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Study on the Effects of Apixaban, Acetylsalicylic Acid, and Rivaroxaban on Heart Valve Thickening in Patients with Aortic Valve Replacement

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The Nordic Aortic Valve Intervention Trial 4 (NOTION-4) is a clinical study focused on patients who have undergone a successful procedure known as *transcatheter aortic valve implantation* (TAVI). This procedure involves placing a new valve in the heart without removing the old, damaged valve. The study aims to explore the effects of different *anti-thrombotic therapies* on a condition called *subclinical leaflet thickening* in the new valve. Subclinical leaflet thickening, also known as HALT, refers to a situation where the leaflets of the valve become thicker without causing noticeable symptoms. This condition is assessed using a special imaging technique called *cardiac CT*.

The study involves several medications, including *Apixaban*, *Acetylsalicylic Acid* (commonly known as aspirin), *Rivaroxaban*, *Dabigatran Etexilate*, *Edoxaban*, *Clopidogrel*, and *Warfarin Sodium*. These medications are used to prevent blood clots, which can be a concern after valve replacement procedures. Participants in the study are randomly assigned to receive one of these medications or a placebo. The purpose of the study is to understand how these medications affect the thickening of the valve leaflets over time.

Throughout the study, participants will undergo regular check-ups and imaging tests to monitor the condition of their heart valves. The study will track the number of patients experiencing leaflet thickening at various intervals, such as 3 months, 1 year, 3 years, and 5 years after the TAVI procedure. Additionally, the study will observe any related health events, such as strokes or bleeding, and assess overall health outcomes like mortality and quality of life. The study is expected to continue until 2030, providing valuable insights into the long-term effects of different anti-thrombotic treatments on heart valve health.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Joining the study

    Participation begins after successful transcatheter bioprosthetic aortic valve implantation (TAVI).

    Eligibility requires residence in Denmark and written informed consent.

  2. Step 2

    Randomization and medication assignment

    Participants are randomly assigned to different anti-thrombotic therapies.

    Medications include apixaban, acetylsalicylic acid, rivaroxaban, dabigatran etexilate, edoxaban, clopidogrel, and warfarin sodium.

    All medications are administered orally.

  3. Step 3

    Initial assessment

    A cardiac CT scan is performed to assess the presence of subclinical leaflet thickening (HALT).

  4. Step 4

    Follow-up assessments

    Cardiac CT scans are conducted at 3 months, 1 year, 3 years, and 5 years after TAVI to monitor HALT.

    The primary endpoint is the number of patients with at least one prosthetic valve leaflet with HALT at one year.

  5. Step 5

    Monitoring and evaluation

    Secondary endpoints include all-cause mortality, thromboembolic events, and major bleeding at 1, 3, and 5 years.

    Other evaluations include ischemic stroke, any type of stroke, cardiovascular mortality, and need for re-intervention.

  6. Step 6

    Quality of life assessment

    Quality of life scores and NYHA classification are assessed throughout the study.

  7. Step 7

    Study completion

    The study is estimated to conclude by August 14, 2030.

Who can join the trial?

6 criteria

  • Patients who have had a successful procedure called transcatheter bioprosthetic aortic valve implantation (TAVI). This is a type of heart valve replacement done without open-heart surgery.
  • Patients who meet the success criteria set by a group called the Valve Academic Research Consortium (VARC)-2. This group sets standards for how well the TAVI procedure should go.
  • Patients must live in Denmark.
  • Patients need to provide written informed consent. This means they agree to participate in the study after being told all the important details.
  • Both men and women can participate.
  • Participants should not be from a vulnerable population, meaning they should be able to make decisions for themselves and not be in a situation where they are easily influenced or at risk.

Who cannot join the trial?

1 criterion

  • Patients who have had a successful procedure called transcatheter bioprosthetic aortic valve implantation (TAVI) cannot participate. This is a medical procedure where a new valve is placed in the heart without open-heart surgery.
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Investigated drugs

  • Aspirin

    is a medication used to reduce pain, fever, or inflammation. In this trial, it is being used as part of an anti-thrombotic strategy to help prevent blood clots in patients with transcatheter bioprosthetic aortic valves.

  • Clopidogrel

    is a medication that helps prevent blood clots by making it harder for platelets in the blood to stick together. It is being used in this trial to study its effects on preventing subclinical leaflet thickening in heart valve patients.

  • Warfarin

    is a blood thinner that helps prevent the formation of harmful blood clots. In this trial, it is being used to see how well it works in preventing leaflet thickening in patients with heart valve replacements.

  • Rivaroxaban

    is an anticoagulant that helps prevent blood clots by inhibiting a specific protein involved in the clotting process. This trial is using rivaroxaban to study its impact on heart valve leaflet thickening.

  • Apixaban

    is another anticoagulant that works by blocking certain clotting proteins in the blood. It is included in this trial to evaluate its effectiveness in preventing leaflet thickening in patients with heart valve implants.

What is already known about the treatment

  • Aspirin

    Aspirin is typically administered orally in tablet form. It is widely recognized in medical literature as a common anti-thrombotic medication. It is primarily used to reduce the risk of blood clots, which can help prevent heart attacks and strokes. At the molecular level, aspirin works by inhibiting an enzyme called cyclooxygenase, which in turn reduces the production of substances that promote inflammation and clotting. It is classified as a non-steroidal anti-inflammatory drug (NSAID).

  • Clopidogrel

    Clopidogrel is usually taken orally in tablet form. It is well-documented in medical literature as an effective anti-platelet medication. It is mainly prescribed to prevent blood clots in patients with heart conditions or after certain procedures like stent placement. Clopidogrel works by blocking a receptor on platelets, preventing them from sticking together and forming clots. It belongs to the class of medications known as platelet aggregation inhibitors.

Investigated diseases

Subclinical Leaflet Thickening (HALT) – This condition involves the thickening of the leaflets of a bioprosthetic aortic valve, which can occur after a transcatheter aortic valve implantation (TAVI). It is often detected through imaging techniques such as cardiac CT scans. The thickening is termed "subclinical" because it may not present noticeable symptoms in patients. Over time, this thickening can potentially affect the valve's function, although it may remain stable without causing significant issues. The progression of HALT is monitored to understand its impact on valve performance and patient health.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2024-518547-38-00Estimated enrolment350 patientsSponsorRegion Hovedstaden

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