PROACT Xa - A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban

Study Overview
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Brief Summary
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Currently, warfarin is the only approved anticoagulation for patients with mechanical valves. The purpose of this study is to determine if participants with an On-X Prosthetic Heart Valve / On-X aortic valve can be maintained safely and effectively on apixaban. Both the On-X aortic valve and apixaban have been approved for use by the US Food and Drug Administration (FDA) but they have not been approved to be used together.

Detailed Description
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There is an unmet clinical need for an alternative to warfarin, such as a direct oral anticoagulant (DOAC), as anticoagulation in participants with an aortic mechanical prosthetic valve. Some participants may be genetically hyper- or hypo-responsive to warfarin, which makes management difficult. Another small group of participants is allergic to warfarin. A much larger group of participants has difficulty maintaining warfarin control due to dietary and drug interactions. Finally, the requirement for routine blood testing makes people reluctant to take warfarin. All of these factors drive younger participants in need of aortic valve replacement (AVR) toward selection of a tissue valve instead of a mechanical valve. Despite multiple studies (randomized, matched and risk adjusted) that show that tissue valves are associated with worse outcomes, younger participants choose this type of valve to avoid warfarin. In addition, multiple clinical studies have shown valve reoperation rates are higher for tissue valves used in these younger participants. Providing an alternative to warfarin anticoagulation may lead younger participants to choose a mechanical valve with greater durability and better clinical outcomes.

Official Title
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A Prospective, Randomized, Active (Warfarin) Controlled, Parallel-arm Clinical Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely and Effectively on Apixaban

Conditions
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Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Failure

Intervention / Treatment
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* Drug: Apixaban 5 MG
* Drug: Apixaban 2.5 MG
* Drug: Warfarin
* Device: On-X Aortic Mechanical Valve


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female at least 18 years of age at the time of giving informed consent. Participants currently receiving warfarin anticoagulation and who are able to receive warfarin with a target INR 2.0 to 3.0. Participants are able to take low-dose aspirin at a dose of 75 -100 mg daily or have a documented contraindication to aspirin use. Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago. Female participants of childbearing potential, including those who are less than 2 years post-menopausal, must agree to, and comply with using a highly effective method of birth control (eg, barrier contraceptives [condom or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], intrauterine devices or sexual abstinence) while partaking in this study. In addition, all women of childbearing potential must agree to continue to use birth control throughout the study until last study visit. Informed of the full nature and purpose of the study, including possible risks and side effects, given ample time and opportunity to read and understand this information, and sign and date the written informed consent before inclusion in the study. Exclusion Criteria: Mechanical valve in any position other than aortic valve. Any cardiac surgery in the three months (90 days) prior to enrollment. Need to be on aspirin >100 mg daily or a P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel, or ticlopidine). Known hypersensitivity or other contraindication to apixaban. On dialysis or a creatinine clearance < 25 mL/min. Ischemic stroke or intracranial hemorrhage within 3 months. Active pathological bleeding at the time of screening for enrollment. Active endocarditis at the time of screening for enrollment. Pregnant, plan to become pregnant, or are breast feeding. On concomitant combined strong P-gp and CYP3A4 inducers or inhibitors. History of non-compliance with recommended monthly INR testing.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Parallel control and treatment arm at a 1:1 ratio.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apixaban<br>Apixaban 5 mg twice daily(BID) or 2.5 mg BID | Drug: Apixaban 5 MG<br>* For patients that do NOT meet the following criteria age ≥ 80 years weight ≤ 60 kilograms creatinine ≥ 1.5 mg/dL (133 micromol/L)<br>Drug: Apixaban 2.5 MG<br>* For patients that meet at least 2 of the following criteria age ≥ 80 years weight ≤ 60 kilograms creatinine ≥ 1.5 mg/dL (133 micromol/L)<br>Device: On-X Aortic Mechanical Valve<br>* Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.<br>* Other names: On-X Ascending Aortic Prosthesis (AAP);|
| Active Comparator: Warfarin<br>Patients randomized to the warfarin arm will continue warfarin in the INR range of (2.0-3.0) | Drug: Warfarin<br>* Active Control Intervention<br>Device: On-X Aortic Mechanical Valve<br>* Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.<br>* Other names: On-X Ascending Aortic Prosthesis (AAP);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-Primary Efficacy Objective | To determine if apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) for patients with an On-X mechanical heart valve implanted in the aortic position for the primary composite outcome of valve thrombosis and valve-related thromboembolism. | 2 years | 
| Co-Primary Efficacy Objective | To determine if apixaban provides acceptable anticoagulation for patients with an On-X mechanical heart valve implanted in the aortic position for the primary composite outcome of valve thrombosis and valve-related thromboembolism compared with an objective performance criterion. | 2 years | 
| Number of major bleeding events (superiority) | To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) in the safety outcome of major bleeding in patients with an On-X mechanical heart valve implanted in the aortic position. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of valve-related thrombotic events (superiority) | To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the primary composite outcome of valve thrombosis and valve-related thromboembolism in patients with an On-X mechanical heart valve implanted in the aortic position. | 2 years | 
| Secondary Efficacy Objective | To compare apixaban with warfarin (INR target range 2.0 - 3.0) for the individual components of the primary outcome (valve thrombosis and valve-related thromboembolism) in patients with an On-X mechanical heart valve implanted in the aortic position. | 2 years | 
| Secondary Efficacy Objective | To compare apixaban with warfarin (INR target range 2.0 - 3.0) for the primary composite outcome of valve thrombosis and valve-related thromboembolism in prespecified subgroups of patients with an On-X mechanical heart valve implanted in the aortic position. | 2 years |