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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. May 6, 2015; 6(2): 17-21
Published online May 6, 2015. doi: 10.4292/wjgpt.v6.i2.17
Clinical relevance of clopidogrel-proton pump inhibitors interaction
Stella D Bouziana, Konstantinos Tziomalos
Stella D Bouziana, Konstantinos Tziomalos, First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
Author contributions: Bouziana SD drafted the paper; Tziomalos K revised the draft critically for important intellectual content.
Conflict-of-interest: We have no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Konstantinos Tziomalos, MD, PhD, Assistant Professor of Internal Medicine, First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Kiriakidi 1, 54636 Thessaloniki, Greece. ktziomalos@yahoo.com
Telephone: +30-2310-994621 Fax: +30-2310-994773
Received: January 13, 2015
Peer-review started: January 15, 2015
First decision: March 6, 2015
Revised: March 24, 2015
Accepted: April 16, 2015
Article in press: April 20, 2015
Published online: May 6, 2015

Abstract

Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal anti-inflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk.

Key Words: Clopidogrel, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Omeprazole, Cardiovascular risk, Proton pump inhibitors

Core tip: Even though pharmacodynamic studies suggest that omeprazole can attenuate the antiplatelet effect of clopidogrel, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination in observational studies. In the only randomized, double-blind, placebo-controlled study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for gastrointestinal events and similar risk for cardiovascular events. Other proton pump inhibitors also do not appear to interact with clopidogrel. However, given the limitations of existing studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk.



INTRODUCTION

Clopidogrel is a first-line antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease or with a history of non-cardioembolic ischemic stroke[1,2]. In addition, clopidogrel is recommended in combination with aspirin for up to 12 mo in patients with acute coronary syndrome (ACS) treated either medically or invasively[3,4]. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the risk of GI bleeding is not negligible in patients treated with this agent[5,6]. Moreover, the risk of GI bleeding further increases in patients who receive clopidogrel in combination with aspirin as well as in the elderly, in patients with a history of prior GI bleeding or with Helicobacter pylori infection, and in those who are also treated with anticoagulants, corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs)[7,8]. In these patients, administration of proton pump inhibitors (PPIs) significantly reduces the risk of GI bleeding associated with clopidogrel treatment[9,10]. Accordingly, PPIs are commonly prescribed in patients treated with clopidogrel to reduce the risk of GI bleeding[11,12].

Even though the administration of PPIs in patients treated with clopidogrel reduces the risk for GI bleeding, some pharmacodynamic studies suggested that the antiplatelet effect of clopidogrel is also attenuated by PPIs[13-15]. This interaction is due to the inhibition by PPIs of the cytochrome (CYP) P450 isoenzyme 2C19, which converts clopidogrel to its active metabolite[16]. Notably, PPIs differ in their ability to inhibit CYP2C19, omeprazole being a more potent inhibitor than the other members of the class[17,18]. Accordingly, some studies showed that omeprazole attenuates the antiplatelet effect of clopidogrel[13-15] but others did not confirm these findings[19,20]. In contrast, esomeprazole, lansoprazole, pantoprazole and rabeprazole did not affect platelet function in patients treated with clopidogrel[13,15,19-22].

However, it is unclear whether these ex vivo findings have clinical importance, i.e., if the co-administration of clopidogrel with omeprazole or other PPIs will result in reduced protection against cardiovascular events. Notably, earlier studies suggested that atorvastatin attenuates the antiplatelet effects of clopidogrel ex vivo but this interaction did not translate into higher cardiovascular morbidity in patients receiving this combination[23-25]. Indeed, observational studies that evaluated the effect of administering PPIs in combination with clopidogrel on cardiovascular events in patients who suffered an ACS or underwent percutaneous coronary intervention (PCI) reported conflicting results. In two early retrospective studies, patients treated with clopidogrel and either omeprazole or pantoprazole had higher risk of recurrent cardiovascular events than those who were given clopidogrel alone[11,26] (Table 1). In contrast, several other retrospective studies reported that neither omeprazole nor pantoprazole increase cardiovascular morbidity when combined with clopidogrel[10,12,27-30] (Table 1). A post-hoc analysis of the randomized controlled Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 also reported similar findings[31] (Table 1). In the same post-hoc analysis and in more recent observational studies, treatment with esomeprazole or lansoprazole was also not associated with increased cardiovascular risk when combined with clopidogrel[29-31] (Table 1).

Table 1 Major observational studies that evaluated the effects of coadministration of clopidogrel and proton pump inhibitors on cardiovascular events.
Ref.PopulationnHazard ratio in patients who received clopidogrel and proton pump inhibitors vs patients treated with clopidogrel alone
[10]Patients hospitalized for ACS or coronary revascularization205960.99 (95%CI: 0.82-1.19, P = NS)
[11]Patients hospitalized for ACS82051.25 (95%CI: 1.11-1.41, P = NR)
[12]Patients hospitalized for ACS564060.98 (95%CI: 0.88-1.10, P = NS)
[26]Patients hospitalized for ACS or coronary stent placement20661.64 (95%CI: 1.16-2.32, P = 0.005)
[27]Patients hospitalized for ACS or coronary stent placement185651.22 (95%CI: 0.99-1.51 P = NS)
[28]Patients hospitalized for ACS136361.27 (95%CI: 1.03-1.57, P = NR)
[29]Patients hospitalized for ACS244710.75 (95%CI: 0.55-1.01, P = NS)
[30]Patients who underwent coronary stent placement130011.20 (95%CI: 0.91-1.58, P = NS)
[31]Patients with ACS undergoing coronary stent placement67950.94 (95%CI: 0.80-1.11, P = NS)

Given the well-known limitations of observational studies, these results should be interpreted with caution. Patients who are given PPIs are frequently older and have more comorbidities and despite the adjustment for these differences there is always potential for residual confounding[10-12,26-31]. Indeed, some studies reported that PPI use is associated with increased risk for cardiovascular events regardless of the use of clopidogrel and in patients treated with ticagrelor, which does require activation by CYP2C19, suggesting that PPI use is a marker of increased cardiovascular risk and frailty[12,30,32,33]. Moreover, none of the above-mentioned studies could adjust for over-the-counter use of PPIs and adherence to treatment[10-12,26-31]. Many patients used PPIs intermittently, a parameter which was not considered in most studies[10-12,26-31]. Finally, most studies evaluated very-high risk patients, i.e., with a recent ACS or PCI, and it is unclear whether these results are applicable to lower-risk patients, e.g., those with stable angina or history of ischemic stroke[10-12,26-31]. Finally, the antiplatelet activity of clopidogrel is affected by several polymorphisms (Table 2)[34] and none of these studies evaluated this parameter[10-12,26-31]. However, both pharmacodynamic and clinical studies suggest that there is no association between CYP2C19 genotype and the impact of PPIs on the antiplatelet effect of clopidogrel[35-37].

Table 2 Polymorphisms that potentially affect the antiplatelet effect of clopidogrel.
PolymorphismMechanism of reduced antiplatelet effect of clopidogrel
CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*7, CYP2C19*8Reduced metabolism of clopidogrel to its active metabolite
C3435T polymorphism of the ABCB1 geneOverexpression of the drug efflux pump P-glycoprotein leading to reduced intestinal absorption of clopidogrel
Q192R polymorphism of the paraoxonase-1 geneReduced metabolism of clopidogrel to its active metabolite

The only randomized, double-blind, placebo-controlled study that assessed the cardiovascular implications of combining clopidogrel and omeprazole is the Clopidogrel and the Optimization of Gastrointestinal Events Trial[9]. In this trial, 3761 patients with an indication for dual antiplatelet treatment with aspirin and clopidogrel were randomly assigned to a fixed-dose combination of clopidogrel/omeprazole (75/20 mg) or clopidogrel plus placebo[9]. The study was designed to end once 143 GI events (primarily bleeding) had occurred but ended prematurely due to interruption of funding after only 55 GI events had occurred[9]. Sample size calculation was not performed for the cardiovascular endpoint (nonfatal myocardial infarction, ischemic stroke, coronary revascularization or cardiovascular death)[9]. Patients treated with clopidogrel/omeprazole combination had reduced risk for GI events (1.1% vs 2.9% in patients treated with clopidogrel plus placebo; P < 0.001) and similar risk for cardiovascular events (4.9% vs 5.7%, respectively; P = 0.98)[9]. Unfortunately, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination[9]. In addition, the pharmacokinetics of the combined omeprazole-clopidogrel pill might be different from free combinations, even though data suggest that spacing the two medications does not affect the inhibitory effect of omeprazole on the antiplatelet action of clopidogrel[9,15,38].

In light of these conflicting data, the American Heart Association, American College of Cardiology and the American College of Gastroenterology issued an expert consensus document recommending that PPIs should be considered only in those patients treated with clopidogrel who are at high-risk for GI bleeding, including those with a previous history of GI bleeding, with Helicobacter pylori infection, who are treated with NSAIDs, corticosteroids or anticoagulants, and the elderly[16]. On the other hand, the United States Food and Drug Administration and the European Medicines Agency revised the labelling of clopidogrel, which now mentions that omeprazole and esomeprazole should be avoided in patients treated with clopidogrel, that other acid-lowering agents with minimal or no inhibitory effects on CYP2C19 should be considered and that lansoprazole and pantoprazole have less inhibitory effect on the antiplatelet action of clopidogrel than omeprazole and esomeprazole[39,40].

In conclusion, even though pharmacodynamic studies suggest that omeprazole can attenuate the antiplatelet effect of clopidogrel, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Other PPIs also do not appear to interact with clopidogrel. However, given the limitations of existing studies, the decision to administer PPIs to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk.

Footnotes

P- Reviewer: Chiu CT, Cosmi E, Leone A, Vassalle C S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ

References
1.  Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126:e354-e471.  [PubMed]  [DOI]
2.  Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236.  [PubMed]  [DOI]
3.  O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-e425.  [PubMed]  [DOI]
4.  Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, Jaffe AS, Jneid H, Kelly RF, Kontos MC. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.  [PubMed]  [DOI]
5.  CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.  [PubMed]  [DOI]
6.  Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.  [PubMed]  [DOI]
7.  Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.  [PubMed]  [DOI]
8.  Barada K, Karrowni W, Abdallah M, Shamseddeen W, Sharara AI, Dakik HA. Upper gastrointestinal bleeding in patients with acute coronary syndromes: clinical predictors and prophylactic role of proton pump inhibitors. J Clin Gastroenterol. 2008;42:368-372.  [PubMed]  [DOI]
9.  Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363:1909-1917.  [PubMed]  [DOI]
10.  Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Daugherty JR, Kaltenbach LA, Stein CM. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010;152:337-345.  [PubMed]  [DOI]
11.  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;301:937-944.  [PubMed]  [DOI]
12.  Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ, Hansen PR, Madsen JK, Køber L, Torp-Pedersen C. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153:378-386.  [PubMed]  [DOI]
13.  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;101:714-719.  [PubMed]  [DOI]
14.  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, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol. 2008;51:256-260.  [PubMed]  [DOI]
15.  Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, Perrin L, LaCreta FP, Hurbin F, Dubar M. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011;89:65-74.  [PubMed]  [DOI]
16.  Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;122:2619-2633.  [PubMed]  [DOI]
17.  Ogilvie BW, Yerino P, Kazmi F, Buckley DB, Rostami-Hodjegan A, Paris BL, Toren P, Parkinson A. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: implications for coadministration with clopidogrel. Drug Metab Dispos. 2011;39:2020-2033.  [PubMed]  [DOI]
18.  Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J, Thorndike D, Wagner A, Chimalakonda A, Rodrigues AD. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012;40:1698-1711.  [PubMed]  [DOI]
19.  Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests. J Cardiovasc Pharmacol. 2010;56:532-539.  [PubMed]  [DOI]
20.  Kwok CS, Loke YK. Effects of proton pump inhibitors on platelet function in patients receiving clopidogrel: a systematic review. Drug Saf. 2012;35:127-139.  [PubMed]  [DOI]
21.  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;157:148.e1-148.e5.  [PubMed]  [DOI]
22.  Yamane K, Kato Y, Tazaki J, Tada T, Makiyama T, Imai M, Jinnai T, Ikeda T, Shirakawa R, Kimura T. Effects of PPIs and an H2 blocker on the antiplatelet function of clopidogrel in Japanese patients under dual antiplatelet therapy. J Atheroscler Thromb. 2012;19:559-569.  [PubMed]  [DOI]
23.  Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003;107:32-37.  [PubMed]  [DOI]
24.  Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation. 2003;108:921-924.  [PubMed]  [DOI]
25.  Saw J, Brennan DM, Steinhubl SR, Bhatt DL, Mak KH, Fox K, Topol EJ. Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J Am Coll Cardiol. 2007;50:291-295.  [PubMed]  [DOI]
26.  Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010;170:704-710.  [PubMed]  [DOI]
27.  Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation. 2009;120:2322-2329.  [PubMed]  [DOI]
28.  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;180:713-718.  [PubMed]  [DOI]
29.  Douglas IJ, Evans SJ, Hingorani AD, Grosso AM, Timmis A, Hemingway H, Smeeth L. Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. BMJ. 2012;345:e4388.  [PubMed]  [DOI]
30.  Schmidt M, Johansen MB, Robertson DJ, Maeng M, Kaltoft A, Jensen LO, Tilsted HH, Bøtker HE, Sørensen HT, Baron JA. Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Aliment Pharmacol Ther. 2012;35:165-174.  [PubMed]  [DOI]
31.  O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL. 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.  [PubMed]  [DOI]
32.  Goodman SG, Clare R, Pieper KS, Nicolau JC, Storey RF, Cantor WJ, Mahaffey KW, Angiolillo DJ, Husted S, Cannon CP. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation. 2012;125:978-986.  [PubMed]  [DOI]
33.  Valkhoff VE, 't Jong GW, Van Soest EM, Kuipers EJ, Sturkenboom MC. Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors. Aliment Pharmacol Ther. 2011;33:77-88.  [PubMed]  [DOI]
34.  Notarangelo MF, Bontardelli F, Merlini PA. Genetic and nongenetic factors influencing the response to clopidogrel. J Cardiovasc Med (Hagerstown). 2013;14 Suppl 1:S1-S7.  [PubMed]  [DOI]
35.  Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363-375.  [PubMed]  [DOI]
36.  Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, Von Beckerath N, Mehilli J, Schömig A, Schuster T. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost. 2010;8:1685-1693.  [PubMed]  [DOI]
37.  Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010;376:1320-1328.  [PubMed]  [DOI]
38.  Ferreiro JL, Ueno M, Capodanno D, Desai B, Dharmashankar K, Darlington A, Charlton RK, Bass TA, Angiolillo DJ. Pharmacodynamic effects of concomitant versus staggered clopidogrel and omeprazole intake: results of a prospective randomized crossover study. Circ Cardiovasc Interv. 2010;3:436-441.  [PubMed]  [DOI]
39.   Available from: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/020839s055ltr.pdf.  [PubMed]  [DOI]
40.   Available from: http: //www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000174/WC500042189.pdf.  [PubMed]  [DOI]