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

Not Applicable

Active, not recruiting

• Conditions: Heart Diseases; Cardiovascular Diseases; Aortic Valve Stenosis; Heart Valve Diseases; Valve Disease, Aortic
• Interventions: Drug: Rivaroxaban; Drug: Acetylsalicylic acid; Drug: Edoxaban; Drug: Clopidogrel; Drug: Dabigatran; Drug: Apixaban; Drug: Warfarin

• Registration Number: NCT06449469
• Lead Sponsor: Rigshospitalet, Denmark

Brief Summary

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.

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 Timeline

• Study Start: 2021-05-01
• Study First Submitted: 2023-07-04
• Study First Submitted QC: 2024-06-05
• Study First Posted: 2024-06-10
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-02
• Last Update Posted: 2025-04-06
• Primary Completion: 2026-04-01
• Study Completion: 2030-04-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 352

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sinus rhythm - DOAC treatment	Rivaroxaban	Can either of the following anti-platelet components: dabigatran, apixaban, rivaroxaban, edoxaban or warfarin. Duration: 3 months, followed by an anti-platelet hereafter.
Sinus rhythm - DOAC treatment	Edoxaban	Can either of the following anti-platelet components: dabigatran, apixaban, rivaroxaban, edoxaban or warfarin. Duration: 3 months, followed by an anti-platelet hereafter.
Sinus rhythm - DOAC treatment	Dabigatran	Can either of the following anti-platelet components: dabigatran, apixaban, rivaroxaban, edoxaban or warfarin. Duration: 3 months, followed by an anti-platelet hereafter.
Sinus rhythm - DOAC treatment	Apixaban	Can either of the following anti-platelet components: dabigatran, apixaban, rivaroxaban, edoxaban or warfarin. Duration: 3 months, followed by an anti-platelet hereafter.
Sinus rhythm - DOAC treatment	Warfarin	Can either of the following anti-platelet components: dabigatran, apixaban, rivaroxaban, edoxaban or warfarin. Duration: 3 months, followed by an anti-platelet hereafter.
Sinus rhythm - Anti-platelet treatment	Acetylsalicylic acid	Can be either of the following anti-platelet components: acetylsalicylic acid or clopidogrel. Duration: Lifelong
Sinus rhythm - Anti-platelet treatment	Clopidogrel	Can be either of the following anti-platelet components: acetylsalicylic acid or clopidogrel. Duration: Lifelong

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Aarhus University Hospital, Skejby; 🇩🇰 Aarhus, Denmark

Rigshospitalet; 🇩🇰 Copenhagen, Denmark