STATE-OF-THE-ART PAPER
Coronary StentsCurrent Status
Scot Garg, MB, ChB and
Patrick W. Serruys, MD, PhD*
Department of Interventional Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands
Manuscript received December 9, 2009;
revised manuscript received June 1, 2010,
accepted June 15, 2010.
* Reprint requests and correspondence: Dr. Patrick W. Serruys, Department of Interventional Cardiology, Ba583a, Thoraxcenter, Erasmus Medical Center, 's-Gravendijkwal 230, Rotterdam 3015 CE, the Netherlands (Email: p.w.j.c.serruys{at}erasmusmc.nl).
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Abstract
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Coronary artery stents revolutionized the practice of interventional cardiology after they were first introduced in the mid-1980s. Since then, there have been significant developments in their design, the most notable of which has been the introduction of drug-eluting stents. This paper reviews the benefits, risks, and current status of Food and Drug Administration-approved drug-eluting stents.
Key Words: bare-metal stents • drug-eluting stents • sirolimus-eluting stents • paclitaxel-eluting stents • zotarolimus-eluting stents • everolimus-eluting stents • stent thrombosis • restenosis • diabetes • cost-effectiveness • stent fracture • left main disease • myocardial infarction • saphenous vein grafts • clopidogrel
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | BMS = bare-metal stent(s) | | CABG = coronary artery bypass grafting | | CAD = coronary artery disease | | CI = confidence interval | | CoCr = cobalt chromium | | CTO = chronic total occlusion | | DAPT = dual antiplatelet therapy | | DES = drug-eluting stent(s) | | EES = everolimus-eluting stent(s) | | FDA = Food and Drug Administration | | HR = hazard ratio | | ISA = incomplete stent apposition | | ISR = in-stent restenosis | | IVUS = intravascular ultrasound | | MACE = major adverse cardiovascular events | | MI = myocardial infarction | | MVD = multivessel disease | | PCI = percutaneous coronary intervention | | PES = paclitaxel-eluting stent(s) | | POBA = plain old balloon angioplasty | | RR = relative risk | | SES = sirolimus-eluting stent(s) | | ST = stent thrombosis | | STEMI = ST-segment elevation myocardial infarction | | SVG = saphenous vein graft | | TLR = target lesion revascularization | | TVR = target vessel revascularization | | UPLMS = unprotected left main stem | | ZES = zotarolimus-eluting stent(s) |
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In 1964, Charles Theodore Dotter and Melvin P. Judkins described the first angioplasty (1). Thirteen years later, Andreas Grüntzig performed the first balloon coronary angioplasty (2), a revolutionary treatment that lead to the birth of a new specialty, interventional cardiology. Since that first procedure, there have been extensive developments and advances that have culminated in percutaneous coronary intervention (PCI) being 1 of the most frequently performed invasive medical procedures in clinical practice today.
Coronary stents, which were first developed in the mid-1980s (3), have ultimately replaced "plain old balloon angioplasty" (POBA) as the preferred method of performing PCI, after the observed improvements in angiographic and clinical outcomes seen with their use (4,5). The majority of PCI procedures now involve a coronary stent, and therefore, interventional cardiologists are faced with a wide choice of coronary stents to implant. This choice ranges from conventional bare-metal stents (BMS) and drug-eluting stents (DES) that are widely used in contemporary practice to newer stents such as DES with biodegradable polymers, DES that are polymer-free, DES with novel coatings, dedicated bifurcation stents, self-expanding stents, and biodegradable stents.
Part 1 of this review discusses the current status of coronary stents and examines some of the unresolved issues surrounding their implantation in contemporary practice. Part 2 will review the vast array of new coronary stents that are currently undergoing evaluation in pre-clinical and clinical trials.
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The Need for Coronary Stents and the Early Period
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There is no dispute that POBA was a pioneering treatment; however, its success was hindered by the problems of acute vessel closure and restenosis (4–6). These problems lead to the development of a second revolutionary treatment, the coronary stent, which was first implanted by Sigwart et al. (3) in 1986 (Fig. 1) (7). This bare metal, self-expanding stent, known as the "Wall" stent was able to provide a scaffold that prevented acute vessel closure and late constrictive recoil (3). Although these initial stents proved effective as "bailout" devices in cases of abrupt or threatened vessel closure, thereby reducing rates of emergency coronary artery bypass surgery (CABG) (8), development was ultimately hampered by the risk of subacute thrombotic coronary artery occlusion, which was observed in up to 18% of cases within 2 weeks of implantation (9). This novel, stent-specific hazard prompted the use of complex anticoagulation regimens that were associated with increased bleeding and prolonged hospitalization (10). Overall, the early success and complication rates seen with these initial coronary stents were not always competitive with those of routine POBA.
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Figure 1 First Human Coronary Stent Implantation, March 1986
(A) A restenotic lesion after balloon angioplasty. (B) The self-expanding WALLSTENT. (C) Immediate results after stenting. (D) Angiographic results at 11-year follow-up.
Reproduced with permission from Carrie et al. (7).
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Coronary stenting only became a widely accepted technique after the publication of the landmark BENESTENT (Belgian Netherlands Stent) trial (11) and the STRESS (Stent Restenosis Study) (12), together with evidence indicating that stenting was safe in the absence of anticoagulation therapy with the use of dual antiplatelet therapy (DAPT) (13–15) and/or adequate stent deployment (16).
By 1999, coronary stenting was performed in 84.2% of PCI procedures (17); however, despite their obvious advantages, there were associated problems and concerns. Most notably, and in addition to the risk of subacute thrombosis, which has already been alluded to, an iatrogenic problem emerged in the form of in-stent neointimal hyperplasia (18–20). This intrastent growth of scar tissue, which was the result of proliferation and migration of vascular smooth muscle cells, and as demonstrated in Figure 2
was directly linked to stent implantation, resulted in restenosis rates of 20% to 30% (21). It was the attempts to minimize this in-stent neointimal hyperplasia, and thereby reduce rates of repeat revascularization, that ultimately lead to the development of another revolutionary treatment: the DES. The dramatic reduction in restenosis rates seen with the use of these DES compared with BMS (22–26) has been the major driving force behind the exponential growth of PCI as a treatment for patients with coronary artery disease (CAD). After the outstanding results from the early pivotal trials with DES, there was an increased confidence to use PCI, so that its use has expanded to lesions subsets that were only previously considered suitable for CABG (27–29). This increased confidence lead to a rapid and unprecedented uptake in their use, so that by 2005, 80% to 90% of all revascularization procedures in the U.S. were performed using a DES (30). In 2006, concerns were raised over the safety profile of these stents (31–33), resulting in an immediate worldwide downturn in their use. These concerns proved a vital stimulus to focus research, and have ultimately lead to the development of newer stents and improved safety, resulting in a resurgence in the use of DES; however, current rates ( 75%) are still below those of 2005 (34).
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DES Initial Phase: "The Rosy Period"
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Sirolimus-eluting stents (SES).
In the late 1990s, numerous pre-clinical studies reported that sirolimus (previously called rapamycin), a macrolide antibiotic that was approved for use as an immunosuppressant to prevent organ rejection, was able to inhibit the cytokine- and growth-factor–mediated proliferation of lymphocytes and smooth muscle cells, resulting in reduced neointimal proliferation (Fig. 3) (35–38). Despite its promise, problems remained over the ability to locally deliver sirolimus at an appropriate and sustained concentration necessary to inhibit neointimal proliferation. Failures with both oral administration and local delivery using special delivery balloons led to the development of a coronary stent with a drug coating, the DES. The first human DES implant was performed by J. Eduardo Sousa in Sao Paulo in December 1999 at the start of the 2 first-in-man studies that recruited a total of 45 patients and reported minimal in-stent neointimal proliferation through to 12-month follow-up (39–41). This research culminated in the development and commercial launch of the stainless steel Cypher SES (Cordis, Warren, New Jersey), the specification of which is summarized in Table 1. The Cypher SES was initially evaluated in the pivotal RAVEL (Randomized Study With the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions) study, which randomly assigned 238 patients with relatively low risk lesions to treatment with the Cypher SES or BMS controls. At 1-year follow-up, the rate of binary stenosis was 0.0% and 26.6% for patients treated with Cypher SES and BMS, respectively (42). These results were subsequently confirmed in the much larger SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) trial that enrolled 1,058 patients with more complex lesions than were seen in the RAVEL study. This study again demonstrated significantly lower rates of target lesion revascularization (TLR) and major adverse cardiovascular events (MACE) after treatment with the Cypher SES compared with BMS controls at 9-month, 2-year, and now 5-year follow-up (43–45).
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Figure 3 Sirolimus
(A) The chemical structure of the macrocylic lactone group of antiproliferative drugs. (B) The mode of action of sirolimus: sirolimus binds to the FK-binding protein 12 (FKBP12), which in turn inhibits the mammalian target of rapamycin (mTOR) pathway. This subsequently prevents the downregulation of the cell division kinase inhibitor p27kip1, thereby inhibiting cell division between phases G1 and S1 of the cell cycle. Sirolimus has a wide dose range, is cytostatic as opposed to cytotoxic, and has additional anti-inflammatory properties through its inhibition of interleukin-2, which reduces T- and B-cell activation. DNA = deoxyribonucleic acid.
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After these initial randomized studies, which ultimately lead to regulatory approval, the performance of the Cypher stent has been assessed in: 1) different patient types, for example, diabetic patients; 2) different clinical settings, including primary PCI for ST-segment elevation myocardial infarction (STEMI); and 3) different lesion types including chronic total occlusions (CTO), saphenous vein grafts (SVG), small coronary vessels, and complex lesions. The results of the most important randomized controlled trials comparing SES and BMS in these different clinical settings are summarized in Table 2
(42–75). As clearly demonstrated, when compared with BMS, the use of SES results in significant reductions in angiographic in-stent late loss, in-stent angiographic (binary) restenosis, and repeat revascularization at both short- and long-term follow-up, with results consistent across numerous different patient and lesion types. Furthermore, meta-analyses of patient data from the initial approval trials reaffirms the sustained advantage of SES over BMS in terms of reduced repeat revascularization, together with comparable rates of death and myocardial infarction (MI) at long-term follow-up (Table 3) (22–26,76).
In addition to randomized data, registries have evaluated the performance of the Cypher stent in the setting of the real-world. The first of these registries was the single-center RESEARCH (Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital) registry, which enrolled 508 consecutive patients who were treated with the Cypher SES irrespective of lesion complexity. Running concurrently with the RESEARCH registry was the multicenter ARTS-II (Arterial Revascularization Therapies Study) registry, which assessed the Cypher stent in 607 patients with 2- and 3-vessel CAD. Results from both registries at short- and long-term follow-up, which now extends to 4 and 5 years, respectively, for the RESEARCH and ARTS-II registries (Fig. 4) (77), mirrors those from other registries and the previously noted randomized studies and meta-analyses, by continuing to demonstrate significantly lower rates of MACE and TLR after the use of the Cypher SES compared with historical BMS controls (77–81).
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Figure 4 Long-Term Clinical Outcomes of SES, BMS, and CABG in ARTS I and II
Long-term clinical outcomes compared for patients treated with sirolimus-eluting stents (SES [red lines]), bare-metal stents (BMS [blue lines]), and coronary artery bypass graft surgery (CABG [black lines]) in the ARTS (Arterial Revascularization Therapy Studies) I and II (77). Kaplan-Meier estimates for freedom from (A) death, (B) death, cerebrovascular accident (CVA), and myocardial infarction (MI), (C) repeat revascularization, and (D) overall major adverse cardiovascular and cerebrovascular events (MACCE).
Reproduced with permission from Serruys et al. (77).
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Paclitaxel-eluting stents (PES).
The TAXUS PES (Boston Scientific, Natick, Massachusetts) was developed almost simultaneously with the SES, gaining regulatory approval 12 months later (Table 1, Fig. 5). Its evaluation has followed a pattern similar to that of the SES, and its first assessment, in the randomized TAXUS I study, reported no binary restenosis at 6-month follow-up (82). Subsequent randomized studies, the most important of which are summarized in Table 4, have demonstrated a significantly lower rate of late loss, angiographic binary restenosis, and repeat revascularization with PES compared with BMS that is consistent across different patient groups including those with simple lesions, STEMI, lesions in the unprotected left main stem (UPLMS), and complex lesions (57,82–96). In addition, patient-level meta-analysis of the initial PES approval trials has confirmed the comparable safety and superior efficacy of PES compared with BMS out to 4-year follow-up (Table 3) (22,24).
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Figure 5 Paclitaxel
(A) The chemical structure and (B) mode of action of paclitaxel, an extract derived from the bark of the Taxus brevifolia (Pacific Yew) tree. Paclitaxel inhibits smooth muscle cell proliferation through the stabilization of microtubules, and thereby inhibits cell division.
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In a fashion similar to the SES, the TAXUS PES stent has been assessed in an unrestricted single-center registry that used the PES as the default stent for all PCI in 576 consecutive real-world patients. Two-year results from the T-SEARCH (Taxus Stent Evaluated at Rotterdam Cardiology Hospital) registry demonstrate similar efficacy in terms of suppression of neointimal growth and reduction of restenosis when compared with historical controls treated with SES (97,98).
TAXUS Express Versus TAXUS Liberté
The first PES to be approved by the Food and Drug Administration (FDA) was the TAXUS PES Express stent. This was subsequently superseded by the TAXUS PES Liberté stent, which was designed to be more deliverable and conformable and to provide a more homogenous drug distribution (99). Table 1 summarizes the main physical properties of both stents, both of which have the same polymer and dose of paclitaxel; however, the Liberté stent has a more uniform cell geometry (Fig. 6) (99), allowing more enhanced and uniform drug delivery, thinner struts (97 µm vs. 132 µm), a smaller profile, and separate stent designs depending on stent diameter. Stents with a diameter of 2.25 to 2.5 mm have a 2-cell design, whereas stents with a diameter >2.75 mm have a 3-cell design. The superiority of the Liberté stent was confirmed through the multicenter noninferiority TAXUS ATLAS (TAXUS Liberté-SR Stent for the Treatment of De Novo Coronary Artery Lesion) clinical trial, which enrolled 871 patients treated with the TAXUS Liberté stent who were compared with a historical population of patients treated with the TAXUS Express-SR stent from the TAXUS IV and V trials (99). In spite of similar inclusion criteria, patients receiving the Liberté stent had treatment for significantly more complex baseline lesions. Nevertheless, the primary end point of 9-month target vessel revascularization (TVR) occurred in 7.0% and 8.0% of patients treated with the Express and Liberté stents, respectively, achieving the pre-specified criteria for noninferiority (p = 0.049). There were no significant differences in other clinical outcomes.
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Figure 6 TAXUS Express and TAXUS Liberté Stents
(A and B) The difference in stent strut distribution between the TAXUS Express and TAXUS Liberté stents. Reproduced with permission from Turco et al. (99). (C and D) Computer simulations illustrating the more uniform drug distribution achieved with the TAXUS Liberté stent. Blue indicates areas of low paclitaxel concentration, whereas red indicates areas of high paclitaxel concentration.
Image courtesy of Boston Scientific, Natick, Massachusetts.
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Two additional multicenter studies confirmed the improved outcomes with the newer Liberté stent. These were the TAXUS ATLAS Small Vessels study and the TAXUS ATLAS Long Lesions study.
The TAXUS ATLAS Small Vessels study, which compared the performance of the 2.25-mm TAXUS Liberté stent in 261 patients with 75 historical controls from the TAXUS V study who had had a lesion treated with a single 2.25-mm TAXUS Express stent (100). In addition to meeting the noninferiority primary end point of 9-month in-segment diameter stenosis, compared with the Express stent, the Liberté stent was shown to significantly reduce the rate of 9-month angiographic restenosis (18.5% vs. 32.7%, p = 0.02) and TLR at 12 months (6.1% vs. 16.9%, p = 0.004). Moreover, at 3-year follow-up, the use of the TAXUS Liberté led to a significant reduction in TLR (10.0% vs. 22.1%, p = 0.008) and MACE (19.5% vs. 32.4%, p = 0.03), together with a numerically lower composite of death/stroke and MI (6.5% vs. 7.4%, p = 0.79) (101).
The TAXUS ATLAS Long Lesions study compared the performance of the 38-mm long TAXUS Liberté stent in 150 patients with lesions between 26 mm and 34 mm in length with that of 145 historical control patients from the TAXUS IV and V studies with similar length lesions treated with a least 1 Express stent (100). In addition to meeting the noninferiority primary end point of 9-month in-segment diameter stenosis, compared with the Express stent, the Liberté stent was also shown to significantly reduce the risk of MI at both 12-month follow-up (1.4% vs. 6.5%, p = 0.002) and 3-year follow-up (2.9% vs. 10.4%, p = 0.01). Moreover, at 3-year follow-up, the use of the Liberté stent led to a 78% reduction in cardiac death (1.5% vs. 6.7%, p = 0.03), with no reported stent thrombosis (ST) (101).
SES versus PES.
Several randomized studies, which are summarized in Table 5, have formally compared outcomes between patients treated with SES or PES for: 1) unselected patients populations; 2) specific patient groups such as diabetic patients or patients with STEMI; and 3) specific lesion types such as UPLMS lesions, long lesions, or lesions in small vessels (102–117). Of note, results at short-term angiographic follow-up demonstrate superior reductions in late loss and binary restenosis with the use of SES; however, long-term angiographic follow-up, which is limited to the SIRTAX (Sirolimus Eluting Versus Paclitaxel Eluting Stents for Coronary Revascularization) study, indicates a greater delayed late loss with SES in that, at 5 years, there was no longer a significant difference in late loss between SES and PES (107). With respect to clinical outcomes, a meta-analysis of 16 randomized trials of SES versus PES, which included 8,695 patients and, where possible, patient-level data, reported significant reductions in TLR (hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.63 to 0.87, p < 0.001) and ST (HR: 0.66, 95% CI: 0.46 to 0.94, p = 0.02) with SES, whereas no significant differences in death (HR: 0.92, 95% CI: 0.74 to 1.13, p = 0.43), or MI (HR: 0.84, 95% CI: 0.69 to 1.03, p = 0.10) were noted at a median of 2-year follow-up (118).
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Table 5 Summary of Major Randomized Trials (>100 Patients in Each Group) Comparing SES to PES in Different Clinical Settings
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Angiographic measures of DES effectiveness.
As suggested by the discussion in the preceding text, angiographic measures such as late lumen loss and binary angiographic stenosis are commonly used surrogates of clinical effectiveness in DES trials (119). Of the 2, binary angiographic stenosis appears a more favorable variable as it requires a single measurement and not, as in the case of late loss, 2 separate measurements several months apart. In addition, the relationship between late loss and TLR is dependent on vessel size, with more late loss being accommodated in larger vessels before triggering a TLR (so-called headroom); conversely, binary angiographic stenosis is independent of vessel size (120).
The relationship between late loss and the risk of binary restenosis has been described as monotomic; in other words, incremental changes in late loss are associated with a predictable increased risk of binary restenosis (121). Conversely, a curvilinear relationship has been described between late lumen loss and TLR, namely, the increased risk of TLR is not linear over the entire range of late lumen loss (122). Using data from the TAXUS IV trial, Ellis et al. (122) demonstrated that the normally low risk of TLR is only significantly increased once late lumen loss reaches a threshold >0.5 to 0.6 mm. This nonlinear relationship serves to explain why significant differences in late loss during follow-up do not invariably translate into differences in clinical outcomes. For example, in the REALITY (Comparison of the Cypher Sirolimus Eluting and the Taxus Paclitaxel Eluting Stent Systems Trial), the significantly higher late lumen loss at 8 months with PES (PES vs. SES: 0.31 mm vs. 0.09 mm, p < 0.001) did not translate into any significant difference in restenosis rate (PES 11.1% vs. SES 9.6%, p = 0.31) or TLR (PES 6.1% vs. SES 6.0%, p > 0.99) at 12 months (105). Moreover, because of this relationship, late lumen loss is regarded as having only limited use in isolation in the assessment of clinical effectiveness among different DES, particularly if absolute levels are low.
Benefits of DES.
Extensive data exist confirming the benefits of DES in terms of reduced rates of restenosis compared with BMS. Results from the largest meta-analysis to date, which included >18,000 patients from 38 DES trials, indicated a reduction in TLR of 70% (p < 0.0001) with the use of SES, and 58% (p < 0.001) with the use of PES, when compared with BMS out to 4 years of follow-up (Table 3) (22). This corresponded to a number needed to treat, to prevent a single revascularization, of only 7 and 8 patients for SES and PES, respectively. Several other similar meta-analyses have also been performed, and their results are summarized in Table 3 (23–26).
Importantly, these impressive results are not only confined to the select patients treated for on-label indications, but also have consistently been reproduced in registries and randomized controlled trials that have included those with patients receiving DES for off-label indications (76,78,123). Of note, a recent large meta-analysis by Kirtane et al. (76) that included >9,000 patients suggests that the benefit in terms of reduced restenosis from DES use appears to be at least as great as in patients treated for off-label indications (HR: 0.46, 95% CI: 0.34 to 0.52, p < 0.01) as opposed to on-label indications (HR: 0.54, 95% CI: 0.48 to 0.62, p < 0.01).
Risks of DES.
Mortality
The concerns that DES increased mortality stemmed from the presentation and publication of 4 studies. 1) A meta-analysis performed by Nordmann et al. (31) using aggregate trial data from 17 randomized studies of patients treated with SES, PES, and BMS that demonstrated a statistically significant increase in noncardiac mortality between 2 and 3 years after SES implantation. 2) The single-center BASKET-LATE (Basel Stent Kosten Effektivitats Trial), which randomly assigned 746 unselected patients to either SES or BMS, and reported a higher rate of death and MI between 7 and 18 months after the index PCI among patients treated with SES compared with BMS (adjusted HR: 2.2, p = 0.03). No significant difference was seen in the rates of ST or thrombosis-related events between groups; however, ultimately the study was underpowered to detect ST events, and limited angiographic evidence was available to confirm that events were actually due to ST (124). 3) The pooled analysis of published data from the Cypher SES trials, RAVEL, SIRIUS, E-SIRIUS (European-Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions), and C-SIRIUS (Canadian-Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) by Camenzind et al. (32), that showed a statistically significant 2.4% increased risk of death and Q-wave MI with the use of SES compared with BMS (6.3% vs. 3.9%, p = 0.03). Much criticism was directed at the use of the peculiar end point of death and Q-wave MI, and the use of aggregate trial data. A subsequent analysis of the same studies by Spaulding et al. (23) using patient-level data indicated that there were no significant differences in death/MI between groups (11.4% SES vs. 10.1% BMS, p = 0.4). 4) The 3-year results of SCAAR (Swedish Angiography and Angioplasty Registry), which reported results from 20,000 patients treated with BMS or DES between 2003 and 2004, and demonstrated a higher overall risk of death for patients receiving DES (adjusted relative risk [RR]: 1.18; 95% CI: 1.04 to 1.35) (33). Subsequent extended analyses to incorporate data from 2005, however, demonstrated a 31% reduction in events during the first 6 months with DES, and no difference in events between DES and BMS during long-term follow-up. That may have been the result of DES use increasing from 22% to 53% of PCI procedures from 2003 to 2005, together with operators traversing the learning curve with DES, and thereby selecting lesions and patients more appropriately, and being more meticulous with ensuring adequate stent deployment, and compliance to DAPT (125). Most recently, data from the registry, extended to include new patients treated in 2006 and now including just under 48,000 patients, showed a similar long-term incidence of death or MI among DES and BMS patients. Moreover, DES were also shown to have a reduced rate of restenosis among high-risk patients (125,126).
In the aftermath of these studies, which caused widespread concern, several patient-based meta-analysis were performed that reassuringly demonstrated the overall comparable outcomes between DES and BMS in terms of death and MI, at both short- and long-term follow-up (Table 3). The largest of these studies, by Stettler et al. (22), reported a similar risk of death for patients treated with SES, PES, or BMS; the risk of MI, although comparable between PES and BMS (p = 0.99), was significantly lower with SES compared with BMS (p = 0.03) (22). Additional meta-analyses were performed at a similar time by Stone et al. (24), Spaulding et al. (23), Kastrati et al. (26), and Mauri et al. (25), and now more recently by Kirtane et al. (76). All reiterated the safety of DES by demonstrating the absence of any significantly increased risk of death and/or MI with the use of DES compared with BMS.
In addition to the data from randomized controlled trials, observation data comparing DES to BMS have been published from numerous registries, which in total include >400,000 patients. The largest single registry published to date includes 262,700 patients from the Medicare registry and demonstrates lower rates of adjusted and unadjusted death, MI, and repeat revascularization after treatment with DES compared with BMS out to 30 months of follow-up (123). A similar advantage in favor of DES was also reported by Kirtane et al. (76) in a meta-analysis of >30 registries, which included >180,000 patients followed up for 12 to 48 months. These data reflect some of inherent differences between randomized studies and observation studies, which provide a better reflection of real-world practice and, owing to the large numbers of patients recruited, may be able to detect differences in infrequent events. Conversely, however, they can be affected by a selection bias and/or incomplete risk adjustment due to unmeasured baseline population differences, factors that may account for the previously noted reductions in mortality and MI.
Off-label indications.
The current on-label indications for DES use, as approved by the U.S. FDA are limited to simple lesions: for SES, de novo lesions  30 mm in length in native coronary arteries with reference vessel diameters of 2.5 to 3.5 mm, and for PES de novo lesions 28 mm in native coronary arteries 2.5 to 3.75 mm in diameter. It follows that off-label indications represent a higher-risk population with more complex lesion morphologies and unstable clinical presentations.
One of the criticisms of early DES trials was that they enrolled stable patients treated with DES for on-label indications. For example, the meta-analyses by Stettler et al. (22), Stone et al. (24), Spaulding et al. (23), Kastrati et al. (26), and Mauri et al. (25) included patients who were treated for essentially stable de novo lesions, which had a mean lesion length of 23 to 24 mm, a mean vessel diameter of 2.7 mm, and were suitably treated with an average of 1.2 to 1.4 stents. There were concerns that the comparative results between DES and BMS seen in these studies did not reflect real-world practice in which 70% to 75% of DES are implanted for off-label indications (127,128).
Unfortunately, the lack of any dedicated trials comparing off-label DES and BMS added to these concerns, and the FDA Circulatory System Devices Advisory Panel that met in December 2006 concluded that there was a need for a comprehensive assessment of the safety and efficacy of off-label DES use (129). This prompted numerous studies, many of which were observational, that ultimately demonstrated that the use DES for off-label indications was associated with poorer clinical outcomes in terms of death, MI, and repeat revascularization when compared with DES use for on-label indications (127,130–132). Of equal importance are the results from registries and randomized controlled trials that suggest that, for off-label indications, the use of a DES is no worse than the use of a BMS (76,133–136), with some studies, such as the Medicare and STENT (Strategic Transcatheter Evaluation of New Therapies) registry actually demonstrating significantly improved outcomes with the use of a DES (123,131). These findings suggest that the overall poor outcome with off-label use is most likely related to patient or lesions characteristics, rather than to specific shortcomings of DES.
ST.
ST has emerged as 1 of the major safety concerns with stenting in today's clinical practice (Fig. 7). Fortunately, it is a rare, but it remains a devastating unpredictable event that has a significant morbidity and mortality (137); the clinical consequences are highly dependent on the myocardial area at risk, its viability, the degree of recruitable collaterals, and the speed of reperfusion therapy. The overall prognosis from ST is poor: 10% to 30% of patients with definite ST will die, whereas a proportion will experience an unexpected out-of-hospital death.
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Figure 7 Stent Thrombosis
(A) Drug-eluting stent implantation in the proximal left anterior descending artery, complicated by (B) stent thrombosis occurring 7 months later, shortly after discontinuation of dual antiplatelet therapy. (C) Gross pathology example of stent thrombosis.
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Early anecdotal reports of ST occurring in the months and years after implantation of a DES (138–140) were substantiated by subsequent studies reporting an annual risk of ST ranging from 0.2% in post-marketing surveillance registries, to 0.5% in trials of multivessel PCI (141–144). The infrequent nature of ST, together with concerns regarding mortality among patients treated with DES, lead to large collaborative meta-analyses, performed using the standardized Academic Research Consortium (ARC) definitions, that demonstrated similar rates of overall ST between DES and BMS (Table 6) (22–26,145). In particular, no difference between DES and BMS was seen for early ST (<30 days) or late ST (30 days to 1 year); however, significantly higher rates of very late ST (>1 year) were seen with DES. Furthermore, registry data from the Rotterdam-Bern group (n = 8,146), the SCAAR (Swedish Angiography and Angioplasty Registry) registry (n = 21,717), and the Pinto Slottow et al. registry (n = 8,000) have all indicated that the risk of very late ST persists at an annual rate of between 0.36% and 0.6%/year to at least 5 years after DES implantation (146–150). The results at 2-year follow-up from both the ARRIVE (The TAXUS Peri-Approval Registry: A Multi-Centre Safety Surveillance) and the STENT registry indicate that the risk of ST is higher for patients treated with DES for off-label indications compared with on-label indications (130,131).
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Table 6 Rates of Overall, Early, Late, and Very Late Stent Thrombosis From Recent Meta-Analyses Comparing DES to BMS
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Uncertainty exists over the exact cause of ST; however, numerous factors have been implicated in increasing the risk of a ST event (Table 7). Of note, data from large-scale registries demonstrate that the multivariate predictors of ST change during follow-up (146,147,151,152). In addition to the early cessation of DAPT, numerous other procedural-related factors such as stent undersizing, lesion length >28 mm, dissection, multiple stent implantation, calcification, and small vessel diameter have been shown to be important factors in the development of early/late but not very late ST (151,152). Conversely, patient factors such as previous brachytherapy and renal failure appear to be more influential in very late ST. This variation in the cause of ST may explain the relatively higher rates of early ST when compared with late/very late ST. For example, in the Dutch Stent registry of 21,009 patients, 437 patient had documented ST of which 32.0%, 41.2%, 13.3%, and 13.5% was categorized as acute, subacute, late, and very late ST, respectively (151).
Two of the most prominent device concerns with the use of DES that deserve additional consideration are their ability to potentially delay endothelialization and induce hypersensitivity reactions through the presence of a drug polymer.
Impaired Endothelialization by Antiproliferative Drugs
The antiproliferative properties of DES impair and/or delay endothelialization so that blood is exposed to thrombogenic stent struts, potentially precipitating ST (138,153–156). Animal studies using scanning electron microscopy have previously demonstrated a greater area of exposed stent struts with the use of DES (SES 3.08 mm2, PES 3.54 mm2) compared with BMS (0.12 mm2) (157). More recently, human studies using optical coherency tomography have also demonstrated differences between different types of DES, with the second generation zotarolimus-eluting stent (ZES) having significantly lower rates of uncovered stent struts when compared with SES at both overlapping sites (0.06% vs. 5.4%) and nonoverlapping sites (0.03% vs. 8.7%) (158). Similar results have been reported by Kim et al. (159), whereas Barlis et al. (160) demonstrated a higher rate of near complete (>95%) strut coverage in a stent with a biodegradable polymer when compared with a stent with a durable polymer (SES [89.3% vs. 63.3%, p = 0.03]). Incomplete strut coverage can also be demonstrated on angioscopy, and has been seen as late as 2 years after implantation of SES (161,162). The restitution of a healthy but not hyperproliferative endothelial lining remains a target of ongoing current research.
Polymer
Conventionally, DES are coated with permanent polymers that facilitate drug release and remain long after drug elution is complete. These permanent polymers can cause delayed healing, impaired stent strut endothelialization, and a hypersensitivity reaction, which can culminate in ST (153,157,163–165) Data from histopathology studies also indicate that these nonerodable polymers can precipitate ST by inducing localized vascular inflammation, hypereosinophilia, thrombogenic reactions, and apoptosis of smooth muscle cells (164–166). Of note, the Cypher SES is coated in a nonerodable poly(ethylene co-vinyl acetate) and poly(n-butyl methacrylate) polymer that has been shown to induce granulomatous and hypersensitivity reactions in animal models and humans (167,168). Similarly, the first-generation TAXUS PES stent has a durable poly(styrene-b-isobutylene-b-styrene) polymer that is associated with medial necrosis, positive remodeling, and excessive fibrin deposition, which likely contribute to the deleterious pathologic changes that can be seen with the TAXUS stent (168).
The potential of these first-generation stents to cause ST due to a permanent polymer has led to extensive research into developing new polymers. These developments have led to the second-generation DES that have more biocompatible nonerodable polymers, which have been shown in animal studies to have a greater degrees of re-endothelialization compared with first-generation stents (157). Research has also led to the design of the newer DES that are described in Part Two of this article, and have biodegradable polymers, novel coatings, or are completely polymer free.
Duration of Antiplatelet Therapy
Although the clinical value and cost effectiveness of long-term clopidogrel (up to 12 months) with BMS after PCI for acute coronary syndrome (ACS) is well established (169–171), the optimal duration of DAPT after DES implantation remains an issue of contention. Central to the discussion are repeated studies that demonstrate that premature (<1 year) discontinuation of DAPT is 1 of the most significant independent predictors of ST (142,151,172,173), with poor patient compliance, surgery, bleeding complications, poor patient education, allergy to clopidogrel, and cost the most frequently cited reasons for cessation (146,172). It was this association between "early" discontinuation of DAPT and ST that led guidelines' authorities and the U.S. FDA advisory panel to recommend 12-month DAPT after DES implantation for all patients without contraindications and bleeding risk (128,174). However, these recommendations were made in the absence of any prospective randomized trials evaluating whether prolonged DAPT actually reduced rates of ST.
This association of cessation of DAPT and ST is complicated by studies that demonstrated that discontinuation of clopidogrel is only a major independent predictor of ST in the first 6 months after PCI, and not beyond. The median time interval for a ST event after the discontinuation of clopidogrel has been shown to be 9 days (interquartile range 5.5 to 22.5) within the first 6 months of the PCI, compared with 104.3 days (interquartile range 7.4 to 294.8) for the period after (173,175). Further complicating the issues are a lack of randomized data and reliance on observational studies, some of which indicate that discontinuing clopidogrel after 6 months does not increase the risk of ST (175,176), whereas others demonstrate that long-term DAPT might be associated with reductions in death and MI (177,178). Other important facts to consider are that <1% of patients who discontinue DAPT experience a ST (179), whereas ST events commonly occur among patients who are still receiving DAPT (173). For example, in the Rotterdam-Bern study, 87% of patients with early ST and 23% of patients with late ST were still taking DAPT at the time of the event (146). Further clouding matters is a possible hyperthrombotic rebound phenomena after clopidogrel discontinuation. That has been suggested by, among others, Ho et al. (180), who observed a clustering of adverse events in the 90-day period after the cessation of clopidogrel in 3,137 ACS patients who were treated either medically or with PCI.
Current registry data assessing long-term use of DAPT show conflicting results. Park et al. (181) reported no benefit in terms of reduced clinical outcomes or ST events in 2,851 patients treated with DES who received DAPT for >12 months. More recently, however, the smaller TYCOON (Two-Year Clopidogrel Need Study) registry has reported more positive results among 443 patients treated with DES who received DAPT for 12 months (n = 173) or 24 months (n = 274). At 4-year follow-up, there was no difference in clinical outcomes; however, significantly lower rates of very late ST (2% vs. 0%, p = 0.03) and overall ST (3% vs. 0.4%, p = 0.02) were seen in the group receiving prolonged DAPT. A major limitation of the study was failure to assess the potentially adverse effects of prolonged DAPT in these patients (182).
It is hoped that several on-going randomized trials will provide additional data to help establish the optimal duration of DAPT. The ISAR-SAFE (Intracoronary Stenting and Angiographic Results: Safety And Efficacy of 6 Months Dual Anti-platelet Therapy After Drug Eluting Stenting) study and the OPTIMIZE (Optimized Duration of Clopidogrel Therapy Following Treatment With the Endeavor Zotarolimus-Eluting Stent (ZES) in the "Real-World") study are both currently randomizing patients treated with DES to either standard therapy of 12 months of DAPT or shorter periods of DAPT ranging from 3 months (OPTIMIZE) or 6 months (ISAR-SAFE) (183,184). Conversely, the DAPT (Dual Anti-Platelet Therapy Trial) will compare outcomes of >20,000 patients treated with BMS and DES who are randomly allocated to DAPT therapy for either 12 or 30 months (185).
These concerns may be rendered immaterial if the initial promise from newer antiplatelet agents, which have recently been assessed in randomized controlled trials, is maintained (Fig. 8
). Prasugrel represents a novel antiplatelet agent that is a more effective inhibitor of the P2Y12 platelet adenosine diphosphate receptor, compared with both ticlopidine and clopidogrel. This results in its antiplatelet activity peaking 60 min after oral administration, compared with 2 to 6 h with clopidogrel (186). In the recent TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial that randomized >13,000 patients with ACS, use of prasugrel was associated with a significant reduction in the primary end point (a composite of cardiac death/nonfatal MI/nonfatal stroke), and rates of MI, TVR, and ST (p < 0.001 for all), when compared with standard therapy with clopidogrel. Of note, the risk of major life-threatening and fatal bleeding was significantly higher with prasugrel (187). A pre-specified substudy analysis involving >12,000 patients who received a stent reported significantly reduced rates of ST in patients receiving prasugrel (1.13% vs. 2.35%, HR: 0.80, p = 0.03), with at least as great a reduction in ST seen in patients treated with a DES (HR: 0.36) compared with a BMS (HR: 0.52) (188).
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Figure 8 Activation of Clopidogrel, Prasugrel, and Ticagrelor
Clopidogrel, prasugrel, and ticagrelor are all absorbed from the gut. Ticagrelor is active immediately, and binds in a reversible fashion to the P2Y12 receptor on the platelet. Prasugrel is first hydrolyzed by esterases, before undergoing hepatic CYP-mediated oxidation to produce the active metabolite that binds irreversibly to the P2Y12 receptor on the platelet for the duration of the platelet's life. Clopidogrel requires 2 oxidation steps within the liver before binding irreversibly to the P2Y12 receptor.
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Ticagrelor is a cyclopentyl triazolopyrimidine and functions as an orally active reversible inhibitor of the platelet adenosine diphosphate receptor P2Y12. In the recently published PLATO (Platelet Inhibition and Patient Outcomes) study, use of ticagrelor compared with clopidogrel in 18,624 patients with ACS resulted in a 16.0% reduction in the primary end point, which was a composite of death from vascular causes, MI, or stroke (9.8% vs. 11.7%, HR: 0.84; 95% CI: 0.77 to 0.92; p < 0.001). Moreover, rates of ST among patients receiving a stent were also significantly lower in those treated with ticagrelor compared with clopidogrel (1.3% vs. 1.9%, p = 0.009). Rates of major bleeding were comparable; however, patients treated with ticagrelor had high rates of non-CABG–related major bleeding (4.5% vs. 3.8%, p = 0.03), which included more instances of fatal intracranial bleeding (189,190). Conversely, patients treated with ticagrelor had a lower risk of CABG major bleeding, which is the likely consequence of its reversibility that enables it to dissipate before surgery.
Clopidogrel Resistance/Nonresponders
In recent times, resistance to aspirin and/or clopidogrel, which may occur in as many as 44% of patients (191,192), has emerged as a potential risk factor for adverse cardiac events, particularly ST (193–195). The underlying mechanism of this nonresponsiveness is not completely understood, but is likely to occur through a combination of clinical, cellular, and genetic factors, together with potential drug interactions (196).
The assessment of clopidogrel resistance has been advanced after developments in patient tests. Importantly, several studies in patients undergoing elective or urgent PCI have reported a correlation between the reactive platelet response to adenosine diphosphate, assessed using the point-of-care assay VerifyNow (Accumetrics, San Diego, California), and clinical outcomes ranging from periprocedural MI to 1-year MACE (197–201). These results indicate the potential importance of platelet function testing; however, in the absence of large-scale clinical trials, these tests can only be regarded as research tools at present.
Despite the potential to identify patients with clopidogrel resistance, no definitive treatment has been fully established, and in view of the potentially fatal consequences, this represents a major clinical problem. Simple measures include ensuring adequate patient compliance and evaluating possible drug interactions. Additional strategies that have been suggested include the following. 1) Use an increased maintenance dose of clopidogrel of 150 mg/day, which may improve clinical outcomes without significantly increasing bleeding (202,203). This treatment for clopidogrel resistance is currently being assessed in the randomized GRAVITAS (Gauging Responsiveness With A VerifyNow assay—Impact on Thrombosis and Safety) study (204). Further anecdotal support for this strategy is provided by the PCI cohort in the randomized CURRENT–OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events–Optimal Anti-platelet Strategy for Interventions) study, which has recently reported the safety and clinical benefits of administering 150 mg/day clopidogrel for 7 days after PCI in patients with ACS or STEMI treated before PCI with a 600-mg loading dose of clopidogrel. The use of the higher dose of clopidogrel led to significant reductions in both definite ST and MI at 30-day follow-up, without any significant increase in stroke or major, fatal, or CABG-related bleeding (205,206). 2) Use additional antiplatelet agents such as glycoprotein IIb/IIIa inhibitors during PCI, and cilostazol, a phosphodiesterase III inhibitor, during maintenance (207–209). 3) Use alternative P2Y12 receptor antagonists such as prasugrel or ticagrelor.
Operator technique.
The importance of operator technique in ensuring adequate stent deployment cannot be overstated in maximizing the benefit and minimizing the risk associated with stent implantation. Specifically, suboptimal or incomplete stent expansion is associated with increased rates of restenosis and TVR, and is a possible precipitant of ST (16,151,210–212).
One of the most common causes of suboptimal stent deployment is stent undersizing, which is aggravated by the use of direct stenting, and by relying solely on coronary angiography to assess stent size together with the underuse of intravascular ultrasound (IVUS). Previous studies demonstrate that reference vessel diameters vary significantly depending on the method of measurement used. For example, Briguori et al. (213) reported a difference between IVUS and angiography of >1.0 mm in 71% and 49% of cases with vessel size diameters <2.75 mm and >2.75 mm, respectively.
As alluded to, IVUS has an important role to play in optimizing stent implantation that extends beyond just minimizing the risk of stent undersizing. Intravascular ultrasound is considerably more accurate than angiography in determining in-stent dimensions, identifying incomplete stent apposition (ISA), and stent-edge dissections.
Clinical Implications
Studies indicate that the main clinical consequences of stent underexpansion are restenosis, ST, and stent fracture.
Restenosis
In BMS studies, minimum stent area was identified as the single most powerful predictor of in-stent restenosis (ISR), with an inverse correlation between post-procedural minimum stent area and both angiographic restenosis and TVR (214,215). After the arrival of DES and the subsequent reduction in TVR, less importance was given to adequate stent deployment. Importantly, observational studies have indicated that not only is minimum stent area still an independent predictor of ISR in patients having DES, but also that the rate of stent underexpansion with DES may be as high as 30% (216–218). This finding reiterates the importance of maximizing final minimal stent area/diameter with noncompliant balloon inflation, thereby reducing suboptimal stent deployment, which may result in improved clinical outcomes. Unfortunately, at present, no randomized data exist investigating this with DES.
ST
Minimum stent area and suboptimal stent expansion represent major post-procedural predictors of ST (211,219,220). Retrospective data from Fuji et al. (211) indicate that lesions leading to ST after successful implantation of a SES stent more often have stent underexpansion, a small minimum stent area, and a residual edge stenosis. The importance of IVUS assessment after stent deployment is reaffirmed by registry data from >7,000 patients treated with BMS indicating that only approximately one-fifth of patients experiencing subacute ST had an optimum PCI result as assessed by IVUS. Moreover, analysis of these thrombosed stents indicates inadequate lumen dilation (final lumen <80% reference lumen), edge dissection, ISA, and plaque prolapse in 78%, 17%, 9%, and 4% of cases, respectively (221).
Incomplete stent apposition can be acute if detected at the time of the procedure, or late if detected at follow-up (Fig. 9) (222). Acute ISA can resolve itself, or if detected at the time of stent implantation, can be treated immediately with balloon dilation. Late ISA can be persistent (present after procedure and at follow-up) or acquired, if only detected on follow-up (223). Some studies (219) but not all (224,225) have suggested that ISA is associated with an increased risk of ST. Moreover, a recent meta-analysis has demonstrated that the risk of late acquired ISA is significantly higher for DES compared with BMS (OR: 4.36, 95% CI: 1.74 to 10.94), whereas the risk of late/very late ST is significantly higher for patients with ISA when compared with patients who do not have ISA (OR: 6.51, 95% CI: 1.34 to 34.91) (226).
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Figure 9 Stent Malapposition
Stent malapposition is seen from the 11 o'clock to 9 o'clock position using Fourier domain optical coherence tomography (Terumo Corp., Tokyo, Japan).
Reproduced with permission from Okamura et al. (222).
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This difference in ISA between DES and BMS may be due to the effect of the antiproliferative drug on the vessel wall, causing positive remodeling, or a result of the decrease in plaque volume behind the stent struts (227). It has also been demonstrated using optical coherence tomography in patients before PCI and at 9-month follow-up that lesions with plaque rupture, thrombus, lipid-rich plaque, and thin-capped fibroatheroma have a greater incidence of ISA than do patients not having those features at baseline (83% vs. 30%, p < 0.001) (228).
It remains unclear exactly how ISA leads to ST. It may be the result of chronic inflammation and delayed healing, causing tissue necrosis and erosion around the stent (153). The link between inflammation, ISA, and ST has been reaffirmed by a histopathology study of ST eosinophil counts demonstrating that not only is very late ST associated with a greater degree of inflammation than other types of ST (early, late, BMS), but also eosinophil counts appear to correlate with the degree of ISA (167). Finally, ISA may serve as a trigger for thrombosis by allowing fibrin and platelet deposition behind stent struts (229).
Stent fracture.
Stent fracture remains an uncommon late complication of DES implantation (230,231) whose true incidence among first-generation DES remains unknown; however, rates of 1% to 2%, 1% to 7.7%, and as high as 29% have been reported in randomized, observational, and autopsy studies, respectively (232–235). Notably, the majority of stent fractures have been reported with the Cypher SES, whereas stent fractures with TAXUS PES and BMS have been seen very rarely. This difference may be related to the increased radio-opacity of the Cypher SES, its closed cell design, and/or the greater neointimal coverage seen with the PES and BMS that may strengthen and stabilize the struts to withstand the mechanical forces that result in stent fracture. Overall, stent fractures can range from a single strut fracture (grade I) through to multiple strut fractures (grade V).
There are a number of suspected causes for stent fractures that include both mechanical and lesion-based factors.
Mechanical Factors
Stent fracture may be the consequence of an excessive mechanical vessel wall stress that occurs from extreme repetitive contraction and flexion of the vessel (233). Of note, this may actually be a protective mechanism for stress relief within the vessel.
Lesion Factors
Predictors for stent fractures have included lesions located in the right coronary artery and/or lesions in very tortuous or severely calcified vessels. Additional factors increasing the risk of stent fracture include implantation of long and/or overlapping stents (Fig. 10), underlying diffuse disease, SVG, and treatment of CTO (230,235–237). In a recent autopsy study, longer stent length, use of the Cypher stent, and longer stent duration were all identified as independent predictors of stent fracture (235).
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Figure 10 Stent Fracture
(A) A long, diffusely diseased left anterior descending artery is treated with 3 sirolimus-eluting stents (white arrows). (B) The initial angiographic result is excellent; however, at (C) 3-months' follow-up, an irregular appearance is seen, and is the result of (D) 4 stent fractures (black arrows) occurring adjacent to regions of stent overlap (red lines).
Reproduced with permission from Popma et al. (236).
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Patients with stent fractures may remain asymptomatic; however, they may present with ACS, ST, or recurrent angina due to clinical restenosis; overall, 70% to 80% of patients with a stent fracture will present with ISR or ST (230,231,233,238). The extent of symptoms appears to be related to the grade of the stent fracture, with few symptoms occurring as a result of grade I to grade IV stent factures, whereas grade V stent fractures are associated with the most adverse clinical events (235). There are no data on definitive treatment; however, repeat PCI, which is the current preferred strategy, appears to provides prompt symptom relief (230,231). Some suggest treatment using a short stent, together with extending DAPT beyond 12 months (239).
Coronary artery aneurysms.
Coronary artery aneurysms are a rare complication of stenting, whose true incidence, clinical course, and treatment are largely unknown (Fig. 11). Nevertheless, studies report an incidence between 0.3% and 6.0% after DES and BMS implantation (240). There are a number of postulated causes for these coronary artery aneurysms, some of which are specific for DES. In general, mechanical causes include the use of oversized balloons or stents, high-pressure balloon inflations, and atherectomy—all of which can cause residual dissection and deep arterial wall injury eventually leading to aneurysm formation (241–243). Of note for DES, the elution of antiproliferative drugs and/or presence of a polymer can lead to delayed re-endothelialization, inflammatory changes in the medial wall, ISA, and hypersensitivity reactions, all of which can result in coronary artery aneurysm formation (240). Data on coronary aneurysms are derived mainly from case reports indicating a variable clinical course that is similar irrespective of whether the aneurysm is after BMS or after DES implantation. In particular, aneurysms have been detected from as early as 3 days after DES implantation (244) and as late as 9 years after BMS implantation (245).
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Figure 11 Coronary Artery Aneurysms
A coronary aneurysm (white arrows) is seen on (A) coronary angiography and on (B) cross-sectional and (C) longitudinal intravascular ultrasound. The aneurysm has led to extensive stent malapposition (B and C).
Reproduced with permission from Alfonso et al. (246).
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Coronary artery aneurysms can be associated with restenosis (246), whereas turbulent and sluggish blood flow in the area of the aneurysm, coupled with a metallic stent, can predispose patients to the risk of ST and/or distal embolization (247,248). Currently, there are no definitive data on the best management of patients with coronary artery aneurysms, treatment of which is complicated by some aneurysms resolving spontaneously (249), whereas others lead to life-threatening complications. In addition to the use of long-term DAPT to minimize the risks of ST, therapeutic options that can be considered include the use of coils and cardiac surgery.
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Second-Generation DES
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The initial coronary stents were composed of 316L stainless steel since this material is radio-opaque and provides adequate radial strength to maintain arterial scaffolding with minimal acute recoil. An alternative to stainless steel is cobalt chromium (CoCr), which exhibits superior radial strength and improved radio-opacity, allowing for thinner stent struts that may reduce restenosis (250–252). Thinner struts can also lead to a reduction in device profile and, hence, an improvement in stent deliverability to the target lesion. The 2 second-generation DES that are currently approved by the U.S. FDA utilize CoCr, and elute "limus" drugs with the aid of more biocompatible polymers than are found on the first-generation DES.
Endeavor ZES.
The second-generation Endeavor ZES (Medtronic, Minneapolis, Minnesota) uses the CoCr Driver stent platform loaded with a permanent "biomimetic" phosphorylcholine polymer (Table 1), which although not biodegradable is biostatic and biocompatible, being a natural component of the cell membrane. The polymer, which releases 95% of the sirolimus analogue, zotarolimus, within 14 days of stent deployment, causes less inflammation compared with the polymers on the Cypher SES stent.
Both animal studies and in vivo studies using angioscopy and optical coherence tomography have shown a greater endothelial coverage of struts with ZES compared with SES and PES (157,253–255). Angioscopy has demonstrated levels of neointimal coverage with ZES that are superior to that SES and comparable to that seen with BMS (253). Similarly, the mean percentage of covered struts seen by optical coherency tomography 3 months after implantation of ZES, SES, and BMS has been reported in separate studies as 99.9%, 85%, and 99.9%, respectively (254,255).
Clinical data on ZES are available from the Real-World E-Registry, and from numerous other trials ranging from the first-in-man ENDEAVOR I study to randomized trials comparing ZES to BMS, SES, and PES (Table 8) (256–269). Data from the "all-comers" E-Registry at 12 months of follow-up, and a pre-specified subgroup of patients who had extended follow-up for 2 years in the E-Five (Endeavor Stent Registry) study, demonstrate comparable outcomes between the randomized ENDEAVOR studies and real-world patients.
The superiority of ZES compared with BMS was demonstrated in the 1,197-patient, randomized ENDEAVOR II study, which reported significantly lower in-stent late loss and angiographic binary restenosis at 9-month follow-up with ZES, together with significantly lower TLR out to 5 years of follow-up. Rates of death, MI, and ST remained comparable between both stents throughout follow-up (258,259).
In the comparison with other DES, data have indicated a relatively poorer performance of ZES compared with PES and SES at short-term follow-up, as indicated by significantly higher late loss and numerically greater TLR (260,264). Results at longer follow-up have been more reassuring after the observed reductions in the absolute difference in TLR between ZES and SES/PES. For example, in the ENDEAVOR III study, the 2.8% absolute difference in TLR between ZES and SES at 1 year was reduced to 1.6% at 5 years (260,262), whereas in the ENDEAVOR IV study, the absolute difference in TLR between ZES and PES was 1.3% and 0.5% at 1 year and 3 years, respectively (264,265). Although at only medium-term follow-up, these results suggest the absence of the "late-catch" phenomenon with ZES.
Conflicting results have been observed when comparing ZES to SES and PES for early and late ST; however, despite this, a consistent benefit has been seen with ZES in terms of reduced very late ST (Fig. 12). Although these current trials are underpowered to detect differences in ST, these inconsistencies with ZES serve to reaffirm data that indicate the lack of association between in-stent late loss and ST (270); moreover, they reiterate the complex pathophysiology underlying ST. The only adequately powered study that will provide definitive data on the safety and efficacy between ZES and SES is the fully enrolled PROTECT (Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial) study. This study has randomly assigned 8,800 "all-comers" patients to treatment with either the ZES or SES, and will report a primary end point of definite/probable ST at 3-year follow-up (271).
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Figure 12 Rates of Stent Thrombosis Comparing ZES to SES or PES
Rates of early/late and very late definite/probable stent thrombosis in randomized trials comparing the Endeavor zotarolimus-eluting stent (ZES [blue bars]) to either the sirolimus-eluting stent (SES [red bars]) or paclitaxel-eluting stent (PES [green bars]). Rates of early/late stent thrombosis are consistently higher with the ZES; however, conversely, very late stent thrombosis rates are consistently lowest with ZES. No differences are significant. ARC = Academic Research Consortium.
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Xience V everolimus-eluting stent (EES).
The Xience V EES (Abbott Vascular, Santa Clara, California) consists of the Multilink Vision CoCr platform with a nonerodable biocompatible polymer and 100 µg/cm2 everolimus, a synthetic derivative of sirolimus (40-O-[2-hydroxyethyl]-rapamycin). The 6- to 8-µm-thick polymer is composed of acrylic and fluorinated polymers and releases 80% of the drug within 30 days, with nearly all the drug released within 4 months (Table 1). This stent is also marketed by Boston Scientific as the Promus stent. In the U.S., the Abbott supply agreement for the Promus stent continues until 2012 when the Promus stent will be replaced by the Promus Element stent.
Clinical data consist of both real-world registries, and randomized trials comparing EES to BMS and PES. Results have consistently demonstrated the safety and efficacy of the EES, together with low rates of ST out to long-term follow-up (Table 9) (272–282).
In brief, the randomized SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System) II, III, IV studies and the COMPARE (Second-Generation Everolimus-Eluting and Paclitaxel-Eluting Stents in Real-Life Practice) study have all compared EES and PES. Two-year follow-up of the SPIRIT II study was the first study to demonstrate "delayed" restenosis with everolimus, a phenomenon previously observed with other DES (283,284); however, this did not appear to have any detrimental effect on clinical outcomes. In fact, at 3-year follow-up, a greater absolute difference in cardiac death, MI, TLR, and MACE in favor of EES was observed when compared with results at both 1- and 2-year follow-up (Fig. 13) (275). Similarly, in the larger SPIRIT III study, the benefit of EES over PES increased during follow-up, and at 3 years, use of EES lead to significant reductions in target vessel failure, target lesion failure, and MACE (278). Recently, 2 important randomized studies assessing EES have reported 12-month outcomes. The SPIRIT IV study, which enrolled 3,690 patients, represents the largest randomized trial comparing 2 DES; and the COMPARE study, which recruited 1,800 patients, was the first randomized all-comers trial of the EES (279,281). Both studies demonstrated significantly superior efficacy and safety with EES compared with PES. In addition, whereas nonsignificantly lower rates of ST have been observed in the SPIRIT II and III studies, the SPIRIT IV and COMPARE studies were the first to demonstrate a significant reduction in ST between 2 DES. At 12-month follow-up, rates of definite/probable ST for EES and PES were 0.29% versus 1.06% (p = 0.003), and 0.7% versus 2.6% (p = 0.002) in the SPIRIT IV and COMPARE studies, respectively.
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Figure 13 Clinical Outcomes in the SPIRIT II Trial
The delayed restenosis observed with the XIENCE V everolimus-eluting stent (EES [white lines]) between 1 year and 2 years may explain the reduction in the absolute difference in (A) cardiac death, (B) myocardial infarction (MI), (C) ischemic target lesion revascularization (TLR), and (D) ischemic major adverse cardiovascular events (MACE) seen between EES and the TAXUS paclitaxel-eluting stent (PES [red lines]) at 2-year follow-up. However, events rates remained lower with EES, and a much larger absolute difference between both stents was observed at 3-year follow-up. HR = hazard ratio.
Reproduced with permission from Garg et al. (275).
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Some have suggested that the superiority of EES has only been demonstrated because it has not been compared with the SES, which historically is regarded as the most efficacious first-generation DES (22,105,106). Important data on this issue will be provided by the EXCELLENT (Efficacy of Xience/Promus Versus Cypher in Reducing Late Loss After Stenting) study, which plans to randomize 1,400 patients to treatment with either EES or SES (285). The study will also investigate the optimal duration of DAPT by comparing outcomes in patients randomly assigned to 6 months or 12 months of DAPT.
The Xience PRIME EES, which represents the latest development of the Xience V stent, has recently gain regulatory approval in Europe. This modified EES has a CoCr platform; however, this is mounted on a new enhanced stent delivery system that enables the stent to be more flexible and deliverable. Furthermore, the stent balloon has higher rate burst pressures, and shorter balloon tapers to minimize the risk of edge dissections. The stent is being evaluated in the prospective, multicenter, nonrandomized SPIRIT PRIME study in 500 patients at 75 hospital centers, with the aim of gaining U.S. FDA approval.
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Issues of Today
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Role of BMS in Contemporary Practice.
Despite the benefits of DES, there is still a role for BMS in the management of patients with CAD. Although reports indicate that DES are used in >75% of PCI procedures in the U.S. (34), their use varies widely from hospital to hospital, and in some U.S. states, DES use is actually less than BMS use. For example, recent data indicate that only 49% of PCI cases in Arkansas used a DES, with rates dropping down to 35% for rural hospitals (286). Irrespective of the specific reasons for this disparity, this report confirms the BMS are still used in contemporary practice. Ultimately, the decision to implant a BMS is guided by both clinical and economic factors.
Clinical justification for stent selection
The overall net clinical benefit of a stent can be summarized after considering the stent's beneficial and adverse effects. The benefits of DES are their significant reduction in repeat revascularization compared with use of a BMS, whereas their adverse effects relate to the increased risk of very late ST and the requirement for prolonged DAPT (22–26). Importantly, the net benefit cannot be assessed by simply determining the difference between these 2 outcomes, as they both have a different incidence and clinical consequence. For example, in a study by Stone et al. (287), the rate of ST and TLR was 3.1% (DES:BMS 1.4:1) and 12.3% (DES:BMS 0.47:1), respectively, whereas the rate of death and MI within 7 days for these events was 91.1% for ST and 3.5% for TLR. Therefore, to assess the overall net clinical benefit, actual mortality must be considered. Extensive data exist to confirm that DES not only significantly reduce restenosis compared with BMS, but do so without increasing the risk of mortality or MI. Thus, the overall net clinical benefit favors DES.
It must be appreciated, however, that this benefit in favor of DES is not universal, and in certain patients and lesions this net benefit may ultimately favor a BMS. The advantage of a DES in terms of reducing restenosis is dependent on lesion characteristics, and the observed benefit is greater in lesions at higher risk for restenosis. For example, the absolute difference in rates of repeat revascularization between DES and BMS for lesions in vessels <3 and >3 mm in diameter in the BASKET trial at 3-year follow-up was 9.1% and 2.0%, respectively (288). Similarly, in the Ontario registry, Tu et al. (289) reported a significantly lower rate of TVR with the use of DES compared with BMS among diabetic patients who had lesions that were >20 mm long in vessels <3 mm in diameter (DES vs. BMS 7.2% vs. 17.6%, HR: 0.38, 95% CI: 0.24 to 0.60, p < 0.001; number needed to treat to prevent TVR = 10). Conversely, no significant different in TVR was seen between DES and BMS when patients were not diabetic and had lesions <20 mm long in vessels >3 mm in diameter (DES vs. BMS 5.3% vs. 5.9%, HR: 0.87, 95% CI: 0.52 to 1.47, p = 0.61; number needed to treat to prevent TVR = 167) (289). The risk of ST is also variable and may be increased for patients who are not willing to, or are unlikely to, comply with DAPT, or for patients awaiting elective surgery (146,172). Therefore, for patients whose risk of restenosis is relatively low (i.e., nondiabetic, large vessel >3 mm in diameter), and/or the risk of ST is relatively high (inability to comply with long-term DAPT), a BMS maybe more appropriate. Ultimately, an evaluation of the overall risk/benefit ratio should play a key role in the clinical decision whether to implant a BMS or DES.
Cost effectiveness
Unfortunately, the discussion of stent selection cannot be made without considering the cost effectiveness of both therapies, in view of the additional initial expense associated with using a DES. Numerous cost-effectiveness analyses have been performed with conflicting results. Of note, many studies group patients treated with different DES together as 1 population, which ultimately can affect the accuracy of cost-effectiveness calculations for individual stents.
Some studies indicate that DES may be cost effective or even cost saving with specific patients, such as those who have lesions with a high risk for restenosis such as diabetic patients, long lesions, and lesions in vessels with small diameters. In the BASKET study, for example, DES were more effective and less expensive for vessels <3.0 mm diameter. For vessels >3.0 mm diameter, although the overall cost per quality-adjusted life-year gained was  39,641 ($59,392), subgroup analysis revealed that the cost per quality-adjusted life-year gained was 6,863 ($10,282) for off-label use, 3,471 ($5,200) for lesions  24 mm in length, and 300 ($450) for patients 65 years of age (290). Conversely, other studies report an incremental cost-effectiveness ratio of >200,000 Canadian dollars per quality-adjusted life year—indicating DES are not cost effective (291).
Importantly, the use of angiographic follow-up in randomized controlled trials and a short period of follow-up are 2 major factors that can bias results in favor of DES. Nevertheless, a recent systematic review evaluated 19 different cost-effectiveness studies that mainly reported results at 1 year, and concluded that the cost effectiveness of DES was unfavorable compared with that of BMS. That was primarily because, although the use of DES was associated with a higher initial cost (700 [$1,060]), they did not increase life expectancy, produced only a small relative reduction in rates of repeat procedures, and led to only a short duration of improved quality of life (291).
Further data suggesting DES are not cost effective come from analysis at 1 year of the outcomes from patients in France enrolled in the TYPHOON (Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated With Balloon Angioplasty), which reported the mean aggregate 1-year costs were 1,142 ($1,711) higher per patient in the SES group compared with the BMS group. The incremental cost-effectiveness ratio was 7,321 ($10,972) per TVR avoided (292).
By restricting follow-up to 1 year, previous cost-effectiveness studies have the potential to miss accounting for the costs incurred with very late ST, thereby introducing bias against BMS. To investigate the impact of long-term follow-up, Bischof et al. (293) performed an analysis using a Markov model to speculate on the cost effectiveness of using DES in the U.S. Medicare setting at 1 to 3 years of follow-up. Their results suggested that DES were not cost effective compared with BMS when used in unselected patients with CAD in the setting of Medicare (293).
In the United Kingdom, the National Institute of Clinical Excellence has taken into account the differences in cost between DES and BMS, and the differences in the risk of restenosis for specific lesions. Therefore, they have recommended DES in cases where lesions are >15 mm in length, in vessels <3.0 mm in diameter, provided the cost difference between BMS and DES is £300 or less (330 [$500]) (294).
The increasing development of DES in the developing world and the expiry of the patent for sirolimus are both likely to lead to reductions in the cost of DES, completely altering the cost-effectiveness evaluations that have previously been performed.
Diabetes Mellitus.
Diabetic patients are known to have an aggressive form of atherosclerosis with less favorable long-term survival after PCI compared with that of nondiabetic patients. Moreover, diabetes mellitus is frequently identified as an independent predictor of ISR (295,296), although the underlying mechanisms for this are poorly understood. Implicated factors include the greater degree of the vascular inflammation and endothelial dysfunction seen in diabetic patients (297,298) together with poor glycemic control (299) and insulin resistance that can aggravate restenosis through the direct growth factor-like effect of insulin on vascular smooth muscle and neointimal cells (300).
BMS versus DES
Registry Data
The most recent registry data come from the MDACR (Massachusetts Data Analysis Center Registry) and the SCAAR registry, which have reported results for 5,051 and 19,004 diabetic patients, respectively. The MDACR, which reported the results of propensity-matched diabetic patients treated with either BMS or DES, demonstrated significantly lower rates of death, MI, and repeat revascularization with DES at 3-year follow-up (301). The SCAAR registry only assessed patients treated with DES and demonstrated that, overall, patients with diabetes were at higher risk of restenosis compared with nondiabetic patients. Interestingly, this was only true for patients treated with SES and ZES; the rate of restenosis for patients treated with PES was not influenced by diabetic status. Ultimately, no mortality difference was demonstrated between the different DES (302).
Randomized Data
The evaluation of diabetic patients with the use of DES is hampered by the distinct lack of dedicated randomized trials. At present, only 10 randomized trials enrolling 1,662 patients have been conducted with DES to specifically assess outcomes in diabetic patients: 4 Cypher SES versus BMS, 5 Cypher SES versus TAXUS PES, and 1 Cypher SES versus ZES (49–53,102–104,303–308). There are no dedicated randomized trials assessing the performance of EES in diabetics, and data are derived from the diabetic patient subgroup (n = 1,185; 786 EES, 399 PES) of the SPIRIT IV trial (279) and the diabetic subgroup of the SPIRIT V study, which randomly assigned 324 patients to EES (n = 215) or PES (n = 104) (309). Similarly, the only data comparing ZES and PES are derived from 477 diabetic patients (241 ZES, 236 PES) in a subgroup analysis of the ENDEAVOR IV study (310).
Safety
Pooled analyses of diabetic subgroups from randomized trials comparing SES to BMS and PES to BMS among diabetic patients have demonstrated conflict results. Spaulding et al. (23) reported significantly higher mortality with the use of SES compared with BMS at 4-years follow-up (12.2% vs. 4.4%, p = 0.004); however, the authors acknowledge that this result may have been a play of chance, particularly in view of the small number of actual deaths in the diabetic subgroup (SES 23 vs. BMS 10). At the same length of follow-up, Kirtane et al. (311) reported comparable mortality between PES and BMS (PES 8.4% vs. BMS 10.3%, p = 0.61), and reassuringly, a collaborative network analysis by Stettler et al. (312) that included 3,850 patients demonstrated no significant difference in mortality between SES, BMS, and PES in the treatment of diabetic patients who received DAPT for >6 months.
Among different DES, no differences in mortality or MI have been noted. A recent meta-analysis (313) of 5 dedicated randomized trials comparing SES to PES—the ISAR-DIABETES (Intracoronary Stenting and Angiographic Results: Do Diabetic Patients Derive Similar Benefit From Paclitaxel-Eluting and Sirolimus-Eluting Stents?), DES-DIABETES (Drug-Eluting Stents in Patients With Diabetes Mellitus), and DiabeDES (Diabetes and Drug Eluting Stent) trials, and studies by Kim et al. (303) and Tomai et al. (307)—that in total enrolled 1,069 patients, with follow-up of as long as 2 years, reported no significant difference between SES and PES with respect to mortality (OR: 0.78, 95% CI: 0.30 to 2.07) or the risk of MI (OR: 0.88, 95% CI: 0.33 to 2.38). No significant differences in mortality, MI, or ST were reported at 12-month follow-up between either ZES and PES, or between EES and PES in the SPIRIT IV study. In the SPIRIT V diabetic cohort, treatment with EES led to a significantly lower risk of the composite of cardiac death/MI (3.7% vs. 9.6%, p = 0.04), which was driven by the significantly lower rate of MI with EES (309). The rate of ST was 0.0% for EES and 1.9% for PES.
Efficacy
Clinical data indicate the superior performance of the SES with respect to BMS and both PES and ZES. The 4 dedicated randomized trials comparing SES to BMS (DECODE [A Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent in the Treatment of Diabetics Patients With Native Coronary Artery Lesions], SCORPIUS [German Multicenter Randomized Single Blind Study of the CYPHER Sirolimus-Eluting Stent in the Treatment of Diabetic Patients With De Novo Native Coronary Artery Lesions], DESSERT [Diabetes Drug-Eluting Sirolimus Stent Experience in Restenosis Trial], and DIABETES [Diabetes and Sirolimus-Eluting Stent]) have collectively enrolled 600 patients, and have all demonstrated significant reductions in their primary end point of in-segment late loss at between 6 and 9 months of follow-up. Furthermore, although not powered to detect differences in clinical outcomes, they have also all shown significant reductions in TLR at follow-up of between 8 and 48 months.
Similarly, 4 of the 5 dedicated randomized trials comparing SES to PES have demonstrated significant reductions in in-segment late loss for SES compared with PES. With respect to reintervention, no significant difference has been shown in any of the individual trials apart from the DES-DIABETES study, which reported a somewhat unexpected 75% reduction in reintervention at 2 years for SES compared with PES (SES 3.5% vs. PES 11%, OR: 0.25, 95% CI: 0.08 to 0.77, p = 0.004). Meta-analysis of these 5 trials, which include a total of 1,069 patients with follow-up of as long as 2 years, has indicated that overall treatment with SES is associated with significant reductions in restenosis (OR: 0.29, 95% CI: 0.18 to 0.47) and reintervention (OR: 0.47, 95% CI: 0.28 to 0.77), compared with PES (313).
The DiabeDES III study is the only randomized comparison involving treatment with ZES. This study randomly allocated 127 diabetic patients to either ZES or SES, and demonstrated significantly lower late lumen loss with SES (0.14 mm vs. 0.74 mm, p < 0.001) at 10-month follow-up (308). In the subgroup of diabetic patients returning for angiographic follow-up in the ENDEAVOR IV study (n = 86), a trend toward higher in-stent late loss was seen in patients treated with ZES compared with SES (0.81 vs. 0.56, p = 0.073), whereas no notable differences in 1-year TLR were seen (310). Similarly, in the SPIRIT IV study, despite significant reductions at 1 year in TLR, TVR, MACE, and target vessel failure among nondiabetic patients treated with EES compared with PES, no significant differences in any of these outcomes were seen among diabetic patients (279). In the SPIRIT V study, EES was shown to be noninferior and subsequently superior to PES with respect to in-stent late loss at 9 months (0.19 mm vs. 0.39 mm, pnoninferority <0.0001, psuperiority = 0.0001); rates of repeat revascularization remained comparable between both stents (309). Some of these results are at variance with the meta-analysis by Kastrati et al. (313), and therefore, reiterate that there is presently no clear evidence to indicate that "limus"-based DES are superior to paclitaxel in the treatment of coronary lesions in diabetic patients.
DES versus CABG for diabetic patients
The CARDia (Coronary Artery Revascularization in Diabetes Trial) is the only randomized trial comparing the management of diabetes with multivessel disease (MVD) between CABG and PCI; however, because of poor recruitment, it was discontinued early after enrolling only 510 of the desired 600 patients, and is therefore largely underpowered. The ultimately negative noninferiority trial found no significant difference in 1-year mortality (3.2% PCI vs. 3.3% CABG, p = 0.83) or the 1-year composite clinical end point of death, nonfatal MI, or nonfatal stroke (10.2% for PCI vs. 11.8% for CABG); however, repeat revascularization was required more frequently in the PCI group (9.9% vs. 2.0%, p = 0.001). Although PCI was performed with DES in only 71% of cases, even these patients had higher rates of repeat revascularization when compared with CABG (7.3% vs. 2.0%, p = 0.013) (314).
More recently, the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) study, although not a dedicated randomized trial of diabetic patients, did enroll 452 diabetic patients (221 CABG, 231 PCI). Results demonstrated a higher rate of major adverse cardiovascular and cerebrovascular events (MACCE) for patients treated with PCI that was mainly driven by significant higher rates of repeat revascularization. Overall, the presence of diabetes increased mortality for both revascularization strategies (315). Further information about the optimal treatment for diabetic patients with MVD will be known with the results of the ongoing FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) trial (316).
STEMI.
Invasive reperfusion therapy has improved the prognosis of patients with STEMI (317,318), and new recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) indicate that DES are a reasonable alternative to BMS for these patients (319). There have been concerns, however, that the use of DES in this setting may predispose to a higher risk of ST (143,320,321), which may result from the following: 1) the trapping of thrombus behind stent struts and subsequent thrombus resolution, which can lead to an increased risk of ISA; 2) the protrusion of stent struts into underlying necrotic core due to overlying plaque rupture; 3) a delay in arterial healing (e.g., greater incomplete stent strut endothelialization and persistent fibrin deposition) that has been recognized at the culprit site in patients with STEMI compared with patients treated for stable angina (322); and 4) high risk of adverse events for patients noncompliant to DAPT, as suggested by results from the PREMIER (Prospective Registry Evaluating Myocardial Infarction: Events and Recovery) study, which reported a significantly increased 11-month mortality among the 13.6% of patients who discontinued DAPT 30 days after their revascularization for ACS or STEMI (172).
Clinical data on outcomes from primary PCI are limited at present by the short duration of follow-up in most studies. The largest randomized primary PCI trial to date, the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) study, has reported angiographic data and clinical outcomes at 13 and 24 months, respectively, among 3,006 STEMI patients treated with PES or BMS. At 13 months, there were significant reductions in in-stent late loss and binary restenosis with PES (91). At 24 months of clinical follow-up, the use of PES was associated with significant reductions in the respective primary and second efficacy end point of ischemia-driven TLR (p < 0.001) and ischemic TVR (p < 0.001). In addition, there were no significant differences at 24 months between PES and BMS in the primary safety end point, a composite of death, MI, stroke or ST (PES 11.0% vs. BMS 11.2%, p = 0.90), or all-cause mortality, cardiac death, reinfarction, or definite/probable ST (92).
A previous meta-analysis by Kastrati et al. (323) of 2,786 patients undergoing primary PCI reported no significant difference in terms of death, MI, or ST between BMS or DES, and significant reductions in the risk of reintervention with DES (HR: 0.38, 95% CI: 0.29 to 0.50, p < 0.001). Unfortunately, follow-up was limited to 2 years (323).
More recently, Brar et al. (324) performed a much larger meta-analysis of 13 randomized trials that included 7,352 patients followed up for a maximum of 2 years. Results again demonstrate no significant difference between BMS and DES in terms of mortality (RR: 0.89, 95% CI: 0.70 to 1.14), MI (RR: 0.82, 95% CI: 0.64 to 1.05), and ST (RR: 0.97, 95% CI: 0.73 to 1.28), whereas the use of DES led to a significant reduction in repeat TVR (RR: 0.44, 95% CI: 0.35 to 0.55, p < 0.001). Notably, this benefit in reduced TVR was consistent in patients irrespective of whether DAPT was given for <6 months or >6 months, or whether follow-up was for 1 year or >1 year. Another important observation was that the benefit seen with DES treatment was greater for patients at highest risk of restenosis (324). A concurrent meta-analysis of 18 registries that included >26,000 patients was performed by the same group, and has shown similar results, with comparative outcomes in terms of death and MI between DES and BMS and significant reductions in terms of repeat revascularization with DES at up to 3-year follow-up (324).
Long-term follow-up data (4 years) that are available from 1 registry and 4 randomized studies have shown conflicting results. The randomized TYPHOON study, the PASEO (Paclitaxel or Sirolimus-Eluting Stent Versus Bare Metal Stent in Primary Angioplasty) study, and the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare Metal Stent in Myocardial Infarction) study, which all randomly assigned STEMI patients to treatment with either DES and BMS, have all shown positive results in favor of using DES with respect to reduced rates of repeat revascularization, and comparable safety at between 4- and 5-year follow-up (58,62,64). Specifically, the TYPHOON study, which randomly allocated 715 STEMI patients to treatment with either BMS or SES, demonstrated no significant differences in rates of death, cardiac death, and MI at 4-year follow-up, whereas rates of TLR and TVR were significantly lower in the SES group. With respect to ST, although the overall rate was comparable between groups (SES 3.6% vs. BMS 4.0%, p = 0.82), very late ST was numerically higher with SES (2.0% vs. 0.8%) (Fig. 14) (64). These results need to be interpreted with caution, considering the extensive exclusion criteria used during enrollment (only 35% of screened patients were enrolled) (63) and that complete follow-up was available for only 70% of patients.
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Figure 14 Rates of Stent Thrombosis Comparing DES to BMS
Rates of early/late and very late definite stent thrombosis (ST) in randomized trials comparing paclitaxel-eluting stents (green bars) and sirolimus-eluting stents (red bars) to bare-metal stents (blue bars) among patients undergoing primary percutaneous coronary intervention at long-term follow-up. Although no differences are significant, the rates of early/late ST are numerically higher with bare-metal stents, whereas the rates of very late ST are numerically greater with drug-eluting stents. ARC = Academic Research Consortium.
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At variance with these results are data from a large single-center registry of 1,738 patients by Kukreja et al. (325) and the 5-year follow-up results of the 619-patient PASSION (Paclitaxel-Eluting Stent Versus Conventional Stent in Myocardial Infarction With ST-Segment Elevation) randomized trial (95). Kukreja et al. (325) reported no overall significant differences between DES (SES, n = 185; PES, n = 1,022) and BMS (n = 531) in all-cause mortality (BMS 16.4% vs. SES 11.4% vs. PES 12.9%) or repeat revascularization (8.0% vs. 7.0% vs. 6.9%, respectively) at a median follow-up of 1,185 days. Moreover, although there were no differences in overall, early, or late ST rates, there were no cases of very late ST in the BMS group compared with a rate of 2.7% and 0.9%, respectively, in the SES group (p = 0.001) and the PES group (p = 0.03).
Similarly, in the PASSION study, which had considerably fewer exclusion criteria compared with the TYPHOON study and enrolled 60% of patients who were screened, no significant differences were observed in overall MACE, mortality, reinfarction, and TLR between patients treated with PES or BMS out to 5-year follow-up. Overall rates of definite/probable ST were comparable (PES 3.9% vs. BMS 3.4%, p = 0.85); however, rates of late/very late ST were approximately 3 times higher among patients treated with PES (3.2% vs. BMS 1.1%, p = 0.09) (Fig. 14). Again, these results must interpreted with caution considering the relatively small sample size and the lack of power to detect differences in ST.
Multivessel CAD.
The debate over the optimal method of revascularizing patients with MVD has raged for many years and continues to this day. The importance of this patient subgroup cannot be under estimated considering the increasing age and multiple comorbidities of patients currently being investigated for CAD, and the correspondingly higher number of patients with MVD ultimately requiring revascularization (326). Historically, CABG has been the accepted treatment for MVD (327); however, advances in the percutaneous treatment of CAD have made PCI a more attractive alternative (28,77,328). Despite this, observational data from real-world practice indicate that for two-thirds of patients with complex CAD, cardiac surgery remains the preferred method of revascularization, findings that have been supported by a recent prospective randomized trial (28,329).
BMS versus CABG
A meta-analysis of the 4 randomized trials comparing outcomes at 5-year follow-up in patients with MVD treated with either a BMS or CABG showed a similar rate of the composite of death, stroke, and MI (PCI 16.7% vs. CABG 16.9%; HR: 1.04, 95% CI: 0.86 to 1.27, p = 0.69); a numerically higher rate of stroke with CABG (PCI 3.1% vs. CABG 3.9%; HR: 1.16, 95% CI: 0.73 to 1.83, p = 0.54); and a significantly higher rate of repeat revascularization with the use of a BMS (29.0% vs. 7.9%; HR: 0.23, 95% CI: 0.18 to 0.29; p < 0.001) (330). A much larger meta-analysis by Bravata et al. (331) that included 23 randomized controlled trials comparing PCI (POBA or BMS; n = 5,019) with CABG (n = 4,944) showed that despite a significantly higher rate of procedure-related stroke after CABG (1.2% vs. 0.6%, p = 0.002), and more frequent repeat revascularization after PCI (absolute risk difference 24% at 1 year and 33% at 5 years), there was no difference in survival between percutaneous and surgical intervention. More recently, Hlatky et al. (332) performed a collaborative analysis using patient data from trials comparing POBA and BMS to CABG and reported somewhat similar findings, with significantly higher stroke rates at 90 days after CABG, significantly higher repeat revascularization after PCI, and no overall significant difference in terms of mortality at a median of 5.9 years of follow-up (PCI 15% vs. CABG 16%, HR: 0.91, 95% CI: 0.82 to1.02, p = 0.12).
BMS versus DES
The development of DES led to significant reductions in the rates of restenosis and repeat revascularization when compared with BMS. Consequently, if PCI is selected, there is little debate over whether to use a DES or a BMS; in fact, some would argue that patients with MVD where a DES cannot be used should be offered surgical revascularization. Currently, no dedicated prospective randomized trials have been performed comparing DES and BMS for patients specifically with MVD, and data supporting the use of DES in these patients, as opposed to BMS, come from the extrapolation of data from registries, nondedicated trials, and subgroup analyses. The ARTS-II study recruited 607 patients with 2- or 3-vessel disease treated with DES, who were then compared with patients with 2- or 3-vessel disease treated with BMS who were recruited in the ARTS-I study. At 5-year follow-up, there was no significant difference in survival (DES 94.5% vs. BMS 92.0%), whereas the use of DES led to significant reductions in repeat revascularizations (20.8% vs. 30.9%, p < 0.001) and overall MACCE (27.5% vs. 41.5%, p < 0.001) (Fig. 4) (77).
At variance with these results is the risk-adjusted outcomes among 60,000 patients undergoing PCI or CABG in the New York cardiac registry (333). Results suggested a significantly higher risk-adjusted survival among the CABG group (HR: 0.64, 95% CI: 0.56 to 0.74), with the difference being most pronounced in patients with 3-vessel disease and proximal left anterior descending artery disease. Complete risk adjustment was impossible to achieve, particularly as clinical judgment could not be adjusted for in this complex cohort of patients.
DES versus CABG
Data comparing the outcomes in patients with MVD treated with DES and CABG were initially derived from the addition of DES arms to the initial BMS-CABG trials, to allow a comparison of outcomes between DES and historical CABG cohorts. This was performed in the ARTS-II study, which at 5 years again demonstrated no significant difference in survival between DES and CABG (DES 94.5% vs. CABG 92.6%), but significantly higher rates of repeat revascularization (20.8% vs. 9.0%, p < 0.001) and MACCE (27.5% vs. 21.1%, p = 0.02) with the use of DES (Fig. 4) (77). A similar approach was performed in the ERACI-III (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Multi-vessel Disease) study, which added 225 DES patients to the 500 patients (225 BMS, 225 CABG) in the ERACI-II study. At 1-year follow-up, freedom from adverse events was significantly greater among patients treated with DES (88.0% vs. 80.5% CABG, p = 0.038), whereas at 3-year follow-up, event rates were equal (77.3%, p = 1.0). This convergence was largely driven by the significantly higher TVR in the PCI cohort at 3 years (5.8% vs. 14.2%, p < 0.002). Of note, mortality was highest in the cohort treated with CABG at both 1-year follow-up (3.1% vs. 7.6%, RR: 0.41, 95% CI: 0.17 to 0.97) and 3-year follow-up (5.7% vs. 9.8%, RR: 0.59, 95% CI: 0.31 to 1.14) (334).
Observation data, again from the New York cardiac registry, of 17,400 patients reported similar rates of unadjusted survival at 18 months between DES and CABG in patients with 3-vessel (93.7% vs. 93.4%, p = not significant) and 2-vessel (95.0% vs. 94.9%, p = not significant) disease. However, after adjustment of variables that are difficult to adjust for, such as the judgment of the treating physician, outcomes in favor of CABG were obtained (94.0% vs. 92.7%, p = 0.03; and 96.0% vs. 94.6%, p = 0.003 for 3- and 2-vessel disease, respectively) (335,336).
The only randomized data comparing DES to CABG in patients with MVD comes from the previously discussed CARDia trial, and the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) study (28,314). The SYNTAX study was a large, prospective, multicenter, "all-comers" trial that assessed outcomes in 1,800 patients with either left main (705 patients: PCI 357, CABG 348) or 3-vessel disease (1,095 patients: PCI 546, CABG 549) randomly allocated to treatment with either PCI (with PES) or CABG (28). The all-comers study design and the use of the SYNTAX score allowed the study to address the important limitations of previously conducted randomized trials comparing PCI and CABG. These limitations included patient selection; for example, in studies comparing BMS to CABG, only 4% of those initially screened were eventually randomized (330), with a common exclusion being patients with impaired left ventricular function (327). Second, all patients with MVD are not the same, and the previous trials did not include any methods of categorizing the extent of MVD or the lesion complexity to allow results to be put into context and stratified according to disease severity.
Among patients with triple-vessel disease, the overall respective rates of death (4.1% vs. 6.5%; p = 0.07), cardiac death (2.3% vs. 4.5%; p = 0.05), stroke (2.3% vs. 1.7%; p = 0.47), MI (2.8% vs. 6.1%; p = 0.009), repeat revascularization (7.5% vs. 17.4%; p < 0.001), and MACCE (14.4% vs. 23.8%; p < 0.001) favored CABG at 2-year follow-up. Moreover, as shown in Figure 15, when outcomes are stratified according to disease complexity using the SYNTAX score, outcomes between PCI and CABG are only comparable among patients in the lowest SYNTAX score tercile (22) (337).
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Figure 15 MACCE Among Patients With Triple-Vessel Disease in the SYNTAX Trial
The rates of major adverse cardiovascular and cerebrovascular events (MACCE [a composite of death, stroke, myocardial infarction, and repeat revascularization]) at 2-year follow-up among patients with triple-vessel disease treated with percutaneous coronary intervention (PCI [blue bars]) or coronary artery bypass graft surgery (CABG [red bars]) in the SYNTAX trial. For patients with a SYNTAX score between 0 and 22, PCI offers a suitable alternative to CABG (339).
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UPLMS Disease.
Using PCI for UPLMS disease was deemed inappropriate according to the 2009 ACC/AHA appropriateness criteria for coronary revascularization, which was in line with guidelines from the U.S. and Europe that both gave PCI for UPLMS a Class III indication for patients suitable for CABG (338,339). However, despite these guidelines, in 2006, approximately one-quarter of UPLMS disease was still treated by PCI (329). More recently, a white paper that includes a comprehensive review of the literature was published in this Journal, and suggests that in specific patients and lesions, PCI may offer a suitable alternative to CABG (340). Following on from this, the 2009 focused update on PCI published by the ACC/AHA has upgraded PCI for UPLMS to a Class IIb indication, and it may be considered for appropriate patients, namely, those with coronary anatomy that is associated with a low risk of procedural complication if treated by PCI and/or clinical conditions that predict an increased risk of adverse surgical outcomes (319). Unfortunately, current studies assessing outcomes in UPLMS stenting are limited by being largely observational with relatively short follow-up.
BMS versus DES
In brief, at present there is only 1 randomized trial comparing outcomes between DES and BMS for PCI of UPLMS (96). Erglis et al. (96) enrolled 103 patients randomly assigned to PCI with either PES or BMS and reported, as expected, that at 6-month follow-up, the use of DES leads to significant reductions in repeat revascularization when compared with BMS without exposing patients to any additional risk of death, MI, or ST. Further comparisons between BMS and DES in UPLMS PCI, from largely nonrandomized, observational studies with follow-up ranging from 6 months to 3 years, report similar findings. These results, however, must be taken in the context of the observational nature of the studies involved and the subsequent limitations that encompasses, such as patient selection and a lack of statistical power to demonstrate differences in events and ST (340).
SES versus PES
Three studies have assessed the outcomes of UPLMS PCI between patients treated with SES and PES (113,341,342). The 607-patient ISAR-LEFT MAIN (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions) study represents the only dedicated randomized study, and at 1 year, there was no significant difference in the primary end point, a composite of death, MI, or TLR, between SES or PES (PES 13.6% vs. SES 15.8%, p = 0.44) (113). In addition, angiographic restenosis at 6- to 9-month follow-up (PES 16.0% vs. SES 19.4%, p = 0.30), mortality (PES 10.7% vs. SES 8.7%, p = 0.64), and UPLMS-specific TLR (PES 9.2% vs. SES 10.7%, p = 0.47) at 2-year follow-up, together with ST were all comparable between SES and PES. Longer follow-up is available from subgroup analyses of the DELFT (Drug-Eluting Stent for Left Main) registry and MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry. At 3-year follow-up, both studies demonstrated similar adjusted rates of death, MI, and TVR, and comparable ST (341,342).
PCI versus CABG
Consistent with the previous discussion on MVD, PCI in patients with UPLMS has shown similar safety outcomes, and consistently higher rates of repeat revascularization compared with CABG. The nonrandomized MAIN-COMPARE registry that enrolled 2,240 patients (1,138 CABG and 1,102 who had PCI: 318 BMS, 784 DES) is the largest single study comparing PCI to CABG to date. At 3-year follow-up, outcomes among a propensity-matched cohort of patients were comparable in terms of death (HR: 1.18 for PCI, 95% CI: 0.77 to 1.80, p = 0.45) and MACCE (HR: 1.10 for PCI, 95% CI: 0.75 to 1.62, p = 0.61), whereas repeat revascularization was significantly higher in the PCI group (HR: 4.76, 95% CI: 2.80 to 8.11, p < 0.001), with DES performing much better than BMS (26). At 5-year follow-up, overall results were unchanged (343). Of note, similar findings have also been reported out to 3-year follow-up in a meta-analysis of 3,773 patients with UPLMS undergoing revascularization by PCI or CABG (344).
The UPLMS subgroup from the SYNTAX trial (357 PCI, 348 CABG) represents the largest cohort of patients randomized to either PCI or CABG. In the overall UPLMS group at 2 years, 22.9% and 19.3% of patients treated with PCI and CABG, respectively, reached the primary end point of MACCE (p = 0.27), a composite of mortality (PCI 5.6% vs. CABG 6.2%, p = 0.77), MI (5.5% vs. 4.1%, p = 0.45), stroke (0.9% vs. 3.7%, p = 0.01), and repeat revascularization (17.3% vs. 10.4%, p = 0.01).
The stratification of outcomes according to the SYNTAX score has demonstrated that for patients with scores between 0 and 32, PCI with PES may be safer and as efficacious as CABG, whereas for patients with scores 33, CABG offers a safer and more efficacious treatment, albeit at a higher risk of stroke (Fig. 16). In the overall SYNTAX study population, 421 of the 1,212 patients with UPLMS disease had a SYNTAX score between 0 and 32, indicating that approximately one-third of patients with UPLMS are suitable for PCI (345).
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Figure 16 MACCE Among Patients With Left Main Disease in the SYNTAX Trial
The rates of safety (death, stroke, and myocardial infarction [MI]) and efficacy (major adverse cardiovascular and cerebrovascular events [MACCE], a composite of death, stroke, MI, and repeat revascularization) among patients with left main disease treated with percutaneous coronary intervention (PCI [blue bars]) or coronary artery bypass graft surgery (CABG [red bars]) in the SYNTAX trial. For SYNTAX scores between 0 and 32, PCI appears to be as safe and efficacious as CABG; for scores of 33 and above, CABG is superior (347).
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The results from the SYNTAX trial have fuelled the debate with respect to the management of UPLMS disease, and prompted the first dedicated UPLMS trial, the EXCEL (Evaluation of Xience Prime Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) study, which will randomize 2,500 patients to revascularization with either the Xience V PRIME EES or CABG. The trial aims to commence enrollment in late 2010 (346).
CTO.
CTOs are encountered in 15% to 30% of patients referred for coronary angiography, and generally regarded as 1 of the few remaining challenges for interventional cardiologists (347). They are associated with lower procedural success rates compared with nonocclusive lesions, with inability to cross the CTO with a wire as the most commonly cited reason for procedural failure (347).
Successful percutaneous recanalization of a CTO, compared with a failed attempt, offers the benefit of a reduction in symptoms, improved left ventricular function, and improved survival (348–351). For example, the 376-patient multicenter TOAST-GISE (Total Occlusion Angioplasty Study–Società Italiana di Cardiologia Invasiva) study reported significant reductions in mortality (1.05% vs. 7.23%, p = 0.005), and a greater rate of angina-free survival (88.7% vs. 75.0%, p = 0.008) among patients with successful CTO-PCI compared with patients who had an unsuccessful CTO-PCI attempt at 12-month follow-up (348). The long-term prognostic benefits of successful versus unsuccessful CTO intervention at both 5- and 10-year follow-up have also been demonstrated by Hoye et al. (351) (93.5 vs. 88.0%, p = 0.02) and Suero et al. (350) (73.5% vs. 65.1%, p = 0.001), respectively. In contrast, however, Prasad et al. (352), who reviewed outcomes over 25 years in a single center, reported that an unsuccessful procedure was not an independent predictor of long-term mortality; whereas de Labriolle et al. (353) also reported that patients with a successful CTO procedure had no survival benefit compared with patients having an unsuccessful procedure.
DES versus BMS
After successful recanalization of a CTO, studies demonstrate consistent improvements in clinical outcomes after implantation of a DES compared with a BMS that have been predominantly driven through reductions in repeat revascularization (66–69,354–360).
Randomized data are limited to the PRISON II (Primary Stenting of Totally Occluded Native Coronary Arteries II) study and the GISSOC II-GISE (Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche II–Società Italiana di Cardiologia Invasiva) study, which both compared outcomes of patients with a CTO treated with BMS or SES. The use of SES compared with BMS led to significant reductions in TLR and TVR, and comparable rates of death, MI, and ST at follow-up ranging from 6 months (PRISON II), to 24 months (GISSOC II-GISE), and out to 5 years (PRISON II) (Table 2) (66–69).
Numerous registries have also reported data from CTO subgroups, and results demonstrate a consistent significant reduction in TLR and MACE after use of DES compared with BMS at short-term follow-up of between 6 and 18 months (357–360). At longer-term follow-up, and consistent with the randomized studies, De Felice et al. (360) reported the maintenance of this advantage with DES out to 3 years among 283 patients treated with SES/PES (n = 124) or BMS (n = 159). Conversely, no significant differences in TLR or MACE were observed among 140 patients (SES 76, BMS 64) in the CTO subgroup of the RESEARCH registry at either 3- or 5-year follow-up (361,362).
A recent meta-analysis of all these studies, which included >4,000 patients with a CTO treated with either a DES (n = 2,390) or BMS (n = 2,004), confirms the superiority of DES in terms of significantly improved efficacy and comparable safety compared with BMS at a mean of 22 months of follow-up (363). It is noteworthy that a strong trend toward a higher rate of ST was observed in the DES-treated cohort (RR: 2.79, 95% CI: 0.98 to 7.97, p = 0.06).
SVG.
SVGs have a limited durability; however, they are still frequently used as conduits in CABG. Their subsequent failure due to atherosclerosis is the most common cause of recurrent ischemia in surgically revascularized patients. Unfortunately, the optimal method of repeat revascularization in these patients is not clearly established. Repeat surgical revascularization exposes patients to an increased risk of morbidity and mortality compared with their primary operation, without evidence of prognostic gain (364,365). Moreover, PCI for SVG is associated with suboptimal results due to high rates of periprocedural MI and high rates of restenosis requiring TLR (366). The high rates of periprocedural MI are thought to relate to the poor development of fibrous caps in the SVG atheroma (367) that increases the likelihood of embolization during stent implantation. The incidence of these periprocedural MIs is reduced after the use of embolic protection devices (368–370); however, despite this, and their class I recommendation for use when technically feasible (174), analysis of the ACC National Cardiovascular Data Registry suggests that they are used in only 22% of SVG PCI (371).
Unlike native vessel lesions, the clear clinical benefits of DES over BMS have been slow to materialize in patients with SVG. Currently there is a paucity of data investigating the benefits of BMS over DES, and what data are available, are largely retrospective (372).
Randomized data
There have been only 2 small dedicated, randomized studies comparing DES to BMS in SVG intervention, which in total have included 155 patients (74,75,373). At short-term follow-up of 6 and 18 months, respectively, both the single-center RRISC (Reduction of Restenosis in Saphenous Vein Grafts With Cypher Sirolimus-Eluting Stent) trial, and the multicenter SOS (Stent or Surgery) study reported, as expected, significant reductions in binary restenosis and TLR after use of DES compared with BMS, together with comparable rates of death and MI (74,373). Long-term data to a median of 32 months are only available in the RRISC trial, and demonstrates catch-up in the repeat revascularization rates in patients treated with DES (75). Moreover, there was a significant increase in late mortality among patients treated with SES as compared with patients treated with BMS (29% vs. 0%, p < 0.001) (75). Because of their small sample sizes, both studies were very underpowered to detect true differences in clinical events.
Registry data
Twenty registries have reported results in patients with SVG PCI, including a total of 5,172 patients (3,091 DES, 2,081 BMS), with outcomes reported between 6 and 34 months of follow-up. Results have been inconsistent, with some reporting advantages for DES over BMS, (131,374–378), and some reporting no difference (379–382). The largest study to date, a subgroup of the large multicenter STENT study, has recently reported 2-year propensity score matched outcomes for 1,000 patients treated with DES or BMS. At 9-month follow-up, the use of DES was associated with significantly reduced rates of MACE (14% vs. 21%, p = 0.001), a lower composite of death or MI (8.7% vs. 14%, p = 0.006), and a lower rate of TVR (HR: 0.36, p < 0.001) and ST (HR: 0.22, p = 0.009). At 2 years, DES-treated patients had significantly better survival, whereas significant reductions in overall MACE and TVR were only noted after adjustment (383).
All trials are summarized in a recently published systematic review (372), which concluded that in comparison to BMS, DES are safe (with the exception of the RRISC trial), and offer consistently reduced late loss and angiographic stenosis. Definitive data are still needed and will be partly obtained from the results of 3 on-going randomized multicenter prospective trials. In the absence of these data, however, for the time being, current results suggest that DES offer an advantage over BMS in terms of reduced restenosis and the need for TLR.
ISR.
The introduction of DES led to a significant reduction in the rates of restenosis; however, they have not been able to eliminate it, resulting in a minority of patients returning with symptoms ranging from the gradual recurrence of angina pectoris to acute presentations with ACS (384,385). Numerous factors have been suggested as the underlying mechanism of this ISR, and these include: 1) biological factors such as resistance to antiproliferative drugs and hypersensitivity reactions; 2) mechanical factors such as stent fractures, polymer peeling, and nonuniform stent strut distribution or drug deposition; and 3) technical factors, including incomplete stent expansion, geographical miss, and barotraumas to unstented segments.
BMS ISR
Historically, numerous therapies have been used in the management of ISR after BMS implantation including POBA, atherectomy, and repeat stenting. Although all these modalities produced satisfactory immediate results, their utilization was hindered by a frequent need for a subsequent repeat revascularization procedure. To address this problem, vascular brachytherapy was introduced as an adjunctive therapy after successful POBA, with subsequent randomized studies confirming that this combination was highly effective at reducing the high rates of repeat TVR after treatment of BMS ISR (386,387). The use of brachytherapy soon fell out of favor, however, not only because of procedural logistics such as the expensive equipment, but also because of results at long-term follow-up, which raised concerns over ST and demonstrated a reduction in efficacy over time with subsequent delayed restenosis and a late TVR catch-up response (388). Perhaps the most important factor, however, in the downfall of brachytherapy was the emergence of DES.
Several studies have compared the performance of DES with brachytherapy in patients with BMS ISR. All studies, ranging from nonrandomized pilot studies to the large randomized SISR (Sirolimus-Eluting Stents Versus Vascular Brachytherapy for In-Stent Restenosis) study and the TAXUS V ISR study (PES vs. brachytherapy), which individually enrolled 400 patients, have shown a consistent benefit with treatment using DES (SES or PES) compared with brachytherapy (389–395). Of note, at long-term follow-up in the TAXUS V ISR study, a greater absolute difference in TLR was seen at 2-year follow-up in favor of PES (9-month  TLR 7.6% vs. 24-month TLR 11.5%), without any compromise on safety (392). Similarly, in the SISR study, the significant reduction in TLR with the use of SES that was observed at 12 months was maintained out to 3-year follow-up (394).
Concurrent with the comparison between DES and brachytherapy, DES have also been compared with POBA in the treatment of ISR after BMS implantation. The first of such studies was the ISAR-DESIRE (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis) study that randomly assigned 300 patients with BMS ISR to treatment with SES, PES, and POBA (116). At 6-month follow-up, treatment with DES had led to significantly lower rates of in-segment angiographic stenosis (POBA 44.6% vs. SES 14.3% vs. PES 21.7%, p < 0.05 for SES and PES vs. POBA), whereas at 12 months, use of DES led to significantly lower rates of TVR (POBA 33% vs. SES 8% vs. PES 19%, p < 0.05 for SES and PES vs. POBA). Overall, rates of mortality and MI were comparable through to 12-month follow-up. A secondary analysis compared outcomes between stents, and demonstrated no significant difference between SES and PES in the rate of angiographic restenosis (p = 0.19), whereas use of SES lead to significantly lower rates of TVR compared with PES (p = 0.02).
This advantage of DES over POBA appears to be preserved long-term, as indicated by the results of the RIBS-II (Restenosis Intra-stent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting) study that randomly allocated 150 patients with BMS ISR to treatment with SES or POBA. At 1-year follow-up (12% vs. 31%, p < 0.005) and 4-year follow-up (24% vs. 35%, p = 0.02), treatment with SES had led to a significantly lower rate of MACE, with comparable rates of death, MI, and ST. Of note, SES implantation was shown to be an independent predictor of event-free survival (396,397).
DES ISR
ISR with DES is likely to become an increasing problem, considering the expanding use of DES in contemporary practice. At present, it is estimated that there are >200,000 cases of DES ISR annually in the U.S. alone (398). Despite this, however, the optimal treatment strategy for this condition remains to be established. The lessons learned from the treatment of BMS ISR suggest that the most appropriate treatment lies with repeat stenting, rather than with brachytherapy and POBA, and this is further supported by the more focal nature of DES ISR, which is a somewhat easier morphological pattern to treat compared with BMS restenosis (399). Other treatment options besides stenting include surgical revascularization for extreme cases and the use of more novel therapies such as drug-eluting balloons, which are discussed in more detail in Part 2 of this supplement.
If stenting is selected, a question that remains under discussion is whether DES ISR should be treated with a DES eluting the same antiproliferative drug or a different class of drug. That has recently been investigated in the ISAR-DESIRE II study, which randomly allocated 450 patients with ISR after SES implantation to treatment with repeat SES implantation or PES (117). At 6-month angiographic follow-up, there were no significant differences in late loss (SES 0.40 mm vs. PES 0.38 mm, p = 0.85) or binary restenosis (19.6% vs. 20.6%, p = 0.69). Similarly, at 12-month clinical follow-up, rates of death, MI, TLR, and ST were also all comparable between treatment strategies. Therefore, patients with SES ISR can be equally effectively treated with repeat SES implantation or PES; however, it is not known whether these results are applicable to ISR occurring after implantation of a second-generation DES. Importantly, the late loss observed after SES implantation was considerably higher than that seen in other studies of SES (Tables 2 and 5), suggesting that patients experiencing SES ISR may be hyporesponsive to the antiproliferative effects of SES. It follows that further investigation is required into the problem of ISR after DES implantation to establish a definitive treatment strategy.
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Conclusions
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Coronary stents are an essential component of contemporary percutaneous revascularization. The introduction of DES led to significant reductions in restenosis, and although their use is associated with an increased risk of late ST, no additional risk of mortality has been demonstrated. The improved outcomes with DES have led to expanding indications for PCI, which is now an accepted treatment for diabetic patients and patients with complex CAD. The persisting concerns over ST have led to improvements in stent design, and although the second-generation DES have demonstrated early improvements in safety, great anticipation remains over the newer stent technology, which is explored in Part 2: Looking Forward.
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Appendix
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For a complete list of all study acronyms and their definitions, please see the online version of this article.
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Footnotes
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Drs. Garg and Serruys report that they have no relationships to disclose.
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References
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1. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction. Description of a new technic and a preliminary report of its application. Circulation 1964;30:654-670.[Abstract/Free Full Text]2. Gruntzig A. Transluminal dilatation of coronary-artery stenosis Lancet 1978;1:263.[CrossRef][Web of Science][Medline] 3. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty N Engl J Med 1987;316:701-706.[Web of Science][Medline] 4. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty N Engl J Med 1979;301:61-68.[Web of Science][Medline] 5. de Feyter PJ, de Jaegere PP, Serruys PW. Incidence, predictors, and management of acute coronary occlusion after coronary angioplasty Am Heart J 1994;127:643-651.[CrossRef][Web of Science][Medline] 6. Sigwart U, Urban P, Golf S, et al. Emergency stenting for acute occlusion after coronary balloon angioplasty Circulation 1988;78:1121-1127.[Abstract/Free Full Text] 7. Carrie D, Elbaz M, Andrieu M, Cantie P, Fourcade J, Puel J. Ten-year clinical and angiographic follow-up of coronary wallstent Am J Cardiol 2000;85:95-98.[CrossRef][Web of Science][Medline] 8. Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stenting for acute and threatened closure complicating percutaneous transluminal coronary angioplasty Circulation 1992;85:916-927.[Abstract/Free Full Text] 9. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a self-expanding coronary-artery stent N Engl J Med 1991;324:13-17.[Web of Science][Medline] 10. van Domburg RT, Foley DP, de Jaegere PP, et al. Long term outcome after coronary stent implantation: a 10 year single centre experience of 1000 patients Heart 1999;82(Suppl 2):II27-II34.[Medline] 11. Serruys PW, de Jaegere P, Kiemeneij F, et al. Benestent Study Group A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease N Engl J Med 1994;331:489-495.[CrossRef][Web of Science][Medline] 12. Fischman DL, Leon MB, Baim DS, et al. Stent Restenosis Study Investigators A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease N Engl J Med 1994;331:496-501.[CrossRef][Web of Science][Medline] 13. Barragan P, Sainsous J, Silvestri M, et al. Ticlopidine and subcutaneous heparin as an alternative regimen following coronary stenting Catheter Cardiovasc Diagn 1994;32:133-138.[Web of Science][Medline] 14. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents N Engl J Med 1996;334:1084-1089.[CrossRef][Web of Science][Medline] 15. Cutlip DE, Leon MB, Ho KK, et al. Acute and nine-month clinical outcomes after "suboptimal" coronary stenting: results from the STent Anti-thrombotic Regimen Study (STARS) registry J Am Coll Cardiol 1999;34:698-706.[Abstract/Free Full Text] 16. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance Circulation 1995;91:1676-1688.[Abstract/Free Full Text] 17. Serruys PW, Kutryk MJ, Ong AT. Coronary-artery stents N Engl J Med 2006;354:483-495.[CrossRef][Web of Science][Medline] 18. Karas SP, Gravanis MB, Santoian EC, Robinson KA, Anderberg KA, King III SB. Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis J Am Coll Cardiol 1992;20:467-474.[Abstract] 19. Gordon PC, Gibson CM, Cohen DJ, Carrozza JP, Kuntz RE, Baim DS. Mechanisms of restenosis and redilation within coronary stents—quantitative angiographic assessment J Am Coll Cardiol 1993;21:1166-1174.[Abstract] 20. Hoffmann R, Mintz GS, Dussaillant GR, et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996;94:1247-1254.[Abstract/Free Full Text] 21. Moliterno DJ. Healing Achilles—sirolimus versus paclitaxel N Engl J Med 2005;353:724-727.[CrossRef][Web of Science][Medline] 22. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis Lancet 2007;370:937-948.[CrossRef][Web of Science][Medline] 23. Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:989-997.[CrossRef][Medline] 24. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents N Engl J Med 2007;356:998-1008.[CrossRef][Medline] 25. Mauri L, Hsieh WH, Massaro JM, Ho KK, D'Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents N Engl J Med 2007;356:1020-1029.[CrossRef][Medline] 26. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:1030-1039.[CrossRef][Medline] 27. Seung KB, Park DW, Kim YH, et al. Stents versus coronary-artery bypass grafting for left main coronary artery disease N Engl J Med 2008;358:1781-1792.[CrossRef][Medline] 28. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease N Engl J Med 2009;360:961-972.[CrossRef][Medline] 29. Serruys PW, Garg S. Percutaneous coronary interventions for all patients with complex coronary artery disease: triple vessel disease or left main coronary artery disease. Yes? No? Don't know? Rev Esp Cardiol 2009;62:719-725.[CrossRef][Web of Science][Medline] 30. Jeremias A, Kirtane A. Balancing efficacy and safety of drug-eluting stents in patients undergoing percutaneous coronary intervention Ann Intern Med 2008;148:234-238.[Abstract/Free Full Text] 31. Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a meta-analysis Eur Heart J 2006;27:2784-2814.[Abstract/Free Full Text] 32. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern Circulation 2007;115:1440-1455discussion 1455.[Free Full Text] 33. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[CrossRef][Medline] 34. Maluenda G, Lemesle G, Waksman R. A critical appraisal of the safety and efficacy of drug-eluting stents Clin Pharmacol Ther 2009;85:474-480.[CrossRef][Web of Science][Medline] 35. Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB, Marks AR. Rapamycin inhibits vascular smooth muscle cell migration J Clin Invest 1996;98:2277-2283.[Web of Science][Medline] 36. Burke SE, Lubbers NL, Chen YW, et al. Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin J Cardiovasc Pharmacol 1999;33:829-835.[CrossRef][Web of Science][Medline] 37. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle Circulation 1999;99:2164-2170.[Abstract/Free Full Text] 38. Marx SO, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis Circulation 2001;104:852-855.[Free Full Text] 39. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study Circulation 2001;103:192-195.[Abstract/Free Full Text] 40. Rensing BJ, Vos J, Smits PC, et al. Coronary restenosis elimination with a sirolimus eluting stent: first European human experience with 6-month angiographic and intravascular ultrasonic follow-up Eur Heart J 2001;22:2125-2130.[Abstract/Free Full Text] 41. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up Circulation 2001;104:2007-2011.[Abstract/Free Full Text] 42. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization N Engl J Med 2002;346:1773-1780.[CrossRef][Web of Science][Medline] 43. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery N Engl J Med 2003;349:1315-1323.[CrossRef][Web of Science][Medline] 44. Weisz G, Leon MB, Holmes Jr. DR, et al. Two-year outcomes after sirolimus-eluting stent implantation: results from the Sirolimus-Eluting Stent in de Novo Native Coronary Lesions (SIRIUS) trial J Am Coll Cardiol 2006;47:1350-1355.[Abstract/Free Full Text] 45. Weisz G, Leon MB, Holmes Jr. DR, et al. Five-year follow-up after sirolimus-eluting stent implantation: results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) trial J Am Coll Cardiol 2009;53:1488-1497.[Abstract/Free Full Text] 46. Morice MC, Serruys PW, Barragan P, et al. Long-term clinical outcomes with sirolimus-eluting coronary stents: five-year results of the RAVEL trial J Am Coll Cardiol 2007;50:1299-1304.[Abstract/Free Full Text] 47. Schampaert E, Cohen EA, Schluter M, et al. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS) J Am Coll Cardiol 2004;43:1110-1115.[Abstract/Free Full Text] 48. Schofer J, Schluter M, Gershlick AH, et al. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS) Lancet 2003;362:1093-1099.[CrossRef][Web of Science][Medline] 49. Sabate M, Jimenez-Quevedo P, Angiolillo DJ, et al. Randomized comparison of sirolimus-eluting stent versus standard stent for percutaneous coronary revascularization in diabetic patients: the Diabetes and Sirolimus-Eluting Stent (DIABETES) trial Circulation 2005;112:2175-2183.[Abstract/Free Full Text] 50. Jimenez-Quevedo P, Sabate M, Angiolillo DJ, et al. Long-term clinical benefit of sirolimus-eluting stent implantation in diabetic patients with de novo coronary stenoses: long-term results of the DIABETES trial Eur Heart J 2007;28:1946-1952.[Abstract/Free Full Text] 51. Pilar Jimenez-Quevedo. Four years follow-up of DIABETES trial. Paper presented at: i2 Summit, American College of Cardiology Scientific Sessions; March 29–31, 2009; Orlando, Florida. 52. Maresta A, Varani E, Balducelli M, et al. Comparison of effectiveness and safety of sirolimus-eluting stents versus bare-metal stents in patients with diabetes mellitus (from the Italian Multicenter Randomized DESSERT Study) Am J Cardiol 2008;101:1560-1566.[CrossRef][Web of Science][Medline] 53. Baumgart D, Klauss V, Baer F, et al. One-year results of the SCORPIUS study: a German multicenter investigation on the effectiveness of sirolimus-eluting stents in diabetic patients J Am Coll Cardiol 2007;50:1627-1634.[Abstract/Free Full Text] 54. Diaz de la Llera LS, Ballesteros S, Nevado J, et al. Sirolimus-eluting stents compared with standard stents in the treatment of patients with primary angioplasty Am Heart J 2007;154:164.e1-164.e6.[CrossRef][Medline] 55. van der Hoeven BL, Liem SS, Jukema JW, et al. Sirolimus-eluting stents versus bare-metal stents in patients with ST-segment elevation myocardial infarction: 9-month angiographic and intravascular ultrasound results and 12-month clinical outcome results from the MISSION! Intervention Study J Am Coll Cardiol 2008;51:618-626.[Abstract/Free Full Text] 56. Atary JZ, van der Hoeven BL, Liem SS, et al. Three-year outcome of sirolimus-eluting versus bare-metal stents for the treatment of ST-segment elevation myocardial infarction (from the MISSION! Intervention Study) Am J Cardiol 2010;106:4-12.[CrossRef][Web of Science][Medline] 57. Di Lorenzo E, De Luca G, Sauro R, et al. The PASEO (PaclitAxel or Sirolimus-Eluting Stent Versus Bare Metal Stent in Primary Angioplasty) randomized trial J Am Coll Cardiol Intv 2009;2:515-523.[Abstract/Free Full Text] 58. Di Lorenzo E, Sauro R, Varricchio A, et al. Benefits of drug-eluting stents as compared with bare metal stent in ST-segment elevation myocardial infarction: 4 year results of the PaclitAxel or Sirolimus-Eluting stent vs bare metal stent in primary angiOplasty (PASEO) randomized trial Am Heart J 2009;158:e43-e50.[CrossRef][Medline] 59. Menichelli M, Parma A, Pucci E, et al. Randomized trial of Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction (SESAMI) J Am Coll Cardiol 2007;49:1924-1930.[Abstract/Free Full Text] 60. Violini R, Musto C, De Felice F, et al. Maintenance of long-term clinical benefit with sirolimus-eluting stents in patients with ST-segment elevation myocardial infarction 3-year results of the SESAMI (Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction) trial J Am Coll Cardiol 2010;55:810-814.[Abstract/Free Full Text] 61. Valgimigli M, Percoco G, Malagutti P, et al. Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a randomized trial JAMA 2005;293:2109-2117.[Abstract/Free Full Text] 62. Tebaldi M, Arcozzi C, Campo G, Percoco G, Ferrari R, Valgimigli M. The 5-year clinical outcomes after a randomized comparison of sirolimus-eluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction J Am Coll Cardiol 2009;54:1900-1901.[Free Full Text] 63. Spaulding C, Henry P, Teiger E, et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction N Engl J Med 2006;355:1093-1104.[CrossRef][Medline] 64. Spaulding C. Four year follow-up of the TYPHOON study, a multicenter, randomised, single-blind trial to assess the use of the Cypher sirolimus eluting stent in acute myocardial infarction patients treated with balloon angioplasty. Paper presented at: EuroPCR; May 19, 2009; Barcelona, Spain http://www.pcronline.com/Lectures/2009/4-year-follow-up-of-the-TYPHOON-study-a-randomised-trial-comparing-the-Sirolimus-eluting-stent-to-bare-metal-stents-during-PCI-for-acute-myocardial-infarction 2006Accessed July 14, 2009. 65. Pache J, Dibra A, Mehilli J, Dirschinger J, Schomig A, Kastrati A. Drug-eluting stents compared with thin-strut bare stents for the reduction of restenosis: a prospective, randomized trial Eur Heart J 2005;26:1262-1268.[Abstract/Free Full Text] 66. Suttorp MJ, Laarman GJ, Rahel BM, et al. Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II): a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions Circulation 2006;114:921-928.[Abstract/Free Full Text] 67. Rahel BM, Laarman GJ, Kelder JC, Ten Berg JM, Suttorp MJ. Three-year clinical outcome after primary stenting of totally occluded native coronary arteries: a randomized comparison of bare-metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions (Primary Stenting of Totally Occluded Native Coronary Arteries [PRISON] II study) Am Heart J 2009;157:149-155.[CrossRef][Web of Science][Medline] 68. van den Branden BJL, Rahel BM, Laarman GJ, Kelder JC, Ten Berg JM, Suttorp MJ. Five-year clinical outcome after primary stenting of totally occluded native coronary arteries: a randomised comparison of bare metal stent implantation with Sirolimus-eluting stent implantation for the treatment of total coronary occlusions (PRISON II study). Paper presented at: EuroPCR; May 2010; Paris, France. 69. Rubartelli P, Petronio AS, Guiducci V, et al. Comparison of sirolimus-eluting and bare metal stent for treatment of patients with total coronary occlusions: results of the GISSOC II-GISE multicentre randomized trial Eur Heart J 2010 June 20[E-pub ahead of print]. 70. Ardissino D, Cavallini C, Bramucci E, et al. Sirolimus-eluting vs uncoated stents for prevention of restenosis in small coronary arteries: a randomized trial JAMA 2004;292:2727-2734.[Abstract/Free Full Text] 71. Menozzi A, Solinas E, Ortolani P, et al. Twenty-four months clinical outcomes of sirolimus-eluting stents for the treatment of small coronary arteries: the long-term SES-SMART clinical study Eur Heart J 2009;30:2095-2101.[Abstract/Free Full Text] 72. Kelbaek H, Thuesen L, Helqvist S, et al. The Stenting Coronary Arteries in Non-Stress/Benestent Disease (SCANDSTENT) trial J Am Coll Cardiol 2006;47:449-455.[Abstract/Free Full Text] 73. Kelbaek H, Klovgaard L, Helqvist S, et al. Long-term outcome in patients treated with sirolimus-eluting stents in complex coronary artery lesions: 3-year results of the SCANDSTENT (Stenting Coronary Arteries in Non-Stress/Benestent Disease) trial J Am Coll Cardiol 2008;51:2011-2016.[Abstract/Free Full Text] 74. Vermeersch P, Agostoni P, Verheye S, et al. Randomized double-blind comparison of sirolimus-eluting stent versus bare-metal stent implantation in diseased saphenous vein grafts: six-month angiographic, intravascular ultrasound, and clinical follow-up of the RRISC trial J Am Coll Cardiol 2006;48:2423-2431.[Abstract/Free Full Text] 75. Vermeersch P, Agostoni P, Verheye S, et al. Increased late mortality after sirolimus-eluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC trial J Am Coll Cardiol 2007;50:261-267.[Abstract/Free Full Text] 76. Kirtane AJ, Gupta A, Iyengar S, et al. Safety and efficacy of drug-eluting and bare metal stents: comprehensive meta-analysis of randomized trials and observational studies Circulation 2009;119:3198-3206.[Abstract/Free Full Text] 77. Serruys PW, Onuma Y, Garg S, et al. 5-Year clinical outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions J Am Coll Cardiol 2010;55:1093-1101.[Abstract/Free Full Text] 78. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the "real world": the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry Circulation 2004;109:190-195.[Abstract/Free Full Text] 79. Daemen J, Kukreja N, van Twisk PH, et al. Four-year clinical follow-up of the rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital registry Am J Cardiol 2008;101:1105-1111.[CrossRef][Web of Science][Medline] 80. Serruys PW, Ong ATL, Morice M-C, et al. Arterial Revascularisation Therapies Study Part II: Sirolimus-eluting stents for the treatment of patients with multivessel de novo coronary artery lesions EuroIntervention 2005;1:147-156.[Medline] 81. Serruys PW, Daemen J, Morice MC, et al. Three-year follow-up of the ARTS-II—sirolimus-eluting stents for the treatment of patients with multivessel coronary artery disease EuroIntervention 2008;3:450-459.[Medline] 82. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions Circulation 2003;107:38-42.[Abstract/Free Full Text] 83. Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions Circulation 2003;108:788-794.[Abstract/Free Full Text] 84. Silber S, Colombo A, Banning AP, et al. Final 5-year results of the TAXUS II trial: a randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for de novo coronary artery lesions Circulation 2009;120:1498-1504.[Abstract/Free Full Text] 85. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease N Engl J Med 2004;350:221-231.[CrossRef][Web of Science][Medline] 86. Ellis SG, Stone GW, Cox DA, et al. Long-term safety and efficacy with paclitaxel-eluting stents: 5-year final results of the TAXUS IV clinical trial (TAXUS IV-SR: Treatment of de novo coronary disease using a single paclitaxel-eluting stent) J Am Coll Cardiol Intv 2009;2:1248-1259.[Abstract/Free Full Text] 87. Stone GW, Ellis SG, Cannon L, et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial JAMA 2005;294:1215-1223.[Abstract/Free Full Text] 88. Ellis SG, Cannon L, Mann T, et al. Final 5-year outcomes from the TAXUS V de novo trial: long-term safety and effectiveness of the paclitaxel-eluting TAXUS stent in complex lesions (abstr) Am J Cardiol 2009;104:135D. 89. Dawkins KD, Grube E, Guagliumi G, et al. Clinical efficacy of polymer-based paclitaxel-eluting stents in the treatment of complex, long coronary artery lesions from a multicenter, randomized trial: support for the use of drug-eluting stents in contemporary clinical practice Circulation 2005;112:3306-3313.[Abstract/Free Full Text] 90. Grube E, Dawkins K, Guagliumi G, et al. TAXUS VI final 5-year results: a multicentre, randomised trial comparing polymer-based moderate-release paclitaxel-eluting stent with a bare metal stent for treatment of long, complex coronary artery lesions EuroIntervention 2009;4:572-577.[Medline] 91. Stone GW, Lansky AJ, Pocock SJ, et al. Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction N Engl J Med 2009;360:1946-1959.[CrossRef][Web of Science][Medline] 92. Stone GW. HORIZONS-AMI. Two-year follow from a prospective randomised trial of heparin plus glycoprotein IIb/IIIa inhibitors vs. bivalirudin and paclitaxel eluting vs. bare metal stents in STEMI. Paper presented at: Transcatheter Cardiovascular Therapeutics; September 23, 2009; San Francisco, CA. 93. Laarman GJ, Suttorp MJ, Dirksen MT, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention N Engl J Med 2006;355:1105-1113.[CrossRef][Medline] 94. Dirksen MT, Vink MA, Suttorp MJ, et al. Two year follow-up after primary PCI with a paclitaxel-eluting stent versus a bare-metal stent for acute ST-elevation myocardial infarction (the PASSION trial): a follow-up study EuroIntervention 2008;4:64-70.[Medline] 95. Vink MA. Five-year clinical follow-up of the PASSION trial: primary PCI with a paclitaxel-eluting stent versus a bare-metal stent in acute ST-elevation myocardial infarction. Paper presented at: Annual Scientific Session/i2 Summit of the American College of Cardiology; March 16, 2010; Atlanta, Georgia. 96. Erglis A, Narbute I, Kumsars I, et al. A randomized comparison of paclitaxel-eluting stents versus bare-metal stents for treatment of unprotected left main coronary artery stenosis J Am Coll Cardiol 2007;50:491-497.[Abstract/Free Full Text] 97. Ong AT, Serruys PW, Aoki J, et al. The unrestricted use of paclitaxel- versus sirolimus-eluting stents for coronary artery disease in an unselected population: one-year results of the Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry J Am Coll Cardiol 2005;45:1135-1141.[Abstract/Free Full Text] 98. Daemen J, Keiichi T, Kristensen SD, et al. Two-year clinical follow-up of the unrestricted use of the paclitaxel-eluting stent compared with the sirolimus-eluting stent as part of the Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry EuroIntervention 2006;2:330-337.[Medline] 99. Turco MA, Ormiston JA, Popma JJ, et al. Polymer-based, paclitaxel-eluting TAXUS Liberte stent in de novo lesions: the pivotal TAXUS ATLAS trial J Am Coll Cardiol 2007;49:1676-1683.[Abstract/Free Full Text] 100. Turco MA, Ormiston JA, Popma JJ, et al. Reduced risk of restenosis in small vessels and reduced risk of myocardial infarction in long lesions with the new thin-strut TAXUS Liberte stent: 1-year results from the TAXUS ATLAS program J Am Coll Cardiol Intv 2008;1:699-709.[Abstract/Free Full Text] 101. Turco MA. TCT-380: TAXUS ATLAS Small Vessel and TAXUS ATLAS Long Lesion trials. Long-term benefit of TAXUS Liberté versus TAXUS Express in small vessels and long lesions. Am J Cardiol 2009;104:141D. 102. Lee SW, Park SW, Kim YH, et al. A randomized comparison of sirolimus- versus paclitaxel-eluting stent implantation in patients with diabetes mellitus J Am Coll Cardiol 2008;52:727-733.[Abstract/Free Full Text] 103. Lee SW, Park SW, Kim YH, et al. A randomized comparison of sirolimus- versus paclitaxel-eluting stent implantation in patients with diabetes mellitus: 2-year clinical outcomes of the DES-DIABETES trial J Am Coll Cardiol 2009;53:812-813.[Free Full Text] 104. Dibra A, Kastrati A, Mehilli J, et al. Paclitaxel-eluting or sirolimus-eluting stents to prevent restenosis in diabetic patients N Engl J Med 2005;353:663-670.[CrossRef][Web of Science][Medline] 105. Morice MC, Colombo A, Meier B, et al. Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions. The REALITY trial: a randomized controlled trial. JAMA 2006;295:895-904.[Abstract/Free Full Text] 106. Windecker S, Remondino A, Eberli FR, et al. Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization N Engl J Med 2005;353:653-662.[CrossRef][Web of Science][Medline] 107. Raber L. SIRTAX-LATE: five-year clinical and angiographic follow-up from a prospective randomized trial of sirolimus-eluting and paclitaxel-eluting stents. Paper presented at: Transcatheter Cardiovascular Therapeutics; September 22, 2009; San Francisco, CA. 108. Galloe AM, Thuesen L, Kelbaek H, et al. Comparison of paclitaxel- and sirolimus-eluting stents in everyday clinical practice: the SORT OUT II randomized trial JAMA 2008;299:409-416.[Abstract/Free Full Text] 109. Goy JJ, Stauffer JC, Siegenthaler M, Benoit A, Seydoux C. A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology: the TAXi trial J Am Coll Cardiol 2005;45:308-311.[Abstract/Free Full Text] 110. Berger A, Stauffer JC, Seydoux C, Siegenthaler M, Benoit A, Goy JJ. Three-year follow-up of the first prospective randomized comparison between paclitaxel and sirolimus stents: the TAXi-LATE trial Catheter Cardiovasc Interv 2007;70:163-166.[Web of Science][Medline] 111. Lee JH, Kim HS, Lee SW, et al. Prospective randomized comparison of sirolimus- versus paclitaxel-eluting stents for the treatment of acute ST-elevation myocardial infarction: pROSIT trial Catheter Cardiovasc Interv 2008;72:25-32.[Web of Science][Medline] 112. Kim HS, Lee JH, Lee SW, et al. Long-term safety and efficacy of sirolimus- vs. paclitaxel-eluting stent implantation for acute ST-elevation myocardial infarction: 3-year follow-up of the PROSIT trial Int J Cardiol 2009 Sept 25[Epub ahead of print]. 113. Mehilli J, Kastrati A, Byrne RA, et al. Paclitaxel- versus sirolimus-eluting stents for unprotected left main coronary artery disease J Am Coll Cardiol 2009;53:1760-1768.[Abstract/Free Full Text] 114. Kim YH, Park SW, Lee SW, et al. Sirolimus-eluting stent versus paclitaxel-eluting stent for patients with long coronary artery disease Circulation 2006;114:2148-2153.[Abstract/Free Full Text] 115. Mehilli J, Dibra A, Kastrati A, Pache J, Dirschinger J, Schomig A. Randomized trial of paclitaxel- and sirolimus-eluting stents in small coronary vessels Eur Heart J 2006;27:260-266.[Abstract/Free Full Text] 116. Kastrati A, Mehilli J, von Beckerath N, et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial JAMA 2005;293:165-171.[Abstract/Free Full Text] 117. Mehilli J, Byrne RA, Tiroch K, et al. Randomized trial of paclitaxel- versus sirolimus-eluting stents for treatment of coronary restenosis in sirolimus-eluting stents: The ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study J Am Coll Cardiol 2010;55:2710-2716.[Abstract/Free Full Text] 118. Schomig A, Dibra A, Windecker S, et al. A meta-analysis of 16 randomized trials of sirolimus-eluting stents versus paclitaxel-eluting stents in patients with coronary artery disease J Am Coll Cardiol 2007;50:1373-1380.[Abstract/Free Full Text] 119. Popma J, Almonacid A. Angiographic markers of restenosis after drug-eluting stent implantation: surrogates for late clinical outcomes? J Interv Cardiol 2009;22(Suppl):64-71.[CrossRef] 120. Pocock SJ, Lansky AJ, Mehran R, et al. Angiographic surrogate end points in drug-eluting stent trials: a systematic evaluation based on individual patient data from 11 randomized, controlled trials J Am Coll Cardiol 2008;51:23-32.[Abstract/Free Full Text] 121. Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary restenosis for drug-eluting stent comparison Circulation 2005;111:3435-3442.[Abstract/Free Full Text] 122. Ellis SG, Popma JJ, Lasala JM, et al. Relationship between angiographic late loss and target lesion revascularization after coronary stent implantation: analysis from the TAXUS-IV trial J Am Coll Cardiol 2005;45:1193-1200.[Abstract/Free Full Text] 123. Douglas PS, Brennan JM, Anstrom KJ, et al. Clinical effectiveness of coronary stents in elderly persons: results from 262,700 Medicare patients in the American College of Cardiology-National Cardiovascular Data Registry J Am Coll Cardiol 2009;53:1629-1641.[Abstract/Free Full Text] 124. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents J Am Coll Cardiol 2006;48:2584-2591.[Abstract/Free Full Text] 125. Serruys PW, Daemen J. The SCAAR registry or the Swedish yo-yo EuroIntervention 2007;3:297-300.[Medline] 126. James SK, Stenestrand U, Lindback J, et al. Long-term safety and efficacy of drug-eluting versus bare-metal stents in Sweden N Engl J Med 2009;360:1933-1945.[CrossRef][Medline] 127. Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents JAMA 2007;297:2001-2009.[Abstract/Free Full Text] 128. Farb A, Boam AB. Stent thrombosis redux—the FDA perspective N Engl J Med 2007;356:984-987.[CrossRef][Medline] 129. Shuchman M. Debating the risks of drug-eluting stents N Engl J Med 2007;356:325-328.[CrossRef][Web of Science][Medline] 130. Lasala JM, Cox DA, Lewis SJ, et al. Expanded use of the TAXUS Express Stent: two-year safety insights from the 7,500 patient ARRIVE registry programme EuroIntervention 2009;5:67-77.[Medline] 131. Brodie BR, Stuckey T, Downey W, et al. Outcomes and complications with off-label use of drug-eluting stents: results from the STENT (Strategic Transcatheter Evaluation of New Therapies) group J Am Coll Cardiol Intv 2008;1:405-414.[Abstract/Free Full Text] 132. Beohar N, Davidson CJ, Kip KE, et al. Outcomes and complications associated with off-label and untested use of drug-eluting stents JAMA 2007;297:1992-2000.[Abstract/Free Full Text] 133. Applegate RJ, Sacrinty MT, Kutcher MA, et al. "Off-label" stent therapy 2-year comparison of drug-eluting versus bare-metal stents J Am Coll Cardiol 2008;51:607-614.[Abstract/Free Full Text] 134. Ko DT, Chiu M, Guo H, et al. Safety and effectiveness of drug-eluting and bare-metal stents for patients with off- and on-label indications J Am Coll Cardiol 2009;53:1773-1782.[Abstract/Free Full Text] 135. Marroquin OC, Selzer F, Mulukutla SR, et al. A comparison of bare-metal and drug-eluting stents for off-label indications N Engl J Med 2008;358:342-352.[CrossRef][Medline] 136. Roy P, Buch AN, Javaid A, et al. Impact of "off-label" utilization of drug-eluting stents on clinical outcomes in patients undergoing percutaneous coronary intervention Am J Cardiol 2008;101:293-299.[CrossRef][Web of Science][Medline] 137. Serruys PW, Daemen J. Are drug-eluting stents associated with a higher rate of late thrombosis than bare metal stents?. Late stent thrombosis: a nuisance in both bare metal and drug-eluting stents. Circulation 2007;115:1433-1439discussion 1439.[Free Full Text] 138. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy Lancet 2004;364:1519-1521.[CrossRef][Web of Science][Medline] 139. Liistro F, Colombo A. Late acute thrombosis after paclitaxel eluting stent implantation Heart 2001;86:262-264.[Abstract/Free Full Text] 140. Kerner A, Gruberg L, Kapeliovich M, Grenadier E. Late stent thrombosis after implantation of a sirolimus-eluting stent Catheter Cardiovasc Interv 2003;60:505-508.[CrossRef][Web of Science][Medline] 141. Urban P, Gershlick AH, Guagliumi G, et al. Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry Circulation 2006;113:1434-1441.[Abstract/Free Full Text] 142. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents JAMA 2005;293:2126-2130.[Abstract/Free Full Text] 143. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up Am J Cardiol 2006;98:352-356.[CrossRef][Web of Science][Medline] 144. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents Circulation 2006;113:1108-1113.[Abstract/Free Full Text] 145. Roukoz H, Bavry AA, Sarkees ML, et al. Comprehensive meta-analysis on drug-eluting stents versus bare-metal stents during extended follow-up Am J Med 2009;122:581.e1-581.e10.[CrossRef][Medline] 146. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study Lancet 2007;369:667-678.[CrossRef][Medline] 147. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008;52:1134-1140.[Abstract/Free Full Text] 148. Onuma Y. Incidence of late stent thrombosis up to 5 years after implantation of drug eluting stents in clinical practice. Paper presented at: Meeting of the European Society of Cardiology; August 31, 2009; Barcelona, Spain. 149. Pinto Slottow TL, Steinberg DH, Roy PK, et al. Observations and outcomes of definite and probable drug-eluting stent thrombosis seen at a single hospital in a four-year period Am J Cardiol 2008;102:298-303.[CrossRef][Web of Science][Medline] 150. James SK, Wallentin L, Lagerqvist B. The SCAAR-scare in perspective EuroIntervention 2009;5:501-504.[Medline] 151. van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry J Am Coll Cardiol 2009;53:1399-1409.[Abstract/Free Full Text] 152. Lasala JM, Cox DA, Dobies D, et al. Drug-eluting stent thrombosis in routine clinical practice: two-year outcomes and predictors from the TAXUS ARRIVE registries Circ Cardiovasc Interv 2009;2:285-293.[Abstract/Free Full Text] 153. 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;48:193-202.[Abstract/Free Full Text] 154. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans Circulation 2003;108:1701-1706.[Abstract/Free Full Text] 155. 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;115:2435-2441.[Abstract/Free Full Text] 156. Ong AT, McFadden EP, Regar E, de Jaegere PP, van Domburg RT, Serruys PW. Late angiographic stent thrombosis (LAST) events with drug-eluting stents J Am Coll Cardiol 2005;45:2088-2092.[Abstract/Free Full Text] 157. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents J Am Coll Cardiol 2008;52:333-342.[Abstract/Free Full Text] 158. Guagliumi G, Musumeci G, Sirbu V, et al. Optical coherence tomography assessment of in vivo vascular response after implantation of overlapping bare-metal and drug-eluting stents J Am Coll Cardiol Intv 2010;3:531-539.[Abstract/Free Full Text] 159. Kim J-S, Jang I-K, Kim J-S, et al. Optical coherence tomography evaluation of zotarolimus-eluting stents at 9 month follow up: comparison with sirolimus-eluting stents Heart 2009;95:1907-1912.[Abstract/Free Full Text] 160. Barlis P, Regar E, Serruys PW, et al. An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: a LEADERS trial sub-study Eur Heart J 2010;31:165-176.[Abstract/Free Full Text] 161. Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings J Am Coll Cardiol 2006;47:2108-2111.[Abstract/Free Full Text] 162. Awata M, Kotani J, Uematsu M, et al. Serial angioscopic evidence of incomplete neointimal coverage after sirolimus-eluting stent implantation: comparison with bare-metal stents Circulation 2007;116:910-916.[Abstract/Free Full Text] 163. van der Giessen WJ, Lincoff AM, Schwartz RS, et al. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries Circulation 1996;94:1690-1697.[Abstract/Free Full Text] 164. Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004;109:701-705.[Abstract/Free Full Text] 165. Nebeker JR, Virmani R, Bennett CL, et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project J Am Coll Cardiol 2006;47:175-181.[Abstract/Free Full Text] 166. Virmani R, Liistro F, Stankovic G, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans Circulation 2002;106:2649-2651.[Abstract/Free Full Text] 167. Cook S, Ladich E, Nakazawa G, et al. Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis Circulation 2009;120:391-399.[Abstract/Free Full Text] 168. Nakazawa G, Ladich E, Finn AV, Virmani R. Pathophysiology of vascular healing and stent mediated arterial injury EuroIntervention 2008;4(Suppl C):7-10. 169. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Lancet 2001;358:527-533.[CrossRef][Web of Science][Medline] 170. Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial JAMA 2002;288:2411-2420.[Abstract/Free Full Text] 171. Weintraub WS, Mahoney EM, Lamy A, et al. Long-term cost-effectiveness of clopidogrel given for up to one year in patients with acute coronary syndromes without ST-segment elevation J Am Coll Cardiol 2005;45:838-845.[Abstract/Free Full Text] 172. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry Circulation 2006;113:2803-2809.[Abstract/Free Full Text] 173. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment Circulation 2007;116:745-754.[Abstract/Free Full Text] 174. Smith Jr. SC, Feldman TE, Hirshfeld Jr. JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention) J Am Coll Cardiol 2006;47:e1-e121.[Free Full Text] 175. Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4 year period Eur Heart J 2009;30:2714-2721.[Abstract/Free Full Text] 176. Kimura T, Morimoto T, Nakagawa Y, et al. Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation Circulation 2009;119:987-995.[Abstract/Free Full Text] 177. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation JAMA 2007;297:159-168.[Abstract/Free Full Text] 178. Brar SS, Kim J, Brar SK, et al. Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions J Am Coll Cardiol 2008;51:2220-2227.[Abstract/Free Full Text] 179. Serruys PW, Daemen J. Late stent thrombosis: a nuisance in both bare metal and drug-eluting stents Circulation 2007;115:1433-1439.[Free Full Text] 180. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome JAMA 2008;299:532-539.[Abstract/Free Full Text] 181. Park D-W, Yun S-C, Lee S-W, et al. Stent thrombosis, clinical events, and influence of prolonged clopidogrel use after placement of drug-eluting stent: data from an observational cohort study of drug-eluting versus bare-metal stents J Am Coll Cardiol Intv 2008;1:494-503.[Abstract/Free Full Text] 182. Tanzilli G, Greco C, Pelliccia F, et al. Effectiveness of two-year clopidogrel + aspirin in abolishing the risk of very late thrombosis after drug-eluting stent implantation (from the TYCOON [two-year ClOpidOgrel need] study) Am J Cardiol 2009;104:1357-1361.[CrossRef][Web of Science][Medline] 183. Feres F. Update from ongoing DAPT studies: Brazil OPTIMIZE randomised trial. Paper presented at: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA. 184. Byrne RA, Schulz S, Mehilli J, et al. Rationale and design of a randomized, double-blind, placebo-controlled trial of 6 versus 12 months clopidogrel therapy after implantation of a drug-eluting stent: the Intracoronary Stenting and Antithrombotic Regimen: Safety And EFficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) study Am Heart J 2009;157:620-624.e2.[CrossRef][Web of Science][Medline] 185. Mauri L. Updates from ongoing DAPT studies: United States: DAPT randomized trialPaper presented at: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA http://www.tctmd.com/txshow.aspx?tid=939078&id=83980&trid=938634 2009Accessed October 27, 2009. 186. Van de Werf F. New antithrombotic agents: are they needed and what can they offer to patients with a non-ST-elevation acute coronary syndrome? Eur Heart J 2009;30:1695-1702.[Abstract/Free Full Text] 187. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2007;357:2001-2015.[CrossRef][Medline] 188. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial Lancet 2008;371:1353-1363.[CrossRef][Web of Science][Medline] 189. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2009;361:1045-1057.[CrossRef][Medline] 190. Schomig A. Ticagrelor—is there need for a new player in the antiplatelet-therapy field? N Engl J Med 2009;361:1108-1111.[CrossRef][Web of Science][Medline] 191. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting Thromb Res 2005;115:101-108.[CrossRef][Web of Science][Medline] 192. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement Thromb Haemost 2003;89:783-787.[Web of Science][Medline] 193. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Jukema JW, Huisman MV. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis Am Heart J 2007;154:221-231.[CrossRef][Web of Science][Medline] 194. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study J Am Coll Cardiol 2005;46:1827-1832.[Abstract/Free Full Text] 195. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation Catheter Cardiovasc Interv 2003;59:295-302.[CrossRef][Web of Science][Medline] 196. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives J Am Coll Cardiol 2007;49:1505-1516.[Abstract/Free Full Text] 197. Patti G, Nusca A, Mangiacapra F, Gatto L, D'Ambrosio A, Di Sciascio G. Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Platelet Reactivity Predicts Outcome) study J Am Coll Cardiol 2008;52:1128-1133.[Abstract/Free Full Text] 198. Marcucci R, Gori AM, Paniccia R, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up Circulation 2009;119:237-242.[Abstract/Free Full Text] 199. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation Eur Heart J 2008;29:992-1000.[Abstract/Free Full Text] 200. Cuisset T, Hamilos M, Sarma J, et al. Relation of low response to clopidogrel assessed with point-of-care assay to periprocedural myonecrosis in patients undergoing elective coronary stenting for stable angina pectoris Am J Cardiol 2008;101:1700-1703.[CrossRef][Web of Science][Medline] 201. de Miguel Castro A, Cuellas Ramon C, Diego Nieto A, et al. Post-treatment platelet reactivity predicts long-term adverse events better than the response to clopidogrel in patients with non-ST-segment elevation acute coronary syndrome Rev Esp Cardiol 2009;62:126-135.[CrossRef][Web of Science][Medline] 202. Lemesle G, Delhaye C, Sudre A, et al. Impact of high loading and maintenance dose of clopidogrel within the first 15 days after percutaneous coronary intervention on patient outcome Am Heart J 2009;157:375-382.[CrossRef][Web of Science][Medline] 203. Angiolillo DJ, Bernardo E, Palazuelos J, et al. Functional impact of high clopidogrel maintenance dosing in patients undergoing elective percutaneous coronary interventions. Results of a randomized study. Thromb Haemost 2008;99:161-168.[Web of Science][Medline] 204. Teirstein P. Updates from ongoing DAPT studies: United States: GRAVITAS randomized trialPaper presented a: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA http://www.tctmd.com/txshow.aspx?tid=939078&id=83972&trid=938634 2008Accessed October 27, 2009. 205. Mehta SR. A randomized comparison of a clopidogrel high loading and maintenance dose regimen versus standard dose and high versus low dose aspirin in 25,000 patients with acute coronary syndromes: results of the CURRENT OASIS 7 trial. Paper presented at: European Society of Cardiology; August 30, 2009; Barcelona, Spain. 206. Mehta SR. CURRENT-STEMI PCI: double-dose vs. standard-dose clopidogrel in ACS patients undergoing PCI for STEMIPaper presented at: Transcatheter Cardiovascular Therapeutics; September 24, 2009; San Francisco, CA http://www.tctmd.com/txshow.aspx?tid=938642&id=81330&trid=938634 2008Accessed October 27, 2009. 207. Cuisset T, Frere C, Quilici J, et al. Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study J Am Coll Cardiol Intv 2008;1:649-653.[Abstract/Free Full Text] 208. Valgimigli M, Campo G, de Cesare N, et al. Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel study Circulation 2009;119:3215-3222.[Abstract/Free Full Text] 209. Angiolillo DJ, Capranzano P, Goto S, et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study Eur Heart J 2008;29:2202-2211.[Abstract/Free Full Text] 210. de Jaegere P, Mudra H, Figulla H, et al. Intravascular ultrasound-guided optimized stent deployment. Immediate and 6 months clinical and angiographic results from the Multicenter Ultrasound Stenting in Coronaries Study (MUSIC Study). Eur Heart J 1998;19:1214-1223.[Abstract/Free Full Text] 211. Fujii K, Carlier SG, Mintz GS, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study J Am Coll Cardiol 2005;45:995-998.[Abstract/Free Full Text] 212. Alfonso F, Suarez A, Perez-Vizcayno MJ, et al. Intravascular ultrasound findings during episodes of drug-eluting stent thrombosis J Am Coll Cardiol 2007;50:2095-2097.[Free Full Text] 213. Briguori C, Tobis J, Nishida T, et al. Discrepancy between angiography and intravascular ultrasound when analysing small coronary arteries Eur Heart J 2002;23:247-254.[Abstract/Free Full Text] 214. de Feyter PJ, Kay P, Disco C, Serruys PW. Reference chart derived from post-stent-implantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography Circulation 1999;100:1777-1783.[Abstract/Free Full Text] 215. Hoffmann R, Mintz GS, Mehran R, et al. Intravascular ultrasound predictors of angiographic restenosis in lesions treated with Palmaz-Schatz stents J Am Coll Cardiol 1998;31:43-49.[Abstract/Free Full Text] 216. Hong MK, Mintz GS, Lee CW, et al. Intravascular ultrasound predictors of angiographic restenosis after sirolimus-eluting stent implantation Eur Heart J 2006;27:1305-1310.[Abstract/Free Full Text] 217. Takebayashi H, Kobayashi Y, Mintz GS, et al. Intravascular ultrasound assessment of lesions with target vessel failure after sirolimus-eluting stent implantation Am J Cardiol 2005;95:498-502.[CrossRef][Web of Science][Medline] 218. de Ribamar Costa Jr. J, Mintz GS, Carlier SG, et al. Intravascular ultrasound assessment of drug-eluting stent expansion Am Heart J 2007;153:297-303.[CrossRef][Web of Science][Medline] 219. Cook S, Wenaweser P, Togni M, et al. Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation Circulation 2007;115:2426-2434.[Abstract/Free Full Text] 220. Uren NG, Schwarzacher SP, Metz JA, et al. Predictors and outcomes of stent thrombosis: an intravascular ultrasound registry Eur Heart J 2002;23:124-132.[Abstract/Free Full Text] 221. Cheneau E, Leborgne L, Mintz GS, et al. Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study Circulation 2003;108:43-47.[Abstract/Free Full Text] 222. Okamura T, Serruys PW, Regar E. Three-dimensional visualization of intracoronary thrombus during stent implantation using the second generation, Fourier domain optical coherence tomography Eur Heart J 2010;31:625.[Free Full Text] 223. Mintz GS. What to do about late incomplete stent apposition? Circulation 2007;115:2379-2381.[Free Full Text] 224. Hoffmann R, Morice MC, Moses JW, et al. Impact of late incomplete stent apposition after sirolimus-eluting stent implantation on 4-year clinical events: intravascular ultrasound analysis from the multicentre, randomised, RAVEL, E-SIRIUS and SIRIUS trials Heart 2008;94:322-328.[Abstract/Free Full Text] 225. Hong MK, Mintz GS, Lee CW, et al. Late stent malapposition after drug-eluting stent implantation: an intravascular ultrasound analysis with long-term follow-up Circulation 2006;113:414-419.[Abstract/Free Full Text] 226. Hassan AK, Bergheanu SC, Stijnen T, et al. Late stent malapposition risk is higher after drug-eluting stent compared with bare-metal stent implantation and associates with late stent thrombosis Eur Heart J 2009;31:1172-1180.[CrossRef][Web of Science][Medline] 227. van der Hoeven BL, Liem SS, Dijkstra J, et al. Stent malapposition after sirolimus-eluting and bare-metal stent implantation in patients with ST-segment elevation myocardial infarction: acute and 9-month intravascular ultrasound results of the MISSION! intervention study J Am Coll Cardiol Intv 2008;1:192-201.[Abstract/Free Full Text] 228. Kubo T, Imanishi T, Kitabata H, et al. Comparison of vascular response after sirolimus-eluting stent implantation between patients with unstable and stable angina pectoris: a serial optical coherence tomography study J Am Coll Cardiol Img 2008;1:475-484.[Abstract/Free Full Text] 229. Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780-782.[Free Full Text] 230. Sianos G, Hofma S, Ligthart JM, et al. Stent fracture and restenosis in the drug-eluting stent era Catheter Cardiovasc Interv 2004;61:111-116.[CrossRef][Web of Science][Medline] 231. Surmely JF, Kinoshita Y, Dash D, et al. Stent strut fracture-induced restenosis in a bifurcation lesion treated with the crush stenting technique Circ J 2006;70:936-938.[CrossRef][Web of Science][Medline] 232. Lee MS, Jurewitz D, Aragon J, Forrester J, Makkar RR, Kar S. Stent fracture associated with drug-eluting stents: clinical characteristics and implications Catheter Cardiovasc Interv 2007;69:387-394.[CrossRef][Web of Science][Medline] 233. Aoki J, Nakazawa G, Tanabe K, et al. Incidence and clinical impact of coronary stent fracture after sirolimus-eluting stent implantation Catheter Cardiovasc Interv 2007;69:380-386.[CrossRef][Web of Science][Medline] 234. Lee SH, Park JS, Shin DG, et al. Frequency of stent fracture as a cause of coronary restenosis after sirolimus-eluting stent implantation Am J Cardiol 2007;100:627-630.[CrossRef][Web of Science][Medline] 235. Nakazawa G, Finn AV, Vorpahl M, et al. Incidence and predictors of drug-eluting stent fracture in human coronary artery a pathologic analysis J Am Coll Cardiol 2009;54:1924-1931.[Abstract/Free Full Text] 236. Popma JJ, Tiroch K, Almonacid A, Cohen S, Kandzari DE, Leon MB. A qualitative and quantitative angiographic analysis of stent fracture late following sirolimus-eluting stent implantation Am J Cardiol 2009;103:923-929.[CrossRef][Web of Science][Medline] 237. Doi H, Maehara A, Mintz GS, et al. Classification and potential mechanisms of intravascular ultrasound patterns of stent fracture Am J Cardiol 2009;103:818-823.[CrossRef][Web of Science][Medline] 238. Brilakis ES, Maniu C, Wahl M, Barsness G. Unstable angina due to stent fracture J Invasive Cardiol 2004;16:545.[Medline] 239. Carter AJ. Drug-eluting stent fracture promise and performance J Am Coll Cardiol 2009;54:1932-1934.[Free Full Text] 240. Aoki J, Kirtane A, Leon MB, Dangas G. Coronary artery aneurysms after drug-eluting stent implantation J Am Coll Cardiol Intv 2008;1:14-21.[Abstract/Free Full Text] 241. Slota PA, Fischman DL, Savage MP, Rake R, Goldberg S. Frequency and outcome of development of coronary artery aneurysm after intracoronary stent placement and angioplasty. STRESS Trial Investigators. Am J Cardiol 1997;79:1104-1106.[CrossRef][Web of Science][Medline] 242. Baumbach A, Bittl JA, Fleck E, et al. Acute complications of excimer laser coronary angioplasty: a detailed analysis of multicenter results. Coinvestigators of the U.S. and European Percutaneous Excimer Laser Coronary Angioplasty (PELCA) Registries. J Am Coll Cardiol 1994;23:1305-1313.[Abstract] 243. Bell MR, Garratt KN, Bresnahan JF, Edwards WD, Holmes Jr DR. Relation of deep arterial resection and coronary artery aneurysms after directional coronary atherectomy J Am Coll Cardiol 1992;20:1474-1481.[Abstract] 244. Gupta RK, Sapra R, Kaul U. Early aneurysm formation after drug-eluting stent implantation: an unusual life-threatening complication J Invasive Cardiol 2006;18:E140-E142.[Medline] 245. Porto I, MacDonald S, Banning AP. Intravascular ultrasound as a significant tool for diagnosis and management of coronary aneurysms Cardiovasc Intervent Radiol 2004;27:666-668.[CrossRef][Web of Science][Medline] 246. Alfonso F, Perez-Vizcayno MJ, Ruiz M, et al. Coronary aneurysms after drug-eluting stent implantation: clinical, angiographic, and intravascular ultrasound findings J Am Coll Cardiol 2009;53:2053-2060.[Abstract/Free Full Text] 247. Feres F, Costa Jr. JR, Abizaid A. Very late thrombosis after drug-eluting stents Catheter Cardiovasc Interv 2006;68:83-88.[CrossRef][Web of Science][Medline] 248. Aziz S, Morris JL, Perry RA. Late stent thrombosis associated with coronary aneurysm formation after sirolimus-eluting stent implantation J Invasive Cardiol 2007;19:E96-E98.[Medline] 249. Sano K, Mintz GS, Carlier SG, et al. Volumetric intravascular ultrasound assessment of neointimal hyperplasia and nonuniform stent strut distribution in sirolimus-eluting stent restenosis Am J Cardiol 2006;98:1559-1562.[CrossRef][Web of Science][Medline] 250. Kastrati A, Mehilli J, Dirschinger J, et al. Intracoronary Stenting and Angiographic Results: Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO) trial Circulation 2001;103:2816-2821.[Abstract/Free Full Text] 251. Pache J, Kastrati A, Mehilli J, et al. Intracoronary Stenting and Angiographic Results: Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO-2) trial J Am Coll Cardiol 2003;41:1283-1288.[Abstract/Free Full Text] 252. Kereiakes DJ, Cox DA, Hermiller JB, et al. Usefulness of a cobalt chromium coronary stent alloy Am J Cardiol 2003;92:463-466.[CrossRef][Web of Science][Medline] 253. Awata M, Nanto S, Uematsu M, et al. Angioscopic comparison of neointimal coverage between zotarolimus- and sirolimus-eluting stents J Am Coll Cardiol 2008;52:789-790.[Free Full Text] 254. Kim J-S, Jang I-K, Fan C, et al. Evaluation in 3 months duration of neointimal coverage after zotarolimus-eluting stent implantation by optical coherence tomography: the ENDEAVOR OCT trial J Am Coll Cardiol Intv 2009;2:1240-1247.[Abstract/Free Full Text] 255. Kim JW, Seo HS, Park JH, et al. A prospective, randomized, 6-month comparison of the coronary vasomotor response associated with a zotarolimus- versus a sirolimus-eluting stent: differential recovery of coronary endothelial dysfunction J Am Coll Cardiol 2009;53:1653-1659.[Abstract/Free Full Text] 256. Meredith IT, Ormiston J, Whitbourn R, et al. First-in-human study of the Endeavor ABT-578-eluting phosphorylcholine-encapsulated stent system in de novo native coronary artery lesions: Endeavor I trial EuroIntervention 2005;1:157-164.[Medline] 257. Meredith IT, Ormiston J, Whitbourn R, Kay IP, Muller D, Cutlip DE. Five-year clinical follow-up after implantation of the endeavor zotarolimus-eluting stent: ENDEAVOR I, first-in-human study Catheter Cardiovasc Interv 2009;74:989-995.[CrossRef][Web of Science][Medline] 258. Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholine-encapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial Circulation 2006;114:798-806.[Abstract/Free Full Text] 259. van Leeuwen F. Randomised trial comparing the ENDEAVOR zotarolimus-eluting stent and the Driver bare metal stent in single de novo native coronary artery lesions: five-year clinical follow-up of ENDEAVOR II. Paper presented at: EuroPCR; May 19–22, 2009; Barcelona, Spain. 260. Kandzari DE, Leon MB, Popma JJ, et al. Comparison of zotarolimus-eluting and sirolimus-eluting stents in patients with native coronary artery disease: a randomized controlled trial J Am Coll Cardiol 2006;48:2440-2447.[Abstract/Free Full Text] 261. Eisenstein EL, Leon MB, Kandzari DE, et al. Long-term clinical and economic analysis of the Endeavor zotarolimus-eluting stent versus the Cypher sirolimus-eluting stent: 3-year results from the ENDEAVOR III trial (randomized controlled trial of the Medtronic Endeavor drug [ABT-578] eluting coronary stent system versus the Cypher sirolimus-eluting coronary stent system in de novo native coronary artery lesions) J Am Coll Cardiol Intv 2009;2:1199-1207.[Abstract/Free Full Text] 262. Kandzari D, Mauri L, Popma J, et al. ENDEAVOR III: 5 year final outcomes. Paper presented at: The American College of Cardiology Scientific Sessions; March 14–16, 2010; Atlanta, GA. 263. Hamm C. 5 Years later and more than 20,000 patients studied: the ENDEAVOR clinical programPaper presented at: EuroPCR; May 19–22, 2009; Barcelona, Spain http://www.pcronline.com/Lectures/2009/5-years-later-and-more-than-20-000-patients-studied-the-ENDEAVOR-clinical-programme 2009Accessed June 20, 2009. 264. Leon MB, Mauri L, Popma JJ, et al. A randomised comparison of the Endeavor zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de novo native coronary lesions: 12-month outcomes from the ENDEAVOR IV trial J Am Coll Cardiol 2010;55:543-554.[Abstract/Free Full Text] 265. Leon M. The ENDEAVOR and ENDEAVOR Resolute zotarolimus-eluting stent: comprehensive update of the clinical trial program (featuring the first presentation of the ENDEAVOR IV 3-year results)Paper presented at: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA http://www.tctmd.com/txshow.aspx?tid=939082&id=84004&trid=938634 2010Accessed October 28, 2009. 266. Park SJ. Comparison of sirolimus- and paclitaxel-eluting stents vs zotarolimus-eluting stents in real world practice: the ZEST randomized controlled trial. Paper presented at: i2 Summit at the American College of Cardiology Scientific Sessions; March 29–31, 2009; Orlando, FL. 267. Rasmussen K, Maeng M, Kaltoft A, et al. Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial Lancet 2010;375:1090-1099.[CrossRef][Web of Science][Medline] 268. Lotan C, Meredith IT, Mauri L, Liu M, Rothman MT, EFI Safety and effectiveness of the Endeavor zotarolimus-eluting stent in real-world clinical practice: 12-month data from the E-Five Registry J Am Coll Cardiol Intv 2009;2:1227-1235.[Abstract/Free Full Text] 269. Meredith I. Real world outcomes in patients with coronary artery disease treated with the endeavor ZES: 2-year results from the E-Five Registry. Paper presented at: EuroPCR; May 2009; Barcelona, Spain. 270. Rivero F, Moreno R, Barreales L, et al. Lower levels of in-stent late loss are not associated with the risk of stent thrombosis in patients receiving drug-eluting stents EuroIntervention 2008;4:124-132.[Medline] 271. Camenzind E, Wijns W, Mauri L, et al. Rationale and design of the Patient Related OuTcomes with Endeavor versus Cypher stenting Trial (PROTECT): randomized controlled trial comparing the incidence of stent thrombosis and clinical events after sirolimus or zotarolimus drug-eluting stent implantation Am Heart J 2009;158:902-909.e5.[CrossRef][Web of Science][Medline] 272. Serruys PW, Ong ATL, Piek JJ, et al. A randomised comparison of a durable polymer everolimus-eluting stent with a bare metal coronary stent: the SPIRIT FIRST trial EuroIntervention 2005;1:58-65.[Medline] 273. Wiemer M, Serruys PW, Miquel-Hebert K, et al. Five-year long-term clinical follow-up of the XIENCE V everolimus eluting coronary stent system in the treatment of patients with de novo coronary artery lesions: the SPIRIT FIRST trial Catheter Cardiovasc Interv 2010;75:997-1003.[Web of Science][Medline] 274. Serruys PW, Ruygrok P, Neuzner J, et al. A randomised comparison of an everolimus-eluting coronary stent with a paclitaxel-eluting coronary stent: the SPIRIT II trial EuroIntervention 2006;2:286-294.[Medline] 275. Garg S, Serruys PW, Onuma Y, et al. Three-year clinical follow-up of the XIENCE V everolimus-eluting coronary stent system in the treatment of patients with de novo coronary artery lesions. The SPIRIT II trial. J Am Coll Cardiol Intv 2009;2:1190-1198.[Abstract/Free Full Text] 276. Garg S, Serruys PW, Miquel-Hebert K. Four year clinical follow up of the XIENCE V everolimus eluting coronary stent system in the treatment of patients with de novo coronary artery lesions: the SPIRIT II trial Catheter Cardiovasc Interv 2010In press. 277. Stone GW, Midei M, Newman W, et al. Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease: a randomized trial JAMA 2008;299:1903-1913.[Abstract/Free Full Text] 278. Stone GW. The XIENCE V-PROMUS everolimus-eluting stent: comprehensive update of the clinical trial programPaper presented at: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA http://www.tctmd.com/txshow.aspx?tid=939082&id=84006&trid=938634 2008Accessed October 28, 2009. 279. Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease N Engl J Med 2010;362:1663-1674.[CrossRef][Medline] 280. Chevalier B. SPIRIT V single arm study: 2 year follow-up. Paper presented at: EuroPCR; May 25–28, 2010; Paris, France. 281. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial Lancet 2010;375:201-209.[CrossRef][Web of Science][Medline] 282. Onuma Y, Kukreja N, Piazza N, et al. The everolimus-eluting stent in real-world patients: 6-month follow-up of the X-SEARCH (Xience V Stent Evaluated at Rotterdam Cardiac Hospital) registry J Am Coll Cardiol 2009;54:269-276.[Abstract/Free Full Text] 283. Aoki J, Abizaid AC, Ong AT, Tsuchida K, Serruys PW. Serial assessment of tissue growth inside and outside the stent after implantation of drug-eluting stent in clinical trials. Does delayed neointimal growth exist?. EuroIntervention 2005;1:235-255.[Medline] 284. Claessen BE, Beijk MA, Legrand V, et al. Two-year clinical, angiographic, and intravascular ultrasound follow-up of the XIENCE V everolimus-eluting stent in the treatment of patients with de novo native coronary artery lesions: the SPIRIT II trial Circ Cardiovasc Interv 2009;2:339-347.[Abstract/Free Full Text] 285. Park KW, Yoon JH, Kim JS, et al. Efficacy of Xience/Promus versus Cypher in rEducing Late Loss after stENTing (EXCELLENT) trial: study design and rationale of a Korean multicenter prospective randomized trial Am Heart J 2009;157:811-817 e1.[CrossRef][Web of Science][Medline] 286. Reuters Drug-Eluting Stent Penetration Lowest in Arkansas, Outnumbered by Bare-Metal Stents http://www.reuters.com/article/pressRelease/idUS75669+21-Sep-2009+PRN20090921?sp = true September 21, 2009Accessed October 24, 2009. 287. Stone GW, Ellis SG, Colombo A, et al. Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation Circulation 2007;115:2842-2847.[Abstract/Free Full Text] 288. Pfisterer M, Brunner-La Rocca HP, Rickenbacher P, et al. Long-term benefit-risk balance of drug-eluting vs. bare-metal stents in daily practice: does stent diameter matter?. Three-year follow-up of BASKET. Eur Heart J 2009;30:16-24.[Abstract/Free Full Text] 289. Tu JV, Bowen J, Chiu M, et al. Effectiveness and safety of drug-eluting stents in Ontario N Engl J Med 2007;357:1393-1402.[CrossRef][Web of Science][Medline] 290. Brunner-La Rocca HP, Kaiser C, Bernheim A, et al. Cost-effectiveness of drug-eluting stents in patients at high or low risk of major cardiac events in the Basel Stent KostenEffektivitats Trial (BASKET): an 18-month analysis Lancet 2007;370:1552-1559.[CrossRef][Web of Science][Medline] 291. Neyt M, Van Brabandt H, Devriese S, De Laet C. Cost-effectiveness analyses of drug eluting stents versus bare metal stents: a systematic review of the literature Health Policy 2009;91:107-120.[CrossRef][Web of Science][Medline] 292. Canoui-Poitrine F, Jeanblanc G, Alberti C, et al. Cost effectiveness of sirolimus-eluting stents compared with bare metal stents in acute myocardial infarction: insights from the TYPHOON trial Appl Health Econ Health Policy 2009;7:19-29.[Medline] 293. Bischof M, Briel M, Bucher HC, Nordmann A. Cost-effectiveness of drug-eluting stents in a US Medicare setting: a cost-utility analysis with 3-year clinical follow-up data Value in Health 2009;12:649-656.[CrossRef][Web of Science] 294. National Institute for Health and Clinical Excellence Final appraisal determination: drug-eluting stents for the treatment of coronary artery disease http://guidance.nice.org.uk/TA/WaveR/4 2009Accessed July 2010. 295. Lemos PA, Hoye A, Goedhart D, et al. Clinical, angiographic, and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation in complex patients: an evaluation from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) study Circulation 2004;109:1366-1370.[Abstract/Free Full Text] 296. Abizaid A, Kornowski R, Mintz GS, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation J Am Coll Cardiol 1998;32:584-589.[Abstract/Free Full Text] 297. Kereiakes DJ, Young JJ. Percutaneous coronary revascularization of diabetic patients in the era of drug-eluting stents Rev Cardiovasc Med 2005;6(Suppl 1):48-58.[CrossRef] 298. Aronson D, Bloomgarden Z, Rayfield EJ. Potential mechanisms promoting restenosis in diabetic patients J Am Coll Cardiol 1996;27:528-535.[Abstract] 299. Corpus RA, George PB, House JA, et al. Optimal glycemic control is associated with a lower rate of target vessel revascularization in treated type II diabetic patients undergoing elective percutaneous coronary intervention J Am Coll Cardiol 2004;43:8-14.[Abstract/Free Full Text] 300. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management JAMA 2002;287:2570-2581.[Abstract/Free Full Text] 301. Garg P, Normand SL, Silbaugh TS, et al. Drug-eluting or bare-metal stenting in patients with diabetes mellitus: results from the Massachusetts Data Analysis Center Registry Circulation 2008;118:2277-2285.[Abstract/Free Full Text] 302. Frobert O, Lagerqvist B, Carlsson J, Lindback J, Stenestrand U, James SK. Differences in restenosis rate with different drug-eluting stents in patients with and without diabetes mellitus: a report from the SCAAR (Swedish Angiography and Angioplasty Registry) J Am Coll Cardiol 2009;53:1660-1667.[Abstract/Free Full Text] 303. Kim MH, Hong SJ, Cha KS, et al. Effect of paclitaxel-eluting versus sirolimus-eluting stents on coronary restenosis in Korean diabetic patients J Interv Cardiol 2008;21:225-231.[CrossRef][Web of Science][Medline] 304. Chan C, Zambahari R, Kaul U, et al. A randomized comparison of sirolimus-eluting versus bare metal stents in the treatment of diabetic patients with native coronary artery lesions: the DECODE study Catheter Cardiovasc Interv 2008;72:591-600.[CrossRef][Web of Science][Medline] 305. Jensen LO, Maeng M, Thayssen P, et al. Neointimal hyperplasia after sirolimus-eluting and paclitaxel-eluting stent implantation in diabetic patients: the Randomized Diabetes and Drug-Eluting Stent (DiabeDES) intravascular ultrasound trial Eur Heart J 2008;29:2733-2741.[Abstract/Free Full Text] 306. Maeng M, Jensen LO, Galloe AM, et al. Comparison of the sirolimus-eluting versus paclitaxel-eluting coronary stent in patients with diabetes mellitus: the diabetes and drug-eluting stent (DiabeDES) randomized angiography trial Am J Cardiol 2009;103:345-349.[CrossRef][Web of Science][Medline] 307. Tomai F, Reimers B, De Luca L, et al. Head-to-head comparison of sirolimus- and paclitaxel-eluting stent in the same diabetic patient with multiple coronary artery lesions: a prospective, randomized, multicenter study Diabetes Care 2008;31:15-19.[Abstract/Free Full Text] 308. Jensen LO. DiabeDES III Trial: hyperplasia and angiographic late lumen loss after sirolimus eluting and zotarolimus eluting stent implantation in diabetic patients. Paper presented at: European Society of Cardiology; September 2009; Barcelona, Spain. 309. Grube E. SPIRIT V diabetic randomised control trial 1 year resultsPaper presented at: EuroPCR; May 25–28, 2010 http://www.pcronline.com/Lectures/2010/SPIRIT-V-diabetic-randomised-control-trial-1-year-results 2008Accessed May 29, 2010. 310. Kirtane AJ, Patel R, O'Shaughnessy C, et al. Clinical and angiographic outcomes in diabetics from the ENDEAVOR IV trial: randomized comparison of zotarolimus- and paclitaxel-eluting stents in patients with coronary artery disease J Am Coll Cardiol Intv 2009;2:967-976.[Abstract/Free Full Text] 311. Kirtane AJ, Ellis SG, Dawkins KD, et al. Paclitaxel-eluting coronary stents in patients with diabetes mellitus: pooled analysis from 5 randomized trials J Am Coll Cardiol 2008;51:708-715.[Abstract/Free Full Text] 312. Stettler C, Allemann S, Wandel S, et al. Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis BMJ 2008;337:a1331.[Abstract/Free Full Text] 313. Kastrati A. Sirolimus-eluting stents versus paclitaxel eluting stents in patients with coronary artery disease and diabetes mellitus: meta-analysis of randomised trials. Paper presented at: Transcatheter Cardiovascular Therapeutics; September 2009; San Francisco, CA. 314. Kapur A, Hall RJ, Malik IS, et al. Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients: 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial J Am Coll Cardiol 2010;55:432-440.[Abstract/Free Full Text] 315. Banning A, Westaby S, Morice MC, et al. Comparison of cardiac surgery and paclitaxel-eluting stents in nondiabetic and diabetic patients with left main and/or 3-vessel coronary artery disease J Am Coll Cardiol 2010;55:1067-1075.[Abstract/Free Full Text] 316. Farkouh ME, Dangas G, Leon MB, et al. Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial Am Heart J 2008;155:215-223.[CrossRef][Web of Science][Medline] 317. Fox KA, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial Lancet 2005;366:914-920.[CrossRef][Web of Science][Medline] 318. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials Lancet 2003;361:13-20.[CrossRef][Web of Science][Medline] 319. Kushner FG, Hand M, Smith Jr. SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2009;54:2205-2241.[Free Full Text] 320. Ong AT, Hoye A, Aoki J, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation J Am Coll Cardiol 2005;45:947-953.[Abstract/Free Full Text] 321. Tolleson TR, Newby LK, Harrington RA, et al. Frequency of stent thrombosis after acute coronary syndromes (from the SYMPHONY and 2nd SYMPHONY trials) Am J Cardiol 2003;92:330-333.[CrossRef][Web of Science][Medline] 322. Finn AV, Nakazawa G, Kolodgie F, Virmani R. Drug eluting or bare metal stent for acute myocardial infarction: an issue of safety? Eur Heart J 2009;30:1828-1830.[Free Full Text] 323. 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;28:2706-2713.[Abstract/Free Full Text] 324. Brar SS, Leon MB, Stone GW, et al. Use of drug-eluting stents in acute myocardial infarction: a systematic review and meta-analysis J Am Coll Cardiol 2009;53:1677-1689.[Abstract/Free Full Text] 325. Kukreja N, Onuma Y, Garcia-Garcia HM, Daemen J, Van Domburg R, Serruys PW. Primary percutaneous coronary intervention for acute myocardial infarction: long-term outcome after bare metal and drug-eluting stent implantation Circ Cardiovasc Interv 2008;1:103-110.[Abstract/Free Full Text] 326. Singh M, Rihal CS, Gersh BJ, et al. Twenty-five-year trends in in-hospital and long-term outcome after percutaneous coronary intervention: a single-institution experience Circulation 2007;115:2835-2841.[Abstract/Free Full Text] 327. Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease N Engl J Med 2001;344:1117-1124.[CrossRef][Web of Science][Medline] 328. Serruys PW. ARTS I—the rapamycin eluting stent; ARTS II— the rosy prophecy Eur Heart J 2002;23:757-759.[Free Full Text] 329. Kappetein AP, Dawkins KD, Mohr FW, et al. Current percutaneous coronary intervention and coronary artery bypass grafting practices for three-vessel and left main coronary artery disease. Insights from the SYNTAX run-in phase. Eur J Cardiothorac Surg 2006;29:486-491.[Free Full Text] 330. Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous coronary intervention with stenting and coronary artery bypass surgery for multivessel coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS, ERACI-II, MASS-II, and SoS trials Circulation 2008;118:1146-1154.[Abstract/Free Full Text] 331. Bravata DM, Gienger AL, McDonald KM, et al. Systematic review: the comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft surgery Ann Intern Med 2007;147:703-716.[Abstract/Free Full Text] 332. Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials Lancet 2009;373:1190-1197.[CrossRef][Web of Science][Medline] 333. Hannan EL, Racz MJ, Walford G, et al. Long-term outcomes of coronary-artery bypass grafting versus stent implantation N Engl J Med 2005;352:2174-2183.[CrossRef][Web of Science][Medline] 334. Rodriguez AE, Maree AO, Mieres J, et al. Late loss of early benefit from drug-eluting stents when compared with bare-metal stents and coronary artery bypass surgery: 3 years follow-up of the ERACI III registry Eur Heart J 2007;28:2118-2125.[Abstract/Free Full Text] 335. Hannan EL, Wu C, Walford G, et al. Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease N Engl J Med 2008;358:331-341.[CrossRef][Medline] 336. Daemen J, Kukreja N, Serruys PW. Drug-eluting stents vs. coronary-artery bypass grafting N Engl J Med 2008;358:2641-2642author reply 2643–4.[CrossRef][Web of Science][Medline] 337. Morice MC. Multivessel disease lessons from SYNTAX (early results and 2 year follow-up): interventional perspectives. Paper presented at: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA. 338. Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology J Am Coll Cardiol 2009;53:530-553.[Free Full Text] 339. Smith Jr. SC, Feldman TE, Hirshfeld Jr. JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention) J Am Coll Cardiol 2006;47:1-121.[Abstract/Free Full Text] 340. Kandzari DE, Colombo A, Park SJ, et al. Revascularization for unprotected left main disease: evolution of the evidence basis to redefine treatment standards J Am Coll Cardiol 2009;54:1576-1588.[Abstract/Free Full Text] 341. Meliga E, Garcia-Garcia HM, Valgimigli M, et al. Impact of drug-eluting stent selection on long-term clinical outcomes in patients treated for unprotected left main coronary artery disease: the Sirolimus Vs Paclitaxel Drug-Eluting Stent for Left Main Registry (SP-DELFT) Int J Cardiol 2009;137:16-21.[CrossRef][Web of Science][Medline] 342. Lee JY, Park DW, Yun SC, et al. Long-term clinical outcomes of sirolimus- versus paclitaxel-eluting stents for patients with unprotected left main coronary artery disease: analysis of the MAIN-COMPARE (revascularization for unprotected left main coronary artery stenosis: comparison of percutaneous coronary angioplasty versus surgical revascularization) registry J Am Coll Cardiol 2009;54:853-859.[Abstract/Free Full Text] 343. Park D-W, Seung KB, Kim Y-H, et al. Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (revascularization for unprotected left main coronary artery stenosis: comparison of percutaneous coronary angioplasty versus surgical revascularization) registry J Am Coll Cardiol 2010;56:117-124.[Abstract/Free Full Text] 344. Naik H, White AJ, Chakravarty T, et al. A meta-analysis of 3,773 patients treated with percutaneous coronary intervention or surgery for unprotected left main coronary artery stenosis J Am Coll Cardiol Intv 2009;2:739-747.[Abstract/Free Full Text] 345. Serruys PW. Left main lessons from SYNTAX (early results and 2 year follow-up): interventional perspectivesPaper presented at: Transcatheter Cardiovascular Therapeutics; September 21, 2009; San Francisco, CA http://www.tctmd.com/txshow.aspx?tid=9390768&id=83938&trid=938634 2009Accessed September 21, 2009. 346. Kappetein AP, Sabik III JF, Serruys PW, Stone GW. Evaluation of Xience Prime versus coronary artery bypass surgery for effectiveness of left main revascularisation. The EXCEL trial. http://www.sbhci.org.br/pdf/EXCELSitequalificationquestionnaire.pdf 2009Accessed November 1, 2009. 347. Stone GW, Reifart NJ, Moussa I, et al. Percutaneous recanalization of chronically occluded coronary arteries: a consensus document: part II Circulation 2005;112:2530-2537.[Free Full Text] 348. Olivari Z, Rubartelli P, Piscione F, et al. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE) J Am Coll Cardiol 2003;41:1672-1678.[Abstract/Free Full Text] 349. Kirschbaum SW, Baks T, van den Ent M, et al. Evaluation of left ventricular function three years after percutaneous recanalization of chronic total coronary occlusions Am J Cardiol 2008;101:179-185.[CrossRef][Web of Science][Medline] 350. Suero JA, Marso SP, Jones PG, et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience J Am Coll Cardiol 2001;38:409-414.[Abstract/Free Full Text] 351. Hoye A, van Domburg RT, Sonnenschein K, Serruys PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992–2002 Eur Heart J 2005;26:2630-2636.[Abstract/Free Full Text] 352. Prasad A, Rihal CS, Lennon RJ, Wiste HJ, Singh M, Holmes Jr DR. Trends in outcomes after percutaneous coronary intervention for chronic total occlusions: a 25-year experience from the Mayo Clinic J Am Coll Cardiol 2007;49:1611-1618.[Abstract/Free Full Text] 353. de Labriolle A, Bonello L, Roy P, et al. Comparison of safety, efficacy, and outcome of successful versus unsuccessful percutaneous coronary intervention in "true" chronic total occlusions Am J Cardiol 2008;102:1175-1181.[CrossRef][Web of Science][Medline] 354. Ge L, Iakovou I, Cosgrave J, et al. Immediate and mid-term outcomes of sirolimus-eluting stent implantation for chronic total occlusions Eur Heart J 2005;26:1056-1062.[Abstract/Free Full Text] 355. Hoye A, Tanabe K, Lemos PA, et al. Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions J Am Coll Cardiol 2004;43:1954-1958.[Abstract/Free Full Text] 356. 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;151:682-689.[CrossRef][Web of Science][Medline] 357. Werner GS, Krack A, Schwarz G, Prochnau D, Betge S, Figulla HR. Prevention of lesion recurrence in chronic total coronary occlusions by paclitaxel-eluting stents J Am Coll Cardiol 2004;44:2301-2306.[Abstract/Free Full Text] 358. Nakamura S, Muthusamy TS, Bae JH, Cahyadi YH, Udayachalerm W, Tresukosol D. Impact of sirolimus-eluting stent on the outcome of patients with chronic total occlusions Am J Cardiol 2005;95:161-166.[CrossRef][Web of Science][Medline] 359. Hoye A, Ong ATL, Aoki J, et al. Drug-eluting stent implantation for chronic total occlusions: comparison between the sirolimus- and paclitaxel-eluting stent EuroIntervention 2005;1:193-197.[Medline] 360. De Felice F, Fiorilli R, Parma A, et al. Clinical outcome of patients with chronic total occlusion treated with drug-eluting stents Int J Cardiol 2009;132:337-341.[CrossRef][Web of Science][Medline] 361. Garcia-Garcia HM, Daemen J, Kukreja N, et al. Three-year clinical outcomes after coronary stenting of chronic total occlusion using sirolimus-eluting stents: insights from the rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry Catheter Cardiovasc Interv 2007;70:635-639.[CrossRef][Web of Science][Medline] 362. Shen ZJ, Garcia-Garcia HM, Garg S, et al. Five-year clinical outcomes after coronary stenting of chronic total occlusion using sirolimus-eluting stents: insights from the rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital (RESEARCH) registry Catheter Cardiovasc Interv 2009;74:979-986.[CrossRef][Web of Science][Medline] 363. Colmenarez HJ, Escaned J, Fernandez C, et al. Efficacy and safety of drug-eluting stents in chronic total coronary occlusion recanalization: a systematic review and meta-analysis J Am Coll Cardiol 2010;55:1854-1866.[Abstract/Free Full Text] 364. Taggart DP. Arterial or venous conduits for redo coronary artery bypass grafting? Heart 1998;80:1-2.[Free Full Text] 365. Yap CH, Sposato L, Akowuah E, et al. Contemporary results show repeat coronary artery bypass grafting remains a risk factor for operative mortality Ann Thorac Surg 2009;87:1386-1391.[Abstract/Free Full Text] 366. Savage MP, Douglas Jr. JS, Fischman DL, et al. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. Saphenous Vein De Novo Trial Investigators. N Engl J Med 1997;337:740-747.[CrossRef][Web of Science][Medline] 367. Ratliff NB, Myles JL. Rapidly progressive atherosclerosis in aortocoronary saphenous vein grafts. Possible immune-mediated disease. Arch Pathol Lab Med 1989;113:772-776.[Web of Science][Medline] 368. Mauri L, Cox D, Hermiller J, et al. The PROXIMAL trial: proximal protection during saphenous vein graft intervention using the Proxis embolic protection system: a randomized, prospective, multicenter clinical trial J Am Coll Cardiol 2007;50:1442-1449.[Abstract/Free Full Text] 369. Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts Circulation 2002;105:1285-1290.[Abstract/Free Full Text] 370. Stone GW, Rogers C, Ramee S, et al. Distal filter protection during saphenous vein graft stenting: technical and clinical correlates of efficacy J Am Coll Cardiol 2002;40:1882-1888.[Abstract/Free Full Text] 371. Mehta SK, Frutkin AD, Milford-Beland S, et al. Utilization of distal embolic protection in saphenous vein graft interventions (an analysis of 19,546 patients in the American College of Cardiology-National Cardiovascular Data Registry) Am J Cardiol 2007;100:1114-1118.[CrossRef][Web of Science][Medline] 372. Brilakis ES, Saeed B, Banerjee S. Drug eluting stents in saphenous vein graft intervention: a systematic review EuroIntervention 2010;5:722-730.[Medline] 373. Brilakis ES, Lichtenwalter C, de Lemos JA, et al. A randomized controlled trial of a paclitaxel-eluting stent versus a similar bare-metal stent in saphenous vein graft lesions: the SOS (Stenting of Saphenous Vein Grafts) trial J Am Coll Cardiol 2009;53:919-928.[Abstract/Free Full Text] 374. Ge L, Iakovou I, Sangiorgi GM, et al. Treatment of saphenous vein graft lesions with drug-eluting stents: immediate and midterm outcome J Am Coll Cardiol 2005;45:989-994.[Abstract/Free Full Text] 375. Lee MS, Shah AP, Aragon J, et al. Drug-eluting stenting is superior to bare metal stenting in saphenous vein grafts Catheter Cardiovasc Interv 2005;66:507-511.[CrossRef][Web of Science][Medline] 376. Hoffmann R, Pohl T, Koster R, Blindt R, Boeckstegers P, Heitzer T. Implantation of paclitaxel-eluting stents in saphenous vein grafts: clinical and angiographic follow-up results from a multicentre study Heart 2007;93:331-334.[Abstract/Free Full Text] 377. Minutello RM, Bhagan S, Sharma A, et al. Long-term clinical benefit of sirolimus-eluting stents compared with bare metal stents in the treatment of saphenous vein graft disease J Interv Cardiol 2007;20:458-465.[CrossRef][Medline] 378. Applegate RJ, Sacrinty M, Kutcher M, Santos R, Gandhi S, Little W. Late outcomes of drug-eluting versus bare metal stents in saphenous vein grafts: propensity score analysis Catheter Cardiovasc Interv 2008;72:7-12.[CrossRef][Web of Science][Medline] 379. Chu WW, Rha SW, Kuchulakanti PK, et al. Efficacy of sirolimus-eluting stents compared with bare metal stents for saphenous vein graft intervention Am J Cardiol 2006;97:34-37.[Web of Science][Medline] 380. Ellis SG, Kandzari D, Kereiakes DJ, et al. Utility of sirolimus-eluting Cypher stents to reduce 12-month target vessel revascularization in saphenous vein graft stenoses: results of a multicenter 350-patient case-control study J Invasive Cardiol 2007;19:404-409.[Medline] 381. Wohrle J, Nusser T, Kestler HA, Kochs M, Hombach V. Comparison of the slow-release polymer-based paclitaxel-eluting Taxus-Express stent with the bare-metal Express stent for saphenous vein graft interventions Clin Res Cardiol 2007;96:70-76.[CrossRef][Web of Science][Medline] 382. Bansal D, Muppidi R, Singla S, et al. Percutaneous intervention on the saphenous vein bypass grafts—long-term outcomes Catheter Cardiovasc Interv 2008;71:58-61.[CrossRef][Web of Science][Medline] 383. Brodie BR, Wilson H, Stuckey T, et al. Outcomes with drug-eluting versus bare-metal stents in saphenous vein graft intervention: results from the STENT (Strategic Transcatheter Evaluation of New Therapies) Group J Am Coll Cardiol Intv 2009;2:1105-1112.[Abstract/Free Full Text] 384. De Labriolle A, Bonello L, Lemesle G, et al. Clinical presentation and outcome of patients hospitalized for symptomatic in-stent restenosis treated by percutaneous coronary intervention: comparison between drug-eluting stents and bare-metal stents Arch Cardiovasc Dis 2009;102:209-217.[CrossRef][Web of Science][Medline] 385. Bainey KR, Norris CM, Graham MM, Ghali WA, Knudtson ML, Welsh RC. Clinical in-stent restenosis with bare metal stents: is it truly a benign phenomenon? Int J Cardiol 2008;128:378-382.[CrossRef][Web of Science][Medline] 386. Waksman R, Raizner AE, Yeung AC, Lansky AJ, Vandertie L. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controlled trial Lancet 2002;359:551-557.[CrossRef][Web of Science][Medline] 387. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting N Engl J Med 2001;344:250-256.[CrossRef][Web of Science][Medline] 388. Waksman R, Ajani AE, White RL, et al. Five-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis Circulation 2004;109:340-344.[Abstract/Free Full Text] 389. Saia F, Lemos PA, Sianos G, et al. Effectiveness of sirolimus-eluting stent implantation for recurrent in-stent restenosis after brachytherapy Am J Cardiol 2003;92:200-203.[CrossRef][Web of Science][Medline] 390. Feres F, Munoz JS, Abizaid A, et al. Comparison between sirolimus-eluting stents and intracoronary catheter-based beta radiation for the treatment of in-stent restenosis Am J Cardiol 2005;96:1656-1662.[CrossRef][Web of Science][Medline] 391. Stone GW, Ellis SG O, Shaughnessy CD, et al. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial JAMA 2006;295:1253-1263.[Abstract/Free Full Text] 392. Ellis SG, O'Shaughnessy CD, Martin SL, et al. Two-year clinical outcomes after paclitaxel-eluting stent or brachytherapy treatment for bare metal stent restenosis: the TAXUS V ISR trial Eur Heart J 2008;29:1625-1634.[Abstract/Free Full Text] 393. Holmes Jr. DR, Teirstein P, Satler L, et al. Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the SISR randomized trial JAMA 2006;295:1264-1273.[Abstract/Free Full Text] 394. Holmes Jr. DR, Teirstein PS, Satler L, et al. 3-Year follow-up of the SISR (Sirolimus-Eluting Stents Versus Vascular Brachytherapy for In-Stent Restenosis) trial J Am Coll Cardiol Intv 2008;1:439-448.[Abstract/Free Full Text] 395. Lee SW, Park SW, Park DW, et al. Comparison of six-month angiographic and three-year outcomes after sirolimus-eluting stent implantation versus brachytherapy for bare metal in-stent restenosis Am J Cardiol 2007;100:425-430.[CrossRef][Web of Science][Medline] 396. Alfonso F, Perez-Vizcayno MJ, Hernandez R, et al. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial J Am Coll Cardiol 2006;47:2152-2160.[Abstract/Free Full Text] 397. Alfonso F, Perez-Vizcayno MJ, Hernandez R, et al. Long-term clinical benefit of sirolimus-eluting stents in patients with in-stent restenosis: results of the RIBS-II (Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting) study J Am Coll Cardiol 2008;52:1621-1627.[Abstract/Free Full Text] 398. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2009;119:480-486.[Free Full Text] 399. Cosgrave J, Melzi G, Biondi-Zoccai GG, et al. Drug-eluting stent restenosis the pattern predicts the outcome J Am Coll Cardiol 2006;47:2399-2404.[Abstract/Free Full Text]
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Abstract
The Need for Coronary...