Complex Coronary Cases Supported by: Abbott Vascular Inc Boston Scientific Corp Terumo Vascular Corp Trireme Medical Inc Astra Zeneca Spectranetics Corp

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

November 18th 2014 Case #65: PR, 74 yr M Presentation: Patient with new onset cresendo CCS Class III angina and severe inferior and moderate lateral wall ischemia on stress MPI. A cardiac cath on October 31st 2014 revealed 3 V CAD, LVEF 60% and Syntax score 22. Patient underwent RA and 2 Promus Premier DES to 90% calcified distal RCA lesion. Pt was maximized on medical therapy but still has CCS class II angina. Prior History: Hypertension, Hyperlipidemia, Ex-smoker Medications: All once daily dosage Metoprolol XL 50mg, ISMN 30mg, Clopidogrel 75mg, ASA 81mg, Atorvastatin 40mg 3

Case# 65: cont… Cardiac Cath 1031/2014: Right Dominance 3 V CAD with LVEF 60% RCA: severely calcified 80-90% lesions in distal RCA LM: no obstruction LAD: 60% mid LAD calcified lesions LCx: 90% calcified lesion bifurcation lesions in prox LCx, 80% OM1 and 90% in OM2 (Medina 1,1,1) SYNTAX Score was : 22 Course: Pt underwent RA+ DES x2 (Promus Premier) to dRCA Plan Today: PCI of moderately calcified bifurcation lesions of LCx and OM branches using Chocolate balloon PTCA and planned 2 stents strategy. SYNTAX Score now : 17 4

Appropriateness Criteria for Coronary Revascularization

Special Balloon Chocolate® PTCA TriReme Medical Inc. Device description Nitinol Constraining Structure Unique Dilatation Pillows and Grooves Mechanism of operation Controlled, Predictable, Uniform Inflation Reduced “Dog-Boning” Enhanced Dispersal of Dilatation Forces Specifications 5F or 6F guide catheter compatible depending on balloon size Range of balloon sizes (2.0/2.5/3.0/3.5mm x 10/15/20mm) Product Approval and Indication The Chocolate® PTCA Balloon Dilatation Catheter is indicated for balloon dilatation of the stenotic portion of coronary artery or bypass graft stenosis for the purpose of improving myocardial perfusion. FDA 510k clearance and CE MARK.

The Chocolate PTCA Balloon Designed to provide predictable, uniform, and atraumatic dilatation Unique nitinol “constraining structure” (CS) Uniformly distributes circumferential forces (calcific or eccentric lesions) – no “dog boning” Shields vessel wall from torsional shear stress caused by balloon “unfolding” Modifies plaque via: “Pillows”: vessel dilatation without cutting or scoring “Grooves”: stress relief, plaque modification Reduces dissections and recoil – improved lumen size Fast deflation, concentric secondary profile The Chocolate PTCA Balloon Designed to provide predictable, uniform, and atraumatic dilatation Unique nitinol “constraining structure” (CS) Uniformly distributes circumferential forces (calcific or eccentric lesions) – no “dog boning” Shields vessel wall from torsional shear stress caused by balloon “unfolding” Modifies plaque via: “Pillows”: vessel dilatation without cutting or scoring “Grooves”: stress relief, plaque modification Reduces dissections and recoil – improved lumen size Fast deflation, concentric secondary profile

Flow-Limiting Dissections with PTCA With conventional balloons, inflation can result in vessel trauma leading to dissections. Three reasons are torsional, radial, and longitudinal stress!

Balloon Inflation Dynamics Conventional Balloon Chocolate Balloon Nominal > Nominal Nominal > Nominal Chocolate’s unique design facilitates plaque modification Valleys allow plaque extrusion & remodeling Higher pressure enhances pillows Pillows project beyond constraining structure

The Chocolate PTCA Balloon Clinical indications In situations where DES more problematic (DCB “friendly” lesions) Small vessels Bifurcations (esp. ostial branch) DAPT contra-indications Vessel preparation before BVS For routine use, instead of conventional PTCA balloons

Issues Involving The Case Update in Bifurcation Lesion PCI Update on Revascularization in Diabetics

Issues Involving The Case Update in Bifurcation Lesion PCI Update on Revascularization in Diabetics

Coronary Artery Bifurcation Lesion Interventional Techniques Interventional Bifurcation Techniques One Stent Technique (OST) Kissing Stent Technique (SKS) Crush Stent Technique (CrST) ? OST with SBR Dilatation (SBT) ‘T’ Stent Technique (TST) Culotte Stent Technique (CUT)

Significant Post Stenting SB Stenosis: QCA vs. FFR (Jailed side branch lesions, n=94) FFR Functionally significant stenosis 38% of lesions 75% % Stenosis Koo et al. JACC 2005;46:633.

Randomized Comparison of FFR-Guided and Angiography-Guided Provisional Stenting for True Coronary Bifurcation Lesions: The DKCRUSH-VI Trial

DKCRUSH VI Trial: Study Design Medina 1,1,1/0,1,1 bifurcation lesions, SB≥2.5 mm FFR group (n=160) Angio group (n=160) Jailed wire, MV Stenting SB FFR<0.8 Ostial SB: DS>70%, B/C dissection, TIMI<3 If yes, Kissing balloon inflation No No If still yes, SB Stenting, FKBI 1-year clinical/13-m angio F/U Chen and Stone, TCT 2014

DKCRUSH VI Trial: Procedural Findings FFR group (n=160) Angio group (n=160) Measuring SB-FFR SB stenting in 61 (38.1%) patients Success (n=145, 90.6%) Failure (n=15) Success Failure (n=51, 83.6%) (n=10, 16.4%) FFR ≥0.8 FFR <0.8 KBT (n=70) (n=75) KBI FFR≥0.8 FFR<0.8 (n=49) (n=26) Stenting SB (success in 22, 77.3%; failure in 8, 22.7%) Stenting MV (100%) FFR<0.8 (n=4) FFR≥0.8 (n=8) Failure (n=3) SB PCI, any: 56.3% SB stenting attempted: 25.9% P=0.07 P=0.01 SB PCI, any: 63.1% SB stenting attempted: 38.1% Chen and Stone, TCT 2014

DKCRUSH VI Trial: 1-Year Clinical Outcomes Angio Group (n=160) FFR Group (n=160) p=1.00 p=0.74 % p=0.82 p=0.56 p=0.56 Chen and Stone, TCT 2014

DKCRUSH VI Trial: Distribution of Restenosis Pre-Specified Definition Chen and Stone, TCT 2014

Post hoc definition DKCRUSH VI Trial: Distribution of Restenosis Post hoc analysis if in-segment resetenosis* Location Angio group FFR group P Value Proximal MV 3.4 1.7 0.68 Distal MV 9.2 0.01 Side Branch 11.8 21.2 0.037 * Defined as a QCA DS>50%; Segment=stented + P/D 5-mm MV, main vessel Chen and Stone, TCT 2014

Medina 111/011 bifurcation with SB ≥2.5 mm Non-LM distal bifurcation DEFINITION Study: Description of Complex Bifurcation Lesion Definitions Medina 111/011 bifurcation with SB ≥2.5 mm LM distal bifurcation Non-LM distal bifurcation SB DS ≥70% SB lesion length ≥10 mm SB DS ≥90% SB lesion length ≥10 mm Yes Yes No Yes With any 2 minors Simple With any 2 minors Yes Yes Complex Chen et al., J Am Coll Cardiol Intv 2014; Article in Press

DEFINITION Study: Independent Factors of MACE at 1 Y After Stenting by Regression Analysis (Training Group n=1,500) Chen et al., J Am Coll Cardiol Intv 2014; Article in Press

DEFINITION Study: Flow Chart 2058 patients with Medina 111/011 bifurcation lesions 3828 patients with Medina 111/011 bifurcation lesions 558 patients excluded -- 544 SB <2.5 mm -- 14 lost during F/U 558 patients excluded -- 544 SB <2.5 mm -- 14 lost during F/U 1550 patients with Medina 111/011 bifurcation and SB ≥2.5 mm (Training Group) 3660 patients with Medina 111/011 bifurcation and SB ≥2.5 mm (Study Group) To build criteria of lesions complexity To test the predictive value for worse clinical events Chen et al., J Am Coll Cardiol Intv 2014; Article in Press

DEFINITION Study: Clinical Outcomes in Complex and Simple Groups (n=3660) Complex (n=1108) Simple (n=2552) In-Hospital Outcomes At 1-Year Outcomes p=<0.001 p=0.004 % p=<0.0001 p=<0.001 % p=<0.001 p=<0.001 p=0.12 p=0.26 p=0.08 p=0.07 MI Cardiac TVR MACE ST death MI Cardiac TVR MACE ST death Chen et al., J Am Coll Cardiol Intv 2014; Article in Press

DEFINITION Study: Clinical Outcomes in 2-Stent and Provisional Stent in Complex Groups (n=1108) Two Stent (n=537) Provisional Stent (n=571) In-Hospital Outcomes At 1-Year Outcomes p=0.14 p=1.34 % p=0.03 p=0.03 % p=0.07 p=0.04 p=0.90 p=0.37 NS NS MI Cardiac TVR MACE ST death MI Cardiac TVR MACE ST death Chen et al., J Am Coll Cardiol Intv 2014; Article in Press

BABILON Trial: Flow Chart Randomization Drug-eluting Balloon (DEB) DES Sequential MB/SB dilatation with plain balloon Sequential MB/SB dilatation with DEB (1:1 balloon:artery relation 2. Provisional T-stenting with BMS/MB Provisional T-stenting with DES (everolimus)/MB Final Kissing with regular balloons at operator’s discretion 3 months dual antiplatelet therapy 12 months dual antiplatelet therapy 9-month angiographic follow-up (primary endpoint: late luminal loss, LLL), and global restenosis 2-year clinical follow-up (secondary endpoint: MACE, clinical events) López Minguez et al., EuroIntervention 2014;10:50

BABILON Trial: 24-Month Clinical Events pDEB group (n=52) DES group (n=56) p=0.11 p=0.05 p=0.03 % p=0.67 p=1.0 p=1.0 López Minguez et al., EuroIntervention 2014;10:50

Issues Involving The Case Update in Bifurcation Lesion PCI Update on Revascularization in Diabetics

MASS II Study: Mortality Rate at 10-Year F/U for Diabetic and Non-Diabetic Patients Diabetic (n=232) Non-Diabetic (n=399) N=88 N=115 N=64 N=141 N=80 N=123 Hueb et al., Circulation 2010;122:949

VA CARDS Study: CONSORT Flow Diagram Enrollment 6678 Pts screened for eligibility 6471 Excluded ● 6080 Not angiography eligible ● 173 Declined to participate ● 218 Other reasons 207 Randomized Allocation 103 Assigned to CABG group 104 Assigned to PCI group 1 Misrandomized 5 Withdrawn due to early study termination 2 Misrandomized 1 Withdrawn due to early study termination Follow-up Analysis 97 Included in the intention-to-treat analyses 101 Included in the intention-to-treat analyses Kamalesh et al., JACC;2013:61:808

VA CARDS Study: Primary Endpoints Occurrence Rate at 2Years CABG (n=97) PCI (n=101) 95% CI [0.42-2.07] 95% CI [1.07-10.30] % 95% CI [0.06-16.49] Kamalesh et al., JACC;2013:61:808

FREEDOM Trial: Estimates of Key Outcomes at 5 Years after Randomization PCI (n=943) p=0.005 CABG (n=957) p=0.049 p=<0.001 p=0.12 % p=0.003 Primary End Death MI Stroke 1-Yr TVR Farkouh et al., N Engl J Med 2012;367:2375 33

FREEDOM Trial: Estimates of the Composite Primary Outcome Farkouh et al., N Engl J Med 2012;367:2375 34

SPIRIT V Trial: 1 Year Clinical Outcome in Diabetics EES (n=215) PES (n=104) p=0.71 p=0.05 p=0.25 % p=0.40 p=0.11 Grube et al., Am Heart J 2012;163:867

ESSENCE-DIABETES Trial: Clinical Outcomes At 12 Months EES (n=149) SES (n=151) p=0.22 p=0.12 p=0.45 p=0.50 p=1.0 Death MI ST Ischemia- MACE driven TVR Kim et al., Circulation 2011;124:886

ISAR-LEFT-MAIN 2 Study: ZES vs ISAR-LEFT-MAIN 2 Study: ZES vs. EES for Unprotected LM CAD 1 Year Clinical Outcomes ST (Def/Prob) 0.93% 0.61% ZES (n=324) EES (n=326) p=0.24 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

Network Plot of Treatment Comparisons Banglore et al., Circ Cardiovasc Interv 2014;7:518

Median Rate of Primary and Secondary Outcomes From Mixed Treatment Comparison Analysis Banglore et al., Circ Cardiovasc Interv 2014;7:518

Mixed Treatment Comparison Analyses for CABG vs. PCI in Diabetics Outcome of All-Cause Mortality Bangalore et al., Circ Cardiovasc Interv. 2014;7:518

Mixed Treatment Comparison Analyses for CABG vs. PCI in Diabetics Outcome of MI Outcome of Stroke Bangalore et al., Circ Cardiovasc Interv. 2014;7:518

Mixed Treatment Comparison Analyses for CABG vs. PCI in Diabetics Outcome of Repeat Revascularization Bangalore et al., Circ Cardiovasc Interv. 2014;7:518

Sensitivity Analysis: Mixed Treatment Comparison Analyses for CABG vs. PCI in Diabetics Outcome of All-Cause Mortality Using Counts Data and Frequentlist-Based Approach Bangalore et al., Circ Cardiovasc Interv. 2014;7:518

FREEDOM Trial: Estimates of the Composite Primary Outcome at 5 yrs Farkouh et al., N Engl J Med 2012;367:2375 45

Potential Primary Outcome of Death, MI or Stroke if FREEDOM Trial is done with CoCr EES

The FREEDOM Insulin Subgroup Analysis Estimates of the Primary Endpoint by Treatment Received and Insulin Use Primary Composite Outcome at 5 Years by Insulin Use Primary Composite Outcome at 5 Years by Treatment and Insulin Use Dangas et al., J Am Coll Cardiol 2014;64:1189

Treatment Effect of CABG vs PCI in Non-ITDM and ITDM Groups The FREEDOM Insulin Subgroup Analysis Treatment Effect of CABG vs PCI in Non-ITDM and ITDM Groups PCI (n=631) CABG (n=617) PCI (n=325) CABG (n=277) Non-ITDM ITDM p=0.40 p=0.40 % p=0.64 p=0.81 p=0.81 p=0.64 % p=0.33 p=0.33 Death/ Mortality 1-Y MACCE 1-Y TVR stroke/MI Death/ Mortality 1-Y MACCE 1-Y TVR stroke/MI Dangas et al., J Am Coll Cardiol 2014;64:1189

FREEDOM Follow-On Registry Protocol Title Long-term Outcomes in patients who underwent revascularization in the FREEDOM Trial Abbreviated Title FREEDOM Follow-On Registry Name of Sponsor Valentin Fuster Mount Sinai School Of Medicine Foundation Study Objective To assess the long-term event rate (death, non-fatal MI, or non-fatal stroke) following revascularization by PCI/DES or CABG in subjects with diabetes and multivessel CAD Study Design Prospective, multicenter observational registry Study Centers Up to 91 sites that participated in the FREEDOM main trial Study Population Approximately 1,000 subjects will be enrolled in the Follow-On registry, comprised of FREEDOM Trial survivors who consent to this registry Duration of Participation Subjects will be evaluated at Baseline (in-person) and annually thereafter via telephone up to 36-months Eligibility Criteria Inclusion Criteria: Subjects of the FREEDOM trial in the past and agreed for Follow-up Signed written informed consent There are no exclusion criteria for this observational registry. Primary Endpoint The primary endpoint is the composite of death, non-fatal MI, or non-fatal stroke, the same as for the FREEDOM main trial Secondary Endpoints Secondary endpoints include: all-cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, and repeat revascularization

Take Home Message: Updates in Bifurcation Lesion PCI and Revascularization in Diabetics Bifurcation lesion PCI involving FFR has limited value but a prospective strategy of identifying complex bifurcation lesion is useful and has better outcomes with the use of 2-stents. Drug eluting balloon is inferior to DES in bifurcation lesion even as the provisional side branch strategy Despite the superior outcomes of CABG in FREEDOM trial using first generation DES, data are emerging that newer generation DES especially CoCr EES has potential to have similar outcomes to CABG in multivessel diabetic pts. Future trials of revascularization in complex CAD in diabetic patients will be needed for the final answer.

Question # 1 Following is the true statement regarding DK CRUSH VI trial: Higher MACE rate with Angio guided PCI Lower Stent Thrombosis with FFR guided PCI Higher overall TVR in Angio guided PCI Higher side branch restenosis in FFR guided PCI Higher MACE rates with Angio guided PCI

Question # 2 Following is the true statement from the DEFINITION study of bifurcation lesion PCI: MACE rates were similar in simple vs. complex group Outcomes were better with 2-stent strategy vs. Provisional strategy in Complex group Rates of MI are similar in simple vs. complex group Rates of Stent Thrombosis are similar in simple vs. complex group It is tough to predict which bifurcation lesion is simple or complex

Question # 3 Mixed treatment comparison analysis of various PCI types and CABG have shown the following not to be true: A. Higher mortality with SES/PES vs. CABG B. Higher TVR with PCI vs. CABG C. Lower stroke rates with PCI vs. CABG D. Higher MI rates with PCI vs. CABG E. PCI with CoCr EES has higher mortality and TVR vs. CABG

Question # 1 The correct answer is D Following is the true statement regarding DK CRUSH VI trial: Higher MACE rate with Angio guided PCI Lower Stent Thrombosis with FFR guided PCI Higher overall TVR in Angio guided PCI Higher side branch restenosis in FFR guided PCI Higher MACE rates with Angio guided PCI The correct answer is D

Question # 2 The correct answer is B Following is the true statement from the DEFINITION study of bifurcation lesion PCI: MACE rates were similar in simple vs. complex group Outcomes were better with 2-stent strategy vs. Provisional strategy in Complex group Rates of MI are similar in simple vs. complex group Rates of Stent Thrombosis are similar in simple vs. complex group It is tough to predict which bifurcation lesion is simple or complex The correct answer is B

Question # 3 The correct answer is E Mixed treatment comparison analysis of various PCI types and CABG have shown the following not to be true: A. Higher mortality with SES/PES vs. CABG B. Higher TVR with PCI vs. CABG C. Lower stroke rates with PCI vs. CABG D. Higher MI rates with PCI vs. CABG E. PCI with CoCr EES has higher mortality and TVR vs. CABG The correct answer is E