Eric Wierda & Bimmer Claessen
In the early years of percutaneous coronary intervention (PCI) the only available method to treat coronary stenoses was balloon angioplasty. However, balloon angioplasty alone, also known as plain old balloon angioplasty (POBA) was hampered by a few important technical limitations. For example, an important early complication of POBA was acute vessel closure, which could only be treated with emergency coronary artery bypass graft surgery (CABG). Moreover, acute vessel recoil at the site of balloon inflation led to suboptimal early results of POBA, and restenosis rates were frequently reported to be >20%. The introduction of coronary artery stents, pioneered by Julio Palmaz, Richard Schatz, Cesare Gianturco and Gary Roubin, led to important advances in PCI. By virtually eliminating acute vessel closure, hospitals were PCIs were performed no longer needed a surgical backup team, and for many years now PCIs are performed in hospitals without cardiothoracic surgery departments. Moreover, restenosis rates were reduced by as much as 50% with the use of bare metal stents (BMS) compared with POBA. However, the introduction of the BMS also introduced the complication of stent thrombosis which occurs in 2-5% of patients depending on lesion and patient characteristics. More recently, at the beginning of the current millennium drug-eluting stents (DES) caused another revolution in PCI. Again, restenosis rates were cut in half compared with BMS and the latest generation of DES with bio-compatible polymers have been shown to reduce stent thrombosis compared with BMS. This section provides an overview about technical specifications, and data on safety and efficacy of different types of coronary artery stents.
Bare Metal Stents
Bare-metal stents are made of different types of metals, for example stainless steel, nitinol, cobalt-chromium or platinum-chromium. Stents can be either self-expanding, or balloon-expandable, and exert a scaffolding force to prevent acute recoil of the treated coronary artery stenosis. Bare-metal stents were introduced in the 1980s in an effort to prevent acute vessel occlusion and restenosis, two common complications after POBA. An early report on the use of BMS in coronary arteries was cause for optimism, in 19 patients who received stainless-steel BMS in the mid-1980s (before the era of dual antiplatelet therapy, DAPT) two acute stent occlusions occurred, and one patient died (without suspicion for a thrombotic occlusion), and no further restenosis or occlusions were observed up to nine-month follow-up.
However, a study published in 1991 in the New England Journal of Medicine reported sobering outcomes in a series of 105 patients undergoing BMS implantation. Complete occlusion of the coronary artery stent was observed in 24% of patients at follow-up coronary angiography after one month. Out of the 27 occlusions, 21 occurred within the first 14 days after stent implantation. Moreover, restenosis (defined as >50% diameter stenosis at follow-up) was observed in 14% of patients with patent stents. An excerpt from the accompanying editorial reflects the disappointment that ensued “I believe that the introduction of most these new devices will be of passing interest only. The development of mechanical interventions (such as stents) that attempt to overcome the response to injury caused by intravascular therapeutic interventions (such as balloon angioplasty) is probably futile.”
During the 1990s, important developments in pharmacology, stent implantation technique, and BMS technology resulted in markedly improved outcomes after PCI with BMS compared to the aforementioned early experiences.
- Pharmacology: Stenting with dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor (at that time, ticlopidine) instead of a large variety of combinations of warfarin with varying antiplatelet agents was introduced by Antiono Colombo et al. Angiographically documented stent thrombosis occurred in 1.6% of patients after 6 months.
- High-pressure stenting: The same dr. Antiono Colombo also used a radically new technique for stent implantation in his case series; high-pressure balloon inflation (>10 Atm) led to adequate apposition of the stent to the vessel wall and adequate expansion of stent struts. These technical aspects of stent implantation have since been shown to be paramount in preventing stent thrombosis, as flow disturbances caused by malapposed or underexpanded stent struts form an important trigger for stent thrombosis.z
- Bare-metal stent technology: Improvements in BMS technology led to decreased restenosis rates and to increased deliverability of stents to coronary artery lesions. The first generation of coronary artery stents were typically made of stainless steel with a strut thickness of >100µm. The introduction of a cobalt-chromium alloy, which allowed for similar radial strength and radiopacity at smaller strut thicknesses led to a variety of thin-strut stent designs (with stent thickness of <100 µm).
The long-term effect of these improvements in pharmacology, implantation technique and BMS technology led to the widespread uptake of coronary artery stenting. As a result, ever more complex lesions were treated with PCI instead of coronary artery bypass graft surgery (CABG). However, PCI of complex lesions (e.g. in patients with diabetes mellitus, bifurcation lesions, chronic total occlusions) remained challenging to treat with BMS, as restenosis rates were >10%, even with state-of-the art techniques.
The next major development in intracoronary stent technology was the drug-eluting stent (DES). Introduced at the start of the current millennium, these devices typically consist of a bare-metal stent platform, coated with a polymer, which releases an anti-inflammatory or cytotoxic drug over a period of several months after stent implantation. The drugs used in DES can be broadly divided into two distinct classes: 1) Sirolimus and its analogues (everolimus, zotarolimus, biolimus A9), and 2) Paclitaxel. Sirolimus is a compound first discovered in a soil sample from Easter Island (Rapa Nui) and is therefore also known as rapamycin. Sirolimus acts by inhibiting the mammalian target of rapamycin (mTOR) which results in a cytostatic effect. Moreover, the mechanisms of several additional anti-restenotic properties are incompletely understood; inhibition of total protein and collagen synthesis involved in extracellular matrix formation, inhibition of smooth muscle cell migration, and promoting a contractile rather than a proliferative phenotype.  Analogues of sirolimus are typically chemically engineered biosimilar molecules with improved lipophilicity in order to improve the uptake of the antirestenotic agent by the vessel wall. The other type of drug used on DES, paclitaxel is a cytotoxic agent, and is also used as a chemotherapeutic agent in much higher systemic doses. The cytotoxic properties of paclitaxel help to prevent formation of neo-intima after stent implantation.
First-Generation Drug-Eluting Stents: The CYPHER sirolimus-eluting stent (SES) was the first commercially available DES, which has since become obsolete and is no longer marketed. It consisted of a stainless steel stent platform (with a relatively thick strut thickness of 140 µm) coated with a durable polymer which released the drug sirolimus. The first randomized controlled trial with DES, the RAVEL trial (Randomized study with the sirolimus-eluting Bx Velocity balloon-expandable stent) included 238 patients with a single de novo coronary artery lesion and randomized patients to treatment with the SES or an otherwise identical BMS. The RAVEL trial showed an impressive 0% rate of target lesion revascularization (TLR) with the SES compared with 23% with BMS. Subsequent randomized trials included patients with ever more complex lesions which consistently showed the superiority of the SES compared to BMS in terms of the need for repeat revascularization.
The TAXUS paclitaxel-eluting stent (PES) is the other first-generation DES, and is also currently no langer commercially available. The first generation TAXUS stent used a stainless steel stent platform coated with a durable polymer which eluted paclitaxel. A number of large clinical trials compared stenting with the PES vs. BMS and reported significant advantages with the PES in terms of reduced need for repeat revascularization. However, there was an important safety issue with the first generation DES; the occurrence of very late stent thrombosis (>1 year after stent implantation). As stent thrombosis is a relatively rare complication (typically occurring at a rate of <1% per year), these issues were only discovered after data from several randomized controlled trials were pooled. A meta-analysis of >5000 patients showed significantly increased rates of very late stent thrombosis with first-generation DES compared with BMS. The pathophysiological mechanisms for late stent thrombosis with DES included prothrombotic effects of the non-biocompatible polymers. Moreover, the large strut thickness of first-gerenation DES was problematic; on top of the thick-strut stent platforms was a layer of polymer on both the luminal- and abluminal stent surfaces. Furthermore, particularly with the TAXUS stent there were issues with stent coverage with neointima. Because of the aggressive action of the cyotoxic paclitaxel, many struts remained uncovered with neointima in lesions treated with TAXUS stents, which may be a trigger for very late stent thrombosis.
Current-Generation Drug-Eluting Stents: Stent technology has evolved significantly since the first DES were introduced. Important improvements have been made in the stent platform, the polymer, and the antirestenotic drugs.
Stent platforms are the metal backbones of the DES. First-generation DES were designed as a standard BMS coated with a polymer and drug. The stent designs of current-generation DES are mainly different from their first-generation predecessors because of a thinner strut thickness. An overview of strut thicknesses of first-generation and current-generation DES is shown in table 1. Another advancement in stent platform design is the use of novel metallic alloys such as cobalt-chromium and platinum-chromium rather than stainless steel. These alloys allow for thinner struts with equal radiopacity and radial support.
Improvements in polymer design were again aimed at minimizing the thickness of the polymer. This can be achieved by decreasing the thickness of the polymer itself, or by only coating the abluminal side of the stent with the polymer. Moreover, as the polymers of first-generation DES were thought to be responsible for the increased rates of very late stent thrombosis, an effort was made to create bio-inert and biocompatible polymers e.g. the fluoropolymer (not unlike a Teflon layer in an anti-sticking pan) used in the XIENCE everolimus-eluting stent. Other stent types employ a bioresorbable polymer which is broken down over a period of several months, essentially leaving a BMS behind. However, the benefits of a bioresorbable polymer seem to be limited as shown by a large network meta-analysis involving 63,242 patients showing that durable polymer everolimus-eluting stents (such as XIENCE and PROMUS) and zotarolimus-eluting stents (such as RESOLUTE) had a superior safety profile compared with biolimus-eluting bioresorbable DES. Yet another type of stent (BIOFREEDOM) uses no polymer at all, but elutes a drug from small reservoirs on its abluminal surface. This stent has shown superior outcomes in terms of repeat revascularization when compared to a similar BMS, but has not been compared against other DES types in a randomized controlled trial.
Improvements in antirestenotic drugs have been relatively modest compared with the aforementioned improvements in stent platforms and polymers. Experiences with first-generation DES led the interventional cardiology community to conclude that sirolimus and its analogues were superior to paclitaxel for use on a DES. The cytotoxic properties of paclitaxel are probably too aggressive for the purpose of preventing formation of neointima, the more subtle anti-inflammatory and cytostatic effects of sirolimus seem to be better suited for this purpose. Several analogues of sirolimus have been developed, these are chemically altered forms of the drug with improved lipophilicity such as biolimus A9 or zotarolimus.
|DES type||Drug Eluted||Stent Material||Strut thickness||Polymer||Polymer thickness||Polymer type|
|Cypher SES||First-generation||Sirolimus||316L stainless steel||140µm||3-layer permanent polymer||14µm||Durable|
|Taxus PES||First-generation||Paclitaxel||316L stainless steel (Express, Liberté), Platinum chromium (Element)||Express: 132µm, Liberté: 97µm Element: 81µm||3-layer Styrene-isobutylene-Styrene copolymer||17.8µm||Durable|
|Resolute ZES||Current-generation||Zotarolimus||L-605 cobalt chromium alloy||89µm||3-layer permanent biomimetic polymer; BioLinx (Endeavor Resolute)||5.6 µm||Durable|
|Xience V™/Promus EES||Current-generation||Everolimus||L-605 cobalt chromium alloy||81µm||2-layer permanent polymer||8µm||Durable|
|Promus Element EES||Current-generation||Everolimus||Platinum-chromium alloy||81µm||2-layer permanent polymer||8µm||Durable|
|Biomatrix Flex/Nobori BES||Current-generation||Biolimus A9||316L stainless steel||112µm||Abluminal side-only Bioaborbable polymer (fully absorbed within 6-9 months)||15µm||Bioresorbable|
|BioFreedom BES||Current-generation||Biolimus A9||316L stainless stell||119 µm||No polymer||n/a||No polymer, drug eluted from abluminal stent surface|
|Synergy EES||Current-generation||Sirolimus||Platinum-chromium alloy||74 µm||PLGA (poly lactic-co-glycolic acid)||4 µm||Bioresorbable, abluminal side onyl|
|Orsiro SES||Current-generation||Everolimus||L-605 cobalt chromium alloy||60 µm||proBIO passive coating (amorphous silicon carbide) and BIOlute bioresorbable PLLA (poly-L-lactide) active coating||7.4 µm on abluminal surface, 3.5 µm on luminal surface||Hybrid polymer, partly durable, partly bioresorbable|
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