Contemporary Outcomes with Chronic Total Occlusion Revascularization David E. Kandzari, MD, FACC, FSCAI Chief Scientific Officer Director, Interventional Cardiology Piedmont Heart Institute Atlanta, Georgia david.kandzari@piedmont.org

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, Boston Scientific, Medtronic CardioVascular, Biotronik, St. Jude Medical/Thoratec Consulting Fees/Honoraria Boston Scientific Corporation, Medtronic CardioVascular, Micell, St. Jude Medical Major Stock Shareholder/Equity None Royalty Income None Ownership/Founder None Intellectual Property Rights None Other Financial Benefit None

CTO Revascularization: Clinical Outcomes What is the procedural success and safety following CTO PCI with contemporary CTO PCI? What are the clinical and health status outcomes following CTO PCI with contemporary technique and advanced generation DES? Are the clinical outcomes following CTO PCI similar to non- CTO PCI? In what clinical settings might CTO PCI influence the risk of major adverse events?

0.9% pericardiocentesis, 0.2% stroke Appleton Cardiology, WI Baylor Heart and Vascular Hospital, TX Columbia University, NY Central Arkansas VAMC, AR Dallas VAMC/UTSW, TX Henry Ford Hospital, MI Massachusetts General Hospital, MA Medical Center of the Rockies, CO Minneapolis VAMC, MN PeaceHealth St. Joseph MC, WA Piedmont Heart Institute, GA San Diego VAMC and UCSD, CA St Luke’s Mid America Heart Institute, MO Torrance Medical Center, CA UPMC Medical Center, PA 1/2012 to 9/2016 15 centers, 1,974 lesions Technical success: 88% Major complications: 2.6% 0.6% mortality, 0.9% MI 0.9% pericardiocentesis, 0.2% stroke 0.1% CABG, 0.3% re-PCI Successful technique

Temporal Trends in CTO PCI Success Michael, Karmpaliotis, Brilakis, Kandzari et al. CCI 2015

Temporal Trends in Contrast/Fluoroscopy Utilization Michael, Karmpaliotis, Brilakis, Kandzari et al. CCI 2015

Outcomes Following CTO PCI Evidence of Quality of Life Benefit No CTO n=1833 Baseline Health Status        SAQ Physical Limitation Score 72.1 ± 26.9 77.9 ± 23.4 0.016      SAQ Angina Frequency Score 70.1 ± 28.1 72.9 ± 23.6 0.212      SAQ Quality of Life Score 54.3 ± 25.5 56.0 ± 25.4 0.487      Rose Dyspnea Score 1.9 ± 1.5 1.7 ± 1.5 0.209 6-Month Health Status 96.2 ± 12.8 95.7 ± 12.9 0.742 91.0 ± 19.0 93.2 ± 15.1 0.126 80.6 ± 21.4 80.5 ± 19.9 0.951 1.0 ± 1.4 0.9 ± 1.3 0.497 Safley D, Grantham JA, Jones P, and Spertus JA , ACC 2012

PERSPECTIVE Trial 500 CTO Patients Percutaneous Revascularization at Piedmont for Chronic Total Occlusions Survey 500 CTO Patients Primary Endpoints: CTO Procedural Success (<50% residual stenosis and > TIMI 2 Flow) 1 Year Death/MI/TLR (MACE) Secondary Endpoints: Change in angina frequency and quality of life (SAQ, EQ5D) from baseline to 1 year Adherence to and classification of AUC Pre/post PCI SYNTAX score for assessment of completeness of revascularization Procedural resource utilization and medication adherence Clinicaltrials.gov Identifier NCT01946724

CTO Percutaneous Revascularization Need for Randomized Trial Is mortality appropriate as singular endpoint? Failed CTO PCI part of ITT or OMT? Management of Variable operator experience Selection bias Treatment bias Crossover to revascularization

CTO Percutaneous Revascularization Need for (Feasibility of) Randomized Trials?

CTO Percutaneous Revascularization Need for (Feasibility of) Randomized Trials?

Successful vs Failed CTO Revascularization ‘Open Artery Hypothesis’ Study Year N Follow-Up Yrs Mortality Difference (%) P Value Suero 2001 2,007 10 27 vs 35 0.001 Hoye 2003 854 5 6.5 vs 12.0 0.02 Buller 1,458 1 10.0 vs 19.0 Olivari 376 1.1 vs 7.2 0.005 Aziz 2007 543 1.7 2.5 vs 7.3 0.004 Prasad 2008 1,267 22 vs 28 0.025 Valenti 486 2 8.4 vs 12.6 Thompson 487 7 13 vs 26 0.09 DeLabroille 172 4.9 vs 5.3 0.30 Mehran 2011 1,791 2.9 6.0 vs 8.6 0.01 Jones 2012 836 4.5 vs 17.2 <0.0001 George 2014 13,443 2.7 7.0 vs 10.0 Jaguszewski 2015 1,110 3 2.2 vs 4.2 0.056 Ramunddal 2016 6,442 6 15% ARR 0.034 Lee 1,173 4.6 8.0 vs 7.1 0.83 N=32,445 Absolute Risk Difference +0.9% to -15.0%

Repeat Revascularization Relative to Successful CTO PCI CABG 100% 22.1% 11.5% CABG 3% Jones et al. JACC Intv 2012

Successful CTO PCI 802/1,035 (77%) 66% 1st Generation DES Clinical and Angiographic Outcomes Following CTO PCI Florence CTO PCI Registry, 2003 to 2010 1 Year Events N=802 Successful CTO PCI 802/1,035 (77%) 66% 1st Generation DES Mean stent length 52 mm 82% Angiographic Follow-up Retrograde 3.1% (25/802) 1st Generation PES and SES (N=508) TLR 14.1 Reocclusion 10.1 Everolimus Eluting Stents (N=294) 10.5 3.0 STAR (N=34) 32.3 57.0 RE SciComm SYNTAX Stat requests_15SEP08_v2.xls.doc Data Expressed As Percent

EXPERT CTO XIENCE EES 1 Year Clinical Outcomes Hierarchical Composite (%) MACE ARC MI definition 18.5 Protocol MI definition 10.0 TLF 15.8 9.1 TVF 16.7 Non-Hierarchical Components (%) Death 1.9 Myocardial Infarction ARC definition 13.9 Protocol definition 3.4 Clinically-Driven TLR 6.3 TLR - CABG 0.5 TLR - PCI 5.8 RE SciComm SYNTAX Stat requests_15SEP08_v2.xls.doc Kandzari et al. JACC Intv 2015

EXPERT CTO Myocardial Infarction According to CK MB Elevation 5.4% 12/220 3.6% 8/220 1.8% 4/220 RE SciComm SYNTAX Stat requests_15SEP08_v2.xls.doc Kandzari et al. JACC Intv 2015

Prognostic Significance of Periprocedural MI in CTO PCI RE SciComm SYNTAX Stat requests_15SEP08_v2.xls.doc Predictors of PPMI: Renal Failure OR 4.25, 95% CI 1.59-11.35, P=0.004 Retrograde OR 2.27, 95% CI 1.34-3.84, P=0.002 Non CTO target lesion PCI OR 1.74, 95% CI 1.17-2.59, P=0.006 Stent Number OR 1.38, 95% CI 1.07-1.77, P=0.011 Lee et al. JACC Intv 2016

DES in CTO Revascularization Era Trials Comparison Reocclusion %, RR Restenosis, 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 3.2 SES vs 1 EES 10.5 SES vs 9.1 EES 11.6 SES vs 7.9 EES EXPERT CTO, ACE CTO, Florence Registry, PRISON IV EES, BP-SES Observational and Randomized 2.2 BP-SES vs 1.4 EES Florence 3.0% PRISON IV: BP-SES 8.0%, EES 2.1% Florence 10.5% (MACE) EXPERT CTO 6.3% (TLR) PRISON IV 10.5% BP-SES, 4.0% EES

Survival According to CTO PCI Success Comparisons with Non-CTO PCI and PCI Failure 5 Year Survival sCTO PCI 4.5% vs non-CTO PCI 6.7%, P=0.10 17.2% 6.7% 4.5% Jones et al. JACC Intv 2012

CTO PCI Outcome Comparisons with Non-CTO PCI 2 Year Outcomes with R-ZES P Value Total Stent Length (mm) 48.7 ± 30.1 30.1 ± 19.8 <0.001 TLF 9.1 10.4 0.55 Cardiac Death 2.8 2.7 0.84 TVMI 4.2 0.40 TLR 4.8 5.2 0.88 Def/prob ST 1.2 1.1 0.76 Kelbaek et al. Eurointervention 2014

An Interventional Risk Treatment Paradox Negative Impact of CTO Treatment on Clinical Outcomes in SYNTAX Trial CTO Prevalence PCI 26.3%, CABG 36.4% CTO Location 68.1% in proximal/mid vasculature PCI success rate 49.4% Presence of CTO strongest independent predictor of incomplete revascularization (HR 2.70) 4-Year MACCE Farooq et al. J Am Coll Cardiol 2013

Survival According to Completeness of Revascularization in CTO Patients George et al. JACC 2014

Impact of CTO in Patients with ACS and LV Dysfunction Author Study Population/ N (%) CTO Study Duration HR (95% CI) for Mortality P Value Claessen JACC Intv 2009 Single Center 3,277 STEMI/ 420 (13%) 5 years 1.9 (1.4-2.8) <0.001 Lexis CCI 2011 TAPAS 1,071 STEMI/ 90 (8%) 2.1 years 2.41* (1.26-4.61) 0.008 Claessen EHJ 2012 HORIZONS-AMI 3,602 STEMI/ 297 (8%) 3 years 1.97 (1.19-3.25) <0.01 Ramunddal CRT 2012 SCAAR 17,730 NSTEMI/ 1,621 (9%) 6 years 1.69 (1.40-2.04) Tajstra JACC Intv 2016 COMMIT HF 675 LVEF <35/ 278 (41% 1 year 1.84 RR (1.18-2.85) 0.006 *Cardiovascular mortality

Impact of CTO in Patient Survival Hazard of CTO highest in: Younger patients (<70 yrs) STEMI

Impact of CTO in Patients with ACS EXPLORE Trial 300 STEMI Pts with Non-Infarct Related Artery CTO RANDOMIZE CTO PCI within 7 days of STEMI Optimal Medical Therapy Primary Endpoints: 1. LVEF by MRI 2. LVEDV by MRI Clinical Outcomes at 1 Through 5 Years van der Schaaf et al. Trials 2010; www.exploretrial.com

Impact of CTO in Patients with ACS EXPLORE Trial CTO Success 72% (predicted 80%) No difference in clinical outcome at 4 months CTO-PCI (n=136) No CTO-PCI (n=144) Difference (95%CI) p LVEF (%) 44∙1 (12∙2) 44∙8 (11∙9) -0∙8 (-3∙6 to 2∙1) 0∙597 Henriques et al. TCT 2015; JACC 2016

Clinical Outcomes Following CTO PCI Summary In absence of randomized trial data, successful CTO PCI is consistently associated with survival advantage compared with failed CTO PCI Mechanism translating benefit: completeness of revascularization, target vessel identity, improvement in LV function, reduction in arrhythmic potential Trial design and conduct remains a limitation CTO PCI is associated with durable reductions in repeat (surgical) revascularization CTO treatment results in at least similar improvement in health status and quality of life as non-CTO PCI With contemporary DES, the ‘gap’ in clinical outcome between CTO and non- CTO PCI has been bridged Despite greater lesion complexity, similar rates of TLR, ST, MACE compared with non- CTO PCI Benefit of CTO PCI may be especially relevant in selected pts with high ischemic burden, MVD, recent ACS