LONG-TERM EVENTS IN SIROLIMUS-ELUTING STENTS: a specific focus on diseased saphenous vein grafts from the randomized DELAYED-RRISC trial Pierfrancesco Agostoni, MD On behalf of the DELAYED-RRISC (Death and Events at Long-term follow up AnalYsis: Extended Duration of the Reduction of Restenosis In Saphenous vein grafts with Cypher stent) Investigators Antwerp Cardiovascular Institute Middelheim Antwerp, Belgium

RRISC Trial Reduction of Restenosis In Saphenous vein grafts with Cypher stent Prospective, randomized, double-blind, non industry sponsored, single center, trial comparing SES vs. BMS in SVG lesions 75 patients with 96 lesions localized in 80 diseased SVG were included Enrollment: September 2003-November 2004 Primary endpoint : 6-month in-stent late loss Secondary endpoints (all at 6 months follow up): – Binary angiographic restenosis (in-stent/in-segment) – Clinical events (death, MI, TLR, TVR) Vermeersch, Agostoni et al. JACC 2006

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 Recent MI (<7 days) RRISC Trial Reduction of Restenosis In Saphenous vein grafts with Cypher stent Vermeersch, Agostoni et al. JACC 2006

75 patients (with 96 lesions) meeting the inclusion criteria 37 patients (49 lesions) randomized to BMS 38 patients (47 lesions) randomized to SES 37 patients (49 lesions) available for 6-month angiographic follow up 35 patients (44 lesions) available for 6-month angiographic follow up 1 patient died 2 patients refused angio follow up randomization No patient was lost to follow up. All patients, but 1 (dead) available for 6-month clinical follow up. 204 patients screened (September 2003-November 2004) Patients excluded (reason): 2 patients (age >85 years) 18 patients (acute MI) 7 patients (MI within the last 7 days) 3 patients (creatinine >3 mg/dL) 40 patients (vein graft with RVD >4.0 mm) 12 patients (distal anastomotic disease) 38 patients (restenotic lesions) 8 patients (enrolled in other trials) 1 patient (no informed consent ) Vermeersch, Agostoni et al. JACC 2006

BMS (n=37) SES (n=38) P- value Age (years)72 ± 873 ± Men33 (89%)31 (82%)0.36 Family history29 (78%)25 (66%)0.23 Hypertension21 (57%)22 (58%)0.84 Hypercholesterolemia31 (84%)33 (87%)0.74 Current smoker4 (11%)2 (5%)0.46 Diabetes Mellitus5 (14%)6 (16%)0.78 Body mass index (Kg/m 2 )26.4 ± ± History of heart failure7 (19%)6 (16%)0.72 Prior myocardial infarction15 (41%)17 (45%)0.71 Prior coronary angioplasty15 (41%)12 (32%)0.42 Unstable angina pectoris19 (51%)23 (60%)0.41 Ejection Fraction (%)72 ± 1268 ± Age of the grafts (years)12.6 ± ± Baseline characteristics Vermeersch, Agostoni et al. JACC 2006

BMS (lesions=49) SES (lesions=47) P- value Degenerated saphenous vein grafts17 (41.5%)19 (48.7%)0.51 Recipient native vessel territory 0.11 Left anterior descending/diagonal6 (12.2%)9 (19.2%) Circumflex/obtuse marginal26 (53.1%)15 (31.9%) Right coronary artery17 (34.7%)23 (48.9%) Angiographic evidence/suspect of thrombus12 (24.5%)17 (36.2%)0.21 Moderately/heavily calcified lesions9 (18.4%)8 (17%)0.86 Number of stents per patient1.46 ± ± Number of stents per lesion1.11 ± ± Total stent length per patient (mm)33.4 ± ± Total stent length per lesion (mm)25.2 ± ± Stent diameter (mm)3.36 ± ± Successful direct stenting44 (89.8%)44 (93.6%)0.50 Post-dilatation7 (14.3%)14 (29.8%)0.09 Maximal balloon diameter (mm)3.44 ± ± Maximal inflation pressure (atm)18.8 ± ± Vermeersch, Agostoni et al. JACC 2006

p=0.001 p=0.9 p= p=0.01 Prox edgeDist edgeIn-stentIn-segment Late Loss Analysis Vermeersch, Agostoni et al. JACC 2006 BMS SES

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 Binary Restenosis Vermeersch, Agostoni et al. JACC 2006

6-month MACE BMS 37 n=37 SES 38 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 TLR (per-patient)8 (21.6%)2 (5.3%)0.047 TVR TVR (per-patient)10 (27%)2 (5.3%)0.012 Cumulative 6-month MACE11 (29.7%)6 (15.8%) Due to safety issues recently raised with DES (ESC/WCC 2006), we decided to further follow up our patients, in order to analyze long-term events. -In September 2006, a new approval was obtained from the local Ethics Committee to extend the follow-up. -A new informed consent was obtained from all the patients. -All patients were contacted between September and December 2006 (no lost to follow up). -Blinding was maintained for patients and referring physicians/cardiologists. Vermeersch, Agostoni et al. JACC 2006

BMS 37 n=37 SES 38 n=38 P value Death010 (26.3%)0.001 Myocardial infarction1 (2.7%)4 (10.5%)0.35 TLR3 (8.1%)7 (18.4%)0.30 TVR4 (10.8%)11 (28.9%)0.05 MACE after 6-month up to 32 months (median f.u.)

BMS 37 n=37 SES 38 n=38 P value Death011 (28.9%)<0.001 Myocardial infarction2 (5.4%)7 (18.4%)0.15 TLR11 (29.7%)9 (23.7%)0.55 TVR14 (37.8%)13 (34.2%)0.74 MACE15 (40.5%)22 (57.9%)0.13 Other PCI (not TLR/TVR)14 (37.8%)12 (31.6%)0.57 Double anti-platelet therapy19 (51.4%)19 (50%)0.91 Single anti-platelet therapy14 (37.8%)15 (39.5%)0.88 No anti-platelet therapy4 (10.8%)4 (10.5%)0.97 Statin therapy27 (73%)29 (76.5%)0.74 Cumulative MACE

Stent Thrombosis (ARC criteria) BMS 37 n=37 SES 38 n=38 P value Definite02 (5.2%) 1 fatal at 13 months 1 non fatal at 30 months 0.49 Probable00- Possible03 (7.9%) 1 sudden death at 7.5 months 1 sudden death at 11.5 months 1 sudden death at 35 months 0.30 Total05 (13.1%) Fisher Exact Log Rank

TimeCause of deathAnti-thrombotic therapy 5 monthsprogressive heart failureTP 7.5 monthssudden out-of-hospital deathTP, W 11.5 monthssudden out-of-hospital deathASA, TP 14.5 monthsprogressive heart failure after MI due to thrombosis of the index stent - (suspended 1 week before MI for knee surgery) 16 monthsmetastatic urothelial carcinoma- (stop 1 month before for severe anemia) 19 monthsmetastatic colon carcinoma- (stop 2 months before for anorexia) 22 monthsprogressive MOF after peri-operative (limb ischemia) MI (no stent thrombosis of the stent) - (suspended 1 week before MI for AICD change) 23.5 monthspost-operative (AVR and ReDo CABG for progression of CAD) infection ASA, TP 30 monthsprogressive Parkinson diseaseASA, TP 33 monthsprogressive MOF after ReDo CABG (documented in-stent restenosis) ASA, TP 35 monthssudden out-of-hospital deathASA, TP Causes of Death

Conclusions The use of BMS was associated with lower long-term mortality than the use of SES for SVG disease. Also the 6-month reduction in repeated revascularization procedures shown with the use of SES was lost at longer- term follow-up. However: this is secondary post-hoc analysis, the play of chance should be strongly considered, “hidden” factors unrelated to stent type could have influenced the final results. Further studies are required before conclusions can be made about the safety or harm of using SES for SVG lesions.

DELAYED-RRISC Investigators Steering Committee: Pierfrancesco Agostoni, MD Paul Vermeersch, MD Other Investigators: Stefan Verheye, MD, PhD Glenn Van Langenhove, MD, PhD Frank Van den Branden, MD Paul Van den Heuvel, MD Carl Convens, MD Data Monitoring: Christine Jacobs, RN Nancy Aerts, RN Anne-Rose Gustin (Incubate, Cardiac Solutions) CEC Committee: Giuseppe M. Sangiorgi, MD Giuseppe G.L. Biondi-Zoccai, MD Statistical Analysis: Pierfrancesco Agostoni, MD