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The Issue Clopidogrel (Plavix) is a commonly used medication in patients with cardiovascular disease. It works by interfering with the activity of platelets (blood elements responsible for clotting) and is often combined with acetylsalicylic acid (ASA) in patients who have had a myocardial infarction or stent. It is also used in selected patients with stroke. In 2007, clopidogrel was the second leading drug worldwide, with more than US$7.3 billion in sales, which is not surprising given the prevalence of cardiovascular and cerebrovascular diseases. Scientists have known for some time that clopidogrel is a prodrug – that is, it has no effect on platelets until it is converted by the liver into its active form. The liver’s ability to “turn on” clopidogrel is determined, in part, by genetics. Some patients (particularly those of Asian descent) lack the enzyme that converts clopidogrel to its active form. Recently, however, scientists have observed that some drugs can also interfere with this same process by blocking the primary liver enzyme responsible for this crucial step in the activation of clopidogrel. Of the drugs that could interfere with the activation of clopidogrel, by far the most important are the proton pump inhibitors (PPIs). These drugs are extremely popular, and millions of Canadians take one of these drugs for a variety of common acid-related disorders, including gastroesophageal reflux disease and peptic ulcer disease, and as a preventative measure against stomach injury from anti-inflammatory drugs such as ASA. Given the popularity of PPIs and the large number of patients treated with clopidogrel, it is likely that millions of patients take these drugs in combination worldwide. Some PPIs, but not others, interfere with the activity of the enzyme responsible for converting clopidogrel to its active form. Several laboratory-based studies have shown that certain PPIs appear to reduce the effect of clopidogrel in platelets, making blood “stickier” and more likely to clot. These findings support the notion that, in some patients, PPIs could reduce the effect of clopidogrel and increase the risk of cardiac events. However, until recently, no published studies characterized the clinical significance of the drug interaction between clopidogrel and PPIs. A recent study conducted at ICES and funded in part by the Ontario Ministry of Health and Long-Term Care provided the first large-scale insight into the clinical consequences of this extremely common drug interaction (Juurlink et al. 2009).

ICES Report: New Findings Highlight Potential Risks of Common Drug Combination in Cardiac Patients