Coronary Artery Bypass Grafting, Deep Venous Thrombosis, Postoperative Atrial Fibrilation, Stroke, Systemic Embolism
Conditions
Keywords
apixaban, anticoagulant, CABG, thrombosis, fibrillation
Brief summary
In this open-label, prospective, randomized pilot study, patients who develop atrial fibrillation after isolated coronary artery bypass grafting surgery will be identified. Patients with persistent atrial fibrillation (\>12 hours) or recurrent sustained atrial fibrillation (\>2 episodes of atrial fibrillation lasting longer than 30 minutes) will be candidates for inclusion. Upon meeting study inclusion and exclusion criteria, and after informed consent, patients will be randomized to either the standard of care (warfarin per protocol) or apixaban arms of the trial. Routine postoperative care after CABG will occur in both groups. Upon discharge, anticoagulation in both groups will be managed by the anticoagulation clinic. Patients will be followed for 30 days after surgery.
Interventions
DRUGApixaban
Study arm that patient can be randomized to. Apixaban is a novel, orally active, potent, direct selective inhibitor of coagulation FXa that directly and reversibly binds to the active site of FXa and exerts anticoagulant and antithrombotic effects by diminishing the conversion of prothrombin to thrombin.
DRUGWarfarin
Study arm that patient can be randomized to. Warfarin therapy has been the mainstay of therapy for patients with POAF. While the duration of therapy is usually short (3-4 weeks), complications of anticoagulation do occur. Additionally, warfarin therapy for POAF is associated with increased length of stay, need for monitoring, and bleeding complications.
Sponsors
Bristol-Myers Squibb
Sanford Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed Written Informed Consent * Patients diagnosed with new-onset persistent or recurrent atrial fibrillation after isolated CABG surgery. Persistent atrial fibrillation is defined as an episode of \>12 hours. Recurrent atrial fibrillation is defined as two or more episodes of atrial fibrillation lasting longer than 30 minutes. * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. Patients undergoing isolated CABG must have this tested and documented prior to the procedure, and this will be verified prior to randomization. * Women must not be breastfeeding. * WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s): 30 days of treatment plus 5 half-lives of study drug Apixaban (3 days) or warfarin (8 days) plus 30 days (duration of ovulatory cycle) for a total of 38 days post-treatment completion. * Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s): 30 days of treatment plus 5 half-lives of study drug Apixaban (3 days) or warfarin (8 days) plus 90 days (duration of sperm turnover) for a total of 98 days post-treatment completion.
Exclusion criteria
* Atrial fibrillation due to a reversible cause other than recent surgery * Patients diagnosed with persistent or paroxysmal atrial fibrillation chronically before undergoing surgery * Patients with mechanical heart valves * Patients currently experiencing active bleeding precluding initialization of anticoagulation therapy in the opinion of their managing physician, or with increased bleeding risk (as determined by the attending surgeon) believed to be a contraindication to anticoagulation at the time of randomization Planned major surgery requiring stoppage of anticoagulation therapy during trial period * Stroke within the previous 7 days * Moderate or severe mitral stenosis * Conditions other than atrial fibrillation that required anticoagulation (prosthetic mechanical heart valve) * Patients taking warfarin, apixaban, rivaroxaban, dabigatran, edoxaban, clopidogrel, ticagrelor, or enoxaparin at home for any indication in the 15 days prior to surgery * Patients requiring the use of clopidogrel or ticagrelor during the study period * Severe renal insufficiency (serum creatinine level of \>2.5 mg/dL or CrCL\<25 ml/min) for consecutive measurements * Allergies to warfarin or apixaban, or components of warfarin or apixaban
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Strokes | 30 days | Efficacy will be measured by the freedom from stroke during the study period. Events relating to stroke will be adjudicated using pre-determined definitions by independent committee members that remain blinded to the patient's treatment arm. |
| Number of Participants With Thromboembolytic Events | 30 days | Efficacy will be measured by the freedom from thromboembolytic events during the study period. Events relating to thromboembolytic events will be adjudicated using pre-determined definitions by independent committee members that remain blinded to the patient's treatment arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Units of Blood Given After Initiation of Anticoagulation Medication | 30 days | Units of blood or blood products given after the first dose of anticoagulation. |
| Total Post-operative Length of Stay | 30 days | This will be measured from the date/time of the end of the subject's surgery until the date/time of the patient's discharge from the hospital. This will be measured in hours, to the nearest tenth of an hour. |
| Time in Therapeutic Range of INR, if on Warfarin | 30 days | Time in therapeutic range of INR, if on warfarin, (eg. 2-3), measured as a percentage and defined for each patient using the Rosendaal equation |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Apixaban Apixaban is to be dosed at 5 mg by mouth twice daily, except in the case of the criteria listed below in dose modifications. The duration of therapy will be at least 30 days. The patient's physician may determine that anticoagulation therapy should be continued after the study period, based on their examination of the patient at the 30-day post-operative examination.
Apixaban: Study arm that patient can be randomized to. Apixaban is a novel, orally active, potent, direct selective inhibitor of coagulation FXa that directly and reversibly binds to the active site of FXa and exerts anticoagulant and antithrombotic effects by diminishing the conversion of prothrombin to thrombin. | 28 |
| Warfarin While patients are hospitalized, warfarin will be dosed daily, with daily INR monitoring per hospital protocol. Daily doses may vary from 0.5mg to 15mg by mouth, as determined by patient specific factors such as patient size, hepatic function, INR, concomitant medications, diet, or other factors. Based on these factors or others not listed, there may also be days in which the patient is prescribed to not get does not receive a dose of warfarin.
After discharge from the hospital, warfarin dosing will be subsequently managed by an anticoagulation clinic, per established protocols. All patients will have a goal INR of 2-3 during the duration of the study. The duration of therapy will be at least 30 days. The patient's physician may determine that anticoagulation therapy should be continued after the study period, based on their examination of the patient at the 30-day post-operative examination.
Warfarin: Study arm that patient can be randomized to. Warfarin therapy has been the mainstay of therapy for patients with POAF. While the duration of therapy is usually short (3-4 weeks), complications of anticoagulation do occur. Additionally, warfarin therapy for POAF is associated with increased length of stay, need for monitoring, and bleeding complications. | 28 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Apixaban | Warfarin | Total |
|---|---|---|---|
| Age, Continuous | 71.0 years STANDARD_DEVIATION 8.1 | 69.5 years STANDARD_DEVIATION 7.5 | 70.2 years STANDARD_DEVIATION 7.8 |
| Body Mass Index | 32.4 kg/meter-squared STANDARD_DEVIATION 6.1 | 31.1 kg/meter-squared STANDARD_DEVIATION 5.6 | 31.7 kg/meter-squared STANDARD_DEVIATION 5.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 28 Participants | 27 Participants | 55 Participants |
| Region of Enrollment United States | 28 Participants | 28 Participants | 56 Participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Male | 25 Participants | 20 Participants | 45 Participants |
| Weight | 98.6 kg STANDARD_DEVIATION 20.5 | 92.7 kg STANDARD_DEVIATION 17.2 | 95.6 kg STANDARD_DEVIATION 19 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 28 |
| other Total, other adverse events | 14 / 28 | 7 / 28 |
| serious Total, serious adverse events | 1 / 28 | 1 / 28 |
Outcome results
Primary
Number of Participants With Strokes
Efficacy will be measured by the freedom from stroke during the study period. Events relating to stroke will be adjudicated using pre-determined definitions by independent committee members that remain blinded to the patient's treatment arm.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | Number of Participants With Strokes | 0 participants |
| Warfarin | Number of Participants With Strokes | 0 participants |
p-value: 1Chi-squared
Primary
Number of Participants With Thromboembolytic Events
Efficacy will be measured by the freedom from thromboembolytic events during the study period. Events relating to thromboembolytic events will be adjudicated using pre-determined definitions by independent committee members that remain blinded to the patient's treatment arm.
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants With Thromboembolytic Events | 0 Participants |
| Warfarin | Number of Participants With Thromboembolytic Events | 0 Participants |
Secondary
Time in Therapeutic Range of INR, if on Warfarin
Time in therapeutic range of INR, if on warfarin, (eg. 2-3), measured as a percentage and defined for each patient using the Rosendaal equation
Time frame: 30 days
Population: INR values are not measured for Apixaban. Apixaban is dose adjusted based on renal function, body weight, and age, but Warfarin requires laboratory monitoring due to other factors that may affect therapeutic affects such as prescribed and over-the-counter medications, consumption of alcoholic beverages, or a diet with inconsistent intake of vitamin K content.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Warfarin | Time in Therapeutic Range of INR, if on Warfarin | 56.8 percentage | Standard Deviation 22.4 |
Secondary
Total Post-operative Length of Stay
This will be measured from the date/time of the end of the subject's surgery until the date/time of the patient's discharge from the hospital. This will be measured in hours, to the nearest tenth of an hour.
Time frame: 30 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Total Post-operative Length of Stay | 167.5 hours | Standard Deviation 76.6 |
| Warfarin | Total Post-operative Length of Stay | 143.1 hours | Standard Deviation 53.2 |
p-value: 0.17t-test, 1 sided
Secondary
Units of Blood Given After Initiation of Anticoagulation Medication
Units of blood or blood products given after the first dose of anticoagulation.
Time frame: 30 days
Population: 2 units of blood were given per patient
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Apixaban | Units of Blood Given After Initiation of Anticoagulation Medication | 6 total units of blood |
| Warfarin | Units of Blood Given After Initiation of Anticoagulation Medication | 2 total units of blood |