Platelet inhibition by ticagrelor is not affected by proton pump inhibitors: results from the PLATO PLATELET substudy

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1 Platelet inhibition by ticagrelor is not affected by proton pump inhibitors: results from the PLATO PLATELET substudy Shankar B Patil 1, Dominick J Angiolillo 2, Bhaloo Desai 2, Rosemary Ecob 1, Steen Husted 3, Hakan Emanuelsson 4, Christopher P Cannon 5, Richard C Becker 6, Lars Wallentin 7, Robert F Storey 1 1 Department of Cardiovascular Science, University of Sheffield, Sheffield, and NIHR Cardiovascular Biomedical Research Unit, Sheffield, United Kingdom 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 1

2 Disclosures for Dr Shankar Patil Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Research support and travel grants from AstraZeneca No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare No relevant conflicts of interest to declare 2

3 Activation/inactivation of clopidogrel S O N Cl OCH 3 O OCH O OCH 3 3 COOH CYPs Clopidogrel Esterases N O S Cl CYPs N HS Cl 2-Oxo-clopidogrel R O OH N S Cl SR26334 (Inactive) CYP = cytochrome P450. Farid NA, et al. Clin Pharmacol Ther. 2007;81:

4 Ticagrelor Non-thienopyridine Reversible binding to the P2Y 12 receptor Direct acting (not a prodrug) Level of platelet inhibition depends on plasma concentration 4

5 Proton pump inhibitors (PPIs) and clopidogrel PPIs recommended to prevent bleeding associated with dual anti-platelet therapy Evidence of decreased pharmacodynamic effect of clopidogrel when administered with PPIs that inhibit CYP2C enzymes Clinical studies and registries provide conflicting data on effect of PPIs on clinical outcomes in clopidogrel-treated patients 5

6 PRI (%) Interaction of clopidogrel and omeprazole NS VASP PRI (%) on Day 1 VASP PRI (%) on Day P< Gillard M et al. J Am Coll Cardiol 2008;51: Omeprazole Group Placebo

7 PLATO Study Design NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naïve; randomized within 24 hours of index event (N=18,624) Clopidogrel If pre-treated, no additional loading dose; if naïve, standard 300-mg loading dose, then 75-mg qd maintenance; (additional 300 mg allowed pre-pci) Ticagrelor 180-mg loading dose, then 90-mg bid maintenance; (additional 90 mg pre-pci)

8 PLATO PLATELET substudy 69 patients in the PLATO study at 2 centres (Sheffield, UK, and Jacksonville, USA) participated in the maintenance phase of this substudy. Platelet responses were assessed during maintenance therapy (treatment with study medication for at least 28 days). In this analysis, platelet responses were compared in those currently or not currently receiving treatment with a PPI in each group (32 clopidogrel patients and 37 ticagrelor patients) Light transmittance aggregometry (LTA) with ADP, VerifyNow P2Y12 and VASP assays were performed prior to maintenance dose ( trough ) and 2-4h after dosing ( peak ) 8

9 % Platelet aggregation, mean (SE) PLATO PLATELET Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): maximum LTA response (ADP 5μM) p <0.01 p < C T C T Trough Peak Storey RF et al. JACC 2010; in press LTA = light transmittance aggregometry; SE = standard error

10 Platelet reaction units (PRU), mean (SE) PLATO PLATELET Responses to maintenance doses of clopidogrel (C) and ticagrelor (T): VerifyNow P2Y 12 assay 500 p <0.001 p < C T C T Trough Peak Storey RF et al. JACC 2010; in press SE = standard error

11 Type of proton pump inhibitors used according to treatment group Clopidogrel n=13 Ticagrelor n=12 Omeprazole 3 5 Esomeprazole 3 2 Lansoprazole 6 5 Rabeprazole 1 0 Pantoprazole 0 0 Storey RF et al. JACC 2010; in press

12 Demographics according to treatment groups Clopidogrel n=32 P value Ticagrelor n=37 P value PPI No PPI PPI No PPI n=13 n=19 n=12 n=25 Age, mean years Weight, mean Kg Smoker, n (%) 4 (23) 3 (16) (33) 10 (40) 1.00 Diabetes, n (%) 3 (23) 5 (26) (17) 5 (20) 1.00

13 % Platelet aggregation, mean LTA responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose 100 PPI No PPI 80 p= p=0.59 p= p= Ticagrelor Clopidogrel Ticagrelor Clopidogrel Storey RF et al. JACC 2010; in press Maximum LTA response to ADP 20μm Final LTA response to ADP 5μm LTA = light transmittance aggregometry; PPI = proton pump inhibitor

14 % Platelet aggregation, mean LTA responses during maintenance therapy according to treatment with PPIs: 2 4 hours post-maintenance dose 100 PPI No PPI 80 p= p=0.68 p= p=0.73 Ticagrelor Clopidogrel Ticagrelor Clopidogrel Storey RF et al. JACC 2010; in press Maximum LTA response to ADP 20μm Final LTA response to ADP 5μm LTA = light transmittance aggregometry; PPI = proton pump inhibitor

15 Platelet reaction units (PRU), mean VerifyNow P2Y 12 responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose 300 p=0.005 PPI No PPI p= Ticagrelor Clopidogrel VerifyNow P2Y 12 response Storey RF et al. JACC 2010; in press PPI = proton pump inhibitor

16 Platelet reaction units (PRU), mean VerifyNow P2Y 12 responses during maintenance therapy according to treatment with PPIs: 2 4 hours post-maintenance dose p=0.005 PPI No PPI p= Ticagrelor Clopidogrel VerifyNow P2Y 12 response Storey RF et al. JACC 2010; in press PPI = proton pump inhibitor

17 Platelet reactivity index (%), mean VASP responses during maintenance therapy according to treatment with PPIs: pre-maintenance dose 100 PPI No PPI 80 p= p= Ticagrelor Clopidogrel VASP response Storey RF et al. JACC 2010; in press PPI = proton pump inhibitor

18 Platelet reactivity index (%), mean VASP responses during maintenance therapy according to treatment with PPIs: 2 4 hours post-maintenance dose 100 PPI No PPI 80 p= p= Ticagrelor Clopidogrel VASP response Storey RF et al. JACC 2010; in press PPI = proton pump inhibitor

19 Conclusions Clopidogrel-treated patients on PPI had higher platelet reactivity compared to patients not on PPI. Ticagrelor-treated patients had low levels of platelet reactivity regardless of whether or not they were receiving PPI. PPI usage does not appear to attenuate the inhibitory effects of ticagrelor on platelet function. 19