Clopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution?

European Journal of Medical Research

M Gross²  E Holinski-Feder¹  A Laner¹  H Bottheim²  M Kollmer²  R Olze²  S Kenngott² 

[1] Medizinisch-Genetisches Zentrum MGZ, München, Germany;Internistische Klinik Dr Müller, München, Germany

关键词: Rabeprazole;    Omeprazole;    Clopidogrel;    Drug Interactions;    Proton Pump Inhibitors;   

Others  :  1093141
DOI  :  10.1186/2047-783X-15-5-220

 received in 2010-02-26, accepted in 2010-03-29,  发布年份 2010

【 摘 要 】

Background

Dual therapy with aspirin and clopidogrel increases the risk of gastrointestinal bleeding. Therefore, co-therapy with a proton pump inhibitor (PPI) is recommended by most guidelines. However, there are warnings against combining PPIs with clopidogrel because of their interactions with cytochrome P450 isoenzyme 2C19 (CYP2C19).

Methods

The effects of the combined or separate intake of 20 mg of omeprazole and 75 mg of clopidogrel on the clopidogrel-induced inhibition of platelet aggregation were measured in four healthy subjects whose CYP2C19 exon sequences were determined. The effects of co-therapy with 10 mg of rabeprazole were also examined.

Results

Two subjects showed the wild-type CYP2C19 sequence. The concurrent intake of omeprazole had no effect on clopidogrel-induced platelet inhibition in these subjects. Two subjects were heterozygous for the *2 allele, with predicted reduced CYP2C19 activity. One of them was a clopidogrel non-responder. In the second heterozygous subject, omeprazole co-therapy reduced the clopidogrel anti-platelet effect when taken simultaneously or separately. However, the simultaneous intake of rabeprazole did not reduce the clopidogrel effect.

Conclusion

The clopidogrel-PPI interaction does not seem to be a PPI class effect. Rabeprazole did not affect the clopidogrel effect in a subject with a clear omeprazole-clopidogrel interaction. The separate intake of PPI and clopidogrel may not be sufficient to prevent their interaction.

【 授权许可】

   
2010 I. Holzapfel Publishers

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM, Harrington RA, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Hlatky MA, Kaul S, Lindner JR, Moliterno DJ, Mukherjee D, Schofield RS, Rosenson RS, Stein JH, Weitz HH, Wesley DJ: American College of Cardiology Foundation Task Force on clinical expert consensus documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2008, 52(18):1502-1517.
• [2]Fischbach W, Malfertheiner P, Hoffmann JC, Bolten W, Bornschein J, Götze O, Höhne W, Kist M, Koletzko S, Labenz J, Layer P, Miehlke S, Morgner A, Peitz U, Preiss J, Prinz C, Rosien U, Schmidt W, Schwarzer A, Suerbaum S, Timmer A, Treiber G, Vieth M: S3-guideline "helicobacter pylori and gastroduodenal ulcer disease" of the German society for digestive and metabolic diseases (DGVS) in cooperation with the German society for hygiene and microbiology, society for pediatric gastroenterology and nutrition e. V., German society for rheumatology. Z Gastroenterol 2009, 47(12):1230-1263.
• [3]Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J: Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost 2006, 4(11):2508-2509.
• [4]Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J: Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, dou ble-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008, 51(3):256-260.
• [5]Petersen K-U: Relevance of metabolic activator pathways: The example of clopidogrel and prasugrel. Arzneimittelforschung 2009, 59(5):213-227.
• [6]Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA: Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 1997, 25(7):853-862.
• [7]Li X-Q, Andersson TB, Ahlström M, Weidolf L: Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metabol Dispos 2004, 232(8):821-827.
• [8]Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS, Lachno DR, Salazar D, Winters KJ: Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007, 5(12):2429-2436.
• [9]Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G: Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009, 373(9660):309-317.
• [10]Pezalla E, Day D, Pulliadath I: Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol 2008, 52(12):1038-1039.
• [11]Aubert R, Epstein RS, Teagarden JR, Xia F, Yao J, Desta Z, Skaar T, Flockhart DA: Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study (abstract 3998). Circulation 2008, 118:S815.
• [12]Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS: Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009, 301(9):937-944.
• [13]Gupta E, Bansal D, Sotos J, Olden K: Risk of adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors following percutaneous coronary intervention. Dig Dis Sci 2009, in press.
• [14]O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD: 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(9694):989-997.
• [15]Dunn SP, Macaulay TE, Brennan DM, Campbell CL, Charnigo RJ, Smyth SS, Berger PB, Steinhubl SR, Topol EJ: 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:S815.
• [16]Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L: French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009, 360(4):363-375.
• [17]Zairis MN, Tsiaousis GZ, Patsourakos NG, Georgilas AT, Kontos CF, Adamopoulou EN, Vogiatzidis K, Argyrakis SK, Fakiolas CN, Foussas SG: The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. Can J Cardiol 2010, 26(2):e54-e57.
• [18]Depta JP, Bhatt DL: Omeprazole and clopidogrel: Should clinicians be worried? Cleve Clin J Med 2010, 77(2):113-116.
• [19]Laine L, Hennekens C: Proton pump inhibitor and clopidogrel interaction: fact or fiction? Am J Gastroenterol 2010, 105(1):34-41.
• [20]Gross M, Petersen K-U: PPI for dual therapy with clopidogrel: to use or not to use? Z Gastroenterol 2010, 48:420-423.
• [21]Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM: A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009, 180(7):713-718.
• [22]Cuisset T, Frere C, Quilici J, Poyet R, Gaborit B, Bali L, Brissy O, Morange PE, Alessi MC, Bonnet JL: Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009, 54(13):1149-1153.
• [23]Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B: Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009, 157(1):148.e1-e5.
• [24]Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, Schömig A, Kastrati A, von Beckerath N: Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009, 101(4):714-719.
• [25]Small DS, Farid NA, Payne CD, Weerakkody GJ, Li YG, Brandt JT, Salazar DE, Winters KJ: Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008, 48(4):475-484.
• [26]Tóth O, Calatzis A, Penz S, Losonczy H, Siess W: Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006, 96(6):781-788.
• [27]Kirchheiner J, Glatt S, Fuhr U, Klotz U, Meineke I, Seufferlein T, Brockmöller J: Relative potency of proton-pump inhibitors-comparison of effects on intragastric pH. Eur J Clin Pharmacol 2009, 65(1):19-31.