1. Inhibitory Effects of Ticagrelor Compared to Clopidogrel on Platelet Function in Patients with Acute Coronary Syndromes The PLATO PLATELET Substudy Storey RF 1, Angiolillo DJ 2, Patil SB 1, Desai B 2, Ecob R 1, Husted S 3, Emanuelsson H 4, Cannon CP 5, Becker RC 6, Wallentin L 7 1 Department of Cardiovascular Science, University of Sheffield, and NIHR Cardiovascular Biomedical Research Unit, Sheffield, UK 2 University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USA 3 Århus University Hospital, Århus, Denmark 4 AstraZeneca, Mölndal, Sweden 5 TIMI Study Group, Brigham and Women’s Hospital, Boston, USA 6 Duke Clinical Research Institute, Durham, USA 7 Uppsala Clinical Research Center and Department of Medical Sciences Cardiology, Uppsala University, Uppsala, Sweden J. Am. Coll. Cardiol 2010;56(18):1456-62

2. PLATO PLATELET Objectives: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes. Background: The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes. Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

3. PLATO PLATELET Methods: Patients were randomized to receive either clopidogrel (300- to 600-mg loading dose [LD], 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily). The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days. The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20  M), VerifyNow P2Y12, and VASP phosphorylation assays were performed. Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

4. PLATO PLATELET Results: During maintenance therapy, ticagrelor achieved greater suppression of platelet reactivity compared with clopidogrel. The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20  M) post maintenance dose were 44 ± 15% for clopidogrel and 28 ± 10% for ticagrelor (p<0.001). High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor. The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD. Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

5. Figure 1A. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM) LTA = light transmittance aggregometry; SE = standard error TroughPeak 100 80 60 40 20 0 Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

6. Figure 1B. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 20μM) LTA = light transmittance aggregometry; SE = standard error Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

7. Figure 1C. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM) LTA = light transmittance aggregometry; SE = standard error Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

8. Figure 1D. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 5μM) LTA = light transmittance aggregometry; SE = standard error Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

9. Figure 1E. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y 12 assay SE = standard error Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

10. Figure 1F. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VASP assay SE = standard error Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

11. Figure 2. VerifyNow responses to maintenance doses of clopidogrel (C) and ticagrelor (T) according to geographic location (UK or US) SE = standard error All p = NS Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

12. Figure 3A. Responses to loading doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM) LTA = light transmittance aggregometry Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

13. Figure 3B. Responses to loading doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 20μM) LTA = light transmittance aggregometry Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

14. Figure 3C. Responses to loading doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM) LTA = light transmittance aggregometry Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

15. Figure 3D. Responses to loading doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 5μM) LTA = light transmittance aggregometry Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

16. Figure 3E. Responses to loading doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y 12 assay C T 500 400 300 200 100 0 Platelet reaction units (PRU), mean Pre 4h p <0.01 Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

17. Figure 3F. Responses to loading doses of clopidogrel (C) and ticagrelor (T): VASP assay C T 100 80 60 40 20 0 Platelet reactivity index (%), mean Pre 4h Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

18. Figure 4A. IPA following loading doses of clopidogrel (C) and ticagrelor (T): inhibition of maximum LTA response (ADP 5μM) LTA = light transmittance aggregometry P values determined by unpaired t test or Mann Whitney test Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

19. Figure 4B. IPA following loading doses of clopidogrel (C) and ticagrelor (T): inhibition of final LTA response (ADP 5μM) LTA = light transmittance aggregometry P values determined by unpaired t test or Mann Whitney test Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

20. Suppl. Figure 1A. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM) Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots); LTA = light transmittance aggregometry C T 100 80 60 40 20 0 % Platelet aggregation Trough Peak p <0.001p <0.0001 Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

21. Suppl. Figure 1B. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 5μM) Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots); LTA = light transmittance aggregometry C T 100 80 60 40 20 0 TroughPeak p <0.001 % Platelet aggregation Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

22. Suppl. Figure 1C. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y 12 assay Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots) C T 500 400 300 200 100 0 TroughPeak p <0.0001 Platelet reaction units (PRU) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

23. Suppl. Figure 1D. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VASP assay Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots) C T 100 90 80 70 60 50 40 30 20 10 0 TroughPeak p <0.0001 Platelet reactivity index (%) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

24. Proportion of platelet function responses greater than risk thresholds for ischemic events: pre-maintenance dose LTA = light transmittance aggregometry 100 80 60 40 20 0 % above threshold Maximum LTA response to ADP 20μm >50% Final LTA response to ADP 5μm >14% VerifyNow P2Y 12 >235 PRU VASP PRI >50% p <0.0001 p=0.02 p=0.0001 Ticagrelor Clopidogrel Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

25. Proportion of platelet function responses greater than risk thresholds for ischemic events: 2–4 hours post-maintenance dose LTA = light transmittance aggregometry 100 80 60 40 20 0 % above threshold Maximum LTA response to ADP 20μm >50% Final LTA response to ADP 5μm >14% VerifyNow P2Y 12 >235 PRU VASP PRI >50% p=0.0001 p <0.0001 p=0.01 p <0.0001 Ticagrelor Clopidogrel Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

26. LTA responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose 100 80 60 40 20 0 % Platelet aggregation, mean TicagrelorClopidogrelTicagrelorClopidogrel p=0.59 p=0.054 p=0.04 p=0.21 LTA = light transmittance aggregometry; PPI = proton pump inhibitor Maximum LTA response to ADP 20μm Final LTA response to ADP 5μm PPI No PPI Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

27. LTA responses during maintenance therapy according to treatment with PPIs: 2–4 hours post-maintenance dose 100 80 60 40 20 0 % Platelet aggregation, mean TicagrelorClopidogrelTicagrelorClopidogrel p=0.68 p=0.013 p=0.007 p=0.73 LTA = light transmittance aggregometry; PPI = proton pump inhibitor Maximum LTA response to ADP 20μm Final LTA response to ADP 5μm PPI No PPI Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

28. VerifyNow P2Y 12 responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose TicagrelorClopidogrel p=0.56 p=0.005 PPI = proton pump inhibitor VerifyNow P2Y 12 response PPI No PPI 300 250 200 150 100 50 0 Platelet reaction units (PRU), mean Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

29. VerifyNow P2Y 12 responses during maintenance therapy according to treatment with PPIs: 2–4 hours post-maintenance dose Platelet reaction units (PRU), mean TicagrelorClopidogrel p=0.98 p=0.005 PPI = proton pump inhibitor VerifyNow P2Y 12 response PPI No PPI 300 250 200 150 100 50 0 Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

30. VASP responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose PPI = proton pump inhibitor VASP response 100 80 60 40 20 0 Platelet reactivity index (%), mean TicagrelorClopidogrel p=0.43 p=0.47 PPI No PPI Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

31. VASP responses during maintenance therapy according to treatment with PPIs: 2–4 hours post-maintenance dose PPI = proton pump inhibitor 100 80 60 40 20 0 Platelet reactivity index (%), mean TicagrelorClopidogrel p=0.32 p=0.23 PPI No PPI VASP response Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

32. PLATO PLATELET Conclusions: Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy. Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62