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J Am Coll Cardiol, 2007; 49:181-184, doi:10.1016/j.jacc.2006.08.049 (Published online 28 December 2006).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Long-Term Outcomes After Management of Restenosis or Thrombosis of Drug-Eluting Stents

Gregory J. Mishkel, MD, FACC*,{dagger},{ddagger}, Anna L. Moore, MPH{dagger}, Steve Markwell, MA{ddagger}, M. Coleman Shelton{dagger} and Marc E. Shelton, MD, FACC*,{dagger},{ddagger},*

* Prairie Heart Institute at St. John’s Hospital, Springfield, Illinois
{dagger} Prairie Education & Research Cooperative, Springfield, Illinois
{ddagger} Southern Illinois University School of Medicine, Springfield, Illinois.

Manuscript received February 1, 2006; revised manuscript received August 10, 2006, accepted August 15, 2006.

* Reprint requests and correspondence: Dr. Marc E. Shelton, Prairie Cardiovascular Consultants, Ltd., Prairie Heart Institute, P.O. Box 19420, Springfield, Illinois 62794. (Email: mshelton{at}prairieheart.com).


   Abstract
Top
 Abstract
Patient Population and Methods
 Statistical analyses
 Results
 Discussion
 References
 
OBJECTIVES: The purpose of this study was to examine the outcomes of patients who developed coronary in-stent restenosis (ISR) or stent thrombosis (STH) inside drug-eluting stents (DES).

BACKGROUND: Drug-eluting stents have markedly reduced the incidence of restenosis. However, when restenosis occurs within a DES, its optimal management remains unclear.

METHODS: We retrospectively analyzed clinical and angiographic data from 92 patients who underwent revascularization for ISR (n = 84) or STH (n = 8) within a DES at our institution. Regular follow-ups were available up to 2 years. We recorded the occurrence of major adverse cardiac events (MACE), defined as deaths from all causes, myocardial infarction (MI), or target lesion revascularization (TLR), among patients treated by the "DES sandwich" technique or by other treatment methods.

RESULTS: In-hospital MACE included 1 periprocedural MI and 2 deaths. Over a mean follow-up of 15 ± 6 months, the overall rates of death, MI, and TLR were 8.7%, 2.2%, and 30.6%, respectively. By actuarial analysis, the 12-month TLR and MACE rates were 28.2% and 42.9%, respectively.

CONCLUSIONS: Current treatments of ISR or STH in DES are associated with a high long-term rate of MACE.

Abbreviations and Acronyms
  BMS = bare-metal stent(ing)
  DES = drug-eluting stents
  ISR = in-stent restenosis
  MACE = major adverse cardiovascular events
  MI = myocardial infarction
  PCI = percutaneous coronary intervention
  STEMI = ST-segment elevation myocardial infarction
  STH = stent thrombosis
  TLR = target lesion revascularization

Despite the marked decrease in major adverse cardiovascular events (MACE) attributable to drug-eluting stents (DES), in-stent restenosis (ISR) and stent thrombosis (STH) remain important clinical challenges. The "stent sandwich" technique (stent within a stent) has been applied with mixed results for restenosis after bare-metal stenting (BMS) (1–4). Little information is available, however, regarding the long-term results of this technique for ISR or STH of DES. We present our observations in consecutive patients who developed one of these adverse events after DES implantation.


   Patient Population and Methods
Top
 Abstract
 Patient Population and Methods
Statistical analyses
 Results
 Discussion
 References
 
We identified 92 consecutive patients who developed ISR (n = 84) or STH (n = 8) after DES implantation. All patients had received aspirin, 325 mg, before the initial procedure, followed by ≥75 mg daily indefinitely, along with clopidogrel or ticlopidine for ≥6 months.

The "homo-stent sandwich" technique consisted of re-stenting with the same DES, "hetero-stent sandwich" with a different DES, and "other" techniques included balloon angioplasty, insertion of a BMS, or brachytherapy. In-stent restenosis was defined as a >50% diameter stenosis within the first DES, or within 5 mm of its edges. The morphology of restenotic lesions has been described elsewhere (5). Major adverse cardiac events included death from all causes, myocardial infarction (MI), or target lesion revascularization (TLR). Myocardial infarction was defined as chest pain accompanied by new electrocardiographic changes consistent with ischemia and a creatine kinase (CK)-MB concentration >3-fold the upper normal limit. Target lesion revascularization was defined as re-intervention on the stented segment for chest pain or >70% stenosis on follow-up angiogram. Stent thrombosis was defined as an intraluminal filling defect with contrast staining on 3 sides, representing total or partial stent occlusion, present at the time of a clinically driven, repeat angiography. Patients were followed clinically at 6 months, and 1 and 2 years.


   Statistical analyses
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 Abstract
 Patient Population and Methods
 Statistical analyses
Results
 Discussion
 References
 
Discrete variables are reported as percentages and continuous variables as means ± SD. Chi-square or Fisher exact tests were used to compare discrete variables and Student t tests for continuous variables. Actuarial 6- and 12-month rates of MACE were examined by the Kaplan-Meier method. Values of p < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Patient Population and Methods
 Statistical analyses
 Results
Discussion
 References
 
Between May 2003 and December 2004, among 4,912 lesions treated with DES, 108 (92 patients) required clinically driven revascularization for ISR (n = 103) or STH (n = 8), including 64 lesions treated by homo-stent (61 sirolimus and 3 paclitaxel), and 22 hetero-stent (19 paclitaxel in sirolimus and 3 sirolimus in paclitaxel) sandwich. The other 22 lesions were treated with balloon angioplasty (n = 19), BMS (n = 2), or brachytherapy (n = 1). Within the study period, the clinical need for repeat revascularization within was only 2.2%. The clinical characteristics of the 92 patients who developed ISR/STH and those of 2,813 patients who remained ISR/STH-free are compared in Table 1. Patients who developed ISR/STH were more likely to be persons with diabetes, hypertensive and hypercholesterolemic, more often had histories of MI, prior coronary artery bypass graft surgery, or percutaneous coronary intervention (PCI), and had a lower prevalence of non–ST-segment elevation myocardial infarction (STEMI) and higher prevalence of unstable angina at presentation.


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  		Table 1. Clinical Characteristics of 92 Patients Who Developed ISR/STH in DES Versus Those of 2,813 Patients Who Remained Free of ISR/STH in DES (No ISR/STH)
 
The clinical and angiographic characteristics, and the indications for repeat PCI among the 92 patients, and among the 3 treatment subgroups, are shown in Table 2. Except for a higher prevalence of prior congestive heart failure in the "Others," these subgroups were similar. Three patients required 2 procedures during separate admissions for DES ISR in separate lesions. Clopidogrel was administered for an average of 14.6 ± 6.1 months.


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  		Table 2. Clinical and Angiographic Characteristics of Overall Population and of Each Treatment Group
 
Stent thrombosis occurred in 8 patients and resulted in STEMI in 6. Five patients had early STH within 30 days of implantation, and 3 had late STH after 180 days. Among these 6 STEMI patients, 1 died of MI at 212 days and 1 had recurrent STH at 71 days of follow-up. Two non-STEMI patients who had undergone repeat PCI for STH that occurred within 30 days of initial DES placement died in renal failure and cardiogenic shock, at 4 and 8 days, respectively, after the stent sandwich procedure.

Outcome data were available for 91 patients (99%). Over a mean follow-up of 15.0 ± 6.0 months, the overall rates of death, MI, and TLR were 8.7%, 2.2%, and 30.6%, respectively. The cumulative rates of in-hospital, 6-month, and 12-month adverse clinical events are summarized in Table 3. Recurrent restenosis recurred in 28 patients (30.4%) and 33 lesions (30.6%). Of 6 patients who died after hospital discharge, 3 died of MI at 19, 105, and 212 days, respectively, 1 died of end-stage heart failure at 718 days, 1 died of respiratory failure at 511 days, and 1 died of unknown cause at 219 days of follow-up. Outcomes among treatment subgroups were statistically similar, although the "hetero-stent" treatment group tended to have lower MACE rates and need for repeat revascularization at 12 months.


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  		Table 3. Cumulative In-Hospital, 6-Month, and 12-Month Adverse Clinical Events Among All Patients and in Each Treatment Group
 

   Discussion
Top
 Abstract
 Patient Population and Methods
 Statistical analyses
 Results
 Discussion
References
 
Although stent sandwich has mostly replaced brachytherapy, there is a paucity of data regarding treatments and outcomes in patients with DES restenosis. In contrast with the disappointing results of the RIBS (Restenosis Intrastent: Balloon angioplasty versus elective Stenting) study, where BMS ISR was treated with another BMS, the stent sandwich technique was superior to balloon angioplasty for the treatment of BMS ISR in the ISAR-DESIRE (Sirolimus-Eluting Stent or Paclitaxel-Eluting Stent vs. Balloon Angioplasty for Prevention of Recurrences in Patients With Coronary In-Stent Restenosis) study (6), and other studies have shown promising results with DES implanted for BMS ISR (3,4,7–9). Ours is the first report of the "real-world" performance of stent sandwich in a consecutive series of patients with DES ISR.

In the BMS era, STH was a rare event. It is noteworthy that 8 patients (8.7% of the study population) presented with STH, and that 4 (66.7%) either died or suffered recurrence of STH. This observation highlights recent reports suggesting that DES might be associated with a higher risk of STH, perhaps due to the polymer platform, delayed endothelization, or positive remodeling (10–15). Regardless of the underlying mechanism, it should be emphasized that DES patients who experience thrombotic events are probably at higher risk of recurrent STH, with its catastrophic consequences, than ISR.

The major adverse cardiovascular event rate, including overall mortality, was high in this population and could not be attributed to small vessel size (data not shown). However, patients who had MACE during follow-up had a higher proportion of saphenous vein graft and a lower percentage of edge restenosis. Tentative explanations for the high MACE rate after stent sandwich include: 1) enhanced allergic or inflammatory responses to the polymer or the drug; 2) excessive intimal hyperplastic response inadequately blocked by the drug or amount of drug delivered; 3) insufficient expansion or improper placement of the stent; and 4) individual predisposition to exaggerated neointimal hyperplasia.

Although the difference was not statistically significant, the hetero-stent treatment group tended to have more favorable outcomes at 12 months than the other groups. This might be explained by differences in the tissular response to the different DES, such that an initially poor response to 1 drug would be a signal to implant a DES that delivers another drug with different mechanisms of action. Finally, given the relatively high MACE rate in the DES ISR population, coronary artery bypass surgery should be considered as a viable treatment alternative for complex DES restenosis.

Study limitations.   Our observations were limited to the experience of a single medical center. The absence of randomization to treatment strategy and retrospective design are other limitations of this study, which might have been underpowered to detect differences among treatment strategies.


   Acknowledgments
 
The authors wish to acknowledge the editorial assistance of Dr. Rodolphe Ruffy in the review and revision of this manuscript.


   Footnotes
 
This study was funded, in part, by grants from Cordis Corporation, a Johnson & Johnson company, and from Boston Scientific. Dr. Mishkel has received consulting income from Cordis/Johnson & Johnson, Boston Scientific, Guidant/Abbott, and Medtronic.


   References
Top
 Abstract
 Patient Population and Methods
 Statistical analyses
 Results
 Discussion
 References
 

  1. Alfonso F, Auge JM, Zueco J, et al. RIBS Investigators Long-term results (three to five years) of the Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study J Am Coll Cardiol 2005;46:756-760.[Abstract/Free Full Text]
  2. Chu WW, Torguson R, Pichard AD, et al. Drug-eluting stents versus repeat vascular brachytherapy for patients with recurrent in-stent restenosis after failed intracoronary radiation J Invasive Cardiol 2005;17:659-662.[Medline]
  3. Degertekin M, Regar E, Tanabe K, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis J Am Coll Cardiol 2003;41:184-189.[Abstract/Free Full Text]
  4. 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 JAMA 2005;293:165-171.[Abstract/Free Full Text]
  5. Mehran R, Dangas G, Abizaid A, et al. Angiographic patterns of in-stent restenosis Circulation 1999;100:1872-1878.
  6. Kastrati A, Mehilli J, von Beckerath N, et al. ISAR-DESIRE study Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosisA randomized controlled trial. JAMA 2005;293:165-171.[Abstract/Free Full Text]
  7. Medina A, Suarez de Lezo J, Pan M, et al. Sirolimus-eluting stents for treatment of in-stent restenosis: immediate and late results Tex Heart Inst J 2005;32:11-15.[ISI][Medline]
  8. Holmes DR, Teirstein P, Satler L, et al. Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stentsThe SISR randomized trial. JAMA 2006;295:1264-1273.[Abstract/Free Full Text]
  9. Stone GW, Ellis SG, O’Shaughnessy CD, et al. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stentsThe TAXUS V ISR randomized trial. JAMA 2006;295:1253-1263.[Abstract/Free Full Text]
  10. 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]
  11. 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]
  12. Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent Circulation 2001;104:473-479.
  13. 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.
  14. Joner M, Finn A, Farb A, et al. Pathology of drug eluting stents in humansDelayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.[Abstract/Free Full Text]
  15. Feres F, Costa J, Abizaid A. Very late thrombosis after drug-eluting stents Catheter Cardiovasc Interv 2006;68:83-88.[CrossRef][ISI][Medline]



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