6th September 2025, A/Prof Chee L Khoo
We all have patients at risk of thromboembolism (mainly from atrial fibrillation risks) and atherosclerotic cardiovascular disease (primarily, coronary artery disease). They may require both anti-coagulant as well as anti-platelet therapy. Sometimes, we don’t have a choice as they have high risks for both. Theoretically, they at high bleeding risks. Yet, our cardiology colleagues have to make that difficult decision to continue both. We all have a few of those patients and we seem to get away with minimal bleeding episodes. What does the data tell us about the safety?
In patients with stable coronary artery disease, long-term single antiplatelet therapy is necessary to prevent further atherothrombotic events (1,2). Some of these patients also have atrial fibrillation and ~ 15% of these patients also require long-term anticoagulation therapy (3-5). Naturally, patients with ASCVD and AF are at fairly high risk for both atherothrombotic and bleeding events (5). By putting both on both DOAC and anti-platelet therapy, we are accepting the bleeding risk for benefit of maintaining the anti-platelet therapy. Despite the increased bleeding risk of dual pathway therapy, they continued to be used frequently in practice.
Severe trials in the last 7 years have come up with conflicting results on the benefits or harms of dual pathway therapy vs anti-coagulation monotherapy (6-10). Some of those trials included patients on warfarin which has a higher bleeding risk. Thus, the appropriate regimen for these patients is still under debate.
The AQUATIC trial was a prospective, double-blind, randomised, placebo-controlled trial that was conducted at 51 centres in France (11). Participants had to be over 18 years old and had documented stable coronary syndrome with previous coronary stent implantation more than 6 months before enrolment, had high residual atherothrombotic risk and were receiving an oral anticoagulant (either a direct oral anticoagulant or a vitamin K antagonist) for any reason. High residual atherothrombotic risk were defined in participants as those with:
- diabetes
- diffuse multivessel disease
- chronic kidney disease
- previous stent thrombosis
- peripheral artery disease, or a
- history of complex PCI
The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularisation, or acute limb ischemia. Secondary efficacy outcomes were net adverse clinical events, defined as a composite of death from any cause, an atherothrombotic cardiovascular event, or major bleeding; death from any cause; a composite of cardiovascular death, myocardial infarction, or stroke; cardiovascular death; and an atherothrombotic cardiovascular event. The key secondary safety outcome was major bleeding.
Of 872 participants with stable coronary syndrome and receiving anti-coagulation therapy, 433 patients were assigned to receive aspirin (100 mg once daily) while continuing to receive oral anticoagulation therapy (aspirin group), and 439 patients were assigned to receive placebo while continuing oral anticoagulation therapy. The mean age of the patients was 71.7 years, 85.3% were male, and 72.1% had a history of myocardial infarction. All the patients had a history of PCI, with a median interval of 3 years between the last PCI and the time of enrolment.
89% of the participants were on anti-coagulant therapy for AF. 90% of the anti-coagulant agent were DOACs. At baseline, 67.7% of the patients were receiving single antiplatelet therapy (stratum A), and 32.3% were not receiving antiplatelet therapy at baseline.
Results
The trial was meant to be for a minimal follow up of 24 months but may be up to 48 months depending on the time of enrolment. However, enrolment was stopped early when members of the data and safety monitoring board observed an excess deaths in the aspirin + anti-coagulation group. The median duration of treatment was 1.7 years (interquartile range, 0.7 to 2.8), and the median follow-up was 2.2 years (interquartile range, 1.1 to 3.2).
Now, the reasons one might add an antiplatelet to anti-coagulation therapy would be for reducing cardiovascular events or cardiovascular deaths despite the increasing bleeding risk. One would be prepared to take the risk. However, in this AQUATIC trial the results were surprising.
Adding aspirin to anti-coagulant was associated with increased in primary outcomes, deaths from any cause, cardiovascular deaths and atherosclerothrombotic events. This is in addition to the increase in adverse events, major bleed and any bleed. Not only did aspirin not help reduce events, it caused more adverse events including bleeding. Interestingly, there were previous studies showing similar adverse outcomes (6,9).
In summary, adding aspirin to anti-coagulants in patients with coronary artery disease and atrial fibrillation not only is associated with increase bleeding risks but paradoxically, increase the cardiovascular event risks as well. If we have patients on dual pathway therapy already, should we be asking their cardiologist that question?
References:
1. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 2023; 148(9): e9-e119.
2. Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC guidelines for the management of chronic coronary syndromes. Eur Heart J 2024; 45: 3415-537.
3. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2024; 149(1): e1-e156.
4. Van Gelder IC, Rienstra M, Bunting KV, et al. 2024 ESC guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2024; 45: 3314-414.
5. Schurtz G, Bauters C, Ducrocq G, Lamblin N, Lemesle G. Effect of aspirin in addition to oral anticoagulants in stable coronary artery disease outpatients with an indication for anticoagulation. Panminerva Med 2016; 58: 271-85.
6. Cho MS, Kang D-Y, Ahn J-M, et al. Edoxaban antithrombotic therapy for atrial fibrillation and stable coronary artery disease. N Engl J Med 2024; 391: 2075-86.
7. Lemesle G. Aspirin on top of anticoagulation in patients with concomitant stable coronary artery disease and atrial fibrillation. Circulation 2019; 139: 617-9.
8. Matsumura-Nakano Y, Shizuta S, Komasa A, et al. Open-label randomized trial comparing oral anticoagulation with and without single antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stent implantation. Circulation 2019; 139: 604-16.
9. Yasuda S, Kaikita K, Akao M, et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N Engl J Med 2019; 381: 1103-13.
10. Fukamachi D, Okumura Y, Matsumoto N, et al. Edoxaban monotherapy in nonvalvular atrial fibrillation patients with coronary artery disease. J Interv Cardiol 2022; 2022: 5905022.
11. Lemesle G, Didier R, Steg PG, Simon T, Montalescot G, Danchin N, Bauters C, Blanchard D, Bouleti C, Angoulvant D, Andrieu S, Vanzetto G, Kerneis M, Decalf V, Puymirat E, Mottier D, Diallo A, Vicaut E, Gilard M, Cayla G; AQUATIC Trial Investigators. Aspirin in Patients with Chronic Coronary Syndrome Receiving Oral Anticoagulation. N Engl J Med. 2025 Aug 31.