← Back

AQUATIC

Assessment of Quitting versus Using Aspirin Therapy in Patients with Stabilized Coronary Artery Disease after Stenting Who Require Long-Term Oral Anticoagulation

Share Share Copied! Compare

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: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2507532

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

Content summarized and formatted by NeuroTrials.ai.

AQUATIC

(2025)

Objective

To investigate the efficacy and safety of adding aspirin to long-term oral anticoagulation therapy in patients with chronic coronary syndrome who had undergone stent implantation and on chronic anticoagulation.

Study Summary

• Adding aspirin to oral anticoagulation increased cardiovascular events (HR 1.53, P=0.02)
• Aspirin significantly increased death from any cause (HR 1.72, P=0.01)
• Major bleeding was substantially higher with aspirin (HR 3.35, P<0.001)
• Trial was stopped early due to excess deaths in aspirin group

Intervention

Randomized 1:1 double-blind trial comparing aspirin 100mg daily versus placebo added to continued oral anticoagulation therapy in patients with chronic coronary syndrome and previous stent implantation >6 months.

Inclusion Criteria

Age ≥18 years, documented chronic coronary syndrome with previous coronary stent implantation >6 months before enrollment, high residual atherothrombotic risk features, receiving oral anticoagulant for any reason

Study Design

Arms: Aspirin 100mg daily + oral anticoagulation vs Placebo + oral anticoagulation

Patients per Arm: Aspirin: 433 patients, Placebo: 439 patients

Outcome

• Primary: 16.9% aspirin vs 12.1% placebo for cardiovascular death/MI/stroke/embolism/revascularization/limb ischemia
• Death: 13.4% aspirin vs 8.4% placebo
• Major bleeding: 10.2% aspirin vs 3.4% placebo

Bottom Line

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

Study Design

Study Type: Prospective, double-blind, randomized, placebo-controlled trial
Randomization: Yes
Blinding: Double-blind (patients and investigators)
Sample Size: 872
Follow-up: Median 2.2 years (IQR 1.1-3.2), planned 24-48 months
Centers: 51
Countries: France

Primary Outcome

Definition: Composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia

Control	Intervention	HR/OR	P-value
53 patients (12.1%)	73 patients (16.9%)	1.53 (1.07-2.18)	0.02

Limitations & 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

Citation

N Engl J Med. 2025. DOI: 10.1056/NEJMoa2507532

View Original Publication →

AQUATIC

Assessment of Quitting versus Using Aspirin Therapy in Patients with Stabilized Coronary Artery Disease after Stenting Who Require Long-Term Oral Anticoagulation

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about AQUATIC