Overview

Stented chronic coronary syndrome (CCS) patients, who require long-term oral anticoagulation (OAC), have always proved difficult to treat for antithrombotics. Recent information, however, suggests that a long-standing “safe” addition—of aspirin—could potentially increase risk among this patient population. An overview of the evidence, simply put, follows.

The AQUATIC Trial: Pivotal New Evidence

In August 2025, AQUATIC trial was disclosed at ESC Congress and published simultaneously in the New England Journal of Medicine. It investigated whether aspirin on top of OAC (vs placebo and OAC) improved outcomes in CCS patients with previous stenting and other risk factors. It was stopped early on safety grounds.

•Cardiovascular events (MI, stroke, systemic embolism, death, revascularization, limb ischemia) were more common in the aspirin group: 16.9% vs. 12.1%. Hazard ratio: 1.53 (95% CI: 1.07–2.18; p = 0.019).

•Increased all-cause mortality: 13.4% vs. 8.4%, HR: 1.72 (95% CI: 1.14–2.58; p = 0.010).

•Major bleeding was more than threefold higher: 10.2% vs. 3.4%, HR: 3.35 (95% CI: 1.87–6.00; p < 0.0001).

Bottom line: In high atherothrombotic-risk CCS patients requiring OAC, aspirin on top of anticoagulation increased both cardiovascular outcomes and serious bleeding, and mortality. The trial authors discourage the routine use of aspirin in these circumstances .

What Does Earlier Research Reveal?

Although AQUATIC is the first RCT to compare head-to-head high-risk CCS patients on long-term OAC with aspirin, earlier analysis offers useful context:

• A meta-analysis of 10 RCTs (4,180 patients) compared aspirin + OAC with OAC alone. It found fewer arterial thromboembolic events when adding aspirin (OR 0.66) but not reduced mortality. Risk of major bleeding actually increased (OR 1.43)—albeit largely in patients with mechanical heart valves.

•Earlier network meta-analyses of CCS patients (after PCI) indicate that stroke, major bleeding, and MACE are reduced with monotherapy clopidogrel versus aspirin, and dual-pathway inhibition (for example, aspirin + low-dose rivaroxaban) increases efficacy but heightens the risk of bleeding.

The earlier research has established that while the combination of antithrombotic therapy may be preventing the clot, it is often at the expense of increased bleeding—especially in the case of adding aspirin.

Why Is Aspirin Adverse in This Particular Context?

1. Additive Bleeding Hazard

Risk is cumulative when combining OAC with aspirin—especially in older or high-risk patients.

2. No Demonstrated Additional Benefit

Rather than additive protection, AQUATIC revealed worse cardiovascular events and increased mortality with added aspirin.

3. Patient Complexity

High-risk CCS patients tend to have comorbidities such as diabetes, chronic kidney disease, and multivessel disease—and are thus more susceptible to both ischemic and bleeding complications  .

Clinical Takeaway for Physicians and Patients

•In high-risk patients with CCS on long-term OAC (e.g., for AF), aspirin addition is now to be avoided on the basis of modern RCT evidence.

•Individualize therapy, balancing ischemic and bleeding risks. Consider the following alternatives:

•OAC monotherapy

•P2Y₁₂ inhibitor monotherapy (e.g., clopidogrel)

•Dual-pathway inhibition (limited to selected cases and in close monitoring).

•Guidelines may need to be updated soon, since AQUATIC presents the first direct RCT evidence in this scenario.

Final Thoughts

The AQUATIC trial represents a paradigm shift in the perception of antithrombotic strategy: what was the norm may now hurt those who are most at risk. In high-risk CCS patients on oral anticoagulants, aspirin is no longer an innocent add-on—it seems to cause more harm than benefit.