Clinical trial NCT02664649: Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis
Official title: Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Symptomatic Aortic Stenosis
Eligible for Transcatheter Aortic Valve Replacement
Keywords: TAVR
Apixaban
Anticoagulant
VKA
Antiplatelet therapy
Aortic stenosis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Action Research Group
name: Bristol-Meyers Squibb & Pfizer
First posted: 2016-01-27
Enrollment: 1510
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

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.

Primary outcomes:
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.
timeFrame: up to 13 months
Secondary outcomes:
measure: Presence or not of an indication (other than TAVI) for anticoagulation described in the medical record.
timeFrame: from screening to randomization
measure: 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
timeFrame: up to 13 months
measure: Minor bleedings (BARC 2 or 3a)
timeFrame: up to 13 months
measure: Any bleeding
timeFrame: up to 13 months
measure: Any evidence for valve thrombosis including hypoattenuated leaflet thickening (HALT)
timeFrame: up to 13 months
Other outcomes:
Locations:
city: Paris
country: France
facility: ACTION Study Group, Institut de Cardiologie, Centre Hospitalier Universitaire Pitié Salpêtrière (APHP), UPMC
city: Bad Krozingen
country: Germany
facility: Division of Cardiology and Angiology II, University Heart Center Freiburg
state: Südring 15
city: Massa
country: Italy
facility: Unità Operativa di Cardiologia Fondazione Gabriele Monasterio C.N.R.
state: Via Aurelia Sud
city: Barcelona
country: Spain
facility: Hospitalet de Llobregat-Hospital Universitari de Bellvitge
state: Cardiologia Feixa Llarga, S/n
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Philippe COLLET
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.