The Management of Patients With Incomplete Revascularization Giora Weisz, MD Director of Cardiovascular Clinical Research, Center for Interventional Vascular Therapy Columbia University Medical Center New York, NY

Giora Weisz, MD Ownership Interest (stock, stock options, or other ownership interests): Medicasting

Complete Revascularization Successful dilatation of all significant stenoses in vessels that are of sufficient size supplying viable myocardium Anatomical vs. functional Functional= viable myocardium or ischemia Significant stenosis = 50 or 70% Sufficient size = ≥ 1.5, 2, or 2.5 mm Proximal vs. distal Variation in the definitions of Incomplete Revascularization

Incomplete Revascularization NY State database, DES era Defined as major epicardial arteries, major diagonal and marginals Is Common: 7795/11294 = 69% Range per hospital: 45-89% Hannan et al, J Am Coll Cardiol Intv 2009;2:17–25

Incomplete Revascularization NY State database CR ICR Significant baseline differences between CR & IC Age Gender Race EF Prior MI CV disease PAD DM Renal failure No. of diseased vessels BMS vs. DES Models based upon multivariate analyses adjust for differences in baseline variables but cannot eliminate confounders Hannan et al, J Am Coll Cardiol Intv 2009;2:17–25

Relationship between ICR and 1-yr MACE ACUITY Angiographic Sub-study %DS Threshold ICR CR HR [95% CI] P-value ≥30% 20.4% 15.3% 1.36 [1.11, 1.68] 0.003 ≥40% 21.6% 16.1% 1.38 [1.16, 1.64] 0.0002 ≥50% 23.4% 16.6% 1.47 [1.24, 1.74] <0.0001 ≥60% 25.2% 17.1% 1.55 [1.30, 1.85] ≥70% 26.4% 17.6% 1.59 [1.30, 1.93] Irrespective of the threshold %DS used to define ICR, the presence of ICR after PCI was strongly associated with 1-year MACE. Increased threshold of % DS is associated with higher rates of events (click), increasing from 20.4% to 26.4% MACE at 1 year). Rosner G. Submitted for publication 2012

Outcomes @ 1y (ICR @ 50% DS) Sub-analysis from ACUITY HR [95% CI] P-value MACE 23.4% 16.6% 1.47 [1.24, 1.74] <0.0001 Death 3.1% 2.2% 1.43 [0.90, 2.27] 0.13 MI 12.0% 8.2% 1.50 [1.18, 1.89] 0.0007 Revasc 15.7% 10.2% 1.58 [1.28, 1.96] PCI 12.7% 8.8% 1.45 [1.15, 1.84] 0.002 CABG 3.9% 1.8% 2.32[1.46, 3.69] 0.0003 TVR 10.1% 7.3% 1.39 [1.08, 1.80] 0.01 Non-TVR 10.9% 6.4% 1.76 [1.36, 2.29] Using the threshold of 50% DS to define ICR, the presence of ICR after PCI was strongly associated with 1-year MACE, driven by increased rates of MI and unplanned repeat revascularization. Rosner G. Submitted for publication 2012

PROSPECT: Untreated Disease Outcomes @ 1 y – Non-culprit lesions Any NCL ≥ 50% All NCL < 50% Hazard Ratio P-value MACE 12.6% 4.0% 3.30 [1.71,6.35] 0.001 Cardiac death, arrest, MI 0.0% 0.6% 0.24 Rehospitalization 3.4% 3.89 [1.94,7.79] 0.0001 Revascularization 10.8% 2.82 [1.44,5.51] 0.002 Data from PROSPECT also showed that patients who had non-culprit lesion of at least 50% left untreated, had higher rates of rehospitalization and revascularization.

Angina Status and Cost > $ 4000, p <0.001 8 mo follow up – 2 fold inrease in cost from none to daily Similar across geographic regions Medication costs not significant, but less statin and more anginal meds in daily. Arnold Circ CQO 2009;2:344-353

CAD - Management options Complete revascularization CABG limitations: Cannot vascularize every branch SVG early and degenerative failure PCI challenges: CTO’s Branches <2.5mm Ideally we would like to have CR, but this often not possible.

CAD - Management options Medical Management of Angina / Ischemia Secondary prevention β-Blockers Ca++ Channel inhibitors Nitrates Ranolazine Medical management is often added to treat angina and ischemia.

LB overview of RAN MOA & Anti-anginal ischemic effects 9/10/2018 10:54 PM Ranolazine Ranolazine has anti-ischemic and antianginal effects. Ranolazine does not a) slow heart rate (No bradycardia) b) decrease contractility (No depression of LV function) c) increase coronary or peripheral flow: not a vasodilator (No hypotension) d) slow AV nodal conduction (No PR prolongation) Ranolazine: an inhibitor of Late INa Post-PCI Executive Committee Mtg New York

Ischemia Begets Ischemia  Oxygen Supply: Demand Ischemia Hypoxia, Ischemic metabolites, acidosis, and ROS Ranolazine  MVO2  O2 Supply  Late INa With myocardial ischemia, we have a vicious cycle of “ischemia begets ischemia”. Ischemia cause activation of late Na channels that cause intracellular Ca overload, that results is increased LVEDP which further reduce regional blood flow and increase O2 demand, resulting in more ischemia. Ranolazine inhibit the late Na channel, thus reducing ischemia. Contracture ( LVEDP) (Arrhythmias) [Na+]i Ca++ Overload Modified from: Belardinelli L, et al. Eur Heart. 2006;8 (Suppl. A):A10-A13.

MERLIN: Patients with History of Angina Placebo N=1776 Ranolazine N = 1789 HR P value Primary endpoint 29.4% 25.2% 0.86 p = 0.017 CV death or MI 12.5% 11.9% 0.97 p = 0.71 Recurrent ischemia 21.1% 16.5% 0.78 p = 0.002 Severe recurrent ischemia 14.4% 0.81 p = 0.026 Prompting revascularization 6.4% 4.5% 0.66 p = 0.006 Worsening angina 8.2% 5.6% 0.77 p = 0.048 Similar benefit with R was observed in patents with prior history of angina. As compared to placebo, R resulted in reduced rates of… Wilson S et al. J Am Coll Cardiol 2009;53:1510–6

MERLIN: Patients with History of Angina Treated with PCI for NSTE-ACS Placebo N=443 Ranolazine N = 473 HR P value Primary endpoint 30.2% 21.1% 0.67 p = 0.002 CV mortality 3.4% 1.1% 0.69 p = 0.014 Myocardial Infarction 6.3% 5.3% 0.83 P=0.5 Recurrent ischemia 23% 16.7% Severe recurrent ischemia 11.6% p = 0.023 Prompting revascularization 10.2% 0.60 p = 0.022 Leading to Hospitalization 15.8% 10.8% 0.66 And when looking specifically at the patients that were treated with PCI for the ACS event, adding the treatment with R resulted not only in reduced ischemic symptoms, but also significant reduction in CV morality.

Adjunctive Pharmacotherapy

Principal Investigator: Giora Weisz, MD A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of Ranolazine on Major Adverse Cardiovascular Events in Subjects with a History of Chronic Angina Who Undergo Percutaneous Coronary Intervention with Incomplete Revascularization Principal Investigator: Giora Weisz, MD

Primary Objective To evaluate the efficacy of ranolazine as compared with placebo when used as part of standard medical therapy in chronic angina subjects with incomplete revascularization post-PCI

Study Design Phase III Up to 2600 patients, 200 centers, 14 countries Randomized, Double-Blind, Placebo-Controlled 1:1 placebo vs. ranolazine (1000mg BID) Stratified by: ACS vs. non-ACS DM vs. non-DM Follow-up: event driven, at least 1 yr

Major Inclusion Criteria (1) History of chronic angina (at least 2 episodes on separate days between 30 days to 1 year prior to PCI) Indication for PCI ACS - hospitalization for anginal pain/discomfort within the previous 24h with elevated myocardial enzymes and/or ECG ST-changes Non-ACS - at least one of the following: Previous CABG surgery Previous PCI Multivessel CAD ( 50% stenosis in 2 or more epicardial coronary arteries) Diabetes mellitus

Major Inclusion Criteria (2) Post-PCI evidence of incomplete revascularization: ≥ 50% stenosis in one or more coronary arteries with reference vessel diameter of at least 2.0 mm

Study Endpoints Primary Efficacy Endpoint: Composite of ischemia-driven revascularization or hospitalization Secondary Endpoints: Sudden cardiac death CV death MI Evaluation of QoL study and health related costs

Summary (1) Incomplete revascularization is common and associated with increased rates of revascularization and hospital re-admissions Ranolazine, a late Na+ channel blocker, effectively reduce ischemia and angina and improve exercise tolerance Ranolazine is associated with reduced mortality and ischemic events in patients with history of chronic angina, admitted with ACS, and treated by PCI.

Summary (2) RIVER-PCI, The first study to prospectively evaluate patients with incomplete revascularization 2600 patients from 200 centers in 14 countries Randomization 1:1 – Ranolazine vs. placebo 10 endpoint: ischemia-driven revascularization or hospitalization Integrated QoL and health-related cost

The Management of Patients With Incomplete Revascularization Giora Weisz, MD Director of Cardiovascular Clinical Research, Center for Interventional Vascular Therapy Columbia University Medical Center New York, NY

Optimal %DS to Define ICR ACUITY Angiographic Sub-study Defining ICR with a greater %DS threshold decreased the sensitivity but increased the specificity for 1-year MACE, and was associated with greater rates of MACE in patients with ICR. The overlap point of the two curves represents the “optimal” threshold which balances sensitivity and specificity to predict subsequent MACE in patients with ICR. This occurs at a DS of ~44% Optimal percentage diameter stenosis threshold of incomplete revascularization to predict 1-year major adverse cardiac events. This graph plots sensitivity and specificity versus percentage diameter stenosis (DS) in 1% absolute increments. Sensitivity to detect 1-year major adverse cardiac events (MACE) is increased with lower percent DS cutoff values for incomplete coronary revascularization (ICR), whereas specificity is increased with higher percent DS cutoff values for ICR. The overlap point of the two curves represents the “optimal” threshold which balances sensitivity and specificity to predict subsequent MACE in non-ST-segment elevation acute coronary syndromes. determined by quantitative coronary angiography after percutaneous coronary intervention in a coronary artery with reference vessel diameter ≥2.0 mm. This is roughly equivalent to a visually estimated DS of 55-60%. Rosner G. Submitted for publication 2012

Inspiring Case 70 yr old (2008) 1981, 1998 MI’s 1985 4v CABG 1985-2007 (LIMA-LAD, SVG-OM & Diag, SVG-RCA) 1985-2007 al least 20 angiograms, 16 PCIs:

Long Saga…

Incomplete Revascularization Management of Incomplete Ranolazine Ranolazine for Myocardial Ischemia When you integrate our insights about the impact of ICR, the need to manage it better, and our current knowledge about R and its favorable effects, we can understand the rationales behind the RIVER-PCI study.

MERLIN-TIMI 36 Diabetes Subanalysis for Recurrent Ischemia LB Late Sodium Current Angina Therapy Revised 9.23.09 MERLIN-TIMI 36 Diabetes Subanalysis for Recurrent Ischemia Diabetes Mellitus (n=1477) No Diabetes Mellitus (n=2829) Ranolazine Placebo Ranolazine Placebo 19.2% 15.1% 14.6% Recurrent Ischemia (%) Recurrent Ischemia (%) The favorable effect of R on reducing recurrent ischemia was significantly higher in patients with DM, with 21% reduction in recurrent ischemia 13.3% Hazard Ratio 0.75 (95% CI 0.61-0.93) P=0.008 Hazard Ratio 0.95 (95% CI 0.80-1.11) P=0.50 0 90 180 270 360 0 90 180 270 360 Follow-Up (days) Follow-Up (days) Morrow DA, et al. Circulation. 2009;119:2032-2039.

Angina Status and Outcomes P< 0.001 P< 0.001 Persistent and frequent angina Dose response on death, MI, revasc, hospitalization Dose-response on HRQOL and Physical function Spertus Circ 2002;106:43-49

Extent of Revascularization 90-day Outcome, PROTECT-II Δ IZ 0-2 N=119 Δ IZ 3-5 N=133 Δ IZ 6-11 N=145 p-value MAE 55.1 40.6 41.4 0.036 Death/MI/Stroke/Revasc 40.7 25.6 26.2 0.014 MACCE 33.9 24.1 20.0 0.033 MACCE = Death, Stroke, Large MI*, Revasc.) Popma J. TCT 2011