Platelet function test (what is the clinical relevance)

Platelet Function Test: What Is The Clinical Relevance? 14 th Vietnam National Congress of Cardiology Da Nang City Vietnam 2014 Dr Tan Huay Cheem MBBS, M Med(Int Med) MRCP(UK), FRCP(Edinburgh), FAMS, FACC, FSCAI Director, National University Heart Centre, Singapore Associate Professor of Medicine, Yong Loo Lin School of Medicine National University of Singapore President, Asia Pacific Society of Interventional Cardiology National University Heart Centre, Singapore (NUHCS) Variability in Clopidogrel Response Change in ADP-Induced platelet aggregation 75 mg chronic dosing N=544 0 2 4 6 8 10 0 20 40 60 80 100 Time from loading dose to cath (h) Maximal aggregation 5µmol/L ADP (%) following 600 mg loading dose N=1001 Serebruany et al J Am Coll Cardiol 2005; 45:246 Hochholzer W et al Circulation 2005 Red dot: nonresponder Mechanism of Clopidogrel Response Variability Intestinal Absorption Highly variable absorption capacity with ceiling effect at 600 mg leading dose Inactive Carboxylic Acid Metabolite Clopidogrel (prodrug) P-glycoprotein (MDR1 34357 genotype) Esterases 85% 15% Multistep Conversion CYP1A2 CYP2B6 CY3A4/5 CYP2C9 CYP2C19 Hepatic Cytochrome P450 Isoforms Drug-drug interaction with lipophilic statins Genetic polymorphisms Drug-drug interaction with protein pump Inhibitors Genetic polymorphisms Active Thiol Metabolite P2Y12 Receptor Genetic Polymorphism Genetic polymorphisms Smoking Clopidogrel is frequently chosen in high risk patients Yet, it is a highly unpredictable and overall weak antiplatelet agent How do we rationalise giving this drug blindly to prevent stent thrombosis? Genetic Testing vs Platelet Function Testing Genetic testing • Categorical yes/no answer • Static • Very reproducible • Less sensitive to pre-analytic variables • Slower turnaround Platelet function testing • Continuous so cutpoints needed • Dynamic • Less reproducible • Very sensitive to pre-analytic variables • Fast turnaround Platelet Function Tests: Types and Limitations Platelet Function Tests • Criticised for: (1) Laboratory artifacts (2) Assay variability (3) Lack of standardisation of clopidogrel non responsiveness • Results unconvincing for: (1) “ the tests are crude substitutes for the….interactions ……. in vivo” (2) “ failed to satisfy… the minimal criteria to establish a causal relationship…between the results of the…. test and …… a thromboembolic event” Definitions of Non-/Low Response using LTA Gurbel PA et al Circulation 2003 Müller I et al Thromb Haemostas 2003 Matetzky S et al Circulation 2004 Serebruany VL et al J Am Coll Cardiol 2005 Angiolillo DJ et al Thromb Res 2005 Absolute change in platelet aggregation from baseline < 10% Relative change in platelet aggregation from baseline < 10% Lowest quartile of relative reduction of platelet aggregation Platelet aggregation 2 standard deviations below mean Relative change in platelet aggregation from baseline < 40% (Variable results also depending on the concentration of ADP used) Platelet Function Tests • Platelet Aggregation Light transmittance aggregometry (LTA) Impedance platelet aggregation • Flow Cytometry GPIIb/IIIa receptor activation P-selectin expression Monocyte-platelet aggregates Vasodilator-associated stimulated phosphoprotein (VASP) • Point-of-care Ultegra rapid platelet function analyzer (VerifyNow) Thromboelastagraph (TEG) Plateletworks Cone and plate(let) analyzer (IMPACT) Angiolillo DJ et al J Am Coll Cardiol 2007 [...]... assessed by the VerifyNow P2Y12 test are powerful independent predictors of stent thrombosis within 30 days, with a significant proportion of events independently attributable to clopidogrel hyporesponsiveness • However, the modest sensitivity and specificity of platelet function testing, coupled with the low prevalence of events, implies that testing of platelet ADP antagonist responsiveness is unlikely... Hyporesponsiveness and Stent Thrombosis Platelet Function in Clopidogrel-Treated Patients and Stent Thrombosis N Functional Parameter Clinical Relevance ↓Inhibition of platelet aggregation Stent thrombosis Stent thrombosis Mueller et al Thromb Hemost 2003 105 Barragan et al Cathet Card Intv 2003 36 ↑P2Y12 reactivity ratio 120 ↑P2Y12 reactivity ratio Gurbel et al JACC 2005 platelet aggregation ↑stimulated... reproducibility and thus variance in prevalence of nonresponders These may include the dose of the agonist (5-20 uM), the nature of the anticoagulant (citrate or hirudin/PPACK) and the LTA value (maximal or late platelet aggregation) used Flow Cytometry (Eg Vasodilator-Stimulated Phosphoprotein Phosphorylation VASP-P) • Used to test for antiplatelet drug responsiveness • Highly specific to a given signaling... Major Prospective Trials of Personalised Antiplatelet Therapy Using Platelet Function Test in PCI Patients • GRAVITAS (n= 2 214) • TRIGGER PCI (n=423) • ARCTIC (n= 2 440) GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-PCI PRU ≥ 230 All patients received aspirin (81-162mg daily) R High-Dose Clopidogrel clopidogrel 600mg, then clopidogrel 150mg daily X 6 months... guide clinical decision-making in most individual patients for the prevention of stent thrombosis at 30 days Stone GW et al Lancet 2013; 382: 614-623 Titration of Clopidogrel to Achieve VASP PRI