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J. Am. Coll. Cardiol 2010;56(18):1456-62

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

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J. Am. Coll. Cardiol 2010;56(18):1456-62

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  1. Inhibitory Effects of Ticagrelor Compared to Clopidogrel on Platelet Function in Patients with Acute Coronary Syndromes The PLATO PLATELET Substudy Storey RF1, Angiolillo DJ2, Patil SB1, Desai B2, Ecob R1, Husted S3, Emanuelsson H4, Cannon CP5, Becker RC6, Wallentin L7 1Department of Cardiovascular Science, University of Sheffield, and NIHR Cardiovascular Biomedical Research Unit, Sheffield, UK 2University of Florida College of Medicine-Jacksonville, Jacksonville, FL, USA 3Århus University Hospital, Århus, Denmark 4AstraZeneca, Mölndal, Sweden 5TIMI Study Group, Brigham and Women’s Hospital, Boston, USA 6Duke Clinical Research Institute, Durham, USA 7Uppsala 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 mM), 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 mM) 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. p <0.001 p <0.001 % Platelet aggregation, mean (SE) C T C T Figure 1A. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM) 100 80 60 40 20 0 Trough Peak Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry; SE = standard error

  6. 100 80 60 40 20 0 p <0.01 p <0.01 % Platelet aggregation, mean (SE) C T C T Trough Peak Figure 1B. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 20μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry; SE = standard error

  7. 100 80 60 40 20 0 p <0.01 p <0.001 % Platelet aggregation, mean (SE) C T C T Trough Peak Figure 1C. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry; SE = standard error

  8. 100 80 60 40 20 0 p <0.001 p <0.001 % Platelet aggregation, mean (SE) C T C T Trough Peak Figure 1D. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 5μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry; SE = standard error

  9. 500 400 300 200 100 0 p <0.001 p <0.001 Platelet reaction units (PRU), mean (SE) 235 PRU C T C T Trough Peak Figure 1E. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y12 assay Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 SE = standard error

  10. 100 90 80 70 60 50 40 30 20 10 0 p <0.001 p <0.001 Platelet reactivity index (%), mean (SE) C T C T Trough Peak Figure 1F. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VASP assay Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 SE = standard error

  11. 500 400 300 200 100 0 Platelet reaction units (PRU), mean (SE) UK US UK US UK US UK US Trough Peak Trough Peak C T Figure 2. VerifyNow responses to maintenance doses of clopidogrel (C) and ticagrelor (T) according to geographic location (UK or US) SE = standard errorAll p = NS Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

  12. 100 80 60 40 20 0 p <0.01 p <0.01 p <0.001 % Platelet aggregation, mean C T C T C T C T C T C T Pre 1h 2h 4h 8h 12h Figure 3A. Responses to loading doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 20μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry

  13. 100 80 60 40 20 0 p <0.001 % Platelet aggregation, mean C T C T C T C T C T C T Pre 1h 2h 4h 8h 12h Figure 3B. Responses to loading doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 20μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry

  14. 100 80 60 40 20 0 p <0.01 % Platelet aggregation, mean C T C T C T C T C T C T Pre 1h 2h 4h 8h 12h Figure 3C. Responses to loading doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry

  15. 100 80 60 40 20 0 p <0.01 % Platelet aggregation, mean C T C T C T C T C T C T Pre 1h 2h 4h 8h 12h Figure 3D. Responses to loading doses of clopidogrel (C) and ticagrelor (T): final LTA response (ADP 5μM) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry

  16. 500 400 300 200 100 0 p <0.01 Platelet reaction units (PRU), mean C T C T Pre 4h Figure 3E. Responses to loading doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y12 assay Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

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

  18. p <0.01 100 80 60 40 20 0 p <0.001 p <0.01 % Inhibition, mean C T C T C T C T C T 1h 2h 4h 8h 12h Figure 4A. IPA following loading doses of clopidogrel (C) and ticagrelor (T): inhibition of maximum LTA response (ADP 5μM) LTA = light transmittance aggregometryP values determined by unpaired t test or Mann Whitney test Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

  19. p <0.01 p <0.01 p <0.01 p <0.01 p <0.001 100 80 60 40 20 0 % Inhibition, mean C T C T C T C T C T 1h 2h 4h 8h 12h Figure 4B. IPA following loading doses of clopidogrel (C) and ticagrelor (T): inhibition of final LTA response (ADP 5μM) LTA = light transmittance aggregometryP values determined by unpaired t test or Mann Whitney test Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

  20. 100 80 60 40 20 0 p <0.001 p <0.0001 % Platelet aggregation C T C T Trough Peak 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 Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

  21. 100 80 60 40 20 0 p <0.001 p <0.001 % Platelet aggregation C T C T Trough Peak 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 Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

  22. 500 400 300 200 100 0 p <0.0001 p <0.0001 Platelet reaction units (PRU) C T C T Trough Peak Suppl. Figure 1C. Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y12 assay Data are mean, interquartile range (boxes), 10–90 percentile (whiskers) and outlying data points (dots) Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62

  23. 100 90 80 70 60 50 40 30 20 10 0 p <0.0001 p <0.0001 Platelet reactivity index (%) C T C T Trough Peak 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) 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 Ticagrelor Clopidogrel 100 80 60 40 20 0 p <0.0001 p <0.0001 p=0.02 p=0.0001 % above threshold Maximum LTA response to ADP 20μm >50% Final LTA response to ADP 5μm >14% VerifyNow P2Y12 >235 PRU VASP PRI >50% Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry

  25. Proportion of platelet function responses greater than risk thresholds for ischemic events: 2–4 hours post-maintenance dose Ticagrelor Clopidogrel 100 80 60 40 20 0 p <0.0001 p=0.0001 % above threshold p <0.0001 p=0.01 Maximum LTA response to ADP 20μm >50% Final LTA response to ADP 5μm >14% VerifyNow P2Y12 >235 PRU VASP PRI >50% Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 LTA = light transmittance aggregometry

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

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

  28. VerifyNow P2Y12 responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose PPI No PPI 300 250 200 150 100 50 0 p=0.005 Platelet reaction units (PRU), mean p=0.56 Ticagrelor Clopidogrel VerifyNow P2Y12 response Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 PPI = proton pump inhibitor

  29. VerifyNow P2Y12 responses during maintenance therapy according to treatment with PPIs: 2–4 hours post-maintenance dose PPI No PPI 300 250 200 150 100 50 0 p=0.005 Platelet reaction units (PRU), mean p=0.98 Ticagrelor Clopidogrel VerifyNow P2Y12 response Storey RF et al. J Am Coll Cardiol 2010;56(18):1456-62 PPI = proton pump inhibitor

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

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

  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

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