What is the role of aspirin (acetylsalicylic acid) in a patient with peptic ulcer disease, particularly those with a history of nonsteroidal anti-inflammatory drug (NSAID) use and cardiovascular disease requiring antiplatelet therapy?

Role of Aspirin in Peptic Ulcer Disease

In patients with peptic ulcer disease requiring aspirin for cardiovascular protection, aspirin should be continued or restarted early (within 5 days) with mandatory proton pump inhibitor (PPI) co-therapy, as the cardiovascular mortality risk from aspirin discontinuation substantially outweighs the increased rebleeding risk. 1, 2

Critical Decision Point: Continue or Stop Aspirin?

For Secondary Cardiovascular Prevention (Prior MI, Stroke, Stents)

• Aspirin must be restarted as soon as cardiovascular risk outweighs bleeding risk - typically within 1-5 days after endoscopic hemostasis 1
• Discontinuing aspirin increases thrombotic events 3-fold, with events occurring within 7-10 days (the lifespan of inhibited platelets) 1
• In patients with acute ulcer bleeding who continued aspirin with high-dose IV PPI, rebleeding increased modestly (2-fold, non-significant) but 30-day mortality decreased significantly 1, 2
• For patients with recent coronary stents, aspirin discontinuation carries extremely high stent thrombosis risk - maintain dual antiplatelet therapy with aggressive PPI therapy 2

For Primary Prevention Only

• Stop aspirin and re-evaluate indication - the risk-benefit ratio is unfavorable 2
• Primary prevention prevents 1 MI per 555-794 patients/year but causes 5-7 GI bleeds for each MI prevented 1
• The FDA has declined approval for aspirin in primary prevention due to lack of mortality benefit and increased hemorrhagic stroke 1

Aspirin's Dual Mechanism of Ulcer Causation

Aspirin causes peptic ulcers through two distinct pathways 1:

• Antiplatelet effect: Promotes bleeding from existing lesions (including H. pylori ulcers) by inhibiting platelet aggregation
• Direct mucosal injury: Creates new ulcers through topical irritation and systemic prostaglandin inhibition

Dose-Response Relationship

Even the lowest aspirin doses carry significant bleeding risk - there is no "safe" dose 1:

• 75 mg/day: OR 2.3 for ulcer bleeding (doubles baseline risk) 1
• 150 mg/day: OR 3.2 1
• 300 mg/day: OR 3.9 1
• Recommendation: Use 75-81 mg daily - lowest effective dose 1

Common Pitfall to Avoid

Enteric-coated and buffered aspirin formulations do NOT reduce bleeding risk compared to plain aspirin 1. The relative risks are essentially identical (2.6-3.1 at 325 mg), so do not falsely reassure patients or switch formulations expecting GI protection 1.

Mandatory Gastroprotection Strategy

First-Line: PPI Co-Therapy

All high-risk patients on aspirin require PPI co-therapy 1, 3:

• PPIs reduce upper GI bleeding by 68-87% in aspirin users 3
• Standard once-daily dosing is sufficient (e.g., omeprazole 20 mg, esomeprazole 20 mg) 1
• PPIs are superior to H2-receptor antagonists for aspirin gastroprotection 1

High-Risk Criteria Requiring PPI (any one qualifies) 3:

• Prior upper GI bleeding or peptic ulcer
• Age >60-65 years
• Concurrent anticoagulation (warfarin, DOACs)
• Concurrent corticosteroids
• Concurrent NSAIDs
• H. pylori infection
• Dual antiplatelet therapy

H2-Receptor Antagonists: Limited Role

• H2RAs provide only modest protection and develop tachyphylaxis within 6 weeks 4
• Consider H2RAs only in lower-risk patients not meeting high-risk criteria 3
• Standard doses are insufficient; double-dose H2RAs may have some benefit but are not well-studied 1

Management of Aspirin-Related Ulcer Bleeding

Acute Phase Protocol 1, 2:

1. Endoscopic hemostasis immediately
2. High-dose IV PPI: 80 mg bolus followed by 8 mg/hour infusion for 72 hours 2
3. Restart aspirin within 5 days (for secondary prevention) 2
4. Transition to oral PPI (standard dose, once daily) for long-term maintenance 1

The Clopidogrel Alternative: A Failed Strategy

Switching from aspirin to clopidogrel to "protect the stomach" is contraindicated in patients with prior ulcer bleeding 1:

• Two RCTs definitively showed clopidogrel alone has higher rebleeding rates (8.6-13.6%) than aspirin + PPI (0-0.7%) 1
• The 2008 ACC/ACG/AHA guidelines explicitly recommend against this substitution 1
• Correct strategy: Aspirin + PPI, not clopidogrel monotherapy 1

Dual Antiplatelet Therapy Considerations

• In patients requiring aspirin + clopidogrel with prior bleeding, use aspirin + clopidogrel + PPI 1, 3
• Despite theoretical CYP2C19 interaction concerns, clinical trials show no adverse cardiovascular outcomes with PPI-clopidogrel co-administration 1, 3
• Do not withhold PPIs from patients on clopidogrel when clinically indicated 3

H. pylori Eradication

Test and eradicate H. pylori before starting chronic aspirin therapy in patients with ulcer history 1:

• H. pylori is an independent risk factor for ulcer bleeding in aspirin users (OR 4.7) 1
• Prior ulcer history confers even higher risk (OR 15.2) 1
• However, H. pylori eradication alone is insufficient protection - PPI co-therapy is still required in high-risk patients 1
• In aspirin users with prior bleeding, PPI therapy was equivalent to H. pylori eradication alone for preventing rebleeding, but combination is superior 1

Mortality Considerations

The mortality rate from NSAID/aspirin-induced upper GI bleeding is 5-10% among hospitalized patients 1. This substantial mortality risk must be weighed against:

• The 3-fold increased cardiovascular event risk from aspirin discontinuation 1
• The 8-fold increased mortality at 8 weeks when aspirin is stopped after ulcer bleeding (in secondary prevention patients) 1

In England and Wales, 900 of 10,000 annual ulcer bleeding episodes in persons aged ≥60 years are attributable to prophylactic aspirin use 1.

Practical Algorithm Summary

For patients with peptic ulcer disease and cardiovascular disease:

1. Determine aspirin indication: Secondary prevention (continue) vs. primary prevention (stop) 2
2. If continuing aspirin: Mandatory PPI co-therapy at standard once-daily dose 1, 3
3. Test and treat H. pylori if ulcer history present 1
4. Use lowest effective aspirin dose (75-81 mg daily) 1
5. If acute bleeding occurs: Endoscopy + high-dose IV PPI + restart aspirin within 5 days (secondary prevention) 1, 2
6. Never substitute clopidogrel alone for aspirin in patients with prior ulcer bleeding 1