ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Εξατοµικευµένη αντιαιµοπεταλιακή αγωγή. Ποιο είναι το µέλλον? Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχηµείας - Κλινικής Χηµείας
Disclosures None
Clopidogrel Resistance Response variability Jaremo P. J Intern Med. 2002; 252:233-238
Clopidogrel resistance CYP2C19*1/*2 CYP2C19*1/*1 Good metabolizer Intermediate metabolizer Poor metabolizer
Residual Platelet Reactivity High Residual Platelet Reactivity Low Residual Platelet Reactivity HRPR LRPR 10 µμ ADP 30 days 30 days 5 days 5 days Before treatment Before treatment Kalantzi KI, et al. J Thromb Haemost. 2011;9:875-878 Kalantzi KI, et al. Platelets. 2012; In Press
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
Hazard for early stent thrombosis increases with higher post-treatment platelet aggregation Geisler T, et al. Eur Heart J. 2010
Metabolism of ADP P2Y12 Antagonists Kalantzi KI, et al. Expert Rev Clin Pharmacol. 2012;5:319-336
Patient classification by CYP2C19 genotype Ahmad T, et al. Nat. Rev. Cardiol. 8, 560 571 (2011)
CYP2C19*2 Allelic Variant and MACE TRITON-TIMI 38 Analysis; Clopidogrel in ACS Patients 12.1 Carriers 3 2.4 Non-carriers * Death from cardiovascular causes, myocardial infarction, or stroke P=0.01 6.9 Definite+or+Probable+Stent+Thrombosis+(%) 2 1 Carriers Non-carriers P=0.02 0.6 0 3 0 90 180 270 360 450 0 0 3 0 90 180 270 360 450 Days After Randomization Days After Randomization Mega JL et al. N Engl J Med. 2009;360:354-362.
Relation of CYP2C19 loss-of-function carrier status to clinical outcomes in clopidogrel trials
JAMA, December 28, 2011 Vol 306, No. 24 Conclusion: Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with CV events
ELEVATE-TIMI 56 333 patients with stable CVD On-Treatment Platelet Reactivity Across Genotype and Clopidogrel Daily Dose Mega JL, et al. JAMA 2011;306(20):2221-2228
Variability in response to thienopyridine platelet inhibition Ahmad T, et al. Nat. Rev. Cardiol. 8, 560 571 (2011)
Genotype and clinical outcomes The observations showing an association between CYP2C19 genotype and clinical outcomes during clopidogrel administration are mostly derived from platelet-oriented ischaemic events: PCIrelated MI or stent thrombosis The influence of CYP2C19 genotype on ischaemic event occurrence has not been demonstrated in non-pci patients Genotyping may be more relevant in clopidogrel naive patients to be treated with PCI to determine the optimal initial antiplatelet treatment strategy
Εργαστηριακή διερεύνηση της αποτελεσµατικότητας
Flow Cytometer (FACSCalibur) Optical Lumi-Aggregometer VerifyNow Μultiple electrode platelet aggregometer Haemoscope TEG PFA-100
Prasugrel Inhibition of Platelet Aggregation After Loading Dose in Patients 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
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
The POPular study First head to head comparison multiple platelet function tests in predicting thrombotic and bleeding events Survival free from Primary Endpoint (1 year) Composite of death, non fatal MI, definite stent thrombosis and stroke
The POPular study None of the tests able to discriminate between patients with and without TIMI major and minor bleeding
ARMYDA-PROVE Study Distribution of Platelet Reactivity Mangiacapra F, et al. J Am Coll Cardiol Intv. 2012;5:281 9
Is Tailored Treatment a Solution to Overcome HTPR?
GRAVITAS Study Design 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 Trenk D, et al. JACC. 2012;59;2159-2164 TRIGGER-PCI
TRILOGY ACS Platelet Function Substudy Prasugrel vs Clopidogrel for UA-NSTEMI without Revascularization 30 mg of prasugrel LD or 300 mg of clopidogrel LD 10 or 5 mg/d prasugrel or 75 mg/d clopidogrel Gurbel PA, et al. JAMA. 2012; 308:1785-1794
TRILOGY ACS Prasugrel vs Clopidogrel for UA-NSTEMI without Revascularization 30 mg of prasugrel LD or 300 mg of clopidogrel LD 10 or 5 mg/d prasugrel or 75 mg/d clopidogrel Efficacy Outcomes at 30 Months Roe MT, et al. N Engl J Med 2012
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
Gregg W. Stone, et al.
ADAPT-DES: Stent thrombosis (definite or probable) according to post-pci PRU Stent thrombosis (def/prob) (%) 2 1 PRU >208 (n=3610) PRU 208 (n=4839) HR [95%CI] = 2.54 [1.55, 4.16] P=0.0001 1.3% 0.5% Number at risk: PRU > 208 PRU 208 0 0 3 6 9 12 Months 3610 3450 3420 3380 3152 4839 4688 4654 4631 4341
ADAPT-DES: MI and major bleeding according to post-pci PRU 10 Myocardial infarction HR [95%CI] = 1.47 [1.15, 1.87] P=0.002 10 Major bleeding HR [95%CI] = 0.83 [0.69, 0.99] P=0.04 PRU >208 (n=3610) PRU 208 (n=4839) PRU >208 (n=3610) PRU 208 (n=4839) 5 3.9% 2.7% 5 6.7% 5.6% 0 0 6 12 Months 0 0 6 12 Months
ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow PRU >208 for subsequent 1-year adverse events (n=8,583) Event Adj HR [95%CI] P value ST, def/prob 2.49 [1.43, 4.31] 0.001 - Definite 3.05 [1.62, 5.75] 0.0006 MI 1.42 [1.09, 1.86] 0.01 Major bleeding 0.73 [0.61, 0.89] 0.002 Death, all-cause 1.20 [0.85, 1.70] 0.30 Variables in model: age, gender, diabetes, hypertension, hyperlipidemia, current smoking, prior MI, CKD, stable vs NSTEMI vs STEMI, hemoglobin, WBC, platelet count, creatinine clearance, MVD, premature DAPT discontinuation within 6 months, PRU >208 (forced in), ARU >550 (forced in)
ADAPT-DES: Multivariable propensity score adjusted risk of VerifyNow ARU >550 for subsequent 1-year adverse events (n=8,583) Event Adj HR[95%CI] P value ST, def/prob 1.46 [0.58, 3.64] 0.42 - Definite 1.60 [0.57, 4.48] 0.37 MI 0.81 [0.46, 1.42] 0.46 Major bleeding 0.65 [0.43, 0.99] 0.04 Death, all-cause 1.42 [0.83, 2.43] 0.20 Variables in model: age, gender, diabetes, hypertension, hyperlipidemia, current smoking, prior MI, CKD, stable vs NSTEMI vs STEMI, hemoglobin, WBC, platelet count, creatinine clearance, MVD, premature DAPT discontinuation within 6 months, PRU >208 (forced in), ARU >550 (forced in)
ADAPT-DES: Conclusions and Implications On-treatment hyporesponsiveness to clopidogrel after DES was an independent predictor of 1-year ST and MI, but was also protective against major bleeding, both of which were strongly related to mortality On-treatment clopidogrel hypo-responsiveness was not independently predictive of 1-year mortality Hyporesponsiveness to Aspirin was unrelated to ST, MI or death, but may be related to bleeding, questioning the utility of aspirin in pts treated with DES
Clopidogrel Responsiveness Study (300 mg) A Fingerprint of Clopidogrel Response Variability 2 Hours 24 Hours 24 Resistance = 63% 20 Resistance Resistance = 31% Patients (%) 12 10-30 (-20,-10] (-30,-20] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60-30 (-20,-10] (-30,-20] (-10,0] (0,10] (10,20] (20,30] (40,50] (30,40] (50,60] >60 5 Days 30 Days 22 Resistance Resistance = 31% 28 Resistance = 15% Patients (%) 11 14 Resistance -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60-30 (-20,-10] (0,10] (20,30] (40,50] >60 Δ Aggregation (%) (-30,-20] (-10,0] (10,20] (30,40] Δ Aggregation (%) (50,60] Gurbel PA et al. Circulation. 2003;107:2908-2913.
VASP analysis 5-days 1-month Responders Non-responders 22,2% CHS 11,1% 77,8% 88,9% Tsoumani M, et al. Expert Opin Pharmacother. 2012; 13: 149-158.
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;9:875-878 Kalantzi KI, et al. Platelets. 2012; In Press
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)
CURRENT OASIS 7 Τhe use of a double dose of clopidogrel for 7 days, as compared with the standard dose, did not reduce the incidence of the primary outcome of CV death, MI or stroke at 30 days The CURRENT OASIS 7 Investigators. NEJM. 2010;363:930-42.
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: 1233 43.