1. In-Stent Restenosis and Late Stent Thrombosis
Daniel M Kolansky MD
Associate Professor of Medicine
University of Pennsylvania Medical Center
Director, Cardiac Care Unit
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania USA
August 2011

2. Disclosures
No relevant disclosures or conflicts of interest within the past twelve months

3. Stent Restenosis Pathophysiology of restenosis is different
Balloon angioplasty restenosis:
occurs primarily because of elastic recoil and negative remodeling of the vessel
Stent restenosis:
occurs primarily because of neointimal hyperplasia
Cutlip et al. JACC 2002; 40:2082-9

4. Restenosis after angioplasty or atherectomy: early adaptive enlargement and then late vessel constriction
From Kimura et al Circulation 1997: 96:475. Courtesy of Jeff Popma MD
Values are in mm2.

5. Stent Restenosis Different mechanism than after balloon angioplasty
Stent restenosis is secondary to tissue ingrowth (neointimal hyperplasia) within the stent

6. Pathway Leading to In-Stent Restenosis After Stent Implantation
Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42
Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply.

7. In-Stent Restenosis: Definitions
“Angiographic” Restenosis
Late lumen loss with > 50% diameter stenosis in follow-up
“Clinical” Restenosis
Symptom or ischemia recurrence with >50% diameter stenosis,
Or >70% diameter stenosis without symptoms
Modified from Dangas et al. JACC 2010; 56:

8. In-Stent Restenosis after Bare Metal Stenting
STRESS and BENESTENT (1994) – original BMS trials
improved initial result (larger MLD) with stenting and reduction in 6 month restenosis compared to balloon angioplasty
Angiographic Restenosis Rate at 6 months:
About 30%
Clinical Restenosis (TLR) at 6 months:
About 10%
Serruys PW et al. N Engl J Med 1994;331
Fischman DL et al. N Engl J Med 1994;331:

9. Benestent Trial: Stent vs Balloon Angioplasty
Figure 1. Cumulative Frequency Distribution Curves for the Two Study Groups, Showing Minimal Luminal Diameters Measured before and after Intervention and at Follow-up, the Percentage of Stenosis at Follow-up, and the Percentage of Patients with Clinical End Points. Significant differences were apparent that consistently favored the stent group over the angioplasty group with respect to the increased minimal luminal diameter at intervention (Panel A) and follow-up (Panel B), the percentage of stenosis at follow-up (Panel C), and the incidence of major clinical events (Panel D). The vertical dashed line in Panel D indicates the end of the study.
Serruys PW et al. N Engl J Med 1994;331:

10. STRESS Trial: BMS vs Angioplasty
Kaplan-Meier Curves for Revascularization of the Target Lesion
Figure 2. Kaplan-Meier Curves for Revascularization of the Target Lesion. Fewer patients in the stent group than in the angioplasty group required revascularization of the target lesion because of ischemia.
Fischman DL et al. N Engl J Med 1994;331:

11. Minimal Lumen Diameter at Base Line, Immediately after Stent Placement or Angioplasty, and at Follow-up
Figure 1. Minimal Diameter of the Lumen at Base Line, Immediately after Stent Placement or Angioplasty, and at Follow-up. There was no difference in base-line values between the stent and angioplasty groups. Immediately after the procedure, the patients in the stent group had a larger minimal luminal diameter than those in the angioplasty group. Six months later, both groups had reduced values, and a significant difference in diameter persisted between the two groups.
Fischman DL et al. N Engl J Med 1994;331:

12. BMS: Clinical Restenosis
Continues to increase out to about 1 year
Usually about half of angiographic restenosis rate

13. Clinical restenosis rates: target lesion revascularization (TLR), target vessel revascularization (TVR), or target vessel failure (TVF):
at 6, 9, or 12 months
Cutlip, D. E. et al. J Am Coll Cardiol 2002;40:

14. Long-Term Clinical Outcomes of SES, BMS, and CABG in ARTS I and II
Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42

15. Predictors of clinical restenosis
Final Minimum Lumen Diameter (MLD)
Reference Diameter
Stent length
Lesion length
Diabetes
From Cutlip et al; JACC 2002; 40:2082-9

16. Patterns of In-Stent Restenosis
Focal
Diffuse
Articulation or Gap
Margin
Intra-stent
Proliferative
Total Occlusion
Focal Body
Multifocal
Adapted from Mehran R et al. Circulation 1999;100:
Courtesy of Popma, J

17. In-Stent Restenosis after Drug Eluting Stenting (DES)

18. Drug Eluting Stents: Restenosis
Substantial reduction in angiographic restenosis and in Target Lesion Revascularization compared to BMS
Similar long term results for both Sirolimus- eluting stents (SES) and Paclitaxel-eluting stents (PES)
Some very late stent restenosis does occur
Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42
Raber L. SIRTAX-LATE; TCT: September 22, 2009; San Francisco, CA

19. Cypher Sirolimus DES vs Bare Metal Stent
(SIRIUS TRIAL)
Figure 2. Rates of Target-Lesion Revascularization (Either Percutaneous Transluminal Coronary Angiography or Coronary-Artery Bypass Grafting) and Odds Ratios at 270 Days for Various Subgroups of Patients. For the analyses in terms of vessel diameter and lesion length, the variable was dichotomized at the median value. P<0.001 for all comparisons between groups. CI denotes confidence interval.
Moses JW et al. N Engl J Med 2003;349:

20. Late TLR “Creep” seen with All DES in long term followup
Endeavor II
(n=581/598)
Sirius
(n=501/525)
Taxus IV
(n=618/650) R 2 = R 2 = R 2 = 10 10 10
9.4
9.1 8 8 8
7.9
7.8
7.2
7.2
6.8
6.9 6
6.5 6 6
5.9
TLR (%)
6.3
TLR (%)
5.6
4.9 4 4 4
4.4 2 2 2
n/a 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Years of Follow-up
Years of Follow-up
Years of Follow-up
4 Year Clinical Results of TAXUS IV, Stone, ACC 2006
4 year Outcomes in the Sirius Trial, Leon, TCT 2006
Endeavor II 4 year : Fajadet et al. PCR 2008
Modified from Popma, J

21. Possible Mechanisms of Restenosis after DES
Biological Factors
Drug resistance
Hypersensitivity
Mechanical Factors
Stent underexpansion or nonuniform strut distribution
Stent fracture
Technical Factors
Barotrauma outside stented segment
Residual uncovered atherosclerotic plaque
Modified from Dangas et al. JACC 2010; 56:

22. Stent Underexpansion
from Dangas et al. JACC 2010; 56:

23. Stent Fracture
from Dangas et al. JACC 2010; 56:

24. Patterns of DES restenosis affect subsequent outcome
Study of 250 restenotic DES lesions
Divided into focal (65%) and nonfocal (35%)
Treated with repeat DES (57% of focal, 69% of nonfocal), or POBA
Recurrent restenosis occurred in only 18% of focal lesions vs 51% of nonfocal lesions
TLR higher in the nonfocal group as well (10% vs 23%)
Diabetes also a strong predictor of recurrent restenosis
Cosgrave et al. J Am Coll Cardiol 2006;47:2399–404

25. Treatment of In-Stent Restenosis
IVUS useful to identify fracture, underexpansion
Underexpansion: treat with high pressure balloon angioplasty
Focal instent restenosis: a role for balloon angioplasty
DES placement most common treatment for ISR of either BMS or DES
Brachytherapy remains an option for recurrent stent restenoses

26. DES is the Treatment of Choice for In-Stent Restenosis
Two trials of DES for in-stent restenosis of BMS
SISR Randomized Trial: Sirolimus-eluting stents result in superior clinical and angiographic outcomes
TAXUS V ISR Randomized Trial: reduced clinical and angiographic restenosis at 9 months and improved event-free survival.
Holmes, D. R. et al. JAMA 2006;295:
Stone, G. W. et al. JAMA 2006;295:
Mukherjee, D and Moliterno, D. JAMA. 2006;295(11):

27. Target Vessel Failure after Sirolimus DES or vascular brachytherapy for BMS in-stent restenosis: 12% vs 22%
Figure 3. Target Vessel Failure The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk, 1.7; 95% confidence interval, ; P = .02). P = .02 by the Wilcoxon test and P = .01 by the log-rank test. Error bars indicate ±1.5 times the SE.
Holmes, D. R. et al. JAMA 2006;295:

28. Paclitaxel-DES or vascular brachytherapy for BMS in-stent restenosis
Cumulative Event Rates to 9 months for :
Ischemic Target Lesion Revascularization
Ischemic Target Vessel Revascularization,
Major Adverse Cardiac Events to 9 Months
Stone, G. W. et al. JAMA 2006;295:

29. DES for treatment of DES restenosis
Only one randomized trial: ISAR-DESIRE 2
Sirolimus (SES) or Paclitaxel (PES) stents for Sirolimus in-stent restenosis
Angiographic restenosis 20%
TLR about 16%
No difference between SES or PES
Mehilli, J. et al. J Am Coll Cardiol 2010;55:

30. ISAR DESIRE-2: DES for DES In-Stent Restenosis:
Angiographic Restenosis at 6 to 8 Months and Clinical Restenosis at 1 Year
Mehilli, J. et al. J Am Coll Cardiol 2010;55:

31. Algorithm for the Treatment of DES Restenosis
Dangas, G. D. et al. J Am Coll Cardiol 2010;56:

32. Stent Thrombosis

33. Stent Thrombosis Infrequent but serious complication:
Occurs from 0.6% to 5% in studies
Substantial mortality associated with stent thrombosis
Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42

34. Stent Thrombosis: a Multifactorial Problem
Lesion
Long lesions
Small diameter
Multivessel
AMI
Diabetes
Bifurcations
Technical
Underexpansion
Incomplete wall apposition
Crush technique
Overlapping
Stent
Thrombosis
Stent Thrombosis is a local problem, like restenosis. We can try to passivate every platelet, but at a high risk to the patient, OR we can make stents less thrombogenic with a passivating strategy.
Stent
Material
Polymer Matrix
Antirestenosis agent
Patient
Antiplatelet noncompliance
Plavix bioavailability
Adapted and modified from: Kereiakes D., et. al., Rev Cardiovasc Med. 2004;5(1):9-15.
Courtesy of Popma, J

35. Risk Factors
Strongest predictor: absence of clopidogrel at the time of the event
Ongoing long term studies to determine optimal duration of dual antiplatelet therapy
From Garg, S. et al. J Am Coll Cardiol 2010;56:S1-S42

36. Stent Thrombosis: ARC Definitions
ARC Categories of evidence:
Definite - Angiographic-pathological conformation
Probable - Unexplained death < 30 days or Target vessel MI
Possible - Unexplained death > 30 days
ARC Timing
Acute: 0 – 24 h post stent implantation
Sub-acute: 2 – 30 days
Late: > 30 days – 1 year
Very late: > 1 year
Adapted from Cutlip DE, et al. Circulation. 2007;115;

37. DES and Stent Thrombosis
Early concerns raised of increased rates of late stent thrombosis with DES
Appropriate dual antiplatelet therapy is required (DAT)
Period of risk requiring DAT is longer with DES due at least in part to delayed neointimal coverage
Pfisterer M, et al, for the BASKET-LATE Investigators. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol. 2006; 48: 2584

38. DES and BMS Stent Thrombosis
Stent thrombosis rates not significantly different between BMS and DES in more recent analyses
Stent thrombosis rates for DES
SIRIUS Trial: 0.7% (one yr) to 1.2 % (five yr)
Real world data: 3.3% (4 yr, Bern-Rotterdam)
Weisz G, et al. Five-year follow-up after sirolimus-eluting stent implantation results of the SIRIUS Trial. J Am Coll Cardiol 2009; 53:1488 .
Wenaweser P, et al Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol. 2008;52: 1134.
Mauri, L et al. Stent Thrombosis in Randomized Clinical Trials of Drug-Eluting.N Engl J Med 2007; 356:

39. Stent Thrombosis for DES vs BMS: No significant difference
 The overall occurrence of stent thrombosis was not different between treatment groups.
Roiron C et al. Heart 2006;92:

40. Stent Thrombosis for DES or BMS in STEMI
No significant difference between DES or BMS in several studies out to 3-5 years
Suggestion that LST and VLST may be more common after DES (single study)
Brodie, B. et al. J Am Coll Cardiol Intv 2011;4:30-38
Ziada, K, Charnigo, R, Moliterno, D. J Am Coll Cardiol Intv 2011;4:39-41

41. SIRTAX Late: concerns for ongoing incidence of late thrombosis
Raber L. SIRTAX-LATE: : TCT; September 22, 2009; San Francisco, CA

42. Mortality after DES
Concerns raised about excess mortality with DES compared to BMS, perhaps related to late stent thrombosis
Long term outcomes appear to be equivalent in recent large trials:
SCAAR Registry 2009: no difference
James SK et al for the SCAAR Study Group. N Engl J Med 2009;360:
Kirtane AJ, et al. Safety and Efficacy of Drug-Eluting and Bare Metal Stents. Comprehensive Meta-Analysis of Randomized Trials and Observational Studies. Circulation. 2009; 119:

43. Meta-analysis of all-cause mortality with DES vs BMS
No difference seen
Group A
Randomized Clinical Trials
Group B
Observational Data
Kirtane A J et al. Circulation 2009;119:

44. Summary Stent Restenosis incidence has declined
Newer generation stents
Better implantation technique
Widespread use of DES
Treatment of in-stent restenosis: DES
Stent Thrombosis
Implantation technique important
Appropriate duration of dual antiplatelet therapy
Ongoing trials