NPC Archive Item: EMEA statement on possible interaction between clopidogrel and proton pump inhibitors

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4th June 2009

Concomitant use of proton pump inhibitors (PPIs) and clopidogrel is not advisable unless absolutely necessary, the EU Committee for Medicinal products for Human Use (CHMP) and its Pharmacovigilance Working Party (PhVWP) has concluded. This is due to concerns that PPIs may reduce the effectiveness of clopidogrel. In a public statement on the possible interaction, the European Medicines Agency (EMEA) said that product information for all clopidogrel-containing medicines will be amended to reflect this.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) have issued this advice:

  • The need for PPI therapy in patients who are also taking clopidogrel should be reviewed at their next appointment: only use these medicines concomitantly when essential
  • Prescribe PPIs strictly in line with their licensed indications
  • Check that patients who are taking clopidogrel are not buying over-thecounter omeprazole.

Healthcare professionals should continue to follow NICE guidance on prescribing clopidogrel (see below). Proton pump inhibitors (PPIs) should not be used with clopidogrel unless absolutely necessary. This new advice presents a good opportunity to review people on clopidogrel and a PPI, and stopping either the clopidogrel if it is being used outside NICE guidance or beyond the recommended period, or the PPI, or both. If the original reason for using clopidogrel was due to intolerable gastrointestinal (GI) symptoms on aspirin alone, changing the prescription to aspirin plus a PPI would seem a reasonable approach.

What is the background to this?
The EMEA has concluded that, taken together, recent studies suggest that a significant interaction might occur between clopidogrel and PPIs, making clopidogrel less effective when given with these medicines. This could result in patients being at an increased risk of thrombotic events, including acute myocardial infarction (MI).

One possible explanation for this observation is that some PPIs prevent the conversion of clopidogrel into its biologically active form in the body, reducing its effectiveness. However, different PPIs have different capacity to affect the metabolism of clopidogrel – as the outcome studies have not fully reflected the different effects of PPIs on activation of clopidogrel, there may be more than one explanation for the effect of this class of medicines on clopidogrel.

Taking all the data into account, the CHMP has recommended that the product information for all clopidogrel-containing medicines should be amended to discourage concomitant use of PPI and clopidogrel-containing medicines unless absolutely necessary. The CHMP also recommended that further information is needed on the inhibition of clopidogrel metabolism by other medicines, and the implications of genetic variation which results in a small proportion of individuals (so called ‘CYP2C19 poor metabolisers’) being unable to fully convert clopidogrel to its active form, regardless of interactions with other medicines.

The US Food and Drug Administration (FDA) has also recently updated its information about its ongoing safety review of clopidogrel, which we first blogged in February. The FDA point out that some reports suggest that certain PPIs may make clopidogrel less effective, by inhibiting the enzyme that converts clopidogrel to the active form of the drug (Gilard M et al 2008, Gilard M et al 2006), whereas other reports do not suggest this effect (Small DS et al 2008, Siller-Matula JM et al 2009). The FDA stated that it has no evidence that H2-receptor antagonists or antacids interfere with the antiplatelet activity of clopidogrel.

Are there any differences between PPIs in regard to this interaction?
Neither the EMEA statement nor the FDA information makes reference to any individual PPI being any more or less likely to interact with clopidogrel than any other. A recent case control study found an increased risk of recurrent MI among people taking clopidogrel who were current users of PPIs compared with PPI non-users. Stratified analysis suggested that pantoprazole did not share this association but the 95% confidence interval on the odds ratio was wide. However, available results from the Clopidogrel Medco Outcomes Study (recently presented at the Society for Cardiovascular Angiography and Interventions [SCAI] conference) suggest that all the PPIs studied (omeprazole, lansoprazole, pantoprazole and esomeprazole) increased the risk of hospitalisation for MI, stroke, unstable angina or repeat revascularisation in people taking clopidogrel after coronary stenting compared with the no-PPI control group.

How does this relate to NICE guidance?
Healthcare professionals should continue to follow NICE guidance on prescribing clopidogrel. NICE guidance on the use of clopidogrel in acute coronary syndrome (ACS) recommends the use of clopidogrel in combination with low-dose aspirin in patients who have non-ST elevation ACS who are at moderate to high risk of myocardial infarction or death. The guidance defines this group as patients with ECG changes and/or raised cardiac markers.

NICE guidance on secondary prevention of occlusive vascular events, which applies to patients who have had an occlusive vascular event or have symptomatic peripheral arterial disease, recommends clopidogrel on its own only for those who are intolerant of low-dose aspirin. Aspirin intolerance is defined as proven hypersensitivity to aspirin-containing medicines or a history of severe dyspepsia induced by low-dose aspirin.

Further information on the use of clopidogrel is available on the antiplatelets section and other cardiovascular sections of NPC.

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