Proton Pump Inhibitors and Clopidogrel
2009; Lippincott Williams & Wilkins; Volume: 120; Issue: 23 Linguagem: Inglês
10.1161/circulationaha.109.907295
ISSN1524-4539
Autores Tópico(s)Diabetes Treatment and Management
ResumoHomeCirculationVol. 120, No. 23Proton Pump Inhibitors and Clopidogrel Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBProton Pump Inhibitors and ClopidogrelPutting the Interaction in Perspective David N. Juurlink, MD, PhD David N. JuurlinkDavid N. Juurlink From the Department of Medicine, Sunnybrook Health Sciences Centre; Departments of Medicine, Pediatrics, and Health Policy, Management, and Evaluation, University of Toronto; and the Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Originally published23 Nov 2009https://doi.org/10.1161/CIRCULATIONAHA.109.907295Circulation. 2009;120:2310–2312Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 23, 2009: Previous Version 1 Drug interactions are a complex topic tethered to our daily clinical activities by 2 unfortunate facts. The first is that avoidable drug interactions harm an unknown but undoubtedly large number of patients every year. The second is that we know very little about the real-world consequences that ensue when one drug is superimposed on another.Article see p 2322With this background, the recently postulated drug interaction between proton pump inhibitors (PPIs) and clopidogrel is in a league of its own, spawning a flurry of research and editorializing in a relatively short time, and more is on the way. This attention reflects several factors, including the blockbuster status of the implicated drugs, a theoretically at-risk population in the tens of millions, and guidelines that recommend near-universal use of PPIs in patients taking clopidogrel, most of whom will also be taking aspirin.1 However, skepticism about the clinical importance of this drug interaction is easily understood, especially among clinicians who sense déjà vu with the thematically similar interaction between atorvastatin and clopidogrel first described in 2003 but now largely dismissed.2In this issue of Circulation, Rassen and colleagues3 report a well-executed retrospective cohort study of this drug interaction using multijurisdictional data and a highly sophisticated approach to multivariable adjustment. The results suggest that adding a PPI to clopidogrel therapy is associated with an increased risk of myocardial infarction or death (adjusted rate ratio, 1.22; 95% confidence interval, 0.99 to 1.51). This effect size is consistent with previous observational studies but just fails to meet the conventional threshold for statistical significance. The authors conclude that although adding a PPI to clopidogrel therapy may increase the risk of adverse events, the incremental risk is probably not very large. This interpretation is a sensible one, but myocardial infarction and death are not trivial events, and residual uncertainty about this drug interaction is inevitable.In this editorial, I outline the pharmacological basis of the drug interaction between clopidogrel and PPIs, provide a brief overview of the conflicting evidence relative to its clinical significance, and explain why clinical studies of this topic are expected to yield small effect sizes. Finally, I suggest 3 simple management strategies for clinicians confronting this interaction in daily practice.Basis of the InteractionAn inert prodrug, clopidogrel is metabolized first to a thiolactone intermediate and then to an active metabolite, R-130964, which binds irreversibly to ADP receptors on the platelet surface. These 2 steps are catalyzed by multiple cytochrome (CYP) enzymes, although CYP2C19 is important to both.4 Loss-of-function polymorphisms in the gene encoding for CYP2C19 are associated with a reduced response to clopidogrel and an increased risk of adverse cardiovascular events.5–7As with most CYP enzymes, the activity of CYP2C19 can be influenced by other drugs, and CYP2C19 inhibitors can theoretically attenuate the antiplatelet effect of clopidogrel by hindering its bioactivation. Fortunately, many CYP2C19 inhibitors are rarely used nowadays, but some (such as fluoxetine and fluvoxamine) are relatively common, and alternatives should be considered in patients taking clopidogrel. Importantly, other drugs that are metabolized by CYP2C19 can competitively inhibit the enzyme by mutually exclusive competition for its catalytic site. By far the most relevant drugs in this class are the PPIs. Competitive inhibition of CYP2C19 by PPIs is the theoretical basis for the interaction between these drugs and clopidogrel.Evidence Supporting a Meaningful InteractionPlatelet Aggregation StudiesThe earliest evidence suggesting an interaction between PPIs and clopidogrel involved a study of 105 patients receiving aspirin and clopidogrel after high-risk angioplasty.8 The platelet reactivity of each patient was assessed by vasodilator-stimulated phosphoprotein phosphorylation, and those values were ≈25% higher in PPI-treated patients than in patients not treated with PPIs (P=0.007). The attenuation of the effect of clopidogrel by PPIs was confirmed in a subsequent clinical trial of 124 patients receiving acetylsalicylic acid and clopidogrel after coronary stenting who were randomized to 7 days of omeprazole (20 mg daily) or placebo.9Several other studies provide additional evidence of a pharmacodynamic interaction between PPIs and clopidogrel. In a recently published prospective study of 201 patients undergoing elective percutaneous coronary intervention, nonresponse to clopidogrel was 6-fold more common among patients taking a PPI compared with patients not taking a PPI (P=0.012). Other studies have observed consistent findings with omeprazole but not with esomeprazole or pantoprazole,10–13 although variability and uncertainty regarding PPI dose are features of some studies.Observational StudiesAlong with the report of Rassen and colleagues, other observational studies have explored the clinical consequences of the PPI-clopidogrel interaction.14,15 These studies use different observational approaches in distinct data sets but reach similar conclusions: specifically, that use of a PPI in combination with clopidogrel is associated with a roughly 25% increase in the risk of various adverse events, including acute myocardial infarction, death, or rehospitalization for acute coronary syndrome. In 2 published studies, no association was seen between PPI use and adverse events among patients not receiving clopidogrel.14,15 Two other observational studies, presented to date only as abstracts, also suggest an increased risk of adverse events,16,17 although one of these17 is often mischaracterized as showing no evidence of interaction.The major limitation of observational studies is their limited ability to fully account for confounding, a particularly salient concern in the context of the PPI-clopidogrel interaction. One does not have to think terribly hard to envision ways in which patients who are treated with PPIs might be at increased risk for cardiovascular events compared with those who are not. However, if PPIs were simply a surrogate marker of increased risk, an association with cardiovascular events would be expected in patients regardless of clopidogrel use; this is clearly not the case.14,15Evidence Against a Meaningful InteractionTwo recent studies raise legitimate questions about the clinical relevance of the PPI-clopidogrel interaction. The first was a posthoc analysis of a large clinical trial in which 6795 patients received clopidogrel after an acute coronary syndrome;18 a third of these patients also received a PPI in a nonrandomized fashion. In the primary analysis, PPI use was not associated with an increased risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 0.94; 95% confidence interval, 0.80 to 1.11). Importantly, this was not a randomized trial of the effect of PPIs on clopidogrel, and patients were generally younger and healthier than those in practice.Further evidence against a meaningful interaction has emerged from the preliminary findings of the Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial, in which 3627 patients taking aspirin after an acute coronary syndrome or stent implantation were randomized to clopidogrel alone or clopidogrel plus low-dose omeprazole.19 Omeprazole was associated with a reduction in the risk of composite gastrointestinal events but no increase in the risk of cardiovascular events, including secondary analyses of acute myocardial infarction or revascularization. The lack of a clinically apparent interaction in the COGENT study may reflect the active treatment, CGT-2168, which contained 75 mg clopidogrel around a core of delayed-release omeprazole. By temporally separating the absorption of clopidogrel from that of omeprazole, the formulation may have effectively circumvented any competitive inhibition of CYP2C19 by omeprazole.Observations on the Magnitude of EffectA balanced assessment of the interaction between PPIs and clopidogrel incorporates principles of pharmacology and epidemiology, including several considerations that have largely escaped scrutiny in discussions of this topic. Collectively, these issues explain why studies of the PPI-clopidogrel interaction are expected to yield relatively small effects and provide insights into how to manage the interaction in practice.The first point worth making is that in most platelet aggregation studies, PPIs attenuate rather than abolish the effect of clopidogrel. In the seminal publication of Gilard et al,9 the mean vasodilator-stimulated phosphoprotein platelet reactivity index decreased from 83.9% at baseline to 51.4% during treatment with omeprazole and clopidogrel. In other words, some pharmacodynamic effect of clopidogrel is clearly evident despite concomitant PPI use, presumably because alternate cytochrome P450 pathways allow formation of the active metabolite.4The magnitude of the benefit of clopidogrel also warrants mention. Depending on the indication, the benefit of clopidogrel when added to aspirin is generally very modest. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, for example, 1 composite event (cardiovascular death, nonfatal myocardial, or stroke) was averted for every 47 patients treated with clopidogrel.20 Although clinically important, this effect is small in absolute terms, and PPI-mediated attenuation of the antiplatelet effects of clopidogrel cannot cause harm in patients who were destined to receive no benefit from clopidogrel in the first place.Finally, the pharmacokinetics of PPIs are a particularly important consideration. Competitive inhibition of CYP2C19 is anticipated only when PPI levels are sufficient to interfere with metabolism of other substrates, including clopidogrel. Most PPIs are rapidly eliminated, with t1/2 values ranging from 30 minutes to 2 hours; consequently, any inhibition of CYP2C19 is likely to be short-lived. From a practical perspective, this means that patients taking a PPI once daily should have no difficulty metabolizing CYP2C19 substrates, including clopidogrel, for most of the day.These 3 factors—a modest effect of clopidogrel that is only partially attenuated by PPI therapy, and only then in patients who take clopidogrel in close temporal sequence with a PPI—collectively contribute to the relatively small effect size anticipated in studies of this interaction.Dealing With the Interaction in PracticeHow clinicians should respond to the PPI-clopidogrel interaction remains a matter of debate. Some have suggested that PPIs should simply be avoided in patients taking clopidogrel. This is bad advice and reflects the gross oversimplification of an exceedingly complex topic. Others have argued that the PPI-clopidogrel interaction is of no consequence. Although this is probably true for most patients, it is a potentially hazardous position to adopt given the sheer number of patients taking these drugs together, the gravity of the clinical consequences, and the ease with which a meaningful interaction can be avoided.For clinicians uncertain how to address this drug interaction in practice, I propose 3 simple steps:Evaluate the necessity of PPI therapy. Although PPIs are necessary for some patients, many others take the drugs for dubious indications. In these patients, treatment with a histamine H2 antagonist or antacid may suffice.Consider using pantoprazole when a PPI is indicated. This suggestion stems from the observation that pantoprazole is less likely than omeprazole to inhibit CYP2C19,21 does not appear to attenuate the pharmacodynamic response to clopidogrel,10,13 and displayed no association with recurrent myocardial infarction in a large observational study of patients receiving clopidogrel.14 Other PPIs may also be relatively safe, but more data are needed. Lansoprazole is the most potent CYP2C19 inhibitor and is probably best avoided.21Stagger the dosing of medications. This is perhaps the most important strategy and exploits the rapid metabolism of clopidogrel and the transient nature of PPI-mediated CYP2C19 inhibition. When dual therapy is necessary, taking a PPI at least 4 hours after clopidogrel should minimize the risk of interaction.SummaryThe PPI-clopidogrel interaction has been the subject of much study and debate in a relatively short period of time. There is no doubt that a pharmacodynamic interaction exists; at issue is its clinical relevance. For the majority of patients, the interaction likely poses no serious threat. However, for an unidentifiable subset of patients carrying the wrong mix of drugs, doses, comorbidities, and genetics, a clinically important drug interaction remains a real possibility. As we await further research on the phenomenon of drug-induced clopidogrel resistance, a cautious approach that exploits the basic pharmacology of these drugs is a sensible and easily achievable way to safely prescribe PPIs in patients taking clopidogrel.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.I thank John Horn, Moira Kapral, Michael Paterson, and Donald Redelmeier for insightful comments on preliminary drafts of this editorial. I also thank Eric Cohen, Dennis Ko, Chris Morgan and Sam Radhakrishnan for clinical insights.DisclosuresNone.FootnotesCorrespondence to Dr David Juurlink, G Wing 106, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5. E-mail [email protected] References 1 Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM. 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 Clinical Expert Consensus Documents. Circulation. 2008; 118: 1894–1909.LinkGoogle Scholar2 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.LinkGoogle Scholar3 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.LinkGoogle Scholar4 Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. October 19, 2009. DOI: dmd.109.029132v2-dmd.109.029132 Available at: http://dmd.aspetjournals.org. Accessed October 19, 2009.Google Scholar5 Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Buonamici P, Antoniucci D, Abbate R, Gensini GF. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics. 2007; 17: 1057–1064.CrossrefMedlineGoogle Scholar6 Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006; 108: 2244–2247.CrossrefMedlineGoogle Scholar7 Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360: 354–362.CrossrefMedlineGoogle Scholar8 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: 2508–2509.CrossrefMedlineGoogle Scholar9 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.CrossrefMedlineGoogle Scholar10 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: 148–145.CrossrefMedlineGoogle Scholar11 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.CrossrefMedlineGoogle Scholar12 Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M. Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res. September 24, 2009. DOI: 10.1016/j.thromres.2009.08.016. Available at: http://www.sciencedirect.com. Accessed October 19, 2009.Google Scholar13 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: 1149–1153.CrossrefMedlineGoogle Scholar14 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.CrossrefMedlineGoogle Scholar15 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.CrossrefMedlineGoogle Scholar16 Aubert RE, 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. Circulation. 2008; 118 (suppl): S28–10–2008.Abstract.Google Scholar17 Dunn SP, Macaulay TE, Brennan DM. 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:S815-10-2008. Abstract.Google Scholar18 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: 989–997.CrossrefMedlineGoogle Scholar19 Bhatt DL. COGENT: A prospective, randomized, placebo-controlled trial of omeprazole in patients receiving aspirin and clopidogrel. Presented at: Transcatheter Cardiovascular Therapeutics; September 24, 2009; San Francisco, Calif.Google Scholar20 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.CrossrefMedlineGoogle Scholar21 Li XQ, Andersson TB, Ahlstrom 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 Metab Dispos. 2004; 32: 821–827.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Morin K, Parrotta M, Eibl J and Marsh D (2021) A Retrospective Cohort Study Comparing In-Person and Telemedicine-Based Opioid Agonist Treatment in Ontario, Canada, Using Administrative Health Data, European Addiction Research, 10.1159/000513471, 27:4, (268-276), . Morin K, Eibl J, Caswell J, Rush B, Mushquash C, Lightfoot N, Marsh D and Lim S (2020) Evaluating the effectiveness of concurrent opioid agonist treatment and physician-based mental health services for patients with mental disorders in Ontario, Canada, PLOS ONE, 10.1371/journal.pone.0243317, 15:12, (e0243317) Morin K, Eibl J, Gauthier G, Rush B, Mushquash C, Lightfoot N and Marsh D (2020) A cohort study evaluating the association between concurrent mental disorders, mortality, morbidity, and continuous treatment retention for patients in opioid agonist treatment (OAT) across Ontario, Canada, using administrative health data, Harm Reduction Journal, 10.1186/s12954-020-00396-x, 17:1, Online publication date: 1-Dec-2020. Muñoz-Torrero J, Zamorano J, Rico-Martín S, Rivas M, Bacaicoa M, Robles R, Sanchez-Bacaicoa C and Monreal M (2020) Proton pump inhibitors and risk for recurrent ischemic events or death in outpatients with symptomatic artery disease, Atherosclerosis, 10.1016/j.atherosclerosis.2019.11.002, 292, (84-89), Online publication date: 1-Jan-2020. Morin K, Eibl J, Caswell J, Gauthier G, Rush B, Mushquash C, Lightfoot N and Marsh D (2019) Concurrent psychiatry for patients enrolled in opioid agonist treatment: a propensity score matched cohort study in Ontario Canada, Substance Abuse Treatment, Prevention, and Policy, 10.1186/s13011-019-0213-6, 14:1, Online publication date: 1-Dec-2019. Eibl J, Wilton A, Franklyn A, Kurdyak P and Marsh D (2019) Evaluating the Impact of Prescribed Versus Nonprescribed Benzodiazepine Use in Methadone Maintenance Therapy: Results From a Population-based Retrospective Cohort Study, Journal of Addiction Medicine, 10.1097/ADM.0000000000000476, 13:3, (182-187), Online publication date: 1-May-2019. Casula M, Scotti L, Galimberti F, Mozzanica F, Tragni E, Corrao G and Catapano A (2018) Use of proton pump inhibitors and risk of ischemic events in the general population, Atherosclerosis, 10.1016/j.atherosclerosis.2018.08.035, 277, (123-129), Online publication date: 1-Oct-2018. LaBelle B, Franklyn A, PKH Nguyen V, Anderson K, Eibl J and Marsh D (2018) Characterizing the Use of Telepsychiatry for Patients with Opioid Use Disorder and Cooccurring Mental Health Disorders in Ontario, Canada, International Journal of Telemedicine and Applications, 10.1155/2018/7937610, 2018, (1-7), . Bykov K, Schneeweiss S, Glynn R, Mittleman M, Bates D and Gagne J (2017) Updating the Evidence of the Interaction Between Clopidogrel and CYP2C19-Inhibiting Selective Serotonin Reuptake Inhibitors: A Cohort Study and Meta-Analysis, Drug Safety, 10.1007/s40264-017-0556-8, 40:10, (923-932), Online publication date: 1-Oct-2017. Fisher L and Fisher A (2017) Acid-Suppressive Therapy and Risk of Infections: Pros and Cons, Clinical Drug Investigation, 10.1007/s40261-017-0519-y, 37:7, (587-624), Online publication date: 1-Jul-2017. Ford N (2016) The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway, The Journal of Clinical Pharmacology, 10.1002/jcph.769, 56:12, (1474-1483), Online publication date: 1-Dec-2016. Vernaz N, Rollason V, Adlere L, Combescure C, Poncet A, Bonnabry P and Desmeules J (2016) Snapshot of the prescribing practice for the clopidogrel and esomeprazole coprescription and cost evaluation of the application guidelines, Pharmacology Research & Perspectives, 10.1002/prp2.234, 4:3, (e00234), Online publication date: 1-Jun-2016. Juurlink D, Gomes T, Paterson J, Hellings C and Mamdani M (2015) Trends in the coprescription of proton pump inhibitors with clopidogrel: an ecological analysis, CMAJ Open, 10.9778/cmajo.20140078, 3:4, (E428-E431), Online publication date: 26-Nov-2015. Eibl J, Gomes T, Martins D, Camacho X, Juurlink D, Mamdani M, Dhalla I and Marsh D (2015) Evaluating the Effectiveness of First-Time Methadone Maintenance Therapy Across Northern, Rural, and Urban Regions of Ontario, Canada, Journal of Addiction Medicine, 10.1097/ADM.0000000000000156, 9:6, (440-446), Online publication date: 1-Nov-2015. Ancrenaz V, Desmeules J, James R, Fontana P, Reny J, Dayer P and Daali Y (2012) The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro, British Journal of Pharmacology, 10.1111/j.1476-5381.2012.01946.x, 166:8, (2362-2370), Online publication date: 1-Aug-2012. RENY J, COMBESCURE C, DAALI Y and FONTANA P (2012) Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis, Journal of Thrombosis and Haemostasis, 10.1111/j.1538-7836.2012.04756.x, 10:7, (1242-1251), Online publication date: 1-Jul-2012. Warden B, Willman A and Williams C (2012) Antithrombotics for secondary prevention of noncardioembolic ischaemic stroke, Nature Reviews Neurology, 10.1038/nrneurol.2012.33, 8:4, (223-235), Online publication date: 1-Apr-2012. Chen J, Yuan Y, Leontiadis G and Howden C (2012) Recent Safety Concerns With Proton Pump Inhibitors, Journal of Clinical Gastroenterology, 10.1097/MCG.0b013e3182333820, 46:2, (93-114), Online publication date: 1-Feb-2012. Holguín H, Ceballos M and Amariles P (2012) Relevancia clínica de la interacción clopidogrel y omeprazol: revisión sistemática, Revista Colombiana de Cardiología, 10.1016/S0120-5633(12)70100-6, 19:1, (25-32), Online publication date: 1-Jan-2012. HARMSZE A, VAN WERKUM J, SOUVEREIN P, BREET N, BOUMAN H, HACKENG C, RUVEN H, TEN BERG J, KLUNGEL O, DE BOER A and DENEER V (2011) Combined influence of proton-pump inhibitors, calcium-channel blockers and CYP2C19*2 on on-treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention, Journal of Thrombosis and Haemostasis, 10.1111/j.1538-7836.2011.04483.x, 9:10, (1892-1901), Online publication date: 1-Oct-2011. Páramo J (2011) Nueva era en la terapia antiplaquetar basada en los resultados de ensayos clínicos recientes, Medicina Clínica, 10.1016/j.medcli.2010.09.015, 137:11, (504-508), Online publication date: 1-Oct-2011. Leontiadis G, Yuan Y and Howden C (2011) The Interaction Between Proton Pump Inhibitors and Clopidogrel and Upper Gastrointestinal Bleeding, Gastrointestinal Endoscopy Clinics of North America, 10.1016/j.giec.2011.07.005, 21:4, (637-656), Online publication date: 1-Oct-2011. Hsiao F, Mullins C, Wen Y, Huang W, Chen P and Tsai Y (2011) Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome, Pharmacoepidemiology and Drug Safety, 10.1002/pds.2202, 20:10, (1043-1049), Online publication date: 1-Oct-2011. Ferreiro J, Ueno M, Tomasello S, Capodanno D, Desai B, Dharmashankar K, Seecheran N, Kodali M, Darlington A, Pham J, Tello-Montoliu A, Charlton R, Bass T and Angiolillo D (2011) Pharmacodynamic Evaluation of Pantoprazole Therapy on Clopidogrel Effects, Circulation: Cardiovascular Interventions, 4:3, (273-279), Online publication date: 1-Jun-2011. Disney B, Watson R, Blann A, Lip G and Anderson M (2011) Review article: proton pump inhibitors with clopidogrel - evidence for and against a clinically-important interaction, Alimentary Pharmacology & Therapeutics, 10.1111/j.1365-2036.2011.04585.x, 33:7, (758-767), Online publication date: 1-Apr-2011. Pasina L, Nobili A, Tettamanti M, Salerno F, Corrao S, Marengoni A, Iorio A, Marcucci M and Mannucci P (2011) Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-esophageal reflux disease in a cohort of hospitalized elderly, European Journal of Internal Medicine, 10.1016/j.ejim.2010.11.009, 22:2, (205-210), Online publication date: 1-Apr-2011. Lobos Bejarano J, Otero I and Ainscough R (2011) El uso de omeprazol más clopidogrel y ácido acetilsalicílico en pacientes coronarios reduce notablemente las complicaciones gastrointestinales sin aumentar los episodios cardiovasculares, FMC - Formación Médica Continuada en Atención Primaria, 10.1016/S1134-2072(11)70066-4, 18:3, (176), Online publication date: 1-Mar-2011. Kolandaivelu K and Bhatt D (2011) Antiplatelet Therapy in Coronary Heart Disease Prevention, Cardiology Clinics, 10.1016/j.ccl.2010.10.001, 29:1, (71-85), Online publication date: 1-Feb-2011. Gerhard T (2010) Clopidogrel and proton pump inhibitors: a clinically meaningful interaction?, Pharmacoepidemiology and Drug Safety, 10.1002/pds.2071, 20:2, (214-218), Online publication date: 1-Feb-2011. Kwok C, Nijjar R and Loke Y (2011) Effects of Proton Pump Inhibitors on Adverse Gastrointestinal Events in Patients Receiving Clopidogrel, Drug Safety, 10.2165/11584750-000000000-00000, 34:1, (47-57), Online publication date: 1-Jan-2011. de Aquino Lima J and Brophy J (2010) The potential interaction between clopidogrel and proton pump inhibitors: a systematic review, BMC Medicine, 10.1186/1741-7015-8-81, 8:1, Online publication date: 1-Dec-2010. Ferreiro J, Ueno M, Capodanno D, Desai B, Dharmashankar K, Darlington A, Charlton R, Bass T and Angiolillo D (2010) Pharmacodynamic Effects of Concomitant Versus Staggered Clopidogrel and Omeprazole Intake, Circulation: Cardiovascular Interventions, 3:5, (436-441), Online publication date: 1-Oct-2010. Paikin J, Eikelboom J, Cairns J and Hirsh J (2010) New antithrombotic agents—insights from clinical trials, Nature Reviews Cardiology, 10.1038/nrcardio.2010.101, 7:9, (498-509), Online publication date: 1-Sep-2010. Potter B and Le Lorier J (2010) Letter by Potter and Le Lorier Regarding Article, "Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome", Circulation, 122:5, (e414-e414), Online publication date: 3-Aug-2010. Momary K and Cavallari L (2010) Clopidogrel and Proton Pump Inhibitors: Between a Rock and a Hard Place, Pharmacotherapy, 10.1592/phco.30.8.762, 30:8, (762-765), Online publication date: 1-Aug-2010. Kolandaivelu K and Bhatt D (2010) Overcoming 'resistance' to antiplatelet therapy: targeting the issue of nonadherence, Nature Reviews Cardiology, 10.1038/nrcardio.2010.71, 7:8, (461-467), Online publication date: 1-Aug-2010. (2010) Current awareness: Pharmacoepidemiology and drug safety, Pharmacoepidemiology and Drug Safety, 10.1002/pds.1851, 19:6, (i-xiii) December 8, 2009Vol 120, Issue 23 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.907295PMID: 19933929 Originally publishedNovember 23, 2009 Keywordsproton pump inhibitorsdrugsclopidogrelEditorialspharmacoepidemiologycoronary artery diseasePDF download Advertisement SubjectsPharmacology
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