Aortic Valve Disease, Aortic Valve Stenosis, Aortic Valve Failure
Conditions
Brief summary
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
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.
Interventions
DRUGApixaban 5 MG
For patients that do NOT meet the following criteria * age ≥ 80 years * weight ≤ 60 kilograms * creatinine ≥ 1.5 mg/dL (133 micromol/L)
DRUGApixaban 2.5 MG
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)
DRUGWarfarin
Active Control Intervention
DEVICEOn-X Aortic Mechanical Valve
Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.
Sponsors
Duke Clinical Research Institute
Artivion Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parallel control and treatment arm at a 1:1 ratio.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Valve Thrombosis and Valve-related Thromboembolism | through study closure, a median follow-up of 13.5 months | Valve thrombosis was defined as any thrombus, not caused by infection, attached to or near an implanted On-X valve that occluded part of the blood-flow path, interfered with valve function, or was sufficiently large to warrant treatment other than continued oral anticoagulation. Valve-related thromboembolism was defined as any thromboembolic stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism to an organ or limb that was not associated with infection or an intracardiac tumor and was definitely or possibly related to the valve. |
| Major Bleeding | through study closure, a median follow-up of 13.5 months | Major bleeding defined as any episode of internal or external bleeding that caused death, hospitalization, or permanent injury or necessitated transfusion, pericardiocentesis, or reoperation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Apixaban Apixaban 5 mg twice daily(BID) or 2.5 mg BID
Apixaban 5 MG: For patients that do NOT meet the following criteria
* age ≥ 80 years
* weight ≤ 60 kilograms
* creatinine ≥ 1.5 mg/dL (133 micromol/L)
Apixaban 2.5 MG: 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)
On-X Aortic Mechanical Valve: Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago. | 433 |
| Warfarin Patients randomized to the warfarin arm will continue warfarin in the INR range of (2.0-3.0)
Warfarin: Active Control Intervention
On-X Aortic Mechanical Valve: Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago. | 430 |
| Total | 863 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 4 | 13 |
| Overall Study | Withdrawal by Subject | 9 | 16 |
Baseline characteristics
| Characteristic | Apixaban | Warfarin | Total |
|---|---|---|---|
| Age, Customized | 56 years | 55 years | 56 years |
| BMI | 29.9 kg/m^2 | 30.1 kg/m^2 | 29.9 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants | 20 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 400 Participants | 406 Participants | 806 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 3 participants | 5 participants | 8 participants |
| Race/Ethnicity, Customized Black or African American | 8 participants | 14 participants | 22 participants |
| Race/Ethnicity, Customized Multiracial | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Other | 7 participants | 3 participants | 10 participants |
| Race/Ethnicity, Customized Unknown | 17 participants | 13 participants | 30 participants |
| Race/Ethnicity, Customized White | 395 participants | 390 participants | 785 participants |
| Sex: Female, Male Female | 102 Participants | 105 Participants | 207 Participants |
| Sex: Female, Male Male | 331 Participants | 325 Participants | 656 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 433 | 1 / 430 |
| other Total, other adverse events | 16 / 433 | 6 / 430 |
| serious Total, serious adverse events | 11 / 433 | 18 / 430 |
Outcome results
Primary
Composite of Valve Thrombosis and Valve-related Thromboembolism
Valve thrombosis was defined as any thrombus, not caused by infection, attached to or near an implanted On-X valve that occluded part of the blood-flow path, interfered with valve function, or was sufficiently large to warrant treatment other than continued oral anticoagulation. Valve-related thromboembolism was defined as any thromboembolic stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism to an organ or limb that was not associated with infection or an intracardiac tumor and was definitely or possibly related to the valve.
Time frame: through study closure, a median follow-up of 13.5 months
Population: Patient years is determined by the number of events in the Intention to Treat group (all randomized participants) divided by the amount of person-time at risk.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | Composite of Valve Thrombosis and Valve-related Thromboembolism | 20 events per patient-years |
| Warfarin | Composite of Valve Thrombosis and Valve-related Thromboembolism | 6 events per patient-years |
Primary
Major Bleeding
Major bleeding defined as any episode of internal or external bleeding that caused death, hospitalization, or permanent injury or necessitated transfusion, pericardiocentesis, or reoperation.
Time frame: through study closure, a median follow-up of 13.5 months
Population: On treatment group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | Major Bleeding | 17 event |
| Warfarin | Major Bleeding | 21 event |