2yrs 2-6yrs >6yrs BMS 0% 22% 42% DES 29% 41% Nakazawa et al. J Am Coll Cardiol 2011;57:

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1 Pathology of In-stent Neoatherosclerosis in BMS and DES 197 BMS, 103 SES, and 106 PES with implant duration >30 days The incidence of neoatherosclerosis was significantly greater in DES (31%) than BMS (16%; p < 0.001). Median stent duration with neoatherosclerosis was shorter in DES than BMS (420 days v 2,160 days, p < 0.001). 2yrs 2-6yrs >6yrs BMS 0% 22% 42% DES 29% 41% 7 BMS and 3 DES had TCFA or plaque rupture occurring with shorter implant durations for DES (1.5±0.4 years) compared to BMS (6.1± years). Nakazawa et al. J Am Coll Cardiol 2011;57:

2 Percentage of Patients With Atherosclerotic Changes in DES Versus BMS in Relation to Duration of Implant at Autopsy Nakazawa et al. J Am Coll Cardiol Img 2009;2:625-8

3 In-stent Morphologies and OFDI Appearance Histology Collagen-rich neointima Proteoglycan-rich neointima Fibrin deposition OFDI description bright and homogenous tissue, smooth luminal surface relatively dark tissues, smooth luminal surface relatively light around luminal area following by attenuation, heterogenous tissues with irregular surface Signal Analysis Intensity Attenuation Strong Gentle Medium Gentle Medium Moderate Lipid core dark area without clear borders, more cholesterol crystal content likely to be darker* Weak Steep Foamy Macrophage accumulation Organized thrombus thin bright layer and following shadow Very Strong Steep dark area independent of surrounding tissues Weak Angiogenesis One or numerous black holes NA NA Calcified neointima a dark mass delineated with clear borders Weak Gentle Sudden Virmani et al. J Am Coll Cardiol Img 2009;2:625-8

4 Disruption of neointima In-stent calcification Neoangiogenesis

5 Organized thrombus Ca++ Ca++

6 TCFA in neointima

7 Macrophage infiltration on luminal surface

8 OCT and In-stent Neoatherosclerosis after BMS - I <6months >5years # Lipid laden intimal 0 67% Intimal disruption 0 38% Thrombus 5% 52% Intraintimal neovasacularization 0% 62% Takano et al. J Am Coll Cardiol 2009;55:26-33 In 39 pts (60 BMS) who underwent OCT imaging 6.5±1.3ys after BMS implantation, lipid-rich neointima was found in 20 stents (33.3%) in 16 pts (41%) with an average fibrous cap thickness of 56.7±5.8µ. Six pts had plaque disruption and 6 patients had mural thrombus. Hou et al. Heart. 2010;96:

9 OCT and In-stent Neoatherosclerosis after BMS - II >5 years <1 year P-value # Homogeneous neointima* 39.5±28.5% 94.2±11.5% < Heterogeneous neointima* 60.5%±28.5% 5.8±11.5% < Microvessels* Peri-stent 25.6±18.6% 6.8±8.6% < Neointima 13.1±12.8% 0 < Disrupted neointima 18.6% Intraluminal material 20.9% 2.6% 0.02 With shadowing 16.2% Without shadowing 4.7% 2.6% 1.0 *of sections throughout the stent Habara et al. Circ Cardiovasc Interv 2011;4:232-8

10 Normal Intima and Atherosclerotic Intima Thrombus, Intimal Disruption, and Neovascularization Takano et al. J Am Coll Cardiol 2010;55:26-32

11 In-stent Neoatherosclerosis after DES (n=50, median follow-up of 32 months) 52% lesions had at least one in-stent TCFA-like neointima 58% had at least one in-stent neointimal rupture. Patients presenting with unstable angina showed Thinner fibrous cap (55µ vs. 100µ, p=0.006) Higher incidence of TCFA-like neointima (75% vs. 37%, p=0.008) Higher incidence of neointimal rupture (75% vs. 47%, p=0.044) Higher incidence of thrombi (80% vs. 43%, p=0.010) and red thrombi (30% vs. 3%, p=0.012) Kang et al. Circulation 2011;123:

12 (composite of TCFA-like neointima, neointimal rupture, and red thrombus)

13 Late in-stent neoatherosclerosis in DES Microvessel TCFA-like neointima Calcium Neointimal rupture

14 Red thrombus White thrombus

15 VH Composition of Neointima at Various Follow-Up Times in 117 ISR Lesions Combining 47 BMS and 70 DES >36Mo (n=26) 52.2* 5.6* 27.2* 15.0* 24-36Mo (n=15) 54.9* 7.1 # 25.8* 12.2* 12-24Mo (n=12) # 6-12Mo (n=42) <6Mo (n=22) (%) *p<0.01 and # p<0.05, vs. lesions at follow-up time <6 months Kang et al. Am J Cardiol. 2010;106:1561-5

16 VH Composition of Neointima at Various Follow-Up Times in 70 DES Restenosis Lesions >36Mo (n=0) 24-36Mo (n=10) 53.3* 6.2 # 26.4* 13.1* 12-24Mo (n=11) # 6-12Mo (n=33) <6Mo (n=16) (%) *p<0.01 and #p<0.05, vs. lesions at follow-up time <6 months

17 Various Neointimal VH Composition at the Maximal %IH Sites 6-mo Taxus %NC 8% %DC 2% 9-mo Taxus %NC 28% %DC 8% 22-mo Taxus %NC 39% %DC 20% 48-mo BMS %NC 40% %DC 25% 57-mo BMS %NC 57% %DC 15%

18 VH-IVUS comparison of neointimal hyperplasia within 23 DES vs 15 BMS Follow-up was similar between DES (38 mos) vs. BMS (40 mos). % NC volume was significantly greater in DES than BMS: 19.5% vs. 12.1% (p=0.006) significantly increased with time in BMS (p=0.007), but not in DES (p=0.24) was greater in DES than in BMS at at any given time point. VH-IVUS in-stent VH-TCFAs were detected only in DES: 34.8% vs. 0% (p=0.013) Wakabayashi et al. J Inv Cardiol 2011;23:262-8

19 Late DES Catch-Up Among IVUS Substudy Patients %IH volume 25 Cypher FIM (SR) Baseline Early* 2 years *defined as 4-9 months Cypher FIM (FR) ASPECT (low dose) ASPECT (high dose) TAXUS-II Double Dose Diabetes (single dose SES) Double Dose Diabetes (double dose SES) AMC (SES) AMC (PES)

20 IVUS analysis of 23 very late DES thrombosis cases at Asan Medical Center LSM was observed in 17 DES patients (73.9%) Disease progression with neointimal rupture within the stent was observed in 10 DES patients (43.5%) and reference segment plaque rupture in another 5 DES patients (21.7%) Lee et al. J Am Coll Cardiol 2010;55:

21 Proximal Distal mm

22 Correlation of IVUS Findings With Aspirates in 28 Patients with Very Late DES Thrombosis 28 pts with very late DES ST and 26 controls LSM in 73% of very late DES ST segments. Maximal LSM area measured 6.2±2.4mm 2, and length measured 9.4±9.5mm. LSM area exceeded 5.0mm 2 in 5 of 8 segments (63%) Controls WBCs p Eos p Spontaneous MI 291±94± 7±10± Early ST-BMS 146±117 1±1 Early ST-DES 73±117 1±2 Very late ST-BMS 84±50 2± Very late ST-DES 283±149 20±24 LSM area correlated with total eosinophil count (p=0.008) Cook et al. Circulation 2009;120:391-9

23 Comparison Among OCT, VH-IVUS, and Grayscale IVUS Neotintimal rupture OCT + OCT - Grayscale IVUS Grayscale IVUS TCFA VH-IVUS VH-IVUS Agreement=50% Agreement=78% Thrombus Grayscale IVUS Grayscale IVUS Agreement=44% Kang et al. Circulation 2011;123:

24 Conclusion There is emerging evidence -- from pathology, VH- IVUS, and especially OCT (but least with grayscale IVUS) -- of the development of in-stent neoatherosclerosis While not a universal finding, in-stent neoatherosclersis is more common in DES than in BMS and occurs earlier in DES than in BMS In-stent neoatherosclerosis is responsible for some cases of very late stent thrombosis as well as late catch-up (late in-stent restenosis).