ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ. Αμφιλεγόμενα θέματα για το ρόλο των αντιαιμοπεταλιακών και αντιπηκτικών φαρμάκων σε ασθενείς υψηλού καρδιαγγειακού κινδύνου

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1 ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Αμφιλεγόμενα θέματα για το ρόλο των αντιαιμοπεταλιακών και αντιπηκτικών φαρμάκων σε ασθενείς υψηλού καρδιαγγειακού κινδύνου Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχημείας - Κλινικής Χημείας

2 Disclosures I have received Research grants as well as honoraria from AstraZeneca Hellas, Bayer Hellas ABEE, Boehringer Ingelheim Hellas SA, Bristol Myers Squibb AE, Elpen, Pfizer Hellas SA and Sanofi Hellas

3 Antithrombotic drugs Tsoumani M, Tselepis AD. CPD 2016

4 Αντιαιμοπεταλιακά-αντιπηκτικά φάρμακα Αμφιλεγόμενα θέματα Αντίσταση Εργαστηριακή παρακολούθηση Διάρκεια θεραπείας διπλής αντιαιμοπεταλιακής αγωγής Τριπλή αντιαιμοπεταλιακή αγωγή Συνδυασμός αντιαιμοπεταλιακών-αντιπηκτικών Διάγνωση-Αντιμετώπιση αιμορραγικού κινδύνου Αντίδοτα Χρόνος διακοπής-επανέναρξης της αγωγής κατά τη διάρκεια επέμβασης Παρεμβάσεις γεφύρωσης κατά τη διάρκεια επεμβάσεων

5 Αντίσταση στην Αντιαιμοπεταλιακή Αγωγή High on-treatment Platelet Reactivity (HTPR) Ασπιρίνη Κλοπιδογρέλη

6 Risk of any cardiovascular event in HTPR to Aspirin patients Prevalence: 5-65% (mean: 24%) Krasopoulos G, et al. BMJ, 2008

7 HTPR to Clopidogrel Kaplan-Meier analysis for the cumulative incidence of stent Thrombosis and for the composite of death or stent thrombosis Sibbing D, et al. J Am Coll Cardiol 2009;53:849 56

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9 20-30% στους Καυκάσιους Varenhorst Ch, et al. Eur Heart J. 2009;30:

10 Definite or Probable Stent Thrombosis (%) CYP2C19*2 Allelic Variant and MACE TRITON-TIMI 38 Analysis; Clopidogrel in ACS Patients 12.1 Carriers P=0.01 Non-carriers Carriers P= Non-carriers 0.6 * Death from cardiovascular causes, myocardial infarction, or stroke Days After Randomization Days After Randomization Mega JL et al. N Engl J Med. 2009;360:

11 Προθρομβωτική κατάσταση στο Τ2ΣΔ Αυξημένη αιμοπεταλιακή ενεργότητα the Diabetic Platelet Αυξημένη πηκτικότητα Διαταραχές ινωδόλυσης Ενδοθηλιακή δυσλειτουργία

12 Prothrombotic mechanisms in DM Vazzana Ν, et al. Thromb Res. 2012;129:

13 Platelet aggregation (%) INFLUENCE OF DM ON CLOPIDOGREL EFFECTS Acute Phase of Treatment DM No-DM P=0.04 8% Long-term Phase of Treatment P=0.002 P< % 14% 6% 56% 78% hrs post 300 mg LD Non-responders (Platelet inhibition <10%) Low responders (Platelet inhibition 10-29%) Responders (Platelet inhibition >30%) 20 0 DM No DM DM No DM ADP 20 M ADP 6 M Angiolillo DJ et al. Diabetes. 2005;54: Angiolillo DJ et al. J Am Coll Cardiol. 2006;48:

14 % Event-Free Survival HIGH PLATELET REACTIVITY AND MACE IN DM 100% MACE (CV death, STEMI, UA/NSTEMI, stroke) % Log Rank, p = % >62% HPR (n=45) <62% non-hpr (n=128) ROC defined cut-off value 20 0 HR: 3.35; 95% CI, ; p= Months Angiolillo DJ et al. J Am Coll Cardiol. 2007;50:1541-7

15 ADP Receptor Antagonists IN DM Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach TRITON-TIMI ( ) PLATO ( ) CURRENT OASIS ( ) (PCI Cohort) New Drug/Approach Better Standard Clopidogrel Better Ferreiro JL et al. Circulation :

16 Εργαστηριακή διερεύνηση της αποτελεσματικότητας των αντιαιμοπεταλιακών φαρμάκων

17 Flow Cytometer (FACSCalibur) Optical Lumi-Aggregometer VerifyNow Μultiple electrode platelet aggregometer Haemoscope TEG PFA-100

18 Evidence for P2Y12 Receptor Reactivity Associated With Post-PCI Ischemic and Bleeding Events Tantry US, et al. J Am Coll Cardiol 2013;62:

19 Platelet function or genetic testing Platelet function or genetic testing may be considered in selected patients treated with clopidogrel, including those with a history of stent thrombosis, suspected noncompliance, as well as persistent high on-treatment platelet reactivity or high bleeding risk in the presence of stents in critical coronary segments (e.g. left main trunk). ESC Guidelines for NSTEMI 2015

20 Διάρκεια θεραπείας με DAPT

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27 The DAPT risk prediction model Patients with high DAPT score ( 2) achieved a greater benefit of prolonged DAPT than those with low DAPT score (<2) Park Y, et al. Circ J. 2016;80:

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31 Τριπλή αντιαιμοπεταλιακή αγωγή

32 Antiplatelet effects of different treatment strategies to optimize platelet inhibition in DM Τσουμάνη ΜΕ, και συν. Καρδιά και Αγγεία. 2014;

33 Cilostazol-Based TAPT Role in ACS/PCI

34 Change of P2Y12 Reaction Units p < by ANOVA p < p = (%) 43±24 p = ±28 11±23 Jeong YH et al. Circ Cardiovasc Interv 2010:3:17-26.

35 ACCEL-DM STUDY A Pharmacodynamic Study of TRIPLE versus DOUBLE in high-risk T2DM patients after PCI TRIPLE group: Cilostazol (100 mg b.i.d.), clopidogrel (75 mg/d), aspirin (200 mg/d) for 30d DOUBLE group: Clopidogrel (150 mg/d) and aspirin (200 mg/d) for 30d Jeong Y-H, et al. Diabetes Care 2012;35:

36 Cilostazol-Based TAPT: Effect on Restenosis DES In-Stent Restenosis Rate Pooled Analysis of DECLARE Trials Triple (n=586) P interaction = Standard (n=587) % % % 91% 15% 43% P= P=0.004 P=0.019 Cypher Taxus Endeavor Lee SW et al. Am J Cardiol 2013;112:

37 Efficacy of cilostazol on CV outcomes in PCI A meta-analysis of randomised trials ( 14,116 patients) MACE 32% reduction No difference in bleeding Bangalore S, et al. Open Heart 2014;1:e000068

38 Vorapaxar-Based TAPT

39 PARs in human platelets PAR-1: High affinity receptor Human Platelet PAR-4: low affinity receptor

40 Proteolytic Activation of PAR-1 by Thrombin Extracellular cleavage Cleavage site site Hirudin-like binding site Tethered ligand SFLLRN Intracellular

41 PAR-1 Antagonist SPRI A PAR-1 antagonist should block tethered ligand mechanism Thrombin LDPR SFLLRNP LDPR NRLLFS Vorapaxar X Signal 41

42 Stable patients with previous MI CV Events Bleeding Scirica ΒΜ, et al. Lancet. 2012; 380:

43 FDA Approved Vorapaxar Ιn May 2014, FDA approved vorapaxar, Zontivity (Merck & Co Inc's), in patients with prior MI or with PAD.

44 Incidence of CV death, MI or Stroke with vorapaxar vs placebo stratified by diabetic status ARD: absolute risk difference; HR: hazard ratio; NNT: number needed to treat Cavender MA, et al. Circulation. 2015;131:

45 DOACs Target Sites Factor IX Factor VII FIXa Factor X FVIIa Anti-FXa Apixaban Rivaroxaban Edoxaban Factor Xa Factor II (Prothrombin) Factor IIa (Thrombin) Anti-FIIa Dabigatran Fibrinogen Fibrin

46 Risk factor-based point-based scoring system - CHA 2 DS 2 -VASc *Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates.

47 Estimates risk of major bleeding for patients on anticoagulation to assess risk-benefit in AF care

48 Συστάσεις ESC 2012 Επιλογή αντιπηκτικής αγωγής

49 Laboratory monitoring of DOACs

50 Nο Laboratory Monitoring in Daily Practice Predictable pharmacokinetics and pharmacodynamics Rapid onset of action Wide therapeutic window Fixed dose Clinical trials without monitoring

51 Laboratory Monitoring is Sometimes necessary Bleeding or thrombotic event High risk for bleeding Elective or urgent surgery Suspected overdose Renal or hepatic dysfunction Bridging from one anticoagulant to another Compliance monitoring Pts with low body weight or obese pts Co-medications (potential drug interactions)

52 Influence of DOACs on clotting tests PT aptt TT or Ecarin Clotting Time Anti-Xa (Chromogenic assays) dtt (Hemoclot, etc) Dabigatran Rivaroxaban Apixaban

53 Τριπλή αντιθρομβωτική αγωγή Αντιαιμοπεταλιακά-DOACs

54 ATLAS ACS 2 TIMI 51: Rivaroxaban in Patients with a Recent ACS Connolly SJ et al. Presented at ESC 2010 Mega JL, et al. N Engl J Med 2012;366:9-19

55 ATLAS ACS 2 TIMI 51 Connolly SJ et al. Presented at E Mega JL, et al. N Engl J Med 2012;366:9-19

56 ESC 2015 Guidelines on NSTE-ACS with AF Eur Heart J. 2015

57 Αντίδοτα

58 Idarucizumab: Mechanism of Action Thrombin Idarucizumab Thrombin-bound Dabigatran 37kDa 350-fold higher affinity 47,8kDa Free Dabigatran No procoagulant activity Dabigatran Active Metabolites Short Half-life KIDNEYS

59 A multicentre, open-label, single-arm Phase III trial 50-ml bolus *Other than bleeding Pollack CV, et al. Thromb Haemost 2015; 114:

60 RE-VERSE AD Primary endpoint in Group A: Reversal of dabigatran anticoagulation based on dtt and ECT Pollack CV, et al. NEJM. 2015;373:511-20

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