06 Oct NEJM: AQUATIC Study Evaluates Risks/Benefits of Aspirin With On Oral Anticoagulation In Chronic Coronary Syndrome
Aspirin in Patients with Chronic Coronary Syndrome Receiving Oral Anticoagulation
MedicalResearch.com Interview with:
Prof. Lemesle
Gilles Lemesle, M.D., Ph.D
Lille University Hospital, Lille, France
Guillaume Cayla, M.D., Ph.D
Université de Montpellier, France
Martine Gilard, M.D., Ph.D
Hospital Cavale Blanche, Brest, France
MedicalResearch.com: What is the background for this study?
Response: Patients with chronic coronary syndrome (CCS) and receiving long-term oral anticoagulation (OAC), mainly but not solely for atrial fibrillation, are at high risk of both atherothrombotic events on one side and bleeding events on the other side.
Therefore, the optimal antithrombotic management for these patients with CCS requiring OAC after stenting is critical, especially in those patients at high residual atherothrombotic risk.
Previous studies reported that in this specific context, the addition of antiplatelet therapy on top of OAC increases bleeding without a clear benefit on ischemic outcomes. Nevertheless, these studies presented several limitations, which restricted the applicability of their results in clinical pratice. They were indeed all open-labelled, included patients without stenting and/or at low atherothrombotic risk, and focused on Asian patients who have different atherothrombotic and bleeding risks as compared to Europeans.
Thus, the rationale of the AQUATIC trial comes from the need to better identify the optimal antithrombotic regimen in high-risk patients with CCS and previous stenting, who receive long-term OAC, in order to optimize the atherothrombotic/bleeding risks in this population. The AQUATIC trial analyzed the efficacy and safety of adding aspirin to OAC, a combination that is still commonly used for this high-risk population in clinical daily practice.
MedicalResearch.com: How was it executed -please describe the methodology?
Response: The AQUATIC is a double-blind, placebo-controlled, parallel-group, randomized trial conducted at 51 centers in France. The study was funded by the French ministry of health and an unrestricted grant from Bayer Healthcare.
Eligible patients had CCS and previous coronary stent implantation (>6 months before inclusion), were at high atherothrombotic risk, and required long-term OAC for any reason.
High atherothrombotic risk was defined as either a history of percutaneous coronary intervention (PCI) during an acute coronary syndrome (ACS) (with ≥1 stent(s) >6 months) or history of PCI (>6 months) outside the context of ACS but with high-risk features such as diabetes, chronic renal failure, multivessel disease (involvement of 3 coronary vessels), history of complex PCI (left main, chronic total occlusion, 3 lesions), history of stent thrombosis or history of peripheral artery disease.
Patients were randomized 1:1 to aspirin or placebo on top of OAC (either a direct OAC [DOAC] or vitamin K antagonist [VKA]). Randomization was stratified by centre, type of oral anticoagulant (DOAC or VKA), and baseline antithrombotic regimen at inclusion (stratum A or stratum B). Patients on oral anticoagulants and a single antiplatelet agent (stratum A) were randomly assigned to continue with a single antiplatelet agent (aspirin) or stop the antiplatelet agent (aspirin), while patients who had been on an oral anticoagulant alone (stratum B) were randomly assigned to start aspirin or not.
Patient visits were scheduled every 6 months during follow-up.
The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction (MI), stroke, systemic embolism, coronary revascularization and acute limb ischemia. Secondary efficacy outcomes included net adverse clinical events defined as a composite of all-cause death, atherothrombotic cardiovascular event, or major bleeding; all-cause death; a composite of cardiovascular death, MI or stroke; cardiovascular death; atherothrombotic cardiovascular events; The key secondary safety outcome was major bleeding using the International Society on Thrombosis and Haemostasis (ISTH) definition.
Enrollment was prematurely stopped on April 16, 2024 on the recommendation of the Data Safety Monitoring Board who observed an excess in all-cause mortality in one group.
MedicalResearch.com: What are the main findings?
Response: The final intention to treat population included 872 patients: 433 were assigned to aspirin (on top of OAC) and 439 to placebo.
Concerning the baseline patient characteristics, mean age was 71 years, with 85% of males. Of note, 70% of the PCI were performed during an acute coronary syndrome, and a quarter of the patients underwent PCI between 6 months and 1 year at randomization. The median delay between the last PCI and inclusion was 3 years. The main indication for OAC was AF in close to 90% of the cases, with a median CHA2D2S-VASc score of 4. DOACs were the preferred OAC and used in the vast majority of the cases 90% (vs. 10% of VKA). The mean creatinine clearance was 71.4 mL/min and 37.4% of the patients had history of diabetes.
The primary efficacy outcome occurred in significantly more patients in the aspirin group as compared to the placebo group (16.9% vs. 12.1%; adjusted hazard ratio [aHR] 1.53; 95% confidence interval [CI] 1.07 to 2.18; p=0.019). All-cause death also occurred in significantly more patients in the aspirin group vs. placebo (13.4% vs. 8.4%; aHR 1.72; 95% CI 1.14 to 2.58; p=0.010). The risk of major bleeding (ISTH definition) was more than three-fold higher in the aspirin group as compared to the placebo group (10.2% vs. 3.4%; aHR 3.35; 95% CI 1.87 to 6.00; p<0.0001). The risk of MI was similar between the 2 groups and only one stent thrombosis occurred in each group during follow-up.
Results were consistent across the different subgroups.
MedicalResearch.com: What should readers take away from your report?
Response: Other studies have investigated antithrombotic therapy for stable coronary artery disease and AF, but AQUATIC is the first double blinded, placebo controlled, randomized trial to include patients who had prior stenting and a high atherothrombotic risk. Of note, the risk of events was 7 to 8 higher in AQUATIC than in previous trials in the field.
The AQUATIC trial reported an increased rate of major cardiovascular events (composite primary efficacy endpoint), all-cause mortality and major bleeding in the aspirin group of patients with CCS at high atherothrombotic risk requiring long-term OAC therapy. Thus, aspirin negatively impacted the outcomes and its use should be discouraged even in patients at high residual atherothrombotic risk.
Thus, the AQUATIC trial seems to solve the doubt of treatment management in CCS patients with stenting and a need for OAC, and it could probably impact next ESC Guidelines according to its strong randomized design and results showing the risk of prolonging aspirin use in this specific high-risk population.
Disclosures: Gilles LEMESLE reports consultant/lecture fees from Alnylam, Amarin, Amgen, Astra Zeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston, MSD, Novartis, Novonordisk, Organon, Pfizer, Sanofi Aventis
Martine GILARD reports no relationship with industry
Guillaume CAYLA reports research grants/consultant fees/lectures fees from Amgen, AstraZeneca, Abbott, Bayer, Biotronik, Bristol-Myers Squibb, Edwards, Microport, Medtronic, Pfizer, Shockwave Medical
Citation:
Aspirin in Patients with Chronic Coronary Syndrome Receiving Oral Anticoagulation
Authors: Gilles Lemesle, M.D., Ph.D., Romain Didier, M.D., Ph.D., Philippe Gabriel Steg, M.D. https://orcid.org/0000-0001-6896-2941, Tabassome Simon, M.D., Ph.D., Gilles Montalescot, M.D., Ph.D., Nicolas Danchin, M.D., Christophe Bauters, M.D., Ph.D., +13 , for the AQUATIC Trial Investigators Author Info & Affiliations
Published August 30, 2025 DOI: 10.1056/NEJMoa2507532
https://www.nejm.org/doi/abs/10.1056/NEJMoa2507532
and presented at ESC 2025
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Last Updated on October 6, 2025 by Marie Benz MD FAAD
