Should we Monitor Anti-Platelet Treatment?

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

19. Platelet Reactivity And Early Drug-Eluting Stent Thrombosis Sibbing et al. JACC 2009;53:849-56 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

20. Clinical Characteristics Associated With Low Response to Cloopidogrel Sibbing et al. JACC 2009;53:849-56 normal response Low response p n = 1285 n = 323 BMI 27.3 + 4.2 28.3 + 4.9 < 0.001 Ejection Fraction 54.9 + 10.9 53.2 + 12.6 0.03 Diabetes mellitus 27.4% 34.1% 0.02 Active smokers 12.1% 18.6% 0.002 ACS 31.4% 39.9% 0.001 Platelet count 213 + 62 236 + 64 < 0.001 Time from loading (h) 4 (2-15.5) 3 (2-7) < 0.001

21. Clinical Outcome According to Clopidogrel Response Sibbing et al. JACC 2009;53:849-56 P = < 0.001 0.07 0.02 0.005 0.03

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

23. 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

24. Non-emergent PCI : ACS and Stable angina (n= 1122) Loading dose (LD) -ASA 250mg -Clopidogrel 600mg DESIGN 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

25. VASP after first LD 66 ± 11 67 ± 10 VASP after sensitization  37 ± 12† † p <0.01 Platelet reactivity monitoring 17 patients (8%)

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

27. Secondary end-point: MACE  Endpoint n, (%) Control (n= 214) VASP-guided (n= 215) p Cardiovascular death 4 (1.8) 0 0.06 Myocardial infarction 10 (4.8) 1 (0.5) 0.01 Urgent revascularization 5 (2.3) 0 0.06 All MACE 19 (8.9) 1 (0.5) < 0.001

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

32. 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

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

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

42. 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)