Patras University Hospital

Patras University Hospital

Thrombin generation Coagulation Thrombin PAR-1 ASPIRIN Thromboxanex 5HT A 2 Collagen PAR-4 x TPα GPVI 5HT 2A PLATELET ACTIVATION ADP P2Y 1 ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE CANGRELOR Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen Aggregation α IIb β 3 Patras University Hospital GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Patras University Hospital

Indication in STEMI patients CURRENT ACTIVE CURRENT CASPAR CASPAR CASPAR Indication in patients after MI, IS, or with established PAD Indication in UA/NSTEMI patients CARESS COMMIT CCS2 CHARISMA CHARISMA CHARISMA COMMIT CCS2 COMMIT CCS2 COMMIT CCS2 CLARITY CLARITY CLARITY CLARITY CLARITY CARESS CARESS CARESS CARESS CARESS MATCH MATCH MATCH MATCH MATCH MATCH MATCH CHARISMA COMMIT CCS2 CLARITY CARESS MATCH CREDO CREDO CREDO CREDO CREDO CREDO CREDO CREDO CREDO CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CURE (PCI-CURE) CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CLASSICS CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE CAPRIE 1996 2000 2001 2002 2004 2004 2005 2005 2006 2007 2008 2008 Publication Date Patras University Hospital

Primary Endpoint MI/Stroke/CV Death 0.14 Cumulative Hazard Rate 0.12 0.10 0.08 0.06 0.04 0.02 Placebo + ASA* Clopidogrel + ASA* The primary outcome occurred in 9.3% of pts in the clopidogrel + ASA group and 11.4% in the placebo + ASA group. P=0.00009 N=12,562 20% RRR 0.00 Patras University Hospital 0 3 6 9 12 Months of Follow-Up 12,562 pts within 24 hours after ACS: clopidogrel (300/75 mg) (6259 pts) or placebo (6303 pts) in addition to aspirin for 3 to 12 months *Other standard therapies were used as appropriate. Yusuf S et al. N Engl J Med. 2001;345:494-502.

Patras University Hospital

Patras University Hospital Price et al. EHJ 2008

Patras University Hospital

Patras University Hospital Mega et al. NEJM 2009

12% of PR variation Renal Failure Patras University Hospital

Variation in Response to Antiplatelet Therapy Treatment Failure Complex Biologic Processes Poor Compliance Patras University Hospital Inadequate Response On Lab Test Bleeding Time LTA, PFA-100 Ultegra,Flow Cytom., VASP, VerifyNow Resistance Inadequate Biologic Response

Patras University Hospital Schomig, NEJM 2009

IPA (20 µm ADP, %) 100 80 60 40 20 0 *** *** 0.5 2 4 6 8 12 16 20 24 Hours Patras University Hospital *** CAD patients on ASA PRINCIPLE-TIMI 44 Prasugrel 60 mg Clopidogrel 600 mg ***p<0.0001 Prasugrel vs. Clopidogrel Wiviott SD et al. Circulation 2007 ***

Ticagrelor is metabolized by CYP3A4/5 isoforms Patras University Hospital

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 IPA % 50 * // 40 30 20 10 0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Patras University Hospital // Onset Maintenance Time (hours) Offset Gurbel PA et al. Circulation 2009

Patras University Hospital

Patras University Hospital

No evidence to support use of SCAD 2013 prasugrel/ticagrelor in SCAD pts post-stenting Patras University Hospital

Patras University Hospital

Benefit of Clopidogrel 600/150 for 7 days vs. 300/75, at the expense of an increase in study-defined major bleedings Driven by MI NNT=166 NNT=142 7855 pts who did not undergo PCI no significant difference in end point Patras University Hospital Mehta at al. Lancet 2010

15 CV-Death, MI, CVA Clopidogrel 12.1 138 NNT = 46 Patients (%) 10 Prasugrel 9.9 5 0 Non-CABG major bleeds Prasugrel Clopidogrel 0 30 60 90 180 270 360 450 Days 2.4 1.8 35 NNH = 167 Patras University Hospital Wiviott SD et al NEJM 357: 2001-2015

NNT=71 It's impressive. I like it. But do I believe it? I'm not sure! Improved survival rate with ticagrelor might be due to the decrease in the risk of thrombotic events without a concomitant increase in the risk of major bleeding Patras University Hospital Cannon. et al NEJM 2010

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Class-I recommendation across the board of ACS (USAP, NSTEMI, STEMI) Clopidogrel recommended only if newer agents unavailable or contraindicated Patras University Hospital

Class-I ACS 2011 Ticagrelor 180/90 mg regardless of Tx strategy, including Clopidogrel pretreated pts Prasugrel 60/10 mg in P2Y12 naïve pts, planned for PCI, unless high risk of bleeding Clopidogrel 300/600/75 mg recommended only if newer agents unavailable or contraindicated Double Clopidogrel for 7 days in PCI pts without risk of bleeding (IIa) Ticagrelor or Clopidogrel post-cabg (IIa) Patras University Hospital

NSTEMI + Troponin 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 Double-blind 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 bailout, at 7 days Patras University Hospital Montalescot G et al. Am Heart J 2011;161:650-656

15 Pre-treatment 10.0 CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout Pre-treatment 10.8 Endpoint (%) 10 5 No Pre-treatment 9.8 Hazard Ratio, 1.02 (95% 0.84, 1.25) P=0.81 No Pre-treatment 10.8 Hazard Ratio, 0.997 (95% 0.83, 1.20) P=0.98 No. at Risk, Primary Efficacy End Point: No pre-treatment Pre-treatment Patras University Hospital 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

5 4 Hazard Ratio, 1.90 (95% 1.19, 3.02) P=0.006 Hazard Ratio, 1.97 (95% 1.26, 3.08) P=0.002 Endpoint (%) 3 2 Pre-treatment 2.6 All TIMI Major Bleeding Pre-treatment 2.9 1 0 No Pre-treatment 1.4 No Pre-treatment 1.5 No. at Risk, All TIMI Major Bleeding: No pre-treatment Pre-treatment Patras University Hospital 0 5 10 15 20 25 30 Days From First Dose 1996 2037 1947 1972 1328 1339 1297 1310 1288 1299 1284 1297 1263 1280

Stroke Elderly Conservative Tx (No PCI) PPI Co-Administration Diabetes (Insulin Tx) Renal Failure STEMI Patras University Hospital

Patras University Hospital

No significant treatment-by-stroke history interaction RRR 38% RRR 19% Among pts with a prior stroke or TIA, rate of PLATO defined and non CABG related major bleeding were not significantly different between pts assigned to ticagrelor and clopidogrel No of pts with prior stroke in previous ACS trials is low and the number of excess intracranial bleedings by novel dual antiplatelet therapy even much lower. Routinely treating ACS patients with previous stroke or TIA with novel platelet inhibitors cannot be advised yet Verheugt FWA. Beware of novel antiplatelet therapy in ACS patients with previous stroke. Circulation 2012 Patras University Hospital

In PLATO we did not really see the same concerns, so the over-75s were still the same mortality benefit with ticagrelor compared to clopidogrel as seen in the under-75s and so with ticagrelor, we don't have any particular cautions. Patras University Hospital

Medically Managed UA/NSTEMI Patients Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort Age < 75 years) Median Time to Enrollment = 4.5 Days Medical Management Decision 72 hrs (No prior clopidogrel given) 4% of total Medical Management Decision 10 days (Clopidogrel started 72 hrs in-hospital OR on chronic clopidogrel) 96% of total Clopidogrel 1 300 mg LD + 75 mg MD Prasugrel 1 30 mg LD + 5or 10 mg MD Clopidogrel 1 75 mg MD Prasugrel 1 5or 10 mg MD Patras University Hospital Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke 1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or 75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.

HR (95% CI): 0.96 (0.86, 1.07) P = 0.45 HR (95% CI): 1.23 (0.84, 1.81) P = 0.29 Patras University Hospital NEJM 2012

In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients < 75 years of age No statistical differences in major, life-threatening, or fatal bleeding with prasugrel vs. clopidogrel Secondary analysis of pts aged >75 years (n=2083), who received 5 mg of prasugrel: In pts > 75 yrs and in pts < 60 kg appears to be safe, because there was no increased risk in bleeding Patras University Hospital

Patras University Hospital JACC 2010

Patras University Hospital JACC 2010

Negative studies were mainly studies with low event rates, (COGENT, TRITON-TIMI 38, Collet). In studies with high event rates and high death rates, you start seeing an impact with this prescription of PPIs along with clopidogrel Patras University Hospital JACC 2010

Negative studies were mainly studies with low event rates, (COGENT, TRITON-TIMI 38, Collet) In studies with high event rates and high death rates, you start seeing an impact with this prescription of PPIs along with clopidogrel Patras University Hospital JACC 2010

Patras University Hospital

Patras University Hospital

Patras University Hospital Most common PPIs used were omeprazole and pantoprazole

Substantial treatment effect among patients randomized to prasugrel who were taking a PPI Patients who were not treated with a PPI had lower event rates overall Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

ACS pts managed with a planned non-invasive strategy Ticagrelor achieved a clinically important reduction in ischaemic events and mortality, without increasing major bleeding, compared with clopidogrel. Patras University Hospital BMJ 2011

Patras University Hospital Ferreiro J L, Angiolillo D J Circulation 2011;123:798-813

Patras University Hospital

TGL TGL Patras University Hospital

In consecutive type 2 DM pts with ACS 24 hrs post-pci with DES, 90 mg ticagrelor twice daily vs. 10 mg prasugrel once daily. Patras University Hospital

Patras University Hospital Montalescot G, Silvain J Circulation 2010;122:1049-1052

Of 85 HD patients, 70 (82.4%) showed clopidogrel HTPR (mean, 294.5 69.2 PRU). Compared with clopidogrel responders, poor responders had a lower hemoglobin level and platelet count. In multivariate analysis, use of omeprazole was associated independently with higher risk of HTPR (relative risk, 1.23; 95% CI, 1.01-1.57; P 0.04). Patras University Hospital Alexopoulos et al. AJKD 2012

Patras University Hospital A worrying level of prasugrel resistance was observed in 19% of the cases.

Of 27 patients eligible for platelet reactivity assessment, 24 (88.9%) had high on-treatment platelet reactivity We have observed an inadequate response to ticagrelor in a small minority of treated Pts First report of ticagrelor resistance in patients receiving this medication as a maintenance treatment Patras University Hospital Alexopoulos et al. AJKD 2012

Patras University Hospital

Patras University Hospital

Class-I ACS 2012 Ticagrelor 180/90 mg with no restriction Prasugrel 60/10 mg in clopidogrel naïve pts, if <75 yrs, no-stroke/tia Clopidogrel 300/600/75 mg recommended only if newer agents unavailable or contraindicated ppci Ticagrelor & Prasugrel post-fibrinolysis: Class-III Patras University Hospital

Patras University Hospital

Patras University Hospital

Alexopoulos D, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST elevation myocardial infarction. Circ Cardiovasc Interv. 2012;5:797 804 Patras University Hospital

Patras University Hospital

HN S 4Na + _ O Cl O O P P _ Cl _ O O O P O _ O O N N O OH OH N F F N S F HN S ATP analogue MW=800 Daltons Intravenously administered Almost-immediate" platelet inhibition Very short biological half-life: 3-6 minutes HO N N O OH OH N F F N S F Like ticagrelor, cangrelor is reversible. Normalization of platelet function within 1 hour Patras University Hospital

A pooled pt level analysis of three pivotal CHAMPION trials suggests that cangrelor (the Medicines Company) can reduce the risk of periprocedural thrombotic complications during PCI compared with placebo or clopidogrel, at the expense of some mild bleeding CEP: Absolute difference 1.9% and RRR 19% ST: Absolute difference 0.3% and RRR 41% The FDA accepted the manufacturer's new drug application (NDA) for cangrelor in July 2013. Patras University Hospital

3 GMMMG recommendations March 2009 Drafts Nov 2010, Jan 2011 Massive drop in Clopidogrel cost Plavix 35.64 Patras University Hospital

Ποιό από τα παρακάτω είναι σωστό Α. H πρασουγρέλη και η τικαγκρελόρη είναι αντιστρεπτοί αναστολείς του P2Y12 υποδοχέα Β. ΗτικαγκρελόρηστοSTEMI δρα πιο γρήγορα από την πρασουγρέλη Γ. Ο συνδυασμός τικαγκρελόρης ή πρασουγρέλης με μπιβαλιρουδίνη απαγορεύεται λόγω αιμορραγιών Δ. Κανένα από τα παραπάνω Patras University Hospital

Patras University Hospital

Γυναίκα 68 ετών με ΣΔ υποβάλλεται σε PCI @ DES λόγω ACS (Stent thrombosis). Ποιό από τα παρακάτω ίσως είναι καλύτερο? Α. H πρασουγρέλη Β. Η τικαγκρελόρη Γ. H κλοπιδογρέλη σε διπλάσια δόση (150 mg) Δ. Όλα ίδια είναι... Patras University Hospital

So far, there have been no large randomized trials directly comparing prasugrel and ticagrelor ST rates were halved with prasugrel and cut by 27% with ticagrelor in their respective trials Prasugrel benefits type 2 diabetes patients Patras University Hospital

Γυναίκα 79 ετών με ΣΔ, σοβαρή ΧΝΑ και STEMI, υποβάλλεται σε ppci. Καταληλότερη αγωγή: Α. Πρασουγρέλη 60 +10 Β. Τικαγκρελόρη 180 + 90 χ 2 Γ. Κλοπιδογρέλη 600 + 150 για 7 ημέρες Δ. Κλοπιδογρέλη 600 + 75 Ε. Τα Β και Δ είναι αποδεκτά Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Γυναίκα 79 ετών με ΣΔ, σοβαρή ΧΝΑ και STEMI, υποβάλλεται σε ppci. Καταληλότερη αγωγή: Κλοπιδογρέλη 600 + 75 Patras University Hospital

Γυναίκα 60 ετών με STEMI, υποβάλλεται σε θρομβόλυση και πρόκειται να διακομιστεί για καθετηριασμό. Καταληλότερη αγωγή: Α. ASA + Πρασουγρέλη 60/10 Β. ASA + Τικαγκρελόρη 180/90 χ 2 Γ. ASA + Κλοπιδογρέλη 600/150 για 7 ημέρες Δ. ASA + Κλοπιδογρέλη 300/75 Ε. Τα Β και Δ είναι αποδεκτά Patras University Hospital

Prasugrel and ticagrelor have not been studied as adjuncts to fibrinolysis and should not be given. Patras University Hospital

Ασθενής με ΣΔ και ήπια ΧΝΑ μετά από ACS @ PCI (DES) παρουσιάζει ενδονοσοκομειακή εντερορραγία υπό ASA-τικαγκρελόρη. Καταληλότερη αγωγή: Α. Διακοπή ASA-τικαγκρελόρης => ASA+Πρασουγρέλη 5 αργότερα Β. Διακοπή ASA-τικαγκρελόρης => ASA+Τικαγκρελόρη Γ. Διακοπή ASA-τικαγκρελόρης => ASA+Κλοπιδογρέλη 75 αργότερα Δ. Όλα τα παραπάνω είναι αποδεκτά Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Άνδρας με ΚΜ υπό Sintrom και STEMI, υποβάλλεται σε ppci (BMS) Καταληλότερη αγωγή: Α. ASA + Πρασουγρέλη 60/10 + OAC Β. ASA + Τικαγκρελόρη 180/90 χ 2+ OAC Γ. ASA + Κλοπιδογρέλη 600/150 για 7 ημέρες + OAC Δ. ASA + Κλοπιδογρέλη 300/75 + OAC Ε. Κλοπιδογρέλη 300/75 + OAC Patras University Hospital

Prasugrel and ticagrelor have not been studied as adjuncts to OAC and should not be given. Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Άσθενής 78 ετών με Ηχ γαστρορραγίας, μετά από PCI πρόκειται να λάβει ASA-κλοπιδογρέλη και PPI Α. Συνταγογραφούμε ομεπραζόλη/εσομεπραζόλη χωρίς πρόβλημα Β. Καλύτερα να λάβει παντοπραζόλη (CYP2C19 ουδέτερη) Γ. Καλύτερη επιλογή η ρανιτιδίνη Δ. Καλύτερα να λάβει πρασουγρέλη και PPΙ Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Άσθενής 78 ετών με Ηχ γαστρορραγίας, μετά από PCI πρόκειται να λάβει ASA-τικαγκρελόρη και PPI Α. Συνταγογραφούμε ομεπραζόλη/εσομεπραζόλη χωρίς πρόβλημα Β. Καλύτερα να λάβει παντοπραζόλη (CYP2C19 ουδέτερη) Γ. Καλύτερη επιλογή η ρανιτιδίνη Δ. Καλύτερα να λάβει πρασουγρέλη και PPΙ (Trilogy) Patras University Hospital

Patras University Hospital

Patras University Hospital

Άσθενής 78 ετών με Ηχ ΑΕΕ, και γαστρορραγίας, μετά από PCI @ DES έλαβε ASA-κλοπιδογρέλη και PPI. Μετά από ένα έτος: Α. H ASA αυξάνει πολύ τον κίνδυνο αιμορραγίας. Καλύτερα να λάβει μόνο κλοπιδογρέλη έναντι ASA-PPI Β. Η μονοθεραπεία με κλοπιδογρέλη έχει περισσότερες αιμορραγίες σε σχέση με ASA-PPI Γ. Δε χρήζει PPI Δ. Καλύτερα να λάβει πρασουγρέλη και PPI Ε. Τα Β και Δ είναι αποδεκτά Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Patras University Hospital

Άνδρας με ΣΔ, 73 ετών, με μέτρια ΧΝΑ. Διάγνωση Ca προστάτου προς χ/γείο 3 mo μετά από ACS @ PCI (νεότερο DES) υπό πρασουγρέλη. Ιστορικό ST προ 2ετίας. Καταληλότερη στρατηγική: Α. Αναβολή χ/γείου για 3 μήνες (αν επιτρέπεται) κ μετά διακοπή πρασουγρέλης Β. Διακοπή πρασουγρέλης 7 ημέρες και χ/γείο => Επανέναρξη αργότερα στα 5 mg => 10 mg Γ. Διακοπή πρασουγρέλης 5 ημέρες => GPI-IV bridging => επανέναρξη πρασουγρέλης Δ. Διακοπή πρασουγρέλης 5 ημέρες => Κλοπιδογρέλη Ε. Τα Α & Δ Patras University Hospital

80 year old man post ppci for inferior STEMI, 43 days later interrupted a fixed combination of DAPT including ASA 100 mg and clopidogrel 75 mg o.d. Θα προσδιορίζατε το PRU? Patras University Hospital

Patras University Hospital 80 year old man post ppci for inferior STEMI, 43 days later interrupted a fixed combination of DAPT including ASA 100 mg and clopidogrel 75 mg o.d. PRU = 460. Τι θα δώσετε?

Patras University Hospital