Complex Coronary Cases Supported by: Abbott Vascular Inc Boston Scientific Corp Terumo Vascular Corp Vascular Solutions Inc Cardiovascular Science Inc AstraZeneca Pharmaceuticals The Medicines Company Trireme Medical

Disclosures Samin K. Sharma, MBBS, FACC Speaker’s Bureau – Boston Scientific Corporation, Abbott Vascular Inc, ABIOMED, CSI, Trireme Medical Annapoorna S. Kini, MBBS, FACC Nothing to disclose Sameer Mehta, MBBS, FACC Consulting Fees – The Medicines Company

January 19th 2016 Case #79: RO, 78 yrs M Presentation: Patient with long standing history of stable angina, presented with new onset of CCS Class III angina and + stress MPI for moderate anterior and inferior ischemia. A cardiac cath done on October 20th 2015 revealed two vessel CAD; 80% prox LCx and 100% proximal LAD lesions and LVEF 50%. Pt underwent Promus Premier DES to pLC (2.75/24mm) and did well Prior History: Hypertension, Asthma, COPD, s/p PPM Medications: All once daily dosage ASA 81mg, Carvedilol 12.5mg, Clopidogrel 75mg, ISMN 30mg, Simvastatin 40mg, Enalapril 5mg, Inhalers 3

Case# 79: cont… Cardiac Cath 10/20/2015: Right Dominance SYNTAX Score was: 26.5 Cardiac Cath 10/20/2015: Right Dominance II V CAD with LVEF 50% due to antero-apical hypokinesis LM: mild diffuse disease LAD: 100% prox LAD, distal vessel fills well via RCA collaterals LCx: 80% proximal LCx Hospital course: Pt underwent Promus Premier DES (2.75/24) to prox LCx post dilated by 3/12mm NC Quantum balloon with excellent results. Pt continued to have class II angina symptoms Plan Today: Planned PCI of LAD CTO via antegrade or retrograde approach (Syntax score 23) 4

Appropriateness Criteria for Coronary Revascularization

Issues Involving The Case MACE & femoral vascular complications in relation to radial procedure volume in contemporary practice Changing predictors of CTO recanalization success in contemporary practice

Issues Involving The Case MACE & femoral vascular complications in relation to radial procedure volume in contemporary practice Changing predictors of CTO recanalization success in contemporary practice

MATRIX Trial: Clinical Outcomes % Primary endpoint All-cause MI Stroke Urgent TVR ST BARC bleed (mortality/MI/stroke) mortality def/prob 2, 3, or 5 p=0.03 p=<0.0001 p=0.66 p=0.34 p=1.00 p=0.20 p=0.05 Radial access (n=4197) Femoral access (n=4207) Valgimigli et al., Lancet 2015;385:2465

MATRIX Trial: Co-Primary Composite Outcomes at 30 Days All-cause mortality, MI or Stroke All-cause mortality, MI, Stroke, or BARC Bleeding 3 or 5 Valgimigli et al., Lancet 2015;385:2465

MATRIX Trial: Stratified Analysis of Co-primary Outcomes All-Cause Mortality, MI, or Stroke or BARC Bleeding 3 or 5 Valgimigli et al., Lancet 2015;385:2465

MATRIX Trial: Radial vs. Femoral Access in ACS Differential MACE Rates in Various Radial Centers Death/MI Bleeding Mortality Death/MI/ Bleeding Mortality Death/MI Bleeding Mortality Stroke Stroke Stroke Radial Femoral % p=<0.02 for Radial PCI in High vs Low Radial Center p=<0.0001 for Femoral PCI in High vs Low Radial Center Low Radial PCI Center Intermediate Radial PCI Center High Radial PCI Center (14.9 – 64.4%) (65.4 -79.0%) (80.0 – 98.0%) Many Letters to the editor for Valgimigli et al., Lancet 2015;385:2465

The Campeau Radial Paradox Study Population Azzalini et al., J Am Coll Cardiol Intv 2015;8:1854

The Campeau Radial Paradox: Vascular Access Site Complications Azzalini et al., J Am Coll Cardiol Intv 2015;8:1854

The Campeau Radial Paradox: VASC Rates All catheterizations across historical vs contemporary cohorts Diagnostics and therapeutic catheterizations separately Azzalini et al., J Am Coll Cardiol Intv 2015;8:1854

The Campeau Radial Paradox: VASC Stratified by VASC Risk Score Azzalini et al., J Am Coll Cardiol Intv 2015;8:1854

The Campeau Radial Paradox: VASC Stratified by Propensity of Undergoing FA Azzalini et al., J Am Coll Cardiol Intv 2015;8:1854

Possible Reasons for Radial Paradox: - First, the higher the VASC rates observed in contemporary FA patients remained clinically meaningful and statistically significant despite adjustment with an accurate multivariate model . - Second, the attributable risk of VASCs showed an inverse relationship with the number of comorbid conditions: the risk of a femoral VASC attributable to RA was greatest in patients with the lowest baseline risk of a VASC and in patients with the lowest propensity of undergoing FA, that is, the patients with clinical characteristics for which the operator would usually favor using RA. - Third, these findings were consistent in patients undergoing diagnostic catheterizations and hence not influenced by improving interventional devices and techniques. - Fourth, these findings have recently been alluded by the other groups who also observed unusually high rates of VASCs in FA patients in radial centers.

Recommendations to minimize the Radial Paradox - Improve femoral access by use of fluoroscopy, ultrasound and micro-puncture techniques - Use of Bivalirudin as anti-coagulations - Properly trained vascular closure device use - Delay systemic anticoagulation during radial procedures until selective coronary angiogram has been done, to avoid FA puncture in fully anticoagulated pt in case of crossover to FA Continuous education of young Interventionalists in FA access techniques with formal teaching, training on simulators and maintaining a minimal FA procedural volume.

RIVAL Trial: Various Outcomes by Radial PCI Volume Jolly et al., Lancet 2011;377:1409

MATRIX Trial: Forest Plot of the Updated Meta-Analysis of trial Patients with ACS Valgimigli et al., Lancet 2015;385:2465

PCI inHosptals Without On-Site Surgical Backup Focused Update Sept 2015 Primary PCI: indications and Procedural Aspects Vascular Access The use of radial artery access can be useful to decrease access site complications. PCI inHosptals Without On-Site Surgical Backup I IIa IIb III A

Issues Involving The Case MACE & femoral vascular complications in relation to radial procedure volume in contemporary practice Changing predictors of CTO recanalization success in contemporary practice

Predictors of CTO Procedural Success Multivariate analysis from TOAST-GISE Variables Hazard Ratio p Length ≥15 vs. <8 mm 3.9 0.028 Severe calcification 3.5 0.023 Duration ≥ 180 days 3.1 0.013 Multi-vessel disease 2.3 0.009 Bridge collaterals present 2.2 Stump morphology 0.048 Key Message: XIENCE V® provides the right combination of technology with a deliverable, efficacious, and safe platform. Throughout this section you will present the key features of XIENCE V®, including the Multi-Link vision stent, the Multi-Link Vision stent delivery system, the everolimus elution profile, and the fluorinated copolymer. You will also show how these features work together to provide deliverability, efficacy, and safety. Olivari et al., J Am Cardiol Coll 2003;41:1672 29 29

Overall procedural success was 72.5% in 1657 consecutive CTO Lesions; Scoring model was developed in the derivation cohort of 1143 (70%) and then validated in 514 (30%) pts.

Multivariable Analysis Angiographic Score Predicting CTO PCI Success Multivariable Analysis Alessandrino et al., J Am Coll Cardiol Intv 2015;8:1540

Angiographic Score Predicting CTO PCI Success Independent Predictive Variables Scored According to OR OR Score Severe calcified lesion 2.72 +2 Previous CABG 2.49 +1.5 Lesion length ≥ 20 mm 2.04 Previous MI 1.60 +1 Blunt stump 1.39 Non-LAD CTO location 1.56 Alessandrino et al., J Am Coll Cardiol Intv 2015;8:1540

Angiographic Score Predicting CTO PCI Success Procedural Success Rate According to CL-Score Value in the Derivation and Validation Groups Class 0 Class 1 Class 2 Class 3 Cl-SCORE 0-1 CL-SCORE >1 <3 CL-SCORE ≥ 3 <5 CL-SCORE ≥ 5 Derivation 378 426 292 47 Validation 162 193 133 22 Alessandrino et al., J Am Coll Cardiol Intv 2015;8:1540

The Evaluating Xience and Left Ventricular Function in PCI on Occlusions After STEMI (EXPLORE) Trial The Impact of PCI for Concurrent CTO on Left Ventricular Function in STEMI Patients

Patients with STEMI + CTO LVEF and LVEDV MRI at 4 month EXPLORE Trial Design Patients Patients with STEMI treated with pPCI and with a non-infarct related CTO. Patients with STEMI + CTO Design Global, multi-center, randomized, prospective two-arm trial with either PCI of the CTO or no CTO intervention after STEMI. Blinded evaluation of endpoints. 1:1 CTO-PCI < 7d No CTO-PCI Objective To determine whether PCI of the CTO within 7 days after STEMI results in a higher LVEF and a lower LVEDV assessed by MRI at 4 months LVEF and LVEDV MRI at 4 month Henriques, TCT 2015

EXPLORE Trial: Flowchart 304 patients randomly assigned 150 randomized to CTO-PCI 154 randomized to No CTO-PCI 2 withdrew consent 0 withdrew consent 148 CTO-PCI (1 refusal of CTO-PCI) 154 No CTO-PCI 148 with clinical follow-up 154 with clinical follow-up 12 primary imaging endpoints not available 6 poor imaging quality 6 Imaging not available 10 primary imaging endpoints not available 5 with poor imaging quality 5 imaging not available 136 analyzed for primary imaging endpoints 144 analyzed for primary imaging endpoints Henriques, TCT 2015

EXPLORE Trial: CTO-PCI Treatment Arm   CTO-PCI (n=147) Number of days from primary PCI to CTO PCI (mean, SD) 5 (+2) Number of days from randomization to CTO PCI (mean, SD) 2 Multiple CTO arteries treated 6 (4%) Technique CTO procedure Antegrade only 124 (84%) Retrograde 23 (16%) Crossboss/ Stingray (3%) PCI successful, self-reported 117 (80%) PCI successful, corelab adjudicated 106 (72%) Everolimus eluting stent 95 (90%) Number of stents used (median, IQR) (1-3) Henriques, TCT 2015

EXPLORE Trial: Primary Endpoint #1 (LVEF at 4months) CTO-PCI (n=136) No CTO-PCI (n=144) LVEF (%) p=0.60 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∙60 Henriques, TCT 2015

EXPLORE Trial: Primary Endpoint #2 (LVEDF at 4months) CTO-PCI (n=136) LVEF (%) No CTO-PCI (n=144) p=0.70   CTO-PCI (n=136) No CTO-PCI (n=144) Difference (95%CI) p LVEDV (mL) 215∙6 (62∙5) 212∙8 (60∙3) 2∙8 (-11.6 to 17.2) 0.70 Henriques, TCT 2015

Take Home Message: Higher MACE/Vascular complications in high radial centers and Predictors of first time CTO success Recent data have suggested higher MACE and vascular complications at centers with high radial procedure volume. This may just be due to lack of expertise in femoral access due to too much emphasis on radial technique. Hence continuing femoral access technique education is of prime importance in ‘emerging breed of radial interventionalists’ Clinical and lesion related factors can easily identify CTO lesions likely to be associated with successful procedure. Hence these factors can easily be used in selecting the CTO lesions likely to be associated with +outcomes. Initial short term randomized data have shown no effect in LV functional parameters with CTO recanalization

Question # 1 Following statements are true for the radial paradox except: Higher femoral complications in high vs low radial centers Higher MACE rates in high vs low radial centers C. Higher vascular complications in low vs high radial centers D. Higher femoral vascular complications with both diagnostic and therapeutic procedures in high vs low radial centers E. Higher femoral complications at high radial centers in patients at low risk of vascular complications

Question # 2 Meta-analysis of RCT in ACS have shown that the Radial procedures are associated with following lower adverse cardiac events compared to femoral procedures; Mortality Non-CABG bleeding Myocardial infarction Stent thrombosis A and B A, B and C

Question # 3 Following are the independent predictors of successful CTO recanalization except: A. Severe calcified lesion B. Prior CABG C. Blunt stump D. Non-LAD CTO location E. Duration of CTO

Question # 1 The correct answer is C Following statements are true for the ‘radial paradox’ except: Higher femoral complications in high vs low radial centers Higher MACE rates in high vs low radial centers C. Higher vascular complications in low vs high radial centers D. Higher femoral vascular complications with both diagnostic and therapeutic procedures in high vs low radial centers E. Higher femoral complications at high radial centers in patients at low risk of vascular complications The correct answer is C

Question # 2 The correct answer is D Meta-analysis of RCT in ACS have shown that the Radial procedures are associated with following lower adverse cardiac events compared to femoral procedures; Mortality Non-CABG bleeding Myocardial infarction A and B A, B and C The correct answer is D

Question # 3 The correct answer is E Following are the independent predictors of successful CTO recanalization except: A. Severe calcified lesion B. Prior CABG C. Blunt stump D. Non-LAD CTO location E. Duration of CTO The correct answer is E