Ανηιαιμοπεηαλιακή Αγωγή. Δημήτπιορ Αλεξόποςλορ MD, FESC, FACC Καθηγητήρ Καπδιολογίαρ Παν/μίος Πατπών

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1 Ανηιαιμοπεηαλιακή Αγωγή Δημήτπιορ Αλεξόποςλορ MD, FESC, FACC Καθηγητήρ Καπδιολογίαρ Παν/μίος Πατπών

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

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4 18 Θεραπεσηικά διλήμμαηα 1. Κλοπιδογρέλη ένανηι νέων παραγόνηων-rct 2. Καηεσθσνηήριες οδηγίες 3. Πραζοσγκρέλη ή Σικαγκρελόρη? 4. Προθόρηιζη 5. Τπερήλικες 6. Λιποβαρείς 7. Ιζηορικό εγκεθαλικού/σια 8. Διαβήηης 9. ΥΝΑ 10. STEMI 11. Θρομβόλσζη 12. Αιμορραγικός κίνδσνος/ανηιπηκηικά 13.σγτορηγούμενα θάρμακα 14.Ρόλος γονοηύπηζης 15.Ελεγτος λειηοσργικόηηηας αιμοπεηαλίων 16.Διάρκεια διπλής ανηιαιμοπεηαλιακής αγωγής 17. Κόζηος? 18. Πλειοηρόποι δράζεις?

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7 Cumulative incidence (%) PLATO: primary endpoint: K-M estimate of time to major CV event (composite of CV death, MI or stroke) No. at risk Ticagrelor9333 Clopidogrel Months after randomization Clopidogrel Ticagrelor (HR, 0.84; 95% CI, ; P<0.001) ΝΝΣ 54 Wallentin L, et al. N Engl J Med. 2009;361:1045.

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9 Wallentin L, et al. N Engl J Med. 2009;361:1045.

10 18 Θεραπεσηικά διλήμμαηα 1. Κλοπιδογρέλη ένανηι νέων παραγόνηων 2. Καηεσθσνηήριες οδηγίες 3. Πραζοσγκρέλη ή Σικαγκρελόρη? 4. Προθόρηιζη 5. Τπερήλικες 6. Λιποβαρείς 7. Ιζηορικό εγκεθαλικού/σια 8. Διαβήηης 9. ΥΝΑ 10. STEMI 11. Θρομβόλσζη 12. Αιμορραγικός κίνδσνος/ανηιπηκηικά 13.σγτορηγούμενα θάρμακα 14.Ρόλος γονοηύπηζης 15.Ελεγτος λειηοσργικόηηηας αιμοπεηαλίων 16.Διάρκεια διπλής ανηιαιμοπεηαλιακής αγωγής 17. Κόζηος? 18. Πλειοηρόποι δράζεις?

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14 Appropriateness of overall P2Y12 inhibitor selection initially and at discharge Int J Cardiol Aug 15. doi:pii: S (13)

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18 Ticagrelor vs prasugrel in acute coronary syndrome patients with high onclopidogrel platelet reactivity following PCI Alexopoulos D, et al. JACC 2012;60:193

20 Am Heart J 2009;158:285

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22 ACCOAST design NSTEMI + Troponin 1.5 i tl ames UN lo cal l Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 Double-blind b value n~4100 (event driven) Prasugrel 30 mg Placebo CABG or Medical Management (no more prasugrel) Coronary Angiography Prasugrel 30 mg Coronary Angiography Prasugrel 60 mg CABG or Medical Management (no prasugrel) PCI PCI Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days 1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days

23 Endpoint (%) 1 Efficacy End days (All Patients) 15 Pre-treatment 10.0 CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout Pre-treatment No Pre-treatment 10.8 No Pre-treatment Hazard Ratio, 1.02 (95% 0.84, 1.25) P=0.81 Hazard Ratio, (95% 0.83, 1.20) P=0.98 No. at Risk, Primary Efficacy End Point: No pre-treatment Pre-treatment Days From First Dose

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27 Alexopoulos D, et al Am Heart J 2013;165:73-79

28 CV death, MI or stroke (%) PLATO elderly patient subgroup analysis: Primary composite endpoint according to age Ticagrelor Clopidogrel p for interaction = Age (years) Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results No interaction between age and treatment was observed [Husted 2011:I] Husted S, et al. J Am Coll Cardiol 2011;57:E1099;

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34 James, Circ 2012

35 Prevalence of contraindications and conditions for precaution for prasugrel administration in a real world acute coronary syndrome population. (N=646/1016) Alexopoulos et al, J Thromb Thrombolysis 2011

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37 Patras University Hospital Prevalence of CON/SWP for use of P2Y12 inhibitors N=1280 Clopidogrel Prasugrel Ticagrelor CON -Hypersensitivity 1(0.1) 0(0) 1(0.1) -Active pathological bleeding 4(0.3) 4(0.3) 4(0.3) -Previous stroke/tia NA 45(3.5) ΝA -History of intracranial hemorrhage ΝΑ NA 6(0.5) -Severe hepatic impairment (Child Pugh class C) -Moderate or severe hepatic impairment (Child Pugh class B or C) 0(0) 0(0) NA ΝΑ NA 1(0.1)

38 Prevalence of at least 1 CON/SWP and the prescription rates at discharge for each P2Y12 inhibitor. At least 1 CON Clopidogrel 5(0.4%) Prasugrel 49(3.8%) Ticagrelor 12(0.9%) Patients with CON/SWP to all the 3 P2Y12 inhibitors were prescribed with descending frequency clopidogrel, ticagrelor and prasugrel

40 PRASUGREL CLOPIDOGREL Montalescot G et al Lancet 2009

41 CV death, MI, or stroke (%) PLATO diabetes: Primary composite endpoint Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.88( ) 16.2% 14.1% 10 p for interaction = % 8.4% 5 0 No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.83( ) Days after randomisation. Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results No interaction between diabetes status and treatment was observed (p=0.49) James S, et al. Eur Heart J 2010;31:

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46 Alexopoulos D, et al, 2012 Mar;59(3):469-71

47 Alexopoulos D, et al. AJKD 2012

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53 Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST elevation myocardial infarction. Alexopoulos D et al. Circ Cardiovasc Interv. 2012;5:797

54 . Alexopoulos et al

55 Patras University Hospital CirculationCardiovIntv 2014

57 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.

58 Off label 45 patients 3 patients BARC 1 events

59 Patras University Hospital High Platelet Reactivity in ST Segment Elevation Myocardial Infarction Post Thrombolysis: A Pharmacodynamic Comparison of Ticagrelor versus High Dose of Clopidogrel. Xanthopoulou.. Alexopoulos, ACC /57 (61.4%) of thrombolyzed STEMI s loaded with 300 mg of clopidogrel had HPR

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63 Incidence of in-hospital bleeding by BARC type and transfusions. Xanthopoulou et al. Intern J Cardiol 2014 Multivariate predictors of in-hospital BARC type 2 bleeding events.

64 In-hospital bleeding rates in propensity matched pairs of patients who were clopidogrel-treated or novel P2Y12 inhibitor-treated (n=552) Clopidogrel Novel P2Y12 P value inhibitor Bleeding BARC type 1 16(2.9) 29(5.3) 0.07 Bleeding BARC type 2 15(2.7) 33(6.0) 0.01 Bleeding BARC type 2 4(0.7) 15(2.7) 0.02 access site related Bleeding BARC type 2 11(2.0) 18(3.3) 0.2 non access site related Transfusion 5(0.9) 9(1.6) 0.2

65 In-hospital bleeding rates in propensity matched pairs of patients who were ticagrelor or prasugrel-treated (n=329) Ticagrelor Prasugrel P value Bleeding BARC type 1 25(7.6) 19(5.8) 0.4 Bleeding BARC type 2 21(6.4) 12(3.6) 0.2 Bleeding BARC type 2 10(3.0) 7(2.1) 0.5 access site related Bleeding BARC type 2 11(3.3) 5(1.5) 0.2 non access site related Transfusion 4(1.2) 3(0.9) 0.7

66 Ticagrelor vs prasugrel one-month maintenance therapy: Impact on platelet reactivity and bleeding events. Alexopoulos et al, Thromb Haemost Sep 2014

67 Bleeding events and HPR at one-month in propensity matched pairs of patients who were ticagrelor or prasugrel-treated. Prasugrel Ticagrelor P value Bleeding BARC type 1 N =221 N=221 60(27.1) 79(35.7) 0.05 Bleeding BARC type 2 5(2.3) 5(2.3) 1.0 HPR 12(5.4) 0(0) <0.001 BARC=Bleeding Academic Research Consortium; HPR=high platelet reactivity; MD=maintenance dose.

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72 Prevalence of at least 1 C/SWP concerning safety or efficacy A B Venn diagram showing the prevalence of at least 1 C/SWP for each P2Y12 inhibitor concerning safety (A) and efficacy (B) separately Alexopoulos et al. Circ J 2013;78:180

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75 JACCIntv 2011;4:404

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82 Platelet reactivity measurements reveal patient noncompliance during ticagrelor maintenance therapy. PR post ticagrelor maintenance dose. N=210 Median, (Q1-Q3) are indicated by dotted lines. Noncompliant patients are shown as red bars. PR=Platelet reactivity, PRU= Platelet reaction units. Alexopoulos D, Can J Cardiol 2013;29:1743e13

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86 Patras University Hospital

87 CE Mark approval for use with DAPT Xience Prime and Xience V (everolimus-eluting): Resolute Integrity (Zotarolimus-eluting): 3 months 1 month

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90 Nikolic et al, EHJ 2013;34:220

91 Intern J Cardiol 2013;168:4497

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94 An example of transthoracic Doppler echocardiography images in a single patient LAD baseline (A) and maximal at 110μg/kg/min adenosine infusion rate (B) CBFV recorded at Day 15 while under prasugrel. Same patient s images of baseline (C) and maximal at 110μg/kg/min adenosine infusion rate CBFV (D) on Day 30, while under ticagrelor. The respective ratios of maximalcbfv/baseline CBFV are shown (B, D).

95 AUC of LAD maxcbfv at gradually increasing doses of adenosine. Alexopoulos et al, Circ Cardiovasc Interv 2013;6:277

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97 Varenhorst et al, JACC 2012;60:1623

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100 Turning Basic Research into Clinical Success P2Y 12 Receptor Inhibitors in Acute Coronary Syndromes: From the Research Laboratory to the Clinic and Vice Versa Key Words Introduction Abstract