Why is concomitant use of Omeprazole (a Proton Pump Inhibitor, PPI) and Clopidogrel (an antiplatelet medication) contraindicated?

From the Guidelines

Omeprazole and clopidogrel should not be taken together due to the potential reduction in clopidogrel's effectiveness, which may increase the risk of serious cardiovascular events, as stated in the 2024 ESC guidelines for the management of chronic coronary syndromes 1. This interaction occurs because omeprazole inhibits the liver enzyme CYP2C19, preventing clopidogrel from being converted to its active form, which is necessary for its blood-thinning effects. Some key points to consider:

• The use of proton pump inhibitors, such as omeprazole, with clopidogrel may reduce the exposure to clopidogrel's active metabolite, potentially increasing the risk of ischemic events or stent thrombosis 1.
• Alternative medications, such as pantoprazole, which has less effect on CYP2C19, or H2 blockers like famotidine, may be recommended for patients who need both acid suppression and antiplatelet therapy.
• The FDA advises healthcare providers to reevaluate the need for starting or continuing treatment with a PPI, including omeprazole, in patients taking clopidogrel, as there is no evidence that other drugs that reduce stomach acid interfere with the antiplatelet activity of clopidogrel 1.
• Patients taking clopidogrel should consult their healthcare provider if they are currently taking or considering taking a PPI, including omeprazole, to evaluate their specific cardiovascular risk and gastrointestinal needs. It is essential to consult a healthcare provider before making any medication changes, as they can assess the individual's risk and needs, and provide guidance on the best course of treatment, as highlighted in the 2024 ESC guidelines 1.

From the FDA Drug Label

7.2 CYP2C19 Inhibitors Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition Omeprazole or Esomeprazole Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart.

You can't take omeprazole and clopidogrel together because omeprazole inhibits the enzyme CYP2C19, which is necessary for clopidogrel to be metabolized into its active form, resulting in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition 2.

• Concomitant use of these two medications can lead to decreased effectiveness of clopidogrel.
• Alternative anti-platelet therapy should be considered when using omeprazole 3.

From the Research

Interaction between Omeprazole and Clopidogrel

• The use of omeprazole with clopidogrel has been shown to reduce the antiplatelet effect of clopidogrel due to competitive inhibition of cytochrome P450 2C19 isoenzyme 4.
• This interaction may increase the risk of myocardial infarction recurrence, as CYP2C19 activates clopidogrel 5.
• Studies have found that omeprazole coadministration with clopidogrel results in lower CYP2C19 enzyme activity and increased platelet reactivity 6.

Comparison with Pantoprazole

• Pantoprazole, another proton pump inhibitor, has been found to have no significant inhibitory effect on CYP2C19 and does not reduce the antiplatelet effect of clopidogrel 4, 6.
• The concomitant use of pantoprazole and clopidogrel has been shown to be cost-effective compared to the use of omeprazole and clopidogrel 5.
• Patients taking pantoprazole with clopidogrel did not show any significant changes in platelet activity or CYP2C19 enzyme activity 6.

Clinical Implications

• The use of omeprazole with clopidogrel has been associated with an increased risk of ischemic stroke 7.
• Clinicians should be aware of the potential interaction between omeprazole and clopidogrel and consider alternative proton pump inhibitors, such as pantoprazole, for patients at risk of gastrointestinal bleeding 8.
• Further studies are needed to fully understand the clinical implications of this interaction and to determine the best course of treatment for patients taking clopidogrel and proton pump inhibitors.