Multivessel PCI: Pearls of Wisdom (?) for Success Jeffrey W. Moses, MD Professor of Medicine Director, Interventional Cardiac Therapeutics Columbia University Medical Center Director Complex Coronary Interventions St. Francis Hospital, Roslyn, LI

I have relevant financial relationships Consultant BSC Abiomed Abbott Jeffrey Moses MD   I have relevant financial relationships Consultant BSC Abiomed Abbott

Can PCI be done as safely as CABG? MVD Pearls Can PCI be done as safely as CABG?

SYNTAX Score 5 Year MACCE Lowest SYNTAX Tertile (0-22) SYNTAX SCORE No. & Location of lesion Left Main Tortuosity 3 Vessel Thrombus Bifurcation CTO Calcification SYNTAX SCORE SYNTAX Score Dominance 5 Year MACCE Lowest SYNTAX Tertile (0-22) 50 All Patients p=0.43 3-Vessel CAD only p=0.0005 CABG 33.3% 32.1% PCI 25 Cumulative Event Rate (%) Exhibit 33 28.6% 26.8% 12 24 36 48 60 12 24 36 48 60 Months Since Allocation Months Since Allocation Mohr, et al. Lancet 2013;381:629-38 3 3

SYNTAX Score 5 Year MACCE Middle SYNTAX Tertile (23-32) SYNTAX SCORE No. & Location of lesion Left Main Tortuosity 3 Vessel Thrombus Bifurcation CTO Calcification SYNTAX SCORE SYNTAX Score Dominance 5 Year MACCE Middle SYNTAX Tertile (23-32) 50 All Patients p=0.008 3-Vessel CAD only p=0.0008 37.9% 36.0% CABG (n=897) PCI (n=903) 25 Cumulative Event Rate (%) Exhibit 33 25.8% 22.6% 12 24 36 48 60 12 24 36 48 60 Months Since Allocation Months Since Allocation Mohr, et al. Lancet 2013;381:629-38 4 4

SYNTAX Score 5 Year MACCE Highest SYNTAX Tertile (33+) SYNTAX SCORE No. & Location of lesion Left Main Tortuosity 3 Vessel Thrombus Bifurcation CTO Calcification SYNTAX SCORE SYNTAX Score Dominance 5 Year MACCE Highest SYNTAX Tertile (33+) p<0.0001 50 All Patients 3-Vessel CAD only p=0.0005 CABG (n=897) PCI (n=903) 44.0% 41.9% 25 Cumulative Event Rate (%) Exhibit 33 26.8% 24.1% 12 24 36 48 60 12 24 36 48 60 Months Since Allocation Months Since Allocation Mohr, et al. Lancet 2013;381:629-38 5 5

Farooq V et al. Lancet 2013;381:639-50 100 80 60 58.4% 4-year Mortality (%) 40 31.5% 20 15.1% 6.8% 3% 0.6% 1.3% 20 40 60 80 100 Total Points Farooq V et al. Lancet 2013;381:639-50

MVD Pearls Can I Completely Revascularize? (at least as well as the surgeon)

Complete Revascularization vs. Incomplete Revascularization in SYNTAX Patients (%) P=0.052 P=0.049 P=0.059 P=0.046 P=0.23 All-cause Death Cardiac Death MI CVA All-cause Revascul-arization Stent Throm- bosis Death/CVA /MI MACCE Farooq et al, JACC 2013;xx:xxx-xxx 8

Residual SS in SYNTAX Trial Low Baseline SYNTAX Score (0-22) Intermediate Baseline SYNTAX Score (23-32) High Baseline SYNTAX Score (≥33) 60% 60% 60% Residual SYNTAX Score Log–rank P value .022 Log–rank P value <.001 Log–rank P value <.001 50% 50% >0–4 >4–8 >8 50% 40% 40% 40% 39.1% 34.1% Estimated Event Rate 30% 30% 30% 23.8% 20% 20% 20% 13.8% 12.9% 11.5% 10% 10% 10.1% 10% 10.2% 7.7% 8.2% 9.3% 6.7% 0% 0% 0% 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 All-Cause Death (y) All-Cause Death (y) All-Cause Death (y) Farooq Circ 2013;128:141 Kereiakes et al, Rev Cardiovasc Med. 2014;15:24-30 9

Residual SS in SYNTAX Trial All-cause Death All-cause Revascularization MACCE 60% Log–rank P value <.001 60% Log–rank P value <.001 60% Log–rank P value <.001 Residual SYNTAX Score 59.5% 50% 50% 0 (n–386) >0–4 (n–184) >4–8 (n–167) >8 (n–153) 50% 40% 40% 40% 41.3% 35.3% 32.0% 35.3% Estimated Event Rate 30% 30% 29.9% 30% 27.7% 27.2% 20% 20% 20% 18.1% 11.4% 10% 8.7% 10% 10% 8.5% 0% 0% 0% 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 All-Cause Death (y) All-cause Revascularization (y) MACCE (y) Farooq Circ 2013;128:141 Kereiakes et al, Rev Cardiovasc Med. 2014;15:24-30 10

MVD Pearls Aggressively approach CTOs

13,443 stable patients who underwent 14,439 procedures, 2005 to 2009 Long-term Follow-up of Elective CTO Angioplasty: Analysis from the UK Central Cardiac Audit Database 13,443 stable patients who underwent 14,439 procedures, 2005 to 2009 Procedural success was 70.6% and mortality 5.6% Successful revascularization of at least 1 CTO decreased mortality (adjusted HR 0.72; 95% CI 0.62-0.83; P < .001) Mortality risk was lower in patients who had complete revascularization of all vessels than in those whose procedures were partial (adjusted HR 0.70; 95% CI 0.56-0.87; P =.002) or failed (adjusted HR 0.61; 95% CI 0.50-0.74; P < .001) Implications: Successful PCI and complete revascularization of all vessels both improve long-term survival in patients with CTO. George S, et al. J Am Coll Cardiol. 2014;64:235-243

MVD Pearls SYNTAX score is not an absolute indicator of MACE especially with newer generation stents

Girasis et al, Euro Heart J 2011; “in press” SIRTAX: SYNTAX Score Is Not a Measure of Absolute Risk: Different Stent, Different Outcomes % 60 60 SES PES SES PES 50 50 P=0.46 P=0.98 P=0.001 P=0.95 P=0.35 P=0.21 40 40 MACE 1Y DEATH 1Y 30 30 23.9 20 20 9.0 7.5 8.6 4.9 10 6.6 7.3 10 1.5 1.4 0.7 2.1 0.0 CSSLOW n=282 CSSMID n=283 CSSHIGH n=283 CSSLOW n=282 CSSMID n=283 CSSHIGH n=283 Girasis et al, Euro Heart J 2011; “in press” 14

Adjusted Event Rates: Death BMS vs 1st Gen DES vs. 2nd Gen DES SCAAR: 94,384 consecutive pts in Sweden 2006-2010 (BMS 64,631; 1st gen DES 19,202; 2nd gen DES 10,551 1st gen = Cypher, Taxus , Endeavor. 2nd gen = Resolute, Xience, Promus Element Adjusted Event Rates: Death Months Adj HR of 2nd gen DES vs. 1st gen DES: 0.77 [0.63–0.95] vs. BMS: 0.55 [0.46–0.67] BMS 1st gen DES 2nd gen DES 6% 5% 4% 3% 2% 1% 0% 3 6 9 12 15 18 21 24 Death (%) Current and future DES and Past/Present/Future DES Fellows Sarno G et al. EHJ 2012;33:606–13 15

MVD Pearls Evaluate Diabetes in the overall context of the patient and anatomy

1 Endpoint: Death, Stroke, or MI FREEDOM: 1900 pts with diabetes +MVD randomized to SES/PES vs. CABG 1 Endpoint: Death, Stroke, or MI 30 PCI/DES CABG 26.6% 20 18.7% Death, Stroke, MI, % 13.0% 10 11.9% P = 0.005 1 2 3 4 5 6 Years PCI/DES 953 848 788 625 416 219 40 CABG 943 814 758 613 422 221 44 Farkouh ME et al. NEJM 2012 17

SYNTAX Score I vs II: The SYNTAX Trial Interactions: Diabetes Diabetes was not an independent predictor of mortality or MACE in either the CABG or PCI arm, and had a negative interaction effect Pinteraction = 0.67 Log HR PCI CABG No Yes Farooq V et al. Lancet 2013;381:639-50

Network Plot of Treatment Comparisons DES SES BMS POBA PES CABG CoCrEES Network plot of treatment comparisons. Nodes and lines are weighted according to the number of studies providing direct comparisons between 2 treatments. BMS indicates bare metal stent; CABG, coronary artery bypass graft surgery; CoCrEES, cobalt–chromium everolimus-eluting stent; PES, paclitaxel-eluting stent; POBA, plain old balloon angioplasty; PtCrEES, platinum–chromium everolimus-eluting stent; SES, sirolimus-eluting stent; ZES-E, zotarolimus-eluting stent-endeavor; and ZES-R, zotarolimus-eluting stent-resolute. ZES-R ZES-E PtCrEES Copyright© American Heart Association, Inc. All rights reserved. Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525

Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525 Mixed treatment comparison analyses for coronary artery bypass graft surgery (CABG) vs percuDEs vs CABG in DMtaneous coronary intervention (PCI) for the outcome of all-cause mortality Outcome: Mortality Treatment Control Favor PCI Favor CABG Rate Ratio 95% Crl POBA BMS PES SES ZES-E ZES-R CoCr EES vs. CABG 1.25 1.29 1.57 1.43 1.32 1.45 1.11 0.81 0.95 1.15 1.06 1.82 0.31 0.67 1.82 1.79 2.19 1.97 2.32 8.81 1.84 Mixed treatment comparison analyses for coronary artery bypass graft surgery (CABG) vs percutaneous coronary intervention (PCI) for the outcome of all-cause mortality. BMS indicates bare metal stent; CoCr EES, cobalt–chromium everolimus-eluting stent; CrI, credibility interval; PES, paclitaxel-eluting stent; POBA, plain old balloon angioplasty; RR, rate ratio; SES, sirolimus-eluting stent; ZES-E, zotarolimus-eluting stent-endeavor; and ZES-R, zotarolimus-eluting stent-resolute. 0.00 1.00 2.00 3.00 RR (95% Crl) Copyright© American Heart Association, Inc. All rights reserved. Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525

Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525 Mixed treatment comparison analyses for coronary artery bypass graft surgery (CABG) vs percutaneous coronary intervention (PCI) for the outcome of myocardial infarction Outcome: MI Treatment Control Favor PCI Favor CABG Rate Ratio 95% Crl POBA BMS PES SES ZES-E ZES-R CoCr EES vs. CABG 1.16 1.50 1.43 1.22 1.55 0.72 0.35 0.77 0.76 0.66 0.63 0.24 0.27 3.56 2.65 2.44 2.04 3.60 5.03 1.60 Mixed treatment comparison analyses for coronary artery bypass graft surgery (CABG) vs percutaneous coronary intervention (PCI) for the outcome of myocardial infarction. BMS indicates bare metal stent; CoCr EES, cobalt–chromium everolimus-eluting stent; CrI, credibility interval; PES, paclitaxel-eluting stent; POBA, plain old balloon angioplasty; RR, rate ratio; SES, sirolimus-eluting stent; ZES-E, zotarolimus-eluting stent-endeavor; and ZES-R, zotarolimus-eluting stent-resolute. 0.10 1.00 10.00 RR (95% Crl) Copyright© American Heart Association, Inc. All rights reserved. Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525

Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525 Mixed treatment comparison analyses for coronary artery bypass graft surgery (CABG) vs percutaneous coronary intervention (PCI) for the outcome of repeat revascularization Outcome: Repeat revascularization Treatment Control Favor PCI Favor CABG Rate Ratio 95% Crl POBA BMS PES SES ZES-E ZES-R PtCr EES CoCr EES vs. CABG 4.41 3.18 1.81 1.47 2.35 2.40 3.02 1.31 1.80 2.11 1.19 0.95 1.30 1.01 0.72 0.74 10.97 5.01 2.77 2.23 4.18 5.84 13.26 2.29 Mixed treatment comparison analyses for coronary artery bypass graft surgery (CABG) vs percutaneous coronary intervention (PCI) for the outcome of repeat revascularization. BMS indicates bare metal stent; CoCr EES, cobalt–chromium everolimus-eluting stent; CrI, credibility interval; PES, paclitaxel-eluting stent; POBA, plain old balloon angioplasty; PtCr EES, platinum–chromium everolimus-eluting stent; RR, rate ratio; SES, sirolimus-eluting stent; ZES-E, zotarolimus-eluting stent-endeavor; and ZES-R, zotarolimus-eluting stent-resolute. RR (95% Crl) 0.10 1.00 10.00 Copyright© American Heart Association, Inc. All rights reserved. Bangalore S et al. Circ Cardiovasc Interv. 2014;7:518-525

MVD Pearls Carefully decide on treatment order If staging make sure to treat the “culprit” in the first session in symptomatic patients Try to bootstrap for complex lesions to minimize risk of an ultracomplex vessel For CTO consider treating donor vessel to allow for retrograde option

MVD Pearls Optimize lesion preparation MVD has a higher propensity for calcification Think Angiosculpt, CB Roto, Orbital

MVD Pearls Rational use of hemodynamic support

When Do I Consider Support? Last Remaining Vessel Severe LV dysfunction: support for ischemic stress and contrast load LV dysfunction with prospect of uncontrolled interruption of coronary flow Difficult wiring Difficult stent delivery High risk of no reflow (i.e., SVGs, Roto, thrombus)

Comparison of Support Devices IABP ECMO TandemHeart Impella CP Catheter Size 7.5-9.0 21/18 21/17/15 9 Cannula Size 8.5-10 13 # Insertion Sites 1 2 Anticoagulation + +++ ++/+++ Transeptal No Yes Limb ischemia Priming volume Unloads Directly LV Requires stable rhythm Improve hemodynamics 27

PROTECT II Trial Design Patients Requiring Prophylactic Hemodynamic Support During Non-Emergent High Risk PCI on Unprotected LM/Last Patent Conduit and LVEF≤35% OR 3 Vessel Disease and LVEF≤30% R 1:1 IABP + PCI IMPELLA 2.5 + PCI Primary Endpoint = 30-day Composite MAE* rate Follow-up of the Composite MAE* rate at 90 days * Major Adverse Events (MAE): Death, MI (>3xULN CK-MB or Troponin) , Stroke/TIA, Repeat Revasc, Cardiac or Vascular Operation of Vasc. Operation for limb ischemia, Acute Renal Dysfunction, Increase in Aortic insufficiency, Severe Hypotension, CPR/VT, Angio Failure

MACCE Outcomes Based on the Extent of Revascularization (All Patients, N=413) IABP IMPELLA p=0.489 p=0.007 90 Day MACCE ↓ 46% MACCE N=54 N=65 N=145 N=133 Limited Revascularization D IZ [0-2] Extensive Revascularization D IZ [3-11] Extent of Revascularization

Be Prepared to Consider Certain Cases for PCI after Heart Team Evaluation High CABG risk Low EF Severe COPD CKD Unusual comorbidities

MVD Pearls Consider the patient’s point of view While “Death and MI” may be key to clinical trialists the patient may believe otherwise

Two Very Different Procedures…

How Do Patients Weigh Outcomes? 224 respondents “SYNTAX eligible” for 3VD revascularization Attribute Relative Weight Risk of Death within 3 yrs 0.23 Risk of Stroke within 3 yrs 0.18 Risk of MI within 3 yrs 0.14 Risk of Revasc. within 3 yrs 0.11 Expected ΔLife Expectancy over 7 yrs 0.17 Extent of Procedure (length, hospital stay, recovery time) 66% Captured by MACCE Endpoint 34% of total weight is not captured Tong et al, Ann Thor Surg 2012 33

Scenario Presented PCI CABG Hospital stay 2 day 4 day Recovery 1 week 6 weeks Death 6% 3% MI 7% CVA 2% Revasc 20% 10% Life expectancy 1 year? Blinded – 83% CABG Open – 73% CABG PCI Choice: more familiarity with PCI, High socioeconomic status Tong et al, Ann Thor Surgery 2012;94:1908

Palmerini et al. JACC 2012;60:798-805 Risk of Stroke with CABG vs PCI: Meta-analysis of 8 RCTs: 30-day Follow-up MASS II 2/205 3.09 (0.62, 15.50) 6/203 GABI 0/182 5.20 (0.25, 109.07) 2/177 BARI 2/915 3.52 (0.73, 17.01) 7/914 ERACI 2 0/225 5.04 (0.24, 105.67) 2/225 AWESOME 2/222 1.44 (0.24, 8.71) 3/232 ARTS 1 4/600 1.49 (0.42, 5.32) 6/605 EAST 1/198 3.09 (0.32, 30.01) 3/194 1 .00574 174 Study PCI OR (95% CI) CABG PCI worse CABG worse 4.02 (0.85, 19.03) 2/546 8/549 SYNTAX 3VD I-squared=0% 2.62 (1.40, 4.91) 13/3093 37/3099 Fixed effects Random effects 0.42% 1.19% ∆=0.77% Palmerini et al. JACC 2012;60:798-805

Is it Really 3 VD ? FAME: “Downgrading” Multivessel Disease with FFR 86% 3VD and 57% 2VD reclassified >1 vessel Tonino et al, JACC 2010;55:2816-21

FAME 3: Study Flow: All Comers with 3 V CAD (not involving LM) Heart team identifies lesions for PCI/CABG and then patient is randomized FFR-Guided PCI with Resolute DES Stent all lesions with FFR ≤ 0.80 (n=750) Perform CABG based on coronary angiogram (n=750) Primary: One Year follow-up for Death, MI, CVA, Revascularization Key Secondary: Three Year follow-up for Death/MI/CVA Non-inferior Design NCT02100722

Conclusions Multivessel PCI is appropriate for a large group of patients Reflexive CABG referral is unwarranted Careful assessment of patient, anatomy and treatment plan are essential for optimal results