Principal Investigator: Craig Selzman
Keywords: Aortic Valve , On-X , Apixaban , Warfarin Department: Cardiothoracic Division
IRB Number: 00133138
Specialty: Cardiothoracic Surgery
Sub Specialties:
Recruitment Status: Not yet recruiting

Contact Information

Alyssa Messina
alyssa.messina@hsc.utah.edu
8015853752

Brief Summary

PROACT Xa is designed to determine if patients with an On-X aortic valve, alone or as an On-X Ascending Aortic Prosthesis, can be maintained safely and effectively on the factor Xa inhibitor apixaban (Eliquis). The primary outcome is a composite rate of valve thrombosis and valve-related thromboembolism, which will be used for co-primary analyses. The first co-primary analysis will determine whether apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) in patients with an On-X mechanical heart valve implanted in the aortic position. The second co-primary analysis will compare the composite rate for apixaban-treated participants to updated OPC for FDA-approved mechanical heart valves in the aortic position. This is an open-label study in which patients who are at least 3 months out from implantation of an On-X valve in the aortic position will be randomized in a 1:1 fashion to either apixaban 5 mg twice daily or 2.5 mg twice daily in selected participants meeting reduced dose criteria or warfarin adjusted to an INR of 2.0-3.0. Participants will be followed for at least 2 years after randomization with at least 800 patient-years of follow-up in each randomized group. If the primary efficacy hypothesis is proven, the data will be used to support a change in the On-X valve device label to state that apixaban is an acceptable alternative to warfarin for anticoagulation in patients 3 or more months after implantation of an On-X valve in the aortic position.

Objectives and Outcomes:
Co-Primary Efficacy Objectives
• 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
• 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 (OPC)1
Primary Safety Objective
• To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the safety outcome of major bleeding in patients with an On-X mechanical heart valve implanted in the aortic position

Secondary Efficacy Objectives

• 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
• 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
• 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 pre-specified subgroups of patients with an On-X mechanical heart valve implanted in the aortic position

 

This is a prospective, multicenter, open-label, randomized active controlled clinical trial to determine if apixaban is non-inferior 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. A co-primary efficacy objective will 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 OPC (Wu et al., 2014). Each participant will be followed for at least 2 years and each randomized arm will achieve at least 800 patient-years.
The study will consist of approximately 1000 participants (randomized 1:1 with approximately 500 participants in each of the apixaban and warfarin arms) at a minimum of 3 sites and up to 60 sites in North America, and potentially in Europe and/or Japan, who are 18 years of age or older, at least 3 months out from an On-X aortic valve implantation, and currently anticoagulated with warfarin.
Participants will be randomized to either continue warfarin with a target INR of 2.0 to 3.0 or switch to apixaban 5 mg twice daily (BID), or 2.5 mg BID in participants with 2 or 3 of the following characteristics:
• age ≥ 80 years
• weight ≤ 60 kilograms
• creatinine ≥ 1.5 mg/dL (133 micromol/L)
For participants randomized to apixaban, INR testing will be performed on the current warfarin dose with the following algorithm to initiate apixaban:
1. INR < 2; stop warfarin and start apixaban
2. INR 2.0 to 3.0; hold warfarin for 2 days, start apixaban on day 3
3. INR > 3.0 to 4.0; hold warfarin for 4 days, start apixaban on day 5
4. INR > 4.0; hold warfarin for 2 days, recheck INR, refer to steps 1, 2, or 3

Inclusion Criteria

Participants are eligible to be included in the study if all of the following criteria apply:
1. Male or female at least 18 years of age at the time of giving informed consent.
2. Able to receive warfarin with a target INR 2.0 to 3.0.
3. Able to take low-dose aspirin at a dose of 75 -100 mg daily or have a documented contraindication to aspirin use.
4. Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) prior to enrollment
5. If female participant of childbearing potential, including those who are less than 2 years post-menopausal, she must agree to and be able to use 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) continuously through the study until the last study visit.  (An amendment will be submitted to add pregnant women if a participant becomes pregnant.)
6. Able to provide written informed consent.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:
1. Mechanical valve in any position other than aortic valve.
2. Any cardiac surgery in the 3 months (90 days) prior to enrollment
3. Need to be on aspirin >100 mg daily or a P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel, or ticlopidine).
4. Known hypersensitivity or other contraindication to apixaban.
5. On dialysis or a creatinine clearance < 25 mL/min.
6. Experienced an ischemic stroke or intracranial hemorrhage within 3 months of screening for enrollment.
7. Active pathological bleeding at the time of screening for enrollment
8. Active endocarditis at the time of screening for enrollment.
9. Pregnant at the time of screening for enrollment, plan to become pregnant at any point during the study, or are breast feeding at the time of screening for enrollment.
10. On concomitant combined strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) inducers or inhibitors
11. History of non-compliance with recommended monthly INR testing