Coronary stent thrombosis: current insights into new drug-eluting stent designs.

The advances of interventional cardiology have been achieved by new device development, finding appropriate drug regimes, and understanding of pathomechanism. Drug-eluting stents (DES) implantation with dual anti-platelet therapy reduced revascularization without increasing mortality or myocardial infarction compared with bare-metal stenting. However, late-term stent thrombosis (ST) and restenosis limited its value and raised the safety concern. Main mechanisms of this phenomenon are impaired endothelialization and hypersensitivity reaction with polymer. The second generation DES further improved safety and/or efficacy by using thinner stent strut and biocompatible polymer. Recently, new concept DES with biodegradable polymer, polymer-free and bioabsorbable scaffold are under investigation in the quest to minimize the risk of ST.

INTRODUCTION

Bare metal stents (BMS) prevent acute recoil and negative remodeling by maintaining radial force with enlarging luminal dimensions as a result of the ability to act as a scaffold,1 thereby reducing the incidence of angiographic restenosis, repeated revascularization, ischemic re-occlusion, and emergency coronary artery bypass grafting (CABG).2-5

Vascular injury after stent implantation leads to the proliferation and migration of vascular smooth muscle cells through the cell cycle pathway, which results in the development of neointimal hyperplasia and in-stent restenosis.6 Drug-eluting stents (DES) consist of a standard metallic stent and a polymer coating with anti-proliferative drugs such as sirolimus or paclitaxel mixture. These drugs are released over a period of time with the aid of a polymer. This local delivery system allows for drug application at the precise site and time of vessel injury with a decreased risk of toxicity due to systemic release.7 By preventing the proliferation of smooth muscle and other cell types associated with the formation of neointimal hyperplasia, DES were expected to decrease late luminal loss and restenosis.

THE FIRST-GENERATION DES

1. Benefits of DES

The Randomized Study with the Sirolimus-eluting Bx Velocity Balloon Expandable Stent (RAVEL) study was the first randomized trial to compare BMS and DES.8 A total of 238 patients at 19 medical centers were randomly assigned to sirolimus-eluting stents (SES) or BMS. At 6 months, the degree of neointimal proliferation (late luminal loss) was significantly lower in the SES (-0.01±-0.33 mm) than in the BMS (0.80±-0.53 mm, p<0.001) group. During a follow-up period of up to 1 year, the overall rate of major cardiac events was 5.8% in the SES group and 28.8% in the BMS group (p<0.001). This difference was entirely due to a higher rate of revascularization of the target vessel in the BMS group.

The Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions (SIRIUS) trial included more study populations (1058 patients), the frequent presence of diabetes (in 26% of patients), and a high percentage of patients with longer lesions (mean, 14.4 mm) and small vessels (mean, 2.80 mm) compared with the RAVEL study.9 In that study, SES also demonstrated a significant benefit with respect to target lesion revascularization (TLR) and less neointima hyperplasia, which was assessed by using angiography and intravascular ultrasonography. Paclitaxel-eluting stents (PES) showed similar angiographic and clinical outcomes with SES in the TAXUS II and IV trials.10,11 Both DES were approved by the US Food and Drug Administration (FDA) for patients with a newly diagnosed single lesion less than ≤30 mm in length and 2.5 to 3.5 mm in diameter for SES and ≤28 mm in length and 2.5 to 3.75 mm in diameter for PES in clinically stable patients without additional serious medical conditions after these trials. Use of DES in patients with these characteristics is called "on-label." The findings of the 5-year follow-up data from these trials are as follows: 1) efficacy to clinical restenosis maintained and 2) safety profiles such as stent thrombosis, myocardial infarction (MI), and death occurred similarly in the BMS and DES groups.12-15

DES reduced restenosis without long-term safety concerns in complex lesions such as left main lesions, long lesions, small vessels, and chronic total occlusion.16-21 Recent studies have shown similar clinical outcomes during long-term follow-up in high-risk patients who had acute MI or diabetes mellitus.22-29

2. Safety concerns

Intracoronary stent thrombosis (ST) is an infrequent but devastating complication after percutaneous coronary intervention (PCI). Because intracoronary stents are generally implanted in proximal segments of major coronary arteries, acute thrombotic occlusion of stents is usually associated with severe ischemia or MI (-50 to 70-80%) that often leads to death (-20 to 40%).30,31 Early (<30 days) or late ST (30 days to 1 year) occurred similarly between BMS and DES; however, significantly higher rates of very late ST (>1 year) were seen with DES in a large collaborative meta-analysis.31,32 Registries of all comers treated with DES showed that very late ST developed at an annual rate about 0.3-0.6%/year after DES implantation.32,33

The main mechanisms of this phenomenon are impaired endothelialization and hypersensitivity reaction with the polymer. The anti-proliferative agents impair endothelialization and the blood is then exposed to the stent struts more, potentially precipitating ST. Postmortem pathological specimens and angioscopy of DES reveal a significant number of uncovered struts with an inflammatory reaction.34-37 Polymers facilitate drug release in DES, but remain long after completion of drug elution. That could cause localized vascular inflammation, eosinophilia, apoptosis of smooth muscle cells, and thrombosis.38-40

THE SECOND-GENERATION DES

The new DES designs should be safer by decreasing ST, which is more effective for reducing restenosis, especially for high-risk PCI, with more durable results for decreasing rates of late restenosis or thrombosis compared with the first-generation DES.41 The four key components of DES are drug, polymer, stent platform, and stent delivery system. The second-generation DES are designed to provide better stent deployment, safety, and efficacy by improving the key components. In 2008, the zotarolimus-eluting stents (ZES) and the everolimus-eluting stents (EES) were approved by the US FDA for use and are referred to as "second-generation" DES. Their anti-proliferative drug is released from a thin coating of a biocompatible polymer on a flexible stent frame with thin struts.42

1. Advances in design

The prominent differences between the first- and the second-generation DES designs are the stent strut and the polymer. The stent scaffold design has a role in determining performance, including deliverability, side branch access, and the surface area for drug delivery. The initial stent scaffold was 316L stainless steel because this material is radio-opaque and provides enough radial strength to prevent acute recoil. Several studies have shown that thinner struts may reduce restenosis, facilitate endothelialization, and decrease thrombogenicity.43-45 Therefore, stent platform materials have moved from stainless steel to cobalt chromium (CoCr) and platinum chromium (PtCr), which allow for thinner struts while preserving radial strength and recoil.

Phosphorylcholine is used as a polymer of ZES. Its molecular design improves surface biocompatibility and lowers the risk of causing inflammation or thrombosis.46 Another contemporary biocompatible polymer is the fluoropolymer that is used in EES. The fluoropolymer surface elicits a biological response known as fluoropassivation that minimizes the fibrin deposition and thrombogenicity, thereby reducing the inflammatory reaction and enhancing endothelial healing.47,48

The second-generation DES were associated with more strut coverage, re-endothelialization, and less endothelial dysfunction in several pathologic and coronary imaging studies.49-53

2. Clinical studies of ZES

ZES are inferior to SES and PES with respect to the angiographic finding of in-stent late loss. In terms of clinical outcomes, ZES have similar or better outcomes compared with PES.54,55 The data on ZES compared with SES are less definitive but there appears to be similar safety but higher rates of target vessel revascularization (TVR) with ZES.55-57 The rapid elution of zotarolimus from a polymer may be related to the high rate of late loss compared with other DES. After 1 year, however, ZES showed superior safety outcomes (death/MI, ST) compared with both SES and ZES,58,59 and the TLR rate of ZES was closer to that of SES, possibly because of the late catch phenomenon.59

The Resolute ZES use dual polymer technology that extends the release of zotarolimus and drug exposure to the vessel to 4 months for decreasing in-stent late loss. Patients with ZES experienced more TVR rates than did patients with EES in real-world practice.60 In contrast, the Resolute ZES had similar revascularization rates and safety profiles compared with EES even in patients with complex PCI during 1 to 2 years of follow-up.61-63 According to a recent optical coherence tomography (OCT) study, the Resolute ZES had better suppression of neointimal growth but a higher proportion of uncovered and malapposed struts compared with ZES.64 Longer follow-up data are needed for the new generation of ZES.

3. The current workhorse: EES

EES were superior to PES in preventing both restenosis (TVR) and thrombosis (MI, ST) in two large randomized controlled studies.65,66 At least, EES were not inferior to SES. Three randomized trials and one observational study demonstrated similar angiographic late loss and ST rates between EES and SES.67-70 One randomized trial and one observational study reported less ST with EES.71,72 In a large cohort study and a meta-analysis, the second-generation DES, especially EES, had superior efficacy and safety compared with the first-generation DES (SES and PES).73,74

There are many published studies demonstrating the efficacy and safety of EES in high-risk patients. Table 1 briefly summarizes these studies. EES had comparable results in this high-risk group.75-82 During long-term follow-up (4-5 years), EES showed durable efficacy without the late catch phenomenon and safety compared with BMS and PES.83,84

TABLE 1

Studies of EES in high-risk groups

EES: everolimus-eluting stent, PRECOMBAT: premier of randomized comparison of bypass surgery versus angioplasty using sirolimus-eluting stent in patients with left main coronary artery disease, SES: sirolimus-eluting stent, MI: myocardial infarction, TVR: target vessel revascularization, PCI: percutaneous coronary intervention, CABG: coronary artery bypass grafting, TLR: target lesion revascularization, PES: paclitaxel-eluting stent, ISR: in-stent restenosis, XAMI: xiencev stent vs. cypher stent in primary PCI for acute myocardial infarction, AMI: acute myocardial infarction, ACS: acute coronary syndrome, ESSENCE-DIABETES: everolimus-eluting stent versus sirolimus-eluting stent implantation for de novo coronary artery disease in patients with diabetes mellitus, DM: diabetes mellitus, SPIRIT: clinical evaluation of the xience V everolimus eluting coronary stent system.

PROMISING NEW DES DESIGNS WITH EVIDENCE

1. DES with a small amount of a biodegradable polymer

Stent polymers have potential effects on hypersensitivity and inflammation, which could be translated into ST. DES with biodegradable polymers can offer the anti-restenotic effects of a DES initially and the safety benefits of a BMS after degradation of the polymer.85 There are several representative published studies about biodegradable polymers.

In the Limus Eluted from A Durable vs. ERodable Stent Coating (LEADERS) trial, 1707 patients with both stable and unstable coronary artery disease were randomly assigned to either a biolimus- (a sirolimus analog) eluting stent (BES) with a biodegradable polymer applied only to the abluminal (outer) surface or to an SES. The BES was noninferior to the SES for the primary composite endpoint of cardiac death, MI, or clinically indicated TVR at 9 months. The rate of definite ST was also similar (2.5% vs. 2.2%).86 According to the Optical Coherence Tomography (OCT) substudy of the LEADERS trial, biodegradable stents showed more complete strut coverage at an average follow-up of 9 months compared with SES.87 By reducing the risk of cardiac events associated with very late ST, BES with a biodegradable polymer improved long-term clinical outcomes for up to 4 years of follow-up of the LEADERS trial.88

Other trials such as the Intracoronary Stenting and Angiographic Restenosis-Test Equivalence Between 2 Drug-Eluting Stents (ISAR-TEST) 3 and 4 reported comparable results with SES in terms of both efficacy and safety.69,89,90 A meta-analysis using the results of the ISAR-TEST 3, ISAR-TEST 4, and LEADERS studies showed that biodegradable polymer DES reduced definite ST and TLR at 3 years compared with SES.91

2. Polymer-free DES

The polymer-free stent may be associated with less chronic inflammation and improved vascular healing. The difficulty in designing a polymer-free stent is achieving adequate levels of the antiproliferative drug over time to effectively inhibit neointimal hyperplasia and restenosis. Like ZES, polymer-free DES suffer high late loss during short-term follow-up, but are less susceptible to late restenosis.89,92

Dual polymer-free DES use two anti-proliferative agents (sirolimus and probucol) that target a different part of the cell cycle for improving the anti-restenosis effect.85 This concept was evaluated in the ISAR-TEST 2 and 5. The ISAR-TEST 2 study randomly assigned 1007 patients to SES (n=335), ZES (n=339), or a dual polymer-free DES (n=333). Safety profiles were similar among the 3 groups. TLR rates were significantly lower with dual polymer-free DES than with ZES and were comparable between dual polymer-free DES and SES at 2 years of follow-up. However, the increase in TLR and binary restenosis between the 1- and 2-year follow-up was significantly higher with SES.93,94 The ISAR-TEST 5 study showed that dual polymer-free DES were noninferior to ZES in terms of the rate of primary endpoints (cardiac death, target-vessel related MI, target lesion revascularization) out to 12 months.95 Table 2 briefly summarizes the advantages of the new DES designs over the first-generation DES.

TABLE 2

Published advantages over the first-generation DES

DES: drug-eluting stent, BMS: bare metal stent, ACS: acute coronary syndrome, DM: diabetes mellitus, ZES: zotarolimus-eluting stent, EES: everolimus-eluting stent, PF: polymer-free.

3. Bioresorbable scaffold

Complete bioabsorbable stent platforms are currently undergoing clinical trials. Potential advantages over current DES are as follows: 1) the removal of the scaffold facilitates the return of vessel vasomotion, adaptive shear stress, late luminal enlargement, and the reduction of scaffold thrombosis; 2) a reduction in the requirements for long-term dual anti-platelet therapy, thereby reducing the bleeding complications; 3) allowance for future revascularization and the use of noninvasive imaging techniques such as computed tomography or magnetic resonance imaging for follow-up.96 The A Bioabsorbable Everolimus-Eluting Coronary Stent System for Patients With Single De-Novo Coronary Artery Lesions (ABSORB) study showed complete stent resorption, arterial healing, and restoration of normal vascular function.97 The second generation of bioabsorbable stents has overcome the shortcomings of the first generation (early bioresorption and device shrinkage).98 Several randomized studies have recently commenced to demonstrate the efficacy and safety of bioabsorbable stents. However, many obstacles, such as higher cost, a thicker device, and long-term safety, should be overcome to use this stent.

In conclusion, the first-generation DES were limited in value because of late-term ST and restenosis. The second-generation DES, the current workhorse, further improved safety and efficacy by the use of thinner stent struts and biocompatible polymers. Recently, DES with new concept designs such as biodegradable polymers, polymer-free stents, and bioabsorbable scaffolds have shown promising results. However, more well-organized studies with large-scale and long-term follow-up are needed before these new DES become the next workhorse.