Clinical trial NCT04217447: Assessment of Quitting Versus Using Aspirin Therapy in Patients Treated with Oral Anticoagulation for Atrial Fibrillation or Other Indication with Stabilized Coronary Artery Disease
Official title: Assessment of Quitting Versus Using Aspirin Therapy in Patients Treated with Oral Anticoagulation for Atrial Fibrillation or Other Indication with Stabilized Coronary Artery Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Coronary Artery Disease
Keywords: atrial fibrillation
oral anticoagulation
antithrombotic therapy
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2020-01-03
Enrollment: 874
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: It's a prospective, randomized, double-blind, placebo controlled, parallel-group, multi-center study.
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Primary efficacy outcome : rate of composite of cardiovascular mortality and thrombotic cardiovascular events
timeFrame: within 24-48 months
measure: Primary safety outcome : rate of major bleeding
timeFrame: within 24-48 months
Secondary outcomes:
measure: Secondary efficacy outcomes : rate of composite of CV mortality, MI, stroke; CV mortality; all cause of death; thrombotic cardiovascular events.
timeFrame: within 24-48 months
measure: Secondary safety outcomes : rate of major and clinically relevant non major bleeding
timeFrame: within 24-48 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHRU d'Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Annecy
country: France
facility: CH d'Annecy-Genevois
city: Antibes
country: France
facility: CH d'Antibes
city: Antony
country: France
facility: Hopital privé d'Antony
city: Arras
country: France
facility: CH d'Arras
city: Avignon
country: France
facility: CH d'Avignon
city: Bayonne
country: France
facility: CH de la Côte Basque - Bayonne
city: Bordeaux
country: France
facility: Hôpital Haut Lévêque -CHU Bordeaux-Pessac
city: Brest
country: France
facility: CHU de Brest
city: Bron
country: France
facility: Hôpital Louis Pradel - Bron
city: Cannes
country: France
facility: CH Pierre Nouveau -Cannes
city: Cergy-Pontoise
country: France
facility: Centre Hospitalier René Dubos - Cergy Pontoise
city: Chalon-sur-Saône
country: France
facility: CH Chalon sur Saône
city: Chartres
country: France
facility: CH Louis Pasteur - Chartres - Le Coudray
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand
city: Compiègne
country: France
facility: CH Compiègne
city: Corbeil-Essonnes
country: France
facility: CH Sud Francilien Corbeil-Essonnes
city: Créteil
country: France
facility: Hôpital Henri Mondor - Créteil
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: GHM - Grenoble
city: Grenoble
country: France
facility: CHU de Grenoble
city: Haguenau
country: France
facility: CH Haguenau
city: La Réunion
country: France
facility: Clinique St Clothilde -La Réunion
city: Lens
country: France
facility: CH de Lens
city: Lille
country: France
facility: CHRU de Lille
city: Limoges
country: France
facility: CHU de Limoges
city: Lyon
country: France
facility: CH St Joseph-St Luc Lyon
city: Marseille
country: France
facility: Marseille-Hôpital Nord
city: Marseille
country: France
facility: Marseille- Hôpital La Timone
city: Martigues
country: France
facility: CH Martigues
city: Melun
country: France
facility: Clinique Les Fontaines - Melun
city: Montpellier
country: France
facility: CHU de Montpellier
city: Montpellier
country: France
facility: Clinique du Millénaire - Montpellier
city: Nîmes
country: France
facility: CHU de Nîmes
city: Orléans
country: France
facility: CHR d'Orléans
city: Paris
country: France
facility: Paris-Lariboisière
city: Paris
country: France
facility: Paris-St Antoine
city: Paris
country: France
facility: Paris-Pitié-Salpêtrière
city: Paris
country: France
facility: Paris-HEGP Cardiologie
city: Paris
country: France
facility: Paris-HEGP Médecine vasculaire
city: Paris
country: France
facility: Paris-Bichat
city: Pau
country: France
facility: CH de Pau
city: Poitiers
country: France
facility: CHU de Poitiers
city: Périgueux
country: France
facility: CH Périgueux
city: Rennes
country: France
facility: CHU de Rennes
city: Rouen
country: France
facility: Clinique St Hilaire - Rouen
city: Rouen
country: France
facility: CHU de Rouen
city: Seclin
country: France
facility: CH de Seclin
city: Strasbourg
country: France
facility: Clinique Rhena - Strasbourg
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Toulouse
country: France
facility: Clinique Pasteur-Toulouse
city: Tours
country: France
facility: CHRU de Tours
city: Vandœuvre-lès-Nancy
country: France
facility: CHU de Nancy - Hôpitaux de Brabois
city: Versailles
country: France
facility: Hôpital André Mignot - CH de Versailles
Study officials:
References: