Complex Coronary Cases Supported by: Abbott Vascular Inc Boston Scientific Corp Terumo Vascular Corp Vascular Solutions Inc Cardiovascular Science Inc AstraZeneca Pharmaceuticals The Medicines Company

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

February 17th 2015 Case #68: MW, 60 yrs M Presentation: Patient without prior history of MI, presented with new onset CCS Class II angina and high-risk stress MPI for anterior and inferior ischemia with infarction and TID. A cardiac cath on Jan 8th 2015 revealed 2 V CAD and LVEF 40% and SYNTAX score 21. Pt underwent PCI using Promus Premier DES to mid RCA and did well. Still has moderate angina largely due to residual multiple diffuse LAD lesions Prior History: Hypertension, NIDDM, Hyperlipidemia, +F/H, Ankylosing Spondylitis Medications: All once daily dosage Metoprolol XL 50mg, Amlodipine 5mg, Metformin XL 1000mg, ASA 81mg, Atorvastatin 40mg, Clopidogrel 75mg, Methotrexate 5mg 3

Case# 68: cont… Cardiac Cath 1/8/2015: Right Dominance II V CAD with LVEF 40% RCA: 90% lesion in mid, large size LM: No obstruction LAD: 90% heavily calcified mid LAD with 99-100% distal lesion; moderate size with diffuse disease, mild diffuse D1 LCx: 80% heavily calcified prox LCx lesion, large size vessel Pt underwent PCI of mid RCA with Promus Pr DES (3/28mm) SYNTAX Score was : 21 Plan Today: PCI of diffusely diseased multiple calcified lesions of mid and distal LAD. Now SYNTAX score is 17. 4

Appropriateness Criteria for Coronary Revascularization

Issues Involving The Case Complete vs. Incomplete Revascularization in Stable CAD Management Options in Refractory Angina

Issues Involving The Case Complete vs. Incomplete Revascularization in Stable CAD Management Options in Refractory Angina

Arms of “All-Comers” SYNTAX Population Flow Chart of Frequency of Complete Revascularization (CR) vs In-Complete Revascularization (ICR) in PCI and CABG; Arms of “All-Comers” SYNTAX Population Farooq et . al., J Am Coll Cardiol 2013;61:282 8

SYNTAX Trial PCI Group: 4-Year Clinical Outcomes by Complete vs. Incomplete Revascularization Complete Revascularization (n=578) Patients (%) p=<0.001 Incomplete Revascularization (n=510) p=0.011 p=0.052 p=0.059 p=0.046 p=0.23 Farooq et . al., J Am Coll Cardiol 2013;61:282 9

SYNTAX Trial CABG Group: 4-Year Clinical Outcomes by Complete vs SYNTAX Trial CABG Group: 4-Year Clinical Outcomes by Complete vs. Incomplete Revascularization Complete Revascularization (n=1031) Patients (%) Incomplete Revascularization (n=483) p=0.013 p=0.07 p=0.039 p=0.026 p=0.64 p=0.01 p=0.076 p=0.98 Farooq et . al., J Am Coll Cardiol 2013;61:282 10

Four-Year MACCE in the SYNTAX Trial: Stratified by Presence of ICR vs. CR in Patients with CTOs PCI Group: CTO (N= 286) CABG Group: CTO (N= 554) P-value 0.024 P-value 0.015 ICR: 39.9% ICR: 27.8% CR: 26.6% CR: 18.7% Farooq et . al., J Am Coll Cardiol 2013;61:282 11

The Residual SYNTAX Score (rSS) Rationale: Calculated as the SYNTAX score of untreated lesions after the procedure Strengths: The residual SYNTAX Score (rSS) has the potential to get a standardized quantification of incomplete revascularization linked to potential prognostic implications. º rSS = 0 means complete revascularization º rSS > 0 quantifies increasing levels of incomplete revascularization Minus the Lesions underwent revascularization SYNTAX Score

SYNTAX Trial: The Residual SYNTAX Score (rSS) Généreux et al., J Am Coll Cardiol 2012;59:2165

The Residual SYNTAX Score Components in Patients with Incomplete Revascularization According to Tertile Residual SS 1-2 (n=523) Residual SS >2-8 (n=578) Residual SS >8 (n=501) P Value Severe calcification 0.0 1.7 11.8 <0.001 CTO 0.2 10.0 43.1 Bifurcation/trifurcation 30.9 57.3 Aorto-ostial lesion 0.7 0.3 Lesion length >20 mm 0.6 24.7 70.1 Small vessel/diffuse dz 78.2 52.4 52.7 Généreux et al., J Am Coll Cardiol 2012;59:2165

Residual SYNTAX Score: 1-Year Outcomes According to the rSS P = 0.006 P = 0.32 (%) P = 0.007 P = 0.001 P = 0.23 Death UTVR MACE MI ST Généreux et al., J Am Coll Cardiol 2012;59:2165

The Residual SYNTAX Score: Death Généreux et al., J Am Coll Cardiol 2012;59:2165

SYNTAX Trial-PCI arm: Complete and Incomplete Revascularization Stratified by Baseline SYNTAX Score Residual SYNTAX Score 0 (n=386) >0-4 (n=184) >4-8 (n=167) >8 (n=153) p=<0.001 p=0.06 p=<0.001 % n=290 n=310 Farooq et al., Circulation 2013;128:141

SYNTAX Trial-PCI Arm: 5-Year Clinical Outcomes Based on the Residual Syntax Score after TAXUS DES Farooq et al., Circulation 2013;128:141

SYNTAX Trial-PCI Arm: 5-Year Clinical Outcomes Based on the Residual Syntax Score after TAXUS DES Farooq et al., Circulation 2013;128:141

SYNTAX Trial-PCI Arm: 5-Year Clinical Outcomes Based on the Residual Syntax Score after TAXUS DES Farooq et al., Circulation 2013;128:141

SYNTAX Trial-PCI Arm: 5-Year Clinical Outcomes Based on the Residual Syntax Score after TAXUS DES Farooq et al., Circulation 2013;128:141

Issues Involving The Case Complete vs. Incomplete Revascularization in Stable CAD Management Options in Refractory Angina

Refractory Angina Pectoris Definition By the ESC Joint Study Group Refractory Angina is defined as: “a chronic condition (≥3 months) characterized by the presence of angina caused by coronary insufficiency in the presence of CAD, which is not amenable to a combination of medical therapy, angioplasty, or coronary bypass surgery” in patients with evidence of ischemia. Patients can be suboptimal candidates for revascularization for many reasons, including having unsuitable coronary anatomy (severe diffuse atherosclerosis, or the absence of targets or lack of graft conduits for CABG surgery), the presence of substantial comorbidities (severe left ventricular dysfunction, peripheral artery disease, or chronic kidney disease), or because of advanced age.

Management Options in Refractory Angina Pharmacologic Non-Invasive Invasive Oral nitrate Enhanced External Counterpulsation (EECP) Trans-myocardial Revascularization (TMR) β-blockers Cardiac Rehabilitation Angiogenesis Calcium Channel blockers Exercise Programs Transcutaneous Electrical Nerve Stimulation (TEMS) Ranolazine: MARS, CARISA Self Management Training Spinal Cord Stimulation (SCS) Trimetazidine Thoracic Epidural Anesthesia (TEA) L-Arginine Endoscopic Thoracic Sympathectomy (ETS) Nicorandil Left Stellate Ganglion Block (LSGB) Ivabradine Coronary Sinus Reduction Stent Heart Transplantation

Management Options for Refractory Angina Henry et al., Nat Rev Cardiol 2014;11:78

Emerging Pharmacological Therapies for Refractory Angina Pharmacological Agent Proposed Mechanism of Action Comments Chelation Therapy EDTA (associated with carious vitamins) Mechanism of action uncertain, possibly associated with reduced oxidation of low-density lipoprotein, vasodilatory effects, and enhanced production of tissue plasminogen activator. Remains controversial despite data from the TACT trial. No efficacy on angina per se, but frequently administered to pts with advanced CAD unsuitable for revascularization. Class IIb Rheological agents Intermittent thrombolytics (urokinase) Depletion of plasma fibrinogen, which reduces blood viscosity and improves the rheological properties of blood in the microcirculation. Historical interest. Administered in some of Europe to treat patients with refractory angina. Testosterone Promotes endothelium-dependent relaxation of coronary arteries. Inadequately investigated in patients with ischemic heart disease.

Neurogenic Components of Angina & Treatment Options Henry et al., Nat Rev Cardiol 2014;11:78

Effect of Spinal Cord Stimulation (SCS) on Exercise Capacity Henry et al., Nat Rev Cardiol 2014;11:78

Surgical Operations for Angina Placing a suture around the coronary sinus Partial ligation of the coronary sinus Beck et al., JAMA 1954;156:1226

Coronary Sinus Reducer System Complete system for coronary-sinus reducing device comprises of metal mesh premounted on a balloon catheter shaped like an hour glass when expanded Verhehye et al., N Engl J Med 2015;372:519

Schematic Illustration Describing the Implantation Process of the CS Reducer Konigstein et al., EuroIntervention 2014;9:1158

CT Angiogram of the Device in the Coronary Sinus Denotes Patency at 6 Months Longitudinal CT angiographic view of the device in the coronary sinus show flow of contrast material Cross-sectional CT angiographic view of the device in the coronary sinus show flow of contrast material Verhehye et al., N Engl J Med 2015;372:519

Coronary Sinus Reducer System The most commonly proposed mechanism of benefit are mediated via elevated CS pressure causing: recruitment of coronary collateral flow redistribution of blood from the less-ischemic epicardium to the ischemic sub-endocardium development of new collaterals/blood vessels facilitate the dilatation of constricted sub-endocardial capillaries/arteriole Net result being enhanced perfusion of the ischemic myocardium and consequently hemodynamic parameters and angina symptoms will improve

Change in Canadian Cardiovascular Society (CSS) Angina Class Improvement in CCS Class Mean Change in CCS Class Verhehye et al., N Engl J Med 2015;372:519

CCS Angina Class at Baseline and 6 Months After Randomization Verhehye et al., N Engl J Med 2015;372:519

Changes from Baseline to 6 Months Follow-up Exercise Tolerance Test Verhehye et al., N Engl J Med 2015;372:519

Changes from Baseline to 6 Months Follow-up Dobutamine Stress Echocardiography Verhehye et al., N Engl J Med 2015;372:519

Death/MI were not different between 2 groups; 3 MI / 1 death in Control gp 1 MI / 0 death in Treatment gp

Take Home Message: Complete vs Take Home Message: Complete vs. In-Complete Revascularization (ICR) and Management Options for Refractory Angina Complete revascularization (CR) compared to ICR after PCI or CABG, is associated with lower long-term MACE including death. CABG is associated with lower ICR vs. PCI. Residual Syntax score of >8 is associated with higher death and other major cardiac events. Hence in PCI of complex lesions with high Syntax score, efforts should be made to optimize PCI procedures towards eye for CR Of the various emerging treatment options for refractory angina despite MMT, coronary sinus reducing device seems to have the best potential in reducing angina severity and improving exercise tolerance.

Question # 1 In the SYNTAX trial increasing residual Syntax score is associated with increasing all adverse cardiac events except: Stent thrombosis Target vessel revascularization Myocardial infarction Death MACCE

Question # 2 In pts with high Syntax score, following strategies are associated with higher complete vs. incomplete revascularization except: PCI of all lesions including bifurcation lesion Refer pt preferentially to CABG PCI of all lesions except one difficult mid LAD CTO PCI of all lesions except of non-dominant RCA CTO PCI of ULM lesion including LAD bifurcation except of OM1

Question # 3 Recent randomized trial of Coronary sinus reducer device compared to placebo showed the following: A. Lower incidence of MI B. Higher CCS class III at follow-up C. Lower mortality D. Higher device related complications E. Higher >2 CCS angina class improvement

Question # 1 The correct answer is A In the SYNTAX trial increasing residual Syntax score is associated with increasing all adverse cardiac events except: Stent thrombosis Target vessel revascularization Myocardial infarction Death MACCE The correct answer is A

Question # 2 The correct answer is C In pts with high Syntax score, following strategies are associated with higher complete vs. incomplete revascularization except: PCI of all lesions including bifurcation lesion Refer pt preferentially to CABG PCI of all lesions except one difficult mid LAD CTO PCI of all lesions except of non-dominant RCA CTO PCI of ULM lesion including LAD bifurcation except of OM1 The correct answer is C

Question # 3 The correct answer is E Recent randomized trial of Coronary sinus reducer device compared to placebo showed the following: A. Lower incidence of MI B. Higher CCS class III at follow-up C. Lower mortality D. Higher device related complications E. Higher >2 CCS angina class improvement The correct answer is E