Which is safest with aspirin (acetylsalicylic acid), sertraline or Lexapro (escitalopram)?

Escitalopram (Lexapro) is Safer with Aspirin than Sertraline

When combining an SSRI with aspirin, escitalopram (Lexapro) appears to be the safer choice compared to sertraline, based on bleeding risk data showing lower excess bleeding risk with escitalopram-aspirin combinations.

Bleeding Risk Evidence

The most relevant evidence comes from a large case series analysis examining drug combinations and upper gastrointestinal bleeding (UGIB) risk:

• Sertraline with aspirin produces an excess bleeding risk (RERI) of 0.5 when combining SSRIs with low-dose aspirin 1
• The combination of any SSRI with low-dose aspirin significantly increases UGIB risk, though the magnitude varies by specific agent 1
• Aspirin monotherapy increases UGIB risk approximately 3-fold (IRR 3.1) 1

FDA Labeling Warnings

Both medications carry FDA warnings about bleeding risk when combined with aspirin, but the language differs slightly:

Lexapro (Escitalopram)

• FDA labeling explicitly warns: "Taking Lexapro with aspirin, NSAIDs, warfarin, or other blood thinners may add to this risk" of bleeding 2
• Advises patients to "tell your healthcare provider if you have any unusual bleeding or bruising" 2

Sertraline

• FDA labeling lists "medicines used to thin your blood such as warfarin" and "aspirin or other NSAIDs" as important drug interactions 3
• Warns about potential interactions but with less specific bleeding risk emphasis compared to escitalopram 3

Clinical Context from Aspirin Guidelines

Understanding aspirin's baseline bleeding risk is essential:

• Low-dose aspirin (≤100 mg daily) increases major GI bleeding by 58% (OR 1.58) and hemorrhagic stroke by 27% (OR 1.27) 4
• Estimated excess major bleeding events are 1.39 per 1000 person-years for GI bleeding 4
• Bleeding risk increases with age, male sex, and presence of cardiovascular risk factors 4

Practical Recommendations

When aspirin is medically necessary:

• Choose escitalopram over sertraline when initiating SSRI therapy in patients already taking aspirin 1
• Start with the lowest effective SSRI dose and monitor closely for bleeding signs 2, 3
• Educate patients about bleeding warning signs: unusual bruising, black/tarry stools, blood in urine, prolonged bleeding from cuts 2, 3

Risk mitigation strategies:

• Consider proton pump inhibitor co-therapy to reduce GI bleeding risk, particularly in patients with additional risk factors 5
• Avoid additional bleeding risk factors: NSAIDs, anticoagulants, corticosteroids 1
• Monitor more closely in elderly patients (≥65 years) who have higher baseline bleeding risk 4

Important Caveats

Serotonin syndrome risk is equivalent between both agents when combined with aspirin, as aspirin does not have serotonergic properties 2, 3. The primary differentiating factor is bleeding risk.

Individual patient factors matter:

• Patients with history of GI bleeding, peptic ulcer disease, or bleeding disorders require particularly careful consideration 5, 6
• Those taking anticoagulants face substantially higher bleeding risk (RERI 1.9 for aspirin plus anticoagulants) 1
• Renal or hepatic impairment may alter drug metabolism and bleeding risk 2, 3

The combination is not contraindicated - both SSRIs can be used with aspirin when clinically indicated, but escitalopram demonstrates a more favorable safety profile based on available bleeding risk data 1.