Risk of using the combination

Due to clopidogrel’s mechanism of action, it can cause gastrointestinal adverse effects such as bleeding, dyspepsia and ulceration. PPIs are often co-prescribed to reduce the risk of these adverse effects in high-risk patients.

But in using the combination to manage adverse effects, risks associated with using clopidogrel and PPIs due to an interaction are introduced. Clopidogrel is a pro-drug activated by the enzyme CYP2C19. Omeprazole and esomeprazole are inhibitors of this enzyme meaning concurrent use can reduce plasma levels of activated clopidogrel.

Although other PPIs can inhibit CYP2C19 to a lesser extent, clinically significant interactions have not been observed.

Assessing need for the combination

The NICE Clinical Knowledge Summary for antiplatelet treatment recommends patients on clopidogrel are initiated on a PPI if they have a high risk of gastrointestinal adverse effects. Risk factors include:

• older age (especially over 75 years)
• history of gastroduodenal ulcer, GI bleeding, or gastroduodenal perforation
• presence of Helicobacter pylori infection
• concomitant use of medicines that are known to increase the risk of GI bleeds

Initiating a PPI

For patients taking clopidogrel who require PPI therapy, avoid omeprazole and esomeprazole. Use lansoprazole, pantoprazole or rabeprazole in preference.

Initiating clopidogrel

For patients taking omeprazole or esomeprazole who require clopidogrel, switch to an alternative PPI such as lansoprazole, pantoprazole or rabeprazole.

For patients already taking lansoprazole, pantoprazole or rabeprazole who require clopidogrel therapy, no change in PPI in necessary.

Professional advice

The European Society of Cardiology states that omeprazole and esomeprazole have the highest probability of clinically significant interactions with clopidogrel compared to other PPIs. They also state this probability is intermediate with lansoprazole and lowest with pantoprazole and rabeprazole.

Regulatory advice

The Medicines and Healthcare products Regulatory Agency (MHRA) and European Medicines Agency (EMA) advise against concurrent use of clopidogrel with omeprazole and esomeprazole. They do not extend this recommendation to other PPIs.

Licensing information

Clopidogrel

The Summary of Product Characteristics (SPC) for clopidogrel discourages combined use with omeprazole and esomeprazole. It suggests interactions with lansoprazole and pantoprazole as less pronounced.

Omeprazole and esomeprazole

The SPCs for omeprazole and esomeprazole discourage combined use with clopidogrel.

Lansoprazole, pantoprazole and rabeprazole

The SPCs for lansoprazole, pantoprazole and rabeprazole do not list an interaction with clopidogrel.

Evidence

As the impact that PPIs have on the cardiovascular outcomes of clopidogrel are unclear, recommendations on interaction management are based on pharmacokinetic data.

Pharmacokinetic data

Omeprazole and esomeprazole

High dose omeprazole (80mg daily) has been shown to reduce the maximum plasma levels of clopidogrel by 49%. Lower doses of omeprazole (20mg daily) are associated with lower reductions in maximum plasma levels of clopidogrel (32%)

Esomeprazole is expected to interact similarly with clopidogrel.

Lansoprazole

Lansoprazole 30mg daily does not reduce the overall exposure of clopidogrel. High dose lansoprazole (60mg daily) does however reduce the clopidogrel maximum plasma levels (18%), albeit to a lesser extent than high dose omeprazole.

Pantoprazole

Pantoprazole slightly decreases the overall exposure of clopidogrel by 14%, although the dose used (80mg daily) exceeds the licensed dose.

Rabeprazole

Rabeprazole decreases the clopidogrel maximum plasma levels by 28% in patients with normal CYP2C19 function, but does not affect the overall exposure.

Cardiovascular outcomes

It is unclear what the extent of any reduction in clopidogrel plasma concentrations from exposure to PPIs contributes to worsened cardiovascular outcomes. Most data comes from observational studies, so definitive conclusions cannot be made.

Studies often look at PPIs as a class, with some showing PPIs are associated with poorer cardiovascular outcomes when taken with clopidogrel and others finding no such effect. Where studies do look at individual PPIs, results are conflicting.

There is some evidence suggesting PPI use is an independent marker of cardiovascular disease whereby patients on PPI therapy already have an elevated baseline risk. This also makes it difficult to establish the clinical significance of the interaction between clopidogrel and PPIs.

Bibliography

Full referencing is available on request.

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