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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

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

May 19th 2015 Case #71: BS, 66 yrs F Presentation: Patient with NIDDM presented with new onset CCS Class II angina and positive ETT, underwent cardiac cath on April 9th 2015 revealing 2 V CAD (multiple lesions in prox-mid LAD and CTO RCA with retrograde collaterals from LAD), LVEF 60% and SYNTAX score 26. Heart team discussion took place and patient elected for PCI. Pt underwent DES PCI (Xience Alpine x2) to prox-mid LAD and did well. Prior History: NIDDM, Hyperlipidemia Medications: All once daily dosage Metoprolol XL 50mg, Lisinopril 5mg, Metformin XL 1000mg, Simvastatin 40mg, Amlodipine 5mg, ASA 81mg 5

Case# 71: cont… Cardiac Cath 4/9/2015: Right Dominance II V CAD with LVEF 60% LM: No obstruction LAD: multiple 70-80% lesions in prox-mid LAD, 70% S1 LCx: mild diffuse disease, 30% OM1 RCA: 100% occlusion prox RCA, distal vessel is large and fills via LAD-septal collaterals Pt underwent PCI of LAD with Xience Alpine (3/33 & 3/12) with excellent results SYNTAX Score was : 26 Plan Today: PCI of CTO RCA via retrograde approach using LAD- 3rd septal collaterals 6

Appropriateness Criteria for Coronary Revascularization

Issues Involving The Case Retrograde CTO Recanalization 2 Key trials from SCAI 2015: PROMETHEUS, TRIAGE

Issues Involving The Case Retrograde CTO Recanalization 2 Key trials from SCAI 2015: PROMETHEUS, TRIAGE

Retrograde Wire Technique of CTO Recanalization

Temporal Trends and Learning Curve for High Volume, Retrograde, Experienced Operators Operators in the retrograde-experienced, high volume group CTO PCI Procedural and In-hospital Outcomes Thompson et al., J Am Coll Cardiol Intv 2009;2:834

Temporal Success of Antegrade and Retrograde Techniques Success with Both Approaches Improved for the Retrograde Operators Over Time Thompson et al., J Am Coll Cardiol Intv 2009;2:834

Increased Use of Retrograde Approach and Technical Success Rate Over Time 2006 2007 2008 2009 2010 2011 30% % Michael et al., Am J Cardiol 2013;112:488 14

Summary of Published Retrograde CTO PCI Series Study Year N Prior CABG % Septal CollateralUsed % Reverse CART, % Technical Success % Major Complic % Flouroscopy Time, min, mean ± SD Contrast Use, ml mean ± SD Sianos 2008 175 10.9 79.4 NR 83.4 4.6 59 ± 29 421 ± 167 Rathore 2009 157 17.8 67.5 84.7 4.5 Kimura 224 17.6 79.0 14.0 92.4 1.8 73 ± 42 457 ± 199 Tsuchikane 2010 93 10.8 82.8 60.9 98.9 0.0 60 ± 26 256 ± 169 Morino 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 15

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 crossing Controlled Antegrade and Retrograde Subintimal Tracking (CART); balloon dilatation or knuckle wire Reverse CART

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.

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 especially Corsair channel dilator to allow an exchange for a CTO-specific guidewire Crossing the total occlusion with the CTO guidewire and dilating the CTO with the retrograde small balloon (1.25-1.5/8-10mmsize) Placing an antegrade guidewire into the distal bed through the recanalized CTO. Rarely exteriorization of the long retrograde guidewire (Viper wire 360cm) is needed to advance antegrade monorail or over-the-wire small balloon 5. Stenting the lesion over the antegrade guidewire

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 compl. Usually after failed antegrade (once or twice) approach Ostial stump occlusion (RCA, LAD, LCx)

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 Retrograde CTO Recanalization 2 Key trials from SCAI 2015: PROMETHEUS, TRIAGE

Late Breaking Trial: PROMETHEUS Study SCAI 2015 Late Breaking Trial: PROMETHEUS Study Clinical Assessment of Patients with Acute Coronary Syndrome Managed with Percutaneous Coronary Intervention and Treated with Prasugrel or Clopidogrel using Academic Center Databases - The PROMETHEUS Study - Presented by Usman Baber, MD

PROMETHEUS Study: Study Schema Hospitalization for Index PCI Post-Hospitalization for Index PCI Index PCI Day 30* Day 90* Day 180* Day 365* *Time (Day) from Index PCI Hospital Admission for index PCI Hospital Discharge for index PCI

PROMETHEUS Study: Data Extraction and Analysis Data Elements pre-specified by Steering Committee Extraction Sheet Local Sites Data Extraction Data Coordinating Center Validation/Quality Check Aggregation Analysis

Propensity Score Histograms Probability to Receive Prasugrel PROMETHEUS Study: Propensity Score Histograms Prasugrel Clopidogrel Probability to Receive Prasugrel

PROMETHEUS Study: Sites 19,914 patients over 8 US Sites from 01 Jan 2010 to 30 June 2013 Aurora Healthcare Anthony DeFranco Mount Sinai Medical, Annapoorna Kini Minneapolis Heart Institute, Craig Strauss UPMC, Catalin Toma Cleveland Clinic, Samir Kapadia Christiana Care, Sandra Weiss Intermountain Heart Institute, Brent Muhlestein Mount Sinai Medical Center (n = 5344) Cleveland Clinic (n = 3146) Christiana Care (n = 2751) Minneapolis Heart Institute (n = 2464) Intermountain Heart Institute (n = 1893) University of Pittsburgh Medical Center (n = 1710) Duke University (n = 1651) Aurora Healthcare (n = 955) Duke University, Sunil Rao

PROMETHEUS Study: Statistical Methods Sample Size Assumptions MACE rate ~ 8.0% at 90 days Relative reduction with prasugrel ~ 20% Minimum of 4,300 prasugrel patients required to achieve 80% power Propensity score adjustment Stratification (Primary) Inverse Probability weighting Matching Covariate adjustment

PROMETHEUS Study: CAD Presentation in Overall Cohort Prasugrel and Clopidogrel Use in Overall Cohort CAD Presentation by Therapy

PROMETHEUS Study: Procedural Characteristics* Prasugrel (n = 4,058) Clopidogrel (n = 15,856) Multivessel disease 1672 (41.2%) 6723 (42.4%) PCI vessel Left Main 84 (2.1%) 583 (3.9%) LAD 1972 (48.6%) 6926 (43.7%) Circumflex 1100 (27.1%) 4795 (30.2%) RCA 1430 (35.2%) 5368 (33.9%) At least one B2/C type lesion 2848 (71.7%) 10763 (75.3%) At least one lesion with moderate/severe calcification 468 (12.0%) 2694 (19.3%) Total stent length 31.4 ± 20.2 30.50 ± 20.9 Minimum stent diameter 3.01 ± 0.49 2.96 ± 0.50 At least one 1st gen DES 297 (7.3%) 2496 (15.7%) At least one 2nd gen DES 3297 (81.2%) 10525 (66.4%) At least one BMS 569 (14.0%) 3927 (24.8%) Procedural anticoagulation Bivalirudin 2743 (67.6%) 11730 (74.0%) GP2b3a inhibitor 1178 (29.0%) 3391 (21.4%) *p <0.05 for all except multivessel disease (p=0.17) and RCA (0=0.096)

PROMETHEUS Study: Overall Unadjusted MACE Clopidogrel (n=15856) Prasugrel (n=4058) 40% p-value<0.001 3.5 [2.9-4.1] 5.7 [5.0-6.5] 8.3 [7.4-9.2] 12.1 [11.0-13.2] 30% 6.2 [5.8-6.6] 9.6 [9.1-10.1] 14.3 [13.7-14.9] 20.7 [20.0-21.3] MACE % 20% 10% 0% 30 90 180 365 Days After PCI

PROMETHEUS Study: Hazard Ratios for Overall MACE

PROMETHEUS Study: Hazard Ratios for Overall MACE

PROMETHEUS Study: Hazard Ratios at 90 Days (Primary Endpoint)

PROMETHEUS Study: Hazard Ratios for MI

PROMETHEUS Study: Hazard Ratios for All-Cause Death

PROMETHEUS Study: Hazard Ratios for Bleeding

PROMETHEUS Study: Hazard Ratios for Bleeding

PROMETHEUS Study: Conclusions The clinical profile of ACS patients treated with clopidogrel as compared to prasugrel differs substantially across US academic medical centers The overall burden of risk factors for both ischemic and hemorrhagic events are much lower in patients treated with prasugrel Although in this study prasugrel use was associated with lower rates of ischemic adverse events, the magnitude of benefit attenuated and was no longer statistically significant after adjusting for baseline differences Analogously, lack of adjusted bleeding difference with prasugrel may reflect selection of patients at very low risk for hemorrhagic complications Recalibrating ‘real-world’ use of prasugrel to better approximate a patient’s ischemic risk may yield a more appreciable therapeutic benefit. Broader use of prasugrel in eligible patients may achieve the therapeutic results seen in clinical trials.

Late Breaking Trial: TRIAGE Study SCAI 2015 Late Breaking Trial: TRIAGE Study Impact of an integrated treatment algorithm based on platelet function testing and clinical risk assessment: Results of the TRIAGE study

TRIAGE Study: Objective Compare outcomes in patients treated with prasugrel vs. clopidogrel at PCI following determination of platelet reactivity in conjunction with clinical risks: Primary Efficacy Endpoint at 1 year MACE = composite of death, non-fatal MI, definite or probable stent thrombosis Primary Safety Endpoint at 1 year Bleeding = BARC 2, 3 or 5

TRIAGE STUDY ALGORITHM PRU tested in the cath lab prior to PCI PRU ≥ 230 = HTPR PRU < 230 = LTPR Group 2 - Age <75y, Weight ≥60kg, No stroke/TIA/malignancy Group 1 - Age ≥ 75y, Weight <60kg, Previous stroke/TIA, malignancy Clopidogrel 75mg HIGH ISCHEMIC RISK Yes No Clopidogrel 75mg Or Prasugrel 5mg HIGH BLEEDING RISK HIGH BLEEDING RISK PRU = P2Y12 reactivity units, VerifyNow Assay (Accumetrics) PRU = P2Y12 reactivity units HTPR = High on treatment platelet reactivity LTPR = Low on treatment platelet reactivity Yes No Yes No Prasugrel 5mg Prasugrel 10mg Clopidogrel 75mg Or Prasugrel 5mg Prasugrel 10mg

TRIAGE Study: Overall Cohort Mean age of 65.9 +9.8 years and 19% women 40% patients at high ischemic risk by study criteria, 58% patients with PRU ≥230 and/or high ischemic risk by study criteria; 34% patients at high bleeding risk by study criteria 72% received Clopidogrel, 28% received Prasugrel

Primary Efficacy Endpoint: MACE (Death, MI, ST) TRIAGE Study: Primary Efficacy Endpoint: MACE (Death, MI, ST) Clopidogrel (n=228) Prasugrel (n=90) 0.15 LogRank Test 0.10 p=0.70 Cumulative incidence, % 4.4% 0.05 3.5% 0.00 30 90 180 365 Days from index PCI

Secondary Ischemic Endpoints TRIAGE Study: Secondary Ischemic Endpoints Clopidogrel (n=228) Prasugrel (n=90) p=NS % Death/ST/Peri-proc Death ST Non-fatal MI Peri-procedural TVR and non-fatal MI MI

TRIAGE Study: Primary Safety Endpoint: BARC Bleeding 2, 3, or 5 LogRank Test p=0.47 0.00 0.05 0.10 0.15 30 90 180 365 Clopidogrel (n=228) Prasugrel (n=90) Cumulative incidence, % 7.9% 5.6% Days from index PCI

Secondary Bleeding Endpoints TRIAGE Study: Secondary Bleeding Endpoints Clopidogrel (n=228) Prasugrel (n=90) p=NS %

TRIAGE Study: Conclusions Use of a clinical risk algorithm to triage real-world PCI patients for choice and intensity of thienopyridine prescription resulted in similar ischemic outcomes in HTPR patients receiving prasugrel and primarily LTPR patients on clopidogrel. There was no untoward increase in bleeding with prasugrel compared with clopidogrel with this algorithm.

Take Home Message: Retrograde CTO recanalization and Current trends in type & choice of antiplatelet therapy Retrograde technique of CTO revascularization is technically challenging requiring extra skills and increases the overall procedural success rates of CTO. It should be attempted after failed antegrade approach(s) except in cases of flush ostial CTOs PROMETHEUS study showed that clinicians consider bleeding ahead of the efficacy in selecting the type of antiplatelet therapy. Also simple algorithms incorporating bleeding and ischemic risk, may minimize the bleeding complications while maintaining the efficacy of the APT .

Question # 1 Following are the Retrograde approaches to CTO recanalization except: Kissing wire technique CART technique Reverse CART technique Direct retrograde wire technique STAR technique

Question # 2 PROMETHEUS study showed that Prasugrel is being used in following % of PCI cases in ACS: <10% 10-30% 30-40% 40-50% >50%

Question # 3 TRIAGE study of PRU based choice of antiplatelet therapy showed the following; A. Significantly lower MACE with Prasugrel vs Clopidogrel B. Significantly lower peri-procedural MI with Prasugrel vs Clopidogrel C. Numerically lower BARC 2,3,5 bleeding with Prasugrel vs Clopidogrel D. Significantly higher bleeding with Prasugrel vs Clopidogrel E. Significantly lower ST with Prasugrel vs Clopidogrel

Question # 1 The correct answer is E Following are the Retrograde approaches to CTO recanalization except: Kissing wire technique CART technique Reverse CART technique Direct retrograde wire technique STAR technique The correct answer is E

Question # 2 The correct answer is B PROMETHEUS study showed that Prasugrel is being used in following % of PCI cases in ACS: <10% 10-30% 30-40% 40-50% >50% The correct answer is B

Question # 3 The correct answer is C TRIAGE study of PRU based choice of antiplatelet therapy showed the following; A. Significantly lower MACE with Prasugrel vs Clopidogrel B. Significantly lower peri-procedural MI with Prasugrel vs Clopidogrel C. Numerically lower BARC 2,3,5 bleeding with Prasugrel vs Clopidogrel D. Significantly higher bleeding with Prasugrel vs Clopidogrel E. Significantly lower ST with Prasugrel vs Clopidogrel The correct answer is C