The addition of aspirin to the treatment of high-risk patients with chronic coronary syndrome who had prior stenting and were receiving long-term oral anticoagulation increased the risk of cardiovascular events, deaths and major bleeding, a randomised trial has found.
The findings of the AQUATIC trial were presented at the European Society of Cardiology (ESC) Congress 2025 and simultaneously published in the New England Journal of Medicine.
Antithrombotic management in patients with chronic coronary syndrome and previous stent implantation who require long-term oral anticoagulation is challenging. This is particularly true in those at high risk of cardiovascular events due to conditions such as diabetes, chronic kidney disease and diffuse multivessel disease.
Principal investigator, Professor Martine Gilard, former director of the interventional cardiology department at Brest University Hospital in France, said: ‘Managing the risk of further cardiovascular events in these patients is challenging and there is limited trial evidence to guide the optimal antithrombotic strategy.’
While adding aspirin to oral anticoagulation is common in clinical practice for this high-risk population, the AQUATIC trial aimed to formally test the efficacy and safety of doing so.
Aspirin and oral anticoagulation
This double-blind, placebo-controlled, parallel-group, randomised trial was conducted at 51 centres in France.
Eligible patients had chronic coronary syndrome and stent implantation more than six months prior, were at high atherothrombotic risk and required long-term oral anticoagulation for any reason but mainly atrial fibrillation.
High atherothrombotic risk was defined as either a history of percutaneous coronary intervention (PCI) during an acute coronary syndrome (with ≥1 stent(s) >6 months) or history of PCI (>6 months) outside the context of acute coronary syndrome, but with high-risk features. For example, diabetes, chronic kidney disease, diffuse multivessel disease, history of complex PCI or peripheral artery disease.
Patients were randomly assigned in a 1:1 ratio to receive 100mg aspirin once daily or placebo. All patients continued to receive their current oral anticoagulation therapy during the trial.
The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularisation or acute limb ischaemia. The key secondary safety endpoint was major bleeding according to the International Society on Thrombosis and Haemostasis definition.
Excess of all-cause mortality
A total of 872 patients were randomised, with 433 assigned to the aspirin group and 439 to the placebo group. Patients had a mean age of 72 years and 14.5% were male.
The primary efficacy outcome event occurred in 73 patients (16.9%) in the aspirin group and 53 patients (12.1%) in the placebo group (adjusted hazard ratio 1.53; 95% confidence interval [CI], 1.07 to 2.18; p=0.019).
All-cause death also occurred in significantly more patients in the aspirin group than the placebo group (13.4% vs 8.4%; adjusted HR 1.72; 95% CI 1.14 to 2.58; p=0.010).
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 risk of major bleeding was more than three-fold higher in the aspirin group (n=44/10.2%) than the placebo group (n=15/3.4%); (HR 3.35; 95% CI 1.87 to 6.00; p<0.001).
A total of 467 and 395 serious adverse events were reported in the aspirin and placebo groups, respectively.
Discourage aspirin use
‘Among patients with chronic coronary syndrome at high atherothrombotic risk who require oral anticoagulation therapy, aspirin significantly increased the risk of major cardiovascular events, all-cause mortality and major bleeding, and its use should be discouraged,’ Professor Gilard said.
‘Other studies have investigated antithrombotic therapy for stable coronary artery disease and atrial fibrillation, but this is the first randomised 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.’
She added that these findings should be ‘considered in future ESC Guidelines to build on current recommendations, which are based on expert consensus’.
Other research presented at the ESC Congress 2025 found that early aspirin discontinuation and transition to a P2Y12 inhibitor monotherapy may lower bleeding risk in those at low ischaemic risk after myocardial infarction.
This article was originally published by our sister publication Hospital Healthcare Europe.
