Ο κ. Γουδέβενος δεν κοµίζει γλαύκας εις Αθήνας

Γλαυκας εις Αθηνας αγει

AΝΤΙΘΡΟΜΒΩΤΙΚΑ

Αντιαιµοπεταλιακά Αντιπηκτικά Ασπιρίνη Ανταγωνιστές Βιτ Κ(Sintrom)

Κλοπιδογρέλη Prasugrel (Efient) Ticagrelor (Brilique) Triflusal (AFLEN) Αναστολείς IIa(θροµβίνης) Διπυριδαµόλη, Cilastazol

Αναστολείς GP IIb/IIIa έµµεσοι: ήπαρίνη, ΧΜΒΗ, Fonta(Arixtra άµεσοι: ενδοφλέβια Μπιβαλιρουδίνη

από το στόµα: anti X: Rivoraxaban(Xarelto) anti II: Dabigatran (Pradaxa)

The evolution of antiplatelet therapy in acute coronary syndrome

85% 15%

DL Bhatt, NEJM 2009; 361(10): 941-943

Προφάρµακο

Ενδιάµεσοςµεταβολίτης

Ενεργόςµεταβολίτης

CYPs [ ήπαρ](3A, 2B6, 2C19, 2C9, 2D6)

Πρασουγρέλη

Εστεράσες [έντερο & ήπαρ]

Χρόνος (h)0 1 2 3 4

Συγκέντρωση

ενεργού

µεταβολίτη

(ng/

mL)

0

200

400

600

800

Pras 60 mg LD

Clop 600 mg LD

Clop 300 mg LD

Υγιείς εθελοντές χωρίς να είναι σε αγωγή µε ΑΣΟ

Pras: Ανιχνεύεται 15’ µετά την δόση φόρτισης και φτάνει το µέγιστο στα 30’

Clop: Ανιχνεύεται 30’ µετά την δόση φόρτισης και φτάνει το µέγιστο σε 1 ώρα

Consequences of the different metabolism

• Fast appearance of its active metabolite ( 15, max30 min)

• Faster and greater mean inhibition of PLT aggregation (IPA)

• No influence of the CYP genotype on its pharmacology

• Much lower variability in the IPA

Προ - φάρµακο

Μετατροπή στον ενεργό µεταβολίτη µέσω του

CYP(ΦΚ)

Αναστολή συσσώρευσης αιµοπεταλίων

(ΦΔ)

Κλινικό αποτέλεσµα

Clinical Trials and Clinical Judgment

The experience and wisdom of a thoughtful physician can make an important contributionto the application of the evidence base that is available

CURRENT TRITON PLATO n: 25 086 n:13 608 n:18 624

75 y 13% 13% 15%PCI 70% 99% 61%CABG 7% 3% 10%NSTEMI 71% 74% 60% PCI 3.2h 2.4 hSTEMI 29% 26% 40% Pr PCI 0.5h <12 h 0.5%

Diabetes Mellitus 30.5 23% 24%FU 30 d 15 months 1 year

CURE n: 12 562 NSTEMI: 100%, PCI: 21%, CABG 16.5%

IPA (%) obtained 4 hours after loading when measured with 20 mol/L ADP with light transmittance aggregometry in patients with ACS

<30 min with 180 mg Ticagrelor same level of inhibitionas with 600mg Clopidogrel at 8 h

CURE clopidogrel for 30 days: 4.3% vs 5.4% (p=0.004)

ΤΙΜΙ major non CABG related

7 ηµέρες

DM

n:3146

n:4 462

n: 7647

Diabetes Mellitus and P2Y12 Inhibitors

Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Net Clinical BenefitDeath, MI, Stroke,

0

5

10

15

0 30 60 90 180 270 360 450Days

Endp

oint

(%)

HR 0.87P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608

-30.0

-22.5

-15.0

-7.5

0

7.5

15.0

1 2

6

-23

Events per 1000 pts

MI Major Bleed(non CABG)

+ All CauseMortalityClop 3.2%Pras 3.0 %

P=0.64

TRITON TIMI 38 Subgroups

of particular concern• Previously known stroke• Elderly(>75 y)• Low body weight (<60 Kg) favourable effects• Diabetes mellitus• STEMI

Angiolillo DJ et al. JACC 2010; 56: 1017-23

0 2

75mg clopidogreln=100

75mg clopidogrel, n=33

10mg prasugrel, n=36

60mg/10mg prasugrel, n=31

4 t (εβδοµάδες)

Angiolillo DJ et al. JACC 2010; 56: 1017-23

*p<0.0001 vs. clopidogrel 75mg†p<0.0001 vs. prasugrel 10mg

Prasugrel vs clopidogrel pharmacology

• Less dependence on CYP enzymes susceptible to genetic variation

• Less drug –drug interaction • More rapid, more consistent (fewer poor

responders), more potent (higher the IPA)• Higher efficacy and lower safety

Δόση Φόρτισης• 60mg

Δόση Συντήρησης• 10mg, 1 x1 για 12µήνες• <60kg: 5mg, 1 x1 για 12µήνες• ≥75ετών: 5mg, 1 x1 για 12µήνες

Περίληψη Χαρακτηριστικών Προϊόντος

ΑntiPLT therapy for individual patients

• The choice and dose of thienopyridine• Invasive strategies• Vascular access• Stent type• Choice and dose of additional antiPLT Antithrombins and • Adjunctive pharmacotherapies

Safety

Significant increase in

serious bleeding(32% increase)

Avoid in pts with prior CVA/TIA

Efficacy

1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%       MI 24%2. An early and sustained benefit3. Across ACS spectrum

Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD

Conclusions

Net clinical benefit significantly favored Prasugrel

Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

Recommendations for the use of Thienopyridines

Prasugrel 60 mg should be given as soon as possible for primary PCI.

MODIFIED Recommendation

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

B

Planned Elective PCIAggregometry and Biomarkers

ASA

Clopidogrel-naive

Clopidogrel600 mg

Prasugrel 60 mg

0.5 hour post-LD Aggregometry and biomarkers

Diagnostic catheterization anatomy suitable for PCI Post-cath aggregometry

Planned GP IIb/IIIa prohibitedn < 180

n = 100 PCI

Post-PCI aggregometry, biomarkers

Primary Endpoint: Mean IPA (6h) in all treated subjects

PHASE I (loading)

PRINCIPLE – TIMI 44

Prasugrel10 mg x

14d14 d clinical events, biomarkers,

aggregometry, CROSSOVER

PRINCIPLE – TIMI 44 (PCI Subjects Only) – Phase II

Clopidogrel 150 mg x 14d

Prasugrel10 mg x

14d 30 d clinical events, biomarkers, aggregometry

Primary Endpoint: Mean IPA (2 and 4 wks) in all treated subjects

PHASE II (Maintenance) PCI

Clopidogrel 150 mg x 14d

Comparison of AntiPLTs agents

• Clopidogrel Prasugrel Ticagrelor• Potency ++ +++ +++• Rapidity of onset + +++ ++++• Variable response Yes No No• Reversibility No No Yes• Hold before CABG(D) 5-7 7-10 2-3• Clinical Experience ++++ + + 0• Bleeding risk + ++ +• Side Effects Rare Rare

Common• Prior Stroke Preferred Contraindicated• Age >75 y Preferred• Diabetes Preferred• Complex stenting Preferred• STEMI Preferred(If PrPCI)