What are the indications for Proton Pump Inhibitors (PPI) with dual antiplatelet therapy?

From the Guidelines

Proton pump inhibitors (PPIs) are recommended for patients on dual antiplatelet therapy (DAPT) who have high gastrointestinal bleeding risk, as stated in the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease 1.

Indications for PPIs with DAPT

The indications for PPIs with DAPT include:

• History of prior gastrointestinal bleeding
• Peptic ulcer disease
• Advanced age (over 65 years old)
• Concomitant use of anticoagulants, steroids, or nonsteroidal anti-inflammatory drugs (NSAIDs)
• H. pylori infection

Recommended PPIs and Dosage

Common PPIs used include:

• Omeprazole 20mg daily
• Pantoprazole 40mg daily
• Esomeprazole 40mg daily These medications should be taken 30 minutes before the first meal of the day for optimal effect and typically continued for the duration of DAPT therapy.

Rationale for PPI Use

PPIs reduce gastrointestinal bleeding risk by decreasing gastric acid production, which helps protect the gastric mucosa from damage caused by antiplatelet agents like aspirin and P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) 1.

Considerations for PPI Interactions with Clopidogrel

While there were historical concerns about potential interactions between PPIs (particularly omeprazole) and clopidogrel reducing antiplatelet efficacy, current evidence suggests the clinical benefit of bleeding prevention outweighs these theoretical concerns 1. Pantoprazole may be preferred when using clopidogrel due to less CYP2C19 enzyme inhibition.

From the FDA Drug Label

5.6 Interaction with Clopidogrel Avoid concomitant use of omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that inhibit CYP2C19 activity Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole, consider alternative anti-platelet therapy [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

The indications for Proton Pump Inhibitors (PPI) with dual antiplatelet therapy are not directly stated in the provided drug label. However, it is advised to avoid concomitant use of omeprazole with clopidogrel due to the potential reduction in pharmacological activity of clopidogrel. Alternative anti-platelet therapy should be considered when using omeprazole 2.

From the Research

Indications for Proton Pump Inhibitors (PPI) with Dual Antiplatelet Therapy

• The use of PPIs is recommended in patients at risk of bleeding to reduce the risk of gastrointestinal (GI) hemorrhage while on dual antiplatelet therapy (DAPT) 3.
• PPIs should be administered in patients on DAPT at risk for GI bleeding, as they can reduce the metabolism of clopidogrel by competing with CYP450 enzymes, mostly CYP2C19 isoform 3.
• Screening for risk factors for upper gastrointestinal bleeding (UGIB) and subsequent prophylactic PPI treatment can help reduce the incidence of UGIB in patients on DAPT 4.
• The concomitant use of PPIs and DAPT can potentially reduce the risk of UGIB, with a significantly lower rate of UGIB in the PPI + DAPT group compared to the DAPT alone group 5.
• PPIs can reduce the risk of GI bleeding in patients treated with DAPT after percutaneous coronary intervention or acute coronary syndrome, without adversely affecting major cardiovascular outcomes 6.

Patient Selection for PPI Therapy

• Patients at risk of GI bleeding, such as those with a history of bleeding or taking medications that increase the risk of bleeding, should be considered for PPI therapy while on DAPT 3, 4.
• Patients who are not at risk of GI bleeding should be prescribed PPIs with caution, as the uncertain benefit of PPIs in these patients and the unclear risk of major adverse cardiovascular events (MACE) suggest that caution should be used when prescribing PPIs 3.
• The use of PPIs may be associated with a reduced risk of all-cause mortality in patients on DAPT, although the evidence is not uniform across all studies 5, 6.

Pharmacokinetic Interactions

• The use of omeprazole, a type of PPI, can reduce the antiplatelet activity of clopidogrel and increase the probability of recurrence of cardiovascular events by competitively inhibiting the CYP450 isoenzyme CYP2C19 7.
• Deuterium clopidogrel, a modified version of clopidogrel, may have better pharmacokinetic and pharmacodynamic properties and be less affected by the concomitant use of omeprazole, reducing drug-drug interactions and addressing the clinical disadvantages of clopidogrel 7.