Clinical Trials and Outcomes with DES in CTO Revascularization Redefining, Refining Standards of Treatment David E. Kandzari, MD, FACC, FSCAI david.kandzari@piedmont.org Director, Interventional Cardiology, Piedmont Heart Institute Chief Scientific Officer, Piedmont Healthcare Atlanta, Georgia

Disclosure Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below Affiliation/Financial Relationship Company Grant/Research Support Abbott Vascular, Cordis Corporation, Medtronic CardioVascular Consulting Fees/Honoraria Abbott Vascular, Cordis Corporation, Medtronic CardioVascular, Micell Technologies Major Stock Shareholder/Equity None Royalty Income None Ownership/Founder None Intellectual Property Rights None Other Financial Benefit None

Evolution of DES as a Standard in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, %, RR Repeat Revascularization,%, RR 1996-1999 GISSOC, TOSCA, STOP, SPACTO, SICCO PTCA vs BMS, Randomized 22 vs 9, 59% 67 vs 37, 45% 35 vs 19, 46% 2003-2009 ACROSS, ASIAN, RESEARCH, etc. DES, Observational 2 8 2006 PRISON II, GISSOC II BMS vs DES, Randomized 15 vs 2, 87% 52 vs 9, 83% 33 vs 7, 79% 2005-2007 ASIAN, RESEARCH, etc. PES vs SES, Observational ─ 18 vs 7, 61% 6 vs 4, 33% 2010 Metanalyses BMS vs DES 10 vs 5, 50% 37 vs 10, 73% 30 vs 5, 83% 2011-- PRISON III, CIBELES SES vs ZES/EES, Randomized EXPERT CTO, ACE CTO EES, Observational

Evolution of DES as a Standard in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, %, RR Repeat Revascularization,%, RR 1996-1999 GISSOC, TOSCA, STOP, SPACTO, SICCO PTCA vs BMS, Randomized 22 vs 9, 59% 67 vs 37, 45% 35 vs 19, 46% 2003-2009 ACROSS, ASIAN, RESEARCH, etc. DES, Observational 2 8 2006 PRISON II, GISSOC II BMS vs DES, Randomized 15 vs 2, 87% 52 vs 9, 83% 33 vs 7, 79% 2005-2007 ASIAN, RESEARCH, etc. PES vs SES, Observational ─ 18 vs 7, 61% 6 vs 4, 33% 2010 Metanalyses BMS vs DES 10 vs 5, 50% 37 vs 10, 73% 30 vs 5, 83% 2011-- PRISON III, CIBELES SES vs ZES/EES, Randomized EXPERT CTO, ACE CTO EES, Observational

Evolution of DES as a Standard in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, %, RR Repeat Revascularization,%, RR 1996-1999 GISSOC, TOSCA, STOP, SPACTO, SICCO PTCA vs BMS, Randomized 22 vs 9, 59% 67 vs 37, 45% 35 vs 19, 46% 2003-2009 ACROSS, ASIAN, RESEARCH, etc. DES, Observational 2 8 2006 PRISON II, GISSOC II BMS vs DES, Randomized 15 vs 2, 87% 52 vs 9, 83% 33 vs 7, 79% 2005-2007 ASIAN, RESEARCH, etc. PES vs SES, Observational ─ 18 vs 7, 61% 6 vs 4, 33% 2010 Metanalyses BMS vs DES 10 vs 5, 50% 37 vs 10, 73% 30 vs 5, 83% 2011-- PRISON III, CIBELES SES vs ZES/EES, Randomized EXPERT CTO, ACE CTO EES, Observational

Evolution of DES as a Standard in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, %, RR Repeat Revascularization,%, RR 1996-1999 GISSOC, TOSCA, STOP, SPACTO, SICCO PTCA vs BMS, Randomized 22 vs 9, 59% 67 vs 37, 45% 35 vs 19, 46% 2003-2009 ACROSS, ASIAN, RESEARCH, etc. DES, Observational 2 8 2006 PRISON II, GISSOC II BMS vs DES, Randomized 15 vs 2, 87% 52 vs 9, 83% 33 vs 7, 79% 2005-2007 ASIAN, RESEARCH, etc. PES vs SES, Observational ─ 18 vs 7, 61% 6 vs 4, 33% 2010 Metanalyses BMS vs DES 10 vs 5, 50% 37 vs 10, 73% 30 vs 5, 83% 2011-- PRISON III, CIBELES SES vs ZES/EES, Randomized EXPERT CTO, ACE CTO EES, Observational

Evolution of DES as a Standard in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, %, RR Repeat Revascularization,%, RR 1996-1999 GISSOC, TOSCA, STOP, SPACTO, SICCO PTCA vs BMS, Randomized 22 vs 9, 59% 67 vs 37, 45% 35 vs 19, 46% 2003-2009 ACROSS, ASIAN, RESEARCH, etc. DES, Observational 2 8 2006 PRISON II, GISSOC II BMS vs DES, Randomized 15 vs 2, 87% 52 vs 9, 83% 33 vs 7, 79% 2005-2007 ASIAN, RESEARCH, etc. PES vs SES, Observational ─ 18 vs 7, 61% 6 vs 4, 33% 2010 Metanalyses BMS vs DES 10 vs 5, 50% 37 vs 10, 73% 30 vs 5, 83% 2011-- PRISON III, CIBELES SES vs ZES/EES, Randomized EXPERT CTO, ACE CTO EES, Observational

Evolution of DES as a Standard in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, %, RR Repeat Revascularization,%, RR 1996-1999 GISSOC, TOSCA, STOP, SPACTO, SICCO PTCA vs BMS, Randomized 22 vs 9, 59% 67 vs 37, 45% 35 vs 19, 46% 2003-2009 ACROSS, ASIAN, RESEARCH, etc. DES, Observational 2 8 2006 PRISON II, GISSOC II BMS vs DES, Randomized 15 vs 2, 87% 52 vs 9, 83% 33 vs 7, 79% 2005-2007 ASIAN, RESEARCH, etc. PES vs SES, Observational ─ 18 vs 7, 61% 6 vs 4, 33% 2010 Metanalyses BMS vs DES 10 vs 5, 50% 37 vs 10, 73% 30 vs 5, 83% 2011-- PRISON III, CIBELES SES vs ZES/EES, Randomized EXPERT CTO, ACE CTO EES, Observational

DES in CTO Revascularization Quantifying the Relative Benefit of DES: ≥3 Year Follow-up 64% RR 62% RR Saeed, Kandzari, Brilakis et al. CCI 2010

DES in CTO Revascularization Quantifying the Relative Benefit of DES: ≥3 Year Follow-up Saeed, Kandzari, Brilakis et al. CCI 2010

CTO Revascularization and Late Safety and Efficacy 3 Year Outcomes ACROSS/TOSCA 4 ∆1-3 Yrs 3 Years Death 2.6 2.6% MI 1.0% 3.2 4.2% TLR 9.8% 1.1 10.9% Stent Thrombosis* MACE 10.3% 4.8% 15.1% Kandzari. *ARC def/probable ST

CTO Revascularization and Late Safety and Efficacy 5 Year Outcomes PRISON II 41 P=0.009 P<0.001 36 P=0.001 34 30 Event (%) 17 17 P=NS P=NS 12 12 8 7 5 5 Suttorp. TCT 2010

CTO Revascularization and Late Safety and Efficacy 5 Year ARC Definite/Probable Stent Thrombosis BMS, N=100 SES, N=100 Index-30 days 1 (d) 31 days to 1 year 1-2 years 2-3 years 2 (d) 3-4 years 2 (1d, 1p) 4-5 years Total 1 8 P=NS for all comparisons Suttorp. TCT 2010

DES Trials in CTO Revascularization Design Primary Endpoint Timeline CIBELES NCT00793221 208 Randomized, Xiencevs. Cypher 9 month in-stent late loss, non-inferiority PCR 2011 PRISON III NCT00428454 300 Randomized, Cypher vs. Endeavor, Resolute 8 month in-segment late loss ACC 2011 ACE CTO NCT01012869 100 Single-arm,XienceV 8 month binary restenosis, OCT TCT 2012 EXPERT CTO NCT Pending 250 Single-arm,Xience V 1 year MACE vs. DES performance goal 2° Endpoints: 1.2 Mini Trek, Progress Guidewires Enrollment 2011

85% adjusted relative reduction ACROSS - CYPHER Influence of Stent Technique on Angiographic Outcomes In treated-segment refers to length of contiguous target segment exposed to balloon inflation In-segment includes stented area plus 5 mm proximal and distal to stent Restenosis is more common in the treated (but not stented) segment than in-stent! 33% absolute reduction 85% adjusted relative reduction ∆working- stent11.1% ∆working- segment10.2% Binary Restenosis (%) ∆segment- stent2.9% Kandzari et al. JACC Interv 2009

Influence of Stent Technique on Angiographic Outcomes DES, Hybrid, BMS 56.7 55.0 53.4 33.3 33.3 23.8 21.7 13.3 11.7 9.3 10.0 1.7 Werner et al. CCI 2006

Stent Fracture Following CTO Revascularization

Stent Fracture Following CTO Revascularization

Non-stent Fracture (N=168) Stent Fracture Following CTO Revascularization Correlates and Outcomes Stent Fracture (N=32) Non-stent Fracture (N=168) P value Stent length, mm 65.5 (49.7, 73.6) 41.9 (28.8,57.0) <0.001 Overlapping stents (%) 100 (30/30) 89.9 (107/119) 0.06 Procedure success (%) 100.00 (32/32) 97.6 (163/167) 1.00 Target lesion revascularization (%) 25.0 (8/32) 6.7 (11/162) 0.005 Major adverse cardiac events (%) 7.4 (12/161) 0.007 Stent thrombosis (%) 3.2 (1/31) 0.6 (1/162) 0.30 Binary restenosis (%) In-segment 9.5 (13/137) 0.017 In-stent 15.6 (5/32) 8.0 (11/137) 0.17 Kandzari et al. JACC Interv 2009

Late Incomplete Apposition and Aneurysm Formation CTO an independent predictor of aneurysm formation Jim et al. Circ J 2011 IVUS identified in  26%~ of CTO cases at follow-up Hong et al. Circulation 2006 Association with VLST Miyazaki J Invasive Cardiol2010

Late Incomplete Apposition and Aneurysm Formation Baseline, Acquired, Persistent, Resolved

Late Incomplete Apposition and Aneurysm Formation

Late Incomplete Apposition and Aneurysm Formation 2 Months 5 Months

Late Incomplete Apposition and Aneurysm Formation Opportunity for Healing? Baseline 2 Months 5 Months

DES in CTO Revascularization Summary PCI with DES in CTO revascularization is a standard of care rather than an exception, often to the extent that ineligibility for DES challenges considerations for attempting CTO Substantial reductions in restenosis and repeat revascularization Similar safety compared with BMS Aside from ↓ABR, long term patency with DES may be associated with preservation of improved LV function DES are a revolutionary step toward improving CTO outcomes but introduce new dilemmas Implications for technique: ↑ restenosis when less DES coverage Strut fracture and LSM may be more common; clinical implications uncertain CTOs represent ideal opportunity to evaluate DES safety and efficacy in the highest lesion complexity Outstanding need for comparative trial of DES (esp. new DES), clinical outcomes and impact of new technologies/techniques