Complex Coronary Cases Supported by: Abbott Vascular Inc Boston Scientific Corp Terumo Vascular Corp Cardiovascular Science Inc Abiomed Inc Chiesi Inc B.Braun Medical 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

CCC Live Case # 123 Present Clinical Presentation Patient Demographics 62 yrs, M Present Clinical Presentation Cresendo CCS class III angina for last 3 months Clinical Variables Stress MPI revealed ischemia in anterior, apical & inferior walls Echo: LVEF 50% CAD Risk Factors Hypertension Hyperlipidemia NIDDM +F/H Medications Aspirin, ISMN, Amlodipine, Metformin, Glyburide, Pioglitazone, Losartan, Atorvastatin, Synthroid, Omeprazole Cath: 3 V CAD, 100% prox RCA, 80% calcified prox LAD/D1 bifurcation, 99% diffuse calcified OM2. Syntax score 39 and LVEF 40%. PCI decided after Heart team discussion Plan: Impella assisted Protected PCI of calcific LAD/D1 bifurcation and LCx-OM2 using rotational atherectomy and multiple DES contralateral injection

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

Issues Involving The Case Key trials from ESC 2019: THEMIS, THEMIS-PCI, ISAR REACT-5, POPULAR-AGE COMPLETE Trial of STEMI Strategy

Issues Involving The Case Key trials from ESC 2019: THEMIS, THEMIS-PCI, ISAR REACT-5, POPular AGE COMPLETE Trial of STEMI Strategy

THEMIS Trial: Background Patients with both established coronary artery disease and type 2 diabetes mellitus are at increased risk of cardiovascular events. Platelet-mediated thrombosis is a major mechanism. Ticagrelor protects against CV events when added to aspirin in acute coronary syndromes and in patients with a history of prior myocardial infarction. Whether patients with diabetes and stable coronary artery disease without a history of prior MI or stroke also derive benefit from dual antiplatelet therapy with aspirin and ticagrelor is unknown. Bhatt et al., Clin Cardiol 2019;42:498

THEMIS Study Design Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Baseline Characteristics Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: History of Disease at Baseline Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Primary Composite Endpoint Cardiovascular Death, MI, Stroke Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Primary Outcomes at 36 Months % Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Clinical Outcomes Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Primary Efficacy Endpoint Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Safety Outcomes p<0.001 p=0.005 % Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Bleeding Outcomes Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: TIMI Major Bleeding - Subgroups Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Safety Outcomes Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Permanent Treatment Discontinuation Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Primary Composite Endpoint Cardiovascular Death, MI, Stroke – on Treatment* * Prespecified analysis with patients censored 3 days after the last dose Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

THEMIS Study: Limitations Dose of ticagrelor was changed from 90 mg bid to 60 mg bid during the trial Though efficacy and bleeding appeared to be consistent between doses There was a significant increase in major bleeding, including traumatic intracranial bleeding (largely subdural), but not fatal bleeding Ticagrelor reversal agent under development Higher rate of treatment discontinuation in the ticagrelor group On treatment analyses show larger and more robust risk reductions, though with the usual caveats (only applies to adherent patients tolerating therapy) Subgroups not powered for efficacy Though better net clinical benefit identified –stay tuned for THEMIS-PCI! Steg et al., N Engl J Med, 2019 Sep 1; Epub ahead of print

Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Background THEMIS was a randomized, double-blind, placebo-controlled trial of ticagrelor versus placebo, on top of low-dose aspirin (75 to 150 mg) in patients with type 2 diabetes mellitus receiving anti-hyperglycemic medications for at least six months, and with stable CAD. We hypothesized that THEMIS patients with prior PCI, (who have been previously treated with DAPT), would be the group most likely to have a favorable balance of efficacy and safety. Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI Study Flow Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Baseline Characteristics By History of PCI Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Primary Efficacy Endpoint CV Death, MI, Stroke (ITT) Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Efficacy Endpoint (ITT Population) Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Efficacy Endpoint (ITT Population) History of PCI No History of PCI % p=0.01 p=0.02 p=0.03 p=0.68 % p=0.76 p=0.62 p=0.51 p=0.44 Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Bleeding Endpoints (Safety Population) History of PCI No History of PCI % p<0.0001 p=0.45 p=0.83 % p<0.0001 p=0.00098 p=0.06 Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Net Clinical Benefit All-cause death, MI, Stroke, Fatal bleeding, or Intracranial hemorrhage (ITT)* *Prespecified definition of Net Clinical Benefit Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Events Prevented or Caused For 1000 Patients Treated 3 Years with Ticagrelor Interaction p=0.012* History of PCI No History of PCI 20 -20 Benefit Harm p=0.002 p=0.79 p=0.005 p=0.9 p=0.0018 p=0.39 Ischemic events prevented Bleeding events caused Net Clinical Benefit* Ischemic events prevented Bleeding events caused Net Clinical Benefit* *Prespecified definition of Net Clinical Benefit Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

THEMIS-PCI: Primary Efficacy Endpoint (On Treatment) History of PCI No History of PCI % p=0.0003 p=0.06 p=0.003 p=0.15 % p=0.70 p=0.59 p=0.51 p=0.48 Bhatt et al., Lancet 2019 Sept 1, Epub ahead of print

Conclusions In stable CAD patients with diabetes and prior PCI, Ticagrelor added to aspirin reduced cardiovascular death, MI, stroke, although with increased major bleeding. This subgroup analysis was Prespecified, pertains to a large, clinically meaningful population, is plausible, and shows a significant interaction for net clinical benefit. This suggests that long term therapy with Ticagrelor in addition to aspirin is a new option for selected patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischemic risk, and low bleeding risk.

Lancet 2019 Sept 1, Epub ahead of print

N Engl J MEd2019 Sep 1. doi: 10. 1056/NEJMe1910813 N Engl J MEd2019 Sep 1. doi: 10.1056/NEJMe1910813. [Epub ahead of print]

Onset and Duration of Ticagrelor Cohorts 7, 8, 9, and 10 to Receive 18-g Fixed Dose of PB2452 with Infusion Duration of 8 H, 12 H, 16 H and 16 H Respectively or Placebo Bhatt et al., N Engl J Med 2019;380:1825

Normalization of Platelet Function After Ticagrelor Reversal Light Transmission Aggregometry Point-of-Care P2Y12 Platelet-Reactivity Test VASP Assay Bhatt et al., N Engl J Med 2019;380:1825

TRITON-TIMI 38 Primary Efficacy Outcomes Death, MI, Stroke PLATO Primary Efficay Outcomes Death, MI, Stroke Wiviott et al., N Engl J Med 2007;357:2001 Wallentin et al., N Engl J Med 2009;361:1045

PRAGUE-18 Study Flow Chart The PRAGUE-18 Study Group N=1,230 Prasugrel Ticagrelor N=634 N=596 No information on the combined EP during 365 days* Without the end-of-treatment data for patients who discontinued the study drugs less than 12 months after randomization N=0 N=3 FU 365 days *The combined efficacy endpoint was cv death, MI, or stroke Motovska et al., J Am Coll Cardiol 2017;71:371

PRAGUE-18 Study: Clinical Endpoints Prasugrel (n=608) Ticagrelor (n=575) % Combined Death MI Stroke Def ST Bleeding ischemic endpoint (death, MI or stroke) p=0.50 p=0.93 p=0.54 p=0.42 p=0.61 p=0.77 Motovska et al., J Am Coll Cardiol 2017;71:371

ISAR-REACT 5: BACKGROUND Wiviott et al., N Engl J Med 2007;357:2001 Wallentin et al., N Engl J Med 2009;361:1045

2018 ESC/EACTS Guidelines on Myocardial Revascularization NSTE-ACS: STEMI: Neumann et al., Eur Heart J 2019;40:87

ISAR-REACT 5 Trail Design Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Baseline Characteristics (1/2) Ticagrelor (n=2012) Prasugrel (n=2006) Age, yrs 64.5 ± 12.0 64.6 ± 12.1 Women, % 23.8 BMI, kg/m2 27.8 ± 4.6 27.8 ± 4.4 Diabetes, % - Insulin-treated, % 23.0 7.1 21.4 6.8 Current smoker, % 34.1 33.4 Arterial hypertension, % 71.3 69.1 Hypercholesterolemia, % 58.7 58.1 Prior MI, % 15.5 16.0 Prior PCI, % 22.5 23.1 Prior CABG, % 5.7 6.5 Cardiogenic shock, % 1.5 1.7 Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Baseline Characteristics (2/2) Ticagrelor (n=2012) Prasugrel (n=2006) Blood pressure - Systolic, mmHg - Diastolic, mmHg 144 ± 25 82 ± 15 143 ± 24 82 ± 14 Heart rate, beats/min 77 ± 16 76 ± 16 Diagnosis at admission, % - Unstable angina - NSTEMI - STEMI 12.4 46.2 41.4 13.0 46.1 40.9 Coronary angiography, % 99.6 99.8 Treatment strategy, % - PCI - CABG - Conservative - Other 83.5 2.3 14.2 <0.1 84.8 1.8 13.4 0.0 Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Angiographic Characteristics Patients with Angiography Ticagrelor (n=2003) Prasugrel (n=2001) Access site, % - Femoral - Radial - Other 62.2 37.3 0.5 63.0 36.5 No. of diseased coronary vessels, % - No obstructive CAD - One vessel - Two vessels - Three vessels 8.5 30.0 26.0 35.5 8.2 29.1 27.7 35.0 Left ventricular ejection fraction, % 51.6 ± 11.3 52.0 ± 11.2 Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Procedural Characteristics Patients with PCI Ticagrelor (n=1676) Prasugrel (n=1701) Target vessel, % - Left main - LAD - LCx - RCA 2.2 44.5 20.6 31.0 42.2 20.3 33.5 Drug-eluting stent, % 89.3 90.7 Periprocedural antithrombotic medication, % - Acetylsalicylic acid - Unfractionated heparin - Low molecular weight heparin - Bivalirudin - GPllb/llla inhibitor 89.7 94.3 4.4 7.5 13.1 90.1 93.8 3.8 8.3 11.6 Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Diagnosis and Drug Therapy at Discharge Ticagrelor (n=2012) Prasugrel (n=2006) Final diagnosis of ACS, % - Unstable angina - NSTEMI - STEMI 91.2 10.3 45.6 44.1 90.5 9.5 44.8 Therapy at discharge, % - Acetylsalicylic acid - Ticagrelor - Prasugrel - Clopidogrel - Oral anticoagulant drugs - Betablocker - ACE inhibitor/ARB - Statin 94.5 81.1 1.1 4.6 4.2 83.1 84.0 91.6 94.9 0.7 80.7 5.9 5.1 83.2 85.4 92.6 Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Clinical Endpoint at 1 Year % Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Clinical Endpoints at 1 Year Primary Endpoint Composite of Death, MI, or Stroke Safety Endpoint BARC Type 3-5 Bleeding Schüpke et al., 2019 Sep 1, Epub ahead of print

ISAR-REACT 5: Subgroup Analysis Schüpke et al., 2019 Sep 1, Epub ahead of print

Summary and Conclusions In ACS patients with or without ST-segment elevation, treatment with Prasugrel as compared with Ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke without increase in major bleeding.

Randomized Comparison of Clopidogrel vs Ticagrelor or Prasugrel in Patients of 70 Years or Older with Non-ST-Elevation Acute Coronary Syndrome POPular AGE Trial

POPular AGE Trial: Background Roffi et al., Eur Heart J 2016;37:267

TRITON-TIMI 38 PLATO

Bleeding Risk Major bleeding 5-fold increase in risk of death “Nuisance” bleeding frequent discontinuation P2Y12 inhibitor thrombotic risk Eikelboom et al., Circulation 2006;114:774 Roy et al., Am J Cardiol 2008;102:1614

Underrepresentation of Elderly in RCTs Elderly underrepresented TRITON TIMI 38: 13% ≥ 75 years1 PLATOL 15% ≥ 75 years2 Registry data: ~35% of NSTEMI population is ≥ 75 years3,4 Selective inclusion of elderly in RCT’s 1. Wiviott et al., N Engl J Med 2007;357:2001 3. De Luca et al., Eur Heart J Acute Cardiovasc Care 2015;4:441 2. Wallentin et al., N Engl J Med 2009;361:1045 4. Hanssen et al., Heart 2012;98:699

Hypothesis Clopidogrel is superior in reducing bleeding risk and non-inferior in net clinical benefit compared to Ticagrelor/Prasugrel in patients of 70 years or older with non-ST-elevation acute coronary syndrome

POPular AGE Trial Design ≥ 70 years with NSTE-ACS R 1:1 Clopidogrel 1dd75 Ticagrelor 2dd90 or Prasugrel 1dd5/10 <72h 12 months Reloading Choice Ticagrelor or prasugrel according to local protocol Gimbel M, ESC 2019

POPular AGE Trial: Primary Endpoint PLATO major and minor bleeding Net clinical benefit: All-cause death, MI, stroke, PLATO major and minor bleeding Gimbel M, ESC 2019

POPular AGE Trial: Secondary Endpoints Gimbel M, ESC 2019

POPular AGE Trial: Baseline Characteristics Gimbel M, ESC 2019

POPular AGE Trial: Baseline Characteristics Gimbel M, ESC 2019

POPular AGE Trial: Primary Safety Outcomes PLATO Major and Minor Bleeding Gimbel M, ESC 2019

POPular AGE Trial: Secondary Safety Outcomes % Gimbel M, ESC 2019

POPular AGE Trial: Co-Primary Net Clinical Benefit Outcomes Death, MI, Stroke, PLATO major and minor bleeding Gimbel M, ESC 2019

POPular AGE Trial: Secondary Efficacy Outcomes Death, MI, Stroke Gimbel M, ESC 2019

POPular AGE Trial: Subgroup Analysis P-value for interaction Gimbel M, ESC 2019

Conclusions Compared to Ticagrelor/Prasugrel in the POPular AGE trial we conclude: Clopidogrel significantly less bleeding Clopidogrel similar in preventing thrombotic events Therefore, we consider Clopidogrel the preferred treatment in patients ≥ 70 years with NSTE-ACS

Issues Involving The Case Key trials from ESC 2019: THEMIS, THEMIS-PCI, ISAR REACT-5, POPULAR-AGE COMPLETE Trial of STEMI Strategy

Randomized Trials of Culprit vs Complete Revascularization in STEMI PRAMI (n=465) CvLPRIT (n=296) PRIMULTI (n=627) Lesion criteria > 50% DS > 70% DS or > 50% DS in 2 views > 50% DS and FFR <0.80 or > 90% DS Strategy for non-IRA lesions Immediate Immediate or staged within index admission Staged within index admission Randomization After PPCI “During” PPCI Age 62 years 65 years 64 years Bivalirudin or GPIIB/IIIA 79% 83% 97% Primary endpoint D/MI/ref ischaemia D/MI/HF/isch D R D/MI/isch D R Result 23% reduced to 9% (65% Rx effect) 21% reduced to 10% (55% Rx effect) 22% reduced to 13% (44% Rx effect) Early Benefit Yes Safe to postpone

Culprit Artery – Only Versus Multivessel PCI COR LOE Recommendation IIb B-R PCI of a noninfarct artery may be considered in selected patients with STEMI and multivessel disease who are hemodynamically stable, either at the time of primary PCI or as a planned staged procedure.1 1. Modified recommendation from 2013 Guideline (changed class from III: Harm to IIb and expanded time frame in which multivessel PCI could be performed).

COMPLETE TRIAL A Randomized, Comparative Effectiveness Study of Complete versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease After Early Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

COMPLETE Trial: Primary Objective In patients presenting with STEMI and multi-vessel coronary artery disease who have undergone culprit-lesion PCI, the objective is: To determine whether a strategy of routine, staged non-culprit lesion PCI with the goal of complete revascularization is superior to a strategy of culprit lesion-only PCI in reducing the composite of CV death or new MI.

COMPLETE Trial Design Mehta et al., Am Heart J 2019; 215:157 Exclusion Criteria: Intent to revascularize NCL, planned surgical revascularization, prior CABG *Everolimus-eluting stents strongly recommended STEMI with Multivessel CAD and successful PCI to the Culprit Lesion MVD defined as at least one additional non-culprit lesion ≥ 2.5 mm diameter and ≥70% stenosis or 50-69% with FFR ≤0.80 RANDOMIZATION Stratified for intended timing of NCL PCI: During initial hospitalization or after discharge (max 45 d) Co-primary Outcomes: 1. Composite of CV death or new MI 2. Composite of CV death, new MI or IDR Key Secondary Outcome: CV death, new MI, IDR, unstable angina, NYHA class IV heart failure Median Follow-up: 3 years Complete Revascularization Routine staged PCI* of all suitable non-culprit lesions with the goal of complete revascularization N=2016 Culprit-Lesion-Only Revascularization No further revascularization of non-culprit lesions, guideline-directed medical therapy alone N=2025 Guideline-Directed Medical Therapy ASA, P2Y12 inhibitor (Ticagrelor strongly recommended), Statin, BB, ACE/ARB + Risk Factor Modification Actual Time to study NCL PCI in Complete Group (median) During initial hospitalization: 1 day (IQR 1-3) After hospital discharge: 23 days (IQR 12.5-33.5) Mehta et al., Am Heart J 2019; 215:157

COMPLETE Trial Flow Diagram Enrolled and Randomized N=4041 Assigned to Complete Revascularization (Staged Non-Culprit Lesion PCI + OMT) N=2016 Assigned to Culprit Lesion Only Revascularization (Optimal Medical Therapy Alone) N=2025 Received Allocated Intervention (n=1881) Did not receive allocated intervention (n=135) Within 45 days (n=91) Crossover to Culprit Lesion only Revasc (n=78) Patient request (n=24) Physician decision (n=23) Non-culprit lesion not significant (n=31) After 45 days (n=44) Crossover to Culprit Lesion Only Revasc (n=44) Patient request (n=7) Physician decision (n=4) Non-culprit lesion not significant (n=2) Non-culprit lesion PCI not completed ≤45 days (n=31) Lost to Follow-up (n=15) Withdrew Consent (n=6) Included in ITT Analysis (n=2016) Received Allocated Intervention (n=1634) Did not receive allocated intervention (n=391) Within 45 days (n=96) Met protocol criteria for Complete Revasc (n=60) Hospitalization for recurrent MI (n=29) Hospitalization for hemodynamic instability or refractory ischemic heart failure (n=3) Intractable angina despite OMT and documented evidence of ischemia (n=28) Did not meet protocol criteria for Complete Revasc (n=36) Patient request (n=6) Physician decision (n=30) After 45 days (n=295) Met protocol criteria for Complete Revasc (n=138) Did not meet protocol criteria for Complete Revasc (n=157) Lost to Follow-up (n=18) Withdrew Consent (n=3) (n=2025) 1285 index hospitalization (1 day) 596 after discharge (23 days) Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Baseline Characteristics   Complete N=2016 Culprit-only N=2025 Age (yrs) 61.6 62.4 Gender (% male) 80.5 79.1 Diabetes (%) 19.1 19.9 Chronic renal insuff. (%) 2.0 2.3 Prior MI (%) 7.3 7.6 Current smoker (%) 40.6 38.9 Hypertension (%) 48.7 50.7 Dyslipidemia (%) 37.9 39.4 Prior PCI (%) 7.0 Prior stroke (%) 3.2 3.1 Hemoglobin A1C 6.3 LDL (mmol/L) Creatinine (µmol/L) 84.7 85.2   Complete N=2016 Culprit-only N=2025 Sx onset to Culprit PCI (%) <6 hours 69.4 67.1 6~12 hours 16.1 17.7 >12 hours 14.5 15.3 Discharge Meds (%) ASA 99.8 99.5 P2Y12 Inhibitor 99.4 99.7 Ticagrelor 64.4 63.3 Prasugrel 9.6 8.3 Clopidogrel 25.6 28.2 Beta blocker 88.1 89.1 ACEi/ARB 85.5 84.6 Statin 98.2 97.2 Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Procedural Characteristics   Complete N=2016 Culprit-only N=2025 Index PCI for STEMI Primary 91.9% 93.1% Pharmaco-invasive 3.2% 3.0% Rescue 4.9% 3.9% Radial access 80.8% 80.7% Residual diseased vessels 1 76.1% 77.1% ≥2 23.9% 22.9% NCL location Left main 0.4% 0.1% LAD 38.0% 41.2% Proximal LAD 9.8% 10.4% Mid LAD 21.7% 23.7% Circumflex 36.4% 35.6% RCA 25.3% 23.2% Complete N=2016 Culprit-only N=2025 NCL diameter 2.8 mm 2.9 mm Mean NCL stenosis (visual) 79.3% 78.7% NCL stenosis (visual)   50-69% and FFR<0.80 0.8% 0.6% 70-79% 41.3% 45.1% 80-89% 33.5% 32.6% 90-99% 22.3% 19.7% 100% 2.1% 2.0% SYNTAX score (Core Lab) Baseline 16.3 16.0 Culprit lesion specific 8.8 8.6 Non-culprit lesion specific 4.5 Residual (after index PCI) 7.2 7.0 Complete revascularization was achieved in 90.1% after NCL PCI (SYNTAX score = 0) Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: First Co-Primary Outcomes CV Death or New MI Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Secondary Co-Primary Outcomes CV Death, New MI, or IDR Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Efficacy Outcomes   Complete Revasc. N=2016 Culprit Lesion Only N=2025 HR (95% CI) P value N (%) %/year Co-Primary Outcomes CV death or MI 158 (7.8) 2.7 213 (10.5) 3.7 0.74 (0.60-0.91) 0.004 CV death, MI or IDR 179 (8.9) 3.1 339 (16.7) 6.2 0.51 (0.43-0.61) <0.001 Key Secondary Outcome CV death, MI, IDR, unstable angina or class IV HF 272 (13.5) 4.9 426 (21.0) 8.1 0.62 (0.53-0.72) Other Secondary Outcomes MI 109 (5.4) 1.9 160 (7.9) 2.8 0.68 (0.53-0.86) 0.002 IDR 29 (1.4) 0.5 0.18 (0.12-0.26) Unstable Angina 70 (3.5) 1.2 130 (6.4) 2.2 0.53 (0.40-0.71) CV death 59 (2.9) 1.0 64 (3.2) 0.93 (0.65-1.32) 0.68 All-cause Death 96 (4.8) 1.6 106 (5.2) 1.7 0.91 (0.69-1.20) 0.51 Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Efficacy Outcomes % p=0.68 Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Subtypes of MI   Complete Revasc. N=2016 Culprit Lesion Only N=2025 HR (95% CI) N (%) %/year Subtype of MI NSTEMI 66 (3.27) 1.11 105 (5.19) 1.78 0.63 (0.46-0.85) STEMI 43 (2.13) 0.72 53 (2.62) 0.88 0.81 (0.54-1.22) Universal MI Definition Type 1 63 (3.13) 1.05 128 (6.32) 2.17 0.49 (0.36-0.66) Type 2 16 (0.79) 0.26 13 (0.64) 0.21 1.24 (0.60-2.58) Type 3 4 (0.20) 0.07 1 (0.05) 0.02 4.04 (0.45-36.17) Type 4a 0.27 8 (0.40) 0.13 2.01 (0.86-4.70) Type 4b 0.62 (0.26-1.49) Type 5 1.00 (0.06-15.92) Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Timing of Non-Culprit Lesion PCI During or After Index Hospitalization % p=0.62 130/1349 101/1353 57/663 88/676 CV Death or New MI % p=0.27 227/1349 113/1353 66/663 112/676 CV Death, New MI, or IDR Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Main Pre-Defined Subgroup Analyses Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

COMPLETE Trial: Safety and Other Outcomes   Complete Revasc. N=2016 Culprit Lesion Only N=2025 HR (95% CI) P value N (%) %/year Stroke 38 (1.9) 0.6 29 (1.4) 0.5 1.31 (0.81-2.13) 0.27 Stent thrombosis 26 (1.3) 0.4 19 (0.9) 0.3 1.38 (0.76-2.49) 0.28 All cause death or new MI 194 (9.6) 3.3 251 (12.4) 4.3 0.77 (0.64-0.93) 0.006 Major bleeding 58 (2.9) 1.0 44 (2.2) 0.7 1.33 (0.90-1.97) 0.15 Contrast-associated acute kidney injury* 30 (1.5) - 1.59 (0.89-2.84) 0.11 NYHA class IV heart failure 56 (2.8) 0.9 1.04 (0.72-1.50) 0.83 Clinically non-significant bleeding 32 (1.6) 27 (1.3) 1.19 (0.71-1.99) 0.50 Mehta et al., N Engl J Med 2019 Sept 1 [Epub ahead of print]

Conclusions In patients with STEMI and multi-vessel coronary artery disease: Compared with culprit-lesion-only PCI, routine non-culprit lesion PCI with the goal of complete revascularization: Reduced CV death or new MI by 26% (P=0.004), NNT = 37 Reduced CV death, new MI or IDR by 49% (P<0.001), NNT = 13 The benefit of complete revascularization was similar in those undergoing non-culprit lesion PCI during the index hospitalization (median 1 day) and several weeks after hospital discharge (median 3 weeks) There were no significant differences in bleeding, stent thrombosis, AKI or stroke

MV PCI in STEMI: Will COMPLETE Trial Change the STEMI Guidelines? STEMI: Complete Revascularization 2016 I IIa IIb III B 2019? I IIa IIb III C

CULPRIT-SHOCK Trial: Primary Endpoints All-Cause Mortality or Renal Replacement Therapy at 1 Year All-Cause Mortality at 30 Days Relative Risk (95% CI) 0.87 (0.76-0.99); P=0.048 59.5% 52.0% Days since randomization Thiele et al., N Engl J Med 2017;377:2419 Thiele et al., N Engl J Med 2018;379:1699

C B CULPRIT-SHOCK Trial: MV PCI in Shock Guideline Evolution ESC STEMI Guidelines 2017 → Revascularization Guidelines 2018 STEMI (NSTEMI), Cardiogenic Shock 2017 I IIa IIb III B 2018 I IIa IIb III C Ibanez et al., Eur Heart J 2018;39:119; Neumann et al. Eur Heart J 2019;40:87

2019 ESC Trials Revolutionary / significant observation Widespread acceptance Change in clinical practice Ticagrelor in DM without prior PCI: Ticagrelor in prior PCI+DM, Clopidogrel in elderly: Prasugrel in ACS, Complete Revas in STEMI: Final result  BETTER INTERVENTION/SURVIVAL

Take Home Message: Recent interventional trials from ESC 2019 and COMPLETE trial of STEMI strategy RCT evaluating the extended role of ticagrelor in diabetic pts with stable CAD failed to show any benefit largely due to higher bleeding. However prior PCI subgroup had net clinical benefit and no increased bleeding. Also elderly pts (>70yrs) with ACS has better outcomes with clopidogrel vs more potent P2Y12 inhibitors and hence should be the first line therapy. The strategy of complete revascularization (done 1 day or 3 weeks later) has shown to be superior to culprit vessel only PCI in STEMI pts with MV CAD as shown in the large randomized COMPLETE Trial. I believe, time has now come to change the STEMI guidelines to make MV PCI as ACC Class I indication in MV STEMI pts.

Question # 1 The correct answer is D THEMIS trial evaluated Ticagrelor vs placebo in all following clinical subset except; Diabetes Prior PCI Stable CAD Prior MI in <1 year E. Absence of stroke The correct answer is D

Question # 2 The correct answer is C POPular AGE trial compared the following scenario except; Pts with Unstable angina Pts >70yrs age Pts with STEMI Clopidogrel vs Ticagrelor/Prasugrel Pts with NSTEMI The correct answer is C

Question # 3 The correct answer is B Following are the results of COMPLETE trial of STEMI strategy except: A. Lower death and MI in complete revsc gp vs culprit only B. Significantly lower death in complete revas gp vs culprit only C. Lower IDR in completer revasc gp vs culprit only D. Similar bleeding rates between complete revasc vs culprit only E. Similar stroke rates between complete revas vs culprit only The correct answer is B