Drug Interactions: Clopidogrel-Proton Pump Inhibitor Interaction: An Update

Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy.

In April 2008, this column discussed the potential interaction between clopidogrel (Plavix) and proton pump inhibitors (PPIs). Since that time, several additional studies on this interaction have been published. This update will attempt to place the newer data into perspective. Because this is a complex interaction, it is important to consider the issues discussed below as new trials are presented.

Clopidogrel is a prodrug that requires metabolic conversion to a thiol metabolite. Recent data have identified that several enzymes, including CYP2C19, CYP3A4, CYP1A2, CYP2C9, and CYP2B6, are involved in the conversion of clopidogrel to its active metabolite.¹ Inhibition of any of these pathways could reduce the antiplatelet activity of clopidogrel. Omeprazole (Prilosec), an inhibitor of CYP2C19, has been reported to reduce the activity of clopidogrel when platelet function is measured.² In addition, CYP2C19 metabolic activity is reduced in 10% to 30% of patients who are genetically poor metabolizers (PMs) for CYP2C19. The effect of CYP2C19 inhibitors on clopidogrel would be expected to be greater in patients who are rapid metabolizers of clopidogrel and be diminished in PMs of clopidogrel.

Although the effect of omeprazole on the antiplatelet activity of clopidogrel has been consistently demonstrated, the effect of this change on the clinical efficacy of clopidogrel is still being debated. One problem is that no standard exists for the degree of platelet inhibition required to produce a clinical benefit and thus no agreement exists on how much diminution in effect is clinically significant. Several retrospective studies have reported reduced clinical efficacy, based on cardiovascular events, of clopidogrel in patients taking PPIs.^3-6 Most of these studies are burdened by differences in confounding variables between the patients receiving PPIs and those who do not. For example, disease states (eg, diabetes, hyperlipidemia, heart failure), genetics (rapid or slow CYP2C19 metabolizers), and drugs (eg, aspirin, beta-blockers, statins, calcium channel blockers) can independently affect patient outcomes. None of the retrospective trials have adequately matched for these variables. Two trials that compared well-matched groups of patients taking clopidogrel found no effect of PPIs on cardiovascular outcomes.^7,8 The only prospective, double-blind trial reported to date also found no difference in cardiovascular outcomes when PPIs were administered with clopidogrel.⁹ It is important to note that although this trial did not show any influence of PPI on clopidogrel outcomes, patients not taking PPIs had an increased risk of gastrointestinal bleeding. Thus, there appears to be a definite risk associated with withholding PPIs from patients who have an indication for them.

The FDA recently reported the results of a trial that again demonstrated the effect of omeprazole on clopidogrel’s antiplatelet activity.¹⁰ This trial compared the antiplatelet activity of clopidogrel 300 mg followed by 75 mg daily for 4 days administered alone and together with 80 mg of omeprazole daily for 5 days taken concurrently or 12 hours after the clopidogrel dose. The maximum platelet inhibition of clopidogrel was modestly reduced by omeprazole from 38% to 30% and from 54% to 47% with concurrent PPI administration and 12-hour dose separation, respectively. The study did not examine the potential for PPIs to reduce the clinical effect of clopidogrel. Based on these data, the FDA notice reported that: “Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction.”¹⁰ The use of an 80-mg dose of omeprazole would produce an estimated plasma concentration of omeprazole 10 to 12 hours after administration that would be similar to that observed 2 to 3 hours after a 20-mg dose, however. Following a usual 20-mg dose of omeprazole, plasma concentrations are nearly undetectable after 8 hours. Therefore, this trial does not provide convincing evidence that separation of the PPI and clopidogrel dose in patients taking usual omeprazole doses would not minimize the magnitude of the interaction.

It appears clear that some PPIs reduce the antiplatelet activity of clopidogrel in some patients. The question is whether this is of clinical importance. Further well-designed and -controlled studies are necessary to define the best approach to patients requiring these drugs. For patients with an indication for PPI therapy, it is important to consider the risk (gastrointestinal bleeding) of withholding a PPI. Until definitive studies are available, separating the dose of omeprazole from clopidogrel may help. For example, administering the PPI 1 hour before breakfast and the clopidogrel at bedtime will provide 14 to 18 hours of separation. While data are limited, selecting a PPI other than omeprazole (or esomeprazole) may also be appropriate. â– 

References

• Kazui M, et al. Identification of the human cytochrome P45o enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Disp. 2010;38:92-99.

• Gilard M, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. J Am Coll Cardiol. 2008;51:256-60.

• Ho PM, 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.

• Juurlink DN, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ.2009;180(7):713-8.

• Pezella E, et al. Initial assessment of clopidogrel impact of a drug interaction between clopidogrel and proton pump inhibitors. JACC. 2008;52:1038—1039.

• Stanek EJ, et al. Abstract O-11: 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. Presented at: The Society for Cardiovascular Angiography and Interventions, 2009; Las Vegas, NV.

• O’Donoghue ML, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomized trials. Lancet. 2009;347:989-97.

• Rassen JA, et al. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation.2009;120:2322-39.

• Bhatt DL, et al. The COGENT Trial. Presented at Transcatheter Cardiovascular Therapeutics, 2009; San Francisco, CA. Available at:http://assets.cardiosource.com/Bhatt_COGENT.ppt.

• Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). Food and Drug Administration. Available online at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm.