MADRID — Among patients with chronic coronary syndrome (stable coronary artery disease) at high atherothrombotic risk and taking an oral anticoagulant, the addition of aspirin led to a higher risk for major bleeding and all-cause death with no reduction in atherothrombotic events in the double-blind randomized AQUATIC trial.

“My take home message is that even in this very high-risk population, the risk of atherothrombotic events does not decrease when aspirin is added if patients are already taking an oral anticoagulant. And aspirin causes significant harm,” senior author of the trial, Martine Gilard, MD, Brest University, Brest, France, stated.

“Our results clearly show that patients taking an oral anticoagulant should not also receive aspirin for long-term treatment, even if they are at high thrombotic risk. I think it’s a very strong message and will change clinical practice.”

Gilard presented the AQUATIC trial on August 31 at European Society of Cardiology (ESC) Congress 2025. The results were also simultaneously published online in The New England Journal of Medicine.

Commenting on the results at an ESC press conference, Dan Atar, MD, Oslo University Hospital, Oslo, Norway, who was not involved in the trial, said: “For the last 10 years we have been progressively decreasing the use of antiplatelet agents in patients on oral anticoagulation. However, the trials have been focused on the acute phase after stenting. For the longer term we have less information. This is exactly where the AQUATIC trial is shedding light. These results are clear and will enter the guidelines. I’m pretty confident about that.”

Aspirin Causing 30,000-50,000 Deaths Annually

Discussing the trial at the ESC Hotline session, Renato Lopes, MD, Duke University, Durham, North Carolina, calculated that the number needed to harm by using aspirin in this population was 46.

“That is one additional death for every 46 patients treated with aspirin. That translates to 30,000-50,000 deaths caused by aspirin annually in patients with coronary artery disease and on an oral anticoagulant,” he said.

“This trial really illustrates very well why we do randomized trials — in this case to find the antithrombotic sweet spot, and in this population, it means stopping aspirin and continuing with the oral anticoagulant alone,” he added.

Trial Stopped Due to Excess Deaths

In her presentation, Gilard explained that in patients with chronic coronary syndrome long-term single antiplatelet therapy is used to prevent recurrent atherothrombotic events. Approximately 15% of these patients also receive long-term anticoagulation therapy for conditions such as atrial fibrillation.

Several previous trials have shown a higher bleeding risk when patients take a full-dose oral anticoagulant and a single antiplatelet agent than with an oral anticoagulant alone. However, these trials were open-label, included low-risk populations in which not all patients had undergone stenting, and individually, did not show a potential benefit of the combination on atherothrombotic events.

Therefore, the appropriate antithrombotic regimen for patients with chronic coronary syndrome who are receiving long-term oral anticoagulants remains unclear, particularly for those with previous stent implantation in whom antiplatelet therapy may be critical to minimize the risk for stent thrombosis, as well as those at high atherothrombotic risk.

The double-blind AQUATIC trial, conducted at 51 centers in France, included patients with chronic coronary syndrome who had undergone a previous stent implantation (more than 6 months previously) and were at high atherothrombotic risk, and were currently receiving long-term oral anticoagulation.

They were randomized to receive aspirin (100 mg once daily) or placebo, with all patients continuing to receive their current oral anticoagulation therapy.

The trial was stopped early at the advice of the independent data and safety monitoring board after a median follow-up of 2.2 years because of an excess of deaths from any cause in the aspirin group. At this time, 872 patients had been enrolled.

Results showed that a primary efficacy outcome event (a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia), had occurred in 16.9% of the aspirin group and in 12.1% in the placebo group (adjusted hazard ratio [AHR], 1.53; 95% CI, 1.07-2.18; P = .02).

Death from any cause occurred in 13.4% in the aspirin group and in 8.4% in the placebo group (AHR, 1.72; 95% CI, 1.14-2.58; P = .01).

Major bleeding occurred in 10.2% in the aspirin group and in 3.4% in the placebo group (AHR, 3.35; 95% CI, 1.87-6.00; P < .001).

“This is the first double-blind trial to address the issue of long term-antiplatelet therapy in patients with chronic coronary syndrome who are taking oral anticoagulation. Results show no benefit and clear harm of adding aspirin. The result is consistent with other recent trials in this field, but this trial moves the field on in that it has a double-blind design and enrolled patients at higher risk of antithrombotic events,” Gilard concluded.

She noted that the AQUATIC patients had a sevenfold higher thrombotic risk than patients in the previous studies, with all patients having received a stent.

‘A Lifelong Issue Affecting Millions’

In his discussion, Lopes explained that patients with atrial fibrillation, who are on anticoagulation, and undergo percutaneous coronary intervention (PCI), are very common in clinical practice.

“These patients are at very high risk for both bleeding and ischemic events. And treating these patients in clinical practice is challenging because we need to think about whether to combine antiplatelet therapy with oral anticoagulants. But by doing this we increase significantly the risk of major bleeding.”

He noted that the AUGUSTUS trial showed that in this patient group dropping aspirin a few days after the PCI and continuing only with the oral anticoagulant (apixaban) and a single P2Y12 inhibitor antiplatelet agent led to better outcomes when compared with patients where aspirin was continued.

“But what about longer term treatment of these patients? What do we do after 6 months or 1 year? This is a true lifelong issue that has not been fully addressed and affects millions of people.”

Lopes noted that there have been four randomized trials performed in Asia, suggesting that stopping antiplatelet therapy (aspirin) completely in this population is associated with less bleeding without increasing ischemic events.

“But AQUATIC is the first double-blind study in this field, and it is a very important and well-done study, which confirms and expands the findings from the trials in Asian populations to the European population.”

Lopes said the bleeding results were expected. “Stopping aspirin will cause less bleeding. We know that.”

But he pointed out that the increase in cardiovascular events in the aspirin group is counterintuitive and difficult to understand. “Why would aspirin be causing more cardiovascular events?”

Gilard responded that there was no difference in actual atherothrombotic events between the two groups, with the difference in the efficacy composite endpoint driven entirely by cardiovascular death.

“I suggest that this is a secondary impact of the increased bleeding with aspirin. Because there is an increase in major bleeding, physicians may have modified the treatment in some way, which caused an increase in cardiovascular death,” she commented.

The AQUATIC trial was an investigator-initiated study and was funded by a grant from the French Ministry of Health and by an unrestricted grant from Bayer Healthcare. Gilard reported no disclosures.