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Assessment of Quitting Versus Using Aspirin Therapy In Patients Treated With Oral Anticoagulation for Atrial Fibrillation With Stabilized Coronary Artery Disease (AQUATIC)

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ClinicalTrials.gov Identifier: NCT04217447
Recruitment Status : Not yet recruiting
First Posted : January 3, 2020
Last Update Posted : January 7, 2020
Sponsor:
Collaborator:
Bayer
Information provided by (Responsible Party):
University Hospital, Brest

Tracking Information
First Submitted Date  ICMJE December 31, 2019
First Posted Date  ICMJE January 3, 2020
Last Update Posted Date January 7, 2020
Estimated Study Start Date  ICMJE April 2020
Estimated Primary Completion Date April 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 3, 2020)
  • Primary efficacy outcome : rate of composite of cardiovascular mortality and thrombotic cardiovascular events [ Time Frame: within 24-48 months ]
    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).
  • Primary safety outcome : rate of major bleeding [ Time Frame: within 24-48 months ]
    The primary safety outcome is the occurrence of major bleeding according to the ISTH (International Society of Thrombosis and Haemostasis) definition
Original Primary Outcome Measures  ICMJE
 (submitted: December 31, 2019)
  • Composite efficacy outcome : cardiovascular mortality and thrombotic cardiovascular events [ Time Frame: within 24-48 months ]
    composite safety outcome (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).
  • Safety outcome : major bleeding [ Time Frame: within 24-48 months ]
    Major bleeding according to the ISTH (International Society of Thrombosis and Haemostasis) definition
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 3, 2020)
  • Secondary efficacy outcomes : rate of composite of CV mortality, MI, stroke; CV mortality; all cause of death; thrombotic cardiovascular events. [ Time Frame: within 24-48 months ]
    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
  • Secondary safety outcomes : rate of major and clinically relevant non major bleeding [ Time Frame: within 24-48 months ]
    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)
Original Secondary Outcome Measures  ICMJE
 (submitted: December 31, 2019)
  • Efficacy outcomes : composite of CV mortality, MI, stroke; CV mortality; all cause of death; thrombotic cardiovascular events. [ Time Frame: within 24-48 months ]
    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
  • Safety outcomes : major and clinically relevant non major bleeding [ Time Frame: within 24-48 months ]
    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)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Assessment of Quitting Versus Using Aspirin Therapy In Patients Treated With Oral Anticoagulation for Atrial Fibrillation With Stabilized Coronary Artery Disease
Official Title  ICMJE Assessment of Quitting Versus Using Aspirin Therapy In Patients Treated With Oral Anticoagulation for Atrial Fibrillation With Stabilized Coronary Artery Disease
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 : 24 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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
It's a prospective, randomized, double-blind, placebo controlled, parallel-group, multi-center study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Coronary Artery Disease
Intervention  ICMJE
  • 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)
  • 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)
Study Arms  ICMJE
  • Active Comparator: Experimental group
    Patients intaking full-dose OAC + ASA 100mg od
    Intervention: Drug: OAC + Aspirin 100mg od
  • Placebo Comparator: Control group
    Patients intaking full-dose OAC + Placebo of ASA 100mg od
    Intervention: Drug: OAC + placebo of Aspirin 100mg od
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: December 31, 2019)
2000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2024
Estimated Primary Completion Date April 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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) 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 >1 year.
    2. History of PCI (>1year) 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 a year 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Martine GILARD, PhD 2 98 34 75 03 ext +33 martine.gilard@chu-brest.fr
Contact: Marie DURANTI marie.duranti@chu-brest.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04217447
Other Study ID Numbers  ICMJE 29BRC19.0116
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Hospital, Brest
Study Sponsor  ICMJE University Hospital, Brest
Collaborators  ICMJE Bayer
Investigators  ICMJE Not Provided
PRS Account University Hospital, Brest
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP