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

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

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

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?

Cumulative incidence (%) PLATO: primary endpoint: K-M estimate of time to major CV event (composite of CV death, MI or stroke) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 No. at risk Ticagrelor9333 Clopidogrel9291 0 2 4 6 8 10 12 8628 8521 Months after randomization 8460 8362 8219 8124 Clopidogrel 6743 6650 Ticagrelor 5161 5096 4147 4047 11.7 9.8 (HR, 0.84; 95% CI, 0.77-0.92; P<0.001) ΝΝΣ 54 Wallentin L, et al. N Engl J Med. 2009;361:1045.

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

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?

Appropriateness of overall P2Y12 inhibitor selection initially and at discharge Int J Cardiol. 2013 Aug 15. doi:pii: S0167-5273(13)01532-5

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

Am Heart J 2009;158:285

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

Endpoint (%) 1 Efficacy End Point @ 7 + 30 days (All Patients) 15 Pre-treatment 10.0 CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout Pre-treatment 10.8 10 No Pre-treatment 10.8 No Pre-treatment 9.8 5 Hazard Ratio, 1.02 (95% 0.84, 1.25) P=0.81 Hazard Ratio, 0.997 (95% 0.83, 1.20) P=0.98 No. at Risk, Primary Efficacy End Point: No pre-treatment Pre-treatment 0 0 5 10 15 20 25 30 1996 2037 1788 1821 Days From First Dose 1775 1809 1769 1802 1762 1797 1752 1791 1621 1616

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

CV death, MI or stroke (%) PLATO elderly patient subgroup analysis: Primary composite endpoint according to age 35 30 25 20 Ticagrelor Clopidogrel 15 10 5 p for interaction = 0.2163 0 25 35 45 55 65 75 85 95 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;

James, Circ 2012

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

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)

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

PRASUGREL CLOPIDOGREL Montalescot G et al Lancet 2009

CV death, MI, or stroke (%) 20 15 PLATO diabetes: Primary composite endpoint Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.88(0.76 1.03) 16.2% 14.1% 10 p for interaction = 0.49 10.2% 8.4% 5 0 No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.83(0.74 0.93) 0 60 120 180 240 300 360 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;31:3006 3016

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

Alexopoulos D, et al. AJKD 2012

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

. Alexopoulos et al

Patras University Hospital CirculationCardiovIntv 2014

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.

Off label 45 patients 3 patients BARC 1 events

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 2014 35/57 (61.4%) of thrombolyzed STEMI s loaded with 300 mg of clopidogrel had HPR

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.

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

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

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

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.

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

JACCIntv 2011;4:404

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

Patras University Hospital

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

Nikolic et al, EHJ 2013;34:220

Intern J Cardiol 2013;168:4497

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).

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

Varenhorst et al, JACC 2012;60:1623

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