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Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis (ATLANTIS)

This study is currently recruiting participants.
Verified February 2017 by Assistance Publique - Hôpitaux de Paris
Sponsor:
ClinicalTrials.gov Identifier:
NCT02664649
First Posted: January 27, 2016
Last Update Posted: February 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Action Research Group
Bristol-Meyers Squibb & Pfizer
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
  Purpose

ATLANTIS is a multicenter, phase IIIb, prospective, open-label, randomized trial.

The objective of this study is to demonstrate superiority of a strategy of anticoagulation with apixaban (Anti-Xa Group) as compared to the current standard of care in patients who have undergone a successful TAVI procedure.

The randomization is stratified according to the presence or not of a mandatory indication for anticoagulation for a reason other than the TAVI procedure (e.g. atrial fibrillation or DVT/PE).


Condition Intervention Phase
Symptomatic Aortic Stenosis Eligible for Transcatheter Aortic Valve Replacement Drug: Apixaban Drug: Standard of care Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Composite of death, myocardial infarction, stroke, systemic embolism, intracardiac or bioprosthesis thrombus, any episode of deep vein thrombosis or pulmonary embolism, life-threatening or disabling or major bleeding at one year follow-up. [ Time Frame: up to 13 months ]
    life-threatening or disabling or major bleeding defined according to th VARC-2 définitions over one year follow-up.


Secondary Outcome Measures:
  • Presence or not of an indication (other than TAVI) for anticoagulation described in the medical record. [ Time Frame: from screening to randomization ]
    Information present in the medical record of the patient

  • First occurrence of any event of the following composite criteria: a) Death, MI, any stroke through one year of randomization, b) Death, any stroke/TIA or systemic embolism c) Each individual parameter of the primary endpoint [ Time Frame: up to 13 months ]
    life-threatening (including fatal) or disabling or major bleeding (BARC 4, 3a, b and c) (primary safety endpoint) as defined according to VARC-2.


Estimated Enrollment: 1510
Actual Study Start Date: August 26, 2016
Estimated Study Completion Date: April 2, 2019
Estimated Primary Completion Date: April 2, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Apixaban

Investigational Product is open label apixaban 5 mg tablets taken orally two times a day for 12 months. Subjects with 2 or more of the following characteristics will take apixaban 2.5 mg tablets orally twice daily: age ≥80 years, body weight <60 kg, serum creatinine ≥1.5 mg/dL [133 μMol/L].

- Also, subjects with severe renal insufficiency [calculated Creatinine Clearance (Cr.Cl.) (Cockroft-Gault) between 15-29 ml/min] will take apixaban 2.5 mg tablets orally twice daily

Drug: Apixaban

Investigational Product is open label apixaban 5 mg tablets taken orally two times a day for 12 months. Subjects with 2 or more of the following characteristics will take apixaban 2.5 mg tablets orally twice daily: age ≥80 years, body weight <60 kg, serum creatinine ≥1.5 mg/dL [133 μMol/L].

- Also, subjects with severe renal insufficiency [calculated Creatinine Clearance (Cr.Cl.) (Cockroft-Gault) between 15-29 ml/min] will take apixaban 2.5 mg tablets orally twice daily

Other Name: Brand name : Eliquis drug class : anticoagulant, factor-Xa inhibitor
Active Comparator: Standard of care
VKA or Antiplatelet therapy
Drug: Standard of care
VKA or Antiplatelet therapy

Detailed Description:

Guidelines on antithrombotic therapy after TAVI are scarce and no randomized evaluation has been performed to demonstrate what the optimal antithrombotic strategy is. The rates of major stroke and of major bleeding on DAPT, the standard of care in TAVI (Class IIb LOE C), are respectively as high as 3% and 10% within the first 30 days excluding the perioperative period. In addition, the rate of MACCE is estimated to be of 15% on DAPT. However, more than half of senior patients display high on-clopidogrel platelet reactivity, less than 1/3 undergo coronary stent implantation prior to valve replacement and more than 1/3 display transient atrial fibrillation (AF) during hospital stay. Anticoagulation appears therefore to be underused in this high stroke risk population and has never been evaluated in post-TAVI procedures. Non-vitamin K Oral Anticoagulants (NOAC) have shown superiority or non-inferiority versus VKA to prevent cardio-embolic events with a consistent reduction in intracranial bleeds in patients with non-valvular AF. Apixaban, a direct anti-Xa inhibitor, is the only NOAC which has demonstrated a mortality benefit associated with significant reductions in embolism and major bleeding versus VKA. In addition, apixaban is the only NOAC which has demonstrated superiority over aspirin to prevent cardio-embolic events with a similar safety profile in non-valvular AF patients with a contraindication to VKA. The investigators therefore formulate the hypothesis that apixaban is superior to SOC to prevent cardiovascular events in post-TAVI procedures.

The main purpose is to demonstrate superiority of a strategy of anticoagulation with apixaban 5mg bid (Anti-Xa Group) with dose adjustment as compared to the current standard of care (SOC Group = VKA or Antiplatelet therapy) as measured by the time from randomization to the first occurrence of any event of the composite endpoint of death, myocardial infarction, stroke/TIA/systemic embolism, intracardiac or bioprosthesis thrombus, episode of deep vein thrombosis or pulmonary embolism, life-threatening or disabling or major bleeding at one year follow-up defined according to VARC2.

Patients who underwent a clinically successful TAVI procedure. Non-inclusion criteria include any recent acute cardiovascular event, mechanical heart valve, necessary use of prasugrel or ticagrelor (new P2Y12 inhibitors), concomitant medical illness associated with reduced survival, end stage renal failure defined as a creatinine clearance < 15mL/min.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients after clinically successful TAVI procedures irrespective of prior antithrombotic treatment are eligible for randomization.
  • Ability to understand and to comply with the study protocol.
  • Written informed consent.
  • Men and women ≥18 years of age.

Exclusion Criteria:

  • Creatinine Clearance < 15mL/min (Cockcroft formula) or patient undergoing dialysis.
  • Mechanical valves.
  • Known severe mitral valve stenosis requiring an intervention.
  • Unsuccessful TAVI requiring re-intervention.
  • Ongoing major bleeding or vascular complication (patients may become candidate to the study once stabilized).
  • Prior history of haemorrhagic stroke with and absolute contraindication to any type of oral anticoagulation therapy (VKA or apixaban) or antiplatelet therapy.
  • Recent cerebro-vascular event (CVE) or transient ischemic attack on anticoagulant therapy - Cardiogenic shock manifested by low cardiac output, vasopressor or respiratory dependence, or mechanical hemodynamic support.
  • Planned major surgery during follow-up defined as high-bleeding risk according to ESC/EHRA and requiring interruption of the study drug with bridging
  • Concomitant medical illness (terminal malignancy) that is associated with expected survival less than one year.
  • Concomitant use of prasugrel or ticagrelor.
  • Following concomitant treatments that are potent inhibitors of CYP3A4: azole antifungals (itracozanole and ketoconazole), macrolide antibiotics (clarithromycine and telithromycin), and protease inhibitors (ritonavir, indinavir, nelfinavir and aquinavir) and nefazadone.
  • Women of childbearing potential (WOCBP)*.
  • Men who are sexually active with WOCBP* partners.

    *Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes

  • Pregnancy and breast feeding.
  • Currently participating in an investigational drug or another device trial within the previous 30 days.
  • Known Liver affection associated with coagulopathy and medical significant risk of bleeding.
  • Active cancer.
  • Inability to give informed consent or high likelihood of being unavailable for follow-up.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02664649


Contacts
Contact: Jean-Philippe COLLET, MD, PhD +33 (0)1 42 16 29 62 jean-philippe.collet@aphp.fr

Locations
France
ACTION Study Group, Institut de Cardiologie, Centre Hospitalier Universitaire Pitié Salpêtrière (APHP), UPMC Recruiting
Paris, France, 75013
Contact: Jean-Philippe COLLET, MD, PhD    +33 (0)1 42 16 29 62    jean-philippe.collet@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Action Research Group
Bristol-Meyers Squibb & Pfizer
Investigators
Principal Investigator: Jean-Philippe COLLET Assistance Publique - Hôpitaux de Paris
  More Information

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02664649     History of Changes
Other Study ID Numbers: P141102
2015-001676-21 ( EudraCT Number )
First Submitted: September 30, 2015
First Posted: January 27, 2016
Last Update Posted: February 23, 2017
Last Verified: February 2017

Keywords provided by Assistance Publique - Hôpitaux de Paris:
TAVR
Apixaban
Anticoagulant
VKA
Antiplatelet therapy
Aortic stenosis

Additional relevant MeSH terms:
Constriction, Pathologic
Aortic Valve Stenosis
Pathological Conditions, Anatomical
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction
Apixaban
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action