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

Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis

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).

Study Overview

• Status: Completed
• Conditions: Symptomatic Aortic Stenosis; Eligible for Transcatheter Aortic Valve Replacement
• Intervention / Treatment: Drug: Apixaban; Drug: Standard of care

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: Interventional
• Enrollment (Anticipated): 1510
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • ACTION Study Group, Institut de Cardiologie, Centre Hospitalier Universitaire Pitié Salpêtrière (APHP), UPMC
• Germany
  • Südring 15
    • Bad Krozingen, Südring 15, Germany, 79189
      • Division of Cardiology and Angiology II, University Heart Center Freiburg
• Italy
  • Via Aurelia Sud
    • Massa, Via Aurelia Sud, Italy, 54100
      • Unità Operativa di Cardiologia Fondazione Gabriele Monasterio C.N.R.
• Spain
  • Cardiologia Feixa Llarga, S/n
    • Barcelona, Cardiologia Feixa Llarga, S/n, Spain, 08907
      • Hospitalet de Llobregat-Hospital Universitari de Bellvitge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	life-threatening or disabling or major bleeding defined according to VARC-2 definitions over one year follow-up.	up to 13 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence or not of an indication (other than TAVI) for anticoagulation described in the medical record.	Information present in the medical record of the patient	from screening to randomization
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	life-threatening (including fatal) or disabling or major bleeding (BARC 4, 3a, b and c) (primary safety endpoint) as defined according to VARC-2.	up to 13 months
Minor bleedings (BARC 2 or 3a)	occurrence of any Minor bleedings (BARC 2 or 3a)	up to 13 months
Any bleeding	occurrence of any bleeding	up to 13 months
Any evidence for valve thrombosis including hypoattenuated leaflet thickening (HALT)	Valve thrombosis including hypoattenuated leaflet thickening (according to ETT results)	up to 13 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Action Research Group; Bristol-Meyers Squibb & Pfizer
• Investigators: Principal Investigator: Jean-Philippe COLLET, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Montalescot G, Redheuil A, Vincent F, Desch S, De Benedictis M, Eltchaninoff H, Trenk D, Serfaty JM, Charpentier E, Bouazizi K, Prigent M, Guedeney P, Salloum T, Berti S, Cequier A, Lefevre T, Leprince P, Silvain J, Van Belle E, Neumann FJ, Portal JJ, Vicaut E, Collet JP; ATLANTIS Investigators of the ACTION Group. Apixaban and Valve Thrombosis After Transcatheter Aortic Valve Replacement: The ATLANTIS-4D-CT Randomized Clinical Trial Substudy. JACC Cardiovasc Interv. 2022 Sep 26;15(18):1794-1804. doi: 10.1016/j.jcin.2022.07.014. Epub 2022 Aug 31.
• Collet JP, Van Belle E, Thiele H, Berti S, Lhermusier T, Manigold T, Neumann FJ, Gilard M, Attias D, Beygui F, Cequier A, Alfonso F, Aubry P, Baronnet F, Ederhy S, Kasty ME, Kerneis M, Barthelemy O, Lefevre T, Leprince P, Redheuil A, Henry P, Portal JJ, Vicaut E, Montalescot G; ATLANTIS Investigators of the ACTION Group. Apixaban vs. standard of care after transcatheter aortic valve implantation: the ATLANTIS trial. Eur Heart J. 2022 Aug 1;43(29):2783-2797. doi: 10.1093/eurheartj/ehac242. Erratum In: Eur Heart J. 2022 Aug 03;:
• Collet JP, Berti S, Cequier A, Van Belle E, Lefevre T, Leprince P, Neumann FJ, Vicaut E, Montalescot G. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial. Am Heart J. 2018 Jun;200:44-50. doi: 10.1016/j.ahj.2018.03.008. Epub 2018 Mar 10.
• Piayda K, Zeus T, Sievert H, Kelm M, Polzin A. Subclinical leaflet thrombosis. Lancet. 2018 Mar 10;391(10124):937-938. doi: 10.1016/S0140-6736(18)30534-8. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2016
• Primary Completion (Actual): October 15, 2020
• Study Completion (Actual): October 15, 2020

Study Registration Dates

• First Submitted: September 30, 2015
• First Submitted That Met QC Criteria: January 22, 2016
• First Posted (Estimate): January 27, 2016

Study Record Updates

• Last Update Posted (Actual): February 25, 2021
• Last Update Submitted That Met QC Criteria: February 24, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: VKA; Apixaban; Anticoagulant; Aortic stenosis; Antiplatelet therapy; TAVR
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Constriction, Pathologic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Apixaban; Anticoagulants; Factor Xa Inhibitors
• Other Study ID Numbers: P141102; 2015-001676-21 (EudraCT Number)