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

Transcription

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

2 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.

3 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 No. of Patients No Pretreatment Pretreatment OR (95% CI) 1.12 ( ).93 ( ).5 ( ).79 ( ).62 ( ) Favors Pretreatment Favors No Pretreatment P for Heterogeneity Trend x Presenting feature Elective PCI NSTE ACS STEMI Loading dose 3 mg 6-9 mg MACE No. of Events No Pretreatment Pretreatment No. of Patients No Pretreatment Pretreatment OR (95% CI) 1.5 ( ).78 ( ).54 ( ).74 ( ).93 ( ) Odds Ratio (95% CI) Favors Pretreatment Favors No Pretreatment Odds Ratio (95% CI) Bellemain-Appaix A et al. JAM A 212;38: P for Heterogeneity Trend x

4 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 Elective (n=3922) NSTE-ACS (n=972) STEMI (n=1359) Dean BB et al. Am J Health-Syst Pharm 21;67:143-7

5 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

6 Cangrelor (ng/ml) Impedance (Ohms) 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 Time (min) Whole Blood Impedance Aggregometry Group A Group B Platelet recovery time ~6 minutes Time (min) Akers WS et al. J Clin Pharm. 21;5:27-35

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

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

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10 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.

11 Phoenix: Death, MI, IDR, Stent Thrombosis within 48 Hrs (n=1,942) Event Rate (%) Cangrelor (n=5,472) Clopidogrel (n=5,47) Hours from Randomization P=.6 NNT = 84 Patient at Risk Cangrelor: Clopidogrel: % 4.7%

12 Death, MI, IDR or ST: Landmark analysis from Phoenix Event Rate (%) Patients at risk: Cangrelor: Clopidogrel: % 4.1% HR (95% CI):.76 (.64,.9) p=.2 Cangrelor Clopidogrel HR (95% CI): 1.16 (.7, 1.9) p= Hours from Randomization End of cangrelor infusion 6 mg clopidogrel given (or placebo) %.6%

13 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

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

15 Phoenix: Stent Thrombosis within 48 Hours (n=1,942) Event Rate (%) Cangrelor (n=5,472) Clopidogrel (n=5,47) OR [95%CI] =.62 (.43,.9) P= Hours from Randomization Patient at Risk Cangrelor: Clopidogrel: %.8%

16 Stent Thrombosis (%) Landmark analysis from Phoenix Patients at risk: Cangrelor: Clopidogrel: Cangrelor Clopidogrel p= Hours from Randomization %.7% End of cangrelor infusion HR [95%CI] =.53 [.35,.79] p=.2 6 mg clopidogrel or placebo given %.1%

17 Comparative Efficacy vs. Safety Outcomes: Champion PHOENIX Event Rate (%) Patients at risk: Cangrelor Efficacy Clopidogrel Efficacy Clopidogrel Cangrelor Cangrelor GUSTO Severe Bleeding.16% Clopidogrel.11% Hours Death/MI/IDR/ST % 4.7% Cangrelor Safety Clopidogrel Safety

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20 ADP-induced platelet aggregation (%) 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:

21 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) Delayed peak effect 1 5 Hour 1 Hour 2 Hours 6 Hours 24 Hours Day 5

22 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:

23 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:

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

26 1,84 pts not randomized

27 Uses for Cangrelor Across the Spectrum of CAD

28 Uses for Cangrelor Across the Spectrum of CAD

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30 (, ), 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/ /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/ Pre-treatment better 1 Weight (%) Odds Ratio (95% CI) 12 value (%) (P value) (.31 to 1.99) 5%, P= (.1 to 2.9).92 (.8 to 1.7).88 (.9 to 2.61) (.74 to 1.3) (.3.82 ( ( (.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

31 (, ), 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/ /3636 Observational analysis of randomized controlled trial ACUITY-PCI 15/ /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/ Pre-treatment better 1 Weight (%) Odds Ratio (95% CI) 12 value (%) (P value) (.25 to 3.95) 13%, P= (.1 to 2.9) 1.1 (.52 to 2.36).92 (.43 to 1.98) (.65 to 1.3) (.3.82 ( ( ( (.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

32 (, ), 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/ / / /9214 Observational analysis of randomized controlled trial ACUITY 411/ /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 (%) (.83.8 ( ( ( (.75 to 1.3) Pre-treatment better 1 Odds Ratio (95% CI).36 ( ( ( ( (.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:g value (%) (P value)

33 (, ), 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/ /915 86/ /3636 Observational analysis of randomized controlled trial ACUITY-PCI 29/ /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) (.25 to 3.95).11 (.1 to 2.9) 1.1 (.52 to 2.36).92 (.43 to 1.98) 44%, P= (.65 to 1.3) ( ( ( ( (.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

34 (, ), 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/ /163 95/633 16/9362 Observational analysis of randomized controlled trial ACUITY 258/ /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/ Weight (%) ( ( ( ( (.94 to 1.45) Pre-treatment better 1 Odds Ratio (95% CI) 1.1 (.42.7 (.2.89 ( ( (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:g value (%) (P value) %, P=.4 %, P=.89 %, P=.52

35 (, ), 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/ /163 19/ /3784 Weight (%) Odds Ratio (95% CI) to 6.44) 25%, P=.27 to 2.7) to 2.12) to 2.15) ( ( ( (.97 Observational analysis of randomized controlled trial ACUITY-PCI 188/3511 7/ (.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/ (.42.7 (.2.89 ( ( (1. *CABG) and non-cabg Non-CABG 7/64 7/574 3/332 17/97 151/ 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:g value (%) (P value) %, P=.89 %, P=.58

36 Largest Pre-loading Trials: Efficacy (ITT) No pre-loading Pre-loading Event rate (%) 12% 1% P= % 1.8% P= % 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

37 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

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

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40 Stent thrombosis (%) 2. Cangrelor (n=5,472) Clopidogrel (n=5,479) % OR [95%CI] = [ ].7%.5. N at risk Cangrelor Clopidogrel 1 2 Hours after Randomization P=.2

41 1.5% 1.2% 1.2% P=.6 1.%.8%.5%.5% 89/1,939 32/ /281 24/1991 All Stable CAD NSTE -ACS STEMI.%

42 No IPST IPST % Mortality (%) 1 8 HR [95%CI] = 11.4 [5.59,21.79] P< % Days from Randomization No at risk: IPST: No IPST:

43 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< % Days from Randomization No at risk: IPST: No IPST:

44 P Int = Clopidogrel (n=547) Cangrelor (n=5469) IPST (%) 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= OR [95%CI] =.76.34,1.73] p= All Stable Angina NSTE-ACS STEMI

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

46 Phoenix: Outcomes in Patients Treated with Heparin vs. Bivalirudin (n=9,628) Clopidogrel 8 7 Cangrelor Bivalirudin only Heparin only

47 Phoenix: Outcomes in Patients Treated with Heparin vs. Bivalirudin (n=9,628) Clopidogrel Cangrelor Bivalirudin only Heparin only Bivalirudin only Heparin only

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

49 Outcomes in Pts Treated with Heparin vs. Bivalirudin (n=21,818) Clopidogrel Cangrelor Bivalirudin only Heparin only Bivalirudin only Heparin only

50 Safety: Non-CABG Bleeding at 48 Hours

51 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 ( ) ( ).2.54 ( ).3 Death 1.12 ( ) ( ).69.5 ( ).4 Major bleeding 1.18 ( ) ( ).7.78 ( ).42 Bellemain-Appaix A et al. JAM A 212;38:257-16

52 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

53 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= No. at Risk: No pre-treatment Pre-treatment

54 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 No Pre-treatment :No. at Risk: No pre-treatment Pre-treatment

55 Dangas GD et al. Circulation. 211;123:

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% % 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= 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

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

59 15 Clopidogrel (n=224) Prasugrel (n=213) % 1 Clopidogrel Prasugrel 2% 5 1% % TIMI Fatal 1 2 TIMI Major

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

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

63 Early stent thrombosis Late stent thrombosis Clopidogrel 2.5 Prasugrel 2.5 HR.41 [ ] P<.1 2 HR.6 [ ] P= % % %.5.5% No reduction in acute stent thrombosis! ancet. 28;371:

64 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:

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66 No morphine (n=25) Morphine (n=95) (N=154) (N=67) 28 PRU 92 (59.7) 53 (79.1) 1.32 ( ).3 23 PRU 84 (54.5) 44 (65.7) 1.17 ( ).23 (N=22) (N=89) HPR Hour 1 Hour 2 Adjusted P value RR (95% CI) 28 PRU 59 (29.2) 47 (52.8) PRU 49 (24.3) 42 (47.2) (N=126) (N=7) Hour 4 ( ) < ( ) <.1 28 PRU 12 (9.5) 17 (24.3) 2.11 ( ).3 23 PRU 7 (5.6) 13 (18.6) ( )

67 82 pts randomized to crushed vs intact ticagrelor 18 mg tablets LD before primary PCI

68 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= p=.2 1 p=.1 p= Hours 24

69 TRITON-TIMI 38 STEMI Primary PCI (<12 ; n=2,438) Secondary PCI (12-14d; n=1,94) Clopidogrel Prasugrel 4%.49 [ ] P =.8.44 [ ] P =.1.58 [ ] P = [ ] P =.2 Clopidogrel Prasugrel.55 [.3-1.] P = [ ] 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: Primary PCI Secondary PCI

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

71 PLATO STEMI: Stent thrombosis Clopidogrel (n=5,648) Ticagrelor (n=5,636) Clopidogrel (n=5,648) Ticagrelor (n=5,636) 2.5 Def ST (%) % % % 2.2% 2. HR [95%CI] =.75 [ ] P=.2 1. HR [95%CI] =.67 [.5-.91] P=.9.5 Def/prob ST (%) Time from PCI/randomization (days) Time from PCI/randomization (days) Steg PG et al. Circulation. 21;122:

72 Timing of ST HR [95%CI] favoring ticagrelor Acute (within 24 hours).94 [ ] Subacute (1 3 days).6 [.39.93] Late (3 days 1 year).48 [.24.96] 4 HR[95%CI] =.66 [ ] 3 Ticagrelor HR[95%CI] =.71 [ ] Clopidogrel STEMI NSTEMI irculation. 213;128:

73 1 Prasugrel 23 PRU Threshold 28 PRU Threshold HTPR Rate (%) 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

74 1% Pre-hospital ticagrelor (n=96) C th l b ti l ( 952) 8% P= % 8.4% 6% 4% 2% 1 % STR 7% prepci TIMI-3 flow prepci STR 7% post- TIMI-3 flow postpci PCI

75 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

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78 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