1. The Efficacy and Safety of Varenicline, a Selective α4β2 Nicotinic Receptor Partial Agonist, for Smoking Cessation in Patients Hospitalized with Acute Coronary Syndrome: A Randomized Controlled Trial Mark J. Eisenberg, Sarah B. Windle, Nathalie Roy, Wayne Old, François Grondin, Iqbal Bata, Ayman Iskander, Claude Lauzon, Nalin Srivastava, Adam Clarke, Daniel Cassavar, Danielle Dion, Herbert Haught, Shamir Mehta, Jean-François Baril, Charles Lambert, Mina Madan, Beth L. Abramson, and Payam Dehghani for the Evaluation of Varenicline in Smoking Cessation for Patients Post-Acute Coronary Syndrome (EVITA) Trial Investigators EV TA Embargoed Until 10:45 a.m. ET, Monday, Nov. 9, 2015

2. Disclosures Drs. Eisenberg, Dehghani and Madan received honoraria from Pfizer Inc. for providing continuing medical education on smoking cessation Dr. Eisenberg received funding and study drug/placebo from Pfizer Inc., to perform the Evaluation of Varenicline in Smoking Cessation for Patients Post-Acute Coronary Syndrome [EVITA] Trial; NCT00794573). EV TA

3. Background Morbidity and mortality substantially increased among patients who continue to smoke following ACS Less than 1/3 remain abstinent after discharge Nicotine replacement therapies (NRTs) – frequently prescribed in-hospital but no RCTs Bupropion (non-NRT) – 3 RCTs and not found to be efficacious Varenicline (non-NRT) – efficacious in healthy smokers and stable CVD patients Little is known about varenicline’s efficacy in ACS patients References: JAMA 2003;290:86-97. Am J Cardiol 2011;108:804-8. How Tobacco Smoking Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General, 2010. The Health Consequences of Smoking: A Report of the Surgeon General, 2004. J Am Coll Cardiol 2013; 61:524-32. Arch Intern Med 2011;171:1055-60. Am J Med 2006;119:1080-7. JAMA 2015;313:687-94. JAMA 2006;296:56-63. Circulation. 2010; 121:221-9. EV TA

4. Objective To assess the efficacy of varenicline in smokers hospitalized with ACS EV TA

5. Study Design Multicenter 40 Canadian and US centers Double-blind Randomized Placebo-controlled Investigator-initiated Funding & study drug/placebo from Pfizer Inc. No role in design, conduct, analysis, or reporting EV TA The complete EVITA Trial methodology is available in: Windle SB et al. Am Heart J 2015;170:635-40.e1

6. Trial Schematic EV TA Randomization Smokers Hospitalized for ACS Informed Consent & Eligibility Assessment Baseline Visit & 1 st Dose In-Hospital Follow-Up Visits Telephone: Weeks 1, 2 & 8 Clinic: Weeks 4, 12 & 24 Primary Endpoint Smoking abstinence at Week 24 Low-Intensity Counselling at Baseline & All Follow-Up Contacts Varenicline for 12 WeeksPlacebo for 12 Weeks

7. Inclusion/Exclusion Main Inclusion Criteria Age ≥ 18 years and motivated to quit smoking Smoke ≥ 10 cigarettes/day on average in the past year Hospitalized with ACS Main Exclusion Criteria History of neuropsychiatric disorders Prior varenicline use, or use of smoking cessation pharmacotherapy at the time of ACS Cardiogenic shock or renal impairment at randomization Hepatic impairment prior to ACS Excessive alcohol use, or current use of: marijuana, non- cigarette tobacco products, OTC stimulants or anorectics EV TA

8. Endpoints Primary Endpoint (ITT) 7-day point prevalence abstinence at week 24 Self-reported abstinence in past week and exhaled CO ≤ 10 ppm Secondary Endpoints (ITT) Continuous abstinence at week 24 Self-reported abstinence since baseline and exhaled CO ≤ 10 ppm at all follow-up visits up to and including week 24 ≥ 50% reduction in daily cigarette consumption at week 24 Safety Endpoints Side effects, SAEs, MACE, neuropsychiatric events SAEs adjudicated by an EEC (blinded to treatment status) Trial monitored by an external DSMB EV TA

9. Trial Flow EV TA Smoking Status for ITT Analysis* n=148 Patients Randomized n=302 Placebo n=151Varenicline n=151 Died n=2 Withdrew Consent n=9 Lost to Follow-Up n=16 Died n=0 Withdrew Consent n=10 Lost to Follow-Up n=18 Treatment Weeks 1-12 Died n=1 Withdrew Consent n=0 Lost to Follow-Up n=5 Died n=0 Withdrew Consent n=2 Lost to Follow-Up n=7 Follow-Up Weeks 13-24 Smoking Status for ITT Analysis* n=151 Week 24 * Assumed that patients who withdrew or who were lost to follow-up returned to smoking at their baseline rate

10. Patient Characteristics Varenicline (n = 151) Placebo (n = 151) Reason for Admission (%) STEMI5755 NSTEMI3540 Unstable angina85 Procedures (%) Cardiac catheterization9998 PCI8385 CABG93 Complications (%) CHF75 Recurrent ischemia51 Ventricular arrhythmia68 Index Hospitalization Median Length of Stay (d)33 Median Time from Admission to 1 st Dose of Study Medication (d) 22 EV TA Varenicline (n = 151) Placebo (n = 151) Demographics Age (y)55 ± 855 ± 10 Male (%)7476 Canada vs. US (%)69 vs. 3164 vs. 36 Smoking (mean ± SD) Years smoked35 ± 1137 ± 12 Cigarettes/day at baseline 22 ± 1121 ± 10 Clinical/Medical History (%) Hyperlipidemia6470 Hypertension5246 Diabetes2217 Prior use of antidepressants 116 Prior MI1719 Prior PCI1219 Prior CABG33 Prior TIA or CVA24

11. Primary Endpoint p<0.001 p=0.012 p<0.001 EV TA NNT: 6.8 ↓ Primary Endpoint

12. Secondary Endpoints p<0.001 p=0.013 p=0.081 NNT: 10.0 ↓ p=0.009 p=0.004 P<0.05 NNT: 8.5 ↓ EV TA

13. Safety Endpoints Varenicline (n = 151) Placebo (n = 151) P-Value SAEs Within 30 Days of Treatment Discontinuation, n (%) Patients with any SAE 18 (11.9)17 (11.3)>0.99 Composite MACE 6 (4.0)7 (4.6)>0.99 Death 2 (1.3)00.50 Myocardial infarction 3 (2.0) 1.00 Unstable angina 1 (0.7)5 (3.3)0.21 Other cardiovascular events 3 (2.0)2 (1.3)>0.99 Neuropsychiatric events Seizure, suicidal ideation 00---- Other 1 (0.7)0>0.99 Other 9 (6.0)8 (5.3)>0.99 Most Common Side Effects – 12-Week Cumulative, n (%) Insomnia 27 (17.9)19 (12.6)0.26 Nausea 21 (13.9)13 (8.6)0.20 Abnormal dreams 23 (15.2)7 (4.6)<0.01 EV TA

14. Conclusions Varenicline, initiated in-hospital following ACS, and in conjunction with low-intensity counseling, is efficacious for smoking cessation Without smoking cessation therapy, less than 1/3 of smokers hospitalized with ACS remain abstinent after discharge Future studies are needed to establish safety in these patients EV TA For more details on the EVITA Trial, please refer to our simultaneous publication in Circulation

15. EV TA Steering CommitteeTrial Coordinator Mark Eisenberg (Chair) Jewish General Hospital/McGill University, Montreal, QC Beth L. Abramson St. Michael's Hospital, Toronto, ON Iqbal Bata Queen Elizabeth II Health Sciences Centre, Halifax, NS Mina Madan Sunnybrook Health Sciences Centre, Toronto, ON Sarah Windle Jewish General Hospital, Montreal, QC Site Investigators Jean-François Baril Dr. Georges-L.-Dumont University Hospital Centre, Moncton, NB Danielle Dion CISSS de Chaudière Appalaches site Hôpital St-Georges, Beauce, QC Thao Huynh Montréal General Hospital, Montréal, QC Shamir R. Mehta McMaster University & Hamilton Health Sciences, Hamilton, ON Neville Suskin London Health Sciences Centre, London, ON Qiangjun Cai McFarland Clinic PC, Ames, IA Naim Farhat North Ohio Research, Elyria, OH Ayman Iskander SJH Cardiology Associates and St. Joseph's Hospital, Liverpool, NY Wayne Old Sentara Cardiovascular Research Institute, Norfolk, VA Mohamed Turki St. Luke's University Hospital, Bethlehem, PA Daniel Cassavar ProMedica Toledo Hospital, oledo, OH Nancy Fillion L’Hôtel-Dieu de Québec, Québec, QC Smadar Kort Stony Brook University, Stony Brook, NY Michael Peters Heart Consultants, Omaha, NE Andrew Weeks Norfolk General Hospital, Simcoe, ON Suresh Chandrasekaran The Oklahoma Heart Hospital Research Foundation, Oklahoma City, OK Eve Gillespie Glacier View Research Institute, Kalispell, MT Charles Lambert Florida Hospital Pepin Heart Institute, Tampa, FL Nathalie Roy CSSS de Chicoutimi, Chicoutimi, QC Brian Wong Sudbury Regional Hospital, Sudbury, ON Mohamed Chebaclo Altru Health System, Grand Forks, ND François R. Grondin CISSS Chaudière-Appalaches, Hôtel-Dieu de Lévis Site, QC John Larry Ohio State University, Columbus, OH Manohara Senaratne Grey Nuns Community Hospital, Edmonton, AB Adam Clarke Valley Regional Hospital, Kentville, NS Herbert Haught Heart Center Research, Huntsville, AL Claude Lauzon CISSS - Chaudière-Appalaches, Thetford Mines, QC Jeffrey Shanes Consultants in Cardiovascular Medicine, Melrose Park, IL David Cleveland Penticton Regional Hospital, Penticton, BC John Henry Heart Consultants, Omaha, NE Pedro Lozano VA Medical Center, Oklahoma City, OK Satyendra Sharma St. Boniface General Hospital, Winnipeg, MB Payam Dehghani Prairie Vascular Research Network, University of Saskatchewan, Regina, SK Michael Hong Buffalo Heart Group, Buffalo, NY Peter McCullough &Thomas Anan Providence Park Hospital, Novi, MI Nalin Srivastava Spartanburg Regional Medical Center, Spartanburg, SC Endpoints Evaluation CommitteeData Safety Monitoring Board Vidal Essebag Montreal General Hospital, Montreal, QC Jafna Cox (Chair) Dalhousie University, Halifax, NS Peter Faris University of Calgary, Calgary, AB Nadia Kahn University of British Columbia, Vancouver, BC Investigators

16. EV TA

18. Sample Size Calculation Assumptions: 7-day PPA rate of 24% at 24 weeks in placebo-treated patients ≥ 15% absolute increase in abstinence rates with varenicline > 80% power and two-tailed α of 0.05 150 patients per study arm (n=300) needed Not powered to examine safety endpoints EV TA

19. Limitations Only enrolled patients motivated to quit smoking Smoking abstinence rates likely optimistic vs. real-world Small sample size Limits ability to definitively address the cardiovascular safety of varenicline Smokers represent a challenging patient population As with other smoking cessation trials, a not insubstantial number of patients withdrew or were lost to follow-up Low-intensity counseling High-intensity counselling could have improved quit rates EV TA