Drug-eluting stents (DES) have been shown to significantly reduce restenosis compared with bare-metal stents (BMS).1,2 Restenosis after BMS implantation is associated with a high rate (30% to 80%) of recurrence3 and carries a significant morbidity rate because it leads to frequent target lesion revascularization (TLR) and has been associated with acute myocardial infarction in approximately 10% of cases.4

The primary mechanism of restenosis after stenting is neointimal hyperplasia, which is likely due to exaggerated vascular smooth muscle cell proliferation in response to medial injury. DES were developed to reduce neointimal hyperplasia by delivering antiproliferative drugs to the angioplasty site. The three components of current DES are the stent struts (scaffolding that is usually made of a radiopaque metal with high radial strength), a biostable polymer that controls drug release and diffusion to the arterial wall, and the antiproliferative drug. Although frequently considered to be a single class, DES can be distinguished based on variations in these components (Table 1).

Since 2003, the US Food and Drug Administration (FDA) has approved four DES platforms: the earlier (frequently termed first-generation) DES include a sirolimuseluting stent (SES) (Cypher, Cordis Corporation, Bridgewater, NJ) and a paclitaxel-eluting stent (PES) (Taxus, Boston Scientific Corporation, Natick, MA). Newer or second-generation DES include a zotarolimuseluting stent (ZES) (Endeavor, Medtronic, Inc., Minneapolis, MN) and an everolimus-eluting stent (EES) (Xience, Abbott Vascular, Santa Clara, CA/Promus, Boston Scientific Corporation). This article reviews the early benefits of first-generation DES, subsequent subsequent safety concerns related to late stent thrombosis with these devices, and notes potential advantages of newer designs that may have similar effectiveness with a lower risk for late stent thrombosis.

EFFECTIVENESS AND EARLY SAFETY OUTCOMES FOR FIRST-GENERATION DES
The pivotal clinical trials of the SES and PES versus their respective BMS counterparts demonstrated approximately 70% relative reduction in TLR at 1 year.5,6 Although such dramatic reductions in clinical restenosis were unprecedented, clinicians were further encouraged by the absence of any apparent increase in stent thrombosis during 1-year follow-up, with rates for DES and BMS at approximately 1% in these pivotal clinical trials, as well as in a subsequent meta-analysis that provided more precision for this estimate.7

After equally encouraging results in small registry studies of more complex lesions,8,9 there was widespread use of SES and PES, including in an array of lesion subsets that had not been included in the pivotal studies for FDA approval. By late 2005, DES were used in more than 90% of the stent procedures performed in the United States.

In the spring and summer of 2006, concerns were raised due to reported observations of increased death and myocardial infarction beyond the first year after DES implantation. The evidence included a post hoc analysis of the BASKET (Basel Stent Kosten Effektivitäts) study, which included 746 patients who survived free of major events and had a significantly higher risk for death or myocardial infarction (MI) between 6 and 18 months, possibly due to more stent thromboses.10 Meta-analyses of the DES clinical trials added to the controversy by reporting increased all-cause death or Q-wave MI for SES versus BMScontroversy by reporting increased all-cause death or Q-wave MI for SES versus BMScontroversy by reporting increased all-cause death or Q-wave MI for SES versus BMS11 in the SES trials at 3 years and increased noncardiac mortality after 1 year for SES but not PES compared with BMS.12 Finally, an incomplete report of 3-year follow-up data from the large, nonrandomized Swedish registry showing increased late mortality for DES compared with BMS fueled the firestorm.13 Much of the concern regarding increased mortality was later tempered by findings of no increase in death or MI for DES compared with BMS in patient-level analyses of 4-year follow-up data of the SES and PES pooled clinical trials.14 There was also a report of more complete 5-year follow-up of the Swedish registry that no longer showed an increase in mortality for DES compared with BMS at any time point.15 The importance of a possible increased risk for late stent thrombosis and the possible relationship to timing of dual-antiplatelet therapy discontinuation had been highlighted as major concerns for ongoing and subsequent clinical trials.11 in the SES trials at 3 years and increased noncardiac mortality after 1 year for SES but not PES compared with BMS.12 Finally, an incomplete report of 3-year follow-up data from the large, nonrandomized Swedish registry showing increased late mortality for DES compared with BMS fueled the firestorm.13 Much of the concern regarding increased mortality was later tempered by findings of no increase in death or MI for DES compared with BMS in patient-level analyses of 4-year follow-up data of the SES and PES pooled clinical trials.14 There was also a report of more complete 5-year follow-up of the Swedish registry that no longer showed an increase in mortality for DES compared with BMS at any time point.15 The importance of a possible increased risk for late stent thrombosis and the possible relationship to timing of dual-antiplatelet therapy discontinuation had been highlighted as major concerns for ongoing and subsequent clinical trials.11 in the SES trials at 3 years and increased noncardiac mortality after 1 year for SES but not PES compared with BMS.12 Finally, an incomplete report of 3-year follow-up data from the large, nonrandomized Swedish registry showing increased late mortality for DES compared with BMS fueled the firestorm.13 Much of the concern regarding increased mortality was later tempered by findings of no increase in death or MI for DES compared with BMS in patient-level analyses of 4-year follow-up data of the SES and PES pooled clinical trials.14 There was also a report of more complete 5-year follow-up of the Swedish registry that no longer showed an increase in mortality for DES compared with BMS at any time point.15 The importance of a possible increased risk for late stent thrombosis and the possible relationship to timing of dual-antiplatelet therapy discontinuation had been highlighted as major concerns for ongoing and subsequent clinical trials.

LATE AND VERY LATE STENT THROMBOSIS FOR FIRST-GENERATION DES VERSUS BMS
At the time of the controversy regarding possible increased late mortality after DES, post hoc analyses of SES and PES clinical trials showed a small but significant increase in stent thrombosis events occurring after 1 year.14 However, it became evident that the definitions of stent thrombosis used in the various clinical trials were nonuniform and had perhaps biased the analysis in favor of BMS by excluding any stent thrombosis that occurred after TLR. A consortium of academic researchers, FDA, and industry was formed to develop standardized clinical trial definitions for endpoints, including stent thrombosis (Table 2).16 The Academic Research Consortium (ARC) has recommended the definite plus probable classification for reporting stent thrombosis events. When this definition was applied across the pooled SES and PES clinical trials, there was no difference during 4-year follow-up for either DES compared with the BMS counterpart.17 Although there were numerically more events in the DES groups beyond 1 year (very late stent thrombosis [VLST]), the difference was no longer significant, and it was observed that events continued to accrue after both DES and BMS implantation. Of note, in the BMS arms, stent thrombosis was associated with prior TLR, with eight of 11 incidences of VLST occurring in patients with intervening TLR. Furthermore, seven of these eight patients had also undergone intracoronary brachytherapy at the time of at least one TLR before the stent thrombosis event. With 5-year follow-up now reported, the frequency of VLST in the SIRIUS (Sirolimus-Eluting Stent for Native Coronary Lesion) trial is almost identical for SES versus BMS (0.8% vs 0.7%),20 whereas in the TAXUS IV trial, the frequency for PES versus BMS is similar (1.4% vs 1%).21

STENT THROMBOSIS AND SECOND-GENERATION DES
Clinical trials using the second-generation EES and ZES have suggested possibly lower rates of VLST (Table 3). At 3 years, in the SPIRIT III (Clinical Evaluation of the Xience V Everolimus-Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) trial, VLST occurred in 0.3% of EES versus 1% of PES (P = .34).18 Interestingly, lower rates of ST at 2 years were also noted in EES patients who discontinued thienopyridine after 6 months of stent implantation compared to their counterpart in the PES arm (0.4% vs 2.6%; P = .10).22 In SPIRIT III, rates of early and late stent thrombosis were similar after EES or PES, and the observed differences in VLST were not statistically significant. Whether longer-term follow-up and larger numbers of patients will confirm these findings or demonstrate significance of the VLST differences requires further study. The differences may also be more significant when more complex lesions are treated. In the SPIRIT IV trial of real-world lesions, a 74% reduction in stent thrombosis was seen even at 1 year for EES compared with PES (0.29% vs 1.1%; P = .004).23

The ZES Endeavor stent system also had less VLST compared with the PES control in the ENDEAVOR IV trial. At 3 years, this difference was highly significant (0.1% vs 1.5%; P = .006), with only one VLST in the ZES group and 11 in the PES group. Interestingly, five of 11 VLST in the PES group occurred during continued dual-antiplatelet therapy (4/11 were taking aspirin alone), whereas the patient who had VLST in the Endeavor group was not taking dual-antiplatelet therapy. 19 Furthermore, pooled studies including more than 2,100 ZES patients (with 5-year follow-up of 1,199 patients) have demonstrated similarly low rates of VLST for ZES compared with the BMS counterpart (0.2% vs 0.3%), representing only two VLST events in the ZES group (Figure 1).24

MECHANISMS FOR STENT THROMBOSIS AND POTENTIAL EFFECTS OF NEW STENT DESIGNS
Early (0–30 days) and late (31 days–1 year) stent thrombosis occurs with nearly equal frequency after BMS and each of the four approved DES types. The predictors of stent thrombosis are also similar within the early and late time intervals and across stent types and include various patient, lesion, and procedural characteristics.25-27 The most important of these factors for early or late stent thrombosis are stent length, residual dissection, diabetes, stent underexpansion, bifurcation lesion, and premature discontinuation of dual-antiplatelet therapy. Although easier delivery and possible lower inflammatory scores related to thinner struts may result in reduced risk for early or late stent thrombosis for the second-generation devices, it is more likely that the technical facets of the procedure and the particularly critical role of dual-antiplatelet therapy in this time period make stent design a less important contributor.

However, VLST after DES is almost entirely related to delayed healing.28-32 Although the effect may be greater with certain lesion types, such as bifurcation and ST-elevation MI culprit lesions, the impact of procedural or technical factors appears to be less, and the biological response to individual DES seems to be a more critical factor. Other factors, such as persistent fibrin and increase in inflammatory cells, are associated with impaired healing response and may lead to late malapposition, which is more frequent in patients with VLST.33

There are several design features that may affect healing. First, flow disturbances caused by increased strut thickness may be a deterrent of endothelial coverage.34 The effect of drug concentration and potential local toxicity may also increase inflammation and interfere with healing.29,32 Nonabsorbable polymers used in first-generation DES have been recognized as an important contributor to VLST, with observed inflammatory reactions due to hypersensitivity or late polymer breakdown.28,31

As a three-component system, newer designs can improve healing and reduce the risk of stent thrombosis by improvement in any of these areas. As noted in Table 1, the EES and ZES have thinner struts, while the EES also has a substantially lower total dose. Both newer devices also have markedly thinner polymers, with other unique polymer characteristics that may increase biocompatibility and reduce inflammatory response.

CONCLUSION
Future improvements in DES technology may provide even safer DES with further reductions in stent thrombosis. Such technological improvements include a next-generation DES with bioabsorbable polymers or a polymerfree DES, and the eventual availability of a totally bioabsorbable stent.

Amjad T. AlMahameed, MD, MPH, is Director of Vascular Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein.

Donald E. Cutlip, MD, is Section Chief, Interventional Cardiology, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts. He has disclosed that he receives grant/research funding from Medtronic, Inc. Dr. Cutlip may be reached at (617) 632-9206; dcutlip@bidmc.harvard.edu.

  1. 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.
  2. 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.
  3. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999;100:1872-1878.
  4. Chen MS, John JM, Chew DP, et al. Bare-metal stent restenosis is not a benign clinical entity. Am Heart J. 2006;151:1260-1264.
  5. Holmes DR Jr, Leon MB, Moses JW, et al. Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation. 2004;109:634-640.
  6. Stone GW, Ellis SG, Cox DA, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation. 2004;109:1942-1947.
  7. Moreno R, Fernandez C, Hernandez R, et al. Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies. J Am Coll Cardiol. 2005;45:954-959.
  8. 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.
  9. 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.
  10. 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 baremetal stents. J Am Coll Cardiol. 2006;48:2584-2591.
  11. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drugeluting stents: a cause for concern. Circulation. 2007;115:1440-1455.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344-2351.
  17. Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356:1020-1029.
  18. Stone GW. SPIRIT III clinical results. Presented at: Transcatheter Therapeutics Conference; September 2009; San Francisco, CA.
  19. Leon MB. Endeavor IV clinical results and update. Presented at: Transcatheter Therapeutics Conference; September 2009; San Francisco, CA.
  20. Weisz G, Leon MB, Holmes DR Jr, 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.
  21. 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). JACC Cardiovasc Interv. 2009;2:1248-1259.
  22. Stone GW, Midei M, Newman W, et al. Randomized comparison of everolimus-eluting and paclitaxel- eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with De Novo Native Coronary Artery Lesions (SPIRIT) III trial. Circulation. 2009;119:680-686.
  23. Stone GW. SPIRIT IV: A prospective, randomized trial comparing an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease. One-year clinical results. Presented at: Transcatheter Therapeutics Conference; September 2009; San Francisco, CA.
  24. Kanzari DE, Leon MB, Wijns W, et al. Long-term clinical results of the Endeavor program: 5-year follow-up. J Am Coll Cardiol. 2010;55A:1805.
  25. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103:1967-1971.
  26. 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.
  27. 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.
  28. 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.
  29. Finn AV, Kolodgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation. 2005;112:270- 278.
  30. Nakazawa G, Finn AV, Joner M, et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation. 2008;118:1138-1145.
  31. Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug-eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007;27:1500-1510.
  32. 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.
  33. 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.
  34. 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.