JFP logo

Funding for this newsletter was provided by AstraZeneca LP.

Concomitant use of proton pump inhibitors and clopidogrel:
What does the evidence really show?

The pharmacodynamic impact of PPIs may not translate into harmful clinical outcomes. Varying reports to date necessitate prospective evaluations for a definitive answer.

David A. Johnson, MD, FACG, FASGE
Professor of Medicine
Chief of Gastroenterology
Eastern Virginia Medical School
Norfolk, Virginia

Danial E. Baker, PharmD, FASHP, FASCP
Professor of Pharmacotherapy
Director, Drug Information Center
College of Pharmacy
Washington State University
Spokane, Washington

Disclosures
Dr. Johnson is a consultant for AstraZeneca, Takeda, Novartis, Xenoport, and Esai; is a clinical investigator for AstraZeneca, Takeda, and Novartis; and has received grant/research support from AstraZeneca and Takeda. Dr. Baker is a consultant for AstraZeneca, Pfizer, Accredo, and Medco Health Solutions and has received grant support from Wolters Kluwer Health, Pfizer, and Novartis.

Funding for medical writing and editorial support for this newsletter was provided by AstraZeneca LP. Medical writing and editorial support was provided by Anny S. Wu, PharmD, and Lisa M. Klumpp Callan, PhD, of Scientific Connexions, Newtown, Pennsylvania.

This newsletter was edited and peer reviewed by The Journal of Family Practice.

Practice recommendations

  • Although a pharmacologic interaction has been reported between clopidogrel and PPIs, no definitive evidence from randomized, placebo-controlled prospective studies with various PPIs shows that this interaction translates into adverse cardiovascular outcomes (A).
  • Further research is needed to define the optimal strategy to reduce gastrointestinal events in patients receiving antithrombotic therapy and to ensure that patients with an increased gastrointestinal risk also can benefit from clopidogrel treatment (B).
  • Ongoing patient need of clopidogrel and PPIs should be continually assessed with continuation/discontinuation of medication based on appropriate clinical needs (B).
  • Additional research and pharmacologic interaction studies are necessary to evaluate the effect of different PPIs at different doses and durations of exposure on clopidogrel efficacy when administered concomitantly with specific PPIs (C).

Strength of recommendation
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

Regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have notified clinicians and consumers through updated prescribing information about possible drug–drug interactions and drug-related adverse events associated with clopidogrel and proton pump inhibitors (PPIs). Clinicians are tasked with evaluating available evidence from clinical studies to determine the risk/benefit of prescribing medications for their patients. Recent data demonstrating that PPIs, specifically omeprazole, can pharmacologically interact with clopidogrel under certain experimental conditions1,2 have raised concerns as to whether this interaction reduces the clinical effect of clopidogrel, thereby putting patients at risk for a coronary event. However, data from retrospective database analyses and randomized, prospective clinical studies have provided conflicting evidence regarding the impact of PPIs on the clinical significance of this interaction.2 This eNewsletter reviews the existing data and clinical implications of study findings.

SOURCES OF EVIDENCE FOR THIS REVIEW
We searched the PubMed database on September 2, 2010, using the terms "clopidogrel" plus "proton pump inhibitor." The search results were limited to articles reported in the English language. Additionally, we searched online for abstracts from national congresses in 2008 and 2009 (Digestive Disease Week and American College of Cardiology) using the same search terms. We included other relevant abstracts and articles from a manual search of reference lists and congresses at the time of submission. We evaluated relevant articles and abstracts by applying levels of evidence to the data using The Journal of Family Practice Applied Evidence Guidelines.3

DO PPIs AFFECT THE PHARMACODYNAMICS OF CLOPIDOGREL?
Clopidogrel is a prodrug metabolized by CYP450 enzymes, including CYP2C19 and CYP3A4, to an active metabolite that inhibits platelet aggregation (FIGURE).4,5 The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to the P2Y12 receptor of the platelet, thereby preventing the subsequent ADP-mediated platelet activation of the glycoprotein GPIIb/IIIa complex resulting in the inhibition of platelet aggregation.4 PPIs also are metabolized by CYP450 enzymes CYP2C19 and CYP3A4.6,7 Coadministration of clopidogrel and PPIs may reduce the efficacy of clopidogrel because of competition at CYP2C19 sites.

FIGURE. Metabolic pathway of clopidogrel.5 Reproduced with permission from PharmGKB and Stanford University. ©PharmGKB.



Reproduced with permission, from Klein TE et al. Integrating genotype and phenotype information: an overview of the PharmGKB Project. Pharmacogenomics. 2001;1:167-170.

Studies assessing the effect of PPIs on the pharmacodynamics of clopidogrel are summarized in TABLE 1.1,6,8-14 To assess this potential interaction, platelet function was evaluated using measures of platelet phosphorylated vasodilator-stimulated phosphoprotein (VASP),1,6,8 ADP-induced platelet aggregation,6,8-10 and inhibition of platelet activity.11-14 VASP is a cytoskeleton- and integrin-associated platelet protein whose phosphorylation correlates with glycoprotein GPIIb/IIIa complex inhibition; therefore, VASP acts as a marker protein for platelet inhibition.15,16 VASP is expressed as a platelet reactivity index (PRI), with a higher PRI correlating with an increase in thrombosis frequency and a decrease in clopidogrel treatment efficiency.1

Effects on measures of platelet aggregation
Studies evaluating platelet aggregation using different PPIs report conflicting results.1,6,8,9 Gilard et al1 demonstrated that the inhibitory effect of clopidogrel on platelets was reduced (P<.0001) in patients (N=124) undergoing elective coronary stent implantation who were treated with omeprazole and clopidogrel compared with clopidogrel alone (level-3 evidence). In contrast, Siller-Matula et al6 reported no differences in mean PRI or ADP-induced platelet aggregation across treatment groups in 300 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) who were treated with clopidogrel alone, clopidogrel and pantoprazole, or clopidogrel and esomeprazole (level-3 evidence).

Studies assessing whether individual PPIs differ in their effect on the pharmacodynamics of clopidogrel also have yielded conflicting results.8-10 In patients with previous coronary stent placement treated with clopidogrel (N=1000), higher ADP-induced platelet aggregation was reported in patients receiving omeprazole compared with those not receiving a PPI (P=.001) (level-3 evidence); however, no difference was seen between patients who received pantoprazole or esomeprazole and patients who did not receive a PPI.9 A study in patients (N=104) undergoing coronary stenting for acute coronary syndrome (ACS) who were taking clopidogrel and aspirin and were randomized to receive pantoprazole had a lower PRI than those randomized to receive omeprazole (P=.007) (level-3 evidence); however, ADP-induced platelet aggregation was not statistically different between the 2 groups.8 A study of 230 patients on dual antiplatelet therapy after angioplasty and stenting for cardiovascular disease reported no difference in antiplatelet activity between patients on concomitant PPI therapy and those not on PPI therapy, irrespective of the type of PPI (ie, pantoprazole, esomeprazole, omeprazole, lansoprazole).10

Degree of inhibition of platelet activity
Other studies have assessed the effect of PPIs on the platelet aggregation inhibition activity of clopidogrel.11-14 In a study of 60 healthy volunteers, the inhibition of platelet activity with a novel combination product containing clopidogrel and omeprazole was similar to that of clopidogrel alone (level-3 evidence).11 In a study of healthy subjects (N=24), lansoprazole did not affect the pharmacokinetics of clopidogrel's inactive metabolite, but tended to lower the inhibition of platelet aggregation after a clopidogrel loading dose; this effect was more pronounced in subjects with higher levels of inhibition of platelet aggregation in response to clopidogrel (level-3 evidence).12 In a post hoc analysis (PRINCIPLE-TIMI 44 trial) of patients undergoing cardiac catheterization with planned PCI who were taking clopidogrel (n=99), concomitant PPI treatment reduced (P≤.03) the inhibition of ADP-induced platelet aggregation of clopidogrel at 2, 6, and 18–24 hours after a clopidogrel 600-mg loading dose compared with that of patients not on a PPI; however, this effect was not significant after 15 days of clopidogrel maintenance therapy (level-3 evidence).13 Another study showed that treatment with omeprazole and clopidogrel reduced (P=.014) the percentage of platelet inhibition in 20 healthy subjects on day 14 compared with treatment with clopidogrel alone (level-3 evidence).14

Clopidogrel prescribing information
The clopidogrel prescribing information4 lists omeprazole as having a drug interaction with clopidogrel based on data from 2 studies. A crossover study of 72 healthy subjects showed concomitant administration of omeprazole 80 mg for 5 days and a 300-mg loading dose of clopidogrel followed by a daily dose of 75 mg reduced the mean inhibition of platelet aggregation by 47% after 24 hours and 30% after 5 days (level-3 evidence).4 A subsequent study in which the same medications and doses were administered to 72 healthy subjects (but with drug dosing separated by 12 hours) yielded similar results, suggesting that drug administration at different times does not prevent their interaction (level-3 evidence).4 However, these 2 studies reported results from ex vivo assays; used omeprazole doses 4 times higher than the FDA-approved dose for maintenance of erosive esophagitis healing, treatment of symptomatic gastroesophageal reflux disease, and treatment of active duodenal ulcer; and were not peer reviewed or fully published.17 Therefore, caution is required when extrapolating these results to potential clinical outcomes.

Pharmacodynamic data pose unanswered questions
Pharmacodynamic data conflict on whether antiplatelet activity decreases when PPIs are taken in conjunction with clopidogrel. The conflicting results may be due to differences in study design or the individual PPI studied, suggesting that the effect of PPIs on the pharmacodynamics of clopidogrel may not be a class effect and may be dependent on the PPI. However, this hypothesis is based only on pharmacodynamic data; an assessment of studies with patient-oriented clinical outcomes would be beneficial.

DO PPIs AFFECT THE CLINICAL EFFICACY OF CLOPIDOGREL?
Published literature13,18-32 and abstracts from congresses33-44 assessing the effect of PPIs on the clinical efficacy of clopidogrel are summarized in Tables 2 and 3, respectively.

Studies suggesting a negative PPI impact
Compared with clopidogrel monotherapy, clopidogrel and concomitant PPI regimens have been shown in retrospective studies (study details in Tables 2 and 3) to increase risk of major adverse cardiac/cardiovascular events,18,19,33-35 all-cause mortality,20,21,34 gastrointestinal complications,19 and rehospitalization,20-23 and have increased the incidence of death36 or stent thrombosis36 (level-2 evidence).

Systematic reviews and observational studies also have provided evidence for negative adverse events associated with concomitant clopidogrel and PPI use. A review of 5 studies (N=29,749) demonstrated that, compared with patients on clopidogrel alone, patients taking a PPI with clopidogrel experienced a higher risk of a major adverse cardiac event (P≤.001) (level-2 evidence).37 Similarly, a systematic review of 23 studies (N=48,674) showed an increased risk of major adverse cardiac events and mortality (P<.001) in patients with coronary artery disease taking clopidogrel and a PPI versus clopidogrel alone (level-2 evidence); however, sensitivity analyses revealed that the impact of PPI use on major adverse cardiac events was influenced by baseline cardiovascular risk (P<.001).24 A systematic review of the literature (N=159,138) reported a 31% increase in the relative risk of myocardial infarction (MI), a 29% increase in the rate of major adverse cardiac events, but no increase in the risk of death in patients who took clopidogrel and a PPI concomitantly compared with those who took clopidogrel alone (level-2 evidence).38 An observational study in 3 large regional health insurance cohorts of patients who underwent PCI or were hospitalized for ACS (N=18,565) showed a numerical, but not significant, increase in cardiovascular events and deaths in patients who were taking a PPI and clopidogrel compared with patients taking clopidogrel alone (level-2 evidence).25 However, the authors concluded that their analysis did not provide conclusive evidence of a clopidogrel–PPI interaction of major clinical relevance because the possible increase in risk was modest, confidence intervals were wide, and there was no consistent evidence of a substantial or significant clopidogrel–PPI interaction.

Studies suggesting no negative PPI effect
In contrast, several studies indicate that the addition of PPIs to clopidogrel treatment has no effect on adverse cardiovascular outcomes. A post hoc analysis evaluating the risk of cardiovascular death, MI, or stroke in patients taking clopidogrel with ACS and undergoing planned PCI (n=6795) reported no difference between patients taking clopidogrel and those taking clopidogrel and a PPI (level-2 evidence).13 A subgroup analysis of 2116 patients undergoing or at high likelihood of undergoing PCI suggested that clopidogrel treatment reduced coronary adverse events at 1 year to a similar degree regardless of whether patients were taking a PPI (level-2 evidence).39

A retrospective cohort study of patients who had been hospitalized for an MI, coronary artery revascularization, or unstable angina pectoris (N=20,596) also reported no difference in the risk for serious cardiovascular disease between patients concomitantly taking clopidogrel and a PPI and those taking clopidogrel alone (level-2 evidence).26 In a retrospective cohort study of 535 patients undergoing PCI, no statistical differences were observed in MI, death, or repeat PCI between patients receiving clopidogrel alone and those receiving concomitant PPI therapy (level-2 evidence).40 Another retrospective analysis of 1506 patients who underwent PCI and stent implantation showed that all-cause mortality and stent restenosis over a median follow-up of 723 days did not differ between patients on antiplatelet therapy alone and those on concomitant antiplatelet and PPI therapies (level-2 evidence).41 Furthermore, a meta-analysis of 93,278 patients taking clopidogrel with and without a PPI showed no differences between the 2 groups in overall mortality (level-2 evidence).27

Interestingly, a positive effect of PPI use with clopidogrel was demonstrated in a retrospective cross-sectional evaluation of 385 patients. Patients on clopidogrel with a higher risk for bleeding who were not prescribed PPI therapy upon discharge were more likely (P=.05) to develop a major bleed than those who were prescribed PPI therapy upon discharge (level-2 evidence).28

Clinical effect of specific PPIs on clopidogrel
Several studies have examined the effects of concomitant treatment with individual PPIs and clopidogrel. A randomized, double-blind, placebo-controlled, phase 3, prospective study in 3761 patients with ACS or undergoing coronary stent placement showed no differences between the fixed-dose combination of clopidogrel 75 mg and omeprazole 20 mg compared with clopidogrel 75 mg alone in the incidence of MI or revascularization (level-1 evidence).29 However, Kreutz et al (N=16,690) reported an increased risk for a major adverse cardiovascular event after coronary stenting in patients taking clopidogrel concomitantly with omeprazole, lansoprazole, pantoprazole, or esomeprazole compared with those who had not taken a PPI (level-2 evidence).30 Similarly, Hall et al showed that concomitant use of clopidogrel and omeprazole, lansoprazole, or pantoprazole resulted in an increased risk of 1-year death or MI compared with using clopidogrel alone in 10,703 cardiovascular patients (level-2 evidence).42 A subset analysis of 659 patients who had been discharged from the hospital after MI or coronary stent placement showed that patients receiving pantoprazole plus clopidogrel had increased risk for the combined rate of rehospitalization for MI or coronary stent placement compared with matched pairs who received clopidogrel alone (P=.008).22

A prospective observational study of 820 patients discharged after PCI demonstrated that patients taking clopidogrel and aspirin with a PPI for 1 year had a higher rate of major adverse cardiac events compared with those who were not taking a PPI, with no differences in the rate of major adverse cardiac events across specific PPI groups (esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole; level-2 evidence).31 In a retrospective, nested, case-controlled study (N=2791), the risk of recurrent MI was higher in patients who had an acute MI and were taking clopidogrel concomitantly with a PPI compared with those taking clopidogrel alone (level-2 evidence); however, stratification of results by the type of PPI indicated that coadministration of pantoprazole and clopidogrel was not associated with an increased risk for a recurrent MI (level-2 evidence).32 A retrospective study of 8311 patients who underwent PCI with drug-eluting stents and received clopidogrel reported increased mortality rates in patients also receiving omeprazole or pantoprazole, but not in those receiving esomeprazole or lansoprazole, compared with patients not taking a PPI (level-2 evidence).43

Clinical efficacy summary
The results of the studies summarized here provide conflicting evidence on the impact of PPI therapy on the clinical efficacy of clopidogrel. Most studies assessed the effect of concomitant clopidogrel and PPI treatment on major adverse cardiac events, deaths, or both. Although findings from some studies suggest a clinical interaction between clopidogrel and PPIs, others do not. The variation between study results is expected given the various types of studies conducted and the various PPIs used in the studies.

Analyses suggesting potential adverse events related to concomitant clopidogrel and PPI treatment have been retrospective and limited in their adjustment for potential confounders. Moreover, hazard ratios of <2.0 in such studies may have resulted from biases inherent to the study design. Prospective studies have not shown an association between adverse cardiovascular events and concomitant use of clopidogrel and a PPI. Further investigations are warranted to determine definitively the clinical implications of concomitant clopidogrel and PPI therapy.

WHAT ARE CLINICAL GUIDELINE RECOMMENDATIONS FOR HEALTH CARE PROVIDERS REGARDING COMBINATION PPI/CLOPIDOGREL THERAPY?
At present, no evidence from a prospective, controlled clinical trial definitively shows that PPIs diminish the ability of clopidogrel to prevent cardiac events.2 The American College of Cardiology, the American College of Gastroenterology, and the American Heart Association issued a joint statement in 2008 advising patients to continue their current medication regimen unless their health care provider advises otherwise.2 However, detailed results from the Clopidogrel Medco Outcomes Study30 prompted the Society for Cardiovascular Angiography and Interventions to recommend that health care providers consider prescribing histaminergic blockers or antacids instead of PPIs for post-stenting patients who are on dual-antiplatelet therapy.45 Similarly, in January 2009, the FDA cautioned health care providers to consider re-evaluating the need to continue or start treatment with a PPI in patients taking clopidogrel.46 In May 2009, the EMA issued a public statement recommending that information for all clopidogrel-containing products be amended to discourage concomitant use of PPIs and clopidogrel-containing medicines unless necessary.47 Recently, the EMA recommended that prescribing information for omeprazole in the European Union be updated to discourage the use of PPIs in patients receiving clopidogrel but also acknowledged that the clinical implications of the interaction are unclear.48

After the 2009 Annual Scientific Sessions of the American Heart Association, the FDA issued an advisory recommending that health care professionals avoid the coadministration of clopidogrel and omeprazole/esomeprazole until further information is available.49 This FDA advisory was based on new data in healthy volunteers that was not published or peer reviewed at that time (see data discussed in the clopidogrel prescribing information section).49 In November 2010, the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association issued a joint expert consensus document stating that "clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both cardiovascular and gastrointestinal complications."50

Although societies and agencies appear to be taking a cautionary approach to concomitant PPI/clopidogrel therapy, they are not necessarily considering whether PPI alternatives, such as histaminergic blockers and antacids, will provide similar levels of effectiveness for gastroprotection. In fact, current guidelines state that PPIs are more effective than other acid suppression agents at relieving GERD symptoms and healing esophagitis.51 Additionally, for patients taking nonsteroidal anti-inflammatory drugs with increased risk of gastrointestinal complications, concomitant use of a PPI is recommended.52 A study evaluating the implementation of PPI treatment for gastroprotection in 429 patients hospitalized for PCI on dual antiplatelet therapy in 2 cardiology centers, one in Europe and one in the US, reported that the proportion of high-risk patients receiving PPI therapy in the Spanish center was higher than in the American center, and the opportunity to initiate PPI co-therapy in high-risk patients was missed in 81.8% of patients not on PPI at admission in US patients versus 24.1% in Spanish patients.53 This suggests that PPIs may be underprescribed in US patients compared with European patients and that efforts should be made to stratify patients by risk and use appropriate strategies for high-risk patients.

WHAT LIES AHEAD?
The studies reviewed herein suggest that additional research (eg, prospective, randomized clinical trials with stratification based on clopidogrel metabolism) and additional pharmacologic interaction studies to evaluate the effect of different PPIs at different doses and durations of exposure on the efficacy of clopidogrel are needed to better understand the interaction between clopidogrel and PPIs. Moreover, evidence for a genetic component contributing to the variability in clopidogrel response raises the possibility of genetic testing to identify individuals at risk for a reduced clopidogrel response or an ischemic event.29,54,55 Furthermore, similar prospective research is warranted with new antiplatelet therapies and antiplatelet therapies in development (eg, prasugrel, ticagrelor) because therapeutic substitution may be appropriate for patients who require PPI therapy.

SUMMARY
Results of these studies raise questions regarding the exact nature of the relationship between ex vivo platelet assays and clinical outcomes in patients. Further research is needed to define the optimal strategy to reduce gastrointestinal events in patients receiving antithrombotic therapy and to ensure that patients with an increased gastrointestinal risk also can benefit from clopidogrel treatment. Data from different types of clinical trials suggest a lack of definitive evidence that this potential drug–drug interaction translates into negative cardiovascular outcomes. Only one randomized, double-blind, placebo-controlled, prospective study of clopidogrel plus omeprazole versus clopidogrel alone has been conducted and showed no differences in the incidence of MI or revascularization.29 However, caution is still recommended when coadministering any PPI (class effect) with clopidogrel until prospective randomized studies are conducted and completed with other PPIs. Awareness of these issues should assist health care practitioners in making appropriate treatment decisions and optimizing clinical care for their patients.

References

  1. Gilard M, Arnaud B, Cornily J-C, 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.
  2. American College of Cardiology (ACC)/American College of Gastroenterology (ACG)/American Heart Association (AHA) joint comment on studies regarding possible interaction of clopidogrel and proton pump inhibitors [news release]. American Heart Association News Release; November 11, 2008. http://www.newsroom.heart.org/index.php?s=43&item=611. Accessed July 12, 2010.
  3. Author guidelines: Applied Evidence. J Fam Pract. 2010. http://www.jfponline.com/AuthorGuidelines.asp?id=1074. Accessed July 15, 2010.
  4. Plavix® [prescribing information]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2009.
  5. Sangkuhl K, Klein TE, Altman RB. Clopidogrel pathway. Pharmacogenet Genomics. 2010; 20:463-465.
  6. Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009;157:148.e1-148.e5.
  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 Metab Dispos. 2004;32:821-827.
  8. Cuisset T, Frere C, Quilici J, et al. 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.
  9. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009;101:714-719.
  10. Gremmel T, Steiner S, Seidinger D, et al. The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by five different platelet function tests. J Cardiovasc Pharmacol. 2010;56:532-539.
  11. Jermano J, Goldsmith M, Jennings LK, et al. Pharmacodynamics and pharmacokinetics of clopidogrel, as Plavix® and as CGT-2168, a novel combination of clopidogrel and omeprazole [abstract PIII-15]. Clin Pharmacol Ther. 2009;85 (suppl): S72-S73.
  12. 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.
  13. 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.
  14. Yun KH, Rhee SJ, Park H-Y, et al. Effects of omeprazole on the antiplatelet activity of clopidogrel. Int Heart J. 2010;51:13-16.
  15. Horstrup K, Jablonka B, Hönig-Liedl M, et al. Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur J Biochem. 1994;225:21-27.
  16. Schwarz UR, Geiger J, Walter U, et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets: definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost. 1999;82:1145-1152.
  17. Prilosec® [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2010.
  18. Gupta E, Bansal D, Sotos J, et al. Risk of adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors following percutaneous coronary intervention. Dig Dis Sci. 2010;55:1964-1968.
  19. van Boxel OS, van Oijen MG, Hagenaars MP, et al. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: Results of a large dutch cohort study. Am J Gastroenterol. 2010;105:2430-2436.
  20. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301:937-944.
  21. Huang CC, Chen YC, Leu HB, et al. Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention. Am J Cardiol. 2010;105:1705-1709.
  22. Stockl KM, Le L, Zakharyan A, et al. Risk of rehospitalization of patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010;170:704-710.
  23. Evanchan J, Donnally MR, Binkley P, et al. Recurrence of acute myocardial infarction in patients discharged on clopidogrel and a proton pump inhibitor after stent placement for acute myocardial infarction. Clin Cardiol. 2010;33:168-171.
  24. Hulot JS, Collet JP, Silvain J, et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010;56:134-143.
  25. Rassen JA, Choudhry NK, Avorn J, et al. 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.
  26. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010;152:337-345.
  27. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther. 2010;31:810-823.
  28. Luinstra M, Naunton M, Peterson GM, et al. PPI use in patients commenced on clopidogrel: a retrospective cross-sectional evaluation. J Clin Pharm Ther. 2010;35:213-217.
  29. Bhatt DL, Cryer BL, Contant CF, et al; on behalf of the COGENT investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363:1909-1917.
  30. Kreutz RP, Stanek EJ, Aubert R, et al. Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: The clopidogrel medco outcomes study. Pharmacotherapy. 2010;30:787-796.
  31. Gaglia MA, Torguson R, Hanna N, et al. Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. Am J Cardiol. 2010;105:833-838.
  32. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180:713-718.
  33. Aubert RE, Epstein RS, Teagarden JR, et al. Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study [abstract 3998]. Circulation. 2008;118(Suppl 2):S815.
  34. Ching G, Li D, McKay R, et al. Proton pump inhibitors increase major adverse cardiac events among post percutaneous coronary intervention patients on clopidogrel [abstract 4324]. Circulation. 2009;120:S936-S937.
  35. Banerjee S, Varghese C, Weideman R, et al. Proton pump inhibitors increase the risk of major adverse cardiovascular events in post-PCI patients who are on clopidogrel [abstract P653]. Eur Heart J. 2009;30(Suppl):92.
  36. Sarafoff N, Sibbing D, Sonntag U, et al. Higher stent thrombosis rate after coronary stenting in patients on dual antiplatelet treatment and concomitant treatment with proton pump inhibitors [abstract 894]. Euro Heart J. 2009;30(Suppl):150.
  37. Singh M, Singh S, Molnar J, et al. Risk of major adverse cardiovascular events in patients on clopidogrel and proton pump inhibitors: a meta-analysis [abstract 5492]. Circulation. 2009;120:S1101.
  38. Siller-Matula JM, Jilma B, Schroer K, et al. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. Eur Heart J. 2010;31:Abstract 620.
  39. 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 [abstract 3999]. Circulation. 2008;118(Suppl 2):S815.
  40. Ramirez JF, Selzer F, Chakaprani R, et al. Proton pump inhibitor and clopidogrel combination is not associated with adverse clinical outcomes after PCI: the NHLBI Dynamic Registry [abstract 2903-7]. J Am Coll Cardiol. 2009;53(suppl 1):A27.
  41. Jarai R, Brosovic I, Tentzeris I, et al. Effects of proton-pump inhibitors on outcome of patients discharged on dual-antiplatelet therapy after percutaneous coronary intervention and stent implantation [abstract P675]. Euro Heart J. 2009;30(Suppl):98.
  42. Hall NL, Mathews KD, May HT, et al. Cardiovascular risk associated with concurrent proton pump inhibitor and clopidogrel therapy: how much? How specific? [abstract 997]. Circulation. 2009;120:S422.
  43. Sweeny JM, Kini A, Muntner P, et al. Mortality associated with proton pump inhibitors following percutaneous coronary interventions with drug eluting stents [abstract 4323]. Circulation. 2009;120:S936.
  44. Simon T, Quandalle PH, Machecourt J, et al. Proton pump inhibitors and clopidogrel response on cardiovascular major events in patients after acute myocardial infarction. Data from the FAST-MI registry of the French Society of Cardiology [abstract P2121]. Euro Heart J. 2009;30(Suppl):335.
  45. Society for Cardiovascular Angiography and Interventions. SCAI statement on "A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: the Clopidogrel Medco Outcomes Study." Washington, DC: The Society for Cardiovascular Angiography and Interventions; 2009. http://www.scai.org/SecondsCount/News/Detail.aspx?cid=fd3f649b-ecaf-4401-bd29-ec74009db354. Accessed July 15, 2010.
  46. US Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). Rockville, MD: The Food and Drug Administration; 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079520.htm. Accessed July 15, 2010.
  47. European Medicines Agency. Public statement on possible interaction between clopidogrel and proton pump inhibitors. Canary Wharf, London, UK: The European Medicines Agency; May 29, 2009. http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500014409.pdf. Accessed July 15, 2010.
  48. European Medicines Agency. Questions and answers on Losec and associated names (omeprazole, 10, 20 or 40 mg capsules and tablets, and 40 mg solution for injection and solution for infusion): outcome of a procedure under Article 30 of Directive 2001/83/EC. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Losec_30/WC500070014.pdf. Accessed July 15, 2010.
  49. US Food and Drug Administration. Public health advisory: updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC) [November 17, 2009]. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm190825.htm. Accessed July 7, 2010.
  50. Abraham NS, Hlatky MA, Antman EM, et al. 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. J Am Coll Cardiol. 2010;56:2051-2066,
  51. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100:190-200.
  52. Shi S, Klotz U. Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol. 2008;64:935-951.
  53. Casado-Arroyo R, Scheiman JM, Polo-Tomas M, et al. Underutilization of gastroprotection for at-risk patients undergoing percutaneous coronary intervention: Spain compared with the United States. Aliment Pharmacol Ther. 2010;32:689-695.
  54. Varenhorst C, James S, Erlinge D, et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Euro Heart J. 2009;30:1744-1752.
  55. Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009;302:849-858.

Distributed by Quadrant HealthCom Inc., 7 Century Drive, Parsippany, NJ 07054. Tel: (973) 206-3434.