What are the indications for proton pump inhibitors (PPIs) in patients on direct oral anticoagulant (DOAC) therapy?

Indications for PPI in DOAC Therapy

Proton pump inhibitors are recommended for patients on DOAC therapy who have increased risk of gastrointestinal bleeding, including those with prior GI bleeding, age >60 years, concurrent use of antiplatelet agents, NSAIDs, steroids, or multiple antithrombotic agents. 1, 2

Risk-Based Approach to PPI Initiation

The decision to prescribe PPIs with DOACs should be based on systematic assessment of GI bleeding risk factors:

High-Risk Patients (PPI Strongly Recommended)

• History of upper GI bleeding - This is the strongest predictor of recurrence and represents a definitive indication for long-term PPI therapy 2
• Age >60 years combined with any additional risk factor 2
• Concurrent antiplatelet therapy (aspirin or P2Y12 inhibitors) 1
• Multiple antithrombotic agents (e.g., DOAC plus antiplatelet) 2
• Concurrent NSAID or corticosteroid use 2
• History of peptic ulcer disease 2
• Helicobacter pylori infection (should be treated) 3

Moderate-Risk Patients (PPI Should Be Considered)

PPIs should be considered even with single DOAC therapy based on individual GI bleeding risk factors, particularly in patients with multiple moderate-risk features 1, 2

Specific Clinical Scenarios

DOACs with Dual Antiplatelet Therapy (DAPT)

A PPI is recommended for the entire duration of combined antithrombotic therapy when DOACs are used with antiplatelet agents 1. This combination carries particularly high bleeding risk and represents a clear indication for gastroprotection 1.

DOACs with Single Antiplatelet Agent

PPI therapy is recommended when DOACs are combined with aspirin or clopidogrel, especially if additional risk factors are present 1, 2. The European Society of Cardiology specifically recommends PPIs for patients at increased risk during any combined antithrombotic therapy 1.

DOAC Monotherapy

For patients on DOAC alone, PPIs should be prescribed based on individual GI bleeding risk stratification 2. Patients with high-risk features (prior GI bleeding, advanced age with comorbidities, chronic NSAID use) warrant PPI therapy even without concurrent antiplatelet agents 2.

Optimal PPI Regimen

• Standard once-daily dosing is appropriate for most patients (e.g., omeprazole 20mg daily, pantoprazole 40mg daily) 1, 2
• Twice-daily dosing should be reserved only for patients with complicated GERD, severe erosive esophagitis, or documented failure of once-daily therapy 1
• Duration of therapy should continue as long as the high-risk condition persists (e.g., ongoing DOAC therapy in a patient with prior GI bleeding) 2

Important Considerations and Pitfalls

Drug Interactions with DOACs

Unlike clopidogrel, DOACs do not have clinically significant interactions with PPIs 4. The CYP2C19-mediated interaction that occurs with clopidogrel and certain PPIs (omeprazole, esomeprazole) is not relevant for DOACs, which have different metabolic pathways 4.

Regular Reassessment

All patients on PPIs should have regular review of ongoing indications, with documentation of the specific reason for continued use 1. This is particularly important because:

• PPIs should not be continued indefinitely without clear indication 1
• Patients without definitive indications should be considered for de-prescribing 1
• However, patients at high risk for upper GI bleeding should NOT be considered for PPI discontinuation 1

Patients Who Should NOT Discontinue PPIs

The following patients should generally continue PPI therapy regardless of concerns about long-term use 1, 2:

• History of upper GI bleeding on antithrombotic therapy 1, 2
• Complicated GERD (severe erosive esophagitis, esophageal ulcer, peptic stricture) 1
• Barrett's esophagus 1
• Eosinophilic esophagitis 1

Evidence on Clinical Outcomes

Recent observational data suggests DOAC-PPI co-therapy is associated with decreased upper GI bleeding (HR 0.79,95% CI 0.76-0.81), supporting the protective effect of PPIs in this population 5. However, this same study found increased mortality with PPI use, likely reflecting residual confounding from sicker patients receiving PPIs rather than a causal effect 5.

A large Medicare study demonstrated that PPI co-therapy reduced hospitalization for upper GI bleeding across all oral anticoagulants, with overall incidence rate ratio of 0.66 (95% CI 0.62-0.69) 6. This protective effect was consistent for all DOACs studied 6.

Clinical Decision Algorithm

1. Assess GI bleeding risk factors at DOAC initiation 2
2. Prescribe PPI if any high-risk factor present (prior GI bleeding, age >60 with additional risks, concurrent antiplatelet/NSAID use) 1, 2
3. Use standard once-daily dosing unless specific indication for higher intensity 1, 2
4. Document the indication clearly in the medical record 1
5. Reassess periodically but do not discontinue in high-risk patients 1, 2
6. Continue PPI for duration of high-risk condition (e.g., as long as on DOAC if prior GI bleeding) 2