ESC Position Paper Offers Guidance on Dual PPI and Antithrombotic Use

While no conclusive evidence exists to support a clinically relevant interaction between proton pump inhibitors (PPIs) and clopidogrel, clinicians should err on the side of caution by prescribing PPIs that are less likely to reduce antiplatelet efficacy. However, alternatives such as ticagrelor and prasugrel show no signs of such interplay, reports a European Society of Cardiology (ESC) expert position paper published online February 20, 2013, ahead of print in the European Heart Journal.

The report, which reviews both pharmacodynamic and clinical studies, provides guidance on PPI and antithrombotic use in patients with cardiovascular disease.

In an e-mail communication, coauthor Stefan Agewall, MD, PhD, of Oslo University Hospital (Oslo, Norway), told TCTMD that the topic represents “an important clinical question which is discussed in the cardiology environment daily,” and is therefore timely.

“Given the large number of patients treated with PPIs and antithrombotic drugs, even a minor reduction in the cardiovascular benefits of antithrombotic drugs may have substantial clinical impact,” Dr. Agewall and colleagues comment in the paper.

Shaun G. Goodman, MD, MSc, of St. Michael’s Hospital (Toronto, Canada), said in an e-mail communication with TCTMD that the paper offers “a thoughtful and concise review of the existing data together with clear recommendations for this sometimes controversial, often confusing topic which has important implications for day-to-day practice.”

Clopidogrel Still Vexes

Simultaneous use of other drugs metabolized through the same pathway as clopidogrel, such as PPIs, has been shown in pharmacodynamic studies to reduce clopidogrel’s efficacy to varying degrees. And while observational studies have provided mixed evidence, no randomized controlled trials have demonstrated an effect on clinical outcomes.

Notably, COGENT—the only randomized trial designed to test for a PPI-clopidogrel interaction—showed in the New England Journal of Medicine in 2010 that omeprazole reduces GI events in patients on clopidogrel and aspirin without affecting cardiovascular event risk.

“In summary, potential negative clinical impacts of some PPIs on the therapeutic efficacy of clopidogrel are still controversial,” the authors write. “In view of the pharmacokinetic data and inconclusive clinical evidence, PPIs with weaker inhibition of CYP2C19 are preferred in combination with clopidogrel compared with those with stronger inhibition such as omeprazole.”

ESC guidelines for NSTEMI and STEMI care, released in 2011 and 2012, respectively, both recommend PPI use in patients receiving dual antiplatelet therapy during the initial phase of ACS, especially in those with a history of GI bleeding or peptic ulcer. A 2010 consensus document from the American College of Cardiology, American College of Gastroenterology, and American Heart Association takes a similar stance.

Yet the US Food and Drug Administration retains the ‘black box’ warning on clopidogrel, first added in 2009 and updated in 2011 to specifically mention omeprazole and esomeprazole.

No Need to Avoid Clopidogrel

As the ESC paper notes, newer antiplatelet drugs such as prasugrel and ticagrelor appear unaffected by PPIs. Dr. Agewall emphasized to TCTMD that a potential interaction should not dissuade clinicians from clopidogrel when other alternatives are available and that cost and bleeding risk also must be weighed.

Dr. Goodman agreed, noting, “I don’t think the fact that the other drugs mentioned failed to show a similar type of interaction to date discourages clopidogrel use. But certainly . . . if there is a question/concern, there are alternatives—especially ticagrelor, since it is an active compound (not a prodrug) and does not require in vivo biotransformation to exert its antiplatelet effect.”

Prasugrel’s metabolism more closely resembles that of clopidogrel, he said, and there is some evidence of PPIs exerting an effect on platelet function but not clinical outcome in patients taking prasugrel, Dr. Goodman explained. “Also, it exerts a consistently higher degree of inhibition of platelet aggregation vs. clopidogrel so even some potential interaction with a PPI might not be enough to have a clinical impact.”

Other Antithrombotics Less of a Concern

A possible effect on aspirin, however, remains “controversial,” the authors say. Explanations for a negative interaction between PPIs and aspirin might include reduced gastric acidity inhibiting aspirin uptake, poor overall health of patients with concomitant GI disorders, or chance.

“So far, there are insufficient data to suggest a clinical interaction between PPI use and the protective efficacy of [aspirin] in patients with CVD,” Dr. Agewall and colleagues write, recommending PPIs to prevent gastric ulceration in aspirin-treated patients at high risk of GI bleeding.

In terms of anticoagulants, the ESC paper reports that warfarin absorption may be accelerated by PPIs, particularly omeprazole. Observational studies, as always, may be subject to selection bias, and the available randomized trials involved only a single warfarin dose. As such, the coauthors say that, for now, “it is appropriate to monitor cautiously patients on [vitamin K antagonists] and PPI co-medication.”

PPIs may also prove useful in alleviating dyspepsia and reducing GI bleeding risk in patients taking dabigatran, they add. “Current evidence indicates that the mild reduction in dabigatran exposure related to PPI usage does not warrant any dose adjustment,” the authors write. Oral factor Xa inhibitors, meanwhile, appear to be uninfluenced by PPIs.

 

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Source:
Agewall S, Cattaneo M, Collet JP, et al. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J. 2013;Epub ahead of print.

 

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