Study Title: The AQUATIC Trial (Assessment of Quitting versus Using Aspirin Therapy in Patients with Stabilized Coronary Artery Disease after Stenting Who Require Long-Term Oral Anticoagulation)

Congress Presented: ESC Congress 2025, Madrid

Link: https://esc365.escardio.org/presentation/312197

Prepared by: Dr. Hakan Çağlıoğlu, Dr. Mustafa Yenerçağ

Introduction:
A proportion of patients with chronic coronary syndrome (CCS) receive oral anticoagulant (OAC) therapy in addition to antiplatelet treatment. Previous studies have demonstrated that the combination of OACs with single antiplatelet agents confers a higher risk of bleeding compared with OAC therapy alone. However, these studies did not include high-risk populations or those with coronary stents. Therefore, the optimal antithrombotic regimen for CCS patients requiring long-term OAC therapy remains uncertain. Observational data suggest that the combination of OACs with single antiplatelet therapy continues to be frequently used in clinical practice.

Objective:
The AQUATIC trial aimed to evaluate the efficacy and safety of adding aspirin (100 mg daily) to long-term oral anticoagulation compared with oral anticoagulation alone in CCS patients with high atherothrombotic risk who had undergone stent implantation ?6 months prior.

Methods:
AQUATIC was a prospective, double-blind, randomized, placebo-controlled trial conducted at 51 centers in France. Participants: Adults (?18 years) with documented CCS, prior coronary stent implantation ?6 months earlier, high residual atherothrombotic risk, and on OAC therapy (direct oral anticoagulant or vitamin K antagonist).

High residual atherothrombotic risk was defined as: stent implantation during an acute coronary syndrome (ACS) ? 6 months earlier, or PCI performed ? 6 months earlier for non-ACS indications, plus at least one of the following: diabetes mellitus, diffuse three-vessel disease, chronic kidney disease (creatinine clearance <50 ml/min), history of stent thrombosis, peripheral artery disease, or history of complex PCI.
Randomization: Patients were randomized 1:1 to receive OAC plus aspirin (100 mg/day) or OAC plus placebo. Follow-up visits were performed every 6 months for 24–48 months.
Primary efficacy endpoint: Composite of cardiovascular death, myocardial infarction (MI), stroke, systemic embolism, coronary revascularization, or acute limb ischemia.
Secondary efficacy endpoints: Net adverse clinical events (atherothrombotic cardiovascular events or major bleeding).
Primary safety endpoint: Major bleeding.

Results:
A total of 872 CCS patients were enrolled: 433 were randomized to the aspirin group (OAC + aspirin 100 mg/day) and 439 to the placebo group (OAC + placebo). All patients had undergone prior PCI. The mean age was 71.7 years, 85.3% were male, and 72.1% had a history of MI. The indication for OAC therapy was atrial fibrillation in 89% of patients.
Primary endpoint: Occurred in 73 patients (16.9%) in the aspirin group vs. 53 (12.1%) in the placebo group (adjusted HR 1.53; 95% CI 1.07–2.18; p=0.02).
Net adverse clinical events: 124 (28.6%) in the aspirin group vs. 76 (17.3%) in the placebo group (HR 1.85; 95% CI 1.39–2.46; p<0.001).
All-cause mortality: 58 (13.4%) in the aspirin group vs. 37 (8.4%) in the placebo group (HR 1.72; 95% CI 1.14–2.58; p=0.01).
Cardiovascular death: 33 (7.6%) vs. 19 (4.3%), respectively (HR 1.90; 95% CI 1.07–3.35).
Atherothrombotic events: 46 (10.6%) vs. 40 (9.1%) (HR 1.27; 95% CI 0.83–1.95).
Stent thrombosis: 1 patient in each group.
Major bleeding: 44 (10.2%) vs. 15 (3.4%) (HR 3.35; 95% CI 1.87–6.00; p<0.001).
Any bleeding: 70 (16.2%) vs. 41 (9.3%) (HR 1.97; 95% CI 1.34–2.89; p<0.001).
Serious adverse events were reported in 201 patients with 467 events in the aspirin group, compared to 192 patients with 395 events in the placebo group.

Conclusions:
In CCS patients at high atherothrombotic risk receiving long-term OAC therapy, the addition of aspirin increased the risk of cardiovascular death, MI, stroke, systemic embolism, coronary revascularization, or acute limb ischemia. Moreover, aspirin significantly increased the risks of all-cause mortality and major bleeding.

Commentary:
From a clinical practice perspective, adding aspirin to OAC therapy in this patient population proved harmful rather than beneficial. In the common scenario of “a patient with a stent and atrial fibrillation,” cardiologists frequently face the dilemma of balancing bleeding against thrombosis. The AQUATIC trial demonstrates that bleeding risk outweighs thrombotic benefit in this setting. Aspirin did not meaningfully reduce atherothrombotic events but significantly increased both mortality and bleeding risk, thereby reinforcing the rationale for OAC monotherapy.

However, as the trial was conducted exclusively in France, its generalizability to other populations remains uncertain; results may differ in Asian cohorts. Furthermore, the underrepresentation of women (majority male participants) limits the universal applicability of findings.
Clinical Implication: Aspirin should not be routinely added to long-term OAC therapy in CCS patients. Future studies in broader and more diverse populations are warranted to test the universality of these findings.