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Complex Coronary Cases Supported by: Abbott Vascular Boston Scientific Corporation Medtronic, Inc. Daiichi Sankyo, Inc. and Lilly USA, LLC

Disclosures Samin K. Sharma, MBBS, FACC Speaker’s Bureau – Boston Scientific Corporation, Abbott, The Medicines Company, Daiichi Sankyo, Inc. and Lilly USA, LLC Annapoorna S. Kini, MBBS, FACC Nothing to disclose Sameer Mehta, MBBS, FACC Consulting Fees – The Medicines Company American College of Cardiology Foundation staff involved with this case have nothing to disclose

February 19th 2013 Case #8: HA, 60 yr M Presentation: Presented on 12/21/2012 with cresendo CCS class II angina and had stress echo revealing lateral and inferior ischemia. Cath revealed 2 V CAD and normal LV function. SYNTAX score 20. Patient had successful PCI using DES (EES) of LCx-HL and did well. Still has residual angina on moderate exertion. Prior History: Hyperlipidemia, Hypertension, +F/H, no prior MI, CML in remission Medications: All once daily dosage Aspirin 81mg, Clopidogrel 75mg, Nebivolol 5mg, Amlodipine 10mg, Simvastatin 40mg, Prednisone 20mg, Synthroid 25mcg 5

Case# 8: cont… SYNTAX score 20 Cardiac Cath 12/21/2012 2 Vessel with LVEF 70% Left Main: Normal LAD: <50% lesion in mid, rest mild diffuse disease LCx: 90% ulcerated LCx-HL lesion, rest non- obstructive RCA: 100% occlusion prox-mid segment with distal vessel large and fills via bridge collaterals and via retrograde collaterals from LAD/LCX Plan Today: - PCI of prox RCA CTO via antegrade/retrograde approach 6

Appropriateness Criteria for Coronary Revascularization

Issues Involving The Case Update on CTO recanalization Status of platelet inhibition (PI) testing

Issues Involving The Case Update on CTO recanalization Status of platelet inhibition (PI) testing

Chronic Total Occlusion (CTO) From Randomized Trials to Daily Practice 1. CTO is present in 20-22% of cath cases but PCI is attempted only in 5-13% of these cases 2. From BARI trial (1994) to SYNTAX trial (2007) , the single most common reason for a patient to be referred to surgery and not randomized was a CTO with low success rate of recanalization 3. Even in the recent era of increasing success rate of CTO recanalization (50-75%), the PCI success rate for CTO lesions in the SYNTAX trial was only 53%

Patients with chronic total occlusion (CTO) Current Perspective on Coronary CTO The Canadian Multicenter CTO Registry Patients with chronic total occlusion (CTO) N = 1697 (18.4% of CAD pts on cath) PCI N = 515 30% Medical therapy N = 747 44% CABG N = 435 26% Attempted CTO PCI N = 162 10% Management of CTO Registry Patients CTO bypassed N = 388 23% 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. Successful CTO PCI N = 123 7% Fefer et al, J Am Coll Cardiol 2012;59:991 11

Management of CTO Registry Patients by Treating Center Current Perspective on Coronary CTO The Canadian Multicenter CTO Registry 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. Management of CTO Registry Patients by Treating Center Fefer et al, J Am Coll Cardiol 2012;59:991 12

Chronic Total Occlusion (CTO) Adverse Factors for PCI Lower success rates: disappointment Longer cases: disrupts the schedule More radiation exposure: dermatitis More resource utilization: without reimbursement Minimal incidence but potentially catastrophic complications: thrombus, dissection, perforation, cardiac tamponade, collaterals shut off, side-branch occlusion, Contrast Induced AKI, MI, uCABG

Patel et al., JACC Cardiovasc Interv 2013;6:128 14

Temporal Trends in Cumulative Angiographic Success Rates and Major Procedural Complication Rates Patel et al., JACC Cardiovasc Interv 2013;6:128 15

Incidence of Angiographic Success and Procedural Complications in CTO PCI % Patel et al., JACC Cardiovasc Interv 2013;6:128 16

Incidence of Procedural Complications in Successful vs Incidence of Procedural Complications in Successful vs. Unsuccessful CTO PCI Outcome Successful Unsuccessful p Value MACE (%) 3.7 4.3 0.68 Death (%) 0.4 1.5 <0.001 Emergent CABG (%) 0.03 0.17 0.74 Stroke (%) 0.07 0.04 Myocardial Infarction (%) 2.8 3.0 0.87 Q-wave MI (%) 0.3 0.5 0.26 Coronary perforation (%) 10.7 Tamponade (%) 0.0 1.7 Vascular complication (%) 0.9 0.20 Contrast nephropathy (%) 5.0 4.6 0.86 Patel et al., JACC Cardiovasc Interv 2013;6:128 17

Chronic Total Occlusion (CTO) Rationales for CTO Recanalization Relief of angina and ischemia Improvement in LV function Reduced need for CABG at long-term Improvement in survival

Meta-Analysis of CTO Outcomes 13 Observational Studies, 7288 patients weighted averaged follow-up 6 years OR for Success vs. Failure 95% Cl p Value Mortality 0.56 0.43-0.72 <0.001 MI 0.74 0.44-1.25 0.26 Subsequent CABG 0.22 0.17-0.27 Residual Angina 0.45 0.30-0.67 0.001 Joyal et al., Am Heart J 2010;160:179. 19

Effect of Successful vs Effect of Successful vs. Failed CTO PCI in All-Cause Mortality During Long-Term Follow-up Author, Year Yr Follow-up PCI Success (n) PCI Failure (n) OR/HR, 95% CI Finci, et al., 1990 2 100 OR: 1.70, 0.40 - 7.32 Warren et al., 1990 2.6 26 18 N/A Ivanhoe et al., 1992 4 317 163 OR: 0.21, 0.05 - 0.83 Angioi et al., 1995 3.6 93 108 OR: 0.37, 0.10 - 1.40 Noguchi et al., 2000 4.3 134 92 OR: 0.28, 0.11 – 0.72 Suero et al., 2001 10 1,491 514 OR: 0.67, 0.54 – 0.83 Olivari et al., 2003 1 289 87 OR: 0.19, 0.03 – 1.14 Hoye et al., 2005 4.5 567 304 OR: 0.52, 0.32 – 0.84 Drozd et al., 2006 2.5 298 161 OR: 0.74, 0.23 – 2.37 Aziz, et al.,2007 1.7 377 166 OR: 0.31, 0.13 – 0.76 Prasad et al., 2007 914 348 OR: 0.82, 0.62 – 1.08 Valenti et al., 2008 344 142 OR: 038, 0.19 – 0.77 de Labriolle et al., 2008 127 45 OR: 1.25, 0.25 – 6.27 Mehran et al., 2011 2.9 1,226 565 HR: 0.63, 0.40 – 1.0 Jones et al., 2012 3.8 582 254 HR: 0.28, 0.15 – 0.52 Joyal et al., 2010 5,056 2,236 OR: 0.56, 0.43 – 0.72 Moses et al., JACC Cardio Interv 2012;5:389 20

Successful Recanalization of CTO Associated with Improved Long-Term Survival 18.2% 6.5% Jones et al., JACC Cardio Interv 2012;5:380 21

Successful Recanalization of CTO Associated with Improved Long-Term Survival Jones et al., JACC Cardio Interv 2012;5:380. 22

Long-Term Outcome of CTO PCI Independent Predictors of Mortality, MI and CABG up to 5 year F/U HR 95% CI p Value Independent predictors of mortality CKD 2.72 1.37-5.39 <0.01 Diabetes mellitus 2.02 1.25-3.26 Age (per-yr increment) 1.09 1.06-1.11 Procedural success of CTO 0.63 0.40-1.00 0.05 Independent predictors of MI 2.50 1.08-5.75 0.03 Independent predictors of CABG CTO located in LAD 1.88 1.16-3.06 0.01 Hypercholesterolemia 0.56 0.35-0.91 0.02 Procedural Success of CTO 0.21 0.13-0.36 Mehran et al. J Am Coll Cardiol Inv 2011;4:952

Change of Lumen Area Between Baseline and 6 Months After CTO Recanalization Park et al., JACC Card Interv 2012;5:827 24

Recanalization of CTO Leads to Lumen Area Increase in Distal Reference Segments 2.24 2.45 2.91 3.05 4.0 4.87 6.85 7.65 Park et al., JACC Card Interv 2012;5:827 25

Retrograde Wire Technique of CTO Recanalization

Retrograde Techniques for CTO Recanalization Typically reserved for LAD or RCA CTOs via septal collaterals; avoid using epicardial collaterals Four techniques: Direct retrograde crossing Kissing wire Controlled Antegrade and Retrograde Subintimal Tracking (CART); balloon dilatation or knuckle wire Reverse CART, LaST

Retrograde Wire Technique for Chronic Total Occlusion Recanalization Four Patterns of Success in Retrograde CTO Recanalization Sumitsuji et al. J Am Coll Cardiol Intv 2011;4:941.

Surmely JF, J Invasive Cardiol. 2006;18:334 Concept of CART Technique Controlled Antegrade and Retrograde Subintimal Tracking Surmely JF, J Invasive Cardiol. 2006;18:334

Temporal Trends In Technical Success of Retrograde CTO PCI in Multicenter Registry Karmpaliotis et al., JACC Cardio Interv 2012;5:1273 30

Summary of Published Retrograde CTO PCI Series Study Year N Prior CABG % Septal Collaterals Used % Reverse CART, % Technical Success % Major Complications % Flouroscopy Time, min, mean ± SD Contrast Use, ml mean ± SD Sianos, et al. 2008 175 10.9 79.4 NR 83.4 4.6 59 ± 29 421 ± 167 Rathore et al. 2009 157 17.8 67.5 84.7 4.5 Kimura et al. 224 17.6 79.0 14.0 92.4 1.8 73 ± 42 457 ± 199 Tsuchikane et al. 2010 93 10.8 82.8 60.9 98.9 0.0 60 ± 26 256 ± 169 Morino et al. 136 9.6 63.9 79.2 US Registry 2012 462 50.0 71.0 41.0 81.4 2.6 61 ± 345 ± 177 Karmpaliotis et al., JACC Cardio Interv 2012;5:1273 31

The procedure involves five key steps: Retrograde PCI: 5 Steps Retrograde PCI for recanalization of CTOs has gained acceptance as a necessary technique to improve success The procedure involves five key steps: Wiring of the collateral from the donor artery into the distal bed of the recipient artery, usually with the use of hydrophilic jacketed guidewires Delivery of over-the-wire microcatheters or balloons to allow an exchange for a CTO-specific guidewire Crossing the total occlusion with the CTO guidewire and dilating the CTO with the retrograde balloon Placing an antegrade guidewire into the distal bed through the recanalized CTO 5. Stenting the lesion

Retrograde Wire Technique for CTO Recanalization When to do Retrograde technique? Minimum 200 CTO cases via antegrade technique Dedicated setup, equipments and ability to handle complications Usually after failed antegrade (once or twice) approach Ostial stump occlusion (RCA, LAD, LCx)

Propensity Score-Matched Event Rates by Stent Type for CTO PCI: 30-Month Follow up DES (n=8,218) BMS (n=2,043) p = 0.04 p = 0.72 % p = 0.74 p = 0.51 Patel et al., J Am Coll Cardio Intv 2012;5:1054 34

CTO PCI: First Generation DES vs. EES First-generation DES (n=294) EES (n=294) p = 0.001 p = <0.001 p = 0.023 % p = 0.002 p = 0.007 p = 0.0198 p = 0.082 35

PRISON III Trial: Cypher vs. ZES-Resolute SES (n=103) ZES-Resolute (n=104) % Teeuwen et al., TCT 2012 36

CIBELES Trial: Clinical and Angio Follow-up SES (n=101) EES (n=106) p=NS for all comparison (trended lower with Xience) % p=0.34 Moreno et al. TCT 2012 37

Fundamental Wire Technique and Current Strategy for Chronic Total Occlusion PCI Procedural Steps of Current CTO-PCI Cotralateral Dual Injection CTO - PCI Single Wire Technique Antegrade approach x2 Parallel Wire Technique Retrograde approach (ostial) Retrograde Wire Cross Kissing Wire Cross IVUS guide re-entry CART Reverse CART Success Failure

Issues Involving The Case Update on CTO recanalization Status of platelet inhibition (PI) testing

Impact of On-Treatment Platelet Reactivity Post-PCI Ischemic/Thrombotic Clinical Events Bonello et al., J Am Coll Cardiol 2010;56:919 40

High On-Treatment Platelet Reactivity in the Setting of PCI PRI >50% by VASP analysis >230 to 238 P2Y12 reaction units by VerifyNow assay >46% maximal 5-µmol/1 ADP-induced aggregation >468 arbitrary aggregation units/min in response to ADP by Multiplate analyzer 41

Incidence of in-hospital major bleeding (5) Incidence of In-hospital TIMI Bleed in Patients with Enhanced Response to Clopidogrel (AU <188) vs. Remaining Patients (AU >188) Incidence of in-hospital major bleeding (5) 2.2 p = 0.005 0.8 Enhanced Remaining responders (n=975) patients (n=1558) Sibbing et al., J of Thrombosis & Haemostasis 2009;8:250

Platelet Reactivity and Clinical Outcome MACE Rates by PRU Quartiles Barr et al., J Am Coll Cardiol 2011;58:1945 43

Clinical Studies Based Platelet Reactivity Measurement by VerifyNow Assay GRAVITAS TRIGGER-PCI ARCTIC DANTE – 75mg vs 150mg Clopidogrel daily TOPAS -1 – 600mg loading and 75mg daily for 6 months with prior PCI 6. ANTARCTIC – patients > 75 years 44

GRAVITAS Study Design Elective or Urgent PCI with DES* R VerifyNow P2Y12 Test 12-24 hours post-PCI by Accumetrics PRU ≥ 230 R High-Dose Clopidogrel† clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel† clopidogrel 75-mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs †placebo-controlled All patients received aspirin (81-162mg daily) Price et al. JAMA 2011;305:1097.

GRAVITAS Trial: Primary Endpoint: CV Death, MI, Stent Thrombosis 4 3 2.3% vs. 2.3% HR 1.01 (95% CI 0.58 – 1.76) p=0.98 CV death, non-fatal MI, or ST % Cumulative Incidence of 2 1 High-Dose Clopidogrel Standard-Dose Clopidogrel 30 60 90 120 150 180 210 No. at Risk High Dose Clopidogrel Standard Dose Clopidogrel 1109 1056 1029 1017 1007 998 747 54 1105 1057 1028 1020 1015 1005 773 53 Observed event rates are listed; P value by log rank test. Price et al. JAMA 2011;305:1097.

TRIGGER PCI Trial: Study Design Elective PCI with DES without GP IIb/IIIa use VerifyNow P2Y12 Test 2-4hrs first clopidogrel MD (75mg) N= 2150 PRU ≥ 206 All patients received aspirin (81-162mg daily) R Prasugrel Loading dose 60mg, then 10mg daily X 6 months Placebo LD,then Clopidogrel 75mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI at 6 mo Key Safety Endpoint: Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 3 and 6 months Trial was halted after 432 pts enrolled because of <2% event rate (projected 7%) in 250 pts reaching 6M mark

Cumulative Composite Incidence of Efficacy Bleeding Events TRIGGER-PCI Study Cumulative Composite Incidence of Efficacy Bleeding Events PAI Data Trenk et al., JACC 2012;59:2159 48

ARCTIC Study: Randomization before planned PCI with DES (n = 2500) Monitoring Treatment Arm 1- Systematic assessment of PD response to clopidogrel + aspirin pre-DES and between day 14 and day 30 2-Adjustment of DAPT dose regimen* if high on-treatment platelet reactivity pre-DES 3-Adjustment of DAPT dose regimen if hyper/hyporesponder during the maintenance phase Conventional Arm 1- No monitoring of PD response 2- DAPT strategy at physician discretion according to routine practice Assessment of the primary endpoint at 1 year (minimal follow-up of 6 months for the last patients) All-cause mortality MI All urgent revascularization Stent thrombosis requiring revascularization or not Ischemic stroke requiring a new hospitalization DAPT =dual antiplatelet therapy *In the absence of high platelet reactivity (HPR), MD regimen is aspirin 75 mg + clopidogrel 75 mg. 49

ARCTIC STUDY Collet et al., NEJM 2012;367:2100 50

ARCTIC STUDY: Incidence of High-On Treatment Platelet Reactivity in the Monitoring Group % Collet et al., NEJM 2012;367:2100

Antiplatelet Therapy in ARCTIC Study Conventional Treatment (N=1227) Monitoring (N=1213) p Value Clopidogrel Before randomization – (%) 89.5 88.5 0.42 After randomization High platelet reactivity – (%) NA 34.5 - Loading dose at time of procedure – (%) 10.2 25.3 <0.001 Prasugrel Before randomization – (%) 0.7 0.6 0.63 0.3 1.2 0.01 Thienopyridine at discharge – (%) Any 99.3 98.7 0.15 93.5 89.4 0.003 5.8 9.3 0.001 Aspirin 98.2 96.7 0.70 High platelet reactivity (%) 7.6 Intravenous loading dose or Additional bolus of ASA in patients with a poor response (%) 84.8 At discharge, in any form or dose – (%) 0.17 GP Ilb/IIIa use – (%) 6.1 30.1 Collet et al., NEJM 2012;367:2100 52

Antiplatelet Therapy in ARCTIC Study Conventional Treatment (N=1227) Monitoring (N=1213) p Value Thienopyridine at f/u between 14-30 days (%) High platelet reactivity NA 15.6 Increase in clopidogrel maintenance dose in patients with a poor response 43.0 Prasugrel maintenance dose 6.0 12.1 <0.001 Aspirin at f/u visit between 14-30 days (%) 3.9 Increase in maintenance dose in patients with a poor response 45.7 Treatment at last visit (%) Clopidogrel 86.4 80.0 Prasugrel 6.1 11.9 Aspirin 96.1 96.0 0.87 Collet et al., NEJM 2012;367:2100 53

ARCTIC STUDY: Incidence of High-On Treatment Platelet Reactivity in the Monitoring Group % Collet et al., NEJM 2012;367:2100

ARCTIC Trial: Monitoring Antiplatelet Therapy for Coronary Stenting Proportion of Patients with Primary Outcome Events (death, MI, stroke/TIA, uRevasc, ST) and Main Secondary Outcome Events (ST, uRevasc) at 1 Year F/U 34.6% 31.1% Collett et al., NEJM 2012:367:2100. 55

ARCTIC Trial: Monitoring Antiplatelet Therapy for Coronary Stenting Study End Points at 1 Year Follow-up* Conventional Treatment (n=1227) Monitoring (n=1213) p = 0.10 p = 0.32 % p = 0.28 p = 0.77 p = 0.76 p = 0.08 p = 0.24 p = 0.51 Primary Secondary Death Death MI Stent Urgent Major or End Point End Point recurrent ACS, thrombosis revasc Minor stroke, TIA bleeding * Patients could have more than one end point Collett et al., NEJM 2012:367:2100. 56

Clinical Studies Based Platelet Reactivity Measurement by VerifyNow Assay GRAVITAS TRIGGER-PCI ARCTIC DANTE – 75mg vs 150mg Clopidogrel daily TOPAS 1 – 600mg loading and 75mg daily for 6 months with prior PCI 6. ANTARCTIC – patients >75 years 57

Routine Testing for Platelet Inhibition by VerifyNow Assay Instrument (Accumetrics) Assessment of platelet aggregation inhibition (PI): - Goal; Optimal response – PRU <230 in maintenance phase on chronic ADP receptor blockers ?PRU 208 - Management if PRU >230; - Make sure about compliance - PPI interaction - ? Genetic testing for 2C19*2 allele polymorphism - If on plavix, then either switch to Prasugrel (30mg LD & 5-10mg MD or double plavix dose to 150mg daily)

Take Home Message: Update on CTO Recanalization and Status of Platelet Inhibition Studies Successful CTO recanalization in appropriately selected cases has shown to improve survival with minimal procedural complications. EES has shown superior results compared to first generation DES with lower reocclusion and repeat restenosis Studies utilizing platelet inhibition measurement guided more intense antiplatelet therapy, have not shown to change MACE outcomes post PCI. Hence routine PI measurement has very limited value in clinical practice.

Question # 1 Successful CTO recanalization is associated with the following except : Improved survival Lower CABG Lower acute complications Improved LV function E. Reduced angina

Question # 2 Following features are associated with high success rates of successful CTO recanalization except: Tapered tip Calcification Good visualization of distal vessel Sidebranch at the site of occlusion E. No bridge collaterals

Question # 3 Following are the PCI studies utilizing platelet inhibition measurement guiding antiplatelet therapy except: ARCTIC trial GRAVITAS trial TRIGGER-PCI trial DANTE trial PLATO trial

Question # 1 Successful CTO recanalization is associated with the following except : Improved survival Lower CABG Lower in-hospital MACE Improved LV function E. Reduced angina The correct answer is C. Recent meta-analysis of published CTO trials showed better survival, lower need for CABG, reduced angina and improved LV function after successful CTO recanalization. But there was no difference in acute MACE. Patel et al., JACC Cardiovasc Interv 2013;6:128

Question # 2 Following features are associated with high success rates of CTO recanalization except: Tapered tip No calcification Good visualization of distal vessel Sidebranch at the site of occlusion E. No bridge collaterals The correct answer is D. Presence of a sidebranch at the site of CTO is associated with high failure rates while other features are favorable for successful recanalization.

Question # 3 Following are the PCI studies utilizing platelet inhibition measurement guiding antiplatelet therapy except: ARCTIC trial GRAVITAS trial TRIGGER-PCI trial DANTE trial PLATO trial The correct answer is E. PLATO trial compared Clopidogrel to Ticagrelor and did not utilize platelet inhibition measurement to guide the therapy. ARCTIC, GRAVITAS and TRIGGER-PCI trials measured platelet inhibition to guide therapy but were negative. DANTE trial comparing 75mg vs. 150mg clopidogrel in poor responders, is ongoing