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Complex Coronary Cases Supported by: Abbott Vascular Inc Boston Scientific Corp Terumo Vascular Corp Cardiovascular Science Inc Abiomed Inc Vascular Solution Corp B-Braun Inc

Disclosures Samin K. Sharma, MD, FSCAI, FACC Speaker’s Bureau – Boston Scientific Co Abbott Vascular Inc, ABIOMED, CSI Annapoorna S. Kini, MD, MRCP, FACC Nothing to disclose Sameer Mehta, MD, FACC Consulting Fees – Medtronic Inc

Nov 21st 2017 Case #101: KB 64 yrs M Presentation: Presented with new onset CCS class II angina and a positive stress MPI for anterior, apical and septal ischemia. A cardiac cath on Nov 7th, 2017 revealed 2 V CAD: prox LAD CTO bifurcation (medina 1,1,1) with 80% D1 bifurcation, 70% LCx-OM2, Syntax score 30 and LVEF 60%. Pt underwent FFR of LCx-OM2 which was 0.91 (-). Pt was maximized on medical therapy with plan for LAD CTO PCI at a future date Prior History: No CAD risk factors, SAQ-7 score 89 Medications: All once daily dosage started after cath ASA 81mg, Clopidogrel 75mg, Metoprolol XL 50mg, Amlodipine 5mg, Atorvastatin 40mg 4

Case# 101: cont… Plan Today: Cardiac Cath 11/7/2017: Right Dominance II V CAD and LVEF 60% LM: No obstruction LAD: 100% occlusion proximally after a 80% bifurcating moderate size D1 (1,1,1) LCx: 70% lesion in OM2 (FFR negative) RCA: mild diffuse disease SYNTAX Score: 30 Plan Today: Planned for PCI of LAD CTO-D1 bifurcation with dedicated 2-stent strategy by mini-crush technique 5

AUC 2017:Anatomic Two-Vessel Disease Patel et al., J Am Coll Cardiol 2017;69:2212

AUC 2017: Physiologic One-Vessel Disease Patel et al., J Am Coll Cardiol March 2017 Article in Press

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Issues Involving The Case Top Three Trials from TCT 2017: DKCRUSH-V, ABSORB III-3Yr, CrossBoss First ORBITA Trial- Sham Controlled Trial of PCI in Stable Single Vessel CAD

Issues Involving The Case Top Three Trials from TCT 2017: DKCRUSH-V, ABSORB III-3Yr, CrossBoss First ORBITA Trial- Sham Controlled Trial of PCI in Stable Single Vessel CAD

484 patients with unprotected LM bifurcations DKCRUSH V Study Design 484 patients with unprotected LM bifurcations Medina 1, 1, 1 and Medina 0, 1, 1 R DK crush stenting Provisional stenting Clinical follow-up: 1, 6, 12 months Angiographic follow-up: 13 months Primary Endpoint: TLF at 12 months Chen SL, TCT 2017

DKCRUSH V Trial: SYNTAX Score NERS II Score Provisional DK Crush Chen SL, TCT 2017

DKCRUSH V Trial: Core Lab Data (n=240) Provisional (n=242) 2- or 3-vessel disease 87.9 88.8 LM lesion - Ostial 2.9 - Shaft/body 7.9 8.7 - Medina 1, 1, 1 85.0 78.5 - Medina 0, 1, 1 15.0 21.5 Calcification 37.1 39.7 Chronic total occlusion 12.1 12.4 TIMI flow grade <3 - Main vessel 20.4 19.8 - Side branch 7.0 Complex bifurcation lesion 35.8 27.3 IVUS assessment 28.3 28.9 Chen SL, TCT 2017

DKCRUSH V Trial: PCI Procedures 482 Patients, 637 Procedures, 1234 Stents in MV and SB DK Crush (n=240) Provisional (n=242) Planned staged procedure 13.8 16.9 Transradial approach 77.9 74.8 6F guiding catheter 54.2 53.3 Side branch dilation* 68.3 39.7 MV stent length 27.9 ± 9.9 mm 28.8 ± 10.4 mm SB stent length 21.0 ± 7.3 mm 21.4 ± 7.4 mm Final kissing inflation* 99.6 78.9 POT 99.2 98.9 IVUS guidance 42.9 40.5 Complete revascularization 72.5 69.4 Procedural time, min* 81.9 ± 37.6 66.1 ± 34.5 Contrast volume, ml** 226.7 ± 81.4 190.9 ± 74.8 Angiographic success 98.3 97.1 * p<0.05, ** p<0.001 Chen SL, TCT 2017

DKCRUSH V Trial: Primary Endpoint Target Lesion Failure Chen SL, TCT 2017

DKCRUSH V Trial: Primary Endpoints at 1-Year DK Crush (n=240) Provisional (n=242) p=0.06 p=0.02 % p=0.03 p=0.48 Chen SL, TCT 2017

DKCRUSH V Trial: Stenting for LM Bifurcations Chen et al., J Am Coll Cardiol 2017;70:2605

DKCRUSH V Trial: Quantitative Coronary Analysis 317 Patients Underwent 13-Month Angiographic Follow-Up DK Crush (n=159) Provisional (n=158) P Value SB lesion length ≥10 mm 50.0 42.9 0.14 SB diameter stenosis, % 65.8 ± 7.9 65.3 ± 8.3 0.87 MV lesion length, mm 22.4 ± 12.9 23.5 ± 12.8 0.36 MV diameter stenosis, % 60.8 ± 7.2 61.8 ± 8.1 0.51 Cross-over to 2 stents - 47.1 LM complex restenosis 7.1 14.6 0.10 - Main vessel 1.9 5.7 0.09 - Side branch* 5.0 12.0 Non-LM restenosis 7.6 0.41 *Restenosis within implanted stents was defined as a QCA DS >50% at FU. Chen SL, TCT 2017

ABSORB II: 4-Year Patient Flowchart 311* and 154** patients still in the study but 5 missed 3 yr FUP Baseline 1-year 2-year 3-year 4-year 1 death 2 withdrawal 7 withdrawal 4 death 3 withdrawal 1 LFU 3 withdrawal 4 death 3 withdrawal 2 LFU, 3 MV, 5 death, 1 LFU 2 MV 1 death, 2 MV, 1 withdrawal 11 no consent ,-2 still in study but missed 3yr FUP 2 death, 8 MV, 3 withdrawal 9 no consent, -3 still in study but missed 3yr FUP At 4 years patients with missing visits (MV) were confirmed as alive and well by site PI. 20 patients did not sign protocol amendment for 4 & 5 year follow-up Chevalier B, TCT 2017

ABSORB II: Device Oriented Composite Endpoint (DoCE)/ Target Lesion Failure (TLF) 5 10 15 20 25 1152 1260 1440 1620 HR [95% CI]= 1.44 [0.15,13.80] p=0.75 (Log rank test) 1.0% 0.7% 5 10 15 20 25 180 360 540 720 900 1080 1260 1440 1620 TLF per WHO (%) Time Post Index Procedure (Days) HR [95% CI]= 2.04 [0.98,4.24] p=0.050 (Log rank test) 11.1% 5.6% BVS (n=335) XIENCE (n=166) Δ = 0.3% DoCE/TLF : Cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization (TLR) Chevalier B, TCT 2017

ABSORB II: 4-Year Clinical Outcomes Composite Endpoint BVS (n=335) XIENCE (n=116) p=0.47 p=0.99 p=0.15 p=0.06 p=0.06 Chevalier et al., EuroIntervention Oct. 31, 2017 Epub

ABSORB III Study Flow and Follow-up Randomized 2:1 N=2008 (ITT) ABSORB N=1322 N=1312 Xience N=677 N=686 1-Year Follow-up N=1296 N=671 2-Year Follow-up N=4 lost to follow-up N=6 withdrew consent N=6 lost to follow-up N=3 withdrew consent N=10 lost to follow-up N=2 withdrew consent 99.2% Complete 98.7% Complete 98.0% Complete 97.8% Complete N=1276 N=661 3-Year Follow-up N=14 lost to follow-up N=3 withdrawn by physician/site N=1 other N=8 lost to follow-up N=1 withdrew consent N=1 withdrawn by physician/site 96.5% Complete 96.4% Complete Kereiakes et al., J Am Coll Cardiol 2017 Article in Press

ABSORB III Trial: 3-Year Outcomes with Everolimus-Eluting Bioresorbable Scaffolds Time-to-First Event Curves for TLF Through 3 Years Time-to-First Event Curves for TLF Between 1 and 3 Years Kereiakes et al., J Am Coll Cardiol 2017 Article in Press

ABSORB III Trial: TLF Stratified by Vessel Size Kereiakes et al., J Am Coll Cardiol 2017 Article in Press

ABSORB III Trial: Time-to-First Event Curves for Definite or Probable Device Thrombosis Definite or Probable Thrombosis Through 3 Years Definite or Probable Thrombosis Between 1 and 3 Years Kereiakes et al., J Am Coll Cardiol 2017 Article in Press

ABSORB III Trial: Device Thrombosis Stratified by Vessel Size Kereiakes et al., J Am Coll Cardiol 2017 Article in Press

Kereiakes et al., J Am Coll Cardiol 2017 Article in Press

Randomized Comparison of a CrossBoss First vs Randomized Comparison of a CrossBoss First vs. Standard Wire Escalation Strategy for Crossing Coronary Chronic Total Occlusions: the “CrossBoss First” trial

CrossBoss 1st Trial: Study Flow Chart Brilakis ES, TCT 2017

CrossBoss 1st Trial: Crossing Strategies Variable CrossBoss Guidewire P value (n=122) (n=124) Technical Success, % 88.5 87.1 0.85 First Crossing Strategy, % <.0001 ▪ Antegrade wire escalation 22 98 ▪ Antegrade dissection and re-entry 77 1 ▪ Retrograde Successful Crossing Strategy, % 24 51 50 18 17 ▪ None 8 10 Brilakis ES, TCT 2017

CrossBoss 1st Trial: Primary Endpoints Crossing Time Procedural MACE Randomized Technique p= 1.0 p= 0.32 Variable CrossBoss Guidewire P value (n=122) (n=124) Crossing time (min)b 56 (33, 93) 66 (36, 105) 0.32 Standardized mean difference: 0.094 Brilakis ES, TCT 2017

CrossBoss 1st Trial: Primary Endpoints ISR Cases Crossing Time Procedural MACE Randomized Technique p= 0.30 Variable CrossBoss Guidewire P value (n=25) (n=24) Crossing time (min)b 41 (23, 58) 66 (32, 111) 0.05 Standardized mean difference: 0.534 Brilakis ES, TCT 2017

CrossBoss 1st Trial: Procedural Characteristics and Outcomes Variable CrossBoss Guidewire P value (n=122) (n=124) Procedural Success (%) 85.3 83.1 0.63 Total procedural time (min) 109 (78, 185) (75, 161) 0.67 Total fluoroscopy time (min) 40 (28, 66) 37 (24, 65) 0.34 Total AK radiation dose 2.18 (1.23, 3.56) 2.34 (1.23, 3.91) 0.75 Contrast volume 260 (168, 350) 250 (155, 329) 0.49 Fluoroscopy time (min) at crossing 20 (11, 44) 25 (12, 48) 0.64 AK radiation dose at crossing 0.88 (0.48, 1.97) 1.08 (0.33, 2.44) Brilakis ES, TCT 2017

CrossBoss 1st Trial: Procedural MACE Variable, % CrossBoss Guidewire P value (n=122) (n=124) Procedural MACE 3.3 4.0 1.00 Death 1.6 0.8 0.62 Acute Q wave MI 0.0 0.50 Acute MI 2.5 0.37 Re-PCI Stroke Emergency CABG Pericardiocentesis 3.2 0.06 Perforation 7.3 0.12 Brilakis ES, TCT 2017

CrossBoss 1st Trial: Equipment Costs Brilakis ES, TCT 2017

Conclusions As compared with a primary wire escalation strategy, upfront use of the CrossBoss catheter for crossing CTOs was associated with: similar crossing time similar success and procedural MACE rates similar equipment costs Further studies are needed to determine whether some subgroups (such as in-stent occlusions) are better suited for crossing using the CrossBoss catheter. Brilakis ES, TCT 2017

Issues Involving The Case Top Three Trials from TCT 2017: DKCRUSH-V, ABSORB III-3Yr, CrossBoss First ORBITA Trial- Sham Controlled Trial of PCI in Stable Single Vessel CAD

Benefit of PCI over MT in Stable CAD Decreased angina and antianginal meds (ACME I) Improved exercise tolerance (ACME I) Decreases ischemia on MPI (Nuclear sub-study of Courage Trial) Better quality of life parameter (FAME-2 Trial) Reduce urgent revascularization in FFR <0.81 (FAME-2 Trial) Properly done may reduce 5-Yr death/MI (US gp of Courage Trial)

ORBITA Trial: Background Over 500 000 PCIs per year for stable angina Primarily for angina relief Size of angina relief beyond placebo unknown Unblinded PCI +96 seconds (NEJM 1992) Single drug +55 seconds (JACC 2004)

ORBITA Trial: Principal Hypothesis Symptom Relief in Stable Angina PCI increases exercise time more than placebo procedure Primary endpoint Difference in exercise time increment between the arms For patients to be willing to participate in this first placebo- controlled trial of PCI, duration must be long enough for full hemodynamic effect but not so long as to inhibit recruitment Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

Sample Size Calculation ORBITA Trial Inclusion Criteria To detect 30 sec, at 80% power, within-arm SD 75 sec, Needs 200 randomized patients Stable angina One or more ≥ 70% stenosis in a single vessel Suitable for PCI This sample size is comparable to other trials assessing this question. Sample Size Calculation Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial Design Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial Profile Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial: Blinding Techniques Patient: Headphones and music Sedation Minimum 15 min wait Both arms: DAPT Same post-procedural instructions Same discharge letter Clinical Team: Standardised handover Ward team blinded Both arms: Treated as if PCI No access to cath report Same discharge letter Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial: Stenosis Severity PCI n = 105 Placebo n = 95 P Area stenosis by QCA (%) 84.6 (SD 10.2) 84.2 (SD 10.3) 0.781 FFR 0.69 (SD 0.16) 0.778 iFR 0.76 (SD 0.22) (SD 0.21) 0.751 Al-Lamee R, TCT 2017

ORBITA Trial: Primary Endpoint Change in Total Exercise Time 40 35 30 25 20 15 10 5 PCI Placebo Change in exercise time (seconds) 28.4 (SD 86.3) p=0.001 11.8 (SD 93.3) p=0.235 +16.6 sec (-8.9 to 42.0) p=0.20 Error bars are standard errors of the mean Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial: Secondary Endpoint Results Blinded Evaluation of Ischemia Reduction Peak Stress Wall Motion Index Score PCI (n=80) Placebo (n=57) Pre-randomization 0.18 Follow-up 0.06 0.19 ∆ (Pre-randomization to follow-up) -0.08 (0.17) p=<0.0001 0.02 (0.16) p=0.43 Difference in ∆ between arms -0.09 (-0.15 to -0.04) p=0.001 Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial: Secondary Endpoint Results CCS Class Improved in Both Groups CCS Class at Enrollment Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial Endpoints Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial Endpoints Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial Endpoints Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

ORBITA Trial: Changes in CCS Angina Grade PCI Placebo P Value Enrolment to pre-randomization --- 0.92 Patients assessed (n) 105 95 No change or deterioration (%) 60 62 1 class improvement (%) 26 23 ≥2 class improvement (%) 14 15 Pre-randomization to follow-up 0.63 91 49 55 24 21 Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

Conclusions ORBITA is the first placebo-controlled randomized trial of PCI in stable angina Area stenosis QCA 84.4%, FFR 0.69, iFR 0.76 PCI was safe and physiologically effective PCI significantly reduced ischemic burden as assessed by stress echo In this single vessel, angiographically guided trial there was no difference in exercise time increment between PCI and placebo Al-Lamee R, TCT 2017

ORBITA in Context Single vessel PCI guided by angina + angiogram To allow complete revascularization PCI guided by angina + angiogram In line with common practice Focus is on symptomatic relief Not risk or events Intensive medical therapy In line with Guidelines

https://www.nytimes.com/2017/11/02/health/heart-disease-stents.html

Al-Lamee, et al., Lancet Nov. 2, 2017 Epub

Limitations of the ORBITA Trial: Small sample size Short duration (only 6 weeks as benefit of PCI in FAME2 occurred at 6 months) Super selective 1V CAD population. On MMT & baseline exercise tolerance of >9 min (>10% of PCI population) 29-31% of physiologically negative lesions underwent PCI It will be difficult to replicate sham PCI After 6 weeks, many of these patients will undergo “True PCI” on patients and MD’s preference

Conclusion of the ORBITA Trial “Too much hype for too little gain” Unlike to change our clinical practice

FAME 2 Trial: Cumulative Incidence of MACEs Fearon et al.,Circulation Nov. 2017, Epub

FAME 2 Trial: Clinical Outcomes at 3-Year F/U PCI+MT (n=447) MT alone (n=441) % p=<0.001 p=0.10 p=0.33 p=0.41 p=0.43 Fearon et al.,Circulation Nov. 2017, Epub

FAME 2 Trial: Differences in Angina Patient with CCS II-IV (%) PCI+MT MT alone p=0.42 Patient with CCS II-IV (%) p=<0.001 p=<0.001 p=<0.001 p=0.002 p=0.02 Fearon et al.,Circulation Nov. 2017, Epub

FAME 2 Trial: Differences in Costs PCI+MT Cumulative Cost MT Cumulative Cost PCI+MT Annual Follow-Up Cost MT Annual Follow-Up Cost Fearon et al.,Circulation Nov. 2017, Epub

FAME 2 Trial: Costs During Index Admission and 3-Year Follow-Up Fearon et al.,Circulation Nov. 2017, Epub

FAME 2 Trial: Changes in European Quality of Life-5 Dimensions (EQ-5D) PCI+MT MT alone EQ-5D Index No. 439 432 422 422 406 403 378 383 (%) (98%) (98%) (94%) (96%) (91%) (91%) (85%) (87%) *p<0.05 vs Baseline Fearon et al.,Circulation Nov. 2017, Epub

Fearon et al.,Circulation Nov. 2017, Epub

Take Home Message: Recent Interventional Trials of DKCRUSH-V, ABSORB-III, CROSSBOSS 1st, ORBITA, FAME-2 DKCRUSH-V showed that 2-stent strategy is better then provisional-stent strategy (47% required 2 stents) in dLM bifurcation. ABSORB II and III long-term data continued to show scaffold being inferior to Xience DES. Crossboss 1st strategt of CTO recanalization failed show any advantage over routine wire escalation strategy ORBITA trial of one vessel CAD after optimal maximal medical stabilization failed to show any benefit of PCI on exercise duration and angina relief compared to sham PCI at 6-week follow-up. Trial did show improvement in echo wall motion scores on exercise. ORBITA trial on ground of only 6-weeks duration is unlikely to change our practice as PCI benefit may/will occur after 4-6mths in reducing urgent TLR our MMT alone in lesions <0.80.

Question # 1 DKCRUSH V trial dLM bifurcation PCI revealed the following except: Lower revascularization vs conventional strategy Lower MI vs conventional strategy C. Lower ST vs conventional strategy 2-stents were compared with 1-stent strategy in all cases E. Similar mortality vs conventional strategy

Question # 2 CrossBoss 1st trial of CTO recanalization showed the following except; Similar technical success as wire escalation Similar MACE rates as wire escalation Similar cost as wire escalation Lower pericardial tamponade vs wire escalation Similar procedure time as wire escalation

Question # 3 ORBITA trial comparing True PCI with Sham PCI showed the following except: A. Similar exercise time improvement B. No difference in angina class at follow-up C. Similar medication use at follow-up D. Similar echo wall motion index during exercise E. Similar MACE at follow-up

Question # 1 The correct answer is D DKCRUSH V trial dLM bifurcation PCI revealed the following except: Lower revascularization vs conventional strategy Lower MI vs conventional strategy C. Lower ST vs conventional strategy 2-stents were compared with 1-stent strategy in all cases E. Similar mortality vs conventional strategy The correct answer is D

Question # 2 The correct answer is C CrossBoss 1st trial of CTO recanalization showed the following except; Similar technical success as wire escalation Similar MACE rates as wire escalation Similar cost as wire escalation Lower pericardial tamponade vs wire escalation Similar procedure time as wire escalation The correct answer is C

Question # 3 The correct answer is E ORBITA trial comparing True PCI with Sham PCI showed the following except: A. Similar exercise time improvement B. No difference in angina class at follow-up C. Similar medication use at follow-up D. Similar MACE rates at 6-week follow-up E. Similar echo wall motion index during exercise The correct answer is E