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Symptomatic Aortic StenosisPhase 3ATLANTISNCT02664649

Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis

A Phase 3 study testing Apixaban in people with Symptomatic Aortic Stenosis and Eligible for Transcatheter Aortic Valve Replacement, run by Assistance Publique - Hôpitaux de Paris at 4 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Apixaban
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,510 participants
Where
4 sitesin 4 countries
Study dates
26 Aug 2016to 15 Oct 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 25Show fewer
  • 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.

Who cannot join

None listed.

Trial locations and contacts

4 sites in 4 countries.

4 sites in 4 countries

France1 site
  • ACTION Study Group, Institut de Cardiologie, Centre Hospitalier Universitaire Pitié Salpêtrière (APHP), UPMC

    Paris, 75013

Other trials in France

Germany1 site
  • Division of Cardiology and Angiology II, University Heart Center Freiburg

    Bad Krozingen, Südring 15, 79189

Other trials in Germany

Italy1 site
  • Unità Operativa di Cardiologia Fondazione Gabriele Monasterio C.N.R.

    Massa, Via Aurelia Sud, 54100

Other trials in Italy

Spain1 site
  • Hospitalet de Llobregat-Hospital Universitari de Bellvitge

    Barcelona, Cardiologia Feixa Llarga, S/n, 08907

Other trials in Spain

About this study

Official title: 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).

Read the 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.

Being tested
Apixaban, Standard of care
Keywords
TAVR, Apixaban, Anticoagulant, VKA, Antiplatelet therapy, Aortic stenosis
Medical subject headings
Aortic Valve Stenosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ApixabanDrug

    Also called Brand name : Eliquis drug class : anticoagulant, factor-Xa inhibitor

    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
  • Standard of careDrug

    VKA or Antiplatelet therapy

Study groups in NCT02664649
Study groupRoleWhat they receive
ApixabanExperimentalInvestigational 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
Receives: Drug: Apixaban
Standard of careActive comparatorVKA or Antiplatelet therapy
Receives: Drug: Standard of care

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: up to 13 months

Secondary outcomes (5)
  1. 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

    Measured: from screening to randomization

  2. 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.

    Measured: up to 13 months

  3. Minor bleedings (BARC 2 or 3a)

    occurrence of any Minor bleedings (BARC 2 or 3a)

    Measured: up to 13 months

  4. Any bleeding

    occurrence of any bleeding

    Measured: up to 13 months

  5. Any evidence for valve thrombosis including hypoattenuated leaflet thickening (HALT)

    Valve thrombosis including hypoattenuated leaflet thickening (according to ETT results)

    Measured: up to 13 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2016 (estimated)
  2. Study start26 Aug 2016
  3. Primary completion15 Oct 2020
  4. Study completion15 Oct 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,510 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02664649
Sponsor's protocol ID
P141102
Other IDs
2015-001676-21, 2015
Acronym
ATLANTIS
Status last verified
Feb 2021
First submitted
30 Sep 2015
Last updated
25 Feb 2021
Results posted
No
Data monitoring committee
Yes

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.

    PubMed 36137682
  • 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.

    PubMed 35583186
  • 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.

    PubMed 29898848
  • 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.

    PubMed 29536857

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Apixaban in people with Symptomatic Aortic Stenosis and Eligible for Transcatheter Aortic Valve Replacement, run by Assistance Publique - Hôpitaux de Paris at 4 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in France, Germany, Italy, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02664649, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2021.

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