventionist. Improving stent deliverability has therefore been a focus of industry for many years and modern thin-strut DES are dramatically easier to deliver than thick-strut earlier generation stents such as Cypher and Taxus Express. Deliverability is not just a function of the stent design itself and also depends on the stent delivery system, compromising the balloon and catheter. There are substantial differences between the stent platforms with regards to deliverability, for instance stents with fewer connectors between stent rings (Promus Element (Boston Scientific) and Resolute Integrity/Onyx (Medtronic) have two connectors) are more deliverable than stents with more connectors (Cypher (Cordis) has six connectors). However, bench testing of deliverability depends on the model selected and there is little objective comparative data between contemporary DES. Longitudinal stent deformation Stent distortion occurring due to force applied in the longitudinal axis after initially successful deployment, a phenomenon known as longitudinal stent deformation, has recently been reported [20, 21]. This was shown to be most common in stents using the Element (Boston Scientific) and Driver (Medtronic) platforms and was related to the specific designs of these stents [22, 23]. The Driver platform is no longer commercially available, and the Element platform has been superseded by the Premier platform (Boston Scientific) which has additional connectors between the proximal stent rings to mitigate this issue. There remain differences in longitudinal strength between currently available DES and this should be considered when treating lesions where stent deformation is more likely to occur, such as ostial disease [24]. Stent fracture Stent fracture represents an underdiagnosed cause of late stent failure, which can manifest as restenosis and stent thrombosis. Risk factors for stent fracture include vessel tortuosity, hinge motion, vein graft intervention and long segments of stenting [9]. It occurs more commonly with less flexible stent designs, and was frequently described with the now redundant Cypher stent design, with thick struts and six connectors between rings [9]. However, clinical stent fracture has been described with modern DES, including Xience and Nobori [25, 26]. Bench testing indicates considerable variability in susceptibility to fracture between stent designs, with the Integrity, Element and Premier platforms being less susceptible to fracture than Xience and Biomatrix [27]. In lesions felt to be at increased risk of stent fracture, then the interventionist may consider selecting a more flexible stent with a lower propensity to fracture. Bioabsorbable Stents Permanent metallic implants have several potential undesirable longterm effects. These include long term endothelial dysfunction, abolition of vasomotor contractility, chronic inflammatory reaction, increased thrombogenicity due to uncovered struts and inability to perform surgical grafting a stented site. Bioabsorbable stents have been developed which fully resorb, typically over a period of 1 3 years. ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: /cce2.54 (67 of 69)

5 Stent Selection for PCI P. D Williams & M. Awan Most clinical data relates to the ABSORB scaffold (Abbott Vascular) which has recently been shown to be non-inferior in a randomized controlled trial compared to Xience at 1 year in relatively simple coronary lesions [28]. The ABSORB platform consists of a polylactic acid polymer backbone with thick struts (150 mcm) coated with everolimus. Disadvantages compared to contemporary metallic DES include inferior deliverability, lower radial strength, a limited overexpansion capacity before strut fracture occurs and lack of radio-opacity. Procedural time, radiation, and contrast usage are often higher due to the need for meticulous lesion preparation and frequent use of adjunctive intracoronary imaging. They are therefore currently best reserved for relatively simple lesions and their use in ostial locations, left main stem, or bifurcation lesions, and if there is extensive calcification or severe tortuosity is not recommended. Future iterations of the device with smaller struts may expand the lesion types suitable for treatment with this technology and long-term trial follow-up data is awaited to see if the putative longterm benefits of these devices manifests as clinical benefit. Several other absorbable stents are in various early stages of clinical development [29, 30]. Conclusion The interventional cardiologist has access to a vast array of devices with which to treat obstructive coronary artery disease. Modern drug eluting stents allow the treatment of almost all coronary lesions with excellent acute results and long term safety, and should be considered as default therapy in all PCI cases. Some specific lesion and patient subsets may favor specific stent platforms. In high bleeding risk patients, use of the BioFreedom stent should be considered, which has been shown to have superior safety and efficacy to BMS implantation with only 4 weeks of dual antiplatelet therapy. Ostial lesions may warrant consideration of a stent with good longitudinal strength and extremely tortuous vessels may be best treated with a stent with excellent flexibility and fracture resistance. Absorbable stent platforms potentially represent the future of PCI. However, current devices are more difficult to use than modern DES and long-term clinical data is required to see if these devices do indeed offer the theoretical long-term advantages over permanent metallic implants. Conflict of Interest Dr Williams and Dr. Awan have nothing to disclose. References 1. Serruys, PW, P de Jaegere, F Kiemeneij et al A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N. Engl. J. Med. 331: Fischman, DL, MB Leon, DS Baim et al A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N. Engl. J. Med. 331: Williams, DO, R Holubkov, W Yeh et al Percutaneous coronary intervention in the current era compared with : the National Heart, Lung, and Blood Institute Registries. Circulation 102: Grube, E, KD Dawkins, G Guagliumi et al TAXUS VI 2-year follow-up: randomized comparison of polymerbased paclitaxel-eluting with bare metal stents for treatment of long, complex lesions. Eur. Heart J. 28: Grube, E, S Silber, KE Hauptmann et al TAXUS I: six- and twelve-month results from a randomized, doubleblind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 107: Morice, MC, PW Serruys, JE Sousa et al A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N. Engl. J. Med. 346: Pfisterer, M, HP Brunner-La Rocca, PT Buser et al Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J. Am. Coll. Cardiol. 48: Kastrati, A, J Mehilli, J Dirschinger et al Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation 103: Chakravarty, T, AJ White, M Buch et al Metaanalysis of incidence, clinical characteristics and implications of stent fracture. Am. J. Cardiol. 106: Finn, AV, FD Kolodgie, J Harnek et al Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 112: Schomig, A, A Dibra, S Windecker et al A metaanalysis of 16 randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents in patients with coronary artery disease. J. Am. Coll. Cardiol. 50: Finn, AV, G Nakazawa, M Joner et al Vascular responses to drug eluting stents: importance of delayed healing. Arter. Thromb. Vasc. Biol. 27: Continuing Cardiology Education, doi: /cce2.54 (68 of 69) ª 2017 Hellenic College of Cardiology

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