Article date: April 2010
Clopidogrel is indicated for the prevention of atherothrombotic events in patients who have had a myocardial infarction or ischaemic stroke, or who have established peripheral arterial disease. Combined with aspirin, the brand leader product (Plavix) may also be used to prevent atherothrombotic events in patients with acute coronary syndrome. Proton pump inhibitors (PPIs) are indicated for the treatment of oesophageal reflux disease, dyspepsia, or gastric ulcers, and are frequently co-prescribed with clopidogrel.
Previous advice regarding an interaction
In May 2009, the EU Committee for Medicinal products for Human Use (CHMP) concluded that concomitant use of any PPIs with clopidogrel should be avoided unless considered essential.
See Drug Safety Update, July 2009.
The product information for clopidogrel has been recently updated on the basis of pharmacokinetic, pharmacodynamic, and some clinical outcome data, which demonstrated that omeprazole competitively inhibits the CYP2C19 isoenzyme (which metabolises clopidogrel to its active metabolite); reduces the ability of clopidogrel to inhibit platelet aggregation; and reduces the beneficial effect of clopidogrel in patients. Although evidence for a similar effect on clopidogrel metabolism with the other PPIs was relatively sparse, a precautionary approach for the whole class was adopted in light of the findings of some clinical outcome studies suggesting an attenuation of the cardioprotective effect of clopidogrel by PPIs other than omeprazole.
Since then, new evidence has become available which, although having some methodological limitations, casts some doubt on the clinical relevance of possible interactions between clopidogrel and PPIs. However, the evidence in favour of an interaction with omeprazole and esomeprazole is still a concern.
Recent (unpublished) mechanistic studies in healthy volunteers have indicated that the addition of omeprazole to clopidogrel therapy reduces the inhibition of platelet aggregation, whether the two medicines are given simultaneously or 12 hours apart.
However, post hoc analyses from the PRINCIPLE-TIMI and TRITON-TIMI trials found that use of PPIs (unspecified) reduced platelet function in patients who were randomly assigned clopidogrel, but did not affect clinical outcome.
Furthermore, the COGENT study, which randomly allocated patients to clopidogrel with or without omeprazole, found no effect of concomitant omeprazole on cardiovascular outcome (this study was terminated early after 133 days).
A retrospective study of cardiovascular and gastrointestinal outcome in patients on clopidogrel and aspirin with and without gastroprotective agents found that although PPI use was associated with an increase in adverse cardiovascular events, it was also associated with a significantly reduced incidence of upper GI bleeding.
Summary of available evidence
The available evidence for an interaction between clopidogrel and PPIs is therefore not completely consistent. Nevertheless, pharmacokinetic, pharmacodynamic, and some clinical outcome data suggest a significant interaction for omeprazole, and there is also some evidence in relation to esomeprazole.
It is possible that the findings of clinical studies for the different PPIs are inconsistent because there is true variation in the extent to which they interact with clopidogrel. This inconsistency may also reflect several variables including an individual’s pharmacogenetics, medication compliance, and comorbidities; the doses of clopidogrel and PPI; and the study design.
In light of the most recent evidence, the previous advice (to avoid all PPIs unless absolutely necessary for patients taking clopidogrel) is no longer considered necessary. Nevertheless, as a precaution, concomitant use of clopidogrel with omeprazole or esomeprazole should be discouraged. Information for prescribers and patients will be updated with the latest advice.
The current evidence does not support extending this advice to other PPIs. However, because it is not possible to completely exclude a possible interaction with these PPIs on the basis of available data, the potential risk of a slight reduction in efficacy of clopidogrel should be weighed against the potential gastrointestinal benefit of the PPI.
Advice for healthcare professionals
Concomitant use of clopidogrel and omeprazole or esomeprazole is to be discouraged unless considered essential.
Doctors should check whether patients who are taking clopidogrel are also buying over-the-counter omeprazole and consider whether other gastrointestinal therapies would be more suitable.
Pharmacists should check whether patients buying omeprazole are also taking clopidogrel.
Consider PPIs other than omeprazole or esomeprazole in patients who are taking clopidogrel. Other gastrointestinal therapy such as H2 blockers (except cimetidine) or antacids may be more suitable in some patients.
Discourage concomitant use of other known CYP2C19-inhibiting medicines with clopidogrel because these are expected to have a similar effect to omeprazole and esomeprazole (CYP2C19 inhibitors include fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol).
Article citation: Drug Safety Update April 2010, vol 3 issue 9: 4.