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

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

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

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.

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

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.

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; 56:1897-1907

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;331:496-501.

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;331:489-495.

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;331:496-501.

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;331:496-501.

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

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;40:2082-2089

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

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

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;100:1872-78 Courtesy of Popma, J

In-Stent Restenosis after Drug Eluting Stenting (DES)

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

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;349:1315-1323.

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 = 0.9524 R 2 = 0.9762 R 2 = 0.9973 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

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; 56:1897-907

Stent Underexpansion from Dangas et al. JACC 2010; 56:1897-1907

Stent Fracture from Dangas et al. JACC 2010; 56:1897-1907

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

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

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;295:1264-1273 Stone, G. W. et al. JAMA 2006;295:1253-1263 Mukherjee, D and Moliterno, D. JAMA. 2006;295(11):1307-1309.

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, 1.1-2.8; 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;295:1264-1273

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;295:1253-1263

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;55:2710-2716

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;55:2710-2716

Algorithm for the Treatment of DES Restenosis Dangas, G. D. et al. J Am Coll Cardiol 2010;56:1897-1907

Stent Thrombosis

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

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

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

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;2344-2351

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

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; 356:1020-1029.

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;92:641-649

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

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

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;360:1933-1945. 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: 3198-320

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;119:3198-3206

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