Adding aspirin increased the risk of cardiovascular events, death and major bleeding in high-risk patients with chronic coronary syndrome (CCS) who had prior stenting and were receiving long-term chronic oral anticoagulation (OAC), according to late-breaking research presented in a Hot Line session at the ESC Congress 2025 and simultaneously published in New England Journal of Medicine.

Explaining the rationale of the AQUATIC trial, its Principal Investigator, Professor Martine Gilard from Hospital Cavale Blanche, Brest, France, said, “After stent implantation, many patients with CCS (stable coronary artery disease) are at high risk for future cardiovascular events due to conditions including diabetes, chronic kidney disease and diffuse multivessel disease, and some require long-term anticoagulation, particularly due to atrial fibrillation (AF).

“Managing the risk of further cardiovascular events in these patients is challenging and there is limited trial evidence to guide the optimal antithrombotic strategy. We designed the AQUATIC trial to formally test the efficacy and safety of adding aspirin to OAC, a combination that is commonly used for this high-risk population in clinical practice.”

This was a double-blind, placebo-controlled, parallel-group, randomized trial conducted at 51 centers in France. Eligible patients had CCS and stent implantation (>6 months before), were at high atherothrombotic risk and required long-term OAC for any reason (mainly AF).

High atherothrombotic risk was defined as either a history of percutaneous coronary intervention (PCI) during an acute coronary syndrome (ACS) (with ≥1 stent(s) >6 months) or history of PCI (>6 months) outside the context of ACS but with high-risk features such as diabetes, chronic kidney disease, diffuse multivessel disease (involvement of three coronary vessels), history of complex PCI or peripheral artery disease.

Patients were randomized 1:1 to aspirin or placebo on top of OAC (either a direct OAC or vitamin K antagonists). The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization and acute limb ischemia. The key secondary safety endpoint was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) definition.

The trial was stopped early on the advice of the independent Data Safety Monitoring Board after a median follow-up of 2.2 years due to an excess of all-cause mortality in the aspirin group. The 872 patients randomized had a mean age of 72 years and 14.5% were male.

The primary efficacy outcome occurred in significantly more patients in the aspirin group than the placebo group (16.9% vs. 12.1%; adjusted hazard ratio [HR] 1.53; 95% confidence interval [CI], 1.07 to 2.18; p=0.019). All-cause death also occurred in significantly more patients with aspirin vs. placebo (13.4% vs. 8.4%; adjusted HR 1.72; 95% CI, 1.14 to 2.58; p=0.010).

The risk of major bleeding was more than three-fold higher in the aspirin group than in the placebo group (10.2% vs. 3.4%; HR 3.35; 95% CI, 1.87 to 6.00; p<0.0001).

A total of 467 and 395 serious adverse events were reported in the aspirin and placebo groups, respectively.

In conclusion, Professor Gilard said, “Among patients with CCS at high atherothrombotic risk who require OAC therapy, aspirin significantly increased the risk of major cardiovascular events, all-cause mortality and major bleeding, and its use should be discouraged.

“Other studies have investigated antithrombotic therapy for stable coronary artery disease and AF, but this is the first randomized trial to include patients who had prior stenting and with high atherothrombotic risk − event rates were around seven times higher in AQUATIC than in previous trials.

“Our findings can now be considered in future ESC Guidelines to build on current recommendations, which are based on expert consensus.”