Antiplatelet Therapy in STEMI The Case for Prasugrel

Antiplatelet Therapy in STEMI: The Case for Prasugrel Paul A. Gurbel, M. D. Director, Sinai Center for Thrombosis Research Professor of Medicine Johns Hopkins University School of Medicine Adjunct Professor of Medicine Duke University School of Medicine

Paul A. Gurbel, MD • Consulting: Astra Zeneca, Boehringer Ingelheim Gmb. H, Daiichi Sankyo, Eli Lilly and Company, Merck and Company Inc. , CSL, Janssen. • Grant Support: Astra Zeneca, Daiichi Sankyo, Eli Lilly and Company, CSL, Haemoscope Corporation, Harvard Clinical Research Institute, Duke Clinical Research Institute, National Institute of Health, CORAMED.

400 Loading Dose 300 Clopidogrel (600/75) 200 Prasugrel (60/10) 100 0 0 4 8 12 16 20 Active Metabolite (ng/m. L) Clopidogrel vs. Prasugrel- Pharmacology 100 80 60 40 20 0 0 24 Time from Dose (h) Maximum Platelet Aggregation (%) 2 Time from Dose (h) Maintenance Dose Loading Dose 100 Maintenance Dose 80 60 40 20 10 h 0. 5 1 2 4 DAY 1 Wallentin L et al. Eur Heart J 2008; 29: 21 -30 24 ± 4 Predose 14± 3 29± 3 4

Prasugrel vs. Clopidogrel LD During STEMI: ETAMI Trial VASP-PRI (%) - 62 STEMI-p. PCI pts randomized to 60 mg prasugrel vs. 600 mg clopidogrel in ambulance or ED - VASP-P assay VASP-PRI (%) Baseline Clopidogrel 4 h Prasugrel Zymer U et al. J Am Coll Cardiol Inv 2015; 8: 147 -154 37% 62% 53% 71% 50% 2 h Clopidogrel Prasugrel

Prasugrel vs. Ticagrelor LD During STEMI Platelet Reactivity by Verify. Now P 2 Y 12 assay Patients With HPR (>240 PRU) *p 0. 01 vs Ticagrelor †p 0. 01 vs baseline, ‡p 0. 01 vs 2 h. G Parodi et al. J Am Coll Cardiol 2013; 61: 1601– 6

TRITON-TIMI 38 STEMI All ACS/PCI patients N=13608 UA/NSTEMI patients N=10074 STEMI and LBBB patients N=3534 Primary PCI Secondary PCI N=2438 (69%) N=1094 (31%)* Clopidogrel Prasugrel N=1235 N=1203 N=530 N=564 * 2 patients were missing data for primary or secondary Montalescot G et al. Lancet. 2009; 373: 723 -31

Clopidogrel vs. Prasugrel TRITON-TIMI 38: STEMI/LBBB, n=3, 534 (26%) CV death, non-fatal MI, or non-fatal stroke Def. or prob. stent thrombosis Ticagrelor HR 0. 74 (0. 55– 1. 00) p=0. 05 2. 8% vs. 1. 6% HR=0. 49(. 28–. 84) HR=0· 68(· 54–· 87) HR=. 58(. 36–. 93) HR=0· 79(· 65–· 97) Non-CABG related TIMI major bleeding CV death: CLP PRAS 3. 4% 2. 4% HR 0. 74 (0. 50 -1. 09) CLP TIG 5. 5% 4. 5% HR 0. 83 (0. 67– 1. 02) Montalescot G et al. Lancet. 2009; 373: 723 -31 p= 0. 13 p= 0. 07 HR=. 74(. 39– 1. 38) HR=1· 11(· 70– 1· 77)

Overall PLATO data shows CV mortality benefit with ticagrelor (40% STEMI). A lot has been said about it. There is a trend toward mortality benefit with prasugrel in STEMI. If STEMI population were larger in TRITON, would p have reached significance ?

Efficacy Endpoints at 30 days Clopidogrel Proportion of population (%) Prasugrel 10 p= 0. 004 8 p= 0. 02 p= 0. 01 6 4 p= 0. 04 p= 0. 13 2 p= 0. 008 0 All Death MI UTVR Stent CV Death/ Thrombosis* MI MI/UTVR MI/Stroke * ARC def/probable Montalescot G et al. Lancet. 2009; 373: 723 -31

Efficacy End Points over 15 months Clopidogrel Proportion of population (%) Prasugrel 14 p= 0. 007 12 10 p= 0. 03 p= 0. 02 8 6 p= 0. 11 p= 0. 09 4 p= 0. 02 2 0 All Death MI UTVR Stent CV Death/ Thrombosis* MI MI/UTVR MI/Stroke * ARC def/probable Montalescot G et al. Lancet. 2009; 373: 723 -31

TIMI Major Non-CABG Bleeding Clopidogrel Prasugrel 2. 5 Proportion of patients (%) 2. 4 2. 0 2. 1 1. 5 1. 0 0. 5 HR=1. 11 (0. 70– 1. 77) NNH=333 Age-adjusted HR=1. 19 (0. 75 -1. 89) 0 0 100 200 Time (Days) Montalescot G et al. Lancet. 2009; 373: 723 -31 300 400 p=0. 65

TIMI Life-Threatening Non-CABG Bleeding Life threatening bleeding (%) Clopidogrel Prasugrel p=0. 75 HR=1. 11 (0. 59– 2. 10) NNH=500 Age-adjusted HR=1. 20 (0. 63 -2. 26) Time (Days) Montalescot G et al. Lancet. 2009; 373: 723 -31

Bleeding Events Over 15 Months p=NS 7 p=NS Proportion of population (%) Clopidogrel 6 Prasugrel 5. 1 4. 7 5 4 5. 9 4. 8 p=NS 3 2. 1 2. 4 2. 7 2. 8 p=NS 2 1. 1 1. 3 1 p=NS 0. 3 0. 2 0 Major non-CABG Life threatening Montalescot G et al. Lancet. 2009; 373: 723 -31 Intra-cranial haemorrhage Minor non-CABG Major or minor non-CABG/non-CABG

Net Clinical Benefit at 15 Months p=0. 02 NNT=42 Proportion of population (%) 18 16 14. 7 14. 6 14 p=0. 04 NNT=45 12. 2 12. 5 12 10 8 6 4 2 0 Death / non-fatal MI / non-fatal stroke or major non-CABG bleeding Montalescot G et al. Lancet. 2009; 373: 723 -31 Death / MI /stroke/ major bleeding (CABG and non-CABG) Clopidogrel Prasugrel

North American Paradox Effect of aspirin dose with ticagrelor Mahaffey KW et al. Circulation. 2011; 124: 544 -554

Ten reasons to use Prasugrel over Ticagrelor for STEMI 1) Works well in North Americans 2) No issue with aspirin dose 3) Once a day dosing vs. BID 4) No greater bleeding 5) Dyspnea is a problem with ticagrelor (12. 6%) 6) Ticagrelor is associated with bradycardia– take your chances with inferior STEMI 7) ? More powerful effect on stent thrombosis 8) No issue with dig levels 9) No issues with gout exacerbation 10) No issue with strong CYP 3 A inducers/inhibitors