ΑΝΤΙΑΙΜΟΠΕΤΑΛΙΑΚΑ ΦΑΡΜΑΚΑ ΣΤΟ ΕΜΦΡΑΓΜΑ ΜΥΟΚΑΡΔΙΟΥ ΜΕ ΑΝΑΣΠΑΣΗ ΤΟΥ ST ΔΙΑΣΤΗΜΑΤΟΣ (STEMI) ΚΛΙΝΙΚΗ ΧΡΗΣΗ ΝΕΟΤΕΡΑ ΔΕΔΟΜΕΝΑ

ΑΝΤΙΑΙΜΟΠΕΤΑΛΙΑΚΑ ΦΑΡΜΑΚΑ ΣΤΟ ΕΜΦΡΑΓΜΑ ΜΥΟΚΑΡΔΙΟΥ ΜΕ ΑΝΑΣΠΑΣΗ ΤΟΥ ST ΔΙΑΣΤΗΜΑΤΟΣ (STEMI) ΚΛΙΝΙΚΗ ΧΡΗΣΗ ΝΕΟΤΕΡΑ ΔΕΔΟΜΕΝΑ Παπαδόπουλος Χριστόδουλος Λέκτορας Καρδιολογίας Γ Πανεπιστημιακή Καρδιολογική Κλινική Γ.Ν. Ιπποκράτειο Θεσσαλονίκη

STEMI MANAGEMENT ESC

Ενεργοποίηση αιμοπεταλίων Ρήξη αθηρωματικής πλάκας Ενεργοποίηση και συσσώρευση αιμοπεταλίων

VORAPAXAR ATOPAXAR Thrombin generation Coagulation Αντιαιμοπεταλιακά φάρμακα Thrombin x PAR-1 Thromboxane A 2 PAR-4 TP a x ASPIRIN Collagen GPVI PLATELET ACTIVATION ADP P2Y 1 ADP Dense granule ADP P2Y 12 CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR Alpha granule Coagulation factors Inflammatory mediators Amplification a IIb b 3 a IIb b 3 Fibrinogen x Aggregation a IIb b 3 GP IIb/IIIa ANTAGONISTS 5 GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Efficacy and safety correlated with IPA Adapted from Jeong YH et al. Circ Cardiov Interv 2010;3:17-26 3.5 3.0 2.5 2.0 y = 0.029x + 1.140 R2 = 0.981 ASA+clopidogrel2 ASA1 ASA+prasugrel3 ASA+ticagrelor4 BLEEDING=non-CABG major 1.5 1.0 Placebo y = -0.007x + 0.927 R2 = 0.931 ASA1 0.5 ASA+clopidogrel2 0 ASA+ticagrelor4 EFFICACY=death/MI/stroke ASA+prasugrel3 0 20 40 60 80 IPA (%) 1. Antithrombotic Trialists Collaboration. BMJ 2002;324:71-86; 2. CURE Trial Investigators. N Engl J Med 2001;345:494-502; 3. Wiviott et al. N Engl J Med 2007;357:2001-2015; 4. Wallentin L et al. N Engl J Med 2009;361:1-13 IPA, inhibition of platelet aggregation

Επιλογή θεραπείας και συμβάματα

STEMI ESC GUIDELINES 2012 DAPT 12 μήνες Τουλάχιστον 1 μήνα με BMS Τουλάχιστον 6 μήνες με DES

ESC GUIDELINES 2014

STEMI ESC GUIDELINES 2012 ΘΡΟΜΒΟΛΥΣΗ

ACC 2013 PCI STEMI

ACC 2013 - LYSIS

Aspirin

Targets for platelet inhibition VORAPAXAR ATOPAXAR Coagulation Thrombin x PAR-1 Thromboxane A 2 PAR-4 TP a x ASPIRIN Collagen GPVI ADP P2Y 1 ADP ADP CLOPIDOGREL PRASUGREL ACTIVE METABOLITE Thrombin generation PLATELET ACTIVATION Dense granule x TICAGRELOR CANGRELOR P2Y 12 Alpha granule Coagulation factors Inflammatory mediators Amplification a IIb b 3 a IIb b 3 Fibrinogen x Aggregation a IIb b 3 GP IIb/IIIa ANTAGONISTS 15 GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

% aggregation Arachidonic acid-induced platelet aggregation in 190 IHD patients 100 Compliance rather than aspirin resistance is important 80 60 40 20 0 On chronic ASA 7 days post ASA Post ASA 300 mg Schwartz et al. Am J Cardiol 2005

CURRENT-OASIS 7 Study Design Patients with UA/NSTEMI planned for early invasive strategy, i.e. intend for PCI as early as possible within 24 hrs RANDOMIZE Clopidogrel High-Dose Group Clopidogrel 600 mg loading dose Day 1 followed by 150 mg from Day 2 to 7; 75 mg from Day 8 to 30 Clopidogrel Standard-Dose Group Clopidogrel 300 mg (+ placebo) Day 1 followed by 75 mg (+ placebo) from Day 2 to 7; 75 mg from Day 8 to 30 RANDOMIZE RANDOMIZE ASA low-dose group At least 300 mg Day 1; 75-100 mg from Day 2 to 30 ASA high-dose group At least 300 mg Day 1; 300-325 mg from Day 2 to 30 ASA low-dose group At least 300 mg Day 1; 75-100 mg from Day 2 to 30 ASA high-dose group At least 300 mg Day 1; 300-325 mg from Day 2 to 30 PCI = percutaneous coronary intervention; UA/NSTEMI = unstable angina/non-st-segment elevation myocardial infarction

Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 HR 0.96 (0.85-1.08) P = 0.489 ASA 81-100 mg ASA 300-325 mg 0 3 6 9 12 15 18 21 24 27 30 Days

Clopidogrel

Biotransformation of Action of P2Y 12 -Antagonists Clopidogrel (pro-drug) hce1 CYP1A2, CYP2B6, CYP2C19 Inactive metabolites 2-oxoclopidogrel (intermediate) CYP2B6, CYP2C9 CYP2C19, CYP3A4/5 Active metabolite Prasugrel (pro-drug) hce2 R-95913 (intermediate) CYP2B6, CYP2C9 CYP2C19, CYP3A4/5 R-138727 (active) Reductases M1 (inactive) Conjugation with cysteine R-119251, R-106583 (inactive) Ticagrelor (drug) CYP3A4/5 UDPGT N-dealkylation UDPGT=UDP Glucuronosyltransferase AR- C124910XX (active) M1 - M10 (inactive) UDPGT CYP3A4/5 AR-C133913XX (inactive) EU SPC Brilique. EMA Assessment Report Brilique, 2011 Giorgi MA, et al. Expert Opin Pharmacother 2011;12:1499-1509

Clopidogrel, CYP 2C19 and stent thrombosis Sibbing, D. et al. Eur Heart J 2009 30:916-922

Clinical outcomes according to platelet aggregometry results with MEA Sibbing, D. et al. JACC 2009; 53: 849-56

Prasugrel

IPA, % Healthy Volunteer Crossover Study of Clopidogrel and Prasugrel 100 IPA (20 M ADP) at 24 Hours 80 60 40 20 0-20 N=64 Response to Clopidogrel 300 mg Response to Prasugrel 60 mg Brandt JT, et al. Am Heart J. 2007;153:66.e9-e16. NB The differences in IPA between antiplatelet agents has not yet been correlated with clinical outcomes 30

Επεισόδια (%) 14 12 10 Αποτελέσματα (t=15μήνες, n=3.534) -21% -21% -25% p=0.0221 p=0.025 p=0.0071-25% 8 p=0.0163 6 4 2 0 cv death/mi/stroke cv death/mi/utvr cv death/mi MI Clopidogrel Prasugrel Montalescot G et al. Lancet 2009; 373(9665): 723-731

Επεισόδια (%) 5 Αποτελέσματα, (t=15μήνες, n=3.534) 4-21% 3 p=0.113-42% -30% 2 p=0.023 p=0.09 1 0 TIMI major TIMI life threatening TiMI major/minor Clopidogrel Prasugrel Montalescot G et al. Lancet 2009; 373(9665): 723-731

Επεισόδια (%) 6 5 Ασφάλεια στους 15 μήνες p=0.649 4 3 p=0.646 2 p=0.75 1 p=0.75 0 TIMI major TIMI life threatening TIMI major/minor Intracrannial bleeding Clopidogrel Prasugrel Montalescot G et al. Lancet 2009; 373(9665): 723-731

Events, % Events, % TRITON-TIMI 38: Bleeding Events 4 2 0 1.8 Clopidogrel Prasugrel 2.4 TIMI Major Bleeds ARD 0.6% HR 1.32 P=0.03 NNH=167 1.4 0.9 0.9 Life Threatening ARD 0.5% HR 1.52 P=0.01 Safety Cohort (N=13,457) ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74 ARD = absolute risk difference; HR = hazard ratio; ICH = intracranial haemorrhage; NNH = number needed to harm; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction. Adapted 34 from Wiviott SD, et al. Presented at: American Heart Association Scientific Sessions 2007; 4-7 November, 2007; Orlando, FL. Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015. 1.1 0.1 Pts w/ Prior Stroke / TIA (N=518) 0.4 0.3 0.3 Nonfatal Fatal ICH 3,0 2,0 1,0 0,0 P=0.02 0 ICH 1 2,3

Ticagrelor

IPA % ONSET/OFFSET Study IPA with ADP 5uM (final extent) 100 90 80 70 * * * * * * * * Ticagrelor 180mg LD / 90 mg bd (n=54) Clopidogrel 600mg LD / 75 mg od (n=50) 60 50 40 30 20 * 10 0 Gurbel PA et al. Circulation 2009 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Onset Maintenance Offset Time (hours)

PLATELET REACTION UNITS (PRU) PLATO PLATELET VerifyNow P2Y12 assay comparing maintenance therapy with clopidogrel (C) vs ticagrelor (T) 500 **** **** 400 300 200 235 PRU 100 0 C T C T Storey RF et al. JACC 2010; in press Trough Peak

Platelet reaction units (PRU), mean VerifyNow P2Y 12 responses during maintenance therapy according to treatment with PPIs: 2 4 hours postmaintenance dose 300 PPI No PPI p=0.005 250 200 150 100 50 p=0.98 0 Ticagrelor Clopidogrel VerifyNow P2Y 12 response Storey RF et al. JACC 2010; in press PPI = proton pump inhibitor

PLATO Study Design Moderate- to High-Risk ACS patients (UA/NSTEMI/STEMI, PCI, Medically-Managed, or CABG) (N=18,624) ASA + Clopidogrel 300 mg ld/75 mg od 600 mg ld allowed in PCI ASA + Ticagrelor 180 mg ld/90 mg bd 12-month maximum exposure (Min = 6 mo, Max = 12 mo, Mean = 11 mo) Primary end point: CVD/MI/stroke Secondary end point: CVD/MI/stroke/revascularisation with PCI; CVD/MI/stroke, severe recurrent ischaemia Recruitment October 2006 to July 2008; results to be presented at ESC September 2009 STEMI = ST-segment elevation myocardial infarction; UA = unstable angina.

Cumulative incidence (%) PLATO: time to first primary efficacy event (composite of CV death, MI or stroke) No. at risk Ticagrelor Clopidogrel 13 12 11 10 9 8 7 6 5 4 3 2 1 0 0 60 120 180 240 300 360 Days after randomisation 9,333 9,291 8,628 8,521 8,460 8,362 Curves are Kaplan-Meier rates, HR = hazard ratio; CI = confidence interval 8,219 8,124 Clopidogrel 6,743 6,743 Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 5,161 5,096 11.7 9.8 4,147 4,047

Cumulative incidence (%) Cumulative incidence (%) Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death 7 Clopidogrel 6.9 7 6 5 Ticagrelor 5.8 6 5 Clopidogrel 5.1 4 4 4.0 3 3 Ticagrelor 2 2 1 0 HR 0.84 (95% CI 0.75 0.95), p=0.005 1 0 HR 0.79 (95% CI 0.69 0.91), p=0.001 No. at risk 0 60 120 180 240 300 360 Days after randomisation 0 60 120 180 240 300 360 Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364

Παρόμοιο όφελος με το BRILIQUE αναφορικά με το κύριο τελικό σημείο σε όλες τις κύριες υπο-ομάδες της PLATO HR BRILIQUE (%) Κλοπιδογρέλη (%) (95% CI) Έμφραγμα του μυοκαρδίου/ Καρδιαγγειακός Θάνατος/ Εγκεφαλικό, K-M % PLATO - Συνολικός πληθυσμός 9.8 11.7 0.84 (0.77-0.92) PLATO-INVASIVE PLATO-MEDICAL PLATO-STEMI PLATO-CABG PLATO-DIABETES 9.0 12.0 9.4 10.6 10.7 14.3 10.8 13.1 0.84 (0.75-0.97) 0.85 (0.73-1.00) 0.87 (0.75-1.01) 0.84 (0.60-1.16) Χωρίς Διαβήτη Με Διαβήτη PLATO-RENAL 8.4 14.1 10.2 16.2 0.83 (0.74-0.93) 0.88 (0.76-1.03) Χωρίς ΧΝΝ (<60 ml/min) ΧΝΝ ( 60 ml/min) PLATO-GENETICS 7.9 17.3 8.9 22.0 0.90 (0.79-1.02) 0.77 (0.65-0.90) Κανένα αλλήλιο που οδηγεί σε μειωμένη λειτουργικότητα του CYP2C19 Οποιοδήποτε αλλήλιο που οδηγεί σε μειωμένη λειτουργικότητα του CYP2C19 8.8 8.6 10.0 11.2 0.86 (0.74-1.01) 0.77 (0.60-0.99) Wallentin L, et al. N Engl J Med 2009;361:1045 1057. Cannon CP, et al. Lancet. 2010;375:283-293 Held C, et al. J Am Coll Cardiol 2011;57:672 684. James S, et al. BMJ 2011;342:d3527. Steg PG, et al. Circulation 2010;122:2131 2141. James S, et al. Eur Heart J 2010;31:3006 3016. James S, et al. Circulation 2010;122:1056 1067. Wallentin L, et al. Lancet 2010;376:1320 1328.

Αιμορραγίες

Τικαγρελόρη και ασπιρίνη FDA black box warning re: ticagrelor and high dose aspirin The United States Food and Drug Administration (FDA) released a black box warning stating that ticagrelor should not be used concurrently with doses of aspirin of more than 100 mg daily.8 This warning was placed because sub-group analysis from the PLATO trial suggested that ticagrelor was of less benefit when used with higher doses of aspirin (> 100 mg daily). However, higher aspirin doses are uncommonly used outside of the United States, and the scientific basis for the warning has been challenged recently in the literature. 8, 9

Αναστολή αιμοπεταλίων τικαγρελόρη έναντι πρασουγρέλης

K-M Εκτιμηθέν Ποσοστό Κύριου Τελικού Σημείου ΚΑ θανάτου/εμ/εγκεφαλικού (%) PLATO Non Invasive: Καρδιαγγειακός Θάνατος ή ΕΜ ή Εγκεφαλικό Κύριο Τελικό Σημείο Αποτελεσματικότητας Μη Επεμβατική Αντιμετώπιση 16 14 12 10 8 6 4 2 0 P<0.045 HR: 0.85 (95% CI, 0.73 1.00) 0 60 120 180 240 300 360 14.3% 12% 2.3% ΑRR 15% RRR Ημέρες Μετά την Τυχαιοποίηση Αρχική Πρόθεση για Μη-Επεμβατική Αντιμετώπιση: 28% των ασθενών στην PLATO Ασθενείς σε κίνδυνο ΤΙκαγρελόρη 2,601 2,392 2,326 2,247 1,854 1,426 1,099 Κλοπιδογρέλη 2,615 2,392 2,328 2,243 1,835 1,416 1,109 James S, et al. BMJ 2011;342

Επιλογή αντιαμοπεταλιακών σε διάφορα κλινικά σενάρια

IIb IIIa Inhibitors Abciximab Eptifibatide Tirofiban

IIb IIIa Inhibitors ΕΝΔΕΙΞΗ IIa

Cangrelor

Impedance, ohms Cangrelor Pharmacodynamics Whole-Blood Impedance Aggregometry 16 14 12 Infusion 15 µg/kg bolus + 2 µg/kg/min infusion 10 8 6 4 30 µg/kg bolus + 4 µg/kg/min infusion 2 0 0 20 40 60 80 100 120 140 160 Time, min 55 Steinhubl SR, et al. The Medicines Company. Data on file. Available at: http://clintrialresults.org. Accessed 14 April, 2008.

BRIDGE study design (provisional) ACS treated with clopidogrel, scheduled for CABG Stop clopidogrel x days prior to CABG Placebo infusion Cangrelor infusion PD measurements Stop x hours prior to CABG surgery Primary objective: To assess safety of cangrelor compared to placebo prior to CABG surgery 1 o end point: Bleeding 2 o end points: Inhibition of platelet function, ischaemic events

58 Targeting PAR-1

Vorapaxar Vorapaxar (SCH 530348) is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. Preclinical and early clinical studies have demonstrated vorapaxar to have antithrombotic properties, with no increase in bleeding time or clotting times (aptt, PT, ACT). Galbulimima baccata Himbacine derivative Bark of the Australian Magnolia Found in the tropical zones of eastern Malaysia, New Guinea, northern Australia and the Solomon Islands.

TRACER Study Design Moderate- to High-Risk ACS patients (UA/NSTEMI, PCI, Medically-Managed, or CABG) (N=10,000) Standard therapy + placebo Standard therapy + SCH 530548 40 mg LD then 2.5 mg od 12-month minimum exposure Primary end point: CV death/mi/stroke/recurrent ischaemia with rehospitalisation/urgent coronary revascularisation Study started December 2007 Estimated study completion July 2011

? VORAPAXAR ATOPAXAR Thrombin generation Coagulation Αντιαιμοπεταλιακά φάρμακα Thrombin x PAR-1 Thromboxane A 2 PAR-4 TP a x ASPIRIN Collagen GPVI PLATELET ACTIVATION ADP P2Y 1 ADP Dense granule ADP P2Y 12 CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR Alpha granule Coagulation factors Inflammatory mediators Amplification a IIb b 3 a IIb b 3 Fibrinogen x Aggregation? a IIb b 3 GP IIb/IIIa ANTAGONISTS 63 GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

ORAL New Anticoagulants PARENTERAL TTP889 X TF/VIIa IX TFPI (tifacogin) APC (drotrecogin alfa) Rivaroxaban IXa VIIIa stm (ART-123) Apixaban LY517717 Va YM150 AT Fondaparinux DU-176b Xa Idraparinux Betrixaban TAK 442 II DX-9065a Dabigatran IIa Bivalirudin Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2007

Back up slide

TRITON-TIMI 38 PLATO-Invasive Δημογραφικά στοιχεία TRITON-TIMI38 PLATO-PCI Ασθενείς 13.608 13.408 Διάρκεια 15μήνες 12μήνες UA/NSTEMI 74% 50,5% STEMI 26% 49,5% NEJM 2007; 152: 2001-2015 Lancet 2010; 375: 283-293