Omeprazole, But Not Pantoprazole, Inhibits Clopidogrel's Platelet Response

September 15, 2009

September 15, 2009 (Marseille, France) — Results from a new study suggest that not all proton-pump inhibitors (PPIs) interfere with clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb) to the same degree, with investigators showing that ACS patients treated pantoprazole (Protonix, Wyeth) had a significantly better platelet response to clopidogrel than those treated with omeprazole [1].

"The present study suggests that the degree of the interaction between clopidogrel and PPI is not homogeneous within the class of PPIs and is less marked with pantoprazole than with omeprazole," write lead investigator Dr Thomas Cuisset (INSERM, Marseille, France) and colleagues in the September 22, 2009 issue of the Journal of the American College of Cardiology. "It confirms that the use of omeprazole significantly reduced the antiplatelet activity of clopidogrel, even with a high maintenance dose, and that other PPIs, such as pantoprazole, must be preferred in clopidogrel-treated patients."

The interaction between clopidogrel and PPIs has been debated frequently of late. Clopidogrel is a prodrug converted in the liver to its active form by cytochrome P450 isoenzymes, with P450 2C19 playing a particularly important role. It has been hypothesized that medications also metabolized by CYP 450, including the PPIs, alter the effectiveness of clopidogrel, which can potentially lead to an increased risk of adverse cardiovascular outcomes.

One recent study, reported by heartwire , showed that the addition of any PPI, with the exception of pantoprazole, to clopidogrel in acute-MI patients significantly increased the risk of recurrent infarction. Another retrospective cohort study, also reported by heartwire , involving 8205 patients with ACS taking clopidogrel, showed the concomitant use of clopidogrel and a PPI was associated with an increased risk of adverse outcomes. The PPI data from the large-scale TRITON-TIMI 38 trial, however, suggested no effect of these agents on cardiovascular event rates in either the clopidogrel or prasugrel groups.

The PACA Study

In this French study, known as the Proton Pump Inhibitors and Clopidogrel Association (PACA) trial, investigators randomized 104 patients undergoing coronary stenting for non-ST-segment-elevation ACS to omeprazole or pantoprazole 20 mg. At discharge, all patients were prescribed aspirin 75 mg and clopidogrel 150 mg.

Patients receiving pantoprazole had a significantly better response to clopidogrel--as assessed by platelet-reactivity index (PRI) vasoactive-stimulated phosphoprotein (VASP)--than those treated with omeprazole. Also, 44% of patients treated with omeprazole did not respond to clopidogrel, whereas 23% of patients treated with pantoprazole were nonresponders. There was no significant difference in platelet reactivity with adenosine-diphosphate (ADP)–induced aggregation (ADP-Ag).

The study, according to Cuisset and colleagues, confirms the difference in PPIs in terms of modulating the response to clopidogrel. As the researchers point out, recent guidelines issued by the American Heart Association, American College of Cardiology, and American College of Gastroenterology call for PPI therapy for a majority of patients taking aspirin after MI, including all patients 60 years and older.

"This is of great importance for daily practice because PPIs are now a standard of care for patients receiving dual-antiplatelet therapy to prevent gastrointestinal bleeding," they write.

Recently, the European Medicines Agency (EMEA) issued a public statement on the possible interaction between clopidogrel and PPIs and recommended that product information for all clopidogrel-containing medicines be amended to discourage concomitant use of PPIs unless absolutely necessary.