What are the risks and management strategies for a patient with depression or anxiety taking a Selective Serotonin Reuptake Inhibitor (SSRI) who also requires aspirin for cardiovascular protection, given the potential increased risk of bleeding?

SSRI with Aspirin: Bleeding Risk and Management

The combination of SSRIs with aspirin increases gastrointestinal bleeding risk approximately 4-fold compared to aspirin alone, but this combination should generally be continued when both medications are clinically indicated, with mandatory proton pump inhibitor (PPI) co-prescription for all patients. 1, 2

Magnitude of Bleeding Risk

The bleeding risk with SSRIs and aspirin is quantifiable and clinically significant:

• SSRIs alone increase upper GI bleeding risk with an odds ratio of 1.66 (95% CI 1.44-1.92), translating to a number needed to harm of 3,177 in low-risk populations and 881 in high-risk populations 2
• Aspirin alone carries a GI bleeding risk of 0.49% for intracranial bleeding and 2.66% for gastrointestinal bleeding 3
• The combination of SSRI plus aspirin increases upper GI bleeding risk 4.25-fold (OR 4.25,95% CI 2.82-6.42) compared to no treatment 2
• Low-dose aspirin (75-325 mg) increases major extracranial bleeding with odds ratios of 1.4-1.5 3

Mandatory Risk Mitigation Strategy

All patients requiring both SSRI and aspirin must receive concomitant PPI therapy. 1 This is a Class I recommendation based on multiple guideline sources:

• PPIs reduce upper GI bleeding risk when combined with antiplatelet therapy 4
• European Society of Cardiology specifically recommends PPI use in patients at increased risk for GI bleeding who are taking antiplatelets 1
• For patients ≥75 years or with history of GI bleeding, concurrent use of anticoagulants, antiplatelets, SSRIs or glucocorticoids, concomitant treatment with misoprostol or a PPI is recommended 1

High-Risk Patient Identification

Certain patient characteristics dramatically amplify bleeding risk and require heightened vigilance:

• Age ≥75 years represents a critical threshold for increased GI bleeding risk 3, 1
• History of GI bleeding or peptic ulcer disease places patients at high risk 3, 1
• Concurrent use of NSAIDs with SSRI plus aspirin creates unacceptable cumulative bleeding risk and should be avoided 1, 5
• Patients with cirrhosis or liver failure have substantially increased bleeding risk with SSRIs 6

SSRI Selection Algorithm

When prescribing SSRIs to patients on aspirin, avoid paroxetine and sertraline due to higher bleeding risk trends. 1 Consider the following hierarchy:

• First-line: Bupropion shows decreased bleeding risk compared to SSRIs and represents the safest alternative for patients at high bleeding risk 1
• Second-line: Citalopram or escitalopram have minimal CYP450 interactions and moderate bleeding profiles 7, 8
• Avoid: Paroxetine and sertraline trend toward higher bleeding risk among SSRIs 1
• Alternative: Mirtazapine has minimal CYP450 interactions and no significant platelet effects 7

Aspirin Dosing Considerations

Use the lowest effective aspirin dose (75-100 mg daily) to minimize bleeding risk while maintaining cardiovascular protection. 3

• Aspirin 75-150 mg daily provides 32% reduction in vascular events with lower bleeding risk than higher doses 3
• Aspirin 160-325 mg daily provides only 26% reduction in vascular events but with similar bleeding odds ratios (1.4-1.5) 3
• The ADAPTABLE trial showed no difference in cardiovascular events or major bleeding between 81 mg and 325 mg aspirin in patients with established cardiovascular disease 3
• In the ASCEND trial, aspirin 100 mg daily increased major bleeding from 3.2% to 4.1% (rate ratio 1.29) in diabetic patients 3

Monitoring Protocol

Monitor patients most closely during the first month of SSRI initiation, as bleeding risk peaks during this period. 1

• Educate patients about bleeding warning signs: melena, hematemesis, unusual bruising, prolonged bleeding from minor cuts 5
• Review medication list at each visit to identify new NSAIDs, anticoagulants, or other bleeding risk medications 1
• Assess for new GI symptoms (dyspepsia, abdominal pain) that may herald ulcer development 6

Critical Drug Combinations to Avoid

Never combine SSRI plus aspirin with NSAIDs, as this creates a triple threat for bleeding through additive mechanisms. 1, 5

• NSAIDs combined with SSRIs increase bleeding risk substantially beyond either agent alone 5, 2, 4
• The FDA label for fluoxetine explicitly warns that concomitant use of aspirin, NSAIDs, warfarin, and other anticoagulants may add to bleeding risk 5
• If triple therapy (SSRI + aspirin + anticoagulant) is unavoidable, PPI co-prescription is absolutely mandatory 1

Clinical Decision Framework

When both SSRI and aspirin are indicated:

1. Confirm cardiovascular indication for aspirin (secondary prevention has stronger evidence than primary prevention) 3
2. Prescribe PPI prophylaxis universally for all patients on this combination 1
3. Use lowest effective aspirin dose (75-100 mg daily) 3
4. Select bupropion as first-line antidepressant if clinically appropriate 1
5. If SSRI required, choose citalopram or escitalopram over paroxetine or sertraline 1, 7
6. Eliminate all NSAIDs from the medication regimen 1, 5
7. Intensify monitoring in patients ≥75 years or with prior GI bleeding 3, 1

Absolute vs. Relative Risk Perspective

The absolute increase in bleeding risk, while statistically significant, must be weighed against the cardiovascular benefits of aspirin in appropriate patients. 3

• In the ASCEND trial, aspirin prevented 8.5% vs 9.6% vascular events (12% relative risk reduction) but increased major bleeding from 3.2% to 4.1% 3
• For adults with ASCVD risk >1% per year, the number of events prevented approximates the number of bleeding episodes induced 3
• The combination should not be abandoned solely due to bleeding risk when both medications have clear indications 3