C L I N I C A L F O C U S : C A R D I O M E TA B O L I C H E A LT H , A N D P U L M O N A RY A N D VA S C U L A R M A N A G E M E N T
Coronary Artery Stents: Advances in Technology
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DOI: 10.3810/hp.2014.10.1145
Sameer D. Sheth, MD 1 Robert P. Giugliano, MD, SM 1,2 Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 2 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 1
Abstract: The introduction of percutaneous coronary intervention (PCI) in the late 1970s revolutionized the management of stable and unstable coronary artery disease, providing an effective, quick, safe, and increasingly widely available method for coronary revascularization for many patients. Rapid development in this field led to the introduction of a number of new technologies, including intracoronary stents that have resulted in improved efficacy and long-term safety. In this manuscript we review the experience with the 2 major available classes of stents (bare metal [BMS], drug-eluting [DES]) and describe the delivery systems for these stents. An evidence review of the large trial data comparing balloon angioplasty, BMS, and DES demonstrates the incremental advances over time, with the latest generation of DES achieving the lowest rates of restenosis, stent thrombosis, and recurrent myocardial infarction. In addition, we provide an overview of the latest developments in stent technology, including the introduction of bioresorbable stents and new stent delivery systems. These latest advances are hoped to further improve outcomes while reducing costs due to a reduction in the need for future procedures and hospitalizations due to recurrent coronary disease. Keywords: arterial stenosis; coronary artery stent; coronary balloon angioplasty; percutaneous coronary intervention
Introduction
Correspondence: Robert P. Giugliano, MD, SM, TIMI Study Office, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115. E-mail: [email protected]
The advancement of percutaneous coronary intervention (PCI) has led to its use in the treatment of stable angina, acute coronary syndrome, and more recently multivessel coronary artery disease.1 Pioneered by Dr. Andreas Gruntzig in 1977, coronary balloon angioplasty enabled marked and rapid reduction in arterial stenosis.2 The next 4 decades of scientific and technological innovation led to the introduction of metal stents (in 1986) and drug-eluting stents (in 2003), and to the development of bioresorbable stents.3 Although novel techniques and devices have helped lower mortality rates, cardiovascular disease continues to be the leading cause of death in the United States. In 2010, there were an estimated 492 000 patients undergoing PCI with implantation of a drug-eluting stent.4 As the use and variety of coronary artery stents continue to expand, questions remain regarding their long-term safety and efficacy. A number of reviews have examined the biology, efficacy, and safety of, as well as clinical indications for, the use of coronary artery stents.1,3 This update discusses the historical development and advances in technology of coronary artery stents, reviewing the supporting evidence from recent randomized clinical trials.
Methods
We searched PubMed for review articles on the topic of coronary artery stents. We used the terms coronary artery stents, bare-metal stents, drug-eluting stents, and bio-
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resorbable stents to obtain background data and to identify meta-analyses on these topics. We identified 20 publications that met the search criteria, and after eliminating articles that were not relevant, 8 articles remained. We also collected the primary manuscripts for the ABSORB and ABSORB II trials, and for the DIRECT Study, and used ClinicalTrials.gov to find data on ongoing trials such as DIRECT II. Follow-up manuscripts from the ABSORB trial were reviewed also. Additionally, we searched the US Food and Drug Administration (FDA) website for approved bare-metal stents (BMSs) and drug-eluting stents (DESs). Lastly, risk reduction was calculated from meta-analysis using standard statistical methods.
Types of Stents
There are currently 2 broad classes of stents used in PCI: BMSs and DESs. The BMSs are composed of a thin wire, made of stainless steel or cobalt-chromium alloy, forming a mesh-like tube that can be fitted into the artery (Figure 1).3 The DESs have 3 components: a platform, a carrier, and an antiproliferative agent. The platform is the bare-metal component of stainless steel, cobalt chromium, or platinum chrome. Polymers, nondegradable or bioresorbable, cover the stent surface to act as slow-release drug carriers. The antiproliferative agent acts to suppress neointimal formation by disrupting microtubule disassembly (eg, paclitaxel) or inhibiting mammalian target of rapamycin (eg, sirolimus).1 In the United States, the FDA has approved several stents for use in coronary artery disease (Table 1).
Bare-Metal Stents
The first commercially available BMS, the Palmaz-Schatz stent, was used in 1986 as a way to maintain the integrity of the lumen and prevent elastic recoil.5 Two early randomized controlled trials helped establish the Palmaz-Schatz stent as the standard treatment over balloon angioplasty: the Belgium Netherlands Stent Study (BENESTENT) and the North American Stent Restenosis Study (STRESS).6,7 Both studies showed that coronary stents improved the procedural success rate, reduced the rate of angiographic restenosis, and reduced the need for revascularization compared with balloon angioplasty alone. Advances in material sciences led from stainless steel stents to thin-strut, flexible, stronger cobalt alloy stents. Most recently, the OMEGA trial, a prospective, multicenter, single-arm study, enrolled 328 patients to receive a platinum chromium BMS. The primary end point of target lesion failure (cardiac death, target vessel-related myocardial infarction [MI], and target lesion revascularization) at 9 months showed a low rate, 11.4%, thus supporting the safety and efficacy of this novel BMS.8 Soon, clinicians noticed an increased risk of subacute thrombosis with the widespread use of BMS. As a result, dual antiplatelet therapy with aspirin and ticlopidine (later clopidogrel) was introduced to reduce the incidence of stent thrombosis.9,10 A number of meta-analyses have examined the safety and efficacy of BMS compared with balloon angioplasty (Table 2). The BMSs had similar rates of mortality and
Figure 1. Photograph of bare-metal and drug-eluting stent. (A) Multi-Link RX Ultra bare-metal stent (Abbott Vascular, Abbott Park, IL) made of solid stainless steel in a corrugated ring pattern connected by 3–3–3 links.56 (B) Endeavor Zotarolimus-Eluting Coronary Stent (Medtronic, Minneapolis, MN) of cobalt-chromium with an antiproliferative drug (zotarolimus) contained within a thin polymer coating on its surface.57
84
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Coronary Artery Stents
Table 1. Available Bare-Metal Stents and Drug-Eluting Stents Approved by the US Food and Drug Administration
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Commercial Name
Manufacturer
Bare-metal stents Multi-Link 8 Abbott Vascular Multi-Link Vision Multi-Link Ultra Vision Multi-Link Zeta Coroflex B.Braun Coroflex Blue Veriflex Boston Scientific Integrity Medtronic Driver FDA-approved drug-eluting stents Taxus Express Boston Scientific Taxus Liberté Cypher Cordis, Johnson & Johnson Xience Abbott Vascular Promus Boston Scientific Promus Element Endeavor Medtronic Resolute
Platform Material
Antiproliferative Agent
Dual Antiplatelet Therapya
Cobalt chrome
NA
. 1 month to 12 months
Stainless steel
Paclitaxel
12 months
Stainless steel Cobalt chrome Cobalt chrome Platinum chrome Cobalt chrome
Sirolimus Everolimus Everolimus
Stainless steel Stainless steel Cobalt chrome Stainless steel Cobalt alloy Cobalt chrome
Zotarolimus
Dual antiplatelet therapy refers to aspirin 81 mg daily (continued indefinitely) along with clopidogrel 75 mg daily, prasugrel 10 mg, or ticagrelor 90 mg twice daily for specified period of time.60 a
adverse cardiac events compared with balloon angioplasty, while reducing angiographic restenosis and the need for repeat revascularization. The data supported the prevalent use of stents; however, in-stent restenosis, caused by neointimal hyperplasia inside the BMS, became a growing concern. Eventually, this led to newer technology aimed at preventing complications such as stent thrombosis and in-stent restenosis.
Drug Eluting Stents
The DESs were developed to solve the problem of in-stent restenosis seen with the BMSs. The first-generation DESs released the antiproliferative agent paclitaxel or sirolimus
that was attached to the older bare-metal platforms. The second-generation DESs employed new stent designs with thinner, radiopaque, and stronger materials such as cobalt chromium. The ENDEAVOR and SPIRIT trials showed that newer antiproliferative drugs, everolimus and zotarolimus, improved performance with lower rates of restenosis and late stent thrombosis.11,12 Numerous meta-analyses have compared DES with BMS (Table 3). The results showed similar rates of death, MI, and stent thrombosis; however, DES led to significant reductions in-stent restenosis and the need for target lesion revascularization. Yet, there are important differences between various DESs. First-generation DESs have been associated with
Table 2. Summary of Evidence From Meta-Analyses Comparing Clinical Effectiveness of Bare-Metal Stents Versus Balloon Angioplastya Meta-Analysis
Inclusion Characteristics
No of Trials
No of Patients
Bare-Metal Stents Versus Balloon Angioplasty
Brophy et al61
All clinical trials
29
9918
Similar (death or MI combined)
Agostoni et al62
Small vessels (diameter , 3 mm) Small vessels (diameter , 3 mm) Total coronary occlusion
13
4383
Similar
Similar
11
3541
Similar
Similar
9
1409
Similar
↑ 106% (22%–246%)
Moreno et al63 Agostoni et al64
Death RR (95% CI)
Myocardial Infarction RR (95% CI)
Angiographic Restenosis RR (95% CI)
Repeat Revascularization RR (95% CI)
↓ 48% (31%–63%) ↓ 33% (13%–48%) ↓ 23% (8%–35%) ↓ 64% (43%–77%)
↓ 41% (32%–50%) ↓ 24% (5%–39%) ↓ 25% (9%–39%) ↓ 59% (47%–69%)
Comparisons are made between bare-metal stents and balloon angioplasty in each individual meta-analysis. Risk reduction (95% CIs) was shown in the meta-analysis; consequently risk reduction may have not been observed in individual randomized trials. Abbreviations: MI, myocardial infarction; RR, risk reduction. a
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Table 3. Summary of Meta-Analyses on the Clinical Effectiveness of Drug-Eluting Stents and Bare-Metal Stentsa Meta-Analysis
Stettler et al65 Kastrati et al66 De Luca et al67 Bangalore et al14
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Bangalore et al15
Inclusion Characteristics
No of Trials
No of Patients
Drug-Eluting Stents Versus Bare-Metal Stents Death
Myocardial Infarction
Stent Thrombosis
Target Lesion Revascularization
DESs Compared to Each Other
All clinical trials of DES and BMS DES (PES, SES) and BMS for STEMI DES (PES, SES, ZES) and BMS for STEMI FDA-approved DES and BMS for de novo coronary lesion FDA-approved DES, BP-DES, and BMS
38
18 023
Similar
SES ↓ 19%
Similar
↓ 58%–70%
SES vs PES ↓ ST 46%
8
2786
Similar
Similar
Similar
↓ 62%
11
6298
Similar
Similar
Similar
↓ 43%
76
57 138
Similar
126
106 427
Similar (except CoCr EES ↓ 28%)
Similar ↓ 18%–37% (exclude PES) (except EES ↓ 49%) Similar ↓ 17%–39% (exclude PES) (except CoCr EES ↓ 65%)
Cumulative DES vs BMS Cumulative DES vs BMS EES ∼ SES ∼ ZES-R . PES ∼ ZES . BMS for TLR BP-DES . PES/ ZES-E for TLR
↓ 39%–61%
↓ 38%–63%
Comparisons are made between drug-eluting stents and bare-metal stents in each individual meta-analysis. Data shown in table are ranges in risk reduction of multiple DES compared to BMS. Abbreviations: BMS, bare-metal stent; BP-DES, biodegradable polymer drug-eluting stent; CoCr, cobalt chromium; EES, everolimus eluting stent; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent; ST, stent thrombosis; STEMI, ST-elevation myocardial infarction; TLR, target lesion revascularization; ZES-E, zotarolimus-eluting stent— Endeavor; ZES-R, zotarolimus eluting stent—Resolute. a
an increased risk of very late thrombosis, especially after discontinuation of antiplatelet therapy, and have fallen out of favor.13 Newer generation DESs, such as everolimuseluting stents, have been shown to reduce both the risk of thrombosis over the long term as well as the risk of MI.14 The cobalt-chromium everolimus-eluting stent has been the only stent developed thus far that reduces the risk of death, MI, and stent thrombosis compared with BMSs.15 However, even newer generation DESs cannot prevent restenosis and very late thrombosis; thus, new studies continue to evaluate the safety and efficacy of DESs in the hopes of minimizing adverse events.
New Advances in Stent Technology Bioresorbable Stents
Technological evolution over the last 2 decades has led to the introduction of bioresorbable stents. The 2 most promising materials are polymer-based or absorbable metals. Polylactic acid (PLLA) is a frequently used polymer that degrades into water and carbon dioxide by means of the Krebs cycle. Magnesium-based alloys are an alternative, as they can be absorbed by human tissue. Important features of all bioresorbable stents include radial strength, slow degradation to avoid inflammation or toxic reactions, ease of use and deliverability, and improved visualization.16 This new technology possesses many advantages over metallic stents. First, by eliminating the presence of a permanent metallic foreign body from the vessel wall, inflammation 86
and formation of new atherosclerotic plaques is reduced, ultimately decreasing the risk of stent thrombosis.17−19 Second, by eliminating the stent backbone, there is no longer the fear of permanent caging of a vessel, jailing of side branches, or preventing late lumen enlargement.20 The intent was that the removal of a backbone would lead to the recovery of endothelial function, to an increase in responsiveness of the coronary vessel, and to reduction in cardiovascular events.21 Theoretically, polymer stents should be more flexible and conformable, creating less shear stress on the vessel wall.22 From a physiological perspective, once degraded, the vessel wall would be exposed to the cyclic strain of blood pulsatility.23 The modulation of inflammatory signals could be beneficial, leading to a reduction in atherogenesis.24 Furthermore, patients would not require prolonged dual antiplatelet therapy, thus reducing the risk of bleeding.25 Also, most of the newer devices could be visualized using noninvasive technologies, such as computed tomography angiography or magnetic resonance imaging, until they are fully absorbed.16 Although bioresorbable stents are an exciting development, there are some limitations to their use. Many of the advantages are theoretical and have not yet been demonstrated in large randomized controlled trials. Furthermore, the speed of degradation of these platforms may vary among patients, leading to unpredictable drug delivery. Also, a potential downside is the risk of strut fracture due to limits in expansion and dilation of polymeric devices. Most importantly, further
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Coronary Artery Stents
investigation is needed to determine the safety and efficacy of the different bioresorbable platforms.16 The Igaki-Tamai stent was the first bioresorbable stent implanted in humans. Composed of PLLA, this stent did not employ a drug-eluting system, and implantation required a complex procedure using a thermal balloon.26 The results of the first in-human study, including 15 patient with 25 stents, demonstrated no stent thrombosis, MI, or major cardiac death at 6 months.26 A second study with 50 patients and 84 stents found 97.7% survival at 4 years.27 The first metallic biodegradable stent (AMS-1; Biotronik, Berlin, Germany) was composed of 93% magnesium and 7% rare earth metals.28 Similar to stainless steel stents in mechanical properties, this stent was also balloon expandable, though lacked a drug-eluting polymer. The PROGRESS AMS (Clinical Performance and Angiographic Results of Coronary Stenting with Absorbable Metal Stents) trial, consisting of 63 patients and 71 implanted stents in de novo coronary lesions, reported no death, MI, or stent thrombosis at 12-month follow-up; however, the rate of target lesion revascularization was high: 23.8% at 4 months and 45% at 12 months.28
The ABSORB Trial
One of the earliest studied bioresorbable stents is the everolimus-eluting stent system (BVS; Abbott Vascular, Santa Clara, CA).29 It consists of a bioresorbable PLLA backbone coated with a more rapidly absorbed layer of poly-D,L-lactic acid that contains and controls the elution of everolimus. The stent is balloon expandable and radiolucent, and the polymer degrades by hydrolysis.29 The ABSORB trials (cohorts A and B) were conducted to evaluate the feasibility and safety of the BVS stent system.29,30 The ABSORB cohort A (BVS 1.0) trial was a single-arm prospective, open-label study conducted in 2006 including 30 subjects with a single de novo coronary artery lesion.29 The ABSORB cohort B (BVS 1.1) trial was a single-arm, multicenter, study conducted with a modified BVS stent system in patients with # 2 de novo coronary artery lesions.30 This newer stent modified the platform design and polymer processing to improve mechanical strength, reduce early and late recoil, as well as slow the degradation process to provide longer mechanical support to the vessel.31,32 Cohort B enrolled 101 patients, of whom 45 (cohort B1) were randomized to angiographic and invasive follow-up at 6 and 24 months, whereas 56 (Cohort B2) were randomized to invasive follow-up at 12 and 36 months. The clinical end points for these studies included cardiac death, MI, ischemia-driven target lesion revascularization,
ischemia-driven major adverse cardiac event (MACE; a composite of cardiac death, MI, or ischemia-driven target lesion revascularization), and stent thrombosis assessed at 6 months, 1 year, and 2 years.29,33 Angiography, intravascular ultrasound (IVUS), and optical coherence tomography (OCT) were assessed at 6 months and repeated at 2 years.33 Noninvasive coronary angiography with multislice computed tomography (MSCT) was performed at 18-month and 5-year follow-up.34 The clinical data from cohort A demonstrated a single non– Q-wave MI, and a MACE rate of 3.4% at 6-month follow-up, which remained unchanged at 2, 3, 4, and 5 years, thus providing support for the long-term safety of the device.33,35−37 There was no scaffold thrombosis with MSCT results, showing an area stenosis of the scaffold segment of 31.6% at 18 months (25 patients) compared with 33.3% at 5 years (18 patients).37 Coronary angiography showed diameter stenosis of 27% at 6 months and 2 years.33 Lastly, IVUS and OCT showed bioresorption of the polymeric struts as well as late enlargement of the lumen from 6 months to 2 years.33 The results from cohort B were MACE rates of 4.9%, 6.9%, 9.0%, and 10.0% among the 101 patients at 6 months, 1, 2, and 3 years, respectively.30,38,39 There was no evidence of stent thrombosis at 3-year follow-up.39 Quantitative coronary angiography (QCA) analysis between 6 months and 3 years showed that late luminal loss was unchanged at 0.19, 0.27, 0.27, and 0.29 mm at 6 months, 1, 2, and 3 years, respectively.39,40 Analyses of lesion and stent morphology using IVUS demonstrated enlargement of mean lumen, scaffold, plaque, and vessel lumen area between 6 months and 2 years, with a substantial reduction in plaque at 3 years. Serial review by OCT over 3 years showed late scaffold area enlargement, an increase in neointimal formation, and an increase in strut cores detected, reflecting dismantling of the scaffold.38,39 Furthermore, a study conducted in small vessels (diameter , 2.5 mm) found similar clinical and angiographic outcomes at 2 years.41
ABSORB II Study
The ABSORB II study is a randomized, active-controlled, single-blinded, multicenter clinical trial in 501 patients comparing the second-generation Absorb BVS (poly-L-lactide, thin coating 1:1 amorphous matrix of poly-D,L-lactide, everolimus) with the XIENCE stent system (cobalt chromium alloy, thin biocompatible acrylic, fluorinated everolimusreleasing copolymer).42 Both devices are similar in terms of basic design, everolimus dosage, and elution profile. The primary objective of this trial is to examine safety, efficacy, and performance of the Absorb BVS against the
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current XIENCE stent over 3 years. The co-primary end points include vasomotion measured by the change in mean lumen diameter pre-nitrate and post-nitrate and at 2 years as assessed by QCA (superiority), and minimum lumen diameter post-nitrate minus minimum lumen diameter postprocedure post-nitrate by QCA (noninferiority). Clinical follow-up will include blood analysis of multiple markers, exercise testing, and quality of life questionnaires. Subjects will undergo angiography as well as IVUS at 2-year follow-up. A subgroup will have near-infrared spectroscopy (Lipiscan) at 2-year follow-up, whereas all Absorb BVS subjects will undergo MSCT at 3 years.42
Developing Technology
The REVA stent (Reva Medical Inc, San Diego, CA), a resorbable tyrosine-derived polycarbonate polymer, is a balloon expandable, non–drug-eluting, radiopaque stent. It is metabolized by the Krebs cycle into amino acid, ethanol, and carbon dioxide. Depending on the weight of the polymer, degradation of the stent can take , 12 months to 2 years.16 The REVA Endovascular Study of a Bioresorbable Coronary Stent (RESORB) trial was a 30-patient multicenter, prospective, safety study examining stent strength and restenosis. The rate of target lesion revascularization was 66.7% between 4 and 6 months, in part due to mechanical failures of the polymer.43 This led to a redesign and ongoing clinical testing (ClinicalTrials.gov number NCT01845311) of the secondgeneration ReZolve sirolimus eluting stent. The IDEAL bioresorbable stent (Bioabsorbable Therapeutics, Inc., Menlo Park, CA), made of polyanhydride ester based on salicylic acid and adipic acid, is a balloon expandable, sirolimus-eluting stent containing anti-inflammatory properties.44 The stent is metabolized into salicylate, carbon dioxide, and water over a period of 9 to 12 months. The development of nanoparticle eluting stent technology, in which biodegradable nanoparticles coat a metallic stent, allows for the delivery of various drugs directly to the cell membrane in a controlled manner, thus promoting healing and preventing complications such as restenosis.45 Current research with recombinant DNA and nucleic acid based therapies is looking to prevent in-stent restenosis. The goal is to deliver plasmid DNA or small interfering RNA via stents to target those signal cascades involved in inflammation, vascular remodeling, and apoptosis.45
Delivery System
Early coronary angiography began with the insertion of large catheters into the femoral artery. In the past decade, rapid 88
adoption of a radial artery approach helped reduce vascular complications.46 By injecting contrast through the catheter, a physician is able visualize the coronary vessels and target lesion. A guiding catheter enables a variety of instruments through, including balloon, stent, and IVUS catheters. After identifying the lesion, a balloon catheter can be used to predilate the vessel prior to stent placement. The introduction of a stent begins with placement of a guidewire, over which the expandable stent is mounted over a deflated balloon. Visualized through fluoroscopy, the stent and balloon are positioned, after which the balloon is inflated to place the stent. Postdilation at high pressures reduces risk of stent thrombosis, especially in DES (Figure 2).47
Svelte Integrated Delivery System
Svelte Medical Systems (New Providence, NJ) created a new integrated delivery system (IDS) for drug-eluting stents aimed at improving direct stenting of coronary lesions. Compared to other drug-eluting stents, the IDS employs a balloon-expandable thinner cobalt-chromium strut stent, pre-mounted on a single-lumen fixed-wire delivery system (Figure 3).48,49 The figure shows the components of the Svelte Acrobat System. Once vascular access is obtained, the introducer/delivery system is loaded followed by advancement and deployment of stent. In contrast, the current technique requires loading the guidewire, balloon, and stents separately. The stent is covered by a fully bioresorbable carrier made of amino acids eluting sirolimus. There are fewer steps in this delivery system, leading to a number of benefits, including reduced procedural time, contrast administration, radiation exposure, and costs. On the other hand, many of these advantages are theoretical, and further studies are needed to clarify the safety profile on measures such as late-lumen loss, vascular injury, and in-stent dissection. The future clinical application of a new delivery system is in the treatment of bifurcating, tortuous, and distal lesions that are challenging to reach by conventional methods.48,50−52
DIRECT Study
The DIRECT study was a prospective, single-arm, multicenter study evaluating the Svelte IDS system in ischemic heart disease that is due to a single de novo stenotic coronary lesion.53 There were 30 patients with the primary safety end point of angiographic target vessel failure at 6 months, defined as a composite of cardiac death, target vessel MI, and target vessel revascularization. The primary efficacy end point was angiographic in-stent late lumen loss at 6 months, defined
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Coronary Artery Stents
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Figure 2. Coronary angioplasty and stent delivery. (A) (left to right) A coronary artery is narrowed by plaque and catheter-guided balloon is inflated to compress the plaque against the wall. (B) (left to right) A balloon is expanded over a guide catheter to position a coronary artery stent in the vessel.58
as the difference in minimal lumen diameter postprocedure and at follow-up as measured by QCA.53,54 Follow-up of 29 of 30 patients found that 2 suffered target vessel failure—1 patient requiring a second stent at the distal end of the study stent, and the other patient requiring revascularization proximal to the study stent. No patient suffered death, MI, or stent thrombosis. The study also examined in-stent proliferation, which was visualized by IVUS, and showed reduction in neointimal volume compared to other current DESs.53 In parallel, Diletti et al 48 examined outcomes after implantation of the Svelte IDS in 47 patients, finding a success rate of 97.9%, with no major adverse cardiac events at 30 days postprocedure. This study showed increased late lumen loss at 6 months compared with prior studies of BMSs, although there was not a higher rate of target lesion revascularizations. In terms of safety profile, the Svelte IDS system was found to have a low vascular injury profile, while being as effective as BMSs in the treatment of coronary artery lesions.
DIRECT II Trial
The DIRECT II is an ongoing prospective, randomized controlled, multicenter trial evaluating the safety and efficacy of the Svelte drug-eluting coronary stent IDS compared Figure 3. Svelte integrated delivery system59 (Svelte Medical Systems (New Providence, NJ).
with the Resolute drug-eluting stent (zotarolimus-eluting stent; Medtronic, Minneapolis, MN). This study is enrolling patients with single, de novo coronary artery lesions with primary outcomes of angiographic target vessel failure and in-stent late lumen loss, both at 6 months’ duration. The secondary outcomes include a composite of cardiac death, MI, and all-cause mortality, as well as stent thrombosis, and target lesion revascularization at 1 month, 6 months, and yearly up to 5 years. The planned enrollment is 159 patients with completion date of approximately June 2018.55
Conclusion
Coronary stents represent a remarkable advancement in the treatment of stable and unstable coronary artery disease. The DESs have become the mainstay of treatment and have proven to be safe and effective. The newest everolimuseluting stents have been shown to be the safest; they appear to reduce the risk of death compared to bare-metal stents. Evolution in technology has also led to the development of bioresorbable stents, which appears to be as safe as DESs. Although effectiveness studies are currently ongoing, bioresorbable stents offer the theoretical advantage of a reduced inflammatory and thrombotic potential, possibly reducing restenosis and stent thrombosis, as well as lowering the risk of jailing vessels. Furthermore, innovations in delivery systems allow stents to be placed more efficiently, aiming to reduce costs and improve safety.
Conflict of Interest Statement
Robert P. Giugliano, MD, SM, reports receiving consulting fees from Daiichi Sankyo, Janssen Pharmaceuticals, and Merck; lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Merck, and Sanofi; and grant support through his institution from Daiichi Sankyo, Merck, Johnson and Johnson, Sanofi, and AstraZeneca. Sameer D. Sheth, MD, has no conflicts of interest to declare. © Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 89 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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References 1. Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents. N Engl J Med. 2013;368(3):254–265. 2. Gruntzig AR, Senning Ak, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis. N Engl J Med. 1979;301(2):61–68. 3. Serruys PW, Kutryk MJB, Ong ATL. Coronary-artery stents. N Engl J Med. 2006;(3545):483–495. 4. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–e292. 5. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and re-stenosis after transluminal angioplasty. N Engl J Med. 1987;316(12):701–706. 6. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloonexpandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994;331(8):489–495. 7. Fischman DL, Leon MB, Baim DS, 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. 1994;331(8):496–501. 8. Wang JC, Carria D, Masotti M, et al. CRT-152 nine-month primary endpoint results of the Omega Study: clinical outcomes after implantation of a modern platinum chromium bare metal stent. JACC Cardiovasc Interv. 2014;7(2S):1. 9. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronaryartery stents. N Engl J Med. 1996;334(17):1084–1089. 10. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting : the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation. 2000;102(6): 624–629. 11. Serruys PW, Ong AT, Piek JJ, et al. A randomized comparison of a durable polymer Everolimus-eluting stent with a bare metal coronary stent: the SPIRIT first trial. EuroIntervention. 2005;1(1):58–65. 12. Meredith IT, Ormiston J, Whitbourn R, et al. Four-year clinical follow-up after implantation of the endeavor zotarolimus-eluting stent: ENDEAVOR I, the first-in-human study. Am J Cardiol. 2007; 100(8B):56–61. 13. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med. 2007;356(10):998–1008. 14. Bangalore S, Kumar S, Fusaro M, et al. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-years of follow-up from randomized trials. Circulation. 2012;125(23):2873–2891. 15. Bangalore S, Toklu B, Amoroso N, et al. Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug eluting stents for coronary artery disease: mixed treatment comparison metaanalysis. BMJ. 2013;347:f6625. doi:10.1136/bmj.f6625. 16. Onuma Y, Serruys PW. Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization? Circulation. 2011;123(7):779–797. 17. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435–2441. 18. Nakazawa G, Otsuka F, Nakano M, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011;57(11):1314–1322. 19. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(1):193–202. 20. Serruys PW, Garcia-Garcia HM, Onuma Y. From metallic cages to transient bioresorbable scaffolds: change in paradigm of coronary revascularization in the upcoming decade? Eur Heart J. 2012;33(1):16b–25b.
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21. Kitta Y, Obata JE, Nakamura T, et al. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol. 2009;53(4):323–330. 22. Gijsen FJ, Oortman RM, Wentzel JJ, et al. Usefulness of shear stress pattern in predicting neointima distribution in sirolimus-eluting stents in coronary arteries. Am J Cardiol. 2003;92(11):1325–1328. 23. Resnick N, Yahav H, Shay-Salit A, et al. Fluid shear stress and the vascular endothelium: for better and for worse. Prog Biophys Mol Biol. 2003;81(3):177–199. 24. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995;91(9):2488–2496. 25. Nikolsky E, Mehran R, Dangas G, et al. Development and validation of a prognostic risk score for major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J. 2007;28(16):1936–1945. 26. Tamai H, Igaki K, Kyo E, et al. Initial and 6-month results of biodegradable poly-l-lactic acid coronary stents in humans. Circulation. 2000; 102(4):399–404. 27. Tsuji T, Tamai H, Igaki K, et al. Four-year follow-up of the biodegradable stent (IGAKI-TAMAI stent). Circ J. 2004;68(Suppl 1):135. 28. Erbel R, Di Mario C, Bartunek J, et al. Temporary scaffolding of coronary arteries with bioabsorbable magnesium stents: a prospective, nonrandomised multicentre trial. Lancet. 2007;369(9576):1869–1875. 29. Ormiston JA, Serruys PW, Regar E, et al. A bioabsorbable everolimuseluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet. 2008;371(9616):899–907. 30. Serruys PW, Onuma Y, Ormiston JA, et al. Evaluation of the second generation of a bioresorbable everolimus drug-eluting vascular scaffold for treatment of de novo coronary artery stenosis: six-month clinical and imaging outcomes. Circulation. 2010;122(22):2301–2312. 31. Gomez-Lara J, Brugaletta S, Diletti R, et al. A comparative assessment by optical coherence tomography of the performance of the first and second generation of the everolimus-eluting bioresorbable vascular scaffolds. Eur Heart J. 2011;32(3):294–304. 32. Okamura T, Garg S, Gutierrez-Chico JL, et al. In vivo evaluation of stent strut distribution patterns in the bioabsorbable everolimus-eluting device: an OCT ad hoc analysis of the revision 1.0 and revision 1.1 stent design in the ABSORB clinical trial. EuroIntervention. 2010;5(8): 932–938. 33. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimuseluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet. 2009;373(9667):897–910. 34. Onuma Y, Dudek D, Thuesen L, et al. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. JACC Cardiovasc Interv. 2013;6(10):999–1009. 35. Onuma Y, Serruys PW, Ormiston JA, et al. Three-year results of clinical follow-up after a bioresorbable everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB trial. EuroIntervention. 2010;6(4):447–453. 36. Dudek D, Onuma Y, Ormiston JA, Thuesen L, Miquel-Hebert K, Serruys PW. Four-year clinical follow-up of the ABSORB everolimus-eluting bioresorbable vascular scaffold in patients with de novo coronary artery disease: the ABSORB trial. EuroIntervention. 2012;7(9):1060–1061. 37. Onuma Y, Dudek D, Thuesen L, et al. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimuseluting scaffold in patients with de novo coronary artery disease: the ABSORB Cohort A trial. JACC Cardiovasc Interv. 2013;6(10): 999–1009. 38. Ormiston JA, Serruys PW, Onuma Y, et al. First serial assessment at 6 months and 2 years of the second generation of absorb everolimuseluting bioresorbable vascular scaffold: a multi-imaging modality study. Circ Cardiovasc Interv. 2012;5(5):620–632.
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Coronary Artery Stents 39. Serruys PW, Onuma Y, Garcia-Garcia HM, et al. Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months. EuroIntervention. 2014;9(11):1271–1284. 40. Gogas BD, Bourantas CV, Garcia-Garcia HM, et al. The edge vascular response following implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold and the XIENCE V metallic everolimuseluting stent. First serial follow-up assessment at six months and two years: insights from the first-in-man ABSORB Cohort B and SPIRIT II trials. EuroIntervention. 2013;9(6):709–720. 41. Diletti R, Farooq V, Girasis C, et al. Clinical and intravascular imaging outcomes at 1 and 2 years after implantation of absorb everolimus eluting bioresorbable vascular scaffolds in small vessels. Late lumen enlargement: does bioresorption matter with small vessel size? Insight from the ABSORB cohort B trial. Heart. 2013;99(2):98–105. 42. Diletti R, Serruys PW, Farooq V, et al. ABSORB II randomized controlled trial: a clinical evaluation to compare the safety, efficacy, and performance of the Absorb everolimus-eluting bioresorbable vascular scaffold system against the XIENCE everolimus-eluting coronary stent system in the treatment of subjects with ischemic heart disease caused by de novo native coronary artery lesions: rationale and study design. Am Heart J. 2012;164(5):654–663. 43. Grube E. Bioabsorbable stent: the Boston Scientific and REVA Technology. In: EuroPCR. Barcelona, Spain; 2009. 44. Jabara R, Chronos N, Robinson K. Novel bioabsorbable salicylate-based polymer as a drug-eluting stent coating. Catheter Cardiovasc Interv. 2008;72(2):186–194. 45. Puranik AS, Dawson ER, Peppas NA. Recent advances in drug eluting stents. Int J Pharm. 2013;441(1–2):665–679. 46. Kiemeneij F, Laarman GJ, de Melker E. Transradial artery coronary angioplasty. Am Heart J. 1995;129(1):1–7. 47. Romagnoli E, Sangiorgi GM, Cosgrave J, Guillet E, Colombo A. Drugeluting stenting: the case for post-dilation. JACC Cardiovasc Interv. 2008;1(1):22–31. 48. Diletti R, Garcia-Garcia HM, Bourantas CV, et al. Clinical and angiographic outcomes following first-in-man implantation of a novel thin-strut low-profile fixed-wire stent: the Svelte Coronary Stent Integrated Delivery System first-in-man trial. EuroIntervention. 2013;9(1):125–134. 49. Sarno G, Okamura T, Gomez-Lara J, et al. The coronary Stent-On-AWire (SOAW). EuroIntervention. 2010;6(3):413–417. 50. Caluk J, Osmanovic E, Barakovic F, et al. Direct coronary stenting in reducing radiation and radiocontrast consumption. Radiol Oncol. 2000;44(3):153–157. 51. Ijsselmuiden AJ, Tangelder GJ, Cotton JM, et al. Direct coronary stenting compared with stenting after predilatation is feasible, safe, and more cost-effective in selected patients: evidence to date indicating similar late outcomes. Int J Cardiovasc Intervent. 2003;5(3):143–150. 52. Wilson SH, Berger PB, Mathew V, et al. Immediate and late outcomes after direct stent implantation without balloon predilation. J Am Coll Cardiol. 2000;35(4):937–943.
53. Webster MWI, Harding S, McClean D, et al. First-in-human evaluation of a sirolimus-eluting coronary stent on an integrated delivery system: the DIRECT study. EuroIntervention. 2013;9(1):46–53. 54. Tearney GJ, Regar E, Akasaka T, et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol. 2012;59(12):1058–1072. 55. Safety and efficacy study of the Svelte drug-eluting coronary stent delivery system (DIRECT II). http://clinicaltrials.gov/ct2/show/study/ NCT01788150. Accessed March 28, 2014. 56. Serruys PW, Rensing BJ, eds. Handbook of Coronary Stents, 4th ed. London: Martin Dunitz; 2002. 57. Medtronic’s Endeavor Drug-Eluting Stent Approved by FDA. 2008. http:// www.medgadget.com/2008/02/medtronics_endeavor_drugeluting_ stent_approved_by_fda.html. Accessed December 29, 2013. 58. How is coronary angioplasty done? National Institutes of Health. http:// www.nhlbi.nih.gov/health/health-topics/topics/angioplasty/howdone. html. Accessed March 28, 2014. 59. Svelte Medical Systems, Inc. http://www.sveltemedical.com/info. php?pid=60. Accessed March 28, 2014. 60. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardio vascular Angiography and Interventions. J Am Coll Cardiol. 2011; 58(24):e44–e122. 61. Brophy JM, Belisle P, Joseph L. Evidence for use of coronary stents. A hierarchical bayesian meta-analysis. Ann Intern Med. 2003; 138(10):777–786. 62. Agostoni P, Biondi-Zoccai GG, Gasparini GL, et al. Is bare-metal stenting superior to balloon angioplasty for small vessel coronary artery disease? Evidence from a meta-analysis of randomized trials. Eur Heart J. 2005;26(9):881–889. 63. Moreno R, Fernandez C, Alfonso F, et al. Coronary stenting versus balloon angioplasty in small vessels: a meta-analysis from 11 randomized studies. J Am Coll Cardiol. 2004;43(11):1964–1972. 64. Agostoni P, Valgimigli M, Biondi-Zoccai GG, et al. Clinical effectiveness of bare-metal stenting compared with balloon angioplasty in total coronary occlusions: insights from a systematic overview of randomized trials in light of the drug-eluting stent era. Am Heart J. 2006;151(3):682–689. 65. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drugeluting and bare-metal stents: a collaborative network meta-analysis. Lancet. 2007;370(9591):937–948. 66. Kastrati A, Dibra A, Spaulding C, et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J. 2007;28(22):2706–2713. 67. De Luca G Md PhD, Dirksen MT, Spaulding C, et al. Drug-eluting vs bare-metal stents in primary angioplasty: a pooled patient-level metaanalysis of randomized trials. Arch Intern Med. 2012;172(8):611–621.
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Coronary Artery Stents: Advances in Technology
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DOI: 10.3810/hp.2014.10.1145
Sameer D. Sheth, MD 1 Robert P. Giugliano, MD, SM 1,2 Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 2 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 1
Abstract: The introduction of percutaneous coronary intervention (PCI) in the late 1970s revolutionized the management of stable and unstable coronary artery disease, providing an effective, quick, safe, and increasingly widely available method for coronary revascularization for many patients. Rapid development in this field led to the introduction of a number of new technologies, including intracoronary stents that have resulted in improved efficacy and long-term safety. In this manuscript we review the experience with the 2 major available classes of stents (bare metal [BMS], drug-eluting [DES]) and describe the delivery systems for these stents. An evidence review of the large trial data comparing balloon angioplasty, BMS, and DES demonstrates the incremental advances over time, with the latest generation of DES achieving the lowest rates of restenosis, stent thrombosis, and recurrent myocardial infarction. In addition, we provide an overview of the latest developments in stent technology, including the introduction of bioresorbable stents and new stent delivery systems. These latest advances are hoped to further improve outcomes while reducing costs due to a reduction in the need for future procedures and hospitalizations due to recurrent coronary disease. Keywords: arterial stenosis; coronary artery stent; coronary balloon angioplasty; percutaneous coronary intervention
Introduction
Correspondence: Robert P. Giugliano, MD, SM, TIMI Study Office, 350 Longwood Avenue, 1st Floor Offices, Boston, MA 02115. E-mail: [email protected]
The advancement of percutaneous coronary intervention (PCI) has led to its use in the treatment of stable angina, acute coronary syndrome, and more recently multivessel coronary artery disease.1 Pioneered by Dr. Andreas Gruntzig in 1977, coronary balloon angioplasty enabled marked and rapid reduction in arterial stenosis.2 The next 4 decades of scientific and technological innovation led to the introduction of metal stents (in 1986) and drug-eluting stents (in 2003), and to the development of bioresorbable stents.3 Although novel techniques and devices have helped lower mortality rates, cardiovascular disease continues to be the leading cause of death in the United States. In 2010, there were an estimated 492 000 patients undergoing PCI with implantation of a drug-eluting stent.4 As the use and variety of coronary artery stents continue to expand, questions remain regarding their long-term safety and efficacy. A number of reviews have examined the biology, efficacy, and safety of, as well as clinical indications for, the use of coronary artery stents.1,3 This update discusses the historical development and advances in technology of coronary artery stents, reviewing the supporting evidence from recent randomized clinical trials.
Methods
We searched PubMed for review articles on the topic of coronary artery stents. We used the terms coronary artery stents, bare-metal stents, drug-eluting stents, and bio-
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resorbable stents to obtain background data and to identify meta-analyses on these topics. We identified 20 publications that met the search criteria, and after eliminating articles that were not relevant, 8 articles remained. We also collected the primary manuscripts for the ABSORB and ABSORB II trials, and for the DIRECT Study, and used ClinicalTrials.gov to find data on ongoing trials such as DIRECT II. Follow-up manuscripts from the ABSORB trial were reviewed also. Additionally, we searched the US Food and Drug Administration (FDA) website for approved bare-metal stents (BMSs) and drug-eluting stents (DESs). Lastly, risk reduction was calculated from meta-analysis using standard statistical methods.
Types of Stents
There are currently 2 broad classes of stents used in PCI: BMSs and DESs. The BMSs are composed of a thin wire, made of stainless steel or cobalt-chromium alloy, forming a mesh-like tube that can be fitted into the artery (Figure 1).3 The DESs have 3 components: a platform, a carrier, and an antiproliferative agent. The platform is the bare-metal component of stainless steel, cobalt chromium, or platinum chrome. Polymers, nondegradable or bioresorbable, cover the stent surface to act as slow-release drug carriers. The antiproliferative agent acts to suppress neointimal formation by disrupting microtubule disassembly (eg, paclitaxel) or inhibiting mammalian target of rapamycin (eg, sirolimus).1 In the United States, the FDA has approved several stents for use in coronary artery disease (Table 1).
Bare-Metal Stents
The first commercially available BMS, the Palmaz-Schatz stent, was used in 1986 as a way to maintain the integrity of the lumen and prevent elastic recoil.5 Two early randomized controlled trials helped establish the Palmaz-Schatz stent as the standard treatment over balloon angioplasty: the Belgium Netherlands Stent Study (BENESTENT) and the North American Stent Restenosis Study (STRESS).6,7 Both studies showed that coronary stents improved the procedural success rate, reduced the rate of angiographic restenosis, and reduced the need for revascularization compared with balloon angioplasty alone. Advances in material sciences led from stainless steel stents to thin-strut, flexible, stronger cobalt alloy stents. Most recently, the OMEGA trial, a prospective, multicenter, single-arm study, enrolled 328 patients to receive a platinum chromium BMS. The primary end point of target lesion failure (cardiac death, target vessel-related myocardial infarction [MI], and target lesion revascularization) at 9 months showed a low rate, 11.4%, thus supporting the safety and efficacy of this novel BMS.8 Soon, clinicians noticed an increased risk of subacute thrombosis with the widespread use of BMS. As a result, dual antiplatelet therapy with aspirin and ticlopidine (later clopidogrel) was introduced to reduce the incidence of stent thrombosis.9,10 A number of meta-analyses have examined the safety and efficacy of BMS compared with balloon angioplasty (Table 2). The BMSs had similar rates of mortality and
Figure 1. Photograph of bare-metal and drug-eluting stent. (A) Multi-Link RX Ultra bare-metal stent (Abbott Vascular, Abbott Park, IL) made of solid stainless steel in a corrugated ring pattern connected by 3–3–3 links.56 (B) Endeavor Zotarolimus-Eluting Coronary Stent (Medtronic, Minneapolis, MN) of cobalt-chromium with an antiproliferative drug (zotarolimus) contained within a thin polymer coating on its surface.57
84
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Coronary Artery Stents
Table 1. Available Bare-Metal Stents and Drug-Eluting Stents Approved by the US Food and Drug Administration
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Commercial Name
Manufacturer
Bare-metal stents Multi-Link 8 Abbott Vascular Multi-Link Vision Multi-Link Ultra Vision Multi-Link Zeta Coroflex B.Braun Coroflex Blue Veriflex Boston Scientific Integrity Medtronic Driver FDA-approved drug-eluting stents Taxus Express Boston Scientific Taxus Liberté Cypher Cordis, Johnson & Johnson Xience Abbott Vascular Promus Boston Scientific Promus Element Endeavor Medtronic Resolute
Platform Material
Antiproliferative Agent
Dual Antiplatelet Therapya
Cobalt chrome
NA
. 1 month to 12 months
Stainless steel
Paclitaxel
12 months
Stainless steel Cobalt chrome Cobalt chrome Platinum chrome Cobalt chrome
Sirolimus Everolimus Everolimus
Stainless steel Stainless steel Cobalt chrome Stainless steel Cobalt alloy Cobalt chrome
Zotarolimus
Dual antiplatelet therapy refers to aspirin 81 mg daily (continued indefinitely) along with clopidogrel 75 mg daily, prasugrel 10 mg, or ticagrelor 90 mg twice daily for specified period of time.60 a
adverse cardiac events compared with balloon angioplasty, while reducing angiographic restenosis and the need for repeat revascularization. The data supported the prevalent use of stents; however, in-stent restenosis, caused by neointimal hyperplasia inside the BMS, became a growing concern. Eventually, this led to newer technology aimed at preventing complications such as stent thrombosis and in-stent restenosis.
Drug Eluting Stents
The DESs were developed to solve the problem of in-stent restenosis seen with the BMSs. The first-generation DESs released the antiproliferative agent paclitaxel or sirolimus
that was attached to the older bare-metal platforms. The second-generation DESs employed new stent designs with thinner, radiopaque, and stronger materials such as cobalt chromium. The ENDEAVOR and SPIRIT trials showed that newer antiproliferative drugs, everolimus and zotarolimus, improved performance with lower rates of restenosis and late stent thrombosis.11,12 Numerous meta-analyses have compared DES with BMS (Table 3). The results showed similar rates of death, MI, and stent thrombosis; however, DES led to significant reductions in-stent restenosis and the need for target lesion revascularization. Yet, there are important differences between various DESs. First-generation DESs have been associated with
Table 2. Summary of Evidence From Meta-Analyses Comparing Clinical Effectiveness of Bare-Metal Stents Versus Balloon Angioplastya Meta-Analysis
Inclusion Characteristics
No of Trials
No of Patients
Bare-Metal Stents Versus Balloon Angioplasty
Brophy et al61
All clinical trials
29
9918
Similar (death or MI combined)
Agostoni et al62
Small vessels (diameter , 3 mm) Small vessels (diameter , 3 mm) Total coronary occlusion
13
4383
Similar
Similar
11
3541
Similar
Similar
9
1409
Similar
↑ 106% (22%–246%)
Moreno et al63 Agostoni et al64
Death RR (95% CI)
Myocardial Infarction RR (95% CI)
Angiographic Restenosis RR (95% CI)
Repeat Revascularization RR (95% CI)
↓ 48% (31%–63%) ↓ 33% (13%–48%) ↓ 23% (8%–35%) ↓ 64% (43%–77%)
↓ 41% (32%–50%) ↓ 24% (5%–39%) ↓ 25% (9%–39%) ↓ 59% (47%–69%)
Comparisons are made between bare-metal stents and balloon angioplasty in each individual meta-analysis. Risk reduction (95% CIs) was shown in the meta-analysis; consequently risk reduction may have not been observed in individual randomized trials. Abbreviations: MI, myocardial infarction; RR, risk reduction. a
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Table 3. Summary of Meta-Analyses on the Clinical Effectiveness of Drug-Eluting Stents and Bare-Metal Stentsa Meta-Analysis
Stettler et al65 Kastrati et al66 De Luca et al67 Bangalore et al14
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Bangalore et al15
Inclusion Characteristics
No of Trials
No of Patients
Drug-Eluting Stents Versus Bare-Metal Stents Death
Myocardial Infarction
Stent Thrombosis
Target Lesion Revascularization
DESs Compared to Each Other
All clinical trials of DES and BMS DES (PES, SES) and BMS for STEMI DES (PES, SES, ZES) and BMS for STEMI FDA-approved DES and BMS for de novo coronary lesion FDA-approved DES, BP-DES, and BMS
38
18 023
Similar
SES ↓ 19%
Similar
↓ 58%–70%
SES vs PES ↓ ST 46%
8
2786
Similar
Similar
Similar
↓ 62%
11
6298
Similar
Similar
Similar
↓ 43%
76
57 138
Similar
126
106 427
Similar (except CoCr EES ↓ 28%)
Similar ↓ 18%–37% (exclude PES) (except EES ↓ 49%) Similar ↓ 17%–39% (exclude PES) (except CoCr EES ↓ 65%)
Cumulative DES vs BMS Cumulative DES vs BMS EES ∼ SES ∼ ZES-R . PES ∼ ZES . BMS for TLR BP-DES . PES/ ZES-E for TLR
↓ 39%–61%
↓ 38%–63%
Comparisons are made between drug-eluting stents and bare-metal stents in each individual meta-analysis. Data shown in table are ranges in risk reduction of multiple DES compared to BMS. Abbreviations: BMS, bare-metal stent; BP-DES, biodegradable polymer drug-eluting stent; CoCr, cobalt chromium; EES, everolimus eluting stent; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent; ST, stent thrombosis; STEMI, ST-elevation myocardial infarction; TLR, target lesion revascularization; ZES-E, zotarolimus-eluting stent— Endeavor; ZES-R, zotarolimus eluting stent—Resolute. a
an increased risk of very late thrombosis, especially after discontinuation of antiplatelet therapy, and have fallen out of favor.13 Newer generation DESs, such as everolimuseluting stents, have been shown to reduce both the risk of thrombosis over the long term as well as the risk of MI.14 The cobalt-chromium everolimus-eluting stent has been the only stent developed thus far that reduces the risk of death, MI, and stent thrombosis compared with BMSs.15 However, even newer generation DESs cannot prevent restenosis and very late thrombosis; thus, new studies continue to evaluate the safety and efficacy of DESs in the hopes of minimizing adverse events.
New Advances in Stent Technology Bioresorbable Stents
Technological evolution over the last 2 decades has led to the introduction of bioresorbable stents. The 2 most promising materials are polymer-based or absorbable metals. Polylactic acid (PLLA) is a frequently used polymer that degrades into water and carbon dioxide by means of the Krebs cycle. Magnesium-based alloys are an alternative, as they can be absorbed by human tissue. Important features of all bioresorbable stents include radial strength, slow degradation to avoid inflammation or toxic reactions, ease of use and deliverability, and improved visualization.16 This new technology possesses many advantages over metallic stents. First, by eliminating the presence of a permanent metallic foreign body from the vessel wall, inflammation 86
and formation of new atherosclerotic plaques is reduced, ultimately decreasing the risk of stent thrombosis.17−19 Second, by eliminating the stent backbone, there is no longer the fear of permanent caging of a vessel, jailing of side branches, or preventing late lumen enlargement.20 The intent was that the removal of a backbone would lead to the recovery of endothelial function, to an increase in responsiveness of the coronary vessel, and to reduction in cardiovascular events.21 Theoretically, polymer stents should be more flexible and conformable, creating less shear stress on the vessel wall.22 From a physiological perspective, once degraded, the vessel wall would be exposed to the cyclic strain of blood pulsatility.23 The modulation of inflammatory signals could be beneficial, leading to a reduction in atherogenesis.24 Furthermore, patients would not require prolonged dual antiplatelet therapy, thus reducing the risk of bleeding.25 Also, most of the newer devices could be visualized using noninvasive technologies, such as computed tomography angiography or magnetic resonance imaging, until they are fully absorbed.16 Although bioresorbable stents are an exciting development, there are some limitations to their use. Many of the advantages are theoretical and have not yet been demonstrated in large randomized controlled trials. Furthermore, the speed of degradation of these platforms may vary among patients, leading to unpredictable drug delivery. Also, a potential downside is the risk of strut fracture due to limits in expansion and dilation of polymeric devices. Most importantly, further
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Coronary Artery Stents
investigation is needed to determine the safety and efficacy of the different bioresorbable platforms.16 The Igaki-Tamai stent was the first bioresorbable stent implanted in humans. Composed of PLLA, this stent did not employ a drug-eluting system, and implantation required a complex procedure using a thermal balloon.26 The results of the first in-human study, including 15 patient with 25 stents, demonstrated no stent thrombosis, MI, or major cardiac death at 6 months.26 A second study with 50 patients and 84 stents found 97.7% survival at 4 years.27 The first metallic biodegradable stent (AMS-1; Biotronik, Berlin, Germany) was composed of 93% magnesium and 7% rare earth metals.28 Similar to stainless steel stents in mechanical properties, this stent was also balloon expandable, though lacked a drug-eluting polymer. The PROGRESS AMS (Clinical Performance and Angiographic Results of Coronary Stenting with Absorbable Metal Stents) trial, consisting of 63 patients and 71 implanted stents in de novo coronary lesions, reported no death, MI, or stent thrombosis at 12-month follow-up; however, the rate of target lesion revascularization was high: 23.8% at 4 months and 45% at 12 months.28
The ABSORB Trial
One of the earliest studied bioresorbable stents is the everolimus-eluting stent system (BVS; Abbott Vascular, Santa Clara, CA).29 It consists of a bioresorbable PLLA backbone coated with a more rapidly absorbed layer of poly-D,L-lactic acid that contains and controls the elution of everolimus. The stent is balloon expandable and radiolucent, and the polymer degrades by hydrolysis.29 The ABSORB trials (cohorts A and B) were conducted to evaluate the feasibility and safety of the BVS stent system.29,30 The ABSORB cohort A (BVS 1.0) trial was a single-arm prospective, open-label study conducted in 2006 including 30 subjects with a single de novo coronary artery lesion.29 The ABSORB cohort B (BVS 1.1) trial was a single-arm, multicenter, study conducted with a modified BVS stent system in patients with # 2 de novo coronary artery lesions.30 This newer stent modified the platform design and polymer processing to improve mechanical strength, reduce early and late recoil, as well as slow the degradation process to provide longer mechanical support to the vessel.31,32 Cohort B enrolled 101 patients, of whom 45 (cohort B1) were randomized to angiographic and invasive follow-up at 6 and 24 months, whereas 56 (Cohort B2) were randomized to invasive follow-up at 12 and 36 months. The clinical end points for these studies included cardiac death, MI, ischemia-driven target lesion revascularization,
ischemia-driven major adverse cardiac event (MACE; a composite of cardiac death, MI, or ischemia-driven target lesion revascularization), and stent thrombosis assessed at 6 months, 1 year, and 2 years.29,33 Angiography, intravascular ultrasound (IVUS), and optical coherence tomography (OCT) were assessed at 6 months and repeated at 2 years.33 Noninvasive coronary angiography with multislice computed tomography (MSCT) was performed at 18-month and 5-year follow-up.34 The clinical data from cohort A demonstrated a single non– Q-wave MI, and a MACE rate of 3.4% at 6-month follow-up, which remained unchanged at 2, 3, 4, and 5 years, thus providing support for the long-term safety of the device.33,35−37 There was no scaffold thrombosis with MSCT results, showing an area stenosis of the scaffold segment of 31.6% at 18 months (25 patients) compared with 33.3% at 5 years (18 patients).37 Coronary angiography showed diameter stenosis of 27% at 6 months and 2 years.33 Lastly, IVUS and OCT showed bioresorption of the polymeric struts as well as late enlargement of the lumen from 6 months to 2 years.33 The results from cohort B were MACE rates of 4.9%, 6.9%, 9.0%, and 10.0% among the 101 patients at 6 months, 1, 2, and 3 years, respectively.30,38,39 There was no evidence of stent thrombosis at 3-year follow-up.39 Quantitative coronary angiography (QCA) analysis between 6 months and 3 years showed that late luminal loss was unchanged at 0.19, 0.27, 0.27, and 0.29 mm at 6 months, 1, 2, and 3 years, respectively.39,40 Analyses of lesion and stent morphology using IVUS demonstrated enlargement of mean lumen, scaffold, plaque, and vessel lumen area between 6 months and 2 years, with a substantial reduction in plaque at 3 years. Serial review by OCT over 3 years showed late scaffold area enlargement, an increase in neointimal formation, and an increase in strut cores detected, reflecting dismantling of the scaffold.38,39 Furthermore, a study conducted in small vessels (diameter , 2.5 mm) found similar clinical and angiographic outcomes at 2 years.41
ABSORB II Study
The ABSORB II study is a randomized, active-controlled, single-blinded, multicenter clinical trial in 501 patients comparing the second-generation Absorb BVS (poly-L-lactide, thin coating 1:1 amorphous matrix of poly-D,L-lactide, everolimus) with the XIENCE stent system (cobalt chromium alloy, thin biocompatible acrylic, fluorinated everolimusreleasing copolymer).42 Both devices are similar in terms of basic design, everolimus dosage, and elution profile. The primary objective of this trial is to examine safety, efficacy, and performance of the Absorb BVS against the
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current XIENCE stent over 3 years. The co-primary end points include vasomotion measured by the change in mean lumen diameter pre-nitrate and post-nitrate and at 2 years as assessed by QCA (superiority), and minimum lumen diameter post-nitrate minus minimum lumen diameter postprocedure post-nitrate by QCA (noninferiority). Clinical follow-up will include blood analysis of multiple markers, exercise testing, and quality of life questionnaires. Subjects will undergo angiography as well as IVUS at 2-year follow-up. A subgroup will have near-infrared spectroscopy (Lipiscan) at 2-year follow-up, whereas all Absorb BVS subjects will undergo MSCT at 3 years.42
Developing Technology
The REVA stent (Reva Medical Inc, San Diego, CA), a resorbable tyrosine-derived polycarbonate polymer, is a balloon expandable, non–drug-eluting, radiopaque stent. It is metabolized by the Krebs cycle into amino acid, ethanol, and carbon dioxide. Depending on the weight of the polymer, degradation of the stent can take , 12 months to 2 years.16 The REVA Endovascular Study of a Bioresorbable Coronary Stent (RESORB) trial was a 30-patient multicenter, prospective, safety study examining stent strength and restenosis. The rate of target lesion revascularization was 66.7% between 4 and 6 months, in part due to mechanical failures of the polymer.43 This led to a redesign and ongoing clinical testing (ClinicalTrials.gov number NCT01845311) of the secondgeneration ReZolve sirolimus eluting stent. The IDEAL bioresorbable stent (Bioabsorbable Therapeutics, Inc., Menlo Park, CA), made of polyanhydride ester based on salicylic acid and adipic acid, is a balloon expandable, sirolimus-eluting stent containing anti-inflammatory properties.44 The stent is metabolized into salicylate, carbon dioxide, and water over a period of 9 to 12 months. The development of nanoparticle eluting stent technology, in which biodegradable nanoparticles coat a metallic stent, allows for the delivery of various drugs directly to the cell membrane in a controlled manner, thus promoting healing and preventing complications such as restenosis.45 Current research with recombinant DNA and nucleic acid based therapies is looking to prevent in-stent restenosis. The goal is to deliver plasmid DNA or small interfering RNA via stents to target those signal cascades involved in inflammation, vascular remodeling, and apoptosis.45
Delivery System
Early coronary angiography began with the insertion of large catheters into the femoral artery. In the past decade, rapid 88
adoption of a radial artery approach helped reduce vascular complications.46 By injecting contrast through the catheter, a physician is able visualize the coronary vessels and target lesion. A guiding catheter enables a variety of instruments through, including balloon, stent, and IVUS catheters. After identifying the lesion, a balloon catheter can be used to predilate the vessel prior to stent placement. The introduction of a stent begins with placement of a guidewire, over which the expandable stent is mounted over a deflated balloon. Visualized through fluoroscopy, the stent and balloon are positioned, after which the balloon is inflated to place the stent. Postdilation at high pressures reduces risk of stent thrombosis, especially in DES (Figure 2).47
Svelte Integrated Delivery System
Svelte Medical Systems (New Providence, NJ) created a new integrated delivery system (IDS) for drug-eluting stents aimed at improving direct stenting of coronary lesions. Compared to other drug-eluting stents, the IDS employs a balloon-expandable thinner cobalt-chromium strut stent, pre-mounted on a single-lumen fixed-wire delivery system (Figure 3).48,49 The figure shows the components of the Svelte Acrobat System. Once vascular access is obtained, the introducer/delivery system is loaded followed by advancement and deployment of stent. In contrast, the current technique requires loading the guidewire, balloon, and stents separately. The stent is covered by a fully bioresorbable carrier made of amino acids eluting sirolimus. There are fewer steps in this delivery system, leading to a number of benefits, including reduced procedural time, contrast administration, radiation exposure, and costs. On the other hand, many of these advantages are theoretical, and further studies are needed to clarify the safety profile on measures such as late-lumen loss, vascular injury, and in-stent dissection. The future clinical application of a new delivery system is in the treatment of bifurcating, tortuous, and distal lesions that are challenging to reach by conventional methods.48,50−52
DIRECT Study
The DIRECT study was a prospective, single-arm, multicenter study evaluating the Svelte IDS system in ischemic heart disease that is due to a single de novo stenotic coronary lesion.53 There were 30 patients with the primary safety end point of angiographic target vessel failure at 6 months, defined as a composite of cardiac death, target vessel MI, and target vessel revascularization. The primary efficacy end point was angiographic in-stent late lumen loss at 6 months, defined
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Coronary Artery Stents
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Figure 2. Coronary angioplasty and stent delivery. (A) (left to right) A coronary artery is narrowed by plaque and catheter-guided balloon is inflated to compress the plaque against the wall. (B) (left to right) A balloon is expanded over a guide catheter to position a coronary artery stent in the vessel.58
as the difference in minimal lumen diameter postprocedure and at follow-up as measured by QCA.53,54 Follow-up of 29 of 30 patients found that 2 suffered target vessel failure—1 patient requiring a second stent at the distal end of the study stent, and the other patient requiring revascularization proximal to the study stent. No patient suffered death, MI, or stent thrombosis. The study also examined in-stent proliferation, which was visualized by IVUS, and showed reduction in neointimal volume compared to other current DESs.53 In parallel, Diletti et al 48 examined outcomes after implantation of the Svelte IDS in 47 patients, finding a success rate of 97.9%, with no major adverse cardiac events at 30 days postprocedure. This study showed increased late lumen loss at 6 months compared with prior studies of BMSs, although there was not a higher rate of target lesion revascularizations. In terms of safety profile, the Svelte IDS system was found to have a low vascular injury profile, while being as effective as BMSs in the treatment of coronary artery lesions.
DIRECT II Trial
The DIRECT II is an ongoing prospective, randomized controlled, multicenter trial evaluating the safety and efficacy of the Svelte drug-eluting coronary stent IDS compared Figure 3. Svelte integrated delivery system59 (Svelte Medical Systems (New Providence, NJ).
with the Resolute drug-eluting stent (zotarolimus-eluting stent; Medtronic, Minneapolis, MN). This study is enrolling patients with single, de novo coronary artery lesions with primary outcomes of angiographic target vessel failure and in-stent late lumen loss, both at 6 months’ duration. The secondary outcomes include a composite of cardiac death, MI, and all-cause mortality, as well as stent thrombosis, and target lesion revascularization at 1 month, 6 months, and yearly up to 5 years. The planned enrollment is 159 patients with completion date of approximately June 2018.55
Conclusion
Coronary stents represent a remarkable advancement in the treatment of stable and unstable coronary artery disease. The DESs have become the mainstay of treatment and have proven to be safe and effective. The newest everolimuseluting stents have been shown to be the safest; they appear to reduce the risk of death compared to bare-metal stents. Evolution in technology has also led to the development of bioresorbable stents, which appears to be as safe as DESs. Although effectiveness studies are currently ongoing, bioresorbable stents offer the theoretical advantage of a reduced inflammatory and thrombotic potential, possibly reducing restenosis and stent thrombosis, as well as lowering the risk of jailing vessels. Furthermore, innovations in delivery systems allow stents to be placed more efficiently, aiming to reduce costs and improve safety.
Conflict of Interest Statement
Robert P. Giugliano, MD, SM, reports receiving consulting fees from Daiichi Sankyo, Janssen Pharmaceuticals, and Merck; lecture fees from Bristol-Myers Squibb, Daiichi Sankyo, Merck, and Sanofi; and grant support through his institution from Daiichi Sankyo, Merck, Johnson and Johnson, Sanofi, and AstraZeneca. Sameer D. Sheth, MD, has no conflicts of interest to declare. © Hospital Practice, Volume 42, Issue 4, October 2014, ISSN – 2154-8331 89 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
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