Comparison of a Rivaroxaban-based Strategy With an Antiplatelet-based Strategy Following Successful TAVR for the Prevention of Leaflet Thickening and Reduced Leaflet Motion as Evaluated by Four-dimensional, Volume-rendered Computed Tomography (4DCT)

Study Overview
=================
Brief Summary
-----------------
The aortic valve is located between the left ventricle and the aorta. Patients with symptomatic, severe aortic valve stenosis conventionally have it surgically replaced requiring direct access to the heart through the chest. Transcatheter aortic valve replacement (TAVR) is now a well-established alternative for treating severe aortic valve stenosis. Both types of intervention improve prognosis and alleviate symptoms. The optimal choice of blood thinning therapy after TAVR is unknown. It has been reported that leaflet thrombosis with reduced leaflet motion can occur and this phenomenon has been suggested to be potentially related with neurological events. In addition, the occurence of this phenomenon can be reduced with anticoagulation blood thinning therapy. The purpose of this study is to evaluate if anticoagulation compared to the usual double platelet inhibitor therapy after TAVR can reduce the risk of leaflet thrombosis.

Detailed Description
-----------------
BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become an established therapeutic option for patients with symptomatic, severe aortic valve stenosis, who are ineligible or at high risk for conventional surgical aortic valve replacement (SAVR). It was recently reported that leaflet thickening and reduced leaflet motion, verified by four-dimensional computed tomography (4DCT), was not uncommon after both TAVR and SAVR. It has been emphasized that this phenomenon should be further investigated for its effect on clinical outcomes (e.g. stroke) and valve durability. As this valve leaflet thickening and reduced motion could be reversed by oral anticoagulant (OAC) treatment and was not observed in patients on chronic OAC therapy, it has been hypothesized that this phenomenon could be related to possible leaflet thrombosis or a thrombotic film on the leaflets. AIM: To evaluate whether a rivaroxaban-based strategy, following successful TAVR, compared to an antiplatelet-based strategy, is superior in reducing subclinical valve leaflet thickening and motion abnormalities - as detected by 4DCT-scan. POPULATION: All patients undergoing successful TAVR by ileofemoral or subclavian access with an approved TAVR device will be screened for eligibility. Included subjects must provide written informed consent. Inclusion and exclusion criteria are listed below. DESIGN: The GALILEO-4D trial will be conducted as a substudy of the multicenter, open-label, randomized, event-driven, active-controlled GALILEO trial. Patients will be 1:1 randomized to an antiplatelet-based strategy vs. rivaroxaban-based strategy - the randomization will adopt the same 1:1 randomization of the main GALILEO trial. In case the GALILEO-4D trial should still be continued after completion of the main GALILEO trial, this 1:1 randomization will be continued until inclusion of 150 patients in both treatment groups. In total, 300 patients will be randomized in the GALILEO-4D trial. INTERVENTION: Subjects in the GALILEO-4D substudy will receive the same intervention as in the main GALILEO study. In addition, a 4DCT-scan and echocardiography will be performed at 90 days after randomization. END POINTS: The primary endpoint constitutes the rate of patients with at least one prosthetic leaflet with > 50% motion reduction as assessed by cardiac 4DCT-scan (total N = 300). The secondary endpoints are listed below.

Official Title
-----------------
Randomized Comparison of a Rivaroxaban-based Strategy With an Antiplatelet-based Strategy Following Successful TAVR for the Prevention of Leaflet Thickening and Reduced Leaflet Motion as Evaluated by Four-dimensional, Volume-rendered Computed Tomography (4DCT) - Substudy of the GALILEO-trial

Conditions
-----------------
Aortic Valve Stenosis, Cardiovascular Diseases, Heart Valve Diseases, Ventricular Outflow Obstruction, Thrombosis

Intervention / Treatment
-----------------
* Drug: Acetylsalicylic acid
* Drug: Clopidogrel
* Drug: Rivaroxaban


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Successful TAVR of a native aortic valve stenosis By iliofemoral or subclavian access With any approved/marketed TAVR device Written informed consent Exclusion Criteria: Atrial fibrillation (AF), current or previous, with an ongoing indication for oral anticoagulant treatment Any other indication for continued treatment with any oral anticoagulant Known bleeding diathesis (such as but not limited to platelet count ≤ 50,000/mm3 at screening, hemoglobin level < 8.5 g/dL or < 5.3 mmol/l, history of intracranial hemorrhage, or subdural hematoma) Any indication for dual antiplatelet therapy (DAPT) for more than three months after randomization (such as coronary, carotid, or peripheral stent implantation) Clinically overt stroke within the last three months Planned coronary or vascular intervention or major surgery Severe renal insufficiency (eGFR < 30 mL/min/1.73 m2) or on dialysis, or post-TAVR unresolved acute kidney injury with renal dysfunction ≥ stage 2 Moderate and severe hepatic impairment (Child-Pugh Class B or C) or any hepatic disease associated with coagulopathy Iodine contrast allergy or other condition that prohibits CT imaging

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ASA + Clopidogrel<br>ASA (Acetylsalicylic acid) 75-100mg + Clopidogrel 75mg for 90 days, followed by ASA 75-100mg monotherapy | Drug: Acetylsalicylic acid<br>* Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1)<br>* Other names: Asprin;Drug: Clopidogrel<br>* Drug: Clopidogrel 75 mg OD for first 90 days<br>* Other names: Plavix;|
| Experimental: Rivaroxaban + ASA<br>Rivaroxaban 10mg + ASA 75-100mg for 90 days, followed by rivaroxaban 10mg monotherapy | Drug: Acetylsalicylic acid<br>* Drug: Acetylsalicylic acid: 75 - 100 mg OD (for first 90 days only in arm 1)<br>* Other names: Asprin;Drug: Rivaroxaban<br>* Drug: Rivaroxaban (Xarelto): 10 mg OD (once-daily)<br>* Other names: Xarelto;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Patients With at Least One Prosthetic Leaflet With >50% Motion Reduction as Assessed by Cardiac 4DCT-scan | Reduced systolic leaflet excursion is classified as: (I) normal, (II) mildly reduced (<50%), (III) moderate to severely reduced (>50%), and (IV) immobile. Reduced systolic leaflet excursion is considered significant when it is > 50% or immobile. Quantitative assessment of leaflet motion is performed with a blood pool inversion volume rendered cine reconstruction throughout the cardiac cycle evaluating the bioprosthetic leaflets. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of Prosthetic Leaflets With > 50% Motion Reduction as Assessed by Cardiac 4DCT-scan | The rate of prosthetic leaflets with RLM> grade 3 as assessed by cardiac 4DCT | 3 months | 
| The Rate of Patients With at Least One Prosthetic Leaflet With Thickening as Assessed by Cardiac 4DCT-scan | The rate of patients with at least one prosthetic leaflet with hypoattenuated leaflet thickening (HALT) as assessed by cardiac 4DCT. | 3 months | 
| The Rate of Prosthetic Leaflets With Thickening as Assessed by Cardiac 4DCT-scan | The rate of prosthetic leaflet with HALT as assessed by cardiac 4DCT-scan | 3 months | 
| Aortic Transvalvular Mean Pressure Gradient (mmHg) as Determined by Transthoracic Echocardiography. | Transprosthetic mean pressure gradiënt as determined by transthoracic echocardiography at three months after randomization. scale [0-100] | 3 months | 
| Effective Orifice Area (cm^2) as Determined by Transthoracic Echocardiography. | Effective orifice area (cm2) as determined by transthoracic echocardiography at three months after randomization. scale [0.1-4.0] | 3 months | 
| Death Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (HALT) - as Exploratory Analysis. | Death, Dichotomization by HALT | 3 months | 
| Death Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (RLM)- as Exploratory Analysis. | Death, Dichotomization by RLM | 3 months | 
| Thromboembolic Event Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (HALT)- as Exploratory Analysis. | Thromboembolic event, Dichotomization by HALT | 3 months | 
| Thromboembolic Event Assessed in the Main GALILEO Study and Analyzed in the GALILEO-4D Substudy With Regards to Occurence of the Leaflet Abnormalities (RLM) - as Exploratory Analysis. | Thromboembolic event, Dichotomization by RLM | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart Valve Disease, Randomized Controlled Trial, Transcatheter Aortic Valve Replacement, TAVR, Valve Thrombosis