Clinical relevance of clopidogrel-proton pump inhibitors interaction

Abstract

Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal antiinflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/ omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient's bleeding and cardiovascular risk. Core tip: Even though pharmacodynamic studies suggest that omeprazole can attenuate the antiplatelet effect of clopidogrel, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination in observational studies. In the only randomized, double-blind, placebo-controlled study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for MINIREVIEWS

Systematic review with meta‐analysis: risk of adverse cardiovascular events with proton pump inhibitors independent of clopidogrel

“…Clopidogrel is a first‐line anti‐platelet prodrug indicated for the secondary prevention of atherothrombotic cardiovascular disease . Pharmacokinetic studies have postulated an interaction between PPIs and clopidogrel, arising from metabolism by the same hepatic isoenzyme (CYP2C19) . Inhibition of CYP2C19 by PPIs may reduce the bioavailability of the active metabolites of clopidogrel, and attenuate clopidogrel's cardiovascular benefits .…”

“…[16][17][18] Inhibition of CYP2C19 by PPIs may reduce the bioavailability of the active metabolites of clopidogrel, and attenuate clopidogrel's cardiovascular benefits. [16][17][18] As a result, the United States Food and Drug Administration (FDA) has warned against using clopidogrel in combination with the PPIs omeprazole and esomeprazole. 19 Observational studies and randomised controlled trials have yielded conflicting results as to whether the proposed pharmacokinetic interaction between PPIs and clopidogrel manifests as an increased clinical risk of adverse cardiovascular events.…”

Potential Cardiovascular Risks of Proton Pump Inhibitors in the General Population

“…Thus far, several researchers have discussed whether PPIs may attenuate the cardiovascular protection of clopidogrel for patients with acute coronary syndrome. [23][24][25][26] Additionally, the single use of PPIs also has potentially adverse clinical outcomes in high-risk cardiovascular populations.…”

The management of gastro-oesophageal reflux disease

“…18,19 A randomised trial found no evidence of an increased risk of cardiovascular events in patients taking PPIs and thienopyridines such as clopidogrel. 10,20 There was also no evidence that separating the doses of the two drugs changed cardiac risk. 21 If there are major concerns about the interaction, a PPI with less cytochrome P450 (CYP) metabolism such as rabeprazole may be used.…”