Complex Coronary Cases Supported by: Abbott Vascular Boston Scientific Corp Vascular solution

Disclosures Samin K. Sharma, MBBS, FACC Speaker’s Bureau – Boston Scientific Corporation, Abbott Vascular Inc, AngioScore, DSI/Lilly Inc., ABIOMED, CSI 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

May 20th 2014 Case #59: AM, 62 yr M Presentation: Patient presented on April 15th 2014 with cresendo angina CCS class III and stress MPI + for moderate anterior and mild lateral ischemia with LVEF 55%. A cardiac cath revealed 2 V CAD; multiple lesions of prox LAD/Diagonal bifurcation with TO of mid LAD filling distally via bridge collaterals and 80% lesion in OM3 and LVEF 55%. Pt underwent Promus Premier DES of OM3 without any complications. Pt was maximized on medical therapy but still has CCS class II angina. Prior History: Hypertension, Hyperlipidemia, + F/H, Paroxysmal AFib Medications: All once daily dosage Metoprolol XL 50mg, ISMN 60mg, Zestril 10mg, Clopidogrel 75mg, ASA 81mg, Atorvastatin 40mg, Warfarin 3

Case# 59: cont… Cardiac Cath 4/15/2014: Right Dominance SYNTAX Score: 29 Cardiac Cath 4/15/2014: Right Dominance 2 V CAD with LVEF 55% RCA: Severe diffuse disease, modertae size LM: No obstruction LAD: 80% prox LAD with 80% D1 bifurcation and 100% mid LAD with distal vessel fills via bridge collaterals and retrograde collaterals LCx: 80% OM3 lesion moderate size and other vessels mild diffuse disease Plan Today: PCI of LAD/Diagonal bifurcation and mid LAD CTO 4

Appropriateness Criteria for Coronary Revascularization

Issues Involving The Case EXPERT CTO Trial Update in LM Revascularization

Issues Involving The Case EXPERT CTO Trial Update in LM Revascularization

Long-Term Outcome of PCI for CTO: Multicenter Registry 100 Overall success rate 68% 80 Success Rate (%) 60 40 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 # of cases 76 120 102 185 223 214 231 319 249 72 Success rate (%) 72.4 68.3 67.6 51.4 56.5 65.9 76.2 74.9 77.1 70.8 Annual Success Rates of CTO PCI in the Multinational CTO Registry Mehran et al. JACC Interv 2011;4:952.

Temporal Trends in Cumulative Angiographic Success Rates and Major Procedural Complication Rates 80% 0.5% Patel et al., JACC Cardiovasc Interv 2013;6:128 9

EXPERT CTO Trial Design Prospective, multi-center, single-arm study 3 different study devices with three individual primary endpoints in CTO revascularization: 250 patients enrolled at 20 sites in the United States Guide Wire HT Pilot and HT Progress Initial 138 pts Angioplasty Balloon Mini TREK Initial 88 pts with successful guide wire crossing Stent Xience Prime and Xience V EES 250 pts

EXPERT CTO Trial: Study Population Enrolled N=250 28 Excluded from ITT in whom recanalization and pre-dilatation of the target lesion were not completed and/or study stent was not inserted into the coronary guiding catheter. ITT N=222 (89%) 6 Early Terminations 1 Withdrew consent 1 Death 4 Lost-to-follow-up ITT at 1 Month N=216 4 Early Terminations 2 Deaths 2 Lost-to-follow-up ITT at 6 Months N=212 3 Early Terminations 1 Death 2 Withdrew consent ITT at 1 Year N=209 Kini et al.; ACC i2 2014 Note: One year clinical follow-up rate was 97.3% (216/222)

EXPERT CTO Trial: Enrollment Criteria Key Inclusion Criteria – Symptomatic ischemic heart disease with clinical indication for CTO revascularization – Maximum of one de novo native coronary artery lesion with TIMI 0/1 flow and estimated at least 3 months’ duration – Suitability for placement of coronary stents in occluded segment” No severe tortuosity (angulation ≥ 45º) or location in excessively distal location Key Exclusion Criteria – Evidence of acute MI within 72 hours of the intended treatment – Treatment with a device after successful crossing other than PTCA prior to stent placement (eg, directional or rotational coronary atherectomy, excimer laser, thrombectomy) No restrictions regarding lesion length or treatment strategy (antegrade, retrograde, hybrid)

EXPERT CTO Trial Guide Wire Primary Endpoint: Angiographic Confirmation of Guide Wire in Distal True Lumen and Absence of In-Hospital MACE Guide Wire Cohort (%) [95%CI], N=138 Lower Bound (%) Performance Goal (%) P value 1o Analysis (ARC MI) 79.0 [71.2, 85.5] 72.8 62.5 <0.0001 Guide wire in distal lumen 89.9 [83.6, 94.3] Absence of in-hospital MACE (ARC MI definition) 89.1 [82.7, 93.8] 2o Analysis (protocol MI) 87.7 [81.0, 92.7] 82.3 Absence of in-hospital MACE 97.8 [93.8, 99.5] Kandazari et al.; SCAI 2013

Total Analysis Population EXPERT CTO Trial Balloon Primary Endpoint: Successful Delivery, Performance and Absence of Angiographic and Clinical Complications Evaluable Population N=65 Total Analysis Population N=88 Study Balloon Success (MINI-TREK) (%) [95% CI] 93.8 [85.0, 98.3] 93.2 [85.7, 97.5] Successful delivery to and across lesion 96.9 [89.3, 99.6] 96.6 [90.4, 99.3] Successful inflation and deflation 100.0 [94.3, 100.0] [95.8, 100.0] Absence of clinically significant vessel perforation, flow-limiting dissection, reduction in TIMI flow, or clinically significant arrhythmias following pre-dilatation 97.7 [92.0, 99.7] Achievement of final TIMI 3 flow at conclusion of procedure [94.5, 100.0] 98.9 [93.8, 100.0] Kandazari et al.; SCAI 2013

EXPERT CTO Trial: Baseline Clinical Characteristics Age (years ± SD) 61.7 ± 10.4 Male (%) 81.1 Hypertension (%) 91.9 Dyslipidemia (%) 96.8 Diabetes (%) 40.1 Oral meds (% diabetics) 68.5 Insulin (% diabetics) 30.3 Current Tobacco Use (%) 26.0 Prior MI (%) 29.0 Previous PCI (%) 43.4 Prior CABG (%) 9.9 Number of Diseased Vessels (%) One 76.6 Two 17.1 Three 6.3

EXPERT CTO Trial: Baseline Target Lesion Characteristics Vessel Location (%) LAD LCX RCA LMCA 31.1 15.8 53.2 TIMI 0 (%) 95.9 % Stenosis (Mean ± SD) 99.7 ± 2.1 RVD (mm) (Mean ± SD) 2.7 ± 0.4 MLD (mm) (Mean ± SD) 0.01 ± 0.05 Lesion Length (mm) (Mean ± SD) 36.1 ± 18.5 Occlusion Length (mm) (Mean ± SD) 14.0 ± 10.6 Calcification (%) None/Mild Moderate to severe 50.9 48.8 Collaterals (%) Ipsilateral Contralateral Bridging 92.8 92.6 86.5

EXPERT CTO Trial: Procedural Characteristics N=222 Non-Target Lesions Treated (N) (Mean ± SD) 0.3 ± 0.05 Number of stents/lesion (Mean ± SD) 1.95 ± 0.98 Stent Length (mm) (Mean ± SD) 51.72 ± 27.16 Final TIMI 3 Flow (%) 97.7 Clinically Significant Perforation (%) Procedure Time (minutes) (Mean ± SD) 79.9 ± 48.5 Contrast Volume (mL) (Mean ± SD) 259.0 ± 136.7 Fluoroscopy Duration (minutes) (Mean ± SD) 33.6 ± 23.3 Kini et al.; ACC i2 2014

EXPERT CTO Trial: Procedural Success and Outcomes According to Guide Wire Strategy Per ARC MI Per Protocol MI Overall Procedure Success (%) 89.6% (198/221) 96.4% (213/221) Success by Guide Wire Crossing Method (%) Antegrade Only 90.1 (173/192) 97.9 (188/192) Antegrade crossing 90.3 (168/186) 97.8 (182/186) STAR 85.7 (6/7) 100.0 (7/7) Knuckle wire 100.0 (1/1) Bridgepoint/StingRay 78.3 (18/23) 96.7 (22/23) Retrograde Only 91.7 (11/12) Retrograde crossing Combined Antegrade and Retrograde 81.8 (9/11) CART Reverse CART 77.8 (7/9) Kissing wire technique Multiple crossing techniques 80.0 (4/5) Kini et al.; ACC i2 2014

EXPERT CTO Trial: MI According to CK-MB Elevation (N=220) % Kini et al.; ACC i2 2014

EXPERT CTO Trial: 1 Year Clinical Outcome % Kini et al.; ACC i2 2014

EXPERT CTO Trial: Conclusions As a rigorously conducted, multicenter registration trial representing contemporary CTO PCI, the EXPERT CTO clinical trial successfully met all 3 of its device primary endpoints: Procedural success of 90%+ achieved with guide wires among highest reported and with favorable safety Effectiveness of low-profile angioplasty catheters demonstrated by deliverability, lesion crossing, achievement of luminal gain, low rate of complications, and high rate of procedural success Primary endpoint demonstrates excellent safety and efficacy of Xience EES in this very complex lesion subset of CTO Xience EES was associated with a definite ST rate of 1% and a TLR rate of 6.3% Overall MACE was largely driven by periprocedural MI that did not translate to other adverse events at 1 year Kini et al.; ACC i2 2014

Issues Involving The Case EXPERT CTO Trial Update in LM Revascularization

LMCA Stenosis Location LCX About two third of LMCA Lesions include distal bifurcation; 1/3rd are ostial/shaft lesions 66% Bifurcation LMCA 26% Ostium 8% Body-Shaft LAD

Mohr et al., Lancet 2013;381:629

SYNTAX Trial: Patient Distribution at 5 Years FU 1800 patients enrolled 897 randomly assigned to CABG 903 randomly assigned to PCI 40 withdrew consent 8 lost to follow-up 7 withdrew consent 5 lost to follow-up 849 remained in the study at 1 year 891 remained in the study at 1 year 10 withdrew consent 33 lost to follow-up/other 1 early follow-up 4 withdrew consent 16 lost to follow-up/other 0 early follow-up 805 remained in the study at 5 years 871 remained in the study at 5 years 897 analyzed 903 analyzed Mohr et al., Lancet 2013;381:629

SYNTAX Trial: MACCE Rates in Patients with LM Disease vs. 3 V Disease at 5-Yr FU Left Main Disease 3-Vessel Disease Baseline SYNTAX Score 0-22 Baseline SYNTAX Score 0-22 Baseline SYNTAX Score 23-32 Baseline SYNTAX Score 23-32 Mohr et al., Lancet 2013;381:629

SYNTAX Trial: MACCE Rates in Patients with LM Disease vs. 3 V Disease at 5-Yr FU Left Main Disease 3-Vessel Disease Baseline SYNTAX Score ≥33 Baseline SYNTAX Score ≥33 Mohr et al., Lancet 2013;381:629

DELTA Registry: Cumulative Incidence of MACCE at Follow-up of 5 Yrs PCI Overall (n=1874) CABG Overall (n=900) % Chieffo et al., J Am Coll Cardiol Intev 2012;5:718

DELTA Registry: Study Population Flow Chart Naganuma et al., J Am Coll Cardiol Intev 2014;7:354

DELTA Registry: Cumulative Incidence of In-Hospital MACCE PCI group (n=482) CABG group (n=374) % Naganuma et al., J Am Coll Cardiol Intev 2014;7:354

DELTA Registry: Cumulative Incidence of Follow-Up MACCE at 5 Yrs PCI group (n=482) P= 0.06 CABG group (n=374) % P= 0.009 Naganuma et al., J Am Coll Cardiol Intev 2014;7:354

Freedom from All-cause death DELTA Registry: Death and MACCE event Free in PCI Group vs. CABG Group for ULMCA in Propensity Score-Matched Groups Freedom from All-cause death Freedom from MACCE Naganuma et al., J Am Coll Cardiol Intev 2014;7:354

FINE Registry: MACE at 2-Year Clinical Follow-Up; First-Generation vs FINE Registry: MACE at 2-Year Clinical Follow-Up; First-Generation vs. New-Generation DES First-Generation DES (n=93) p=0.07 New-Generation DES (n=93) p=0.04 % p=0.08 p=0.46 p=1.04 Buchanan et al., EuroIntervention 2013;9:809

ISAR LEFT-MAIN 2 Study: 30 Days Clinical Outcomes p=>0.99 ZES (n=324) EES (n=326) p=0.74 % p=0.47 p=>0.99 p=>0.99 Mehilli et al., JACC 2013;62:2075

ISAR-LEFT-MAIN 2 Study: ZES vs ISAR-LEFT-MAIN 2 Study: ZES vs. EES for Unprotected LM CAD at 1 Year Clinical Outcomes ST (Def/Prob) 0.9% 0.6% ZES (n=324) p=0.24 EES (n=326) p=0.25 % p=0.35 p=0.98 p=0.16 N=237 N=226 Death MI TLR Death, MI Angiographic or TLR restenosis Mehilli et al., JACC 2013;62:2075

Method of Revascularization of Multi-vessel and LM Coronary Artery disease CABG PCI Two-vessel CAD with proximal LAD stenosis A Three Vessel CAD with low CAD burden (i.e., three focal stenosis, low SYNTAX score) Three-vessel CAD with intermediate to high CAD burden (i.e., multiple diffuse lesions, presence of CTO, or high SYNTAX score >32)/DM U/I Isolated left main stenosis U Left main stenosis and additional CAD with low CAD burden (i.e., one to two vessel additional involvement, low SYNTAX score <33) Left main stenosis and additional CAD with intermediate to high CAD burden (i.e., three vessel involvement, presence of CTO, or high SYNTAX score >32) I 39

Method of Revascularization of Multi-vessel and LM Coronary Artery disease CABG PCI Two-vessel CAD with proximal LAD stenosis A Three Vessel CAD with low CAD burden (i.e., three focal stenosis, low SYNTAX score) Three-vessel CAD with intermediate to high CAD burden (i.e., multiple diffuse lesions, presence of CTO, or high SYNTAX score >32)/DM U/I Isolated left main stenosis/ Ostial & shaft lesion U/A Left main stenosis and additional CAD with low CAD burden (i.e., one to two vessel additional involvement, low SYNTAX score <33) U Left main stenosis and additional CAD with intermediate to high CAD burden (i.e., three vessel involvement, presence of CTO, or high SYNTAX score >32) I 41

LM disease (±1, 2 or 3 vessel disease) and SYNTAX score of ≤32 EXCEL Trial (Evaluation of Xience Prime vs. CABG for Examination of LM Disease) LM disease (±1, 2 or 3 vessel disease) and SYNTAX score of ≤32 Randomize 2600 pts Trial finished enrollment after 1800 cases ABBOTT Vascular XIENCE Prime stent CABG The primary endpoint is the composite incidence of death, large MI or stroke at a median FU duration of 3 years, powered for sequential non-inferiority and superiority testing. The major secondary endpoint is the composite incidence of death, MI, stroke or unplanned repeat revascularization. All patients will be followed for 5 years total.

Take Home Message: EXPERT CTO Trial and Status of ULM PCI Contemporary trial of CTO recanalization has shown to have success rate over 90% with very low complication rates and 1 year MACE rates of <10% using Xience EES including 1% ST and 6% TVR rates Recent trials of ULM PCI involving ostial or shaft lesions have shown long-term outcomes similar to the CABG cohort. Hence PCI is a viable option in ostial/shaft ULM lesions with non-extensive concomitant other vessel disease.

Question # 1 Following are the false statements regarding Expert CTO trial: DES is superior to BMS Crossing with Minitrek balloon was achieved in >95% cases Successful guide wire crossing occurred in 90% of cases One year MACE rate was 20% A and D

Question # 2 Following are the false conclusions of 5 year F/U of SYNTAX trial: SYNTAX score predicted MACCE in LM cohort in each tertile MACCE outcomes were similar in LM vs. 3 V CAD cohort LM cohort had higher death rate Incidence of CVA was similar in PCI vs. CABG group All of the above

Question # 3 In the DELTA registry, Ostial/shaft ULM lesions have similar outcomes to CABG except: A. Death rate B. TVR C. MACE D. MACCE E. MI

Question # 1 Following are the false statements regarding Expert CTO trial: DES is superior to BMS Crossing with Minitreck balloon was achieved in >95% cases Successful guide wire crossing occurred in 90% of cases One year MACE rate was 20% A and D The correct answer is E as EXPERT CTO used Xience DES only and MACE rate was 10% at one year. Kini et al, ACCi2 Summit 2014

The correct answer is E as all are the false statements Question # 2 Following are the false conclusions of 5 year F/U of SYNTAX trial: SYNTAX score predicted MACCE in LM cohort in each tertile MACCE outcomes were similar in LM vs. 3 V CAD cohort LM cohort had higher death rate Incidence of CVA was similar in PCI vs. CABG group All of the above The correct answer is E as all are the false statements Mohr et al., Lancet 2013;381:629

The correct answer is B as all others were equal between 2 groups Question # 3 In the DELTA registry, Ostial/shaft ULM lesions have similar outcomes to CABG except: A. Death rate B. TVR C. MACE D. CVA E. MI The correct answer is B as all others were equal between 2 groups Naganuma et al., J Am Coll Cardiol Intev 2014;7:354

Question # 1 Following are the true statements regarding IMA PCI except: 2nd generation DES is superior to BMS in lowering TLR PTCA of IMA anastomosis is associated with higher MACE DES use has shown to improve survival IMA PCI is associated with higher complications then native V IMA PCI is technically challenging The correct answer is B as PTCA of IMA anastomosis have shown to have lower MACE rates compared to stent Gruberg et al., JACC 2000;35:944

Question # 2 Following are the recent randomized trials of Bivalirudin except : HEAT PPCI NAPLES III BRAVE 4 REPLACE 2 BRIGHT The correct answer is D as all other 4 trials are recent and REPLACE trial was done in 2002 ACC i2Summit 2014

Question # 3 Recent RCT of Bivalirudin vs. UFH have shown the following: A. Lower bleeding rates B. Lower MACE rates C. Higher Stent Thrombosis in some trials D. Higher TLR rates E. Lower MI rates The correct answer is C as HEAT PPCI trial has shown higher ST rate in the Bivalirudin arm ACC i2 summit 2014