Highlight
- Aquatic Trial investigated aspirin addition to oral anticoagulation in chronic coronary syndrome (CCS) patients with a history of stenting.
- The study was terminated early due to increased all-cause mortality and primary cardiovascular events in aspirin users versus placebo.
- Aspirin increased risk of major bleeding markedly, without reducing thrombotic complications.
Study Background
Patients with chronic coronary syndrome (CCS), particularly those with history of coronary stenting, remain at elevated risk of atherothrombotic events such as myocardial infarction, stroke, and vascular death. Long-term oral anticoagulation (OAC) is often prescribed for comorbidities like atrial fibrillation to prevent thromboembolism. However, optimal antithrombotic regimens balancing ischemic prevention and bleeding risk are uncertain. Aspirin is widely used to attenuate platelet aggregation, but its role alongside OAC in CCS patients remains controversial due to concern over potential bleeding complications.
Study Design
The Aquatic Trial was a multicenter, double-blind, randomized, placebo-controlled study conducted in France. It enrolled 872 patients with CCS who had undergone coronary stenting more than 6 months prior and were receiving long-term OAC due to high atherothrombotic risk. Participants were randomized 1:1 to aspirin 100 mg daily or placebo, continuing their usual anticoagulation therapy.
The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia. Major bleeding was the key safety outcome, assessed rigorously to capture severe hemorrhagic events.
Key Findings
During a median follow-up of 2.2 years, the trial was stopped early on Data and Safety Monitoring Board recommendation due to safety concerns.
Results revealed that the aspirin group experienced significantly more primary efficacy outcome events than placebo (16.9% vs 12.1%; adjusted hazard ratio [HR] 1.53; 95% confidence interval [CI], 1.07–2.18; P=0.02). Notably, death from any cause was higher in the aspirin arm (13.4% vs 8.4%; HR 1.72; 95% CI, 1.14–2.58; P=0.01).
Major bleeding events were substantially elevated in the aspirin group (10.2%) compared to placebo (3.4%), yielding a HR of 3.35 (95% CI, 1.87–6.00; P<0.001). Serious adverse events were also more frequent with aspirin (467 vs 395 events).
These findings indicate that aspirin addition in this specific patient population not only failed to provide ischemic event reduction but paradoxically increased cardiovascular morbidity and mortality along with bleeding complications.
Expert Commentary
The results from the Aquatic Trial challenge established paradigms around combined antithrombotic therapy in CCS patients on OAC. Conventional wisdom supports aspirin’s antiplatelet effect as additive when superimposed on anticoagulation for high-risk patients. However, the elevated bleeding propensity with aspirin may offset potential ischemic benefits, particularly in a population already exposed to anticoagulants.
Mechanistically, dual pathways suppression—coagulation cascade and platelet aggregation—pose heightened bleeding risks with limited synergistic protection against thrombotic events in chronic stable settings. These findings align with recent guideline trends advocating for minimal antithrombotic regimens tailored individually based on bleeding versus thrombosis risk.
Limitations include early study termination and population restrictions to patients with prior stenting beyond 6 months. Further research may explore subgroups or alternative dosing but current evidence suggests that routine aspirin addition may be harmful in CCS patients stabilized on OAC.
Conclusion
In patients with chronic coronary syndrome on long-term oral anticoagulation therapy, adjunctive aspirin increased the risk of major cardiovascular events, all-cause mortality, and significant bleeding. These data strongly argue against routine combination therapy with aspirin in this clinical context, underscoring the necessity of individualized antithrombotic strategies to optimize outcomes while minimizing bleeding complications.
Clinicians should carefully weigh the bleeding risk when considering aspirin addition to oral anticoagulants in stable coronary artery disease management and reconsider current practice in light of these compelling trial findings.
Funding and Registration
The Aquatic Trial was funded by the French Ministry of Health and Bayer Healthcare. It is registered on ClinicalTrials.gov under the identifier NCT04217447.
References
- Lemesle G, Didier R, Steg PG, et al. Aspirin in Patients with Chronic Coronary Syndrome Receiving Oral Anticoagulation. N Engl J Med. 2025;393(16):1578-1588. doi:10.1056/NEJMoa2507532.
