Tim Henry, MD Director, Division of Cardiology Professor, Department of Medicine Cedars-Sinai Heart Institute

Implications of Pre-loading on Patients Undergoing Coronary Angiography Angiography Define coronary anatomy CABG PCI Medical therapy In 21: ~397, CABG procedures, ~954, PCI procedures, and ~diagnostic 1,29, angiograms were performed in the US Heart Disease and Stroke Statistics--214 Update. Circulation. 213;129:e28-e292.

Clopidogrel Pre-treatment in PCI: Presenting feature Elective PCI NSTE ACS STEMI Loading dose 3 mg 6-9 mg All-cause Mortality No. of Events No Pretreatment Pretreatment 2 5 14 63 3 2 55 28 79 6 No. of Patients No Pretreatment Pretreatment 82 2366 197 3299 984 816 248 111 3338 987 OR (95% CI) 1.12 (.17-7.27).93 (.63-1.36).5 (.26-.96).79 (.54-1.17).62 (.15-2.61) Favors Pretreatment Favors No Pretreatment P for Heterogeneity Trend x 2 2.66.2.1.75 Presenting feature Elective PCI NSTE ACS STEMI Loading dose 3 mg 6-9 mg MACE No. of Events No Pretreatment Pretreatment 53 329 39 363 58 5 414 7 472 62 No. of Patients No Pretreatment Pretreatment 82 2366 197 3299 984 816 248 111 3338 987 OR (95% CI) 1.5 (.7-1.57).78 (.66-.91).54 (.36-.81).74 (.63-.87).93 (.64-1.36).1 1. 1 Odds Ratio (95% CI) Favors Pretreatment Favors No Pretreatment.1 1. 1 Odds Ratio (95% CI) Bellemain-Appaix A et al. JAM A 212;38:257-16. P for Heterogeneity Trend x 2 5.1.8 1.18.28

Timing of Clopidogrel Loading in US Practice EMR Review from 112 US hospitals between 1/26 and 3/28 (n=6,253) 1 8 Before PCI (up to 12 hours prior to PCI) At PCI (in the cath lab) After PCI (up to 6 hours after PCI) Percent 6 4 29 59 43 41 3 33 37 2 12 16 Elective (n=3922) NSTE-ACS (n=972) STEMI (n=1359) Dean BB et al. Am J Health-Syst Pharm 21;67:143-7

Cangrelor HN S 4Na + N N O O O P Cl Cl O P O O O P O O HO O N OH N S CF 3

Cangrelor (ng/ml) Impedance (Ohms) 8 6 4 2 16 14 12 1 8 6 4 Cangrelor: Pharmacokinetics and Platelet Inhibition Pharmacokinetics Group A: 15 mcg/kg bolus + 2 mcg/kg/min (n=9) Group B: 3 mcg/kg bolus + 4 mcg/kg/min (n=9) - Clinical dose 2 4 6 8 1 12 14 16 Time (min) Whole Blood Impedance Aggregometry Group A Group B Platelet recovery time ~6 minutes 2 2 4 6 8 1 12 14 16 Time (min) Akers WS et al. J Clin Pharm. 21;5:27-35

Cangrelor One obvious huge advantage PCI pts unable to take oral meds (sedation, intubation, vomiting, shock, etc.)

Cangrelor But what about routine cangrelor use? It may depend if you routinely pre-load DAPT

CHAMPION PHOENIX Study Design OR Placebo 3 oral (right before PCI or right after, per physician) Cangrelor 2 bolus & infusion (3 ug/kg; 4 ug/kg/min) Clopidogrel 6 mg oral Rand PCI ~3 Placebo 2 bolus & infusion Placebo oral OR Clopidogrel 3 (6 mg or 3 mg oral, per physician) 1 2 to 4 hours 1 Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis. Double blind study medication was administered as soon as possible following randomization. 2 Study drug infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of the treating physician. At the end of the infusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy. 3 Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time of patient randomization, a clopidogrel loading dose of 6 mg or 3 mg was specified by the investigator. MITT = modified intent-to-treat.

Phoenix: Death, MI, IDR, Stent Thrombosis within 48 Hrs (n=1,942) Event Rate (%) 8 7 6 5 4 3 2 1 Cangrelor (n=5,472) Clopidogrel (n=5,47) 6 12 18 24 3 36 42 48 Hours from Randomization P=.6 NNT = 84 Patient at Risk Cangrelor: 5472 5233 5229 5225 5223 5221 522 5217 5213 Clopidogrel: 547 5162 5159 5155 5152 5151 5151 5147 5147 5.9% 4.7%

Death, MI, IDR or ST: Landmark analysis from Phoenix Event Rate (%) Patients at risk: Cangrelor: Clopidogrel: 6 5 4 3 2 1 5.4% 4.1% HR (95% CI):.76 (.64,.9) p=.2 Cangrelor Clopidogrel HR (95% CI): 1.16 (.7, 1.9) p=.57 1 2 6 12 18 24 3 36 42 48 Hours from Randomization 5472 547 5295 5214 5249 5177 End of cangrelor infusion 6 mg clopidogrel given (or placebo) 5233 5162 5229 5159 5225 5155 5223 5152 5221 5151 522 5151 5217 5147.7%.6% 5212 5146

Efficacy Outcomes w/i 2 Hours Champion PHOENIX (mitt) Primary endpoint Cangrelor N=547 Clopidogrel N=5469 OR (95% CI) P value Death/MI/IDR/ST 224 (4.1%) 293 (5.4%).75 (.63,.9).2 Secondary endpoints Stent thrombosis 37 (.7%) 7 (1.3%).53 (.35,.78).1 - IPST 35 (.6%) 54 (1.%).65 (.42,.99).4 - ARC-ST 2 (.%) 17 (.3%).12 (.3,.51).1 MI 192 (3.5%) 243 (4.4%).78 (.64,.95).1 - MB 1x ULN 5 (.9%) 78 (1.4%).64 (.45,.91).1 - Q-MI 9 (.2%) 13 (.2%).69 (.3, 1.62).39 IDR 2 (.%) 12 (.2%).17 (.4,.74).8 Death 7 (.1%) 6 (.1%) 1.17 (.39, 3.47).78

Death, MI, IDR, ST at 48 Hours.2 Cangrelor Better 1. Clopidogrel Better 5.

Phoenix: Stent Thrombosis within 48 Hours (n=1,942) Event Rate (%) 2. 1.5 1..5. Cangrelor (n=5,472) Clopidogrel (n=5,47) OR [95%CI] =.62 (.43,.9) P=.1 6 12 18 24 3 36 42 48 Hours from Randomization Patient at Risk Cangrelor: 5472 5426 5421 5419 5419 5418 5417 5416 5414 Clopidogrel: 547 5392 5389 5388 5386 5385 5385 5383 5383 1.4%.8%

Stent Thrombosis (%) Landmark analysis from Phoenix 2. 1.8 1.6 1.4 1.2 1..8.6.4.2 Patients at risk: Cangrelor: Clopidogrel: Cangrelor Clopidogrel p=.18. 1 2 6 12 18 24 3 36 42 48 Hours from Randomization 5472 547 5435 5413 5432 5396 1.3%.7% End of cangrelor infusion 5426 5392 HR [95%CI] =.53 [.35,.79] p=.2 6 mg clopidogrel or placebo given 5421 5389 5419 5388 5419 5386 5418 5385 5417 5385 5416 5383 5413 5382.2%.1%

Comparative Efficacy vs. Safety Outcomes: Champion PHOENIX Event Rate (%) Patients at risk: Cangrelor Efficacy Clopidogrel Efficacy 7. 6. 5. 4. 3. 2. 1.. Clopidogrel Cangrelor Cangrelor GUSTO Severe Bleeding.16% Clopidogrel.11% 6 12 18 24 3 36 42 48 Hours 5472 547 Death/MI/IDR/ST 5233 5162 5229 5159 5225 5155 5223 5152 5221 5151 522 5151 5217 5147 5213 5147 5.9% 4.7% Cangrelor Safety Clopidogrel Safety 5529 5527 5516 5511 5516 5511 5512 557 5511 555 559 552 558 552 555 55 551 55

ADP-induced platelet aggregation (%) 1 9 8 7 6 5 4 3 2 1 P=.2 Clopidogrel Prasugrel P<.1 P<.1 ADP aggregarton Clop n=49 (%) Pras n=3 (%) P value Baseline 79 ± 1 76 ± 9.2 At PPCI 74± 12 63± 18.2 At 72 hours 47± 18 33± 16.2 Suboptimal IPA (<7%) at time of primary PCI: Clopidogrel: 71% Prasugrel: 53% Admission PPCI 72 hours Beigel R et al. Am J Cardiol 213;112:1551-56

45 % (,) % (,) % (,5) % (,5) 4 35 PRU 3 48% (,72) 12% (,54) Prasugrel Ticagrelor 85% 76% (65,94) (61,89) One hour DBT No intra-procedural effect 9% 84% (78,97) (72,93) All P=NS, except at day 5 (P<.5) 83% 95% (62,97) (92,97) 25 23 28 2 15 Delayed peak effect 1 5 Hour 1 Hour 2 Hours 6 Hours 24 Hours Day 5

PK/PD nalyses performed before and 3 min, 1, 2, 4, 8, and 24 hrs after 3 randomized ticagrelor LD regimens (18 mg, 27 mg, 36 mg) in PPCI (N=52) Franchi F et al. JACC CV Int 215;8:1457 67

3. Clopidogrel (n=5,648) Ticagrelor (n=5,636) 2.5 1.9% Def ST (%) 2. Timing of ST HR [95%CI] favoring ticagrelor Acute ( 24 hours).94 [.43 2.5] 1.5 Subacute (1-3 days).6 [.39.93] 1.4% 1. Late (3 days-1 year) HR [95%CI] =.67 [.5-.91] P=.9.5. 3 6 12 18 24 3.48 [.24.96] No reduction in acute stent thrombosis! 36 irculation. 213;128:155-65

1,84 pts not randomized

Uses for Cangrelor Across the Spectrum of CAD

(, ), p All-cause mortality day 7-3 (all pts) Study Pre-treat Randomized controlled trials ACCOAST 8/237 CREDO /9 CURE* 359/6259 Subtotal 367/6196 Odds Ratio (95% CI) No pre-treat 1/1996 4/915 39/633 44/9214 Observational analysis of randomized controlled trial ACUITY 24/5753 64/177 Observational studies Assali et al 2/235 Feldman et al 2/467 Chan et al 19/4477 Subtotal 23/5179 Total 594/2128 *Follow-up at 9 months Follow-up at 1 year 3/64 3/574 3/332 9/97 477/11954.1.1 Pre-treatment better 1 Weight (%) Odds Ratio (95% CI) 12 value (%) (P value) 3.6.4 62.8 66.8.78 (.31 to 1.99) 5%, P=.35.11 (.1 to 2.9).92 (.8 to 1.7).88 (.9 to 2.61) 29.1.98 (.74 to 1.3) 11.9 12.2 26.2 5.3 1..17 (.3.82 (.14.47 (.14.42 (.18.9 (.75 to 1.7) %, P=.48 to 4.92) to 1.59) to 1.2) to 1.7) 1%, P=.35 1 No pre-treatment better Bellemain-Appaix A et al. BMJ 214;349:g6269

(, ), p All-cause mortality day 7-3 (PCI pts 55%) Study Pre-treat Randomized controlled trials ACCOAST 4/1394 CREDO /9 PCI-CURE 14/1313 Subtotal 18/361 Odds Ratio (95% CI) No pre-treat 4/1376 4/915 13/1345 21/3636 Observational analysis of randomized controlled trial ACUITY-PCI 15/3511 49/1515 Observational studies Assali et al 2/235 Feldman et al 2/467 Chan et al 19/4477 Subtotal 23/5179 Total 146/123 *Follow-up at 9 months Follow-up at 1 year 3/64 3/574 3/332 9/97 79/6121.1.1 Pre-treatment better 1 Weight (%) Odds Ratio (95% CI) 12 value (%) (P value) 5.8 1.3 17.8 24.9.98 (.25 to 3.95) 13%, P=.32.11 (.1 to 2.9) 1.1 (.52 to 2.36).92 (.43 to 1.98) 6.9.92 (.65 to 1.3) 3.4 3.5 7.3 14.3 1..17 (.3.82 (.14.47 (.14.42 (.18.83 (.59 to 1.7) %, P=.48 to 4.92) to 1.59) to 1.2) to 1.17) 6%, P=.38 1 No pre-treatment better Bellemain-Appaix A et al. BM J 214;349:g6269

(, ), p Ischemic MACE* day 7-3 (all pts) Study Pre-treat Randomized controlled trials ACCOAST 23/237 CREDO 61/9 CURE* 275/6259 Subtotal 539/9196 Odds Ratio (95% CI) No pre-treat 195/1996 76/915 346/633 617/9214 Observational analysis of randomized controlled trial ACUITY 411/5753 267/334 Observational studies Assali et al 13/235 Feldman et al 39/467 Chan et al 292/4477 Subtotal 244/5179 Total 1294/2128 * D, MI, D, MI, D, MI, D, MI, 9/64 41/574 34/332 84/97 968/13488 UTVR for all except: CVA for CURE UTVR, CVA for Feldman UTVR, CVA, bail-out GPII for ACCOAST.1 Weight (%) 19.9 11.8 23.3 55. 1.2 (.83.8 (.57.79 (.67.87 (.73 23.4.88 (.75 to 1.3) 2.6 8.2 1.8 21.6 1..1 Pre-treatment better 1 Odds Ratio (95% CI).36 (.15 1.18 (.75.61 (.42.69 (.38.84 (.72 to 1.26) 48%, P=.15 to 1.14) to.93) to 1.4) to.88) 74%, P=.2 to 1.87) to.89) to 1.26) to.98) 52%, P=.5 1 No pre-treatment better Bellemain-Appaix A et al. BMJ 214;349:g6269 12 value (%) (P value)

(, ), p Ischemic MACE* day 7-3 (PCI pts 55%) Study Pre-treat Randomized controlled trials ACCOAST 183/1397 CREDO 61/9 PCI-CURE 59/1313 Subtotal 33/361 Odds Ratio (95% CI) No pre-treat 18/1376 76/915 86/1345 342/3636 Observational analysis of randomized controlled trial ACUITY-PCI 29/3511 13/1528 Observational studies Assali et al 13/235 Feldman et al 39/467 Chan et al 292/4477 Subtotal 344/5179 Total 937/123 * D, MI, D, MI, D, MI, D, MI, 9/64 41/574 34/332 84/97 556/6134 UTVR for all except: CVA for CURE UTVR, CVA for Feldman UTVR, CVA, bail-out GPII for ACCOAST.1.1 Pre-treatment better 1 Weight (%) Odds Ratio (95% CI) 12 value (%) (P value) 2.7 14.7 15.1 5.4.98 (.25 to 3.95).11 (.1 to 2.9) 1.1 (.52 to 2.36).92 (.43 to 1.98) 44%, P=.17 2.9.92 (.65 to 1.3) 9.7 13.9 14.7 38.3 1..36 (.15 1.18 (.75.61 (.42.69 (.38.83 (.69 to.88) 74%, P=.2 to 1.87) to.89) to 1.26) to 1.1) 55%, P=.4 1 No pre-treatment better Bellemain-Appaix A et al. BMJ 214;349:g6269

(, ), p Major bleeding day 7-3 (all pts) Study Pre-treat Randomized controlled trials ACCOAST* 52/237 CREDO* 5/153 CURE 125/6259 Subtotal 227/9349 Odds Ratio (95% CI) No pre-treat 27/1996 38/163 95/633 16/9362 Observational analysis of randomized controlled trial ACUITY 258/5753 128/334 Observational studies Assali et al 26/235 Feldman et al 4/467 Chan et al 36/4477 Subtotal 66/5179 Total 551/2128 *CABG) and non-cabg Non-CABG 7/64 7/574 3/332 17/97 35/13636.1 Weight (%) 9.5 11.3 28.9 49.7 1.91 (1.2 1.34 (.87 1.33 (1.2 1.43 (1.16 44.7 1.16 (.94 to 1.45) 2.7 1.4 1.5 5.5 1..1 Pre-treatment better 1 Odds Ratio (95% CI) 1.1 (.42.7 (.2.89 (.27.89 (.48 1.27 (1.1 to 3.5) to 2.7) to 1.74) to 1.76) to 2.45) to 2.41) to 2.9) to 1.65) to 1.47) 1 No pre-treatment better Bellemain-Appaix A et al. BMJ 214;349:g6269 12 value (%) (P value) %, P=.4 %, P=.89 %, P=.52

(, ), p Major bleeding day 7-3 (PCI pts 55%) Study Pre-treat Randomized controlled trials ACCOAST 19/1397 CREDO 5/153 PCI-CURE 21/1313 Subtotal 9/3763 Odds Ratio (95% CI) No pre-treat 7/1376 38/163 19/1345 64/3784 Weight (%) Odds Ratio (95% CI) to 6.44) 25%, P=.27 to 2.7) to 2.12) to 2.15) 5.4 21.9 1.4 37.7 2.7 (1.13 1.34 (.87 1.13 (.61 1.45 (.97 Observational analysis of randomized controlled trial ACUITY-PCI 188/3511 7/1528 51.5 1.18 (.89 to 1.56) Observational studies Assali et al 26/235 Feldman et al 4/467 Chan et al 36/4477 Subtotal 66/5179 Total 344/12453 5.2 2.7 2.9 1.8 1. 1.1 (.42.7 (.2.89 (.27.89 (.48 1.23 (1. *CABG) and non-cabg Non-CABG 7/64 7/574 3/332 17/97 151/6282.1.1 Pre-treatment better 1 to 2.45) to 2.41) to 2.9) to 1.65) to 1.5) 1 No pre-treatment better Bellemain-Appaix A et al. BMJ 214;349:g6269 12 value (%) (P value) %, P=.89 %, P=.58

Largest Pre-loading Trials: Efficacy (ITT) No pre-loading Pre-loading Event rate (%) 12% 1% P=.98 1.8% 1.8% P=.23 8.3% 8% 6.8% 6% 4% P=.75 2% 1.%.8% % N pts randomized: Pts Stable/ACS: % PCI: Drug: Primary endpoint Follow-up: Published: CREDO PRAGUE 8 ACCOAST 2,116 33% / 67% 86% Clopidogrel 3 mg D/MI/UTVR 28 days 22 1,28 87% / 13% 29% Clopidogrel 6 mg D/MI/CVA/TIA/revasc 7 days 28 4,33 1% 69% Prasugrel 3 mg CD/MI/CVA/urg revasc/gpi 3 days 213

Largest Pre-loading Trials: Major/minor Bleeding Event rate (%) 1% P=.2 Pre-loading 7.8% 8% 6% No pre-loading 5.9% P=.25 4% P<.1 3.5% 3.5% 2% 1.4% 1.2% % N pts randomized: Pts Stable/ACS: % PCI: Drug: Follow-up: Published: CREDO PRAGUE 8 ACCOAST 2,116 33% / 67% 86% Clopidogrel 3 mg 28 days 22 1,28 87% / 13% 29% Clopidogrel 6 mg 7 days 28 4,33 1% 69% Prasugrel 3 mg 3 days 213

Cangrelor: Novel Uses of a Rapidly Acting IV P2Y12 Inhibitor in PCI

Stent thrombosis (%) 2. Cangrelor (n=5,472) Clopidogrel (n=5,479) 1.5 1.3% OR [95%CI] = 1..53 [.35-.79].7%.5. N at risk Cangrelor Clopidogrel 1 2 Hours after Randomization 5472 547 5435 5413 5432 5396 P=.2

1.5% 1.2% 1.2% P=.6 1.%.8%.5%.5% 89/1,939 32/6138 33/281 24/1991 All Stable CAD NSTE -ACS STEMI.%

No IPST IPST 12 1.1% Mortality (%) 1 8 HR [95%CI] = 11.4 [5.59,21.79] P<.1 6 4 2 1.% 5 1 15 2 25 3 8 1727 79 1688 Days from Randomization No at risk: IPST: No IPST: 89 185 84 1781 82 1759 8 1741 8 1735

IPST in Champion PHOENIX 8 No IPST IPST 7 ARC ST (%) 6 5.6% 5 HR [95%CI]= 7.66 [3.11, 18.85] P<.1 4 3 2 1.8% 5 15 2 25 3 77 1691 76 1653 Days from Randomization No at risk: IPST: No IPST: 1 89 185 82 1755 79 1722 77 178 77 1699

P Int =.77 2.5 Clopidogrel (n=547) Cangrelor (n=5469) IPST (%) 2 1.5 OR [95%CI] =.65 [.42,.99] p=.4 OR [95%CI] =.5 [.24,1.5] p=.6 OR [95%CI] =.75 [.38,1.5] p=.42 13 OR [95%CI] =.76.34,1.73] p=.52 1.4 1. 1.5 All Stable Angina NSTE-ACS STEMI

P Int =.77 2.5 Clopidogrel (n=547) Cangrelor (n=5469) OR [95%CI] =.75 [.38,1.5] IPST (%) 2 1.5 OR [95%CI] =.65 [.42,.99] p=.4 OR [95%CI] = 5 [ 24 1 5] 13 OR [95%CI] =.76.34,1.73] 1.4 1. 1.5 All Stable Angina NSTE-ACS STEMI

Phoenix: Outcomes in Patients Treated with Heparin vs. Bivalirudin (n=9,628) Clopidogrel 8 7 Cangrelor 6.7 6 5 4 3 2 1 Bivalirudin only Heparin only

Phoenix: Outcomes in Patients Treated with Heparin vs. Bivalirudin (n=9,628) Clopidogrel Cangrelor 8 6 5.6 4 2 Bivalirudin only Heparin only Bivalirudin only Heparin only

Outcomes in Pts Treated with Heparin vs. Bivalirudin (n=21,818) Clopidogrel 8 Cangrelor 7 6 5.4 47 5 4 3 2 1 Bivalirudin only Heparin only

Outcomes in Pts Treated with Heparin vs. Bivalirudin (n=21,818) Clopidogrel Cangrelor 8 6 4.6 4 2 Bivalirudin only Heparin only Bivalirudin only Heparin only

Safety: Non-CABG Bleeding at 48 Hours

Clopidogrel Pre-loading Before PCI 37,814 pts with stable CAD, NSTE-ACS or STEMI in 15 studies; 7 RCTs (8,68 pts), 2 observational analyses of RCTs (1,945 pts), and 6 observational studies (18,261 pts). Results in 7 RCTs according to clinical presentation Stable CAD OR (95% CI) NSTEACS P N=1636 OR (95% CI) STEMI P OR (95% CI) N=4774 N=2198 P Major coronary event 1.5 (.7-1.57).82.78 (.66-.91).2.54 (.36-.81).3 Death 1.12 (.17-7.27).91.93 (.63-1.36).69.5 (.26-.96).4 Major bleeding 1.18 (.31-4.55).81 1.28 (.98-1.67).7.78 (.42-1.45).42 Bellemain-Appaix A et al. JAM A 212;38:257-16

NSTEMI + Troponin 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 n~41 (event driven) Stopped after 433 randomized Double-blind CABG or Medical Management (no more prasugrel) Prasugrel 3 mg Placebo Coronary Angiography Coronary Angiography Prasugrel 3 mg Prasugrel 6 mg PCI PCI CABG or Medical Management (no prasugrel) Prasugrel 1 mg or 5 mg (based on weight and age) for 3 days 1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days

15 1. 1 Pre-treatment No Pre-treatment 9.8 HR.997 (95% CI.83, 1.2) P=.98 HR 1.2 (95% CI.84, 1.25) P=.81 5 1.8 1.8 5 1 15 2 25 3 1996 237 1788 1821 1775 189 1769 182 1762 1797 1752 1791 1621 1616 No. at Risk: No pre-treatment Pre-treatment

5 HR 1.9 (95% CI 1.19, 3.2) P=.6 4 HR 1.97 (95% CI 1.26, 3.8) P=.2 Pre-treatment 3 2.9 2.6 2 1.5 1.4 1 No Pre-treatment 5 1 15 2 25 3 1996 237 1947 1972 1328 1339 1297 131 1288 1299 1284 1297 1263 128 :No. at Risk: No pre-treatment Pre-treatment

Dangas GD et al. Circulation. 211;123:1745-56

Delayed Clopidogrel Activity in STEMI 6 mg load in 11 STEMI pts compared to 1 healthy controls Blood sampled pre-dose, and at.5, 1, 1.5, 2, 3, 4, 6 and 24 hours post-dose Cmax (active metabolite, ng/ml) 16 9% 14 12 75% 1 Mean 8 Median 6 25% 1% 4 2 STEMI p<.1 p=.23 Healthy control T max (active metabolite, min) p<.1 LTA with 2 μmol/l ADP agonist 35 1 p<.1 p=.29 3 8 25 2 6 15 4 1 2 5 STEMI Healthy control STEMI STEMI Healthy 4 hours 24 hours control postpost6 hours dose dose postdose Heestermans AACM et al. Thromb Res 28;122:776-81

p g pp <5 days prior to CABG p g pp >5 days prior to CABG

15 Clopidogrel (n=224) Prasugrel (n=213) 11.3 3% 1 Clopidogrel Prasugrel 2% 5 1% % TIMI Fatal 1 2 TIMI Major 3 4 5 6 7 8 9 1 11 12 13

ADP-induced platelet aggregation at primary PCI (%) 1 Clopidogrel Prasugrel 8 r2 =.1, p =.3 6 r2 =.15, p =.4 4 2 5 1 Time from thienopyridine loading to primary PCI (min) Beigel R et al. Am J Cardiol 213;112:1551-56

TRITON-TIMI 38 STEMI CV death, MI, stroke (%) 15 Clopidogrel (n=1765) Prasugrel (n=1769) 12.4% 1 1.% 9.5 HR [95%CI] =.79.65.97] P=.2 6.5 5 97% underwent PCI Primary PCI (<12 ; n=2,438) Secondary PCI (12-14d; n=1,94) 5 1 15 2 25 3 35 Days Montalescot G et al. Lancet 29;373:723 31 4 45

Early stent thrombosis Late stent thrombosis Clopidogrel 2.5 Prasugrel 2.5 HR.41 [.29-.59] P<.1 2 HR.6 [.37-.97] P=.3 2 1.6% 1.5 1.5 1 1.5.6% 5 1 15 2 25 3.8%.5.5% 3 9 15 21 No reduction in acute stent thrombosis! ancet. 28;371:1353-63 27 33 39 45

PK/PD nalyses performed before and 3 min, 1, 2, 4, 8, and 24 hrs after 3 randomized ticagrelor LD regimens (18 mg, 27 mg, 36 mg) in PPCI (N=52) Franchi F et al. JACC CV Int 215;8:1457 67

No morphine (n=25) Morphine (n=95) (N=154) (N=67) 28 PRU 92 (59.7) 53 (79.1) 1.32 (1.1-1.59).3 23 PRU 84 (54.5) 44 (65.7) 1.17 (.93-1.49).23 (N=22) (N=89) HPR Hour 1 Hour 2 Adjusted P value RR (95% CI) 28 PRU 59 (29.2) 47 (52.8) 1.89 23 PRU 49 (24.3) 42 (47.2) (N=126) (N=7) Hour 4 (1.4-2.56) <.1 2.6 (1.46-2.89) <.1 28 PRU 12 (9.5) 17 (24.3) 2.11 (1.6-4.21).3 23 PRU 7 (5.6) 13 (18.6).3 2.77 (1.14-6.73)

82 pts randomized to crushed vs intact ticagrelor 18 mg tablets LD before primary PCI

52 pts randomized to crushed vs. intact prasugrel 6 mg tablets LD before primary PCI (morphine in 75%) P2Y12 Reaction Units (PRU) 3 p=.53 p<.1 25 * p=.2 ANOVA p=.8 2 15 p=.2 1 p=.1 p=.18 5 3 1 2 4 6 Hours 24

TRITON-TIMI 38 STEMI Primary PCI (<12 ; n=2,438) Secondary PCI (12-14d; n=1,94) Clopidogrel Prasugrel 4%.49 [.28-.84] P =.8.44 [.22-.87] P =.1.58 [.23-1.54] P =.28.58 [.36-.93] P =.2 Clopidogrel Prasugrel.55 [.3-1.] P =.48.63 [.28-1.39] P =.2 3.1% 2.8% 3% 2.4% 2.5% 2.7% 2.2% 1.9% 2% 1.6% 1.2% 1.1% 1.3% 1.5% 1% % All PCI Primary PCI Secondary PCI All PCI Montalescot G et al. Lancet 29;373:723 31 Primary PCI Secondary PCI

CV death, MI or stroke 12% Clopidogrel (n=4,229) Ticagrelor (n=4,21) 1% 11.% 9.3% 8% 6% 4% 2% % 2 4 6 Months 8 1 12

PLATO STEMI: Stent thrombosis 3. 4. Clopidogrel (n=5,648) Ticagrelor (n=5,636) Clopidogrel (n=5,648) Ticagrelor (n=5,636) 2.5 Def ST (%) 2. 1.9% 1.5 1.4% 1.. 3 2.9% 2.2% 2. HR [95%CI] =.75 [.59-.95] P=.2 1. HR [95%CI] =.67 [.5-.91] P=.9.5 Def/prob ST (%) 3.. 6 12 18 24 3 36 Time from PCI/randomization (days) 3 6 12 18 24 3 36 Time from PCI/randomization (days) Steg PG et al. Circulation. 21;122:2131-2141

Timing of ST HR [95%CI] favoring ticagrelor Acute (within 24 hours).94 [.43 2.5] Subacute (1 3 days).6 [.39.93] Late (3 days 1 year).48 [.24.96] 4 HR[95%CI] =.66 [.45-.95] 3 Ticagrelor HR[95%CI] =.71 [.43-1.17] 2.4 2 Clopidogrel 1.6 1.4 1.1 1 STEMI NSTEMI irculation. 213;128:155-65.

1 Prasugrel 23 PRU Threshold 28 PRU Threshold HTPR Rate (%) 75 468 AU/min Threshold Ticagrelor 23 PRU Threshold 5 28 PRU Threshold 468 AU/min Threshold 25 1 Hour 2 Hour 6 Hour 24 Hour Day 5

1% Pre-hospital ticagrelor (n=96) C th l b ti l ( 952) 8% P=.34 82.2% 8.4% 6% 4% 2% 1 % STR 7% prepci TIMI-3 flow prepci STR 7% post- TIMI-3 flow postpci PCI

3-day MACE (MITT) Pre-hospital ticagrelor (n=96) Cath-lab ticagrelor (n=952) P value D, MI, CVA, UR, def ST 4.5% 4.4%.91 D, MI, urgent revasc 4.3% 3.6%.42 ST definite, <24 hrs %.8%.8 ST definite, 3 days.2% 1.2%.2 ST def/prob, 3 days 2.3% 2.1%.75 Death 3.3% 2.%.8 MI.8% 1.1%.53 Stroke.4%.2%.39 Urgent revascularization.6%.8%.46 GPI bail-out 8.6% 1.5%.17