1. Should we Monitor Anti-Platelet Treatment? Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular Research Hotel Dieu de France Hospital Associate Professor of Medicine Saint Joseph University School of Medicine

2. Should we Monitor Anti-Platelet Treatment? 1.Is there a reliable test to measure platelet function? 2.Is there a variability in the response to anti-platelet therapy? 3.Is a poor response to anti-platelet indicative of adverse cardiovascular outcome? 4.Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?

3. How to Measure Platelets Aggregation? Platelets function is measured in vitro by light transmission aggregometry This method is considered the gold standard Disadvantages: –Limited reproducibility –Complex sample preparation –Cannot be routinely performed

4. WHAT ARE THE ALTERNATIVES TO LIGHT TRANSMISSION AGGREGOMETRY?

5. Rapid Platelet Function Assay Plateletworks An alternative to light transmission aggregometry

6. Plateletworks

8. Excellent Correlation Between Light Transmission Aggregometry and Plateletworks Test (Cathet Cardiovasc Intervent 2001;53:346-351)

9. VERIFYNOW Point of Care Test It measures the rate and extent of changes in light transmittance caused by platelet aggregation in a pre-set tube in which whole blood in placed It thus mimics light transmission aggregometry Samples containing inhibited platelets will produce low level of light transmittance while samples containing normally functioning platelets will aggregate more rapidly, resulting in higher level of light transmittance

10. The VASP test: A Specific Test to Measure P2Y12 Inhibition VASP is not phosphorylated at basal state PGE1 activates VASP phosphorylation ADP inhhibits VASP phosphorylation via the P2Y12 receptor Thus high VASP = active form of P2Y12 receptor Low VASP (high VASP-P) = inhibition of P2Y12 receptor

11. Should we Monitor Anti-Platelet Treatment? 1.Is there a reliable test to measure platelet function? 2.Is there a variability in the response to anti-platelet therapy? 3.Is a poor response to anti-platelet indicative of adverse cardiovascular outcome? 4.Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?

13. Mean aggregation = 80% at 2 hours, 60% at 24 hours, 57% at 5 days and 52% at 30 days (or 48% inhibition at 30 days) Incidence of resistance = 35% at 24 hours and 21% at 30 days (defined as < 10% reduction in aggregation compared to baseline)

14. ACC/AHA Guidelines (2005) Percutaneous Coronary Interventions: Oral Antiplatelet Therapy Prevalence of inadequate response to clopidogrel 4% to 30% Nguyen et al. J Am Coll Cardiol 2005;45:1157-64

16. Clopidogrel Metabolism Clopidogrel is a prodrug It requires oxidation by the hepatic cytochrome P450 to generate the active metabolite Only a small proportion of clopidogrel undergoes metabolism by CYP450 Clopidogrel is mostly hydrolyzed by esterases to an inactive carboxylic acid derivative that accounts for 85% of clopidogrel- related circulating compounds Any drugs that affects CYP450 may affect the efficacy of clopidogrel

17. Should we Monitor Anti-Platelet Treatment? 1.Is there a reliable test to measure platelet function? 2.Is there a variability in the response to anti-platelet therapy? 3.Is a poor response to anti-platelet indicative of adverse cardiovascular outcome? 4.Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?

20. Platelet Reactivity And Early Drug-Eluting Stent Thrombosis 1608 consecutive patients with CAD and planned drug eluting stent implantation All received a loading of 600 mg of clopidogrel prior to stenting Blood was obtained directly prior to PCI ADP induced platelet aggregation was assessed with a point of care assay: Multiple Electrode Platelet Aggregometry (MEA) (principle of impedance aggregometry) Poor response to clopidogrel was prospectively defined by a cutoff point at the upper quintile of MEA measurments Sibbing et al. JACC 2009;53:849-56

21. Clinical Characteristics Associated With Low Response to Cloopidogrel normal responseLow responsep n = 1285n = 323 BMI27.3 + 4.228.3 + 4.9< 0.001 Ejection Fraction54.9 + 10.953.2 + 12.60.03 Diabetes mellitus27.4%34.1%0.02 Active smokers12.1%18.6%0.002 ACS31.4%39.9%0.001 Platelet count213 + 62236 + 64< 0.001 Time from loading (h)4 (2-15.5)3 (2-7)< 0.001 Sibbing et al. JACC 2009;53:849-56

22. Clinical Outcome According to Clopidogrel Response Sibbing et al. JACC 2009;53:849-56 P = < 0.0010.07 0.02 0.005 0.03

23. Dual Resistance to Aspirin and Clopidogrel in Patients Undergoing PCI 150 patients referred for elective PCI All were on aspirin 81 to 325 mg/day for > 1 week Clopidogrel was given immediately following PCI The response to clopidogrel was tested at 24 hours post loading dose 12.7% resistant to aspirin 24% resistant to clopidogrel 47% of aspirin resistant patients were also resistant to clopidogrel J Am Coll Cardiol 2006;47:27-33

24. Incidence of CK-MB Elevation Following PCI According to Aspirin and Clopidogrel Responsiveness Incidence of CK-MB Elevation Following PCI According to Aspirin and Clopidogrel Responsiveness J Am Coll Cardiol 2006;47:27-33

25. EndpointAuthorPlatelet assayn Stent thrombosisBarraganVASP index36 GurbelVASP index, ADP aggregometry120 BuonamiciADP- aggregometry804 BlindtVASP index, ADP aggregometry99 Ischemic events CV death, MI, unstable angina, stroke GurbelADP aggregometry192 Death, MI, stent thrombosis, stroke, ischemia BlidenADP aggregometry100 CV death, acute or subacute ST, ACS, ischemic stroke CuissetADP aggregometry, VASP index195 Death, MI, TLRTrenkADP aggregometry802 CV death, MI, urgent TVRBonelloVASP index144 CV death, acute and subacute stent thrombosis, MI PriceVerifyNow P2Y12380 Link between low-response and thrombotic events

26. Should we Monitor Anti-Platelet Treatment? 1.Is there a reliable test to measure platelet function? 2.Is there a variability in the response to anti-platelet therapy? 3.Is a poor response to anti-platelet indicative of adverse cardiovascular outcome? 4.Does adjustment of anti-platelet therapy according to test’s results, improve the outcome of PCI?

27. TAILORED CLOPIDOGREL LOADING DOSE ACCORDING TO PLATELET REACTIVITY MONITORING DECREASE EARLY STENT THROMBOSIS L Bonello, L Camoin-Jau, S Arques,, P. Rossi, C. Boyer, D Panagides, O Wittenberg, P Barragan, F Dignat-George, F Paganelli. Service de cardiologie, Hôpital Universitaire Nord, Marseille; FRANCE Laboratoire d’hématologie, INSERM UMRS 608, Hôpital conception; Marseille; FRANCE Service de cardiologie, Hôpital d’aubagne, Aubagne; FRANCE Service de cardiologie, Clinique clairval, Marseille; FRANCE Service de cardiologie, Clinique Bouchard, Marseille; FRANCE Service de cardiologie, Hôpital Privé Beauregard, Marseille; FRANCE Laboratoire de statistique, Faculté de la Timone, Marseille; FRANCE Service de cardiologie, Polyclinique les Fleurs, Ollioules, FRANCE Am J Cardiol 2009;103:5-10

28. DESIGN Non-emergent PCI : ACS and Stable angina (n= 1122) Loading dose (LD) -ASA 250mg -Clopidogrel 600mg VASP ≥ 50% Randomization (n=429) CONTROL (n =215)VASP-guided LD (n =214) Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCI Maintenance dose -ASA 160 mg -Clopidogrel 75 mg 1° endpoint: Definite stent thrombosis (ARC definition) 2° endpoints: MACE including CV death, MI and U-TVR TIMI major and minor bleeding at 30 days

29. Platelet reactivity monitoring VASP after first LD66 ± 1167 ± 10 VASP after sensitization  37 ± 12 † 17 patients (8%) † p <0.01

30. Timing of early stent thrombosis All early stent thrombosis occured during the first 7 days Am J Cardiol 2009;103:5-10

31. Secondary end-point: MACE Endpoint n, (%)Control (n= 214) VASP-guided (n= 215) p Cardiovascular death4 (1.8)00.06 Myocardial infarction10 (4.8)1 (0.5)0.01 Urgent revascularization5 (2.3)00.06 All MACE19 (8.9)1 (0.5)< 0.001

32. Secondary end-point: TIMI bleeding No difference in bleeding complication between the 2 groups No intra-cerebral bleeding, no fatal bleeding Majority of patients had PCI through the radial access (55.6%) Control (n= 214) VASP-guided (n= 215) p Major bleeding2 (0.9) 1 Minor bleeding4 (1.9)6 (2.8)0.8 All6 (2.8)8 (3.7)0.8

33. M. Valgimigli, MD, PhD On behalf of 3T/2R Investigators Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel

37. Tailored GP IIb/IIIa Receptor Blockade According to Clopidogrel Resistance 149 Clopidorel resistant patients Resistance defined by inhibition < 30% using light transmission aggregometry Elective PCI Randomized to : –Conventional therapy: 600 mg Clopidogrel –Active therapy: 600 mg Clopidogrel + GP IIb/IIIa blockade Combined end-point of: death, periprocedural MI, stent thrombosis and recurrent ACS at 1 month Cuisset et al. JACC Interventions. 2008;1:649-53

38. Events According to GPIIb/IIIa Blockade in Clopidogrel Resistant Patients P=0.006 Cuisset et al. JACC Interventions. 2008;1:649-53

39. How Can We Solve the Problem Caused by Clopidogrel Resistance? Is the answer by increasing the dose?

47. Should we Monitor Anti-Platelet Treatment? FACTS: 1- More potent anti-platelet therapy is associated with better outcome 2- But it is also associated with more bleeding !!! WHAT TO DO IN PRACTICE: 1- Give all patients potent drugs: double dose clopidogrel, or better: prasugrel. Proven to be better, but risk of bleeding 2- Monitor platelet response and adjust therapy accordingly. Waiting confirmation in large clinical trials (GRAVITAS )