What are the consequences of long-term daily use of 325 mg of aspirin (acetylsalicylic acid) in a patient with a history of cardiovascular disease?

Long-Term Consequences of 325 mg Daily Aspirin in Cardiovascular Disease

For patients with established cardiovascular disease, 325 mg daily aspirin provides no additional cardiovascular benefit compared to 75-100 mg daily but significantly increases gastrointestinal bleeding risk, making the lower dose strongly preferred for long-term maintenance therapy. 1, 2, 3

Cardiovascular Efficacy: No Benefit from Higher Doses

• The ADAPTABLE trial (2021) definitively demonstrated that 325 mg daily aspirin provides no superior protection against death, myocardial infarction, or stroke compared to 81 mg daily in 15,076 patients with established cardiovascular disease followed for median 26.2 months. 4

• Current ACC/AHA guidelines (2025) explicitly recommend 75-100 mg daily as the maintenance dose after acute coronary syndromes, noting that higher doses do not reduce major adverse cardiac events. 1

• Meta-analyses of secondary prevention trials show that aspirin doses from 75 mg to over 1500 mg daily provide equivalent 25% reduction in serious vascular events, with no dose-response relationship for efficacy. 5, 3, 6

Bleeding Complications: Clear Dose-Dependent Harm

Gastrointestinal bleeding and other hemorrhagic complications increase significantly with 325 mg compared to 75-100 mg daily, without any offsetting cardiovascular benefit. 3, 7

• Systematic reviews demonstrate that aspirin doses above 75-81 mg are associated with increased incidence of bleeding events, primarily gastrointestinal tract toxicity, while providing no enhanced efficacy. 3

• The dose-dependent nature of gastrointestinal side effects is well-established, with higher doses causing proportionally more GI symptoms and major bleeding. 2, 7

• In the ADAPTABLE trial, while major bleeding rates were numerically similar between groups (0.63% vs 0.60%), the study was underpowered for bleeding outcomes and showed high crossover rates (41.6% of patients assigned to 325 mg switched to lower doses). 4

Current Guideline Recommendations

All major cardiovascular societies now recommend 75-100 mg (or 81 mg in the US) as the preferred maintenance dose for long-term secondary prevention. 1, 2, 8

• The 2025 ACC/AHA guidelines for acute coronary syndromes specify 75-100 mg daily maintenance dosing after the initial loading dose period. 1

• The 2011 ACC/AHA secondary prevention guidelines recommend aspirin 75-162 mg daily for all patients with coronary artery disease, with preference for the lower end of this range. 1

• After percutaneous coronary intervention, it is reasonable to use 81 mg per day in preference to higher maintenance doses. 1

Specific Clinical Algorithm

For patients currently taking 325 mg daily aspirin for cardiovascular disease:

1. Reduce to 75-100 mg (81 mg in US formulations) daily for maintenance therapy - this provides equivalent cardiovascular protection with lower bleeding risk. 1, 2, 3

2. Continue indefinitely - aspirin should never be discontinued without clear contraindication, as withdrawal increases risk of recurrent acute coronary syndrome events. 1, 8

3. Consider proton pump inhibitor co-therapy if the patient has history of gastrointestinal bleeding or multiple bleeding risk factors (age >65, concurrent anticoagulation, NSAID use, H. pylori infection). 8

4. Reserve 325 mg dosing only for acute loading (162-325 mg non-enteric coated, chewed) during acute coronary syndromes, followed by dose reduction to 75-100 mg within 24-30 days. 1, 2

Common Pitfalls to Avoid

• Do not continue 325 mg long-term based on outdated practice patterns - 96% of patients in ADAPTABLE were already on aspirin before enrollment, and 85.3% were taking 81 mg, reflecting contemporary evidence-based practice. 4

• Avoid concurrent ibuprofen use - NSAIDs can interfere with aspirin's antiplatelet effects and compound bleeding risk. 8

• Do not use enteric-coated formulations for acute situations - non-enteric coated aspirin should be chewed for rapid buccal absorption during acute events. 1, 2

• Never extend aspirin interruption beyond 48 hours perioperatively in patients with ischemic heart disease, as cardiovascular risk becomes unacceptable. 9

Long-Term Consequences Summary

Continuing 325 mg daily aspirin long-term results in:

• No additional cardiovascular event reduction compared to 75-100 mg 4
• Increased gastrointestinal bleeding and hemorrhagic complications 3, 7
• Higher rates of dose discontinuation due to side effects 4
• Unnecessary exposure to bleeding risk without clinical benefit 2, 3

The evidence overwhelmingly supports dose reduction to 75-100 mg daily for all patients with cardiovascular disease requiring long-term aspirin therapy.