Αντίσταση στα αντιαιμοπεταλιακά. Πως μετράται, πότε πρέπει να εκτιμάται, και πως αντιμετωπίζεται Μιχάλης Χαμηλός, MD, PhD, FESC Πανεπιστημιακό Νοσοκομείο Ηαρκλείου
Disclosures Speakers Honoraria: Astra Zeneca Consultation: St Jude Αθήνα, 25/10/2014
ASPIRIN x Thromboxane Coagulation Collagen Thrombin generation Platelet Activation + Aggregation Current treatment options Thrombin Shape change PAR1 A 2 PAR4 TPa Alpha granule GPVI Coagulation factors Inflammatory mediators 5HT 5HT 2A ADP P2Y 1 PLATELET ACTIVATION ATP P2X ADP x a IIb b 3 a IIb b 3 a IIb b 3 Fibrinogen 5HT ADP ATP Dense granule x P2Y 12 Amplification Aggregation GP IIb/IIIa inhibitors CLOPIDOGREL, PRASUGREL ACTIVE METABOLITE TICAGRELOR CANGRELOR Storey RF, Curr Pharm Des 2006
Antiplatelet therapy in PCI ASA+Clopidogrel : Post ACS, Post Stenting (CURE) ASA+Prasugrel : Post PCI in ACS (TRITON-TIMI 38) ASA+Ticagrelor :Post ACS (PLATO) Persistence of recurrent ischemic events Implication of antiplatelet resistance? Αθήνα, 25/10/2014
Antiplatelet Resistance 1. Ορισμός; 2. Πως μετράται; 3. Πότε πρέπει να εκτιμάται; 4. Πως αντιμετωπίζεται; Αθήνα, 25/10/2014
Antiplatelet Resistance 1. Ορισμός; 2. Πως μετράται; 3. Πότε πρέπει να εκτιμάται; 4. Πως αντιμετωπίζεται; Αθήνα, 25/10/2014
Resistance Treatment Failure Resistance: «a drug is unable to hit its pharmacological target, due to inability to reach it (as a consequence of reduced bioavailability, in vivo inactivation,negative interaction with other substances) or to alterations of the target» Treatment Failure : «patients who experience MACE, despite being compliant with the therapy» Αθήνα, 25/10/2014
Aspirin Resistance Prevalence between 5%-60%, depending on: Method End point Population studied Clinical relevance of platelet function testing reflecting the response to aspirin remains unclear Current evidence does not support the prognostic utility of screening for aspirin response in patients after PCI Αθήνα, 25/10/2014
Clinical impact of aspirin resistance Study Population Methods Results Event Mueller 100 pt PTA WBA Platelet aggregation Reocclusion MACE Elkeboom 976 pt, high risk CAD Urinary 11- dehydro TxB2 excretion MACE Gum 325 pt, stable CAD LTA platelet reactivity MACE Chen 151 pt, PCI RPFA platelet reactivity Myocardial necrosis Grotemeyer 180 pt, CVA Platelet aggregates platelet reactivity Vascular events
Clopidogrel Resistance Definition dependent on the test used (prevalence 5%- 44%) Even with the same test, differences in the agonist concentration give variable results Not well defined cut off values used in different studies Αθήνα, 25/10/2014
Variability of response to Clopidogrel Clopidogrel responsiveness should not be considered in a dichotomous way but as a continuous and variable parameter Αθήνα, 25/10/2014 Angiolillo et al. J Am Coll Cardiol 2007
Variability of response to Clopidogrel Genetic Factors Polymorphisms of CYP Polymorphisms of GPIa Polymorphisms of P2Y 12 Polymorphisms of GPIIIa Clopidogrel Response Variability Clinical Factors Failure to prescribe, poor compliance Under-dosing Poor absorption Drug-drug interactions involving CYP3A4 Acute coronary syndrome Diabetes mellitus, insulin resistance Elevated body mass index Cellular Factors Accelerated platelet turnover Reduced CYP3A metabolic activity Increased ADP exposure Up-regulation of the P2Y 12 pathway Up-regulation of the P2Y 1 pathway Up-regulation of P2Y independent pathways Angiolillo et al. J Am Coll Cardiol 2007
Prasugrel Resistance HPR=7,7% (PRU>230) Αθήνα, 25/10/2014 Alexopoulos et al Cur Pharm Design 2013
Ticagrelor Resistance Αθήνα, 25/10/2014 PLATO platelet substudy, JACC 2010
Ticagrelor vs Prasugrel Αθήνα, 25/10/2014 Alexopoulos et al Thromb & Haem 2014
Ticagrelor vs Prasugrel in STEMI Alexopoulos et al Circ Cardiov Interv 2012
Clinical impact of Clopidogrel resistance Metaanalysis of 6 studies and 3059 patients Brar et al JACC 2011
Clinical impact of Clopidogrel resistance Pooled analysis from 17 trials and 9187 patients Aradi et al Am Heart J 2010
ADAPT-DES Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents 11,000 DES pts prospectively enrolled No clinical or anatomic exclusion criteria 11 sites in US and Germany PCI with 1 non-investigational DES Successful and uncomplicated (IVUS/VH substudy; Up to 3000 pts enrolled) Assess platelet function after adequate DAPT loading and GPI washout: Accumetrics VerifyNow Aspirin, VerifyNow P2Y12, and VerifyNow IIb/IIIa assays (results blinded) Clinical FU at 30 days, 1 year and 2 years Angio core lab assessment all STs w/1:2 matching controls clinicaltrials.gov NCT00638794
ADAPT-DES: Relationship between VerifyNow platelet response to DAPT and subsequent 1-year def/prob stent thrombosis (n=8,583) VerifyNow test Def/prob ST No def/prob ST P (n=70) (n=8,513) Aspirin ARU 426 ± 58 419 ± 55 0.30 - ARU 550 7.2% 5.6% 0.54 P2Y12 Base 305 ± 60 310 ± 58 0.56 P2Y12 PRU 234 ± 97 188 ± 97 <0.0001 - PRU >208 65.2% 42.5% 0.0002 - PRU 230 53.6% 34.9% 0.001 P2Y12 % Inhibition 24.8 ± 27.0 40.1 ± 28.2 <0.0001 - Inhibition 11% 44.9% 19.9% <0.0001 IIb/IIIa PAU 194 ± 56 193 ± 54 0.92
ADAPT-DES: MI and major bleeding according to post-pci PRU
ADAPT-DES: Mortality according to post-pci PRU
Antiplatelet Resistance 1. Ορισμός; 2. Πως μετράται; 3. Πότε πρέπει να εκτιμάται; 4. Πως αντιμετωπίζεται; Αθήνα, 25/10/2014
TxA2 specific Platelet Function Tests for Serum thromboxane B 2 Urinary 11-dehydro thromboxane B 2 Arachidonic acid-stimulated Aspirin Platelet aggregometry (turbidimetric/impedance) VerifyNow Aspirin assay Plateletworks Platelet surface activated GP IIb/IIIa/P-selectin/ leucocyte platelet aggregates (flow cytometry) TEG PlateletMapping System Impact cone and plate(let) analyser ThromboVision T-Guide Other PFA-100 PlaCor PRT Αθήνα, 25/10/2014 Modified from Michelson Am J Cardiol 2006
P2Y 12 -specific Platelet Function Tests for P2Y12 receptor VASP (vasodilator stimulated phosphoprotein) phosphorylation ADP-stimulated Platelet aggregometry (turbidimetric/impedance) VerifyNow P2Y12 assay Plateletworks Multiplate Analyzer TEG PlateletMapping System Impact cone and plate(let) analyser ThromboVision T-Guide Other PFA-100 PlaCor PRT Αθήνα, 25/10/2014 Modified from Michelson Am J Cardiol 2006
Point-of-care monitoring of antiplatelet therapy Use at or near patient bedside Easy to use without special skills No sample processing No pipetting Rapid readout Αθήνα, 25/10/2014
Αθήνα, 25/10/2014 Point of care assays
Antiplatelet Resistance 1. Ορισμός; 2. Πως μετράται; 3. Πότε πρέπει να εκτιμάται; 4. Πως αντιμετωπίζεται; Αθήνα, 25/10/2014
How to treat resistance Check non-compliance - interference with other drugs Increase dose of antiplatelet agent Provide additional loading dose Add another antiplatelet agent No change in treatment Αθήνα, 25/10/2014
Biological benefit of higher doses Chronic therapy Loading doses Von Beckerath et al. EHJ 2007 Montalescot et al. JACC 2006
Platelet function-guided treatment Bonello et al, JACC 04/2008
Prasugrel vs hd clopidogrel for NR Alexopoulos et al, JACC Interv 2011
Ticagrelor for clopidogrel NR: RESPOND study Αθήνα, 25/10/2014 Gurbel et al, Circulation 2010
GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-pci PRU 230 R High-Dose Clopidogrel clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel clopidogrel 75-mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs placebo-controlled All patients received aspirin (81-162mg daily)
Pharmacodynamics: Effect of SD vs HD Clopidogrel 500 Standard-Dose P = 0.98 High-Dose P < 0.001 PRU value 400 300 200 Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001 100 0 N=1105 N=1013 N=940 N=1109 N=1012 N=944 ITT population Post-PCI 30 d 6 mo Post-PCI 30 d 6 mo
Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test.
ARCTIC trial design Coronary angiogram PRU>235 VerifyNow P2Y12 + ASA Drug (ASA, clopidogrel, prasugrel, GP2b3a I.) and Dose adjustments if high platelet reactivity Stent-PCI Drug and Dose adjustments if high platelet reactivity at Day 14 Rd 12-month FU Standard of care Stent-PCI Standard of care Primary endpoint at 12 months: Death, MI, stroke, stent thrombosis, urgent revascularization Statistical considerations: Assuming an annual risk of 9% and a 33% relative risk reduction (α risk at 5% and error β of 20%, bilateral test), 2,466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12
Primary Endpoint to 1 year Death, MI, stroke, stent thrombosis, urgent revascularization Monitoring Conventional HR = 1.13 [0.98-1.29] p= 0. 096 34.6% 31.1% 0 100 200 300
Flow-chart TRIGGER-PCI Study Successful PCI with DES without major complication and NO GPIIb/IIIa use N ~6500 Post-PCI VerifyNow P2Y12 Assay (PRU) 2-7 hours after MD of clopidogrel 75 mg at day 1 post-pci Non-Responder Yes PRU > 208 No Responder A N = 1075 Prasugrel arm Prasugrel LD 60 mg Prasugrel MD 10 mg QD + Clopidogrel placebo B N = 1075 Clopidogrel arm Placebo LD Clopidogrel MD 75 mg QD + Prasugrel placebo C N = 4350 Standard Therapy Clopidogrel MD 75 mg QD N = 2,150 33% Non-interventional study (Registry) Clinical Follow-up and blinded VerifyNow Assessment at 90 days, 180 days Primary Endpoint: 6 month CV Death or MI
Disposition of patients in TRIGGER-PCI
Proportion of pts. with high on-treatment platelet reactivity by VerifyNow P2Y12 assay (PRU >208)
Summary of primary and secondary CEC-adjudicated efficacy endpoints Prasugrel N=212 Clopidogrel N=211 p HR (95% CI) Days on study treatment(median) 174 174 - Primary composite efficacy EP: CV death or MI 0 1 (0.5%) - Key secondary efficacy EPs: MI 0 1 (0.5%) - Rehospitalization for cardiac ischemic event 2 (0.9%) 4 (1.9%) 0.992 0.99 (0.14-7.03) Urgent TVR 2 (0.9%) 1 (0.5%) - Definite ST 0 0 - Stroke 0 1 (0.5%) - CV death 0 0 - All cause death 0 1 (0.5%) -
Reason for tailored APLT failure The Majority of Clopidogrel-Response Variability Remains Unexplained by CYP2C19 and Clinical Factors (88%) There are Other Platelet Receptors Involved in Thrombosis Tests used are not the best to discriminate HPR Not well defined cut-off values to use in order to tailor therapy Low risk population in most of the trials Αθήνα, 25/10/2014
Αθήνα, 25/10/2014 2014 ESC/EACTS ravascularization guidelines
Take home messages 1. Platelet function tests have demonstrated interpatient response variability to aspirin and clopidogrel 2. Patient s response variability to clopidogrel can predict clinical outcome 3. No randomized study has proven any benefit after tailoring APT in patients with HPR 4. HPR should be considered as a non modifiable risk factors until future studies show the opposite Αθήνα, 25/10/2014