The Nordic Aortic Valve Intervention Trial 4 (NOTION-4) (NOTION-4)

Prospective Study on the Impact of Different Anti-thrombotic Therapies on Subclinical Leaflet Thickening and Its Temporal Dynamics in Transcatheter Bioprosthetic Aortic Valves (NOTION-4)

A randomized clinical trial investigating the incidence and temporal dynamics of subclinical leaflet thickening by cardiac CT in transcatheter bioprosthetic aortic valves in patients randomised to different anti-thrombotic strategies. Additionally, this study aims to examine a possible association between HALT and thromboembolic events.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Diseases; Cardiovascular Diseases; Aortic Valve Stenosis; Heart Valve Diseases; Valve Disease, Aortic
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Edoxaban; Drug: Dabigatran; Drug: Apixaban; Drug: Acetylsalicylic acid; Drug: Clopidogrel; Drug: Warfarin

Detailed Description

The NOTION-4 trial is an investigator-initiated, randomized, open label, comparative trial conducted at Rigshospitalet in Copenhagen and Skejby Sygehus in Aarhus. All adult patients that have undergone successful TAVI without contraindications for cardiac CT will be invited to participate in this study. Patients with SR and without known other indication for chronic OAC therapy will be randomized 1:1 either to lifelong ASA or to 3 months of DOAC followed by lifelong ASA. Patients with known AF will be randomized 1:1 to lifelong DOAC versus LAAC within 3 months followed by lifelong ASA.

• Study Type: Interventional
• Enrollment (Actual): 352
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital, Skejby
  • Copenhagen, Denmark, 2100
    • Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients who underwent successful TAVI according to Valve Academic Research Consortium (VARC)-2 criteria
• Residing in Denmark
• Provided written informed consent

Exclusion Criteria:

• Atrial fibrillation or any other indication for lifelong oral anticoagulant therapy
• Patient deemed not suitable for DOAC treatment because of previous life-threatening or major bleeding, e.g. intracranial haemorrhage or major gastrointestinal bleeding
• Patients with severe renal insufficiency (eGFR <30 mL/min/1.73 m2)
• Patient with absolute indication for anti-thrombotic therapy, e.g. recent PCI
• Iodine contrast allergy or other condition that prohibits CT imaging
• Age <18 years
• Women of childbearing potential, pregnant or nursing

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: Sinus rhythm - DOAC treatment; Can either of the following anti-platelet components: dabigatran, apixaban, rivaroxaban, edoxaban or warfarin. Duration: 3 months, followed by an anti-platelet hereafter.	Drug: Rivaroxaban; Direct oral anticoagulants (DOAC) treatment will encompass any of the approved drugs: Rivaroxaban, Edoxaban, Dabigatranetexilat, and Apixaban (Table 1). The DOAC dosage will be adjusted according to kidney function (Table 1) and may be adjusted during the study period according to potential changes in guideline recommendations or if new-onset AF would occur in the follow-up period. The specific DOAC prescribed will be determined by the treating physician. If the patient has already been prescribed Marevan before the aortic valve intervention, the patient will continue this medication following the procedure as an oral anticoagulant treatment, which is administered according to current guidelines.; Other Names: SUB29263; Drug: Edoxaban; Direct oral anticoagulants (DOAC) treatment will encompass any of the approved drugs: Rivaroxaban, Edoxaban, Dabigatranetexilat, and Apixaban (Table 1). The DOAC dosage will be adjusted according to kidney function (Table 1) and may be adjusted during the study period according to potential changes in guideline recommendations or if new-onset AF would occur in the follow-up period. The specific DOAC prescribed will be determined by the treating physician. If the patient has already been prescribed Marevan before the aortic valve intervention, the patient will continue this medication following the procedure as an oral anticoagulant treatment, which is administered according to current guidelines.; Other Names: SUB32701; Drug: Dabigatran; Direct oral anticoagulants (DOAC) treatment will encompass any of the approved drugs: Rivaroxaban, Edoxaban, Dabigatranetexilat, and Apixaban (Table 1). The DOAC dosage will be adjusted according to kidney function (Table 1) and may be adjusted during the study period according to potential changes in guideline recommendations or if new-onset AF would occur in the follow-up period. The specific DOAC prescribed will be determined by the treating physician. If the patient has already been prescribed Marevan before the aortic valve intervention, the patient will continue this medication following the procedure as an oral anticoagulant treatment, which is administered according to current guidelines.; Other Names: SUB20521; Drug: Apixaban; Direct oral anticoagulants (DOAC) treatment will encompass any of the approved drugs: Rivaroxaban, Edoxaban, Dabigatranetexilat, and Apixaban (Table 1). The DOAC dosage will be adjusted according to kidney function (Table 1) and may be adjusted during the study period according to potential changes in guideline recommendations or if new-onset AF would occur in the follow-up period. The specific DOAC prescribed will be determined by the treating physician. If the patient has already been prescribed Marevan before the aortic valve intervention, the patient will continue this medication following the procedure as an oral anticoagulant treatment, which is administered according to current guidelines.; Other Names: SUB25425; Drug: Warfarin; If the patient has already been prescribed Marevan before the aortic valve intervention, the patient will continue this medication following the procedure as an oral anticoagulant treatment, which is administered according to current guidelines.; Other Names: SUB05128MIG
Active Comparator: Sinus rhythm - Anti-platelet treatment; Can be either of the following anti-platelet components: acetylsalicylic acid or clopidogrel. Duration: Lifelong	Drug: Acetylsalicylic acid; Antiplatelets decrease platelet aggregation and inhibit thrombus formation. In NOTION-4 acetylsalicylic acid (75 mg once a day) is used as first line choice. For participants who are allergic to acetylsalicylic acid, clopidogrel (75 mg once a day) will be used. If the patient has already been prescribed Clopidogrel before the aortic valve intervention e.g. due to apoplexia, the patient will continue this medication following the procedure as an antiplatelet treatment, which is administered according to current guidelines.; Other Names: SUB12730MIG; Drug: Clopidogrel; Antiplatelets decrease platelet aggregation and inhibit thrombus formation. In NOTION-4 acetylsalicylic acid (75 mg once a day) is used as first line choice. For participants who are allergic to acetylsalicylic acid, clopidogrel (75 mg once a day) will be used. If the patient has already been prescribed Clopidogrel before the aortic valve intervention e.g. due to apoplexia, the patient will continue this medication following the procedure as an antiplatelet treatment, which is administered according to current guidelines.; Other Names: SUB13395MIG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HALT after 1 year	The number of patients with at least one prosthetic valve leaflet with HALT as assessed by cardiac CT at one year after TAVI.	At 1 year after TAVI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of patients with HALT during follow up	The number of patients with at least one prosthetic valve leaflet with HALT as assessed by cardiac CT.	At 3 months, 1 year and 5 years after TAVI
HALT on leaflets	Number of prosthetic leaflets with HALT at CT-scan.	At 3 months, 1 year and 5 years after TAVI
Number of participants with aortic bioprosthetic dysfunction	According to EAPCI/ESC/EACTS definitions	At 3 months, 1 year and 5 years after TAVI
NYHA classification	Assessing NYHA classification over time after TAVI	At 3 months, 1 year and 5 years after TAVI
Number of participants with ischemic stroke	The clinical endpoint of ischemic stroke verified by cerebrovascular imaging after the TAVI-procedure in patients with vs. without HALT.	At 3 months, 1 year and 5 years after TAVI
Number of participants with stroke	Both ischemic and hemorrhagic strokes are included.	At 3 months, 1 year and 5 years after TAVI
Number of participants with all-cause death	All cause mortality	At 3 months, 1 year and 5 years after TAVI
Number of participants with cardiovascular mortality	Cardiovascular mortality as defined in current VARC definition	At 3 months, 1 year and 5 years after TAVI
Number of participants with bleeding	Major bleeding or life-threatening bleeding	At 3 months, 1 year and 5 years after TAVI
Number of participants with re-intervention	valve-in-valve TAVI, paravalvular leak closure, SAVR	At 3 months, 1 year and 5 years after TAVI
Number of participants with bioprosthetic valve failure	Rate of failure according to EAPCI/ESC/EACTS definitions including Rate of valve-related deaths, re-intervention, severe hemodynamic SVD	At 3 months, 1 year and 5 years after TAVI
Quality of life scores with 5-level EQ-5D version (EQ5D-5L)	Assessing changes of quality of life scores after TAVI with 5-level EQ-5D version (EQ5D-5L) where lower scores mean better outcome (score from 1 to 5).	At 3 months, 1 year and 5 years after TAVI
Quality of life scores with EQ Visual Analogue Scale (EQ VAS)	The EQ Visual Analogue Scale (EQ VAS) has minimum score 0 and maximum score 100, where higher scores mean better outcome.	At 3 months, 1 year and 5 years after TAVI
Combined clinical endpoint of all-cause mortality, thromboembolic event, and life-threatening or major bleeding	Combined clinical endpoint of all-cause mortality, thromboembolic event, and life-threatening or major bleeding	At 1 year and 5 years after TAVI

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Aarhus University Hospital Skejby
• Investigators: Principal Investigator: Ole De Backer, PhD, Rigshospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2021
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: July 4, 2023
• First Submitted That Met QC Criteria: June 5, 2024
• First Posted (Actual): June 10, 2024

Study Record Updates

• Last Update Posted (Actual): April 6, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Randomized clinical trial; aortic valve replacement; TAVI; heart valve disease; valvular bioprosthesis; Antitrombotic medication
• Additional Relevant MeSH Terms: Vascular Diseases; Ventricular Outflow Obstruction; Aortic Valve Disease; Aortic Valve Stenosis; Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Aortic Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Protease Inhibitors; Enzyme Inhibitors; Fibrin Modulating Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Antipyretics; Neurotransmitter Agents; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Fibrinolytic Agents; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Clopidogrel; Rivaroxaban; Dabigatran; Aspirin; Apixaban; Warfarin; Edoxaban
• Other Study ID Numbers: 2020-003361-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No