Much Ado About Nothing? Clopidogrel + Omperazole Interaction

If you are like me, you probably received a lot of phone calls from patients and prescribers when the news hit about the potential interaction between clopidogrel and proton pump inhibitors (PPIs).  In January 2009, the Food and Drug Administration (FDA) published data from an ongoing safety review of clopidogrel effectiveness, which resulted in a November 2009 Public Health Advisory that recommended avoiding of the combination of clopidogrel and any PPIs except pantoprazole.^1,2  The strongest recommendation was made against omeprazole and esomeprazole.  The theory behind the recommendation is that clopidogrel requires metabolism by CYP2C19 to its active metabolite.  Omeprazole, esomeprazole, and other drugs can inhibit CYP2C19, thereby potentially decreasing the effectiveness of clopidogrel.  In an October 2010 FDA update, the warning was reiterated, despite the recent e-publication of the Clopidogrel and Optimization of Gastrointestinal Events (COGENT) study.^3,4  So, is it necessary to avoid the combination of clopidogrel and omeprazole?  Do patients on this combination have a higher risk of cardiovascular events than those on clopidogrel alone?

The COGENT study was a prospective randomized double-blind placebo-controlled trial comparing the effects of fixed dose clopidogrel 75mg daily combined with omeprazole 20mg daily or placebo (n=3761). Patients 21 years or older, who required the combination of clopidogrel and aspirin 75-325mg daily for at least one year were included in the trial.  Those who required short- or long-term gastrointestinal (GI) protection, recent fibrinolytic therapy, clopidogrel or another thienopyridine more than 21 days prior to randomization were excluded.  Randomization was stratified based on serologic findings for Helicobacter pylori and concomitant use of any nonaspirin nonsteroidal antiinflammatory drug (NSAID).

There were two pre-specified primary outcomes: GI efficacy [first composite upper GI event (confirmed overt gastroduodenal or upper GI bleeding, presumed occult GI bleeding with a documented clinically significant decrease in hemoglobin or hematocrit, confirmed uncomplicated gastroduodenal ulcer)]; and cardiovascular (CV) safety (time to a composite of death from CV causes, nonfatal myocardial infarction, coronary revascularization, or ischemic stroke).  A blinded independent committee of specialists adjudicated the GI and CV events.  The study was intended to follow patients for up to 2 years, but was stopped early due to loss of funding, and only 180-day data was published.

The median age of patients enrolled in the COGENT study was 68.6 years.  Roughly 4% of patients had a history of GI bleed or ulcer; 8.6% reported concurrent NSAID use at baseline; and 48% were positive for H. pylori.  Previous cardiovascular events included ~71% percutaneous coronary intervention, ~42% acute coronary syndrome, and ~29% myocardial infarction.  Approximately 7-8% of patients had a previous stroke, 80% patients had hypertension, 78% hypercholesterolemia, ~13% were current smokers, and ~30% had diabetes.  Thus, these were patients with high baseline cardiovascular risk.  Although only 59% reported concurrent aspirin use at baseline, aspirin was provided by the investigators, and was included in compliance pill counts.⁵  There were no significant differences in the baseline characteristics between these groups.

The addition of omeprazole to clopidogrel+aspirin significantly decreased the primary composite GI outcome (2.9% clopidogrel+ASA vs. 1.1% clopidogrel, ASA + omeprazole, p<0.001, NNT 56).  Omeprazole also decreased overt gastroduodenal bleeding and upper gastrointestinal bleeding of unknown origin (Table 1). The combination of omeprazole, clopidogrel and ASA did NOT increase the risk of cardiovascular events in this study population (Table 1).

Table 1: Efficacy and safety outcomes from COGENT

Unlike other publications, all of which were retrospective studies, patients in COGENT were known to be on concomitant ASA, which is standard in cardiovascular patients.^4,6-12  Additionally, the treatment groups were well balanced and did not require multivariate analysis or propensity scores to account for differences between patients taking or not taking a PPI.^4,6-16  The COGENT study also utilized an adjudicated process to confirm clinical outcomes, instead of insurance claims data, which was used in the majority of the published retrospective studies.^4,6-10,13

The COGENT trial was halted early, which did not impact the primary GI endpoint, but may have resulted in a Type II error for the cardiovascular safety endpoint.  The study did not determine the prevalence of homozygosity for the loss of CYP 2C19 function, which could decrease the effectiveness of clopidogrel and impact the cardiovascular results.  However, it would not have been powered to determine a statistically significant difference in this mostly Caucasian population and there are no current recommendations to routinely perform pharmacogenomic or platelet function testing.  Thus far, COGENT is the only published prospective randomized controlled trial looking at the addition of omeprazole to clopidogrel and ASA and based on these results, the combination is protective (NNT of 56) and does not increase risk of cardiovascular events (no significant difference).  

In light of this information, should we be recommending to avoid the combination of omeprazole and clopidogrel?  The recent expert consensus document by the American College of Cardiology Foundation, American College of Gastroenterology, and American Heart Association does not make any strong statement to avoid this combination.  Certainly, concurrent clopidogrel and aspirin use increases the risk of GI bleeding events and certain patient populations have a higher risk from other medications, medical problems and history.  Omeprazole is the least expensive PPI currently on the market and does not require a prescription, and the recommendation to use pantoprazole in place of omeprazole is based on pharmacokinetic, not clinical data.^1-2  I believe that the current evidence does not support the FDA’s warning.  We should continue to determine the appropriateness of adding any PPI to clopidogrel and ASA and if a PPI is warranted, omeprazole is an acceptable and proven choice.  What do you think?