Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel

Summary

Patients receiving dual antiplatelet treatment with aspirin and clopidogrel are commonly treated with proton pump inhibitors (PPIs). Attenuating effects on platelet response to clopidogrel have been reported solely for the PPI omeprazole. PPIs differ in their metabolisation properties as well as their potential for drug-drug interactions. The aim of this study was to investigate the impact of different PPIs (pantoprazole, omeprazole, esomeprazole) on platelet response to clopidogrel in patients with previous coronary stent placement under chronic clopidogrel treatment. In a cross-sectional observational study, consecutive patients under clopidogrel maintenance treatment (n=1,000) scheduled for a control coronary angiography were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation (in AU*min) was measured with multiple electrode platelet aggregometry (MEA). From the entire study population, 268 (26.8%) patients were under PPI treatment at the time point of platelet function testing (pantoprazole, n=162; omeprazole, n=64; esomeprazole, n=42). Platelet aggregation (median [interquar-tile range]) was significantly higher in patients with omeprazole treatment (295.5 [193.5–571.2] AU*min) compared to patients without PPI treatment (220.0 [143.8–388.8] AU*min; p=0.001). Platelet aggregation was similar in patients with pantoprazole (226.0 [150.0–401.5] AU*min) or esomeprazole (209.0 [134.8–384.8] AU*min) treatment compared to patients without PPI treatment (p=0.69 and p=0.88, respectively). Attenuating effects of concomitant PPI treatment on platelet response to clopidogrel were restricted to the use of omeprazole. No attenuating effects on platelet response to clopidogrel were observed for pantoprazole or esomeprazole. Specifically designed and randomized clinical studies are needed to define the impact of concomitant PPI treatment on adverse events after percutaneous coronary intervention.

Keywords

Clopidogrel - proton pump inhibitors - platelet aggregation

• References

• 1 Smith Jr SC, Feldman TE, Hirshfeld Jr JW. et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006; 113: e166-286.
• 2 Hollopeter G, Jantzen HM, Vincent D. et al. Identification of the platelet ADP receptor targeted by anti-thrombotic drugs. Nature 2001; 409: 202-207.
• 3 Savi P, Pereillo JM, Uzabiaga MF. et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000; 84: 891-896.
• 4 Brandt JT, Close SL, Iturria SJ. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429-2436.
• 5 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.
• 6 Sibbing D, von Beckerath O, Schömig A. et al. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention. Am J Cardiol 2007; 100: 203-205.
• 7 Lau WC, Gurbel PA, Watkins PB. et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109: 166-171.
• 8 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 2007; 49: 1505-1516.
• 9 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
• 10 Trenk D, Hochholzer W, Fromm MF. et al. Cytoch-rome P450 2C19 681G>A polymorphism and high onclopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51: 1925-1934.
• 11 Buonamici P, Marcucci R, Migliorini A. et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 49: 2312-2317.
• 12 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
• 13 Sibbing D, Braun S, Morath T. et al. Platelet reactivity following clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.
• 14 Bliden KP, DiChiara J, Tantry US. et al. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?. J Am Coll Cardiol 2007; 49: 657-666.
• 15 Angiolillo DJ, Bernardo E, Sabate M. et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50: 1541-1547.
• 16 Bhatt DL, Scheiman J, Abraham NS. et al. ACCF/ ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use. Am J Gastroenterol 2009; 103: 2890-2907.
• 17 Gilard M, Arnaud B, Cornily JC. et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51: 256-260.
• 18 Blume H, Donath F, Warnke A. et al. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf 2006; 29: 769-784.
• 19 Meyer UA. Interaction of proton pump inhibitors with cytochromes P450: consequences for drug interactions. Yale J Biol Med 1996; 69: 203-209.
• 20 Sibbing D, Braun S, Jawansky S. et al. Assessment of ADP-induced platelet aggregation with light transmission aggregometry and multiple electrode platelet aggregometry before and after clopidogrel treatment. Thromb Haemost 2008; 99: 121-126.
• 21 Toth O, Calatzis A, Penz S. et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96: 781-788.
• 22 Dynabyte Informationssysteme GmbH, Homepage. (Accessed October 30, 2008, at www.multiplate.net ).
• 23 Gurbel PA, Becker RC, Mann KG. et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007; 50: 1822-1834.
• 24 De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100: 196-203.
• 25 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005; 54: 2430-2435.
• 26 Geisler T, Grass D, Bigalke B. et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost 2008; 6: 54-61.
• 27 Serebruany V, Pokov I, Kuliczkowski W. et al. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost 2008; 100: 76-82.
• 28 Yousef AM, Arafat T, Bulatova NR. et al. Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel. J Clin Pharm Ther 2008; 33: 439-449.
• 29 Siller-Matula J, Spiel A, Lang I. et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009; 157: 148.e1-148.e5.
• 30 Small DS, Farid NA, Payne CD. et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008; 48: 475-484.
• 31 Sibbing D, Busch G, Braun S. et al. Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention. Eur Heart J 2008; 29: 1504-1509.
• 32 Penz SM, Reininger AJ, Toth O. et al. Glycoprotein Ibalpha inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques. Thromb Haemost 2007; 97: 435-443.
• 33 Breugelmans J, Vertessen F, Mertens G. et al. Multiplate whole blood impedance aggregometry: a recent experience. Thromb Haemost 2008; 100: 725-726.
• 34 Johnson A, Dovlatova N, Heptinstall S. Multiple electrode aggregometry and P2Y₍₁₂₎ antagonists. Thromb Haemost 2008; 99: 1127-1129.
• 35 Stedman CA, Barclay ML. Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 2000; 14: 963-978.
• 36 Schwab M, Klotz U, Hofmann U. et al. Esomeprazole-induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19: evidence from clinical and pharmacokinetic data. Clin Pharmacol Ther 2005; 78: 627-634.
• 37 Li XQ, Andersson TB, Ahlstrom M. et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004; 32: 821-827.
• 38 Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol 2008; 64: 935-951.
• 39 Ho PM, Maddox TM, Wang L. et al. Proton pump inhibitors may attenuate the benefits of clopidogrel among ACS patients: Empirical evidence from 3,311 ACS patients. Circulation. 2008 118: S_1165.
• 40 Dunn SP, Macaulay TE, Brennan DM. et al. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation. 2008 118: S_815.
• 41 Aubert RE, Epstein RS, Teagarden JR. et al. Proton pump inhibitors effect on clopidogrel effectiveness: The Clopidogrel Medco Outcomes Study. Circulation. 2008 118: S_815.