Complex Coronary Cases Supported by: Abbott Vascular Inc Boston Scientific Corp Terumo Vascular Corp Cardiovascular Science Inc Abiomed Inc Chiesi Inc

Disclosures Samin K. Sharma, MD, FSCAI, FACC Speaker’s Bureau – Boston Scientific Co Abbott Vascular Inc, ABIOMED, CSI Annapoorna S. Kini, MD, MRCP, FACC Nothing to disclose Sameer Mehta, MD, FACC

CCC Live Case # 121 Present Clinical Presentation Patient Demographics Cresendo CCS class II angina for last 2 months despite MMT even after last PCI Patient Demographics 82 yrs, F Stable angina s/p CABG and multiple PCIs Clinical Variables Stress MPI revealed ischemia in anterior, apical & inferior walls Echo: LVEF 60% CABG x3 in 1998 s/p last DES PCI of dLAD via LIMA 5/19 CAD Risk Factors Hypertension Hyperlipidemia NIDDM Medications Aspirin, Clopidogrel, Carvedilol, ISMN, Rosuvastatin, Telmisartan, Metformin, Sitagliptin, Hydralazine, Synthroid, Amlodipine, Omeprazole Cath: 3 V CAD, Occluded mid-distal RCA, prox LAD & LCX-OM1, 80% D1, 90% native dLAD with patent LIMA, patent SVG to OM1 & TO SVG to RCA Plan: PCI of multiple 20 yrs old CTO lesions of native m-dRCA guided by contralateral injection

AUC 2017: Two-Vessel Disease Patel et al., J Am Coll Cardiol 2017;69:2212

Issues Involving The Case Recent publications in CTO Interventions Aspirin discontinuation after PCI

Issues Involving The Case Recent publications in CTO Interventions Aspirin discontinuation after PCI

J-CTO Score Sheet Morino et al., J Am Coll Cardiol Intv 2011;4:213

Multivariable Logistic Regression Analysis for Failure of PCI by the EuroCTO CASTLE Model and the Assignment of Risk Scores to the Risk Factors on the Imputed Derivation Set Szijgyarto et al., J Am Coll Cardiol Intv 2019;12:335

EuroCTO (CASTLE) Scoring System Comprised of 2 Clinical Factors and 4 Angiographic Factors: CABG, prior Age, ≥70 years Stump anatomy, blunt or invisible proximal cap Tortuosity degree, severe Length of occlusion, ≥ 20 mm Extent of calcification, severe With 1 point for each factor resulting in score of 0 to 6 J-CTO score: Previously failed attempt, blunt stump, bending, severe calcification and occlusion length >20mm

EuroCTO (CASTLE) Score: Risk Scores and Predicted Probabilities of Failure of PCI for Patients in the EuroCTO Registry Derivation Dataset from 2008 to 2014 Distribution of total risk scores of 14,882 patients with CTO Red line shows predicted procedural failures Szijgyarto et al., J Am Coll Cardiol Intv 2019;12:335

Model Calibration in EuroCTO Registry Derivation Dataset from 2008 to 2014 (n=14,882) Comparison of the observed and predicted probabilities of failure of PCI across the 4 risk groups: tortuosity, calcification, stump , length of CTO Szijgyarto et al., J Am Coll Cardiol Intv 2019;12:335

Risk Scores and Calibration of the CASTLE Model in the EuroCTO Registry Validation Dataset from 2015 and 2016 Comparison of the observed and predicted probabilities of failure of PCI computed by the EuroCTO CASTLE score Distribution of the risk scores of 5,745 pts with CTO Szijgyarto et al., J Am Coll Cardiol Intv 2019;12:335

Observed Rates of Technical Success of CTO PCI CTO PCI across J-CTO Score Strata CTO PCI across EuroCTO (CASTLE) Score Strata Distribution of EuroCTO (CASTLE) Score Strata Distribution of J-CTO Score Strata Kalogeropoulos et al., EuroIntervention 2019 Jul 2 Epub ahead of print

Success Predictors for the J-CTO and EuroCTO (CASTLE) Scores Whole Study Cohort Complex Cases Kalogeropoulos et al., EuroIntervention 2019 Jul 2 Epub ahead of print

Flow Diagram of the Study Selection Process 143 citations identified through database and manual search (after elimination of duplicates) 13 citations fully reviewed Nine studies were included in the meta-analysis (all observational studies) Excluded: 69: Irrelevant 35: Reviews, description of techniques, case reports 23: Non-human 3: Abstracts 4: single arm studies Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

Baseline Characteristics of the Included Studies Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

Baseline Characteristics of the Study Patients and Lesions Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

Technical Success with Radial vs Femoral Approach in CTO PCI (n=10,590) % Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

In-Hospital Outcomes of Radial vs Femoral Approach in CTO PCI (n=10,590) % p=0.13 p<0.001 p=0.07 p=0.63 p=0.80 Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

Pooled Analysis of In-Hospital Events with Radial vs. Femoral Approach in CTO PCI Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

Pooled Analysis of the Technical Success, Access-Site Complications, Major Bleeding, Contrast Volume and Fluoroscopy Time with Pure Radial vs. Femoral Approach in CTO PCI Megaly et al., Circ Cardiovasc Interv 2019;12:e007778

OPEN-CTO: Operator-Reported Approach Used and the Actual Antegrade/Retrograde Strategy That Caused Perforation Hirai et al., J Am Coll Cardiol Intv 2019 Jun 19 Epub ahead of print

Summary of Size and Location of Clinical and Nonclinical Perforations from the OPEN-CTO Registry Hirai et al., J Am Coll Cardiol Intv 2019 Jun 19 Epub ahead of print

Issues Involving The Case Recent publications in CTO Interventions Aspirin discontinuation after PCI

Optimal DAPT duration after DES Implantation 3/6 Months 12 Months 12+ Months Required DAPT Possible DAPT PCI All the RCTs have evaluated abbreviated P2Y12 inhibitor duration: 3-30 months Effectiveness / Safety Uncertain Ischemic Benefit Increased risk for Bleeding!

Aspirin Discontinuation after PCI Background Mandatory 1-month DAPT had been the standard care after BMS implantation. DAPT duration was prolonged after introduction of DES without firm scientific evidence. New generation DES has substantially reduced stent thrombosis. Prolonged DAPT is inevitably associated with increase in bleeding. Bleeding is associated with subsequent mortality risk at least comparable to that of MI. Therefore, very short mandatory DAPT duration after DES might be an attractive option, if not associated with increase in ischemic events disproportionate to the reduction in bleeding events.

Ongoing Studies Examining Abbreviated Duration of DAPT-SAPT ASA Ticagrelor 24M ASA Ticagrelor 15M

GLOBAL LEADERS: Trial Profile Primary endpoint: All-cause death and new Q-wave MI @ 2 years Design: Superiority of the experimental arm vs. Reference arm. Serruys PW, ESC 2018

GLOBAL LEADERS Adherence to Treatment Strategies Primary and Secondary Outcomes at 12 Months (Intention to Treat) Serruys PW, ESC 2018

GLOBAL LEADERS: KM Estimate of Mortality and Safety Outcome at 2 Years Vranckx et al., Lancet 2018;392:940

GLOBAL LEADERS: Primary and Prespecified Secondary Outcomes Experimental Treatment gp (n=7980) Control gp (n=7988) p=0.07 p=0.07 p=0.18 % p=0.77 p=0.14 p=0.90 p=0.98 p=0.39 Death or MI Death MI Stroke Hemorrhagic TVR Def ST BARC 3 or 5 Stroke Vranckx et al., Lancet 2018;392:940

My interpretation is more+: Global leaders has opened the door for future trials of eliminating aspirin after short time post PCI to decrease bleeding without affecting ST

TWILIGHT Study: Evaluation of Ticagrelor Monotherapy in Patients Who Have Undergone High Risk PCI with DES Open-label ticagrelor; double-blinded ASA or placebo Ticagrelor 90 mg bid + Placebo Standard of care therapy at the discretion of treating physician Observation period Open-label after index PCI Ticagrelor 90 mg bid + ASA 81–100 mg od Randomization if event-free (N=8200) Enrollment (N=9000) High-risk patients aged ≥18 years undergoing PCI with at least 1 DES placement 15 months 18 months 3 months Primary endpoint: clinically relevant (BARC class 2, 3, or 5) bleeding during months 3–15 Key secondary endpoint: composite of all-cause death, non-fatal MI, ischaemic stroke

Trial completed enrollment and F/U. Will be presented in TCT Sept 2019 TWILIGHT Study: Enrollment of High-Risk Patients Undergoing PCI With At Least One DES Placement Inclusion Data Age ≥18 years of age Undergoing PCI with at least 1 DES placement Must meet ≥1 criteria from both clinical and angiographic specifications: Clinical: Angiographic: ≥65 years of age Female Troponin positive ACS Established vascular disease (previous MI, documented PAD or CAD/PAD revasc) DM treated with medications CKD (eGFR <60 mL/min/1,73 m2 or CrCl <60 mL/min Multivessel CAD Target lesion stent length >30 mm Thrombotic target lesion Bifurcation lesions with Medina X, 1, 1 classification requiring ≥2 stents Left main ≥50% or proximal LAD ≥70% lesion Calcified target lesion requiring atherectomy Trial completed enrollment and F/U. Will be presented in TCT Sept 2019

10/9/2019

SMART-CHOICE Trial: Study Design 10/9/2019 A Perspective, Multicenter, Randomized, Open-Label, Non-Inferiority Trial 77% Clopidogrel 23% Prasugrel/ Ticagrelor Hahn et al., Am Heart J 2018;199:7

SMART-CHOICE Trial: Study Design 10/9/2019 Hahn et al., JAMA 2019;321:2428

SMART-CHOICE Trial: Adherence of Antiplatelet 10/9/2019 Hahn et al., JAMA 2019;321:2428

SMART-CHOICE Trial: Primary Endpoint (MACCE) 10/9/2019 Hahn et al., JAMA 2019;321:2428

SMART-CHOICE Trial: Time-to-Event Curves for MACCE and Landmark Analysis at 3 Months 10/9/2019 Hahn et al., JAMA 2019;321:2428

SMART-CHOICE Trial: Time-to-Event Curves for Bleeding and Landmark Analysis at 3 Months 10/9/2019 Hahn et al., JAMA 2019;321:2428

SMART-CHOICE Trial: Clinical Outcomes at 12 Months 10/9/2019 Hahn et al., JAMA 2019;321:2428

10/9/2019

STOPDAPT-2: Prospective multicenter open-label randomized trial comparing 1-month versus 12-month DAPT after CoCr-EES implantation with limited exclusion criteria. Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2 Study Flow All EES 60% Clopidogrel 40% Prasugrel Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2: Baseline Clinical Characteristics 1-month DAPT (N=1500) 12-month DAPT (N=1509) Age, years 68.1±10.9 69.1±10.4 Men 79% 77% ACS 38% 39% STEMI 19% 18% Stable CAD 62% 61% Diabetes Severe CKD IV 6% Prior MI 14% 13% Prior PCI 34% 35% CREDO-Kyoto thrombotic risk score High; Intermediate; Low 8%; 21%; 71% 8%; 24%; 68% CREDO-Kyoto bleeding risk score 7%; 27%; 66%

STOPDAPT-2: Procedural Characteristics and Medications 1-month DAPT (N=1500) 12-month DAPT (N=1509) Transradial approach 82% 84% N for target lesions 1.12±0.35 1.14±0.39 Minimal stent diameter, mm 2.98±0.49 2.96±0.48 Total stent length, mm 30.3±16.7 30.5±16.8 SYNTAX Score 8 (5-14) 9 (6-15) Target of LMCA 3% CTO 4% IVUS or CTO 97% 98% ASA 99.8% 100% Clopidogrel 60% 63% Prasugrel (3.75 mg/day) 40% 37% Statin 88% 87% PPI 79% Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2: Persistent DAPT Discontinuation Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2:Primary Endpoint: Net Clinical Benefit CV Death/MI/ST/Stroke/TIMI Major/Minor Bleeding Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2:Major Secondary Ischemic Endpoint CV Death/MI/ST/Stroke Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2: Major Secondary Ischemic Endpoint TIMI Major/Minor Bleeding Watanabe et al., JAMA 2019;321:2414

STOPDAPT-2: Clinical Outcomes at 1 Year 10/9/2019 STOPDAPT-2: Clinical Outcomes at 1 Year P values for superiority p=0.003 p=0.61 p=0.004 p=0.11 p=0.66 % p=0.21 Death MI Def/prob ST Stroke TIMI major/minor Bleeding BARC 3 or 5 Bleeding Watanabe et al., JAMA 2019;321:2414

Take Home Message: Recent data on CTO PCI and Aspirin discontinuation post-PCI Novel new score from Euro CTO club (CASTLE) is yet another simple risk score for prediction of CTO success. It has better discriminatory power then J-CTO score in more complex cases. Data support the use of radial access versus femoral access in less complex CTO with resultant similar success but lower vascular & bleeding complications. Novel approach of limiting aspirin duration as part of DAPT strategy post PCI has taken the momentum now with numerous RCT limiting aspirin duration to 1-3 mths and resulting in similar (or better) efficacy and lower bleeding. Final answer to this question will be revealed by the results of TWILIGHT trial where aspirin was d/c after 3 mths with continued Ticagrelor monotherapy vs routine DAPT.

Question # 1 The correct answer is D Following are the features which makes the EuroCTO CASTLE score except; Prior CABG Age Lesion calcification Prior failed attempt E. Lesion length The correct answer is D

Question # 2 The correct answer is C Following statements are true for the radial access from the meta-analysis of radial vs femoral CTO intervention except; Both approaches have similar technical success Radial approach has lower vascular complication Radial approach is more commonly used in complex cases Radial approach has similar mortality Radial approach has similar procedural complications The correct answer is C

Question # 3 The correct answer is B Following are the RCTs of aspirin discontinuation after PCI except? A. GLOBAL LEADERS B. DAPT C. STOP DAPT-2 D. SMART CHOICE E. TWILIGHT The correct answer is B

Question # 4 The correct answer is C Following statements are true from the aspirin discontinuation trials after PCI except; Aspirin d/c group has lower bleeding Aspirin d/c group has similar or better efficacy Aspirin d/c group has higher ST Aspirin d/c group similar CVA rates Aspirin d/c group has similar primary endpoints in first 1-3M The correct answer is C

Question # 5 The correct answer is B Following statements are true for the TWILGHT trial of aspirin discontinuation post PCI except? A. Pt were randomized after 3 M of DAPT B. Pt received Clopidogrel in the experimental arm C. Primary endpoint of the trial is incidence of bleeding D. Trial duration is 15 months post PCI E. Ticagrelor was used in many stable PCI pts The correct answer is B