Assessment of Quitting Versus Using Aspirin Therapy In Patients Treated With Oral Anticoagulation for Atrial Fibrillation or Other Indication With Stabilized Coronary Artery Disease

NCT ID: NCT04217447

Last Updated: 2025-07-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 874 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-25
• Study Completion Date: 2024-10-28

Brief Summary

• Long-term aspirin (ASA) is the standard recommended antithrombotic therapy in patients with stable coronary artery disease (CAD), especially following stenting (Class I, Level A).
• Long-term oral anticoagulation (OAC) is the standard antithrombotic therapy in patients with atrial fibrillation (AF) associated with one or more risk factor for stroke (Class I, Level A).
• During the first year following acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), several studies evaluating the combination of OAC treatment and antiplatelet therapy are either already published or ongoing.
• At distance of the index ACS and/or PCI, patients with stable CAD and concomitant AF remain at particular high-risk of ischemic (3 to 4 times higher as compared to patients with stable CAD without AF) and bleeding events. Antithrombotic management of these patients is subsequently highly challenging in clinical practice. The European task force suggests that the use of a full-dose anticoagulant monotherapy without any antiplatelet therapy should be the default strategy in such patients with both, AF and stable CAD.
• However, evidences are sparse and weak to support such a strategy (only observational studies with many biases) and no randomized trial has assessed this question. These patients, especially those at high-risk of recurrent ischemic events (post- ACS, diabetes, multivessel CAD…) may benefit from the combination of OAC and aspirin at long-term. Indeed the crude event rate of ischemic events is much higher than the crude event rate of bleeding in this specific population. Ischemic events are 2 to 3 times more frequent than bleeding in daily practice.
• The benefit/risk ratio of these two different strategies (ASA in combination with OAC vs. OAC alone) in patients at high-risk of recurrent coronary and vascular events remains unknown. Dual therapy with full-dose anticoagulation and ASA may lead to higher risk of major bleeding, while stopping ASA in stabilized high-risk patients after PCI may lead to poorer outcome regarding ischemic events.
• The coordinating investigators therefore designed a double blind placebo controlled trial in order to assess the optimal antithrombotic regimen that should be pursued long-life in this subset of patients.

Detailed Description

• Long-term aspirin (ASA) is the standard recommended antithrombotic therapy in patients with stable coronary artery disease (CAD), especially following stenting (Class I, Level A).
• Long-term oral anticoagulation (OAC) is the standard antithrombotic therapy in patients with atrial fibrillation (AF) associated with one or more risk factor for stroke (Class I, Level A).
• During the first year following acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI), several studies evaluating the combination of OAC treatment and antiplatelet therapy are either already published or ongoing.
• At distance of the index ACS and/or PCI, patients with stable CAD and concomitant AF remain at particular high-risk of ischemic (3 to 4 times higher as compared to patients with stable CAD without AF) and bleeding events. Antithrombotic management of these patients is subsequently highly challenging in clinical practice. The European task force suggests that the use of a full-dose anticoagulant monotherapy without any antiplatelet therapy should be the default strategy in such patients with both, AF and stable CAD.
• However, evidences are sparse and weak to support such a strategy (only observational studies with many biases) and no randomized trial has assessed this question. These patients, especially those at high-risk of recurrent ischemic events (post- ACS, diabetes, multivessel CAD…) may benefit from the combination of OAC and aspirin at long-term. Indeed the crude event rate of ischemic events is much higher than the crude event rate of bleeding in this specific population. Ischemic events are 2 to 3 times more frequent than bleeding in daily practice.
• The benefit/risk ratio of these two different strategies (ASA in combination with OAC vs. OAC alone) in patients at high-risk of recurrent coronary and vascular events remains unknown. Dual therapy with full-dose anticoagulation and ASA may lead to higher risk of major bleeding, while stopping ASA in stabilized high-risk patients after PCI may lead to poorer outcome regarding ischemic events.

AQUATIC is a prospective, randomized, double-blind, placebo controlled, parallel-group, multi-center study.

Randomization into 2 treatment groups and stratified on study center, type of OAC (VKA vs. DOAC), antithrombotic treatment received at the time of inclusion (dual therapy combining single antiplatelet therapy + OAC vs. OAC alone).

Experimental group : Patients intaking full-dose OAC + ASA 100mg od.

Control group : Patients intaking full-dose OAC + Placebo of ASA 100mg od.

Note:

• For Apixaban: in case of > 1 of the followings: > 80 years old, weight < 60kg, creatinine level > 133μmol/l; Or a creatinine clearance between 30 and 50 ml/min (Cockroft Formula), the dose of Apixaban will be reduced to 2.5 mg bid.
• For Rivaroxaban: in case of moderate creatinine clearance (Cockroft Formula) (between 30 and 50 ml/min) or severe renal insufficiency (between 15 and 29 ml/min) the dose of Rivaroxaban will be reduced to 15 mg od.
• For Dabigatran: in case of moderate creatinine clearance (Cockroft Formula) (between 30 and 50 ml/min) with age between 75 and 80 years: the dose of Dabigatran will be 150 mg bid or 110 mg bid, according to the ischemic and hemorrhagic risk of the patient. In case of age > 80 years and/or concomitant administration of Verapamil, the dose of Dabigatran will be reduced to 110 mg bid.
• For VKA: target INR (International Normalised Ratio) between 2 and 3.

The primary efficacy objective is to demonstrate, in high-risk stabilized patients after PCI requiring also anticoagulation for AF, the superiority of the dual therapy ASA 100mg od + full-dose of OAC for 24-48 months versus full-dose of OAC alone (+ placebo) on a composite endpoint associating: cardio-vascular (CV) mortality, myocardial infarction, stroke, coronary revascularization, systemic embolism, and acute limb ischemia.

The primary safety objective is major bleeding (ISTH : International Society of Thrombosis and Haemostasis).

The secondary efficacy objectives are evaluation of efficacy of dual therapy SA 100mg od + OAC full ose versus OAC alone (+placebo) for:

• The composite of CV mortality, MI (Myocardial Infarction ), stroke
• CV mortality
• All cause death
• Myocardial infarction (MI)
• Stent thrombosis (definite or probable)
• Stroke (ischemic, hemorrhagic, or stroke of uncertain cause, transient ischemic attack [TIA])
• Coronary revascularization
• Systemic embolism
• Acute limb ischemia

Net clinical benefit:

• All cause mortality
• Major bleeding [define according to the International Society of Thrombosis and Haemostasis (ISTH): an acute, linically overt bleeding accompanied by one or more of the following findings: 2g/dl decline in Hemoglobin level r = 2 red blood cell transfusions over a 24-hour period, leeding of a major organ (intracranial, intramedullary, intraocular, pericardial, interarticular, intramuscular and / or retro peritoneal) or fatal bleeding]
• Thrombotic cardiovascular events:

• Myocardial infarction
• Stent thrombosis
• Stroke (ischemic, hemorrhagic, or stroke of uncertain cause, TIA)
• Any coronary revascularization
• Systemic embolism
• Acute limb ischemia

The secondary safety objectives are :

• Major and clinically relevant non major bleeding (ISTH)
• Major bleeding (TIMI : Thrombolysis In Myocardial Infarction)
• Major bleeding (BARC ≥3 : Bleeding Academic Research Consortium)

All the included patients will be randomized at visit 1 and followed every 6 months until death or the end of the study (i.e. achievement of 2-year follow-up of the last included patient, maximum of 48 month followup for the first included patient).The first patient may require up to 9 visits .

2000 patients are expected to be included.

Inclusion period : 72 months. Duration of patient's participation: 24 to 48 months depending of time of inclusion.

Total study duration: 48 months.

All included patients will remain in the study until death or the end of the trial (i.e. achievement of 2-year follow-up of the last included patient).

Conditions

Coronary Artery Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Experimental group

Patients intaking full-dose OAC + ASA 100mg od

Group Type: ACTIVE_COMPARATOR

OAC + Aspirin 100mg od

Intervention Type: DRUG

Patients will receive full-dose of OAC + Aspirin 100mg od during 24 to 48 months (until death or the end of the study : i.e. achievement of 2-year follow-up of the last included patient, maximum of 48-month followup for the first included patient)

Control group

Patients intaking full-dose OAC + Placebo of ASA 100mg od

Group Type: PLACEBO_COMPARATOR

OAC + placebo of Aspirin 100mg od

Intervention Type: DRUG

Patients will receive full-dose of OAC + placebo of Aspirin 100mg od during 24 to 48 months (until death or the end of the study : i.e. achievement of 2-year follow-up of the last included patient, maximum of 48-month followup for the first included patient)

Interventions

OAC + Aspirin 100mg od

Patients will receive full-dose of OAC + Aspirin 100mg od during 24 to 48 months (until death or the end of the study : i.e. achievement of 2-year follow-up of the last included patient, maximum of 48-month followup for the first included patient)

Intervention Type: DRUG

OAC + placebo of Aspirin 100mg od

Patients will receive full-dose of OAC + placebo of Aspirin 100mg od during 24 to 48 months (until death or the end of the study : i.e. achievement of 2-year follow-up of the last included patient, maximum of 48-month followup for the first included patient)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Patients >18 year-old
• All patients that need anticoagulation with direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA) for AF (paroxysmal, persistent or permanent) or other indication and have a stabilized CAD (free from MI, or coronary revascularization in the past year) but remain at high residual risk of recurrent coronary and vascular events. The use of DOAC will be promoted as recommended by guidelines.
• Two different categories of patients could be included in the study, i) patients treated at the time of inclusion with the association of OAC and single antiplatelet therapy, it will be tested for them aspirin vs. interruption of antiplatelet therapy ii) patients treated with OAC alone at the time of inclusion, it will be tested for them administration of aspirin vs. no additional treatment with aspirin.
• High-risk of coronary and vascular event is defined as follow :

1. History of PCI during an ACS involving placement of ≥1 stent(s) since >6 months.

2. History of PCI (>6 months) outside the context of ACS but with high-risk features of ischemic event recurrences defined as: diabetes, or diffuse multivessel disease (defined by the involvement of the 3 coronary vessels), or chronic kidney disease (creatinine clearance < 50ml/min), or prior stent thrombosis, or complex PCI (defined by: stenting of the last remaining patent coronary artery, left main, at least 3 stents implanted and/or 3 lesions treated, bifurcation with two stents, length of stent >60mm and chronic total coronary occlusion) or the presence of peripheral artery disease (previous limb revascularization bypass or percutaneous angioplasty, previous limb or foot amputation for arterial vascular disease, history of intermittent claudication of peripheral artery stenosis (≥50%) ,previous carotid revascularization or carotid stenosis ≥50%).

• Women of childbearing potential with effective contraception defined as

• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation :

• oral
• intravaginal
• transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation :

• oral
• injectable
• implantable
• intrauterine device (IUD)
• intrauterine hormone-releasing system ( IUS)
• bilateral tubal occlusion
• vasectomised partner
• sexual abstinence

Exclusion Criteria

• Any coronary event within 6 months prior to randomization
• High risk of bleeding defined as recent (≤6 months) ISTH major bleeding event
• Constitutional or acquired haemorrhagic disease including gastrointestinal bleeding and thrombocytopenia
• Planned PCI within the next 6 months after randomization or subject requiring P2Y12 receptor antagonist therapy
• Stroke within 1 month or any history of hemorrhagic stroke
• Any contraindication to aspirin (ASA) or any of these excipients or other NSAIDs (hypersensitivity, allergy, active bleeding)
• Any contraindication to anticoagulant
• History (s) of asthma induced by the administration of salicylates or substances of close activity (especially NSAIDs)
• Evolutionary gastroduodenal ulcer
• Any other gastroduodenal history
• Severe renal insufficiency
• Severe hepatic insufficiency
• Severe, uncontrolled heart failure
• Lactose intolerance
• Pregnancy
• Breastfeeding patients
• Unable (protected adults : tutorship, curatorship) orunwilling to consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

University Hospital, Brest

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

CHRU d'Amiens

Amiens, France, France

CHU d'Angers

Angers, France, France

CH d'Annecy-Genevois

Annecy, France, France

CH d'Antibes

Antibes, France, France

CH d'Arras

Arras, France, France

CH d'Avignon

Avignon, France, France

CH de la Côte Basque - Bayonne

Bayonne, France, France

Hôpital Haut Lévêque -CHU Bordeaux-Pessac

Bordeaux, France, France

CHU de Brest

Brest, France, France

Hôpital Louis Pradel - Bron

Bron, France, France

Centre Hospitalier René Dubos - Cergy Pontoise

Cergy-Pontoise, France, France

CH Chalon sur Saône

Chalon-sur-Saône, France, France

CH Louis Pasteur - Chartres - Le Coudray

Chartres, France, France

CHU de Clermont-Ferrand

Clermont-Ferrand, France, France

CH Compiègne

Compiègne, France, France

CH Sud Francilien Corbeil-Essonnes

Corbeil-Essonnes, France, France

Hôpital Henri Mondor - Créteil

Créteil, France, France

CHU de Dijon

Dijon, France, France

GHM - Grenoble

Grenoble, France, France

CHU de Grenoble

Grenoble, France, France

Clinique St Clothilde -La Réunion

La Réunion, France, France

CH de Lens

Lens, France, France

CHRU de Lille

Lille, France, France

CHU de Limoges

Limoges, France, France

CH St Joseph-St Luc Lyon

Lyon, France, France

Marseille-Hôpital Nord

Marseille, France, France

Marseille- Hôpital La Timone

Marseille, France, France

CH Martigues

Martigues, France, France

CHU de Montpellier

Montpellier, France, France

Clinique du Millénaire - Montpellier

Montpellier, France, France

CHU de Nîmes

Nîmes, France, France

CHR d'Orléans

Orléans, France, France

Paris-Lariboisière

Paris, France, France

Paris-Pitié-Salpêtrière

Paris, France, France

Paris-HEGP Cardiologie

Paris, France, France

Paris-HEGP Médecine vasculaire

Paris, France, France

Paris-Bichat

Paris, France, France

CH de Pau

Pau, France, France

CH Périgueux

Périgueux, France, France

CHU de Poitiers

Poitiers, France, France

CHU de Rennes

Rennes, France, France

Clinique St Hilaire - Rouen

Rouen, France, France

CHU de Rouen

Rouen, France, France

CH de Seclin

Seclin, France, France

Clinique Rhena - Strasbourg

Strasbourg, France, France

CHU de Strasbourg

Strasbourg, France, France

CHU de Toulouse

Toulouse, France, France

Clinique Pasteur-Toulouse

Toulouse, France, France

CHRU de Tours

Tours, France, France

Hôpital André Mignot - CH de Versailles

Versailles, France, France

CHU de Nancy - Hôpitaux de Brabois

Vandœuvre-lès-Nancy, , France

Countries

France

References

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. doi: 10.1056/NEJMoa2507532. Online ahead of print.

Reference Type: DERIVED

PMID: 40888725 (View on PubMed)

Other Identifiers

29BRC19.0116

Identifier Type: -

Identifier Source: org_study_id