Several major leaps in technology and immense research and development have led to the current wide use of drug-eluting stents (DES). Stents were initially developed to reduce the high rates of restenosis and acute vessel closure following balloon angioplasty–induced endothelial cell denudation and coronary artery medial layer tearing.¹ The first bare metal stent (BMS) implantation in a coronary artery was reported by Sigwart et al² in 1987, and the first randomized trial comparing balloon angioplasty and BMS was reported by Fischman et al³ in 1994. As compared to balloon angioplasty, BMS implantation was associated with an improved rate of procedural success, a lower rate of angiographically detected restenosis, similar rates of clinical events after 6 months, and a less frequent need for target vessel revascularization (TVR).³ These results eventually led to the use of BMS as the standard of care for the treatment of de novo coronary stenosis. The use of BMS, however, was associated with a high incidence of in-stent restenosis (ISR) mainly due to intimal hyperplasia.⁴ The high ISR rates in BMS eventually led to the idea of coating the BMS with antiproliferative agents. Therefore, the primary purpose of DES has been the prevention of vessel recoil, negative remodeling, and ISR. First introduced in 2002, first-generation DES have been shown to be superior to BMS with respect to lower rates of clinical and angiographic restenosis and target lesion revascularizations (TLR) as compared to BMS.^5,6 However, following real-world experience, concerns regarding high rates of late stent thrombosis (ST) have emerged,⁷ leading to a change in the recommendations for dual antiplatelet therapy following DES implantation.⁸ The vast research and development leading to a newer generations of DES, better understanding of the mechanisms of ST, and advances in technology, technique, adjunctive pharmacology, and operator experience have resulted in improved outcomes and the widespread use of DES. This eventually lead to the fact that the vast majority of stents being implanted during percutaneous coronary intervention (PCI) in the United States are DES⁹ as well as to the wide endorsement for the use of these stents in US and European clinical guidelines.^10,11

The basic structure of DES includes a metallic strut platform, a polymer, and the drug. Due to the concept of persistent arterial wall inflammation attributed to the polymer and the risk for ST, novel DES designs have been introduced and include the biodegradable polymer and polymer-free DES,¹² discussed later, and the bioresorbable vascular scaffold systems.¹³ A design summary for the first- and second-generation DES available in the United States for clinical use as well as newer platforms with bioresorbable polymer and polymer-free DES are presented in Table 30-1 and Figures 30-1 and 30-2.

Stent Platform

Drug-eluting stents were initially constructed on a stainless steel platform due to their mechanical radial force properties and corrosion resistance. However, these stainless steel stents contained and released nickel, chromate, or molybdenum ions, causing a local inflammatory response leading to ISR.¹⁴ Currently, most second-generation DES are built on a cobalt-chromium platform, which exhibits superior radial strength with remarkably thinner struts (~80 μm) and improves deliverability. Some novel DES are constructed on a platinum-chromium platform. A meta-analysis has shown that compared with BMS, the use of cobalt-chromium everolimus-eluting stents (EES) improves global cardiovascular outcomes, including cardiac survival, myocardial infarction, and overall ST.¹⁵ Novel structural designs feature thinner struts and less metal, offering increased flexibility and deliverability, and thus, they are both more efficacious and safer.¹⁶

Currently, all available DESs are balloon expandable. Symmetric expansion of stents with homogeneous distribution of struts is required for optimal drug delivery. Stent design can be either a closed- or open-cell configuration. A closed-cell stent design has a uniform cell expansion and constant cell spacing when deployed in a curved vessel, which gives uniform drug distribution. An open-cell design has variation in the surface coverage between inner and outer curvatures in the curved vessel but has better conformability to a curved surface at the expense of less uniform distribution.¹⁷ Current second-generation DESs are based on an open-cell design to minimize strut deformation after deployment while maintaining conformability, radial support, and flexibility.¹⁶

Stent Polymers

Stent polymers are large compounds that carry the drug and control the kinetics of its elution. Both first- and second-generation DESs use durable polymers (see Table 30-1). First-generation DESs, compared to second-generation DESs, have thicker and more durable polymers that control the release of sirolimus and paclitaxel. The durable polymers used in first-generation DESs have been associated with nonuniform coating, resulting in erratic drug distribution. In addition, they have been associated with perpetuating local vascular inflammatory reaction and potentially inducing the occurrence of late and very late ST.¹⁸ Therefore, the ideal DES would entirely inhibit restenosis while at the same time promote vascular healing with minimal risk of thrombus formation. DESs have evolved on this premise, initially with thinner polymers to enhance biocompatibility to fully bioabsorbable polymers and scaffolds to eliminate hypersensitivity reactions and local inflammatory response.

Drug Coating of DES

The antiproliferative agents that are used for the platforms of DESs are molecules that are distributed into the arterial wall and exert either immunosuppressive effects (inhibitors of mammalian target of rapamycin [mTOR]) or antiproliferative effects (paclitaxel) on smooth muscle cells. Paclitaxel and the “limus” drugs (eg, sirolimus, everolimus, zotarolimus, umirolimus) are lipophilic agents. In general, the degree of lipophilicity is higher with newer generations of DES. Eventually these substances inhibit migration and proliferation of vascular smooth muscle cells (VSMC). However, their mode of action is different.¹⁹ The limus drugs intracellularly bind to the FK-binding protein 12 (FKBP12) prior to blocking the mTOR pathway and ultimately interrupting the cell cycle. The inhibition of mTOR prevents the degradation of p27kip1, a cyclin-dependent kinase inhibitor that plays an important role in regulating VSMC migration and proliferation. More pertinent to the process of arterial healing, sirolimus is also a potent inhibitor of endothelial cell proliferation by deactivating the p70 S6 kinase pathway, an essential step for cell cycle progression in response to growth factors. Paclitaxel binds to microtubules and stabilizes their structure by shifting the dynamic equilibrium between soluble and insoluble tubulin, thereby enhancing microtubule assembly, resulting in inhibition of cellular replication. Most antimitotic agents used in DES are bonded to a matrix polymer, which acts as a reservoir to ensure drug retention during deployment and uniform distribution on the stent. The type of polymer will determine the drug-eluting kinetics.

The cellular and molecular response to vascular injury is direct repair and vascular healing. However, dysregulation of these responses can result in adverse arterial remodeling, neointimal proliferation, and restenosis.¹⁸ The cellular cascade response to mechanical vascular injury initiated immediately after PCI can be divided into 3 different time phases: (1) an early phase consisting of platelet activation and inflammation, (2) an intermediate phase of granulation tissue corresponding to smooth muscle cell migration and proliferation, and (3) a late phase of tissue remodeling.²⁰ During the early phase, the endothelium undergoes denudation, reendothelialization, and the formation of neoendothelium. After this early phase, endothelial cells proliferate and migrate over the injured areas, while smooth muscle cells and macrophages replace the fibrin clot with granulation tissue. The smooth muscle cells secrete proteoglycans that interact and stabilize the fibrin-rich extracellular matrix. This allows more smooth muscle cells to bind and proliferate while trapping inflammatory cells, which release matrix metalloproteinases that digest proteoglycans and hyaluronan. Ultimately, a more permanent matrix from collagen type I and III production occurs, allowing the wound to completely heal with eventual fibrosis.

The inhibition of intimal hyperplasia of the DES disrupts the physiologic arterial healing of the vessel wall, limiting endothelial coverage of all stent struts (Fig. 30-3). Their antiproliferative effect and the persistence of stent components have been shown to lead to chronic inflammation and impaired arterial healing, with the attendant risk of thrombotic events.²¹ The understanding of the pathophysiology of late ST of the first-generation polymer-based sirolimus-eluting stent (SES) and the paclitaxel-eluting stent (PES) has been derived from animal and human pathologic samples taken after implantation of these devices.¹⁹ The data indicate that both of these first-generation DESs cause substantial impairment in arterial healing characterized by lack of complete reendothelialization and persistence of fibrin when compared with BMS. This delayed healing was the primary substrate underlying all cases of late DES thrombosis at autopsy. However, additional barriers to physiologic healing and late ST have been described, such as penetration of necrotic core, stent malapposition, overlapping stent placement, excessive stent length, and bifurcation lesions.¹⁹ Second-generation DESs covered with everolimus (EES) and zotarolimus (zotarolimus-eluting stent [ZES]) have shown improved endothelial coverage following implantation with the use of sequential optical coherence tomography (OCT). With OCT, both ZES and EES showed comparable neointimal thickness and low rates of uncovered stent struts (3%) at 9 months after stent implantation.²²

The Cypher SES (Cordis Medical, Fremont, CA) and the TAXUS PES (Boston Scientific, Marlborough, MA) were the first US Food and Drug Administration (FDA)-approved DESs. Their major pivotal trials are summarized in Table 30-2.

Sirolimus-Eluting Stent

The Cypher (Cordis) SES uses a stainless steel platform and poly(ethylene-covinyl acetate) (PEVA) and poly(n-butyl methacrylate) (PBMA) as the polymer that carries the drug. The SES was the first FDA-approved DES in the United States. The RAVEL (Randomized Comparison of a Sirolimus-Eluting Stent With a Standard Stent for Coronary Revascularization) trial²³ was the first randomized comparison of an SES with a standard BMS. At 6 months, the degree of neointimal proliferation, manifested as the mean (± standard deviation [SD]) late luminal loss, was significantly lower in the SES group (–0.01 ± 0.33 mm) than in the BMS group (0.80 ± 0.53 mm; P < .001). None of the patients in the SES group, as compared with 26.6% of the BMS group, had restenosis of 50% of the luminal diameter (P < .001). There were no episodes of ST. The overall rate of major adverse cardiac events (MACE) was substantially reduced in the SES group versus the BMS group (5.8% vs 28.8%; P < .001). This difference was driven by a higher rate of TVR in the BMS group. Five-year follow-up of the RAVEL cohort showed 1-, 3-, and 5-year rates of survival free from TLR of 99.2%, 93.8%, and 89.7% in the SES group versus 75.9%, 75.0%, and 74.0% in the BMS group, respectively (log-rank P < .001).²⁴ Rates of all MACE at 5 years were 25.8% in patients treated with SES versus 35.2% in patients assigned to BMS (log-rank P = .03). Additional long-term data were provided by the SIRIUS (Sirolimus-Eluting Stent In Coronary Lesions) family of trials (see Table 30-2) and the SIRIUS extension data²⁵ showing that at 5 years TLR rates were 9.4% versus 24% for SES versus BMS (P < .001) and target vessel failure (TVF) rates were 22.5% versus 33.5% (P < .001).

Increased interest in SES and BMS comparisons led to the evaluation and safety of SES in subgroups of patients at higher risk of restenosis. The C-SIRUS trial²⁶ described that in patients with long lesions in small vessels at higher risk of restenosis the SES significantly reduces angiographic restenosis (2.3% vs 52.3%; P < .001) and TLR (4% vs 18%; P = .05). The Italian DESSERT study²⁷ and the German SCORPIUS study²⁸ showed that SES significantly decreases restenosis rates in diabetic patients compared to BMS. However, use of the SES in the setting of ST-segment elevation myocardial infarction examined in the MISSION trial²⁹ failed to demonstrate superiority of SES as compared to BMS. In that trial, survival rates were comparable between SES and BMS groups (94.3% vs 92.8%, respectively; P = .57), as were the rates of repeat myocardial infarction (10.6% vs 13.7%; P = .40), freedom from death or myocardial infarction (84.4% vs 79.8%, P = .29), and TVF (14.9% vs 21.7%; P = .11). Likewise, rates of overall ST (5.4% vs 2.7%; P = .28) and very late ST (4.1% vs 0.7%; P = .07) did not significantly differ between the SES and BMS groups.

Paclitaxel-Eluting Stent

The TAXUS Liberté (Boston Scientific) PES was approved a few months after the Cypher SES. The family group of trials comparing this PES to BMS were the TAXUS I through TAXUS VI trials.^6,30,31 The TAXUS IV trial³² led to the final FDA approval of the DES. In the TAXUS IV trial, 1314 patients were prospectively randomized to PES or BMS. The PES reduced the 12-month rates of TLR by 73% (4.4% vs 15.1%; P < .0001), TVR by 62% (7.1% vs 17.1%; P < .0001), TVF by 52% (10.0% vs 19.4%; P < .0001), and composite MACE by 49% (10.8% vs 20.0%; P < .0001). The 1-year rates of cardiac death (1.4% vs 1.3%), myocardial infarction (3.5% vs 4.7%), and ST (0.6% vs 0.8%) were similar between the PES and BMS groups. Long-term follow-up data from the TAXUS IV trial³¹ also showed that compared with BMS, the significant reduction of TVR with PES was maintained through 5 years (27.4% vs 16.9%; P < .0001). Similar patterns were observed for the composite MACE (32.8% BMS vs 24.0% PES; P = .0001 at 5 years). ST was comparable as well at 5 years (2.1% BMS vs 2.2% PES; P = .87). The overall revascularization benefits of PES were consistent across multiple subgroups, including gender, diabetes, left anterior descending artery lesion location, reference vessel diameter, lesion length, and multiple stents.