Antiplatelet Therapy For STEMI: The Case for Cangrelor Gary L. Schaer, MD FACC, FAHA, FSCAI Professor of Medicine (Interventional Cardiology) Director, Cardiology Research Rush University Medical Center Chicago IL

Gary L. Schaer MD Consultant; Advisory Board The Medicines Company Disclosure Statement of Financial Interest   Consultant; Advisory Board The Medicines Company AstraZeneca

Cangrelor Pharmacology FDA approved 6/2015 Indication: as an adjunct to PCI for reducing the risk of periprocedural MI, repeat coronary revascularization, and stent thrombosis in patients not treated with a P2Y12 inhibitor or GP IIb/IIIa inhibitor Immediate onset: IV, direct-acting Consistent effect: Not influenced by age, gender, renal function, or genetic variations Rapid offset: Reversible; half-life of 3-6 min; clearance independent of organ function; return of platelet function within 1h

Cangrelor Pharmacokinetic and Pharmacodynamic Profile

Transition to Oral P2Y12 Inhibitors

Champion Phoenix Pivotal Phase 3 trial of 11,145 patients undergoing urgent or elective PCI Randomized (1:1), double blind, double dummy trial Comparator: clopidogrel (300-600mg) according to standard of care Key inclusion: Stable angina, NSTE-ACS or STEMI Key exclusion: Treatment with P2Y12 inhibitor within 7 days Using or plan to use a GPIIb/IIIa inhibitor Primary efficacy endpoint: 48h composite (death, MI, ischemia-driven revascularization, stent thrombosis) Primary safety endpoint: severe bleeding at 48h Bhatt DL et al. NEJM 2013: 368;1303

C-Phoenix – Study Design 2/3 rec’d clopdigorel at the start of PCI, 1/3 at the end of PCI. Median duration of PCI was 22 min. Infusion of cangrelor was for at least 2 hours but could be given up to 4 hours. Median duration of infusion was 122 min. Clopidogrel dose** - patients – 4064 (73%) received 600 mg – 1427 (26%) received 300 mg • Clopidogrel dose* - sites – 6 sites dosed only 300 mg – 118 sites dosed only 600 mg – 27 sites dosed both United States: 99% of patients received 600 mg Clopidogrel timing*** – 3442 (62%) before start of PCI – Median time: -5 minutes – 1997 (36%) after start of PCI – Median time: 20 minutes

C-Phoenix: Baseline Characteristics

C-Phoenix: Primary Efficacy Endpoint (Death, MI, IDR, or ST at 48h) Event Rate (%) OR 0.78 (95% CI, 0.66-0.93); P = 0.005.(Prespecified logistic-regression analysis) (0.8% vs. 1.4%; odds ratio, 0.62; 95% CI, 0.43 to 0.90; P = 0.01) Intraprocedural stent thrombosis: lower in cangrelor group (0.6% vs. 1.0%; odds ratio, 0.65; 95% CI, 0.42 to 0.99; P = 0.04). Use of bailout GPIIb/IIIa inhibitor was 2.3% vs. 3.5%. OR 0.65; 95% CI, 0.52 to 0.82; P<0.001) Hours Since Randomization 2h Bhatt DL et al. NEJM 2013: 368;1303

C-Phoenix: Stent Thrombosis (Key Secondary Endpoint, ARC def) Event Rate (%) OR 0.62 (95% CI, 0.43-0.90); P = 0.01 (0.8% vs. 1.4%; odds ratio, 0.62; 95% CI, 0.43 to 0.90; P = 0.01) Intraprocedural stent thrombosis: lower in cangrelor group (0.6% vs. 1.0%; odds ratio, 0.65; 95% CI, 0.42 to 0.99; P = 0.04). Use of bailout GPIIb/IIIa inhibitor was 2.3% vs. 3.5%. OR 0.65; 95% CI, 0.52 to 0.82; P<0.001) Hours Since Randomization 2h Bhatt DL et al. NEJM 2013: 368;1303

C-Phoenix: Bleeding Events End Point Cangrelor (5529) Clopidogrel (5527) Odds Ratio (95% CI) P Value GUSTO defined bleeding Primary safety endpoint (severe or life threatening) 9 (0.2%) 6 (0.1%) 1.6 (0.53-4.22) 0.44 Moderate bleeding 22 (0.4%) 13 (0.2%) 1.69 (0.85-3.37) 0.13 Severe or moderate 31 (0.6%) 19 (0.3%) 1.63 (0.92-2.90) 0.09 Any blood transfusion 25 (0.5%) 16 (0.3%) 1.56 (0.83-2.93) 0.16 Efficacy and safety: net adverse clinical events Death, MI, IDR, ST or GUSTO severe bleeding 264 (4.8%) 327 (6%) 0.80 (0.68-0.94) 0.008 SAY SOMETHING ABOUT OTHER SAFETY ISSUES – 1% OVERALL INCIDENCE OF DYSPNEA DURING THE INFUSION – MOST OF IT MILD. Bhatt DL et al. NEJM 2013: 368;1303

C-Phoenix: Outcome by Clinical Presentation SAY SOMETHING ABOUT OTHER SAFETY ISSUES – 1% OVERALL INCIDENCE OF DYSPNEA DURING THE INFUSION – MOST OF IT MILD. Bhatt DL et al. NEJM 2013: 368;1303

Efficacy Outcomes at 48h by Treatment Group and Clinical Presentation (mITT Population) SAY SOMETHING ABOUT OTHER SAFETY ISSUES – 1% OVERALL INCIDENCE OF DYSPNEA DURING THE INFUSION – MOST OF IT MILD. Abtan J et al. JACC Intv 2016:9;1905

Cost Cangrelor vials contain 50 mg at $749 Dose: 30mcg/kg bolus x 4mcg/kg/min x 120 min Up to 100 kg = 1 vial @ $749 >100 kg = 2 vials @ $1,498 >200 kg = 3 vial @ $2,100

EKG ACS Management Pathway STEMI Pathway NSTE-ACS Pathway Patient presents with symptoms of ACS EKG No ST-elevation ST-elevation ACS Management Pathway NSTE-ACS Pathway Aspirin 325 mg po or chewed + UFH (not LMWH) DO NOT GIVE TICAGRELOR OR CLOPIDOGREL BEFORE CORONARY ANGIOGRAPHY STEMI Pathway Aspirin 325 mg po or chewed Emergency transfer to cath lab DO NOT GIVE TICAGRELOR OR CLOPIDOGREL BEFORE CORONARY ANGIOGRAPHY Ischemia-Guided Strategy (low risk) Low risk TIMI score (0-1), GRACE (<109) Low risk trop neg female patients Patient or clinician preference in absence of high-risk features Stress test (if + => Cath) Early Invasive Strategy (intermediate to high risk) DO NOT GIVE TICAGRELOR OR CLOPIDOGREL BEFORE CORONARY ANGIOGRAPHY Unfractionated heparin and anti-ischemic therapy Immediate Invasive Cath <2h Refractory or recurrent angina despite Med Rx Severe HF, unstable hemodynamics, malignant arrhythmias Early Invasive Cath <24h No “immediate invasive” features GRACE score >140 Temporal change in Trop New ST-seg depression Delayed Invasive Cath 25-72hs GFR <60 mL/min/1.73m2 EF <40% Early post-MI angina PCI within 6mo or CABG GRACE 109-140 or TIMI >2 Coronary Angiography -> PCI At start of PCI consider cangrelor (bolus + 2hr infusion) + anticoagulant (bivalirudin or UFH) Transition to oral P2Y12 therapy (if surgery not planned prior to discharge): ticagrelor 180 (begin during cangrelor infusion), or clopidogrel 600 mg (must begin immediately after cangrelor d/c).

CANGRELOR FOR STEMI Cost $$$$ Advantages Disadvantages 20%  MI @ 48h 62%  stent thrombosis  Pre-load oral P2Y12   delay if CABG needed Cost $$$$ Reduces need for provisional GPIIbIIIa Excellent safety profile Advantages Disadvantages