Would you recommend extending DAPT >1 year post-MI? 66 year old man, 78 kg NSTEMI 1 year ago 80% proximal LAD, multiple 30-40% proximal and mid Circumflex, 30-50% proximal, mid, and distal RCA stenoses; preserved LV function 2nd generation DES placed in the proximal LAD Discharged on ASA and ticagrelor 90 mg BID Diabetes mellitus (Type 2) - On metformin 1 g BID, empagliflozin 10 mg daily → A1C 6.9% Dyslipidemia - On atorvastatin 80 mg/day and ezetimibe 10 mg/day → LDL-C 1.6 mmol/L Moderate renal dysfunction Creatinine 150 mol/L; eGFR 47 ml/min/1.73m2 (by Cockcroft-Gault),43 ml/min/1.73m2 (by MDRD) Ramipril 2.5 mg daily at discharge titrated up by family MD to 5 mg/day (for vascular protection) Would you recommend extending DAPT >1 year post-MI? Yes No

Previous Myocardial Infarction Mean duration 27 months ~ 36 (5) fewer MIs/Strokes/Vascular Deaths per 1000 patients (~16 per 1000 per year) ~ 3 excess major extracranial bleeds per 1000 patients (~1 per 1000 per year) Antithrombotic Trialists’ Collaboration BMJ 2002;324:71-86

CV Death/MI/Stroke CV Death/MI/Stroke RR 0.81 (0.73-0.90) ACS patients undergoing PCI Moderate-to-high risk ACS patients (except those receiving fibrinolysis) CV Death/MI/Stroke CV Death/MI/Stroke 12 12 12.1 All-cause Mortality: 5.9% vs. 4.5% HR 0.78 (0.69–0.89); p<0.001 11.7 10 10 9.9 9.2 8 8 RR 0.81 (0.73-0.90) HR 0.84 (0.77-0.92) % 6 6 p=0.0004 p=0.0003 4 TIMI Major Bleeding: 1.8% vs. 2.4%, p=0.03 Non-CABG PLATO Bleeding: 3.8% vs. 4.5%, p=0.026 4 2 Clopidogrel (n=6795) 2 Clopidogrel (n=9291) Prasugrel (n=6813) Ticagrelor (n=9333) 3 6 9 12 15 3 6 9 12 Months Months Wiviott et al N Engl J Med 2007;357:2001-15 Wallentin et al N Engl J Med 2009;361:1045-57

Primary Efficacy Outcome: Time to MI, Stroke, or Cardiovascular Death Overall Trial Population (N=15,603) Qualifying CAD, CVD or PAD (n=9,478) 10 10 RRR: 7.1% (95% CI: -4.5%, 17.5%) p=0.22 RRR: 17.1% (95% CI: 4.4%, 28.1%) p=0.01 8.8 8 7.3 8 Moderate bleeding (requiring transfusion) 1.3% vs. 2%, p=0.004 7.3 6.8 6 6 Primary outcome event rate (%) Primary outcome event rate (%) 4 4 The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death) With a median of 28 months of follow-up, the primary event rate was 6.8% in the clopidogrel plus aspirin arm and 7.3% in the placebo plus aspirin arm (p=0.22, relative risk [RR] 0.93, 95% confidence interval [CI] 0.83, 1.05) (Figure 1). This reduction was not statistically significant (p=0.217) 1 The yearly primary outcome events rates were 3.12% and 3.36% for clopidogrel plus ASA vs. placebo plus ASA, respectively Clopidogrel plus ASA prevented 39 primary events overall during the study follow-up1 The Kaplan-Meier curve of the primary endpoint shows that the curves separate very early after randomization, and continue diverging over time, which indicates a continuous trend in favor of the clopidogrel and ASA treatment arm. 1 Bhatt DL, Fox KA, Hacke W, et al. 2006, in press. 2 2 Placebo + ASA Clopidogrel + ASA Placebo + ASA Clopidogrel + ASA 6 12 18 24 30 6 12 18 24 30 Months since randomization Months since randomization Bhatt et al N Engl J Med 2006;354:1706-17 Bhatt et al J Am Coll Cardiol 2007;49:1982-8

Co-Primary Effectiveness Endpoints/Components 55% of the MI benefit with extended DAPT not related to stent thrombosis 12-30 Months Largest benefit in stent thrombosis and MACE reductions seen with 1st (vs. 2nd) generation stents Patients free from ischemic/bleeding events + thieopyridine adherent; 43% post-ACS Cardiac/Vascular: 1.0% vs. 1.1%; p=0.98 Non-Cardiovascular: 1.0% vs. 0.5%; p=0.002 Numerically higher bleeding-, trauma-, or statistically higher cancer-related (not mutually exclusive) deaths with thienopyridine * * Major Adverse Cardiovascular and Cerebrovascular Events (Death, MI, or Stroke) Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66

Primary Safety Endpoint GUSTO Moderate or Severe bleeding 12-30 Months Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66

Stable pts ≥50 yrs with MI 1-3 yrs prior Primary Endpoint Stable pts ≥50 yrs with MI 1-3 yrs prior + tolerating ASA 75-150 mg/d + ≥1 additional atherothrombosis risk factor (age ≥65 yrs, diabetes, 2nd prior MI >1 yr ago, multivessel CAD, CrCl <60 ml/min) Bonaca et al N Engl J Med 2015;372:1791-800

Components of Primary Endpoint All-cause Death: Placebo 5.2% vs. T 60 4.7% vs. T 90 5.2% p=NS Bonaca et al N Engl J Med 2015;372:1791-800

Primary Endpoint: On-Treatment Analysis Bonaca et al Circulation 2015;Abstract and JAMA Cardiol 2016;1:425-32

Bleeding Bonaca et al N Engl J Med 2015;372:1791-800

Events Prevented and Caused Events Prevented and Caused for 1000 Patients Initiated on Ticagrelor 60 mg BID and Followed for 3 Years Bonaca et al J Am Coll Cardiol 2017;70:1368-75

Primary Endpoint: CV Death/MI/Stroke Patients Withdrawn from ADP Receptor Inhibition ≤30 Days from Randomization by Treatment Bonaca et al Eur Heart J 2016;37:1133-42

Primary Endpoint: CV Death/MI/Stroke 27% RRR 14% RRR  RRR P-interaction 0.0097 Greater benefit in continuation of ADPri therapy without interruption after MI vs. re-initiating in patients who have remained stable for an extended period Bonaca et al Eur Heart J 2016;37:1133-42

Efficacy and Safety of Ticagrelor: European Label Subgroup* PEGASUS-TIMI 54 randomized 21,162 patients →10,779 patients were ≤2 years from qualifying MI or ≤1 year from prior ADP receptor inhibitor treatment* 10 Ticagrelor 60 mg bid, EU label (373/5388) Placebo, EU label (463/5391) 9.56% 8 7.85% HR 0.80 (0.70–0.91); p=0.001 6 CV Death: Placebo 3.6% vs. Ticagrelor 2.6% HR 0.71 (0.56-0.90); p=0.004 All-cause Death: Placebo 5.4% vs. Ticagrelor 4.4% HR 0.80 (0.67-0.96); p=0.018 CV Death/MI/Stroke (%) 4 2 180 360 540 720 900 1080 Number at risk (EU*): Placebo Ticagrelor 60 mg BID Days from Randomization 5391 5388 5246 5280 5138 5187 4914 4999 4380 4436 3177 3253 1485 1507 Dellborg et al Eur Heart J 2017;Abstract P3670

Ticagrelor* vs. Placebo Summary of PEGASUS Trial and Subgroup Primary Efficacy Analyses with Ticagrelor 60 mg BID* Ticagrelor* vs. Placebo 1 Bonaca et al N Engl J Med 2015;372:1791-800; 2 Bonaca et al Eur Heart J 2016;37:1133-42; 3 Dellborg et al Eur Heart J 2017;Abstract P3670

PEGASUS* in Context: Statin, ACE Inhibition, Anticoagulation (Lipid-lowering by 1 mmol/L)1,2 Ramipril (ACE Inhibition; HOPE)3 Rivaroxaban 2.5 mg BID + ASA (COMPASS)4 Ticagrelor 60 mg BID + ASA (PEGASUS)5* MACE 21% 22% 24% 25% Death 9% 16% 18% 20% Stroke 15% 32% 42% 36% MI 14% 1CTT Collaboration Lancet 2015;385:1397-1405; 2Collins et al Lancet 2016;388:2532-36; 3HOPE Investigators N Engl J Med 2000;342:145-53; 4Eikelboom et al N Engl J Med 2017;377:1319-30; 5 Bonaca et al Eur Heart J 2016;37:1133-42 * Post-hoc subgroup analyses vs. placebo (n=6258); patients randomized to ticagrelor 60 mg BID (n=6258) ≤30 days from prior ADP receptor inhibitor treatment

Consistency of Benefit With vs. Without Diabetes Bonaca et al J Am Coll Cardiol 2016;67:2719-28 n=1,143 (5%) n=20,017 With vs. Without PAD n=6,806 (32%) Ticagrelor in DM requiring pharmacological therapy (n=5,960) ARR 1.9% 3-yr NNT=53 * Ticagrelor 60 mg BID CV Death: 3.9% vs. 5% p=0.05 All-Cause Death: 8.2%* vs. 14% p=0.007 n=14,355 Bhatt et al J Am Coll Cardiol 2016;67:2732-40

Consistency of Benefit Renal Dysfunction Bonaca et al Circulation 2016;in press n=213 85% ischemic 3-Yr Risk of Stroke n=4,849 (23%) n=20,898 Reduced severity of stroke with Ticagrelor 60 mg BID (p=0.05) No increase in ICH or fatal bleeding Magnani et al Eur Heart J 2016;37:400-8

Consistency of Benefit Multivessel Disease (MVD) 12,558 patients (59.4%) had MVD Coronary Death: Ticagrelor 60 mg HR 0.64 (0.45-0.89) Ticagrelor 90 mg HR 0.64 (0.46-0.90) * * Coronary death, MI, or stent thrombosis Bansilal et al J Am Coll Cardiol 2018;71:489-96

Primary Endpoint – CV Death, MI, or Stroke Extended Aspirin Risk Ratio DAPT Alone (95% CI) Study Events Total Events Total CHARISMA 125 1903 162 1943 PRODIGY 63 732 69 733 ARCTIC-Int’n 3 156 4 167 DAPT 59 1805 108 1771 DES-LATE 56 1512 66 1551 PEGASUS 980 14095 578 7067 TOTAL 1286 20203 987 13232 6.4% 7.5% 0.77 (0.61 - 0.98) 0.91 (0.65 - 1.28) 0.79 (0.18 - 3.51) 0.52 (0.38 - 0.72) 0.85 (0.60 - 1.21) 0.84 (0.76 - 0.94) 0.78 (0.67 - 0.90) P = 0.001 0.2 0.5 1 2 Extended DAPT Better Aspirin Alone Better More Major Bleeding but NO increase in Fatal Bleeding, ICH, non-CV or all-cause death Pts that presented with, or had a history of, a prior MI Udell et al Eur Heart J 2016;37:390-99 and Can J Cardiol 2015;31:S3

Mortality Benefit of Prolonged Dual Antiplatelet Therapy Patients with Prior Myocardial Infarction All-Cause Mortality 0.84 (0.62-1.13) 0.92 (0.78-1.09) 0.87 (0.50-1.50) 0.89 (0.76-1.04) 0.89 (0.81-0.99) P=0.037 Trial CHARISMA1 TRA2P-TIMI 502 DAPT3 PEGASUS-TIMI 544 TOTAL Subgroup MI (n=4,441) MI (n=17,779) MI (n=3,576) 60 mg BID (n=14,112) CV Mortality 0.82 (0.57-1.18) 0.84 (0.68-1.05) 0.67 (0.31-1.44) 0.83 (0.68-1.01) 0.81 (0.69-0.95) P=0.010 Aspirin + Clopidogrel + Prasugrel 135/2160=(6.3%) Aspirin + Clopidogrel + Ticagrelor 202/2160 (9.4%) 1 Bhatt et al J Am Coll Cardiol 2007;49:1982-8; 2 Scirica et al Lancet 2012;380:1317-24; 3 Yeh et al J Am Coll Cardiol 2015;65:2211-21; 4 Bonaca et al N Engl J Med 2015;372:1791-800

Fitchett et al Can J Cardiol 2016;32:S15-34

Recommendations for Individualizing Duration of DAPT After ACS At least 1 year unless very high bleeding risk (e.g., recent GI bleed, prior ICH, concomitant anticoagulant) or significant bleeding in first year Minimum 1-month for BMS or 3 months for 2nd generation DES If increased risk of bleeding (e.g. age>75, prior stroke/TIA, weight<60kg), 1 year is sufficient All others extend beyond 1 year, particularly if additional atherothrombotic risk features (e.g., previous MI, multivessel disease, diabetes, PAD, etc.) or high risk angiographic features (e.g., left main or bifurcation stenting) Ticagrelor 60 mg BID (or clopidogrel 75 mg daily) recommended >1 year Ongoing (at least annual) assessment of ischemic and bleeding risk Bagai et al Circulation 2016;133:2094-98

Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

Mehta et al Can J Cardiol 2018; doi: 10.1016/j.cjca.2017.12.012

Would you recommend extending DAPT >1 year post-MI? 66 year old man, 78 kg NSTEMI 1 year ago 80% proximal LAD, multiple 30-40% proximal and mid Circumflex, 30-50% proximal, mid, and distal RCA stenoses; preserved LV function 2nd generation DES placed in the proximal LAD Discharged on ASA and ticagrelor 90 mg BID Diabetes mellitus (Type 2) - On metformin 1 g BID, empagliflozin 10 mg daily → A1C 6.9% Dyslipidemia - On atorvastatin 80 mg/day and ezetimibe 10 mg/day → LDL-C 1.6 mmol/L Moderate renal dysfunction Creatinine 150 mol/L; eGFR 47 ml/min/1.73m2 (by Cockcroft-Gault),43 ml/min/1.73m2 (by MDRD) Ramipril 2.5 mg daily at discharge titrated up by family MD to 5 mg/day (for vascular protection) Would you recommend extending DAPT >1 year post-MI? Yes No →Ticagrelor 60 mg BID