Complex Coronary Cases Supported by: Abbott Vascular Boston Scientific Corp Abiomed Inc

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

August 19th 2014 Case #62: VE, 59 yr M Presentation: Patient with prior BMS to LAD in 1/2003 for AWMI, presented on August 5th 2014 with new onset CCS class II angina and stress MPI + for mod-to-severe multi-vessel ischemia with TID and LVEF 25%. A cardiac cath revealed 2 V + LM CAD with severe LV dysfunction; CTO distal RCA, 70% distal LM, 80% ulcerated ISR lesion in mid LAD/D2 (SYNTAX score 34). Heart Team consultation was done and CABG declined by the pt. Pt underwent DES to distal RCA and RPDA and did well. Prior History: Hypertension, Hyperlipidemia, IRDM, Smoker Medications: All once daily dosage Metoprolol XL 100mg, ISMN 60mg, ASA 81mg, Clopidogrel 75mg, Insulin, Saxagliptin 5mg, Metformin XR 1000mg, Rosuvastatin 20mg 3

Case# 62 cont… Cardiac Cath 8/5/2014: Right Dominance, LVEF 28% SYNTAX Score: 34 Cardiac Cath 8/5/2014: Right Dominance, LVEF 28% LM: 70% lesion in dLM LAD: 80% ulcerated BMS ISR of mid LAD and 70% D2 LCx: mild diffuse disease RCA: 100% dRCA and distal vessel fills via LAD collaterals Hospital course: Heart Team discussion took place and pt declined CABG and underwent DES x2 of RCA/RPDA. No complications and was discharged home same day Plan Today: PCI of calcific distal LM and LAD with Impella support. OCT will be done to evaluate neo-atheroma in LAD BMS ISR. 4

Appropriateness Criteria for Coronary Revascularization

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) U Isolated left main stenosis 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 Heart Team discussion with refusal to CABG 6

CABG Vs. PCI for Complex/LM CAD

CABG Vs. PCI for Complex/LM CAD

CABG Vs. PCI for Complex/LM CAD

Issues Involving The Case Update in PCI guidelines for stable CAD Newer data on FFR integration during PCI

Issues Involving The Case Update in PCI guidelines for stable CAD Newer data on FFR integration during PCI

J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

Diagnosis of SIHD Invasive Testing for diagnosis of Coronary Artery Disease in Patients with Suspected SIHD: Recommendations Class l Coronary angiography is useful in patients with presumed SIHD who have unacceptable ischemic symptoms despite GDMT and who are amendable to, and candidates for, coronary revascularization. (Level of Evidence: C) Class lla Coronary angiography is reasonable to define the extent and severity of coronary artery disease (CAD) in patients with suspected SIHD whose clinical characteristics and results of noninvasive testing (exclusive of stress testing) indicate a high likelihood of severe IHD and who are amendable to, and candidates for, coronary revascularization. (Level of Evidence: C) Coronary angiography is reasonable in patients with suspected symptomatic (SIHD) who cannot undergo diagnostic stress testing, or have indeterminate or non-diagnostic stress tests, where there is a high likelihood that the findings will result in important changes to therapy. (Level of Evidence: C) Class llb Coronary angiography might be considered in patients with stress test results of acceptable quality that do not suggest the presence of CAD when clinical suspicion of CAD remains high and there is a likelihood that the findings will result in important changes to therapy. (Level of Evidence: C) J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

Coronary Angiography is Indicated in the Following Subsets for Risk Stratification Patients with heart failure and/or reduced ejection fraction. Patients who have experienced sudden cardiac death or sustained ventricular arrhythmia. Patients undergoing preoperative cardiovascular evaluation for non-cardiac surgery (including solid organ transplantation). Evaluation of cardiac disease among patients who are kidney or liver transplantation candidates. J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

Diagnostic Coronary Angiography Without Stress Testing in ISHD May Be Indicated: Long-standing diabetes mellitus and end-organ damage Severe peripheral vascular disease (e.g., abdominal aortic aneurysm) Previous chest (mantle) radiation therapy may have severe CAD – particularly when ischemic symptoms are present Patients with a combination of typical angina, transient heart failure, pulmonary edema, or exertional or unheralded syncope may have severe CAD Non-invasive testing such as rest echocardiography revealing multiple regional wall motion abnormalities or electrocardiography with diffuse ischemic changes in multiple territories Clinicians strongly suspect that s stress test is falsely negative (e.g., a patient with typical angina who also has multiple risk factors for CAD), diagnostic angiography may be warranted When stress testing yields an ambiguous or indeterminate result in a patient with a high likelihood of CAD, coronary angiography may be preferable to another non-invasive test and may be the most effective means to reach a diagnosis. J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

Recommendation for Chelation Therapy 2012 Recommendations 2014 Focused Updated Recommendation Comment Class lll: No Benefit Class llb From TACT Trial Chelation therapy is not recommended with the intent of improving symptoms or reducing cardiovascular risk in patients with SIHD. (Level of Evidence: C) The usefulness of chelation therapy is uncertain for reducing cardiovascular events in patients with SIHD. (Level of Evidence: B) Modified recommendation (changed Class of Recommendation from lll: No benefit to llb and Level of Evidence from C to B). J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

to Improve Survival Recommendation for CAD Revascularization Class l 2012 Recommendations 2014 Focused Updated Recommendation Comment Class lla Class l CABG is probably recommended in preference to PCI to improve survival in patients with multiple CAD and diabetes mellitus, particularly if a LIMA graft can be anastomosed to the LAD artery. (Level of Evidence: B) A Heart Team approach to revascularization is recommended in patients with diabetes mellitus and complex multivessel CAD. (Level of Evidence: C) CABG is generally recommended in preference to PCI to improve survival in patients with DM and multivessel CAD for which revascularization is likely to improve survival (3-vessel CAD or complex 2-vessel CAD involving the proximal LAD). Particularly if a LIMA graft can be anastomosed to the LAD artery, provided that patient is a good candidate for surgery. (LOC: B) Modified recommendation (changed Class of Recommendation from lla to l). New Recommendation J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

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 Death MI Stroke CV Death Endpoint Farkouh et al., NEJM 2012;367:2375 18

FREEDOM Trial: BASELINE CHARACTERISTICS Characteristic PCI/DES CABG P-value Angina 0.25 Stable 68% 71% Unstable 32% 30% LV Ejection Fraction (< 30%) 0.8% 0.3% 0.28 LV Ejection Fraction (< 40%) 3% 2% 0.07 EuroSCORE 27 ± 2.4 2.8 ± 2.5 0.52 SYNTAX score 26.2 ± 8.4 26.1 ± 8.8 0.77 No. of lesions 5.7 ± 2.2 5.7 ± 2.2 0.33 Chronic total occlusion 6% 6% 0.99 Bifurcation 22% 21% 0.06

Verma et al. Lancet Diabetes Endocrinol 2013;1:317

Quality Assessment of Included Randomized Controlled Trials Verma et al., Lancet Diabetes Endocrinol 2013;1:317

All-Cause Mortality at 5-Year (or Longest) Follow-Up Verma et al., Lancet Diabetes Endocrinol 2013;1:317

CABG vs. PCI for Complex/LM CAD

Summary - To address the important issue of deciding between PCI and CABG in patients with diabetes mellitus and complex multi-vessel CAD, a Heart Team approach would be beneficial. - This was an integral component of the FREEDOM, SYNTAX, and BARI trials and is therefore emphasized in this setting. - The Heart Team is a multidisciplinary team composed of the referring cardiologist, an interventional cardiologist and a cardiac surgeon who jointly: Review the patient’s medical condition and coronary anatomy Determine that PCI and/or CABG are technically feasible and reasonable Discuss revascularization options with the patient before a treatment strategy is selected. J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28 [Epub ahead of print]

Issues Involving The Case Update in PCI guidelines for stable CAD Newer data on FFR integration during PCI

Flow Reserve: FFR and CFR Measures integrated hemodynamic effects of epicardial CAD, diffuse atherosclerosis, vessel remodeling and microvascular dysfunction on myocardial tissue perfusion Epicardial arteries Prearteioles, arterioles > 400 µm < 400 µm MBF peak hyperemia CFR = MBF rest FFR CFR

FAME Trial: Optimizing Physiological Revascularization 1005 pts with MVD undergoing PCI with DES were randomized to FFR-guided vs. angio-guided intervention FFR-guided (n=509) 30 days 2.9% 90 days 3.8% 180 days 4.9% 360 days 5.3% Angio-guided (n=496) Days Freedom from death, MI, revasc 60 120 180 240 300 360 0.70 0.75 0.80 0.85 0.90 0.95 1.00 MACE 13.3% vs. 18.2% P=0.02 At 30 days, there is already a absolute diff of 2.9 %, but this is steadily increasing over the year and reaches a value of 5.3% at 1 year Tonino PAL et al. NEJM 2009;360:213 27 27 27 27

FAME Trial: “Downgrading” MV Disease with FFR 3 Vessel Disease 2 Vessel Disease 0-VD 0-VD 3-VD 2-VD 1-VD 1-VD 2-VD 86% 3VD and 57% 2VD reclassified >1 vessel Tonino et al, JACC 2010;55:2816 28

FAME Trial: 2 Year Results of Deferral FFR-guided group;509 patients 1329 stenoses with DS >50% thought to require PCI 513 stenoses deferred (FFR >0.80) 816 stenoses stented 9 late MIs 53 repeat revasc 1 (0.2%) due to a deferred lesion 8 (1.6%) stent-related or due to a new lesion 16 (3.2%) due to a deferred lesion 37 (7.2%) due to ISR or a new lesion Pijls et al., J Am Coll Cardiol 2010;56:177 29

FAME II Trial: Flow Chart Stable patients scheduled for 1, 2 or 3 vessel DES stenting FFR in all targets lesions Randomized Trial Registry At least 1 stenosis with FFR < 0.80 When all FFR >0.80 Randomization 1:1 OMT PCI + OMT OMT 50 % randomly assigned to FU Follow-up after 1 and 6 months and then 1, 2, 3, 4 and 5 years 30

FAME 2 Trial: 888 Patients With Lesions w/FFR ≤0 FAME 2 Trial: 888 Patients With Lesions w/FFR ≤0.80 randomized to PCI vs. OMT De Bruyne et al., NEJM 2012;367:991 31

FAME II Trial Results at 7 Months FFR-Guided PCI (n=447) MT (n=441) p value Primary Endpoint 4.3% 12.7% <0.001 Death 0.2% 0.7% 0.31 Myocardial Infarction 3.4% 3.2% 0.89 Urgent Revascular 1.6% 11.1% Free from Angina at 1 M 71% 48% De Bruyne, et al., NEJM 2012:367:991

Latest Data on FFR Integration in Coronary Revascularization RIPCORD (Curzen et al., Circ Cardiovasc Interv 2014;7:248) 200 patients – After FFR, patient management changed in 26% of patients R3F (Van Belle et al., Circulation 2014;129:173) 1075 patients – FFR classification of the strategy in 43% of patients Aalst Registry (Barbato et al., Eur Heart J 2014 March 18 [Epub ahead of print] 2900 patients - FFR highlighted discordances in 35% of patients ISIS Survey (Toth et al., presented at EuroPCR 2013) 4421 lesions – Angiogram-based decisions discordant with FFR in 34% of patients Mayo Clinic Study (Li et al., Eur Heart J 2013;34:1375) 7358 patients – FFR-guided treatment strategy is associated with a favorable long-term outcome

The RIPCORD Study Method n=200 Patient being investigated for chest pain n=200 Diagnostic Coronary Angiogram by Cardiologist 1 TREATMENT PLAN 1 Medical/PCI/CABG/more info *FFR≤0.8 Cardiologist 1 shown FFR results FFR* of all patent vessels of stentable (≥2.25mm) diameter by Cardiologist 2 TREATMENT PLAN 2 Medical/PCI/CABG/more info Primary endpoint based upon the difference between Plan 1 and Plan 2 Curzen et al., Circ Cardiovasc Interv 2014;7:248

The RIPCORD Study: Primary Endpoint Results Management of Population by Angiogram vs. FFR Summary Agreement about category of management in 147 out of 200 (74%) i.e., after FFR management change in 26% of cases Curzen et al., Circ Cardiovasc Interv 2014;7:248

Insights from a Large French Multicenter FFR Registry Outcome Impact of Coronary Revascularization Strategy Reclassification with FFR at Time of Diagnostic Angiography Insights from a Large French Multicenter FFR Registry 1075 consecutive patients 20 French centers Initial (angiogram-guided) strategy, final (FFR-guided in 95.7%) strategy and 1 yr clinical follow-up Van Belle et al., Circulation 2014;129:173

French Registry, R3F Van Belle et al., Circulation 2014;129:173

4086 stenoses in 2986 patients in whom at least one stenosis was ‘intermediate’ grade One third of the population showed discordance between DS>50% and FFR>0.80

Correlation Between Diameter Stenosis (DS) vs. Fractional Flow Reserve (FFR) Overall Population Left Main, LAD, LCx and RCA Toth et al., E Heart J March 18, 2014 [Epub ahead of print]

7358 patients undergoing PCI 6268 angio-guided, 1090 FFR-guided

Long-Term Adverse Events in the PCI Only Group and FFR-Guided Group 7-yr Follow-up of MACE Death MI Death or MI Li et al., Eur Heart J 2013;34:1375

Long-Term Survival After PCI: Pan-London Registry Clinical Outcomes at 3-5 Yrs Angiography, n=37,090 p=0.03 p=0.11 FFR, n=2767 IVUS, n=1831 % p=0.45 Stent use 1.7 (1.1) 1.1 (1.2) 1.6 (1.3) <.001 Fröhlich et al., JAMA Intern Med 2014;174:1360

Long-Term Survival After PCI: Pan-London Registry FFR-Guided vs Angiography Guided PCI IVUS-Guided vs Angiography Guided PCI Fröhlich et al., JAMA Intern Med 2014;174:1360

Take Home Message: Updated role of FFR in PCI and SIHD guidelines Randomized trials incorporating FFR guided PCI have shown lower MACE/MI/TVR rates and stent usage but no impact on survival. Recent long-term registry data also could not substantiate reduced mortality in FFR guided PCI. CABG now is the Class I indication for multi-vessel CAD in diabetic pts (3 V or complex 2 V CAD with high Syntax score >22 & suitable for LIMA graft & acceptable surgical risk). Heart Team approach in deciding final revascularization in these complex CAD pts is appropriate. Some of these pts may benefit from PCI.

Question # 1 Based on the recent updated guidelines of coronary revascularization in Stable CAD, CABG is preferred over PCI in following scenario except: Three vessel CAD in diabetic Two vessel CAD in diabetic with distal LAD lesion Two vessel CAD in diabetic with prox LAD lesion Two vessel CAD in diabetic with Syntax score 32 Three vessel VAD with mid LAD lesion

Question # 2 Following is the true statement regarding FFR guided PCI except: FFR guided PCI has shown to decrease mortality in RCT FFR guided PCI is associated with significantly lower MI FFR guided PCI is associated with significantly lower TVR FFR guided PCI is associated with significantly lower Death FFR guided PCI is associated with significantly lower MACE

Question # 3 Following is the true statement regarding FFR guided PCI in the Pan-London registry: FFR guided PCI was associated with lower mortality FFR guided PCI is associated with significantly lower MI FFR guided PCI is associated with significantly lower procedural complication FFR guided PCI is associated with significantly lower TVR FFR guided PCI is associated with significantly higher stent use

Question # 1 The correct answer is B as all others are true Based on the recent updated guidelines of coronary revascularization in Stable CAD, CABG is preferred over PCI in following scenario except: Three vessel CAD in diabetic Two vessel CAD in diabetic with distal LAD lesion Two vessel CAD in diabetic with prox LAD lesion Two vessel CAD in diabetic with Syntax score 32 Three vessel VAD with mid LAD lesion The correct answer is B as all others are true J Am Coll Cardiol 2014 Jul 18 and Circulation 2014 Jul 28

The correct answer is A as all others are False Question # 2 Following is the true statement regarding FFR guided PCI except: FFR guided PCI has shown to decrease mortality in RCT FFR guided PCI is associated with significantly lower MI FFR guided PCI is associated with significantly lower TVR FFR guided PCI is associated with significantly lower Death FFR guided PCI is associated with significantly lower MACE The correct answer is A as all others are False

The correct answer is C as all others are true Question # 3 Following is the true statement regarding FFR guided PCI in the Pan-London registry: FFR guided PCI was associated with lower mortality FFR guided PCI is associated with significantly lower MI FFR guided PCI is associated with significantly lower procedural complication FFR guided PCI is associated with significantly lower TVR FFR guided PCI is associated with significantly higher stent use The correct answer is C as all others are true Fröhlich et al., JAMA Intern Med 2014;174:1360