Should the dose of aspirin (acetylsalicylic acid) be decreased when used in combination with P2Y12 inhibitors (e.g. clopidogrel, prasugrel, ticagrelor)?

Aspirin Dosing in Dual Antiplatelet Therapy with P2Y12 Inhibitors

When using aspirin in combination with P2Y12 inhibitors, a low-dose aspirin regimen of 75-100 mg daily is recommended to minimize bleeding risk while maintaining antithrombotic efficacy. 1

Evidence-Based Rationale

Optimal Aspirin Dosing

• The 2016 ACC/AHA guidelines provide a Class I, Level B-NR recommendation for using a daily aspirin dose of 81 mg (range 75-100 mg) when combined with P2Y12 inhibitors 1
• This recommendation is consistent across all clinical scenarios requiring dual antiplatelet therapy (DAPT), including:
  • Patients with acute coronary syndrome (ACS)
  • Patients undergoing percutaneous coronary intervention (PCI)
  • Patients treated with medical therapy alone

Pharmacological Basis

• Large overviews including nearly 200,000 patients have consistently demonstrated that lower aspirin doses (≤100 mg daily) are associated with:
  • Less major bleeding
  • Less total bleeding
  • Comparable ischemic event rates compared to higher doses 1
• Daily aspirin doses as low as 30-50 mg effectively inactivate platelet cyclo-oxygenase-1 enzyme and inhibit thromboxane production 1

P2Y12 Inhibitor Considerations

• The efficacy of ticagrelor appears to be decreased when combined with higher aspirin doses (≥300 mg daily) versus lower doses (≤100 mg daily) 1
• The European Society of Cardiology specifically recommends a low dose of aspirin (75-100 mg daily) when used with P2Y12 inhibitors 1, 2

Clinical Application

For ACS Patients

• For patients with ACS treated with DAPT, maintain aspirin at 81 mg daily (range 75-100 mg) regardless of which P2Y12 inhibitor is used 1
• When using ticagrelor specifically, the recommended maintenance dose of aspirin is 81 mg daily 1

For PCI Patients

• After PCI, it is reasonable to use 81 mg daily of aspirin in preference to higher maintenance doses (Class IIa recommendation) 1
• This applies to both drug-eluting stent (DES) and bare-metal stent (BMS) implantation 1

Potential Pitfalls and Caveats

Bleeding Risk

• Higher aspirin doses (≥160 mg) are associated with increased bleeding risk without improved outcomes 1
• Enteric-coated aspirin should be avoided initially due to delayed and reduced absorption 1

Special Considerations

• A recent study suggests that very-low-dose twice-daily aspirin (20 mg twice daily) with ticagrelor may provide consistent platelet inhibition with improved post-dose hemostasis compared to standard once-daily dosing 3, though this requires further investigation and is not yet recommended in guidelines
• When using proton pump inhibitors (PPIs) to reduce gastrointestinal bleeding risk with DAPT, the low-dose aspirin recommendation remains unchanged 1

In conclusion, when using dual antiplatelet therapy with aspirin and any P2Y12 inhibitor, the optimal aspirin dose that balances antithrombotic efficacy and bleeding risk is 75-100 mg daily (81 mg in the US). Higher doses of aspirin do not provide additional ischemic protection but do increase bleeding risk.