Νεόηερα δεδομένα ζηην ανηιαιμοπεηαλιακή αγωγή αζθενών με καρδιαγγειακή νόζο. Υπάρχει θέζη για ηα γενόζημα ηης κλοπιδογρέλης;

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1 ΠΑΝΔΠΙΣΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΔΡΔΤΝΗΣΙΚΟ ΚΔΝΣΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Νεόηερα δεδομένα ζηην ανηιαιμοπεηαλιακή αγωγή αζθενών με καρδιαγγειακή νόζο. Υπάρχει θέζη για ηα γενόζημα ηης κλοπιδογρέλης; Αλέξανδπορ Γ. Τζελέπηρ, MD, PhD Καθηγηηήρ Βιοχημείαρ - Κλινικήρ Χημείαρ

2 P2Y 12 antagonists Kalantzi KI, et al. Exp Rev Clin Pharm. 2012, Accepted

3 IPA % (20 µm ADP) Prasugrel Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI *** *** Prasugrel 60 mg *** 60 *** 40 Clopidogrel 600 mg 20 ***p< Prasugrel vs. Clopidogrel IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Hours Wiviott SD et al. Circulation 2007;116(25):

4 TRITON-TIMI 38

5 The Incidence of the Primary Safety End Point of Non-CABG- Related Major TIMI Bleeding in the TRITON-TIMI 38 Study Analyses Spinler SA, et al. J Manag Care Pharm. 2009;15(5):

6 TRITON TIMI-38 Prasugrel should not be administered in: Patients with previous stroke >75 years old Weighing <60 kg

8 Ticagrelor Inhibition of platelet reactivity Gurbel PA, et al. Circulation. 2009;120: Gurbel PA, et al. Circulation 2010;121;

9 PLATO Kaplan-Meier estimate of time to first primary efficacy endpoint (composite of CV death, MI or stroke) Wallentin L, et al. N Engl J Med 2009;361:

10 K-M estimated rate (% per year) Non-CABG & CABG related bleeding NS 7.9 Ticagrelor Clopidogrel p= NS p= Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Wallentin L, et al. N Engl J Med 2009;361:

11 New P2Y 12 antagonists The new P2Y12 antagonists, prasugrel and ticagrelor, are characterized by more potent antiplatelet effects and reduce recurrent ischemic event rates compared with clopidogrel among ACS patients These antagonists are associated with an increased risk of bleeding, which has emerged as an important predictor of poor long-term outcomes, including increased mortality Therefore the potential benefits associated in terms of reduction of ischemic events need to be kept in perspective with known bleeding complications

12 Clopidogrel Efficacy and Safety Profile Has been Established in More than 100,000 Patients Ongoing Trials Published Trials Published Trials Indication in STEMI patients Ongoing Trials ACTIVE CURRENT 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 Publication Date Expected Date of Results

13 Clopidogrel Resistance Response variability

14 Association between the CYP2C19*2 Reduced-Function Allele and the Primary Efficacy Outcome or Stent Thrombosis in Subjects Receiving Clopidogrel Mega JL, et al. N Engl J Med 2009;360:354-62

15 Patients (%) Patients (%) Patients (%) Patients (%) The First Clopidogrel Resistance Study (300 mg): A Fingerprint of Clopidogrel Response Variability 2 Hours 24 Hours 24 Resistance Resistance = 63% Resistance 20 Resistance = 31% (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] Aggregation (%) -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] Aggregation (%) 5 Days 30 Days 22 Resistance Resistance = 31% 28 Resistance = 15% Resistance -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60 Aggregation (%) -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] Aggregation (%) Gurbel PA, et al. Circulation. 2003;107:

16 The clopidogrel-induced platelet inhibition are improved in clopidogrel non-responders at 30 days of therapy with 75 mg/day Responders Nonresponders Kalantzi KI, et al. J Thromb Haemost. 2011;9: Kalantzi KI, et al. Platelets. 2012; In Press

17 Effects of Each Additional Bolus of Clopidogrel on the VASP Index in the VASP-Guided Group After the initial dose up to 3 additional boluses of 600 mg may be given in 24 h increments The VASP index was assessed after 12 h until a VASP index below 50% was obtained Bonello et al. J Am Coll Cardiol 2008;51:

18 CURRENT OASIS 7 In patients undergoing PCI for ACS, a 7-day double-dose clopidogrel regimen was associated with a reduction in CV events and stent thrombosis compared with the standard dose. A double-dose clopidogrel regimen can be considered for all patients with ACS treated with an early invasive strategy and intended early PCI Mehta SR. Lancet. 2010; 376:

19 ELEVATE-TIMI patients with stable CVD On-Treatment Platelet Reactivity Across Genotype and Clopidogrel Daily Dose Mega JL, et al. JAMA 2011;306(20):

20 Correlation of IPA with plasma levels of clopidogrel metabolites Compliant patients Predictive value, c-statistic = Noncompliant patients Serebruany V, et al. Am Heart J, 2009; 158:925-32

21 Γελόζεκα άιαηα Κινπηδνγξέιεο Clopidogrel besylate

22 Generic Γελόζεκν Οπζησδώο όκνην Κάζε θαξκαθεπηηθό πξντόλ, θπξίσο ζπλζεηηθό, πνπ έρεη ηελ ίδηα πνηνηηθή θαη πνζνηηθή ζύζηαζε ζε δξαζηηθά ζπζηαηηθά θαζώο θαη ηελ ίδηα θαξκαθνηερληθή κνξθή κε ην πξντόλ αλαθνξάο πνπ έρεη απνιέζεη ηελ πξνζηαζία ηνπ δηπιώκαηνο επξεζηηερλίαο Σα δηαθνξεηηθά άιαηα, εζηέξεο, αηζέξεο, θιπ ζεσξνύληαη σο ην ίδην δξαζηηθό ζπζηαηηθό, εθηόο εάλ δηαθέξνπλ ζηελ αζθάιεηα θαη ηελ απνηειεζκαηηθόηεηα Πξέπεη λα έρνπλ επηδείμεη νκνηόηεηα ζε θιηληθέο κειέηεο βηντζνδπλακίαο Τπόθεηληαη ζηα ίδηα απζηεξά πξόηππα πνηόηεηαο κε ηελ ίδηα αλακελόκελε απνηειεζκαηηθόηεηα θαη αζθάιεηα κε ηα πξσηόηππα Κνζηίδνπλ πνιύ ιηγόηεξν από ηα πξσηόηππα, άξα απνηεινύλ ρακεινύ θόζηνπο θαη πςειήο πνηόηεηαο θάξκαθα γηα ηα εζληθά ζπζηήκαηα πγείαο θαη γηα ηνπο αζζελείο

23 Clopidogrel Clopidogrel Bisulphate Bisulphate ion Clopidogrel Besylate Benzenesulfonic acid (Besylate)

24 Δπίπεδα κεηαβνιηηώλ θινπηδνγξέιεο ζε θπζηνινγηθά άηνκα Inactive carboxylic acid metabolite (SR26334) Clopidogrel Kim S-D, et al. Clin Ther. 2009;31:

25 Αλαζηνιή ηεο ζπζζώξεπζεο ησλ αηκνπεηαιίσλ ζε θπζηνινγηθά άηνκα Kim S-D, et al. Clin Ther. 2009;31:

26 Γελόζεκα θινπηδνγξέιεο Γελ γλσξίδνπκε αλ νη γελόζεκεο κνξθέο θινπηδνγξέιεο είλαη θαξκαθνδπλακηθά ηζνδύλακεο κε ην πξσηόηππν ζθεύαζκα θινπηδνγξέιεο ζηνπο CAD αζζελείο Η θινπηδνγξέιε είλαη ην πην ζεκαληηθό θάξκαθν πνπ ρξεηάδεηαη λα έρεη θαξκαθνδπλακηθή ηζνδπλακία κε ην πξσηόηππν ζθεύαζκα δηόηη εάλ απηή δελ ππάξρεη νη ζπλέπεηεο γηα ηνλ αζζελή ζα είλαη θαηαζηξνθηθέο Έλα αληηζξνκβσηηθό είλαη ην πην ζεκαληηθό θάξκαθν πνπ ζπληαγνγξαθεί ζήκεξα έλαο θαξδηνιόγνο ζηνπο ACS αζζελείο θαη ηδηαίηεξα ζε απηνύο πνπ ππνβάιινληαη ζε αγγεηνπιαζηηθή Professor Paul A. Gurbel 2010

27 CHS versus CB in patients with a history of an ACS

28 Tsoumani ΜΔ, et al. Treatment Strategies Cardiology. 2011; 3(2): Tsoumani ΜΔ, et al. Angiology. 2012, In Press

29 Platelet function tests Clopidogrel resistance: Flow cytometric analysis of VASP-P was performed and the platelet reactivity index (PRI) was calculated. Platelet aggregation to ΑDP (10, 5, 2.5 κμ), AA (10 κμ) and TRAP ((10 κμ) was studied by Light Transmission Aggregometry (LTA). Platelet-mediated inflammatory response: The membrane expression of P-selectin and the circulating platelet-leucocyte conjugates was studied by Flow Cytometry in whole-blood, before and after activation with 100 κm of ADP. Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

30 No difference in the above parameters was observed between CHS and CB groups Tsoumani ΜΔ, et al. Treat Strat Cardiol. 2011; 3(2): Tsoumani ΜΔ, et al. Angiology. 2012, In Press

3% PRI values (mean±sd, 38.6±12.7%) 92.7% Tsoumani ΜΔ, et al.

31 VASP analysis PRI values ranged from 5% to 70.1% CB PRI values (mean±sd, 37.1±14.2%) Responders Non-responders 8.9% 91.1% CHS Responders Non-responders 7.3% PRI values (mean±sd, 38.6±12.7%) 92.7% Tsoumani ΜΔ, et al. Treatment Strategies Cardiology. 2011; 3(2): Tsoumani ΜΔ, et al. Angiology. 2012, In Press

32 Tsoumani ΜΔ, et al. Treatment Strategies Cardiology. 2011; 3(2): Tsoumani ΜΔ, et al. Angiology. 2012, In Press

33 Tsoumani ΜΔ, et al. Treatment Strategies Cardiology. 2011; 3(2): Tsoumani ΜΔ, et al. Angiology. 2012, In Press

34 CHS versus CB in ACS patients undergoing PCI

35 CHS versus CB in ACS patients undergoing PCI Platelet function testing at 5-days of treatment Platelet function testing Before clopidogrel administration (baseline) ACS patients (n=45) ACS patients (n=96) Randomization CHS (Plavix ) 600 mg loading dose, 75 mg/day Aspirin 325 mg loading dose, 100 mg/day LMWH (enoxaparin) 1mg/Kg/12h Atorvastatin (40 mg/day) ACS patients (n=51) CB (Clovelen ) 600 mg loading dose, 75 mg/day Aspirin 325 mg loading dose, 100 mg/day LMWH (enoxaparin) 1mg/Kg/12h Atorvastatin (40 mg/day) Platelet function testing At 1-month of follow-up Angiography was performed in all patients within 72 hours of hospital admission. Patients were then underwent a PCI performed within the first 4 days from clopidogrel loading Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

36 Demographic and Clinical Characteristics of the Study Population No difference in the above parameters was observed between CHS and CB groups Demographic, clinical and laboratory characteristics of the study population Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

37 Platelet function tests Clopidogrel resistance: Flow cytometric analysis of VASP-P was performed and the platelet reactivity index (PRI) was calculated. Platelet aggregation to ΑDP (10, 5, 2.5 κμ), AA (10 κμ) and TRAP ((10 κμ) was studied by Light Transmission Aggregometry (LTA). Platelet-mediated inflammatory response: The membrane expression of P-selectin and the circulating platelet-leucocyte conjugates was studied by Flow Cytometry in whole-blood, before and after activation with 100 κm of ADP. Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

38 5-days VASP analysis CB 1-month 23,5% 76,5% Responders Non-responders 11,8% 88,2% CHS 22,2% 11,1 77,8% Responders Non-responders 88,9 Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

39 Maximoun Aggregation, % Maximum Aggregation, % Platelet aggregatory response to ADP at baseline, 5-Days and 1-Month postclopidogrel loading ADP, 2.5 κm ADP, 5 κμ ADP, 10κΜ Βaseline 5-Days 1-Month CHS ADP, 2.5 κm ADP, 5 κμ ADP, 10κΜ CB Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

40 IPA, % IPA values at 5-Days and 1-Month postclopidogrel loading CHS CB ADP, κm ADP, κm 5-Days 1-Month Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

41 Maximum Aggregation, % Maximum Aggregation, % Platelet aggregatory response to AA and TRAP at baseline, 5-Days and 1-Month postclopidogrel loading Βaseline 5-Days 1-Month AA, 10 κμ TRAP, 10 κμ AA, 10 κμ CHS TRAP, 10 κμ CB Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

42 IPA, % IPA values at 5-Days and 1-Month post-clopidogrel loading CHS CB AA, 10 κμ TRAP, 10 κμ AA, 10 κμ TRAP, 10 κμ 5-Days 1-Month Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

43 P-selectin expression and platelet-leukocyte conjugates in ACS patients treated with CB or CHS Data are expressed as mean ± SD. *p < 0.01, ** p < compared with corresponding baseline values. Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

44 ΤΜΠΕΡΑΜΑΣΑ Η βεζςλική κλοπιδογπέλη (Clovelen ) έσει όμοιο θαπμακαδςναμικό πποθίλ με ηην όξινη θειική κλοπιδογπέλη (Plavix ) ηόζο ζε αζθενείρ με ιζηοπικό ενόρ ACS όζο και ζε ACS αζθενείρ πος ςποβάλλονηαι ζε PCI Με δεδομένο ηην πλειάδα ιδιοζκεςαζμάηων βεζςλικήρ κλοπιδογπέληρ πος είναι ζήμεπα εμποπικά διαθέζιμα, θα ππέπει ηα οποιαδήποηε κλινικά δεδομένα ή επεςνηηικά αποηελέζμαηα πποκύπηοςν από ηη σπήζη αςηών ηων ζκεςαζμάηων ζε CAD αζθενείρ να αναθέπονηαι ζηο ζςγκεκπιμένο ιδιοζκεύαζμα ηο οποίο έσει σπηζιμοποιηθεί και όσι γενικά ζηο άλαρ ηηρ βεζςλικήρ κλοπιδογπέληρ Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13:

45 Ioannina

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