Safety review of Clopidogrel – IMB interim advice on the concurrent use of Proton Pump Inhibitors in patients treated with Clopidogrel

Notice type: Advisory

Date: 12/05/2009


Product name or type:

Problem Or Issue:
The IMB wishes to communicate interim recommendations relating to an ongoing safety review of clopidogrel. This follows the publication of reports suggesting it is less effective in some patients (including those taking proton pump inhibitors) than it is in others, resulting in an increased risk of acute myocardial infarction. However, details of the particular patient groups likely to be affected are not known yet and it is therefore important to consider these preliminary safety reports with caution, until the issue of variability in response to clopidogrel, including the impact of potential drug interactions, is further evaluated

Background Information Or Related Documents:
Clopidogrel is an antiplatelet drug authorized for the prevention of atherothrombotic events in patients suffering from myocardial infarction (heart attack), ischaemic stroke or acute coronary syndrome, or those at risk of these problems. Clopidogrel is a “pro-drug” which means that it has to be metabolized by the body before it can be biologically active and have the effect of preventing blood clots. 

The IMB is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel, or due to co-administration of drugs that can interfere with the metabolism of clopidogrel. 

Interaction between Clopidogrel and Proton Pump Inhibitors

One class of drugs commonly used with clopidogrel is proton pump inhibitors (PPIs). Proton pump inhibitors decrease stomach acid and are used to treat frequent heartburn and stomach ulcers. PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Clopidogrel is metabolised by the liver to an active molecule that inhibits platelet aggregation however evidence is emerging that some PPIs inhibit this pathway and may increase the risk of adverse cardiac outcomes. While some reports suggest that use of certain PPIs may make clopidogrel less effective by inhibiting the enzyme that converts clopidogrel to the active form of the drug, other reports do not support this finding. 

The IMB has no evidence that H2-receptor antagonists or antacids have a similar effect. 

The Journal of the Canadian Medical Association has published the results of a population-based study that aimed to assess the clinical importance of the interaction between proton pump inhibitors (PPIs) and clopidogrel. This research reviewed database records for 13,636 patients who were started on treatment with clopidogrel after an acute myocardial infarction between 2002 and 2007. 782 of these patients were readmitted within 90 days with a second event. Of this latter group, 734 patients were matched with 2,057 controls and analyses were performed for associations between usage of a PPI and cardiac events. Patients who were readmitted were more likely to have co-morbidities such as heart failure, diabetes and renal failure. Despite this additional disease burden they were less likely to be prescribed ACE inhibitors, beta-blockers or statins. 

After correcting for many factors, this analysis found an increased risk in readmission related to cardiac events in current users of PPIs (adjusted odds ratio 1.27, 95% CI 1.03-1.57). Further analysis found no correlation between readmission and H2-receptor antagonists or in readmission among non-users of clopidogrel. On the basis of the limited evidence available to date, it also appears that this interaction does not occur with pantoprazole. 

Notable limitations of this study are the lack of data for some important cardiac risk factors including smoking status, blood pressure and lipid levels. Non-prescription medication data were also unavailable for the analysis. The authors conclude that, “concomitant treatment with clopidogrel and proton pump inhibitors should be minimised“. 

Evaluation of all available data is currently underway; however, until further information on the clinical significance of this interaction is available, the IMB recommends the following: 

Interim Advice for Healthcare Professionals

• Healthcare professionals should be aware of this interaction and the potential to increase cardiac events such as acute myocardial infarction. 

• Healthcare providers should continue to prescribe clopidogrel and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke. 

• Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI in patients taking clopidogrel. The risk-benefit of continuing treatment with a PPI should be considered by the prescribing physician. 

• Healthcare professionals should continue to report suspected adverse reactions associated with clopidogrel/PPIs to the Irish Medicines Board. 

Interim Advice for Patients

• Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a Proton Pump Inhibitor (e.g. omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole.).

Safety review of Clopidogrel – IMB interim advice on the concurrent use of Proton Pump Inhibitors in patients treated with Clopidogrel Document

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