ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Νεώτερααντιαιμοπεταλιακάκαι αντιπηκτικά φάρμακα. Φαρμακοδυναμικά χαρακτηριστικά και κλινική αξιολόγηση Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχημείας - Κλινικής Χημείας
Αιμόσταση Θρόμβωση Φλεβική Αρτηριακή
Αιμόσταση Αγγειοσύσπαση και σχηματισμός αιμοπεταλιακής πλάκας
Αιμόσταση: Πήξη και σταθεροποίηση θρόμβου Ενδογενής οδός Εξωγενής οδός XII XI Ιστικός Παράγων (TF) AT IX VIII X V VII FXa FVa Φωσφολιπίδια Ca ++ II Ινωδογόνο Προθρομβινάση FXa Θρομβίνη Ινώδες
The Fibrinolytic System Marın F,et al. Thrombosis Research 109 (2003) 233 240
Triggers of arterial and venous thrombosis Artery Vein Nigel Mackman, Nature (2008) 451:914 918
Φλεβική θρομβοεμβολική νόσος (VTE) Η VTE χαρακτηρίζεται από την παρεμπόδιση της ροής του αίματος στο φλεβικό δίκτυο εξαιτίας της ύπαρξης θρόμβου Η VTE διακρίνεται σε: Εν τω βάθει φλεβική θρόμβωση (DVT) Πνευμονική εμβολή (PE) Anderson FA, et al. Center for Outcomes Research, University of Massachusetts Medical Center; 1998 Goldhaber SZ. J Am Coll Cardiol 1992;19:246 247
H DVT πιθανώς αρχίζει στις βαλβίδες Στάση (χαμηλό shear stress), Υποξία, Υπερπηκτικό μικροπεριβάλλον, Ακέραιο ενδοθήλιο με διαταραγμένη λειτουργικότητα Πνευμονική εμβολή
Components of Virchow s Triad for thrombogenesis in AF Watson T, et al. Lancet 2009; 373: 155 66
3. Thrombus formation in the left auricle (computer graphics superimposed on in-body photograph) The irregular beating of the heart in atrial fibrillation creates ideal conditions for thrombus formation in the left auricle, especially in patients with mitral valve insufficiency.
7. Cerebral thromboembolism (computer graphics superimposed on in-body photograph) 25 percent of the blood flow from the heart is pumped to the brain. Cerebral thromboemboli most frequently affect the middle cerebral artery.
Stroke in Atrial fibrillation Cerebral circulation Stroke Right atrium Left atrium Results in adnormal blood flow and stasis in the atria
Αρτηριακή Θρόμβωση Ρήξη αθηρωματικής πλάκας Ενεργοποίηση και συσσώρευση αιμοπεταλίων
Rivaroxaban Apixaban Dabigatran
Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction Treatment Better Treatment Worse Warfarin vs. Placebo/Control 6 Trials n = 2,900 Antiplatelet drugs vs. Placebo 8 Trials n = 4,876 100% 50% 0-50% Hart R, et al. Ann Intern Med 2007;146:857.
New Oral Anticoagulants
Δράση των άμεσων αναστολέων της Θρομβίνης FXa στο σύμπλεγμα της Προθρομβινάσης Άμεσοι Αναστολείς της Θρομβινης FΙΙa στο Ινώδες FΙΙa Οι άμεσοι αναστολείς της θρομβίνης αναστέλλουν τόσο τη ελεύθερη όσο και τη δεσμευμένη στο ινώδες θρομβίνη
Δράσεις των άμεσων αναστολέων του Xa FXa στο σύμπλεγμα της Προθρομβινάσης Άμεσοι Αναστολείς του Fxa FXa στο Ινώδες FXa Οι άμεσοι αναστολείς του Xa αναστέλλουν τόσο τον ελεύθερο όσο και τον δεσμευμένο Xa στο σύμπλεγμα της προθρομβινάσης και στο ινώδες
Comparison of the characteristics of new oral anticoagulants Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5 S12
Dabigatran Etexilate Dabigatran Amidine group High polarity not oraly available Dabigatran etexilate Oraly available + tartaric acid Dabigatran etexilate: προφάρμακο Εστεράσες Dabigatran: ενεργός μεταβολίτης
Comparison of the characteristics of new oral anticoagulants (Active 36%) Active 36% Inactive 30% Protein binding >90% >87% 55% 35% (dialysable) Hepatic metabolism CYP3A4 CYP3A4 CYP3A4 Conjugation Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5 S12
Renal Profiles of Anticoagulants Dabigatran Rivaroxaban. Apixaban excretion is also partly dependent on renal function Harder S. J Clin Pharmacol, 2012,
Clinical Pharmacology of the new oral anticoagulants Potpara TS, et al. Adv Ther (2012) 29(6):491 507
New Oral Anticoagulants In AF RE-LY ARISTOLE ROCKET-AF
RE-LY Safety Outcomes Connolly SJ et al. N Engl J Med 2009;361:1139 51
ROCKET-AF Rates of Bleeding Events Connolly SJ et al. Presented at ESC 2010 Patel MR, et al. NEJM. 2011
ARISTOTLE: Bleeding Outcomes Outcome Primary safety outcome: ISTH major bleeding* Apixaban (N=9088) Event Rate (%/yr) Warfarin (N=9052) Event Rate (%/yr) HR (95% CI) P Value 2.13 3.09 0.69 (0.60, 0.80) <0.001 Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001 Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding 4.07 6.01 0.68 (0.61, 0.75) <0.001 GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001 TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001 Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001 Granger CB, et al. N Engl J Med 2011; 365:981-992
Sites of action of antiplatelet agents Kalantzi KI, et al. Expert Rev Clin Pharmacol. 2012;5:319-336
Metabolism of ADP P2Y12 Antagonists Kalantzi KI, et al. Expert Rev Clin Pharmacol. 2012;5:319-336
Clopidogrel Prasugrel Husted S, et al. Cardiov Therap 27 (2009) 259 274
Cangrelor Inhibition of P2Y 12 receptor Direct-acting Competitive Reversible Plasma half-life: 3 to 5 min Platelet function is restored within 1h after cessation of the infusion
Clopidogrel Resistance Response variability Jaremo P. J Intern Med. 2002; 252:233-238
Clopidogrel Resistance 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
Patient classification by CYP2C19 genotype Ahmad T, et al. Nat. Rev. Cardiol. 8, 560 571 (2011)
VASP analysis 5-days 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: 149-158.
Hazard for early stent thrombosis increases with higher post-treatment platelet aggregation Geisler T, et al. Eur Heart J. 2010
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
Relation of CYP2C19 loss-of-function carrier status to clinical outcomes in clopidogrel trials
Is Tailored Treatment a Solution to Overcome HTPR?
GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y 12 Test 12 24 h Post PCI N=5429 PRU?230 No Normal On treatment Reactivity High On treatment Reactivity Random S election N=1109 Randomised N=1105 N=586 High Dose Clopidogrel Clopidogrel 600 mg, then Clopidogrel 150 mg/day Standard Dose Clopidogrel Clopidogrel 75 mg/day Standard Dose Clopidogrel Clopidogrel 75 mg/day DES, drug-eluting stents; PCI, percutaneous coronary intervention; PRU, P2Y12 reaction units. *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs. Placebo-controlled; all patients received aspirin (81-162 mg daily). Price MJ, et al. JAMA. 2011;305:1097-105
GRAVITAS Pharmacodynamic effect of high vs standard clopidogrel dose in patients with HTPR 230 PRU P<0.001 P<0.001 Price MJ, et al. JAMA. 2011;305(11):1097-1105
GRAVITAS Primary Endpoint: CV Death, MI, Stent Thrombosis Price MJ, et al. JAMA. 2011;305(11):1097-1105
Stable CAD and clinical indication for PCI Trenk D, et al. JACC. 2012;59;2159-2164
TRIGGER-PCI Stable CAD and clinical indication for PCI Trenk D, et al. JACC. 2012;59;2159-2164
TRIGGER-PCI Trenk D, et al. JACC. 2012;59;2159-2164 TRIGGER-PCI
ARCTIC Study 2440 patients scheduled for coronary stenting HTPR to Aspirin or Clopidogrel Conventional Treatment Monitoring (N = 1227) (N = 1213) 1 year of follow-up Collet J-P, et al. NEJM 2012
ARCTIC Study ARCTIC Study does not support the routine use of platelet-function testing in patients undergoing coronary stenting Collet J-P, et al. NEJM 2012
Conclusion Validation of laboratory monitoring of antiplatelet treatment Identification of the most accurate laboratory test Standardization of pre-analytical and analytical variables Identification of universal cut-off values The Platelet Function Tests may be useful In high risk patients for stent thrombosis or bleeding CKD DM Multivessel stenosis Genotyping and/or platelet function testing may be considered in selected cases (Class IIb-ESC Guidelines 2011 NSTEMI)
Prasugrel Inhibition of Platelet Aggregation After Loading Dose in Patients s With Elective PCI 100 IPA % (20 µm ADP) 80 60 40 *** *** *** Prasugrel 60 mg Clopidogrel 600 mg *** 20 ***p<0.0001 Prasugrel vs. Clopidogrel 0 0.5 2 4 6 8 12 16 20 24 IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Hours Wiviott SD et al. Circulation 2007;116(25):2923-2932
End Point (%) 15 10 5 0 TRITON TIMI-38 Balance of Efficacy and Safety Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. CV Death/MI/Stroke TIMI Major Non-CABG Bleeds Days Clopidogrel Prasugrel Prasugrel Clopidogrel 0 30 60 90 180 270 360 450 12.1 9.9 2.4 1.8 138 events HR 0.81 (0.73-0.90) P=0.0004 NNT=46 35 events HR 1.32 (1.03-1.68) P=0.03 NNH=167 HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm
TRITON TIMI 38 trial: A pharmacogenetic analysis ABCB1 3435C T and CV outcomes in patients treated with clopidogrel or prasugrel Clopidogrel Prasugrel Mega JL, et al. Lancet 2010
Ticagrelor Inhibition of platelet reactivity IPA, inhibition of platelet aggregation Gurbel PA, et al. Circulation. 2009;120:2577-2585. Gurbel PA, et al. Circulation 2010;121;1188-1199
PLATO: Primary Efficacy Analysis Cardiovascular Death, MI, or Stroke Cumulative Incidence (%) N at risk Ticagrelor 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel HR, 0.84 (95% CI, 0.77-0.92) P<0.001 0 60 120 180 240 300 360 9,333 9,291 8,628 8,521 8,460 8,362 8,219 8 7 6 5 4 3 2 1 0 Days After Randomization 6,743 8,124 6,650 Clopidogrel 5.9 22% Death Ticagrelor 4.5 5,161 5,096 6.9 16% 5.8 Nonfatal MI 4,147 4,047 11.7 9.8 CI=confidence interval; HR=hazard ratio; MI=myocardial infarction This information concerns a use that has not been approved by the US Food and Drug Administration. Wallentin L et al. N Engl J Med. 2009;361:1045-1057.
Non-CABG & CABG related bleeding K M estimated rate (% per year) 9 8 7 6 5 4 3 2 1 p=0.026 4.5 3.8 p=0.025 2.8 2.2 7.4 NS 7.9 Ticagrelor Clopidogrel 5.3 NS 5.8 0 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;361:1045-1057
The PLATO trial: A genetic substudy Kaplan-Meier estimates of events of the primary efficacy outcome in relation to the CYP2C19 genotype Wallentin L, et al. Lancet 2010; 376: 1320 28
CANGRELOR: BRIDGE STOP Context and Objective Bleeding risk Treatment with P2Y 12 inhibitor Thrombosis risk CABG surgery 0 1 2 3 4 5 Days Angiolillo DJ, et al. JAMA. 2012;307(3):265-274
BRIDGE Study design STOP Thienopyridine for 3 days STOP R Placebo (2-7 days) VerifyNow P2Y12 testing daily (same h) VerifyNow P2Y12 1-6 h CABG Cangrelor 0.75µg/kg/min (2-7 days) Angiolillo DJ, et al. JAMA. 2012;307(3):265-274 STOP
Primary efficacy end point Proportion of patients with PRU<240 for all samples during drug infusion Angiolillo DJ, et al. JAMA. 2012;307(3):265-274
Safety end points CABG-related and preoperative bleeding events Angiolillo DJ, et al. JAMA. 2012;307(3):265-274
CANGRELOR: CHAMPION PHOENIX Kaplan Meier Curves for the Primary Efficacy End Point Composite of death from any cause, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization Bhatt DL. NEJM. 2013; 368;14
CANGRELOR: CHAMPION PHOENIX Kaplan Meier Curves for the Key Secondary End Point Stent thrombosis at 48 hours after randomization Bhatt DL. NEJM. 2013; 368;14
CANGRELOR: CHAMPION PHOENIX Safety: non-cabg related bleeding Bhatt DL. NEJM. 2013; 368;14