SIROLIMUS-ELUTING STENTS EFFECTIVELY INHIBIT NEOINTIMAL PROLIFERATION AS COMPARED TO BARE METAL STENTS IN DISEASED SAPHENOUS VEIN GRAFTS: 6-month IVUS results of the RRISC trial

PCI in SVG Percutaneous coronary intervention with stenting as a treatment of diseased vein grafts (6-15% of PCI volume) is associated with: Percutaneous coronary intervention with stenting as a treatment of diseased vein grafts (6-15% of PCI volume) is associated with:  A poor immediate outcome:  distal embolization  A poor long term outcome:  Restenosis (35-60 %) 1,2  Progression of disease of the non-treated segments (native and vein graft) 3 1 Savage et al, NEJM Choussat et al, J Am Coll Cardiol Ellis et al, Am J Cardiol 1997 DES!? DES !? Protectiondevices

RRISC Trial Reduction of Restenosis In Saphenous vein grafts with Cypher sirolimus-eluting stent Prospective, randomized, double-blind, non industry sponsored, trial comparing sirolimus-eluting stents vs. bare metal stents. Prospective, randomized, double-blind, non industry sponsored, trial comparing sirolimus-eluting stents vs. bare metal stents. 75 patients with 96 lesions localized in 80 diseased saphenous vein grafts were included 75 patients with 96 lesions localized in 80 diseased saphenous vein grafts were included Primary endpoint : in-stent late loss Primary endpoint : in-stent late loss Secondary endpoints: Secondary endpoints:  Clinical events (death, MI, TLR, TVR)  Binary angiographic restenosis in-stent/in-segment  IVUS measured neo-intimal hyperplasia volume

Major Inclusion Criteria De novo lesion (stenosis >50%) in a diseased SVG Diameter ranging between 2.5 and 4.0 mm Diagnosis of angina pectoris Osial stenoses & thrombotic/calcific stenoses were allowed No maximum lesion length prespecified Major Exclusion Criteria Impaired renal function Prior stent within 5 mm of target lesion Totally occluded vein grafts Documented LV Ejection Fraction <25% Distal anastomotic stenosis Prior brachytherapy in the index vessel

Late Loss Analysis p=0.001 p=0.9 p= p=0.01 Prox edgeDist edgeIn-stentIn-segment BMS SES

Binary Restenosis In-segment %30.6% 13.6%32.7% p=0.024 p=0.031 In-stent Δ=19.1% RRR=0.58 Δ=19.2% RRR=0.63 BMS SES

6-months Clinical Events BMS n=37 SES n=38 P value In-hospital Death00 Repeat revascularization00 Periprocedural MI1 (2.7%)2 (5.3%)0.99 Between discharge and 6 months Death01 (2.6%)0.99 Myocardial infarction01 (2.6%)0.99 TLR (per-patient)8 (21.6%)2 (5.3%)0.047 TVR (per-patient)10 (27%)2 (5.3%)0.012 Cumulative 6-month MACE11 (29.7%)6 (15.8%)0.15 TVF (per-patient)11 (29.7%)5 (13.2%)0.08

Methods for IVUS Analysis Curad, version 4.32: - semi-automated detection of luminal and stent boundaries in L-mode views Intelligate TM image-based gating method: - elimination of catheter-induced artifacts (saw-tooth appearance), by retrospective selection of end-diastolic frames - selection of 2 IVUS frames/mm for data analysis Detection of stent struts and luminal-intima surface borders: - Volumetric quantitative ultrasound analysis for stent and lumen. - Neo-intimal hyperplasia volume computed as the difference between stent and lumen volume

ClinicalcharacteristicsBMS patients=30 grafts=32 SES patients=29 grafts=29 P value Age (years) 72 ± 8 73 ± Men 26 (86.7%) 23 (79.3%) 0.50 Risk factors: Family history 24 (80.0%) 18 (62.1%) 0.16 Hypertension 18 (60.0%) 20 (69.0%) 0.30 Hypercholesterolemia 25 (83.4%) 25 (86.2%) 0.91 Current smoker 4 (13.3%) 1 (3.4%) 0.39 Diabetes Mellitus 5 (16.7%) 4 (13.8%) 0.99 Body mass index (Kg/m 2 ) 26.1 ± ± Prior myocardial infarction 12 (40.0%) 13 (44.8%) 0.79 Prior coronary angioplasty 12 (40.0%) 8 (27.6%) 0.41 Unstable angina pectoris 15 (50.0%) 17 (58.6%) 0.62 Ejection Fraction (%) 73 ± ± Age of the grafts (years) 13.0 ± ± IVUS Patients

Angiographic characteristics BMS lesions=39 stents=42 SES lesions=34 stents=41 P value Recipient native vessel territory 0.12 Left anterior descending/diagonal 5 (12.8%) 4 (11.8%) Circumflex/obtuse marginal 20 (51.3%) 10 (29.4%) Right coronary artery 14 (35.9%) 20 (58.8%) Angiographic evidence/suspect of thrombus 9 (23.1%) 12 (35.3%) 0.30 Moderately/heavily calcified lesions 7 (17.9%) 6 (17.6%) 0.99 Total stent length per patient (mm) 31.6 ± ± Total stent length per lesion (mm) 23.0 ± ± Use of distal protection device per lesion 34 (87.2%) 28 (82.4%) 0.74 Successful direct stenting 37 (94.9%) 33 (97.1%) 0.99 Post-dilatation 6 (15.4%) 7 (20.6%) 0.76 Stent length (mm) 21.3 ± ± Stent diameter (mm) 3.38 ± ± Maximal balloon diameter (mm) 3.47 ± ± Maximal inflation pressure (atm) 19.1 ± ± IVUS Patients

Number of lesions Neointimal Volume (mm 3 ) Median: 24 mm 3 [8-34] Median: 1 mm 3 [0-13] P< BMS lesions 34 SES lesions BMS SES Volumetric data BMS lesions=39 SES lesions=34 P value Stent length (mm)21.2 [ ]23.4 [ ]0.14 Stent volume (mm 3 )211 [ ]214 [ ]0.23 Lumen volume (mm 3 )175 [ ]205 [ ]0.023 Neointimal volume (mm 3 )24 [8-34]1 [0-13]<0.001 IVUS Analysis

Bidimensional data BMS lesions=39 SES lesions=34 P value Minimum lumen area (mm 2 )5.3 [ ]7.2 [ ]0.02 Minimum stent area (mm 2 )7.8 [ ]8.4 [ ]0.41 Maximum NIH area (mm 2 )3.1 [ ]0.4 [0-2.4]<0.001 Mean NIH area (mm 2 )0.9 [ ]0.1 [0-0.5]<0.001 Circular MLD (mm)2.6 [ ]3.0 [ ]0.02 Projected MLD (mm)2.4 [ ]2.7 [ ]0.03 Minimum stent diameter (mm)3.2 [ ]3.3 [ ]0.40 Maximum NIH diameter (mm)0.6 [ ]0.1 [0-0.4]<0.001 Maximum area stenosis (%)32.6 [ ]5.3 [0-23.0]<0.001 Mean area stenosis (%)10.0 [ ]0.8 [0-5.8]<0.001 Maximum diameter stenosis (%)17.9 [ ]2.6 [0-12.0]<0.001 Mean diameter stenosis (%)5.4 [ ]0.4 [0-2.7]<0.001

IVUS Analysis Overlapping vs. single SES Single SES lesions=29 stents=29 Overlapping SES lesions=5 stents=11 P value Stent length (mm)22.5 [ ]48.6 [ ]<0.001 Luminal volume (mm 3 )193 [ ]399 [ ]0.005 Stent volume (mm 3 )193 [ ]450 [ ]0.004 NIH volume (mm 3 )0 [0-9.7]29.0 [ ]0.015 Lumen volume index (mm 3 /mm)9.4 [ ]9.0 [ ]0.68 Stent volume index (mm 3 /mm)9.5 [ ]9.7 [ ]0.83 NIH volume index (mm 3 /mm)0 [0-0.4]0.6 [ ]0.03 Minimum lumen area (mm 2 )8.0 [ ]5.6 [ ]0.02 Minimum stent area (mm 2 )8.5 [ ]7.0 [ ]0.71 Circular MLD (mm)3.2 [ ]2.6 [ ]0.02 Projected MLD (mm)2.8 [ ]2.5 [ ]0.02 Maximum area stenosis (%)0 [0-16.4]42.2 [ ]0.007 Maximum diameter stenosis (%)0 [0-8.3]23.8 [ ]0.007

IVUS Analysis Overlapping vs. non-overlapping SES segments Non-overlapping SES segment n=11 Overlapping SES segment n=6 P value Region length (mm)17.8 [ ]2.8 [ ]0.005 Luminal volume (mm 3 )149 [ ]20 [14-52]0.003 Stent volume (mm 3 )149 [ ]26 [18-59]0.005 NIH volume (mm 3 )0.3 [0-23.6]6.5 [ ]0.61 Lumen volume index (mm 3 /mm)9.4 [ ]6.9 [ ]0.16 Stent volume index (mm 3 /mm)9.8 [ ]10.4 [ ]0.99 NIH volume index (mm 3 /mm)0 [0-1.3]1.1 [ ]0.05

Conclusions SES determine also in SVG a significant reduction of neointimal hyperplasia as compared to BMS SES determine also in SVG a significant reduction of neointimal hyperplasia as compared to BMS The neointimal response to SES seems higher in the overlapping segments of the stent than in the single layer segments The neointimal response to SES seems higher in the overlapping segments of the stent than in the single layer segments (post-hoc analysis… “hypothesis-generating”!) No late incomplete apposition was noted No late incomplete apposition was noted

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