What are the potential adverse effects of chronic aspirin (acetylsalicylic acid) use, especially in older adults or patients with a history of asthma, nasal polyps, or impaired renal function?

Adverse Effects of Chronic Aspirin Use

Yes, chronic aspirin use carries significant risks including gastrointestinal bleeding (HR 1.31), intracranial hemorrhage (OR 1.31), acute renal injury in predisposed patients, acute interstitial nephritis, and aspirin-exacerbated respiratory disease particularly in patients with asthma and nasal polyps—with these risks being dose-dependent and increasing substantially with age, especially in patients over 60 years. 1, 2

Gastrointestinal Bleeding Risk

The most common and clinically significant adverse effect is major gastrointestinal bleeding:

• Meta-analysis of 35 RCTs demonstrates a hazard ratio of 1.31 (95% CI 1.21-1.42) for major GI bleeding with aspirin doses of 75-325 mg daily 1
• This translates to 1-2 GI bleeding events per 1,000 person-years in average-risk individuals 1
• Risk is dose-dependent: bleeding hazards are higher with 300-325 mg compared to 75-162.5 mg doses 1
• Critical temporal pattern: Major extracranial bleeding occurs primarily in the short term (<3 years) following aspirin initiation, with likelihood increasing with age 1
• After 3 years of use, low-dose (<300 mg) aspirin is not significantly associated with major bleeding events 1

High-risk features for GI bleeding include: 1, 2

• Age ≥60 years
• History of stomach ulcers or bleeding problems
• Concurrent anticoagulant or steroid use
• Concurrent use of other NSAIDs
• ≥3 alcoholic drinks daily
• Male sex, smoking, diabetes, hypertension, lower body weight

Intracranial and Systemic Bleeding

Even low-dose aspirin (81 mg) used for primary prevention increases bleeding risk across multiple sites: 1

• Total major bleeding: OR 1.44 (95% CI 1.32-1.57)
• Extracranial bleeding: OR 1.53 (95% CI 1.39-1.70)
• Major GI bleeding: OR 1.58 (95% CI 1.38-1.80)
• Intracranial bleeding: OR 1.31 (95% CI 1.11-1.54)

Higher doses used for aspirin-exacerbated respiratory disease (650-1300 mg daily) carry substantially greater bleeding risk than cardioprotective doses 1

Aspirin-Exacerbated Respiratory Disease (AERD)

Aspirin causes severe respiratory reactions in patients with the classic triad of asthma, chronic rhinosinusitis with nasal polyps, and NSAID sensitivity: 1, 3, 4

• Prevalence: 0.07% in general population, 7-21% in adults with asthma 1, 4
• Highest risk patients: Those with asthma plus nasal polyps or recurrent sinusitis 1, 3, 4
• This is NOT a true IgE-mediated allergy but a pseudoallergic reaction from COX-1 inhibition that shunts arachidonic acid metabolism toward the leukotriene pathway 1, 3, 4

Clinical manifestations include: 3, 4

• Sudden and severe bronchoconstriction
• Severe asthma exacerbation
• Profuse rhinorrhea
• Anosmia (loss of smell)

Cross-reactivity pattern: 3, 4, 5

• High cross-reactivity with all COX-1 inhibiting NSAIDs
• Low cross-reactivity with selective COX-2 inhibitors (8-11% reaction rate)
• Acetaminophen ≤1000 mg is the safest alternative

Renal Toxicity

Aspirin can cause acute renal injury in predisposed populations, though chronic therapeutic doses rarely cause end-stage renal disease in healthy adults: 6

• High-risk populations for acute renal failure: Patients with glomerulonephritis, cirrhosis, chronic renal insufficiency, and children with congestive heart failure 6
• Short-term therapeutic doses have no effect on creatinine clearance in healthy adults 6
• Acute aspirin intoxication (>300 mg/kg) frequently causes acute renal failure 6
• Acute interstitial nephritis can occur but is less common than acute tubular injury 6

Case-control and prospective studies have failed to identify significant risk of chronic renal failure with aspirin alone in therapeutic doses, with one exception showing only low statistical risk 6

Allergic Reactions

True allergic reactions (distinct from AERD) can occur: 2

• Hives
• Facial swelling (angioedema)
• Asthma (wheezing)
• Anaphylactic shock

These represent IgE-mediated or other immunologic mechanisms separate from the COX-1 inhibition pathway seen in AERD 1, 3

Central Nervous System Effects

Rare but more common in older adults: 1

• Tinnitus (reversible, may indicate high blood levels)
• Psychosis and cognitive changes (most often with indomethacin, but can occur with aspirin)
• Confusion, depression, dizziness, somnolence
• Aseptic meningitis (more common in lupus patients)

Risk Mitigation Strategies

When aspirin is medically necessary despite risks: 1

• Initiate GI prophylaxis in high-risk patients
• Monitor INR closely if combined with anticoagulants (can increase INR by up to 15%)
• Anticipate 3-6 fold increased GI bleeding risk when combined with anticoagulants
• Use lowest effective dose (75-162.5 mg for cardiovascular indications)
• Consider discontinuation in patients >70 years for primary prevention where bleeding risk exceeds cardiovascular benefit 1

For patients with asthma/nasal polyps requiring aspirin: 1, 3, 4

• Formal aspirin challenge testing to confirm AERD diagnosis (80-100% probability with typical history)
• Aspirin desensitization protocols available for selected cases requiring long-term therapy
• Daily continuous aspirin required to maintain desensitized state
• Alternative: selective COX-2 inhibitors or acetaminophen ≤1000 mg

Common Pitfalls to Avoid

• Do not assume all asthmatics are aspirin-intolerant—only 7-21% have AERD 1, 4
• Do not rely on skin testing or IgE testing for AERD diagnosis—these are not useful 3, 4
• Do not overlook temporal bleeding patterns—highest risk is in first 3 years of therapy 1
• Do not ignore age as a critical risk factor—bleeding risk increases substantially after age 60 1, 2
• Do not combine aspirin with anticoagulants without GI prophylaxis in high-risk patients 1