Πποβλημαηιζμοί με ηην ανηιαιμοπεηαλιακή αγωγή ζηο οξύ έμθπαγμα ηος μςοκαπδίος με ανάζπαζη ηος διαζηήμαηορ ST.

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1 Patras University Hospital Πποβλημαηιζμοί με ηην ανηιαιμοπεηαλιακή αγωγή ζηο οξύ έμθπαγμα ηος μςοκαπδίος με ανάζπαζη ηος διαζηήμαηορ ST. Dimitrios Alexopoulos, MD, FACC, FESC Cardiology Department, Patras University Hospital, Patras, Rio, Greece.

2 Patras University Hospital I, Dimitrios Alexopoulos, have received honoraria for lecturing and research grants from: Astra Zeneca Boeringer Ingelheim

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4 Platelet activation-impact on surrogate endpoints Clinical studies/ oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

5 Activation of platelets in STEMI and mechanisms influencing adverse clinical outcomes Alexopoulos D, Intern J Cardiol 2011, Dec 20

6 Platelet activation mechanisms in STEMI patients Impact on surrogate end points Alexopoulos D, Xanthopoulou I, Goudevenos I (submitted)

7 Platelet activation-impact on surrogate endpoints Clinical studies/oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

8 Patras University Hospital Drawbacks of clopidogrel use A marked interindividual response to clopidogrel High platelet reactivity in 1/4 to 1/3 Response to clopidogrel may be influenced by genetic polymorphisms, ethnicity, assay used, timing postloading, age, diabetes mellitus, renal dysfunction, obesity, acuity of the disease, drug-drug interactions, smoking

9 Patras University Hospital However, even after controlling for known factors affecting clopidogrel s pharmacokinetics/ pharmacodynamics, most of their variation remains unexplained Clopidogrel, compared to newer agents- prasugrel and ticagrelor- exhibits a slower onset of action and weaker antiplatelet effect Frelinger AL 3rd, et al J Am Coll Cardiol 2013; 61: Wallentin L, et al Eur Heart J 2008; 29: Gurbel PA,et al Circulation 2009; 120:

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11 Mehta SR, TCT 2009

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15 Proportion of patients (%) Primary EP (CV death, MI and stroke at 15 months) 15 Clopidogrel Prasugrel p=0.002 RRR=32% 10.0 p=0.02 RRR=21% HR=0.79 ( ) NNT=42 Age-adjusted HR=0.81 ( ) Time (Days) Montalescot et al. Lancet 2008 (in press)

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17 Proportion of patients (%) Patras University Hospital Montalescot et al. Lancet 2008 (in press) TRITON TIMI-38 STEMI cohort TIMI major non-cabg bleeding Clopidogrel Prasugrel p= HR=1.11 ( ) NNH=333 Age-adjusted HR=1.19 ( ) Time (Days)

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19 TRITON TIMI-38 STEMI cohort Baseline characteristics of patients with Variable primary or secondary PCI Primary PCI (%) Secondary PCI (%) Age (years) p History of diabetes Prior CABG Multivessel PCI GPIIb/IIIa inhibitor Creatinine clear. < 60mL/min Patras University Hospital

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21 Wallentin L, et al. N Engl J Med. 2009;361: and supplementary tables

22 K-M estimated rate (% per year) All cause mortality 7 6 Clopidogrel Ticagrelor HR 0.82 (95% CI = ), p= No. at risk Months Ticagrelor 4,2014,005 3,962 3,876 3,150 2,413 1,993 Clopidogr 4,2294,029 3,989 3,912 3,195 2,471 1,980 el

23 Stent thrombosis (as per ARC definitions)* Ticagrelor (n=4,201) Clopidogrel (n=4,229) HR for ticagrelor (95% CI) p- value Definite Probable or definite Possible, probable, or definite ( ) 0.69 ( ) 0.73 ( ) Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization *Cutlip et. al., Circulation. 2007;115: By univariate Cox model

24 K-M estimated rate (% per year) Primary safety event: major bleeding Clopidogrel Ticagrelor HR 0.96 (95% CI = ), p= No. at risk Months Ticagrelor 4,1653,431 3,254 3,137 2,440 1,786 1,640 Clopidogr 4,1813,430 3,297 3,159 2,441 1,804 1,635 el

25 Platelet activation-impact on surrogate endpoints Clinical studies/ oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

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27 CHAMPION PHOENIX Study Design CHAMPION PHOENIX N = 10,900 MITT SA/ NSTE-ACS/ STEMI Patients requiring PCI 1 P2Y 12 inhibitor naïve Rand OR Cangrelor 2 bolus & infusion (30ug/kg; 4ug/kg/min) PCI ~30 Placebo 3 oral (right before PCI or right after, per physician) Placebo 2 bolus & infusion OR Clopidogrel 600 mg oral Placebo oral Clopidogrel 3 (600 mg or 300 mg oral, per physician) 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 600 mg or 300 mg was specified by the investigator. MITT=modified intent-to-treat; NSTE-ACS=non-ST-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI. Patras University Hospital

28 Subgroups: Death/MI/IDR/ST at 48 Hours OR [95% CI] Overall 0.79 (0.67,0.93) Age (0.50,1.02) Age < (0.67,0.98) Male 0.84 (0.69,1.03) Female 0.67 (0.50,0.92) Ethnicity: White 0.80 (0.67,0.95) Ethnicity: Non-white 0.70 (0.35,1.41) United States 0.70 (0.53,0.92) Other Countries 0.85 (0.69,1.05) Stable Angina 0.78 (0.63,0.95) NSTE-ACS 0.80 (0.55,1.17) STEMI 0.75 (0.46,1.25) Weight >= (0.66,0.94) Weight < (0.39,1.45) Biomarker Positive 0.90 (0.64,1.27) Biomarker Negative 0.75 (0.61,0.91) Diabetic No 0.74 (0.61,0.90) Diabetic Yes 0.92 (0.67,1.27) Insulin-Dependent Diabetes: Yes 0.74 (0.42,1.31) Insulin-Dependent Diabetes: No 0.79 (0.66,0.94) Prior MI 0.68 (0.47,0.97) No Prior MI 0.84 (0.69,1.02) 0.2 Patras University Hospital Cangrelor Better 1.0 Clopidogrel Better 5.0 P [Int]

29 CHAMPION Trials Study Designs Randomised, Double Blind, Controlled Trials of patients undergoing PCI CHAMPION PHOENIX n=10,942 mitt SA / NSTE-ACS / STEMI P2Y 12 naïve Placebo or clopidogrel before or after PCI Cangrelor bolus then infusion OR Clopidogrel 600 mg or 300 mg oral Clopidogrel 600 mg oral CHAMPION PCI n=8667 mitt SA / NSTE-ACS / STEMI Placebo or clopidogrel before PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral Clopidogrel 600 mg oral CHAMPION PLATFORM n=5301 mitt SA / NSTE-ACS P2Y 12 naïve Placebo or clopidogrel after PCI Cangrelor bolus then infusion Clopidogrel 600 mg oral Clopidogrel 600 mg oral hours PCI ~30

30 Subgroups: Death, MI, IDR, Stent Thrombosis OR [95% CI] P [Int] Overall 0.81 (0.71, 0.91) Age >= (0.52, 0.91) Age < (0.73, 0.96) Male 0.85 (0.74, 0.99) 0.18 Female 0.71 (0.56, 0.89) Ethnicity: White 0.80 (0.70, 0.92) Ethnicity: Non-white 0.87 (0.60, 1.28) United States 0.82 (0.68, 0.98) ROW 0.80 (0.67, 0.94) Stable Angina 0.77 (0.64, 0.93) NSTE-ACS 0.82 (0.68, 0.99) STEMI 0.84 (0.55, 1.27) Weight >= (0.71, 0.92) Weight < (0.52, 1.30) Biomarker Positive 0.79 (0.62, 1.02) Biomarker Negative 0.79 (0.68, 0.91) Diabetic Yes 0.87 (0.69, 1.09) Diabetic No 0.78 (0.67, 0.91) Insulin-Dependent Diabetes: Yes 0.63 (0.41, 0.98) Insulin-Dependent Diabetes: No 0.83 (0.72, 0.94) Prior MI 0.72 (0.57, 0.92) 0.25 No Prior MI 0.85 (0.74, 0.99) Cangrelor better Clopidogrel better Steg et al. Lancet Sep 3, 2013

31 Patras University Hospital In primary PCI: regimens which increase platelet inhibition vs standard clopidogrel result in superior antiischemic effects consistent with the results in the whole trials populations (p-interaction not significant). Although subgroup analyses of the primary PCI populations showed no significant benefit in primary endpoints for more potent antiplatelet regimens versus clopidogrel, no study was designed specifically for primary PCI patients and even PLATO the largest one- was underpowered for detecting differences in this subgroup.

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33 Platelet activation-impact on surrogate endpoints Clinical studies/oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

34 Patras University Hospital P2Y12 receptor inhibitors in acute coronary syndromes: From the research laboratory to the clinic and vice versa. D. Alexopoulos Cardiology (Karger), 2014

35 Thromb Res 2008

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38 Alexopoulos D, et al. Circ J 2012;76:2183

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41 Platelet activation-impact on surrogate endpoints Clinical studies/ oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

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47 Circ Interv 2012; 5:

48 Alexopoulos et al, Circ Cardiovasc Interv. 2012;5:797

49 Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST elevation myocardial infarction. D. Alexopoulos et al, Circ Interv 2012; 5:

50 JACC 2013;61:1601

51 . Alexopoulos et al JACC 2013;62:940-1 Patras University Hospital

52 Platelet activation-impact on surrogate endpoints Clinical studies/ oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

53 Patras University Hospital Intrinsic platelet reactivity Up to 30% patients do exhibit platelet reactivity below the thresholds predicting ischemic risk. It is not clear whether these patients had an even lower platelet reactivity prior to the acute event and the one assessed early in STEMI is increased compared with their baseline platelet reactivity. It is not clear either, whether these patients are at lower risk for future events or at lower need for strong P2Y12 inhibition.

54 Patras University Hospital HPR rates in the acute phase of STEMI. In close dependence primarily on the agent used, timing of platelet function assessment and platelet function test used. Co-administration of commonly used medication leading to platelet activation like e.g. heparin should also be considered.

55 Patras University Hospital At 24 hours following post LD clopidogrel: almost half prasugrel: 3.2% to 4.2% ticagrelor: 0 and 2.8% 6-24 hours post LD might be expected with the VerifyNow and the VASP respectively. No pharmacodynamic studies with cangrelor exclusively in STEMI patients have been published so far

56 Patras University Hospital HPR thresholds value? No platelet reactivity cutoff points specifically for STEMI patients have been identified HPR thresholds used in pharmacodynamic studies in STEMI patients have been obtained from receiver operating characteristic analysis in post-pci studies involving stable or ACS patients Thresholds utility so far in STEMI for at least the first 24 hours, is mostly to characterize the onset of antiplatetelet action and it is not clear whether they carry any ability in predicting upcoming events.

57 Patras University Hospital Is the higher the platelet inhibition, the better? CURRENT OASIS 7: rates of definite stent thrombosis were reduced early (from randomization to 48 h) likely related to more potent platelet inhibition provided by high clopidogrel dose. Despite the undisputed higher antiplatelet potency of ticagrelor over clopidogrel and the overall reduction in stent thrombosis rate in PLATO, no difference in stent thrombosis rate between ticagrelor and clopidogrel in the acute phase (24 hours) was found. Similar findings have been reported with prasugrel in the TRITON TIMI-38. A relative higher significance of technical and stent placement issues rather than the level of platelet inhibition for affecting stent thrombosis rate has been implicated.

58 Patras University Hospital Ticagrelor Loading Dose Versus Clopidogrel Loading and Reloading With Ticagrelor Two-center, randomized, pharmacodynamic study of parallel design STEMI patients randomization immediately after coronary angiography (Hour 0) to: Ticagrelor 180mg LD or Clopidogrel 600mg LD and 2 hours later reloading with Ticagrelor 180mg Platelet reactivity (PR) assessment using the VerifyNow assay at randomization (Hour 0) and at 2, 4, 6 and 24 hours post randomization ClinicalTrials.gov NCT , Alexopoulos et al

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60 Patras University Hospital P2Y12 inhibition and thrombolysis Platelet reactivity is heightened after thrombolytic therapy Role of prasugrel or ticagrelor is unclear. In TRITON TIMI-38, there was a very limited experience with co-administration of thrombolysis with prasugrel, mainly in the secondary PCI cohort. In PLATO, thrombolysis was an exclusion criterion.

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62 Patras University Hospital Adjunctive Antithrombotic Therapy to Support PCI After Fibrinolytic Therapy ACCF/AHA STEMI guidelines 2013

63 Montalescot et al, Lancet 2009

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65 Ticagrelor vs high dose of clopidogrel in ST elevation myocardial infarction patients with high residual platelet reactivity post thrombolysis: a pharmacodynamic comparison Prospective, 2-center, randomized study of parallel design. Patients with STEMI and HPR (defined as PRU 208) 3 to 48 hours post fibrinolysis and standard clopidogrel treatment [300mg loading dose (LD) 75mg maintenance dose (MD)] are randomized pre coronary angiography to: Ticagrelor 180mg LD 90mg bid MD or Clopidogrel 600mg LD 150mg MD. Platelet reactivity (PR) assessment at randomization (Hour 0) and at 2, 24 hours after randomization, as well as pre-discharge, using the VerifyNow assay, in platelet reactivity units (PRU). Primary endpoint is PR at Hour 2 between groups. Patras University Hospital ClinicalTrials.gov NCT , Alexopoulos et al

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67 GReek AntiPlatelet REgistry (GRAPE) 8 GREEK PCI HOSPITALS Jan Aug patients

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69 Multivariate log-poisson regression model for appropriate P2Y12 inhibitor selection initially (A)

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71 681 patients with STEMI

72 Patras University Hospital 30-day outcomes (excluding in hospital events for patients who subjected to P2Y12 inhibitor upgrade at discharge) Clopidogrel treated N =102 P2Y12 inhibitor upgrade N=102 P value BARC type 1 1(1.0) 17(16.7) <0.001 BARC type 2 0(0) 2(2.0) NA BARC type 3 1(1.0) 1(1.0) 1.0 Bleeding BARC any type 2(2.0) 20(19.6) <0.001 MACEs 6(5.9) 4(3.9) 0.7

73 Platelet activation-impact on surrogate endpoints Clinical studies/oral P2Y12 inhibitors Clinical studies/ IV P2Y12 inhibitors Clopidogrel pharmacodynamic studies New P2Y12 inhibitors pharmacodynamic studies Unsettled issues Perspectives Patras University Hospital

74 Level of platelet inhibition? How fast we should achieve this by P2Y12 blockade An immediate, e.g. at first medical contact, platelet inhibition appears as the most attractive pathophysiologic target. Whether this offers clinical superiority over a more conservative approach allowing a few hours delay in antiplatelet activity has to be proved. The combination of cangrelor with prasugrel or ticagrelor appears theoretically as the best possible P2Y12 inhibitors strategy in primary PCI. This too, has to be tested against an oral-only, potent P2Y12 inhibitor regimen. Patras University Hospital

75 Patras University Hospital It is appreciable that the antiischemic benefit provided by a strong antiplatelet regimen may be offset by an accompanying increased bleeding potential. Fortunately, at least in STEMI patients no signs of excess bleeding have been identified so far Future drug combinations particularly if these include other oral antiplatelet (e.g. vorapaxar) or antithrombin (e.g. low dose rivaroxaban?

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78 Infarct size, %LV INFUSE-AMI: Infarct size at 30 days* Median [IQR] 15.1% [6.8, 22.7] Median [IQR] 17.9% [10.3, 25.4] 30 P= IC abciximab N=229 No abciximab N=223 Patras University Hospital *Core laboratory assessed

79 CONCLUSIONS Several areas of unmet need in antiplatelet therapy in patients with STEMI undergoing primary PCI exist. A clear demand for additional research at both basic science and clinical levels to understand the underlying mechanisms by which STEMI patients may benefit. Large randomized clinical studies dedicated to STEMI patients will be necessary to precisely define the impact of P2Y12 blockade by oral -with or without concomitant intravenous- agents on the outcome of this high-risk population. Patras University Hospital

80 TAKE HOME MESSAGES In STEMI, high rate of HPR following 600 mg clopidogrel LD Delay in the onset of action of prasugrel/ticagrelor New agents of marginal clinical superiority to clopidogrel in primary PCI patients Cangrelor: need for more data/comparison to prasugrel/ticagrelor Switching from clopidogrel to prasugrel or ticagrelor may be an alternative for STEMI patients GP IIb/IIIa antagonicts: IIa indication

81 Patras University Hospital Platelet reactivity variability before P2Y12 blockade and its evolution over time, genetic predisposition, antiplatelet agent used, timing and method of platelet function testing significantly affect the rates of high on-treatment platelet reactivity. Although ominus signs of higher bleeding potential of antiplatelet stronger regimens have not appeared in STEMI, this should be carefully tested. Additional research at both the basic science level along with large randomized clinical studies dedicated to STEMI patients are necessary to precisely assess the impact of P2Y12 blockade on the outcome of this high risk population.

82 CURRENT-OASIS 7 In the STEMI subgroup- mostly treated with primary PCI and 40.6% of them receiving a IIb/IIIa inhibitor- the reduction in the primary endpoint with the high dose, was nominally non significant 4.2% vs 5%, [HR (95% CI), 0.83 ( ), p=0.117]. However, the results were consistent with the overall PCI cohort ( p for interaction=0.817).

83 In a substudy of PLATO on angiographic outcomes, in the STEMI subgroup no difference was observed in the incidence of post-pci TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 between ticagrelor and clopidogrel receiving patients consistently with the overall cohort (44). Nevertheless, this was not unexpected since angiography was performed earlier than 1 h post antiplatelet administration in >80% of the cases, when most likely the drugs antiplatelet action had not been developed. Patras University Hospital

84 In a study of pre-hospital bivalirudin administration, bivalirudin treated patients still exhibited higher than controls early stent thrombosis rate. This occurred despite loading with prasugrel or ticagrelor in 50% of the cases suggestive of new oral P2Y12 inhibitors insufficiency to address this risk (46). Patras University Hospital

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90 Patras University Hospital Antiplatelet Therapy to Support Primary PCI for STEMI I IIa IIb III A loading dose of a P2Y 12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include: Clopidogrel 600 mg; or Prasugrel 60 mg; or Ticagrelor 180 mg P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (BMS or DES) during primary PCI 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction

91 Adjunctive Antithrombotic Therapy to Support Reperfusion With Primary PCI (cont.) ACCF/AHA STEMI guidelines 2013 Patras University Hospital

92 Patras University Hospital Results Table 2 Platelet reactivity (VerifyNow PRU) at 0, 2, 4, 6 and 24 hours post randomization Time post randomization Ticagrelor N=16 Clopidogrel Ticagrelor N=13 LS mean difference (95%CI) p-value 0 hour 220.0± ± hour (63.3 to 195.5) 4 hour 89.7 (43.6 to 135.8) 6 hour 57.4 (28.5 to 86.3) 24 hours 50.2 (25.5 to 74.9) (110.8 to 406.3) (47.3 to 176.1) 82.6 (36.2 to 129.1) 23.2 (10.5 to 35.9) ( to 37.9) ( to 60.9) (-81.4 to 30.9) 26.9 (-0.95 to 54.9) Generalized linear model with gamma distribution and logarithmic transformation of the dependent variable, treatment as factor and baseline PR as covariate

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95 Patras University Hospital Results Out of 36 screened patients, 23(63.9%) presented HPR (87% men, 21.7% diabetics) and were all randomized (Ticagrelor N=12, Clopidogrel N=11). Median time of pain onset to fibrinolysis was 2.5( ) hours. There were no differences in baseline and clinical characteristics between groups. The primary endpoint was significantly lower for Ticagrelor compared to high Clopidogrel (79.1 PRU, 95%CIs vs PRU, 95%CIs , p<0.001). PR at Hour 24 and pre-discharge was also significantly lower for Ticagrelor compared to Clopidogrel (32.1 PRU, 95%CIs -3.6 to 67.8 vs PRU, 95%CIs and 20.7 PRU, 95%CIs -7.2 to 48.7 vs PRU, 95%CIs respectively, p<0.001 for both). HPR rates at Hour 2 and 24 were significantly lower for Ticagrelor compared to high Clopidogrel regimen (8.3% vs 90.9%, p<0.001 and 0% vs 45.5%, p=0.01 respectively).

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97 A high platelet reactivity in STEMI patients Negatively impacts on the clopidogrel effect, Predicts PPCI success on angiography, degree of STsegment resolution, extent of myocardial necrosis, Predicts short- and mid-term clinical outcome Is associated with larger intracoronary thrombus and worse post-pci myocardial flow and perfusion. Gawaz M, et al.circulation 1996; 93: Campo G, et al. J Am Coll Cardiol 2006; 48: Matetzky S, et al Circulation 2004; 109: Vavuranakis M, et al. Circ J 2011; 75:

98 Switch and non switch in P2Y12 inhibition: the real life use of clopidogrel and prasugrel in patients with acute myocardial infarction. Insights from the FAST MI 2010 registry Schiele F et al ESC 2012 Nationwide French registry 4169 patients with AMI in 213 centres received thienopyridines, 1259 received prasugrel (31%). 391 received de novo prasugrel, 807 (64%) were treated with clopidogrel first and then switched to prasugrel 11% had a 60mg loading dose of prasugrel. No evidence of excess risk of bleeding or in-hospital complications in the patients who were switched, compared with those who received prasugrel treatment only.

99 Patras University Hospital In-Hospital Switching of ADP Receptor Inhibitors in Myocardial Infarction Patients Treated with Percutaneous Coronary Intervention: Insights from the TRANSLATE-ACS Study. 6,362 MI pts treated with PCI at 196 hospitals from 4/2010-4/2012 Among 4,778 patients initially treated with a 1 st generation ADP receptor inhibitor, 491 (10%) were switched to a 2 nd generation drug Among 1,584 patients initially treated with a 2 nd generation ADP receptor inhibitor, 186 (12%) were switched to a 1 st generation drug BagaiA, et al Circulation 2012;126:A15573

100 Patras University Hospital INFUSE-AMI Trial 452 pts with anterior STEMI Anticipated Sx to PCI <5 hrs, TIMI 0-2 flow in prox or mid LAD Primary PCI with bivalirudin anticoagulation Pre-loaded with aspirin and clopidogrel 600 mg or prasugrel 60 mg Manual aspiration R 1:1 Stratified by symptoms to angio <3 vs 3 hrs, and prox vs mid LAD occlusion No aspiration R 1:1 R 1:1 IC Abcx No Abcx IC Abcx No Abcx Primary endpoint: Infarct size at 30 days (cmri) 2º endpoints: TIMI flow, blush, ST-resolution, MACE (30d, 1 yr)

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102 Montalescot G et al Lancet 2009 Patras University Hospital

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105 Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at Patras University Hospital

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