This Article Free upon publication Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lüscher, T. F. Articles by Virmani, R. Search for Related Content PubMed PubMed Citation Articles by Lüscher, T. F. Articles by Virmani, R. Related Collections Pathophysiology Arterial thrombosis AHA Statements and Guidelines Catheter-based coronary interventions: stents Acute coronary syndromes Acute myocardial infarction Related Article

(Circulation. 2007;115:1051-1058.)
© 2007 American Heart Association, Inc.

Special Report

Drug-Eluting Stent and Coronary Thrombosis

Biological Mechanisms and Clinical Implications

Thomas F. Lüscher, MD; Jan Steffel, MD; Franz R. Eberli, MD; Michael Joner, MD; Gaku Nakazawa, MD; Felix C. Tanner, MD; Renu Virmani, MD

From Cardiology (T.F.L., J.S., F.R.E., F.C.T.), Cardiovascular Center, University Hospital Zürich, Zürich, Switzerland; Cardiovascular Research (T.F.L., J.S., F.C.T.), Physiology Institute, and Center for Integrative Human Physiology (T.F.L., J.S., F.C.T.), University of Zürich, Zürich, Switzerland; and CVPath Institute, Inc (M.J., G.N., R.V.), International Registry of Pathology, Gaithersburg, Md.

Correspondence to Thomas F. Lüscher, MD, Department of Cardiology, University of Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. E-mail cardiotfl{at}gmx.ch

	Abstract

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
Although rare, stent thrombosis remains a severe complication after stent implantation owing to its high morbidity and mortality. Since the introduction of drug-eluting stents (DES), most interventional centers have noted stent thrombosis up to 3 years after implantation, a complication rarely seen with bare-metal stents. Some data from large registries and meta-analyses of randomized trials indicate a higher risk for DES thrombosis, whereas others suggest an absence of such a risk. Several factors are associated with an increased risk of stent thrombosis, including the procedure itself (stent malapposition and/or underexpansion, number of implanted stents, stent length, persistent slow coronary blood flow, and dissections), patient and lesion characteristics, stent design, and premature cessation of antiplatelet drugs. Drugs released from DES exert distinct biological effects, such as activation of signal transduction pathways and inhibition of cell proliferation. As a result, although primarily aimed at preventing vascular smooth muscle cell proliferation and migration (ie, key factors in the development of restenosis), they also impair reendothelialization, which leads to delayed arterial healing, and induce tissue factor expression, which results in a prothrombogenic environment. In the same way, polymers used to load these drugs have been associated with DES thrombosis. Finally, DES impair endothelial function of the coronary artery distal to the stent, which potentially promotes the risk of ischemia and coronary occlusion. Although several reports raise the possibility of a substantially higher risk of stent thrombosis in DES, evidence remains inconclusive; as a consequence, both large-scale and long-term clinical trials, as well as further mechanistic studies, are needed. The present review focuses on the pathophysiological mechanisms and pathological findings of stent thrombosis in DES.

Key Words: stents • thrombosis • pathology • physiology • risk factors • arteries • myocardial infarction

	Introduction

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
With the introduction of balloon-expandable stents, coronary remodeling and, in turn, restenosis were reduced compared with angioplasty alone.^1,2 With the risk of restenosis still in the range of 15% to 20%, however, drug-eluting stents (DES) designed to release pharmacological agents after deployment were developed to inhibit the response to injury mainly responsible for restenosis after bare-metal stent (BMS) implantation (ie, vascular smooth muscle cell migration and proliferation and proteoglycan deposition). As a result, restenosis and target-vessel revascularization could be reduced to rates below 10% after DES implantation.^3,4

In the first series of patients receiving BMS, stent thrombosis was already recognized as a severe complication after implantation owing to its high mortality. With the introduction of P2Y-receptor antagonists (ie, ticlopidine, clopidogrel) for platelet inhibition in combination with acetylsalicylic acid, the incidence of stent thrombosis decreased substantially in stable patients to levels as low as 1%.⁵ Most of the events occurred within the first 10 days after implantation; indeed, stent thrombosis after the first month was extremely rare with BMS.^6,7

Despite reduced restenosis rates, the frequency of in-stent thrombosis has not decreased with DES compared with BMS.^8–12 Indeed, several hundred cases of stent thrombosis have been reported for rapamycin-coated stents.¹³ A number of reports imply that thrombosis rates of DES may even be higher in the "real world" than in clinical trials.^14,15 Notably, many operators have experienced very late stent thrombosis (3 years after implantation and beyond) in a number of patients, which was not seen with BMS. This review will briefly discuss presently available clinical data and focus on pathophysiological mechanisms of in-stent thrombosis in DES.

	Clinical Evidence

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
Numerous reports describe the occurrence of acute (<24 hours), subacute (<30 days), late (>30 days), and very late (>12 months) stent thrombosis after DES implantation.^8,13,16 However, the true incidence of stent thrombosis may be underestimated in clinical trials and could occur at substantially higher rates in the "real-world" setting, where more complex lesions are treated.^14,15 Given the small size of both clinical trials and registries and the low absolute number of stent thromboses, meta-analyses were performed to clarify this issue. Several meta-analyses initially did not reveal an increased risk of stent thrombosis with DES compared with BMS at 9 to 12 months.^10,11,12 Subsequently, 3 additional meta-analyses attracted special attention: In a large analysis of >8000 patients from 2 academic referral hospitals, a substantial cumulative incidence of angiographically documented DES thrombosis was noted (2.9%), yielding a rate of 1.3 per 100 patient-years.¹⁷ In that analysis, however, no patients with BMS were included, and hence, direct comparison of the 2 types of stents was not possible; given the change in percutaneous coronary intervention practice with DES, these data are difficult to interpret. In another study directly comparing DES and BMS, an increase in late thrombosis was noted in DES.¹⁸ Furthermore, a meta-analysis that included total mortality and Q-wave myocardial infarction as end points representing the "inclusive clinical surrogate of stent thrombosis" found an increased cumulative incidence of death or myocardial infarction at the latest available follow-up.⁹ Because coronary patients experience new occlusions at sites distant from the implanted stent and/or fatal arrhythmias, however, such an analysis may overestimate the true stent thrombosis rate. Moreover, interpretation of meta-analyses is restricted because of their inherent limitations, which include selective use of end points, incomplete data sets, and the retrospective nature of their analysis.

	Pathophysiology of In-Stent Thrombosis

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
Several factors that contribute to stent thrombosis have been recognized, which are discussed below.

Procedure-Related Factors
Among the procedure-related factors, smaller final lumen dimensions (stent malapposition and/or underexpansion), stent length, persistent slow coronary blood flow, placement of multiple stents, positive remodeling, dissections, geographic miss, and late stent malapposition due to thrombus resolution appear to be most important for the development of in-stent thrombosis.^19–25 Also, in DES, stent length, stent underexpansion, and residual stenosis have been observed to correlate with an increased risk for stent thrombosis.^26,27 These factors are of great interest because they can be avoided during the intervention, but they are unlikely to differ between BMS and DES.

Patient- and Lesion-Related Factors
Several patient-related factors have been associated with the development of in-stent thrombosis, including low ejection fraction,²¹ diabetes mellitus,²⁸ advanced age,²² and stenting in the setting of an acute coronary syndrome.²⁶ Similarly, in DES, primary stenting in acute myocardial infarction, diabetes mellitus, renal failure, and low ejection fraction appear to be associated with an increased risk for stent thrombosis.^14,26,29,30 In particular, the increased risk in patients with acute coronary syndrome could be due to delayed healing, lack of endothelialization, and presence of a pronounced inflammatory and thrombogenic environment of the exposed necrotic core to flowing blood, accompanied by enhanced platelet reactivity; furthermore, rapamycin and paclitaxel potentiate thrombin-induced expression of tissue factor (see below).

Furthermore, certain lesion characteristics are reported to be associated with an increased risk of stent thrombosis. In DES, this pertains in particular to stenting of bifurcation lesions or in-stent restenosis lesions.^14,29,30 In addition, interventional practice has changed, with advocates of "normal to normal" coronary artery stenting and revascularization of more complex lesions that carry a higher risk of stent thrombosis. This latter aspect makes comparisons of registries with historical controls difficult.

Antiplatelet Therapy
Stents are foreign bodies in the vessel wall and thus induce platelet adhesion and activation of the coagulation cascade. Furthermore, high-pressure implantation with noncompliant balloons induces significant vascular injury, with exposure of thrombogenic molecules of the subintima and media (including plaque material) to the blood stream. As a consequence, only potent platelet inhibition made the procedure feasible, and antiplatelet hyporesponsiveness has been associated with an increased risk for stent thrombosis.³¹ In line with this observation, discontinuation of antiplatelet therapy has been observed to be particularly associated with DES thrombosis.^8,16,32 The appropriate duration of the long-term antiplatelet regimen for prevention of DES thrombosis remains to be assessed in randomized prospective trials; at present, a course of 12 months of dual-antiplatelet therapy may be considered especially in high-risk, real-world patients.

Thrombogenicity of the Stent
A predisposition for the development of stent thrombosis has been observed with certain stent materials; for example, platelet activation was greater during the 30 days after implantation of an open-cell versus a closed-cell stent.³³ Stent strut thickness and polymer type and thickness also play an important role. It has been reported previously that the nonerodable polymers of the Cypher and Taxus DES provoke chronic eosinophilic infiltration of the arterial wall, suggestive of hypersensitivity reactions in a small number of cases.^7,34 However, the causal relationship between polymer-induced inflammation and the incidence of late stent thrombosis has only been proven in a minority of patients possessing a proinflammatory phenotype. Detailed analysis of the morphological changes shows a localized immune response, with predominance of CD45-positive lymphocytes and eosinophils. In fact, our experience shows that all cases of hypersensitivity occur >4 months after DES implantation.⁷ The preclinical experience in a pig model also shows a progressive increase in the presence of granulomatous reactions, including eosinophilic infiltrate, starting at 28 days after Cypher stent implantation: 1 month, 14%; 3 months, 43%; 6 months, 60% (R.V., unpublished data). One possible explanation of these findings is that the hypersensitivity reaction peaks after the complete release of the drug and is likely related to the polymer. In addition, positive remodeling has been observed in vessels showing a hypersensitivity reaction.

Furthermore, drugs loaded on DES may exert a prothrombogenic effect. Rapamycin (sirolimus), a macrocyclic lactone, is used on DES, because it is known to inhibit proliferation and migration of vascular smooth muscle cells, important factors in the development of neointima formation and restenosis, through interference with cell cycle regulators.^35,36 On a subcellular level, rapamycin binds to the FK-binding protein 12 and subsequently inhibits the mammalian target of rapamycin. The mammalian target of rapamycin is a downstream target of the phosphatidylinositol-3 kinase pathway, which in turn is involved in an inhibitory fashion in the regulation of tissue factor in endothelial cells and monocytes.^37–39 As a result, rapamycin inhibition of the mammalian target of rapamycin increases both thrombin- and tumor necrosis factor-–induced endothelial tissue factor expression and activity at concentrations of rapamycin that are encountered in vivo (Figure 1).^38,40

Paclitaxel is a lipophilic diterpenoid that binds to the ß-subunit of the tubulin heterodimer, promoting tubulin polymerization, cell cycle arrest, and, eventually, inhibition of vascular smooth muscle cell migration and proliferation.^41,42 In addition, paclitaxel is known to activate c-Jun NH₂-terminal kinase,^43,44 an important mediator of endothelial and monocytic tissue factor induction.^37,39,45 Consequently, paclitaxel also enhances tissue factor expression and activity in endothelial cells⁴⁴; again, concentrations used in this in vitro study are comparable with local tissue concentrations of paclitaxel after stent deployment.⁴⁶

View larger version (29K): [in this window] [in a new window]   Figure 1. Rapamycin and paclitaxel increase tissue factor (TF) expression. Paclitaxel enhances c-Jun NH2-terminal kinase (JNK) phosphorylation, which in turn leads to an increase in TF protein expression and TF surface activity. The PI3-kinase and its downstream target, the mammalian target of rapamycin (mTOR), inhibit endothelial TF expression; rapamycin inhibits the mammalian target of rapamycin, which leads to a disinhibition of (and thus an increase in) TF expression and surface activity. MKKs indicates map kinase kinases (upstream regulators of JNK); PI-3K, phosphatidylinositol-3 kinase.

In sirolimus-eluting stents, 80% of the rapamycin has eluted by 30 days, whereas paclitaxel-eluting stents have a biphasic drug release profile in vitro with an initial burst during the first 48 hours after implantation followed by a sustained low-level release for at least 2 weeks.⁴⁷ However, both rapamycin and paclitaxel easily penetrate into cells of the vessel wall owing to their lipophilic properties, which leads to chronic retention of the drug in the arterial tissue.^19,46,48 Thus, both rapamycin- and paclitaxel-induced tissue factor expression may contribute to a prothrombotic environment after deployment of DES, particularly in the acute and subacute setting and possibly in late stent thrombosis (Figure 1). The relationship between these findings and stent thrombosis in clinical practice requires further study, particularly to examine the degree and the spatiotemporal pattern of tissue factor expression in the arterial wall after deployment of DES.

Impaired Reendothelialization
Reendothelialization occurs after vascular injury and similarly after stent placement. Traditionally, it was believed that endothelial cells proliferate and migrate from intact neighboring coronary segments, eventually leading to the reendothelialization of the injured segment. In vitro, rapamycin and paclitaxel not only inhibit proliferation and migration of vascular smooth muscle cells but equally suppress endothelial cells,^{7,35,36,38,49–51} thereby potentially impeding reendothelialization (Figure 2). We observed poor endothelial cell junction formation and microthrombi of focal platelet aggregation at 16 months after rapamycin stent implantation in a patient dying of a non-DES–related cause.⁵² It has been proposed that bone marrow–derived endothelial progenitor cells may also be involved in reendothelialization.^53,54 Interestingly, rapamycin inhibits proliferation, migration, and differentiation of human endothelial progenitor cells in vitro.^55,56 Hence, drugs loaded on DES may affect the number as well as the homing and proliferation of endothelial progenitor cells, thus further preventing proper endothelial healing (Figure 2).

View larger version (60K): [in this window] [in a new window]   Figure 2. DES reduce neointima formation but may increase stent thrombogenicity. Effect of sirolimus-eluting/paclitaxel-eluting stent strut on the local vessel wall after implantation. Sirolimus/paclitaxel reduces neointima formation by inhibiting vascular smooth muscle migration and proliferation (green arrows). However, the drugs also inhibit reendothelialization, induce tissue factor (TF), and may prevent homing and proliferation of endothelial progenitor cells (EPCs; red arrows/bars).

In vivo, the time course of endothelial healing after stent implantation varies in different animal models. Although in healthy pigs, endothelialization is similar between BMS and DES at 28 days,⁴⁸ a clear delay of endothelialization in both sirolimus- and paclitaxel-eluting stents was observed in a rabbit iliac-overlapping DES implantation model.⁴⁶ In view of distinct differences with respect to vessel wall reactivity after stent implantation between animals and humans, however, these results cannot be applied entirely to the situation in humans. After BMS implantation, near-complete endothelialization has been suggested to occur by 3 to 4 months.⁶ A morphological autopsy study comparing coronary segments from patients after DES and BMS implantation revealed delayed arterial healing and poorer endothelialization after DES compared with BMS implantation of similar duration (Figure 3).⁷ Indeed, in 23 DES patients in that study, 14 had evidence of late-stent thrombosis, and of these 14 patients, 13 died of a DES-related cause.⁷ Thus, current evidence suggests delayed reendothelialization and arterial healing after implantation of DES compared with BMS, resulting in potentially enhanced thrombogenicity (Figure 4). It is uncertain whether reendothelialization with DES is only delayed or persistently incomplete up to late time points. It is unclear in atherosclerotic human arteries how long it will take for DES to endothelialize. We have shown that in humans, delayed healing is common with current DES and that in those that thrombose, other factors, such as hypersensitivity reaction, bifurcating and ostial stenting, penetration of a necrotic core, stent malapposition, and restenosis, may also be important predictors of thrombosis.

View larger version (94K): [in this window] [in a new window]   Figure 3. Delayed reendothelialization after DES implantation. Time course of arterial healing in BMS, Taxus DES, and Cypher DES from 1 to 8 months after stent implantation. Although some peristrut inflammation is observed in BMS at 1 month, complete arterial healing, including a well-established neointimal layer, is seen at 3 and 8 months’ duration. Taxus DES shows early fibrin deposition surrounding stent struts (*), which persists up to 8 months, as a sign of delayed healing. In contrast, Cypher DES shows predominance of inflammatory cells, including giant cell formation (black arrowheads), at early time points (1 and 3 months), whereas fibrin deposition is stronger at 8 months.

View larger version (29K): [in this window] [in a new window]   Figure 4. Temporal sequence of reendothelialization in BMS and DES.

There is compelling evidence that certain subsets of patients have a favorable long-term outcome after implantation of DES, which results in a reduced need for interventional or surgical revascularization due to sustained suppression of neointimal growth. Factors associated with greater healing from our experience include shorter stent length, less plaque area, less fibrin deposition, and greater endothelialization. Other factors that may influence healing are likely to be patient-related, such as antiplatelet therapy discontinuation, renal failure, diabetes mellitus, and a lower ejection fraction, which have all been reported in clinical studies.¹⁴ Furthermore, there is variability from patient to patient even in wound healing; the response to drug also varies, with some patients requiring a lower drug dose for equivalent benefit. Thus, many factors influence the healing process and vary with individual risk factors.

Risk Factors for Different Time Points of DES Thrombosis
Stent thrombosis may occur acutely (within 24 hours of stent placement), subacutely (up to 30 days after stent implantation), as late thrombosis (after 30 days), or as very late thrombosis (after 12 months). The most important risk factors for acute and subacute stent thrombosis are primary stenting in ST-segment elevation myocardial infarction and acute coronary syndromes.^20,26 Additional risk factors include stent length, congestive heart failure, and a prothrombogenic state, such as metastatic cancer.^19,20,26,27 One of the most significant risk factors for late and very late stent thrombosis appears to be discontinuation of antiplatelet therapy.^26,27 Other predictors are stent underexpansion and residual reference segment stenosis.^19,27

	Design of Future DES

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
The stent coating influences thrombogenicity. Whether a simple chemical coating, such as titanium-nitride-oxide, that diminishes platelet adhesion and fibrinogen binding compared with stainless steel will be effective against restenosis and stent thrombosis remains to be elucidated in large clinical trials.⁵⁷ Coating of stents with substances that potentially facilitate reendothelialization may represent a novel therapeutic approach. For example, in preliminary studies, coating of stents with CD34 antibodies designed to "capture" endothelial progenitor cells proved to accelerate endothelial coverage and appeared safe and feasible in humans.⁵⁸ Similarly, stents loaded with an integrin-binding cyclic Arg-Gly-Asp peptide accelerated endothelialization by attracting endothelial progenitor cells in a porcine model.⁵⁹ Further studies are needed to assess the long-term efficacy and safety of these biologically active stents. Furthermore, a combination of "prohealing" substances (such as vascular endothelial growth factor) with established "antirestenosis" drugs may represent an interesting approach to obtain the benefit of reduced restenosis without the cost of an increased risk for stent thrombosis.

Considering the delay in healing along with the unknown time of reendothelialization of current DES, prohealing strategies such as the use of peroxisome proliferator–activated receptor- agonists, which not only diminish inflammation but also enhance endothelialization, may also represent an interesting new approach for DES.⁶⁰ Given the importance of tissue factor in the initiation of coagulation and thrombosis, we also proposed dimethyl sulfoxide as a novel coating strategy for DES.⁶¹ Dimethyl sulfoxide prevents vascular smooth muscle cell proliferation and migration, ie, the key mechanisms of restenosis; at the same time, dimethyl sulfoxide inhibits tissue factor upregulation in endothelial cells, vascular smooth muscle, and monocytes and prevents thrombotic occlusion in a mouse carotid injury model.⁶¹

	Conclusions

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
The pathogenesis of stent thrombosis is still not fully understood. A combination of factors may be involved, including procedure-related factors, patient-related factors, and lesion characteristics. With DES, biological properties such as thrombogenicity, ie, induction of tissue factor, inhibition of reendothelialization of the stented segment, and distal endothelial dysfunction may increase the risk beyond that seen with BMS. Because premature cessation and resistance to antiplatelet drugs is associated with subacute and late DES thrombosis, prolonged dual-platelet inhibition must be considered, especially in high-risk patients, balanced against the risk of bleeding.

With nearly 6 million DES implanted, and in view of the high morbidity and mortality associated with it, stent thrombosis is an important healthcare issue that requires further clinical study. Consistent with this interpretation, the US Food and Drug Administration issued a statement acknowledging the importance of the increasing concern with respect to DES thrombosis. There was consensus that the on-label use of DES may be associated with a small increase in stent thrombosis compared with bare-metal stents, but that it does not lead to an increased risk of death or myocardial infarction, and that under these conditions, the benefits of DES outweigh a possibly increased risk for stent thrombosis⁶²; the panel left open the possibility, however, that off-label use of DES (ie, use of DES outside the FDA-approved indications) may indeed be associated with an increased risk of death or myocardial infarction compared with the use of BMS owing to an increase in the rate of stent thrombosis.⁶²

Statements that second-generation DES appear to be less prone to stent thrombosis and thus "safer" than first-generation DES appear equally premature because the same uncertainty with respect to long-term safety prevails. Additional in vitro studies of compounds used on DES and autopsy studies of patients with DES dying of cardiac and noncardiac causes would help in understanding the mechanisms of stent thrombosis. Moreover, large-scale, non–corporate-sponsored registries and clinical trials are needed to reliably assess the "true" risk of stent thrombosis with DES. Control of data by non–corporate-sponsored data analysis centers under the auspices of the American Heart Association/American College of Cardiology/European Society of Cardiology, including cardiac surgeons, cardiologists, internists, and cardiac pathologists, is a prerequisite to the unbiased evaluation of current and future DES technologies.

	Acknowledgments

 
Sources of Funding

Research of the authors was supported by the Swiss National Research Foundation (grant No. 3100-068118.02/1 to Dr Lüscher and 3200B0-113328/1 to Dr Tanner) and by the European Union (grant No. G5RD-CT-2001-00532 to Dr Lüscher) and the Bonizzi-Theler Stiftung (to Dr Steffel and Dr Tanner). The authors received unrestricted research grants from Cordis, Biotronik, Boston Scientific, and Medtronic (Dr Lüscher and Dr Eberli). Dr Virmani has received research grants from companies including Medtronic, Abbott, Guidant, and Cordis.

Disclosures

Dr Lüscher and Dr Tanner hold a patent on the potential clinical applications of dimethyl sulfoxide. Dr Virmani is a consultant to Medtronic and Guidant. The remaining authors report no conflicts.

	References

Top Abstract Introduction Clinical Evidence Pathophysiology of In-Stent... Design of Future DES Conclusions References

 
1. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel M-A; 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.[Abstract/Free Full Text]

2. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S; 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.[Abstract/Free Full Text]

3. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002; 346: 1773–1780.[Abstract/Free Full Text]

4. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003; 349: 1315–1323.[Abstract/Free Full Text]

5. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation. 2000; 102: 624–629.[Abstract/Free Full Text]

6. 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]

7. Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. 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]

8. McFadden EP, Stabile E, Regar E, Cheneau E, Ong AT, Kinnaird T, Suddath WO, Weissman NJ, Torguson R, Kent KM, Pichard AD, Satler LF, Waksman R, Serruys PW. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet. 2004; 364: 1519–1521.[CrossRef][Medline] [Order article via Infotrieve]

9. Camenzind E, Steg PG, Wijns W. Safety of drug-eluting stents: a meta-analysis of 1st generation DES programs. Abstract presented at: World Congress of Cardiology 2006, September 2–6, 2006, Barcelona, Spain.

10. Moreno R, Fernandez C, Hernandez R, Alfonso F, Angiolillo DJ, Sabate M, Escaned J, Banuelos C, Fernandez-Ortiz A, Macaya C. Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol. 2005; 45: 954–959.[Abstract/Free Full Text]

11. Bavry AA, Kumbhani DJ, Helton TJ, Bhatt DL. What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention? A meta-analysis. J Am Coll Cardiol. 2005; 45: 941–946.[Abstract/Free Full Text]

12. Bavry AA, Kumbhani DJ, Helton TJ, Bhatt DL. Risk of thrombosis with the use of sirolimus-eluting stents for percutaneous coronary intervention (from registry and clinical trial data). Am J Cardiol. 2005; 95: 1469–1472.[CrossRef][Medline] [Order article via Infotrieve]

13. FDA advises physicians of adverse events associated with Cordis Cypher coronary stents. US Food and Drug Administration Public Health Web Notification. October 29, 2003;T03–T71. Available at: http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01257.html. Accessed February 10, 2007.

14. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005; 293: 2126–2130.[Abstract/Free Full Text]

15. 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]

16. Pfisterer ME, Kaiser CA, Bader F, Brunner-La Rocca HP, Bonetti PO, Buser PT Late clinical events related to late stent thrombosis after stopping clopidogrel: prospective randomized comparison between drug-eluting versus bare-metal stenting. In: Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11–14, 2006; Atlanta, Ga. Abstract 422-11.

17. Daemen J, Wenaweser P, Tsuchida K, Vaina S, Abrecht L, Morger C, Kukreja N, Jüni P, Sianos G, Hellige G, van Domburg R, Hess OM, Boersma E, Meier B, Windecker S, Serruys P. 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. In press.

18. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med. 2006; 119: 1056–1061.[CrossRef][Medline] [Order article via Infotrieve]

19. Kereiakes DJ, Choo JK, Young JJ, Broderick TM. Thrombosis and drug-eluting stents: a critical appraisal. Rev Cardiovasc Med. 2004; 5: 9–15.[CrossRef][Medline] [Order article via Infotrieve]

20. Orford JL, Lennon R, Melby S, Fasseas P, Bell MR, Rihal CS, Holmes DR, Berger PB. Frequency and correlates of coronary stent thrombosis in the modern era: analysis of a single center registry. J Am Coll Cardiol. 2002; 40: 1567–1572.[Abstract/Free Full Text]

21. Moussa I, Di Mario C, Reimers B, Akiyama T, Tobis J, Colombo A. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: frequency, predictors and clinical outcome. J Am Coll Cardiol. 1997; 29: 6–12.[Abstract]

22. Schuhlen H, Kastrati A, Dirschinger J, Hausleiter J, Elezi S, Wehinger A, Pache J, Hadamitzky M, Schomig A. Intracoronary stenting and risk for major adverse cardiac events during the first month. Circulation. 1998; 98: 104–111.[Abstract/Free Full Text]

23. Cheneau E, Leborgne L, Mintz GS, Kotani J, Pichard AD, Satler LF, Canos D, Castagna M, Weissman NJ, Waksman R. Predictors of subacute stent thrombosis: results of a systematic intravascular ultrasound study. Circulation. 2003; 108: 43–47.[Abstract/Free Full Text]

24. Cutlip DE, Baim DS, Ho KK, Popma JJ, Lansky AJ, Cohen DJ, Carrozza JP Jr, Chauhan MS, Rodriguez O, Kuntz RE. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001; 103: 1967–1971.[Abstract/Free Full Text]

25. Chieffo A, Bonizzoni E, Orlic D, Stankovic G, Rogacka R, Airoldi F, Mikhail GW, Montorfano M, Michev I, Carlino M, Colombo A. Intraprocedural stent thrombosis during implantation of sirolimus-eluting stents. Circulation. 2004; 109: 2732–2736.[Abstract/Free Full Text]

26. Park DW, Park SW, Park KH, Lee BK, Kim YH, Lee CW, Hong MK, Kim JJ, Park SJ. 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][Medline] [Order article via Infotrieve]

27. Fujii K, Carlier SG, Mintz GS, Yang YM, Moussa I, Weisz G, Dangas G, Mehran R, Lansky AJ, Kreps EM, Collins M, Stone GW, Moses JW, Leon MB. 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]

28. Silva JA, Ramee SR, White CJ, Collins TJ, Jenkins JS, Nunez E, Zhang S, Jain SP. Primary stenting in acute myocardial infarction: influence of diabetes mellitus in angiographic results and clinical outcome. Am Heart J. 1999; 138: 446–455.[CrossRef][Medline] [Order article via Infotrieve]

29. Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, Regar E, McFadden EP, Sianos G, van der Giessen WJ, de Jaegere PP, de Feyter P, van Domburg RT, Serruys PW. 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]

30. Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, Smith K, Fournadjieva J, Suddath WO, Satler LF, Pichard AD, Kent KM, Waksman R. 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]

31. Wenaweser P, Dorffler-Melly J, Imboden K, Windecker S, Togni M, Meier B, Haeberli A, Hess OM. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol. 2005; 45: 1748–1752.[Abstract/Free Full Text]

32. Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2006; 297: 159–168.[CrossRef][Medline] [Order article via Infotrieve]

33. Gurbel PA, Callahan KP, Malinin AI, Serebruany VL, Gillis J. Could stent design affect platelet activation? Results of the Platelet Activation in STenting (PAST) Study. J Invasive Cardiol. 2002; 14: 584–589.[Medline] [Order article via Infotrieve]

34. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, Davidson CJ, McKoy JM, Raisch DW, Whisenant BK, Yarnold PR, Belknap SM, West DP, Gage JE, Morse RE, Gligoric G, Davidson L, Feldman MD. 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]

35. Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res. 1995; 76: 412–417.[Abstract/Free Full Text]

36. 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.[Medline] [Order article via Infotrieve]

37. Steffel J, Luscher TF, Tanner FC. Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation. 2006; 113: 722–731.[Abstract/Free Full Text]

38. Steffel J, Latini RA, Akhmedov A, Zimmermann D, Zimmerling P, Luscher TF, Tanner FC. Rapamycin, but not FK-506, increases endothelial tissue factor expression: implications for drug-eluting stent design. Circulation. 2005; 112: 2002–2011.[Abstract/Free Full Text]

39. Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem. 2002; 277: 32124–32132.[Abstract/Free Full Text]

40. US Food and Drug Administration. Center for Devices and Radiological Health. Cypher Sirolimus-eluting coronary stent on RAPTOR over-the-wire delivery system or RAPTORRAIL rapid exchange delivery system. Available at: http://www.fda.gov/cdrh/pdf2/p020026.html. Accessed December 17, 2004.

41. Crown J, O’Leary M. The taxanes: an update. Lancet. 2000; 355: 1176–1178.[CrossRef][Medline] [Order article via Infotrieve]

42. Sollott SJ, Cheng L, Pauly RR, Jenkins GM, Monticone RE, Kuzuya M, Froehlich JP, Crow MT, Lakatta EG, Rowinsky EK, Kinsella JL. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest. 1995; 95: 1869–1876.[Medline] [Order article via Infotrieve]

43. Wang TH, Wang HS, Ichijo H, Giannakakou P, Foster JS, Fojo T, Wimalasena J. Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both Ras and apoptosis signal-regulating kinase pathways. J Biol Chem. 1998; 273: 4928–4936.[Abstract/Free Full Text]

44. Stahli BE, Camici GG, Steffel J, Akhmedov A, Shojaati K, Graber M, Luscher TF, Tanner FC. Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2 kinase activation. Circ Res. 2006; 99: 149–155.[Abstract/Free Full Text]

45. Steffel J, Hermann M, Greutert H, Gay S, Luscher TF, Ruschitzka F, Tanner FC. Celecoxib decreases endothelial tissue factor expression through inhibition of c-Jun terminal NH2 kinase phosphorylation. Circulation. 2005; 111: 1685–1689.[Abstract/Free Full Text]

46. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, Skorija K, Weber DK, Gold HK, Virmani R. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 2005; 112: 270–278.[Abstract/Free Full Text]

47. Halkin A, Stone GW. Polymer-based paclitaxel-eluting stents in percutaneous coronary intervention: a review of the TAXUS trials. J Interv Cardiol. 2004; 17: 271–282.[CrossRef][Medline] [Order article via Infotrieve]

48. Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou G, Narayan P, Leon MB, Yeung AC, Tio F, Tsao PS, Falotico R, Carter AJ. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation. 2001; 104: 1188–1193.[Abstract/Free Full Text]

49. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002; 8: 128–135.[CrossRef][Medline] [Order article via Infotrieve]

50. Matter CM, Rozenberg I, Jaschko A, Greutert H, Kruz DJ, Wnendt S, Kuttler B, Joch H, Grunenfelder J, Zund G, Tanner FC, Luscher TF. Effects of tacrolimus or sirolimus on proliferation of vascular smooth muscle and endothelial cells. J Cardiovasc Pharmacol. 2006; 48: 286–292.[CrossRef][Medline] [Order article via Infotrieve]

51. Parry TJ, Brosius R, Thyagarajan R, Carter D, Argentieri D, Falotico R, Siekierka J. Drug-eluting stents: sirolimus and paclitaxel differentially affect cultured cells and injured arteries. Eur J Pharmacol. 2005; 524: 19–29.[CrossRef][Medline] [Order article via Infotrieve]

52. Guagliumi G, Farb A, Musumeci G, Valsecchi O, Tespili M, Motta T, Virmani R. Images in cardiovascular medicine: sirolimus-eluting stent implanted in human coronary artery for 16 months: pathological findings. Circulation. 2003; 107: 1340–1341.[Free Full Text]

53. Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, Matsunaga S, Tateishi K, Nomura T, Takahashi T, Tatsumi T, Matsubara H. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res. 2006; 98: 1405–1413.[Abstract/Free Full Text]

54. Griese DP, Ehsan A, Melo LG, Kong D, Zhang L, Mann MJ, Pratt RE, Mulligan RC, Dzau VJ. Isolation and transplantation of autologous circulating endothelial cells into denuded vessels and prosthetic grafts: implications for cell-based vascular therapy. Circulation. 2003; 108: 2710–2715.[Abstract/Free Full Text]

55. Butzal M, Loges S, Schweizer M, Fischer U, Gehling UM, Hossfeld DK, Fiedler W. Rapamycin inhibits proliferation and differentiation of human endothelial progenitor cells in vitro. Exp Cell Res. 2004; 300: 65–71.[CrossRef][Medline] [Order article via Infotrieve]

56. Chen TG, Chen JZ, Wang XX. Effects of rapamycin on number activity and eNOS of endothelial progenitor cells from peripheral blood. Cell Prolif. 2006; 39: 117–125.[CrossRef][Medline] [Order article via Infotrieve]

57. Windecker S, Simon R, Lins M, Klauss V, Eberli FR, Roffi M, Pedrazzini G, Moccetti T, Wenaweser P, Togni M, Tuller D, Zbinden R, Seiler C, Mehilli J, Kastrati A, Meier B, Hess OM. Randomized comparison of a titanium-nitride-oxide-coated stent with a stainless steel stent for coronary revascularization: the TiNOX trial. Circulation. 2005; 111: 2617–2622.[Abstract/Free Full Text]

58. Aoki J, Serruys PW, van Beusekom H, Ong AT, McFadden EP, Sianos G, van der Giessen WJ, Regar E, de Feyter PJ, Davis HR, Rowland S, Kutryk MJ. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol. 2005; 45: 1574–1579.[Abstract/Free Full Text]

59. Blindt R, Vogt F, Astafieva I, Fach C, Hristov M, Krott N, Seitz B, Kapurniotu A, Kwok C, Dewor M, Bosserhoff AK, Bernhagen J, Hanrath P, Hoffmann R, Weber C. A novel drug-eluting stent coated with an integrin-binding cyclic Arg-Gly-Asp peptide inhibits neointimal hyperplasia by recruiting endothelial progenitor cells. J Am Coll Cardiol. 2006; 47: 1786–1795.[Abstract/Free Full Text]

60. Joner M, Farb A, Cheng Q, Finn AV, Acampado E, Burke AP, Skorija K, Creighton W, Kolodgie FD, Gold HK, Virmani R Pioglitazone inhibits in-stent restenosis in atherosclerotic rabbits by targeting transforming growth factor-ß and MCP-1. Arterioscler Thromb Vasc Biol. 2007; 27: 182–189.[Abstract/Free Full Text]

61. Camici GG, Steffel J, Akhmedov A, Schafer N, Baldinger J, Schulz U, Shojaati K, Matter CM, Yang Z, Luscher TF, Tanner FC. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation. 2006; 114: 1512–1521.[Abstract/Free Full Text]

62. US Food and Drug Administration. Update to FDA statement on coronary drug-eluting stents. Available at: http://www.fda.gov/cdrh/news/010407.html. Accessed February 10, 2007.

Related Article:

Issue Highlights
Circulation 2007 115: 945. [Extract] [Full Text]

This article has been cited by other articles:

				G. Montalescot, J.-S. Hulot, and J.-P. Collet Stent thrombosis: who's guilty? Eur. Heart J., November 2, 2009; 30(22): 2685 - 2688. [Full Text] [PDF]

				C. RAYMOND and V. MENON Dual antiplatelet therapy in coronary artery disease: A case-based approach Cleveland Clinic Journal of Medicine, November 1, 2009; 76(11): 663 - 670. [Abstract] [Full Text] [PDF]

				I. T. Meredith, S. Worthley, R. Whitbourn, D. L. Walters, D. McClean, M. Horrigan, J. J. Popma, D. E. Cutlip, A. DePaoli, M. Negoita, et al. Clinical and Angiographic Results With the Next-Generation Resolute Stent System: A Prospective, Multicenter, First-in-Human Trial J. Am. Coll. Cardiol. Intv., October 1, 2009; 2(10): 977 - 985. [Abstract] [Full Text] [PDF]

				G. S. Mintz and S.-Y. Choi Optimal Stent Expansion and Complete Neointimal Coverage: Does This Association Make Sense? J. Am. Coll. Cardiol. Intv., October 1, 2009; 2(10): 995 - 996. [Full Text] [PDF]

				C. J. Schultz, A. Weustink, N. Piazza, A. Otten, N. Mollet, G. Krestin, R. J. van Geuns, P. de Feyter, P. W.J. Serruys, and P. de Jaegere Geometry and degree of apposition of the CoreValve ReValving system with multislice computed tomography after implantation in patients with aortic stenosis. J. Am. Coll. Cardiol., September 1, 2009; 54(10): 911 - 918. [Abstract] [Full Text] [PDF]

				K. R. Sipido, A. Tedgui, S. D. Kristensen, G. Pasterkamp, H. Schunkert, M. Wehling, P. G. Steg, W. Eisert, F. Rademakers, B. Casadei, et al. Identifying needs and opportunities for advancing translational research in cardiovascular disease Cardiovasc Res, August 1, 2009; 83(3): 425 - 435. [Full Text] [PDF]

				G. G. Camici, J. Steffel, I. Amanovic, A. Breitenstein, J. Baldinger, S. Keller, T. F. Luscher, and F. C. Tanner Rapamycin promotes arterial thrombosis in vivo: implications for everolimus and zotarolimus eluting stents Eur. Heart J., June 29, 2009; (2009) ehp259v1. [Abstract] [Full Text] [PDF]

				H. Ota, M. Eto, J. Ako, S. Ogawa, K. Iijima, M. Akishita, and Y. Ouchi Sirolimus and everolimus induce endothelial cellular senescence via sirtuin 1 down-regulation: therapeutic implication of cilostazol after drug-eluting stent implantation. J. Am. Coll. Cardiol., June 16, 2009; 53(24): 2298 - 2305. [Abstract] [Full Text] [PDF]

				A. Pena, J.-P. Collet, J.-S. Hulot, J. Silvain, O. Barthelemy, F. Beygui, C. Funck-Brentano, and G. Montalescot Can We Override Clopidogrel Resistance? Circulation, June 2, 2009; 119(21): 2854 - 2857. [Full Text] [PDF]

				Y. Takemoto, H. Kawata, T. Soeda, K. Imagawa, S. Somekawa, Y. Takeda, S. Uemura, M. Matsumoto, Y. Fujimura, J.-i. Jo, et al. Human Placental Ectonucleoside Triphosphate Diphosphohydrolase Gene Transfer via Gelatin-Coated Stents Prevents In-Stent Thrombosis Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 857 - 862. [Abstract] [Full Text] [PDF]

				J. R. Costa Jr, A. Abizaid, R. Costa, F. Feres, L. F. Tanajura, A. Abizaid, G. Maldonado, R. Staico, D. Siqueira, A. G.M.R. Sousa, et al. 1-Year Results of the Hydroxyapatite Polymer-Free Sirolimus-Eluting Stent for the Treatment of Single De Novo Coronary Lesions: The VESTASYNC I Trial J. Am. Coll. Cardiol. Intv., May 1, 2009; 2(5): 422 - 427. [Abstract] [Full Text] [PDF]

				P. A. Calvert and M. R. Bennett Restenosis Revisited Circ. Res., April 10, 2009; 104(7): 823 - 825. [Full Text] [PDF]

				R. A. Byrne, J. Mehilli, R. Iijima, S. Schulz, J. Pache, M. Seyfarth, A. Schomig, A. Kastrati, and for the Intracoronary Stenting and Angiographic Re A polymer-free dual drug-eluting stent in patients with coronary artery disease: a randomized trial vs. polymer-based drug-eluting stents Eur. Heart J., April 2, 2009; 30(8): 923 - 931. [Abstract] [Full Text] [PDF]

				K. Nakano, K. Egashira, S. Masuda, K. Funakoshi, G. Zhao, S. Kimura, T. Matoba, K. Sueishi, Y. Endo, Y. Kawashima, et al. Formulation of Nanoparticle-Eluting Stents by a Cationic Electrodeposition Coating Technology: Efficient Nano-Drug Delivery via Bioabsorbable Polymeric Nanoparticle-Eluting Stents in Porcine Coronary Arteries J. Am. Coll. Cardiol. Intv., April 1, 2009; 2(4): 277 - 283. [Abstract] [Full Text] [PDF]

				R. A. Byrne, R. Iijima, J. Mehilli, S. Pinieck, O. Bruskina, A. Schomig, and A. Kastrati Durability of Antirestenotic Efficacy in Drug-Eluting Stents With and Without Permanent Polymer J. Am. Coll. Cardiol. Intv., April 1, 2009; 2(4): 291 - 299. [Abstract] [Full Text] [PDF]

				Y. Han, Q. Jing, B. Xu, L. Yang, H. Liu, X. Shang, T. Jiang, Z. Li, H. Zhang, H. Li, et al. Safety and Efficacy of Biodegradable Polymer-Coated Sirolimus-Eluting Stents in "Real-World" Practice: 18-Month Clinical and 9-Month Angiographic Outcomes J. Am. Coll. Cardiol. Intv., April 1, 2009; 2(4): 303 - 309. [Abstract] [Full Text] [PDF]

				H. Hlawaty, M.-P. Jacob, L. Louedec, D. Letourneur, C. Brink, J.-B. Michel, L. Feldman, and M. Back Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 518 - 524. [Abstract] [Full Text] [PDF]

				L. K. Pendyala, J. Li, T. Shinke, S. Geva, X. Yin, J. P. Chen, S. B. King III, K. A. Robinson, N. A.F. Chronos, and D. Hou Endothelium-Dependent Vasomotor Dysfunction in Pig Coronary Arteries With Paclitaxel-Eluting Stents Is Associated With Inflammation and Oxidative Stress J. Am. Coll. Cardiol. Intv., March 1, 2009; 2(3): 253 - 262. [Abstract] [Full Text] [PDF]

				J. Aoki, A. J. Lansky, R. Mehran, J. Moses, M. E. Bertrand, B. T. McLaurin, D. A. Cox, A. M. Lincoff, E. M. Ohman, H. D. White, et al. Early Stent Thrombosis in Patients With Acute Coronary Syndromes Treated With Drug-Eluting and Bare Metal Stents: The Acute Catheterization and Urgent Intervention Triage Strategy Trial Circulation, February 10, 2009; 119(5): 687 - 698. [Abstract] [Full Text] [PDF]

				B. E. Stahli, G. G. Camici, and F. C. Tanner Drug-eluting stent thrombosis Therapeutic Advances in Cardiovascular Disease, February 1, 2009; 3(1): 45 - 52. [Abstract] [PDF]

				A. K.M. Hassan, S. C. Bergheanu, T. Stijnen, B. L. van der Hoeven, J. D. Snoep, J. W.M. Plevier, M. J. Schalij, and J. W. Jukema 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., January 21, 2009; (2009) ehn553v1. [Abstract] [Full Text] [PDF]

				M. Pfisterer, H. P. Brunner-La Rocca, P. Rickenbacher, P. Hunziker, C. Mueller, F. Nietlispach, G. Leibundgut, F. Bader, C. Kaiser, and for the BASKET Investigators 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., January 1, 2009; 30(1): 16 - 24. [Abstract] [Full Text] [PDF]

				R. Bakhshi, M.J. Edirisinghe, A. Darbyshire, Z. Ahmad, and A.M. Seifalian Electrohydrodynamic Jetting Behaviour of Polyhedral Oligomeric Silsesquioxane Nanocomposite J Biomater Appl, January 1, 2009; 23(4): 293 - 309. [Abstract] [PDF]

				F. Burzotta, A. Parma, C. Pristipino, A. Manzoli, F. Belloni, G. Sardella, S. Rigattieri, A. Danesi, P. Mazzarotto, F. Summaria, et al. Angiographic and clinical outcome of invasively managed patients with thrombosed coronary bare metal or drug-eluting stents: the OPTIMIST study Eur. Heart J., December 2, 2008; 29(24): 3011 - 3021. [Abstract] [Full Text] [PDF]

				L. O. Jensen, M. Maeng, P. Thayssen, A. Kaltoft, H. H. Tilsted, M. Bottcher, J. F. Lassen, K. N. Hansen, L. R. Krusell, K. Rasmussen, et al. Clinical Outcome After Primary Percutaneous Coronary Intervention With Drug-Eluting and Bare Metal Stents in Patients With ST-Segment Elevation Myocardial Infarction Circ Cardiovasc Interv, December 1, 2008; 1(3): 176 - 184. [Abstract] [Full Text] [PDF]

				N. L M Cruden, S. A Harding, and D. E Newby Coronary stent thrombosis in the perioperative period BMJ, November 24, 2008; 337(nov24_1): a2074 - a2074. [Full Text]

				B. Shoulders-Odom Management of Patients After Percutaneous Coronary Interventions Crit. Care Nurse, October 1, 2008; 28(5): 26 - 40. [Full Text] [PDF]

				E. R. Bates Primary Percutaneous Coronary Intervention With Drug-Eluting Stents: Another Chapter in the Stent Controversy Circ Cardiovasc Interv, October 1, 2008; 1(2): 87 - 89. [Full Text] [PDF]

				J. R. Costa Jr, A. Abizaid, R. Costa, F. Feres, L. F. Tanajura, A. Abizaid, L. A. Mattos, R. Staico, D. Siqueira, A. G.M.R. Sousa, et al. Preliminary Results of the Hydroxyapatite Nonpolymer-Based Sirolimus-Eluting Stent for the Treatment of Single De Novo Coronary Lesions: A First-in-Human Analysis of a Third-Generation Drug-Eluting Stent System J. Am. Coll. Cardiol. Intv., October 1, 2008; 1(5): 545 - 551. [Abstract] [Full Text] [PDF]

				M. Takano, M. Yamamoto, D. Murakami, S. Inami, K. Okamatsu, K. Seimiya, T. Ohba, Y. Seino, and K. Mizuno Lack of Association Between Large Angiographic Late Loss and Low Risk of In-Stent Thrombus: Angioscopic Comparison Between Paclitaxel- and Sirolimus-Eluting Stents Circ Cardiovasc Interv, August 1, 2008; 1(1): 20 - 27. [Abstract] [Full Text] [PDF]

				L. T. Newsome, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: Part I. Evolution of Percutaneous Coronary Intervention Anesth. Analg., August 1, 2008; 107(2): 552 - 569. [Abstract] [Full Text] [PDF]

				L. T. Newsome, R. S. Weller, J. C. Gerancher, M. A. Kutcher, and R. L. Royster Coronary Artery Stents: II. Perioperative Considerations and Management Anesth. Analg., August 1, 2008; 107(2): 570 - 590. [Abstract] [Full Text] [PDF]

				M. Joner, G. Nakazawa, A. V. Finn, S. C. Quee, L. Coleman, E. Acampado, P. S. Wilson, K. Skorija, Q. Cheng, X. Xu, et al. Endothelial Cell Recovery Between Comparator Polymer-Based Drug-Eluting Stents J. Am. Coll. Cardiol., July 29, 2008; 52(5): 333 - 342. [Abstract] [Full Text] [PDF]

				P. Holvoet and P. Sinnaeve Angio-Associated Migratory Cell Protein and Smooth Muscle Cell Migration in Development of Restenosis and Atherosclerosis J. Am. Coll. Cardiol., July 22, 2008; 52(4): 312 - 314. [Full Text] [PDF]

				T. Chechi, S. Vecchio, G. Vittori, G. Giuliani, A. Lilli, G. Spaziani, L. Consoli, G. Baldereschi, G. G.L. Biondi-Zoccai, I. Sheiban, et al. ST-segment elevation myocardial infarction due to early and late stent thrombosis a new group of high-risk patients. J. Am. Coll. Cardiol., June 24, 2008; 51(25): 2396 - 2402. [Abstract] [Full Text] [PDF]

				S. R. Dixon, C. L. Grines, and W. W. O'Neill The year in interventional cardiology. J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2355 - 2369. [Full Text] [PDF]

				S. S. Brar, J. Kim, S. K. Brar, R. Zadegan, M. Ree, I.-L. A. Liu, P. Mansukhani, V. Aharonian, R. Hyett, and A. Y.-J. Shen Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions. J. Am. Coll. Cardiol., June 10, 2008; 51(23): 2220 - 2227. [Abstract] [Full Text] [PDF]

				M. I. Hamilos, M. Ostojic, B. Beleslin, D. Sagic, L. Mangovski, S. Stojkovic, M. Nedeljkovic, D. Orlic, B. Milosavljevic, D. Topic, et al. Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2123 - 2129. [Abstract] [Full Text] [PDF]

				A. Jabs, S. Gobel, P. Wenzel, A. L. Kleschyov, M. Hortmann, M. Oelze, A. Daiber, and T. Munzel Sirolimus-induced vascular dysfunction increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2130 - 2138. [Abstract] [Full Text] [PDF]

				J. B. Muhlestein Endothelial dysfunction associated with drug-eluting stents what, where, when, and how? J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2139 - 2140. [Full Text] [PDF]

				M. H. Shishehbor, R. Amini, L. P.J. Oliveria, I. M. Singh, P. Kelly, D. L. Bhatt, S. R. Kapadia, S. G. Ellis, P. L. Whitlow, and S. J. Brener Comparison of Drug-Eluting Stents Versus Bare-Metal Stents for Treating ST-Segment Elevation Myocardial Infarction J. Am. Coll. Cardiol. Intv., June 1, 2008; 1(3): 227 - 232. [Abstract] [Full Text] [PDF]

				C. Filipe, L. Lam Shang Leen, L. Brouchet, A. Billon, V. Benouaich, V. Fontaine, P. Gourdy, F. Lenfant, J.-F. Arnal, A.-P. Gadeau, et al. Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2822 - H2830. [Abstract] [Full Text] [PDF]

				Y. Suzuki, F. Ikeno, T. Koizumi, F. Tio, A. C. Yeung, P. G. Yock, P. J. Fitzgerald, and W. F. Fearon In Vivo Comparison Between Optical Coherence Tomography and Intravascular Ultrasound for Detecting Small Degrees of In-Stent Neointima After Stent Implantation J. Am. Coll. Cardiol. Intv., April 1, 2008; 1(2): 168 - 173. [Abstract] [Full Text] [PDF]

				D. P. Taggart Does prior PCI increase the risk of subsequent CABG? Eur. Heart J., March 1, 2008; 29(5): 573 - 575. [Full Text] [PDF]

				F. Saia, A. Marzocchi, and A. Branzi Review: The safety of drug-eluting stents Therapeutic Advances in Cardiovascular Disease, February 1, 2008; 2(1): 43 - 52. [Abstract] [PDF]

				J. Aoki, A. Kirtane, M. B. Leon, and G. Dangas Coronary artery aneurysms after drug-eluting stent implantation. J. Am. Coll. Cardiol. Intv., February 1, 2008; 1(1): 14 - 21. [Abstract] [Full Text] [PDF]

				American College of Cardiology/American Heart Asso, 2007 Writing Group to Review New Evidence and Upda, S. B. King III, S. C. Smith Jr, J. W. Hirshfeld Jr, A. K. Jacobs, D. A. Morrison, and D. O. Williams 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention J. Am. Coll. Cardiol., January 15, 2008; 51(2): 172 - 209. [Full Text] [PDF]

				S. B. King III, S. C. Smith Jr, J. W. Hirshfeld Jr, A. K. Jacobs, D. A. Morrison, D. O. Williams, 2005 WRITING COMMITTEE MEMBERS, S. C. Smith Jr, T. E. Feldman, J. W. Hirshfeld Jr, et al. 2007 Focused Update of the 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: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee Circulation, January 15, 2008; 117(2): 261 - 295. [Full Text] [PDF]

				K. Egashira, K. Nakano, K. Ohtani, K. Funakoshi, G. Zhao, Y. Ihara, J.-i. Koga, S. Kimura, R. Tominaga, and K. Sunagawa Local Delivery of Anti-Monocyte Chemoattractant Protein-1 by Gene-Eluting Stents Attenuates In-Stent Stenosis in Rabbits and Monkeys Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2563 - 2568. [Abstract] [Full Text] [PDF]

				A. Kastrati, A. Dibra, C. Spaulding, G. J. Laarman, M. Menichelli, M. Valgimigli, E. Di Lorenzo, C. Kaiser, I. Tierala, J. Mehilli, et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction Eur. Heart J., November 2, 2007; 28(22): 2706 - 2713. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

				R. Jaffe and B. H. Strauss Late and Very Late Thrombosis of Drug-Eluting Stents: Evolving Concepts and Perspectives J. Am. Coll. Cardiol., July 10, 2007; 50(2): 119 - 127. [Abstract] [Full Text] [PDF]

				S. A. Spinler and R. L. Wilensky Duration of clopidogrel therapy after placement of drug-eluting intracoronary stent Am. J. Health Syst. Pharm., July 1, 2007; 64(13): 1432 - 1434. [Full Text] [PDF]

				A. V. Finn, G. Nakazawa, M. Joner, F. D. Kolodgie, E. K. Mont, H. K. Gold, and R. Virmani Vascular Responses to Drug Eluting Stents: Importance of Delayed Healing Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1500 - 1510. [Abstract] [Full Text] [PDF]

				T. Matsumoto and P. M. Hwang Resizing the Genomic Regulation of Restenosis Circ. Res., June 8, 2007; 100(11): 1537 - 1539. [Full Text] [PDF]

				G. S. Mintz What to Do About Late Incomplete Stent Apposition? Circulation, May 8, 2007; 115(18): 2379 - 2381. [Full Text] [PDF]

This Article Free upon publication Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lüscher, T. F. Articles by Virmani, R. Search for Related Content PubMed PubMed Citation Articles by Lüscher, T. F. Articles by Virmani, R. Related Collections Pathophysiology Arterial thrombosis AHA Statements and Guidelines Catheter-based coronary interventions: stents Acute coronary syndromes Acute myocardial infarction Related Article