Inter-patient variability and impact of proton pump inhibitors on platelet reactivity after prasugrel

Summary

Although there is considerable variability of platelet reactivity among patients treated with clopidogrel, little is known about inter-individual differences and possible role of proton pump inhibitors (PPIs) after prasugrel. We defined the extent of inter-patient variability, and evaluated the impact of PPI interaction in prasugrel-treated patients with acute coronary syndrome (ACS). Between January 2010 and May 2011, 104 prospective, high-risk patients with ACS were recruited into this multicentre, prospective, observational study. Twelve to 24 hours after receiving 60 mg loading dose of prasugrel, light transmission aggregometry (LTA) and whole blood impedance aggregometry (Multiplate) were used to assess platelet activity. Platelet function measurements were repeated during maintenance phase on reduced (5 mg) or on conventional (10 mg) doses of prasugrel. High platelet reactivity (HPR) was defined according to the consensus document of the Working Group on High On-Treatment Platelet Reactivity (LTA:>46%; Multiplate:>47U). Compared to maintenance doses, 60 mg loading dose of prasugrel provided significantly greater platelet reactivity inhibition (p<0.05). There were no significant differences between the conventional and reduced maintenance doses. Notably, a remarkable inter-patient variability was present in platelet reactivity after all doses of prasugrel, and the prevalence of HPR was significantly higher during the maintenance doses (p<0.05). Although median platelet reactivity values were consistently higher when prasugrel was used in combination with PPIs, these differences were not significant (p≥0.17). Despite potent platelet inhibition, inter-patient variability is present after all tested doses of prasugrel. The 60 mg loading dose is superior to conventional and reduced maintenance doses in terms of platelet reactivity inhibition and regarding the prevention of HPR.

Keywords

ADP receptors - antiplatelet agents - antiplatelet drugs - platelet pharmacology

• References

• 1 Steinhubl SR, Berger PB, Mann 3rd JT. et al. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
• 2 Mehta SR, Yusuf S, Peters RJ. et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
• 3 Bonello L, Tantry US, Marcucci R. et al. Working Group on High On-Treatment Platelet Reactivity. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
• 4 Siller-Matula JM, Jilma B, Schrör K. et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis.. J Thromb Haemost 2010; 8: 2624-2641.
• 5 Rideg O, Komócsi A, Magyarlaki T. et al. Impact of genetic variants on post-clopidogrel platelet reactivity in patients after elective percutaneous coronary intervention.. Pharmacogenomics 2011; 2011; 12: 1269-1280.
• 6 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease.. Eur Heart J 2008; 29: 21-30.
• 7 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease.. Eur Heart J 2006; 27: 1166-1173.
• 8 Wiviott SD, Trenk D, Frelinger AL. et al. PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.
• 9 Jakubowski JA, Payne CD, Li YG. et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry.. Thromb Haemost 2008; 99: 215-222.
• 10 Bonello L, Pansieri M, Mancini J. et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes.. J Am Coll Cardiol 2011; 58: 467-473.
• 11 Sibbing D, Steinhubl SR, Schulz S. et al. Platelet aggregation and its association with stent thrombosis and bleeding in clopidogrel-treated patients: initial evidence of a therapeutic window.. J Am Coll Cardiol 2010; 5: 317-318.
• 12 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-inter-ventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.. J Am Coll Cardiol 2006; 48: 1742-1750.
• 13 Michelson AD, Frelinger 3rd AL, Braunwald E. et al TRITON-TIMI 38 Investigators. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur Heart J 2009; 30: 1753-1763.
• 14 Angiolillo DJ, Badimon JJ, Saucedo JF. et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 201 32: 838-846.
• 15 Sugidachi A, Asai F, Ogawa T. et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties.. Br J Pharmacol 2000; 129: 1439-1446.
• 16 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals.. J Am Coll Cardiol 2005; 45: 246-251.
• 17 Aradi D, Magyarlaki T, Tokés-Füzesi M. et al. Comparison of conventional aggregometry with VASP for monitoring P2Y12-specific platelet inhibition. Platelets 2010; 21: 563-570.
• 18 Erlinge D, Varenhorst C, Braun OO. et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo.. J Am Coll Cardiol 2008; 52: 1968-1977.
• 19 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis.. Lancet 2010; 376: 1312-1319.
• 20 Frelinger 3rd AL, Michelson AD, Wiviott SD. et al. Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44. Thromb Haemost 2011; 106: 219-226.
• 21 O'Donoghue ML, Braunwald E, Antman EM. et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials.. Lancet 2009; 374: 989-997.
• 22 Hochholzer W, Trenk D, Fromm MF. et al. Impact of cytochrome P450 2C19 loss-of-function polymorphism and of major demographic characteristics on residual platelet function after loading and maintenance treatment with clopidogrel in patients undergoing elective coronary stent placement.. J Am Coll Cardiol 2010; 55: 2427-2434.