AQUATIC
Assessment of Quitting versus Using Aspirin Therapy in Patients with Stabilized Coronary Artery Disease after Stenting Who Require Long-Term Oral Anticoagulation
Year of Publication: 2025
Authors: G. Lemesle, R. Didier, P.G. Steg, ..., G. Cayla
Journal: New England Journal of Medicine
Citation: N Engl J Med. 2025. DOI: 10.1056/NEJMoa2507532
Link: https://nejm.org
PDF: Clinical Question
What is the appropriate antithrombotic regimen for patients with chronic coronary syndrome who are at high atherothrombotic risk and receiving long-term oral anticoagulation?
Bottom Line
Among patients with chronic coronary syndrome at high atherothrombotic risk receiving oral anticoagulation, adding aspirin increased cardiovascular events, death, and major bleeding compared to placebo.
Major Points
- Double-blind, placebo-controlled trial stopped early due to excess deaths in aspirin group
- 872 patients with chronic coronary syndrome, previous stent >6 months, high atherothrombotic risk, on oral anticoagulation
- Primary endpoint (cardiovascular death, MI, stroke, embolism, revascularization, limb ischemia) higher with aspirin: 16.9% vs 12.1% (HR 1.53)
- Death from any cause significantly higher with aspirin: 13.4% vs 8.4% (HR 1.72)
- Major bleeding substantially increased with aspirin: 10.2% vs 3.4% (HR 3.35)
- 89% of patients had atrial fibrillation as indication for anticoagulation
- Direct oral anticoagulants used in 89.7% of patients
- Median follow-up 2.2 years, trial stopped early after median treatment duration 1.7 years
Design
Study Type: Prospective, double-blind, randomized, placebo-controlled trial
Randomization: 1
Blinding: Double-blind (patients and investigators)
Enrollment Period: May 2020 to April 2024
Follow-up Duration: Median 2.2 years (IQR 1.1-3.2), planned 24-48 months
Centers: 51
Countries: France
Sample Size: 872
Analysis: Intention-to-treat analysis using marginal Cox frailty model clustered at site level, adjusted for randomization strata. Multiple imputation under missing-at-random assumption. SAS software version 9.4
Inclusion Criteria
- Age ≥18 years
- Documented chronic coronary syndrome with previous coronary stent implantation >6 months before enrollment
- High residual atherothrombotic risk features
- Currently receiving oral anticoagulant (direct oral anticoagulant or vitamin K antagonist) for any reason
- Written informed consent
Exclusion Criteria
- Major protocol deviations
- Contraindications to aspirin or oral anticoagulation
- Life expectancy <12 months
- Other exclusions detailed in supplementary appendix
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age - mean | 71.1±9.6 years | 72.3±9.3 years |
| Male | 85.2% | 85.5% |
| BMI - mean | 28.5±4.9 | 28.3±5.3 |
| Diabetes | 36.9% | 38.0% |
| Hypertension | 67.4% | 70.1% |
| Dyslipidemia | 71.1% | 70.1% |
| Current smoker | 10.9% | 10.4% |
| History of MI | 72.7% | 71.5% |
| History of stroke | 12.3% | 9.0% |
| History of atrial fibrillation | 89.1% | 88.9% |
| CHA2DS2-VASc score - median | 4.0 (3.0-5.0) | 4.0 (3.0-5.0) |
| History of PAD | 12.8% | 16.0% |
| History of heart failure | 26.0% | 27.1% |
| Time since last PCI - median | 3.0 (1.0-6.0) years | 3.0 (1.0-6.0) years |
| Hemoglobin - mean | 14.1±1.8 g/dl | 13.8±1.9 g/dl |
| Creatinine clearance - mean | 72.1±26.6 ml/min | 70.6±26.8 ml/min |
Arms
| Field | Aspirin + Oral Anticoagulation | Control |
|---|---|---|
| Intervention | Aspirin 100 mg once daily plus continued current oral anticoagulation therapy | Placebo once daily plus continued current oral anticoagulation therapy |
| Duration | Until study completion | Until study completion |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia | Primary | 53 patients (12.1%) | 73 patients (16.9%) | 1.53 | 0.02 |
| Net adverse clinical events (death, atherothrombotic event, or major bleeding) | Secondary | 76 patients (17.3%) | 124 patients (28.6%) | 1.85 | <0.001 |
| Death from any cause | Secondary | 37 patients (8.4%) | 58 patients (13.4%) | 1.72 | 0.01 |
| Composite of cardiovascular death, MI, or stroke | Secondary | 34 patients (7.7%) | 46 patients (10.6%) | 1.45 | 0.10 |
| Cardiovascular death | Secondary | 19 patients (4.3%) | 33 patients (7.6%) | 1.9 | |
| Major bleeding (ISTH criteria) | Adverse | 15 patients (3.4%) | 44 patients (10.2%) | 3.35 | <0.001 |
| Any bleeding | Adverse | 41 patients (9.3%) | 70 patients (16.2%) | 1.97 | <0.001 |
| Serious adverse events | Adverse | 395 events in 192 patients | 467 events in 201 patients |
Subgroup Analysis
Subgroup analyses performed according to prespecified clinical factors showed consistent results across different patient characteristics.
Criticisms
- Trial stopped early which might have limited statistical power to investigate superiority for atherothrombotic events
- Conducted at 51 centers but all in single country (France), may limit generalizability
- Slow enrollment partly due to COVID-19 pandemic
- Women were underrepresented (14.7% female), limiting generalizability
- Incidence of very-late stent thrombosis was very low (only 1 event per group)
- Results may not be generalizable to other healthcare systems
Funding
French Ministry of Health (PHRC 18-0342) and unrestricted grant from Bayer Healthcare
Based on: AQUATIC (New England Journal of Medicine, 2025)
Authors: G. Lemesle, R. Didier, P.G. Steg, ..., G. Cayla
Citation: N Engl J Med. 2025. DOI: 10.1056/NEJMoa2507532
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