Apixaban for the Prevention of Latent Biological Valve Thrombosis

Study Overview
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Brief Summary
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Background: The optimal antithrombotic strategy early after aortic valve replacement surgery with a biological valve remains controversial due to lack of high-quality evidence. Either oral anticoagulants or acetylsalicylic acid should be considered for the first three months. Hypo-attenuated leaflet thickening on cardiac compute tomography has been associated with latent bioprosthetic valve thrombosis and may be prevented with anticoagulation. The investigators hypothesize that anticoagulation with apixaban is superior to single antiplatelet therapy with acetylsalicylic acid in reduction of hypo-attenuated leaflet thickening of bioprosthetic valves after aortic valve replacement. Methods: In this prospective, open-label, randomized trial patients without an indication for oral anticoagulation undergoing isolated aortic valve replacement surgery with novel rapid-deployment bioprosthetic valves will be randomized. The treatment group will receive 5 mg of apixaban twice a day for the first three months and 100 mg of acetylsalicylic acid thereafter. The control group will have 100 mg of acetylsalicylic acid once a day indefinitely. After the three-month treatment period a contrast enhanced electrocardiogram-gated cardiac computed tomography will be performed to identify hypo-attenuated leaflet thickening of the bioprosthetic valve. The primary objective of the study is to assess possible superiority of the treatment group in the prevention of hypo-attenuated leaflet thickening three months after randomization. Secondary objective is to assess possible noninferiority for safety of apixaban-based strategy when compared to acetylsalicylic acid at three months. Discussion: Antithrombotic therapy after aortic valve replacement surgery is used to prevent valve thrombosis and systemic thromboembolism. Latent bioprosthetic valve thrombosis is a precursor of clinically significant prosthetic valve dysfunction or thromboembolic event. The hallmark feature of latent bioprosthetic valve thrombosis is hypo-attenuated leaflet thickening on cardiac computed tomography. Subclinical leaflet thrombosis occurs frequently in bioprosthetic aortic valves, more commonly in transcatheter than in surgical valves. There is no evidence on the effect of direct oral anticoagulants on the incidence of hypo-attenuated leaflet thickening after surgical aortic valve replacement with rapid deployment bioprostheses.

Official Title
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Comparison of Apixaban and Aspirin for the Prevention of Latent Bioprosthetic Valve Thrombosis After Aortic Valve Replacement Surgery: Study Protocol for a Prospective Randomized Trial

Conditions
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Aortic Valve Replacement, Antithrombotic Therapy, Bioprosthetic Valve Thrombosis, Rapid Deployment Valves

Intervention / Treatment
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* Procedure: Aortic valve replacement surgery
* Diagnostic Test: Computed tomography
* Diagnostic Test: Echocardiography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Men and women aged 65 or older with aortic valve stenosis undergoing successful isolated first-time aortic valve replacement with a rapid deployment bioprosthetic valve Signed informed consent to participate in the research Exclusion Criteria: Indication for long-term use of anticoagulant therapy Indication for dual antiplatelet therapy Contraindication to anticoagulation or antiplatelet therapy Inability to start the study drug within the planned randomization period History of atrial fibrillation Known hemorrhagic diathesis Presence of other significant heart pathology Prior open-heart surgery Presence of liver failure or other coagulopathy Aortic valve infective endocarditis Severe renal failure Allergy to iodine contrast

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Arm<br>Patients randomised to the intervention arm will receive an open-label dose adjusted apixaban twice a day. The treatment will be continued for three months. After the tree-month treatment period apixaban will be stopped and acetylsalicylic acid will be started. | Procedure: Aortic valve replacement surgery<br>* Patients undergoing first-time isolated aortic valve replacement with a rapid deployment biological prosthesis.<br>Diagnostic Test: Computed tomography<br>* All the study patients will undergo a computed tomography imaging to assess for hypo-attenuated leaflet thickening and reduced leaflet mobility of the biological prosthesis following the three-month treatment period.<br>Diagnostic Test: Echocardiography<br>* All the study patients will undergo a transthoracic echocardiography before hospital discharge and following the three-month treatment period.<br>|
| Active Comparator: Control Arm<br>Patients assigned to the control arm will receive an open-label low dose acetylsalicylic acid indefinitely. | Procedure: Aortic valve replacement surgery<br>* Patients undergoing first-time isolated aortic valve replacement with a rapid deployment biological prosthesis.<br>Diagnostic Test: Computed tomography<br>* All the study patients will undergo a computed tomography imaging to assess for hypo-attenuated leaflet thickening and reduced leaflet mobility of the biological prosthesis following the three-month treatment period.<br>Diagnostic Test: Echocardiography<br>* All the study patients will undergo a transthoracic echocardiography before hospital discharge and following the three-month treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with hypo-attenuated leaflet thickening | Hypo-attenuated leaflet thickening is identified as increased thickness of one or more leaﬂets of the bioprosthetic valve on contrast-enhanced electrocardiogram gated cardiac computed tomography. Grade 3 on a 4-tier semiquantitative grading scale describes more than 50% and less than 75% of leaflet involvement. Grade 3 or higher of hypo-attenuated leaflet thickening of at least one bioprosthetic valve leaflet will be considered. | At the end of treatment at 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with bleeding, thromboembolic event, or death | The safety composite outcome will be comprised of all types of VARC-3 bleeding events, thromboembolic events (myocardial infarction and stroke), and death from any cause. | From enrolment to the end of treatment at 3 months |