According to a study published early online in Circulation, although point estimates indicated a slightly increased risk of myocardial infarction hospitalisation or death in older patients initiating both clopidogrel and a proton pump inhibitor (PPI), conclusive evidence of a clopidogrel-PPI interaction of major clinical relevance was not observed.
Researchers evaluated the potential for increased risk of adverse cardiovascular events among users of clopidogrel with versus without concurrent use of PPIs in 3 large cohorts of patients >/=65 years of age, treated between 2001 and 2005.
The studies included patients who were admitted for acute coronary syndromes and underwent a percutaneous coronary intervention (PCI). MI hospitalisation, revascularisation, and death resulting from any cause were evaluated, and a combined MI hospitalisation and death outcome was the primary endpoint.
A total of 18,565 patients were included in the analysis, of whom 3,996 were PPI users. The exposure of interest was use of a PPI, defined as omeprazole, esomeprazole, lansoprazole, pantoprazole, or rabeprazole, dispensed at any point 21 days before and/or within 7 days after the index event, and dispensed with sufficient supply of the drug to last through the 7 days after the index event. The following results were reported:
• On a pooled basis, 2.6% of those who also initiated a PPI vs 2.1% of PPI nonusers had a myocardial infarction hospitalisation, and 1.5% vs 0.9% died; 3.4% vs 3.1% underwent revascularisation respectively
• The propensity score–adjusted rate ratio for the primary end point of myocardial infarction or death was 1.22 (95% confidence interval, 0.99 to 1.51); for death, 1.20 (0.84 to 1.70); and for revascularisation, 0.97 (95% confidence interval, 0.79 to 1.21).
The researchers concluded that “The results of this large study of community-dwelling patients >/= 65 years of age followed up after PCI or ACS failed to demonstrate a large or statistically significant increase in the relative risk of MI hospitalisation or death owing to concurrent use of clopidogrel and PPIs, as previously reported. However, the data are consistent with the possibility of an interaction with only modest clinical effect in the routine care of older adults.
In a related editorial, the author discusses the study and makes the following recommendations for clinical practice:
• Evaluate the necessity of PPI therapy. Although PPIs are necessary for some patients, many others take the drugs for dubious indications. In these patients, treatment with a histamine H2 antagonist or antacid may suffice.
• Consider using pantoprazole when a PPI is indicated. This suggestion stems from the observation that pantoprazole is less likely than omeprazole to inhibit CYP2C19, does not appear to attenuate the pharmacodynamic response to clopidogrel, and displayed no association with recurrent myocardial infarction in a large observational study of patients receiving clopidogrel. Other PPIs may also be relatively safe, but more data are needed. Lansoprazole is the most potent CYP2C19 inhibitor and is probably best avoided.
• Stagger the dosing of medications. This is perhaps the most important strategy and exploits the rapid metabolism of clopidogrel and the transient nature of PPI-mediated CYP2C19 inhibition. When dual therapy is necessary, taking a PPI at least 4 hours after clopidogrel should minimize the risk of interaction.
[Editor’s note: The US FDA and the MHRA had recently issued practical advice with respect to this interaction – Please see links below]