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

Coronary Artery Disease Clinical Trial

— AQUATIC  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04217447
• Other study ID #: 29BRC19.0116
• Status: Recruiting
• Phase: Phase 3
• Start date: May 25, 2020
• Est. completion date: May 2028

Study information

• Verified date: September 2023
• Source: University Hospital, Brest
• Contact: Martine GILARD, PhD
• Phone: 2 98 34 75 03
• Email: martine.gilard[@]chu-brest.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2000
• Est. completion date: May 2028
• Est. primary completion date: May 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Drug:
• 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)
• 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)

Locations

Country	Name	City	State
France	CHRU d'Amiens	Amiens
France	CHU d'Angers	Angers
France	CH d'Annecy-Genevois	Annecy
France	CH d'Antibes	Antibes
France	Hopital privé d'Antony	Antony
France	CH d'Arras	Arras
France	CH d'Avignon	Avignon
France	CH de la Côte Basque - Bayonne	Bayonne
France	Hôpital Haut Lévêque -CHU Bordeaux-Pessac	Bordeaux
France	CHU de Brest	Brest
France	Hôpital Louis Pradel - Bron	Bron
France	CH Pierre Nouveau -Cannes	Cannes
France	Centre Hospitalier René Dubos - Cergy Pontoise	Cergy-Pontoise
France	CH Chalon sur Saône	Chalon-sur-Saône
France	CH Louis Pasteur - Chartres - Le Coudray	Chartres
France	CHU de Clermont-Ferrand	Clermont-Ferrand
France	CH Compiègne	Compiègne
France	CH Sud Francilien Corbeil-Essonnes	Corbeil-Essonnes
France	Hôpital Henri Mondor - Créteil	Créteil
France	CHU de Dijon	Dijon
France	CHU de Grenoble	Grenoble
France	GHM - Grenoble	Grenoble
France	CH Haguenau	Haguenau
France	Clinique St Clothilde -La Réunion	La Réunion
France	CH de Lens	Lens
France	CHRU de Lille	Lille
France	CHU de Limoges	Limoges
France	CH St Joseph-St Luc Lyon	Lyon
France	Marseille- Hôpital La Timone	Marseille
France	Marseille-Hôpital Nord	Marseille
France	CH Martigues	Martigues
France	Clinique Les Fontaines - Melun	Melun
France	CHR de Metz	Metz
France	GHI Le Raincy-Montfermeil	Montfermeil
France	CHU de Montpellier	Montpellier
France	Clinique du Millénaire - Montpellier	Montpellier
France	CHU de Nîmes	Nîmes
France	CHR d'Orléans	Orléans
France	Paris-Bichat	Paris
France	Paris-HEGP Cardiologie	Paris
France	Paris-HEGP Médecine vasculaire	Paris
France	Paris-Lariboisière	Paris
France	Paris-Pitié-Salpêtrière	Paris
France	Paris-St Antoine	Paris
France	CH de Pau	Pau
France	CH Périgueux	Périgueux
France	CHU de Poitiers	Poitiers
France	CHU de Rennes	Rennes
France	CHU de Rouen	Rouen
France	Clinique St Hilaire - Rouen	Rouen
France	CH de Seclin	Seclin
France	CHU de Strasbourg	Strasbourg
France	Clinique Rhena - Strasbourg	Strasbourg
France	CHU de Toulouse	Toulouse
France	Clinique Pasteur-Toulouse	Toulouse
France	CHRU de Tours	Tours
France	CHU de Nancy - Hôpitaux de Brabois	Vandœuvre-lès-Nancy
France	Hôpital André Mignot - CH de Versailles	Versailles

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Brest	Bayer

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary efficacy outcome : rate of composite of cardiovascular mortality and thrombotic cardiovascular events	The primary efficacy outcome is the incidence of the adjudicated composite of (within 24-48 months): CV mortality; Thrombotic cardiovascular events; Myocardial infarction; Stroke; Any coronary revascularization; Systemic embolism; Acute limb ischemia; An Independent Clinical Events Committee (ICEC) will adjudicate all events (ischemic and bleeding events).	within 24-48 months
Primary	Primary safety outcome : rate of major bleeding	The primary safety outcome is the occurrence of major bleeding according to the ISTH (International Society of Thrombosis and Haemostasis) definition	within 24-48 months
Secondary	Secondary efficacy outcomes : rate of composite of CV mortality, MI, stroke; CV mortality; all cause of death; thrombotic cardiovascular events.	The secondary efficacy outcomes are the occurrence of any of the following events: The composite of CV mortality, MI, stroke; CV mortality; All cause death; Thrombotic cardiovascular events: Myocardial infarction; Stent thrombosis alone (definite or probable); Stroke (ischemic, hemorrhagic, or stroke of uncertain cause, TIA); Any coronary revascularization; Systemic embolism; Acute limb ischemia	within 24-48 months
Secondary	Secondary safety outcomes : rate of major and clinically relevant non major bleeding	The secondary safety outcome are the occurrence of : Major and clinically relevant non major bleeding according to the ISTH definition (ISTH : International Society of Thrombosis and Haemostasis) Major bleeding (TIMI : Thrombolysis in Myocardial Infarction) Major bleeding (BARC =3 : Bleeding Academic Research Consensus)	within 24-48 months