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

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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02664649
Recruitment Status : Active, not recruiting
First Posted : January 27, 2016
Last Update Posted : August 6, 2019
Sponsor:
Collaborators:
Action Research Group
Bristol-Meyers Squibb & Pfizer
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE September 30, 2015
First Posted Date  ICMJE January 27, 2016
Last Update Posted Date August 6, 2019
Actual Study Start Date  ICMJE August 26, 2016
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2018)
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 VARC-2 definitions over one year follow-up.
Original Primary Outcome Measures  ICMJE
 (submitted: January 22, 2016)
Composite of death, myocardial infarction, stroke, peripheral embolism, intracardiac or bioprosthesis thrombus, any episode of deep vein thrombosis or pulmonary embolism, major bleeding at one year follow-up. [ Time Frame: up to 13 months ]
Change History Complete list of historical versions of study NCT02664649 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2018)
  • 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.
  • Minor bleedings (BARC 2 or 3a) [ Time Frame: up to 13 months ]
    occurrence of any Minor bleedings (BARC 2 or 3a)
  • Any bleeding [ Time Frame: up to 13 months ]
    occurrence of any bleeding
  • Any evidence for valve thrombosis including hypoattenuated leaflet thickening (HALT) [ Time Frame: up to 13 months ]
    Valve thrombosis including hypoattenuated leaflet thickening (according to ETT results)
Original Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2016)
  • 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 peripheral embolism c) Each individual parameter of the primary endpoint [ Time Frame: up to 13 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis
Official Title  ICMJE Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis
Brief Summary

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).

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Symptomatic Aortic Stenosis
  • Eligible for Transcatheter Aortic Valve Replacement
Intervention  ICMJE
  • 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
  • Drug: Standard of care
    VKA or Antiplatelet therapy
Study Arms  ICMJE
  • 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

    Intervention: Drug: Apixaban
  • Active Comparator: Standard of care
    VKA or Antiplatelet therapy
    Intervention: Drug: Standard of care
Publications *

*   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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: February 2, 2017)
1510
Original Estimated Enrollment  ICMJE
 (submitted: January 22, 2016)
1509
Estimated Study Completion Date  ICMJE May 31, 2020
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Non-inclusion 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 intracranial haemorrhage.
  • Recent cerebro-vascular event (CVE) or transient ischemic attack on anticoagulant therapy (<6 weeks).
  • 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.
  • Uncontrolled cancer with life expectancy of less than one year.
  • Inability to give informed consent or high likelihood of being unavailable for follow-up.
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Germany,   Italy,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02664649
Other Study ID Numbers  ICMJE P141102
2015-001676-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE
  • Action Research Group
  • Bristol-Meyers Squibb & Pfizer
Investigators  ICMJE
Principal Investigator: Jean-Philippe COLLET Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date August 2019

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