Atrial Fibrillation
Conditions
Keywords
Atrial fibrillation, Non-valvular atrial fibrillation, Catheter ablation, Apixaban, Warfarin, Harvard Clinical Research Institute
Brief summary
The purpose of the prospective, randomized cohort in this study is to assess the safety and efficacy of 2 apixaban treatment strategies (uninterrupted versus interrupted) in subjects planned to undergo catheter ablation for the treatment of non-valvular atrial fibrillation (NVAF). Simultaneously, a retrospective cohort of 300 warfarin-treated individuals, identified by chart review, who are matched to the prospective randomized subjects, will be identified. The purpose of the retrospective warfarin cohort is to compare the efficacy and safety of warfarin(the current clinical practice) to that of apixaban (uninterrupted, interrupted, combined uninterrupted and interrupted).
Detailed description
Prospective, Randomized Cohort Subjects undergoing ablation for NVAF who meet all eligibility criteria and sign informed consent will be enrolled into the study. Subjects will be treated with apixaban for ≥21 days prior to the ablation procedure (for subjects already on apixaban for ≥21 days, it is not necessary to wait 21 days before the ablation procedure. Apixaban dose will be 5 mg b.i.d. per product label, or 2.5 mg b.i.d. in subjects with 2 or more of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. Eligible subjects will then be randomized in a 1:1 ratio to 2 peri-procedural treatment strategies: * Uninterrupted treatment: administer the evening apixaban dose on the day prior to the procedure; administer the morning apixaban dose on the day of the procedure; administer heparin bolus before transseptal puncture to maintain a target activated clotting time \[ACT\] \> 300 seconds; administer the evening apixaban dose after the procedure if there were no peri-procedural complications that necessitate withholding anticoagulation for longer duration. * Interrupted treatment: administer the evening apixaban dose on the day prior to the procedure; do not administer the morning apixaban dose on the day of the procedure; administer heparin bolus before transseptal puncture to maintain a target ACT \> 300 seconds; administer the evening apixaban dose after the procedure if there were no peri-procedural complications that necessitate withholding anticoagulation for longer duration. Randomization will take place prior to the procedure (on the day of the procedure or up to 3 days prior to the procedure) and will be stratified by site. It is anticipated that up to 360 subjects may be enrolled in order to evaluate a total of 300 randomized subjects (150 subjects per treatment arm): Randomized subjects will continue treatment with apixaban for 1 month post procedure. Retrospective, Warfarin Cohort In addition, a chart review of 300 warfarin-treated patients who underwent catheter ablation for NVAF on or after September 1, 2013 in the enrolling centers and who have documented follow-up in the medical record for ≥ 30 days post-ablation procedure will be performed. Patient records for warfarin-treated individuals who meet the applicable inclusion/exclusion criteria and who are matched 1:1 to a subject in the prospective, randomized cohort for age (+/- 5 years), gender and atrial fibrillation (AF) type (paroxysmal vs. persistent), will be identified. Sites will document key demographic and outcome variables. This review will be performed in a blinded manner such that site personnel are blinded to the outcome of each retrospective subject during the subject selection process. Only pre-existing data will be collected for the analysis of this cohort.
Interventions
DRUGInterrupted apixaban
Apixaban dose is administered on the evening prior to the procedure; apixaban dose is held on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration.
DRUGUninterrupted apixaban
Intervention description: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is administered on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration.
Sponsors
Bristol-Myers Squibb
Baim Institute for Clinical Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent. 2. \>18 years of age. 3. NVAF with planned catheter ablation treatment. 4. Planned anticoagulant treatment for at least 1 month after the index procedure. 5. Subject agrees to all required follow-up procedures and visits. 6. For women of childbearing potential (WOCBP): * Must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug. * Must not be breastfeeding * Must agree to follow instructions for method(s) of contraception for a total of 33 days post-treatment completion. 7. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a total of 93 days post-treatment completion. 8. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in this section.
Exclusion criteria
1. History of significant bleeding diathesis or coagulopathy or inability to accept blood transfusions. 2. Known hypersensitivity or contraindication to heparin or apixaban. 3. Subjects with mechanical prosthetic heart valves. 4. History of cerebrovascular accident or transient ischemic attach (TIA) within the last 6 months. 5. Prior intracranial hemorrhage. 6. End-stage renal failure (creatinine clearance rate \<15 mL/minute or on dialysis treatment). 7. Hepatic disease associated with coagulopathy. 8. Current or expected systemic treatment with strong dual inducers of CYP3A4 and P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort). 9. Current or expected systemic treatment with dual antiplatelet therapy, other anticoagulants, or fibrinolytics. 10. Planned or expected surgery, or other invasive procedure that would require interruption of anticoagulation within 1 month of the catheter ablation procedure. 11. Currently enrolled in another investigational device or drug trial that has not completed the primary endpoint or that clinically interferes with the current study endpoints. 12. Co-morbid condition(s) that could limit the subject's ability to participate in the trial or to comply with follow-up requirements, or that could impact the scientific integrity of the trial. 13. Platelet count ≤100,000/mm3. 14. Hemoglobin level \<9 g/dL. 15. Any active bleeding. 16. Prisoners or subjects who are involuntarily incarcerated. 17. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Clinically-Significant Bleeding | Randomization to 1 month post catheter ablation | Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher. |
| Number of Patients With Thrombotic Events | Randomization to 1 month post catheter ablation | Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Composite of Major Bleeding and Thrombotic Events | Randomization to 1 month post catheter ablation | Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher. Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. |
| Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events | Randomization to 1 month post catheter ablation | Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Composite of Major Bleeding and Thrombotic Events | Enrollment to 1 month post catheter ablation | Thrombotic events are defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. Major bleeding is defined as bleeding meeting BARC criteria type 3 or higher. |
| Number of Patients With TIAs or Non-Hemorrhagic Strokes | Enrollment to 1 month post catheter ablation | Number of Patients who had TIAs or non-hemorrhagic strokes. |
| Number of Patients With Clinically-Significant Bleeding | Enrollment to 1 month post catheter ablation | Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher. |
| Number of Patients With Cardiovascular Death | Enrollment to 1 month post catheter ablation | Cardiovascular death is included in this measurement. |
| Number of Patients With Death | Enrollment to 1 month post catheter ablation | Death is included in this measurement. |
| Number of Patients With Major Bleeding | Randomization to 1 month post catheter ablation | Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher. |
| Number of Patients With Thrombotic Events | Enrollment to 1 month post catheter ablation | Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. |
| Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events | Enrollment to 1 month post catheter ablation | Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Interrupted Apixaban Apixaban dose is administered on the evening prior to the procedure; apixaban dose is held on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration.
Interrupted apixaban: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is held on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration. | 145 |
| Uninterrupted Apixaban Apixaban dose is administered on the evening prior to the procedure; apixaban dose is administered on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration.
Uninterrupted apixaban: Intervention description: Apixaban dose is administered on the evening prior to the procedure; apixaban dose is administered on the morning of the procedure; apixaban dose is administered on the evening after the procedure if there were no peri-procedural complications that necessitated withholding anticoagulation for longer duration. | 150 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ablation procedure not initiated | 3 | 2 |
Baseline characteristics
| Characteristic | Interrupted Apixaban | Uninterrupted Apixaban | Total |
|---|---|---|---|
| Age, Continuous | 64.3 Years STANDARD_DEVIATION 10.3 | 62.8 Years STANDARD_DEVIATION 9.9 | 63.5 Years STANDARD_DEVIATION 10.1 |
| Body Mass Index | 30.46 kg/m2 STANDARD_DEVIATION 5.607 | 30.58 kg/m2 STANDARD_DEVIATION 6.441 | 30.52 kg/m2 STANDARD_DEVIATION 6.036 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 134 Participants | 143 Participants | 277 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 133 Participants | 141 Participants | 274 Participants |
| Sex: Female, Male Female | 48 Participants | 49 Participants | 97 Participants |
| Sex: Female, Male Male | 97 Participants | 101 Participants | 198 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 149 | 0 / 151 |
| other Total, other adverse events | 72 / 149 | 75 / 151 |
| serious Total, serious adverse events | 14 / 149 | 15 / 151 |
Outcome results
Primary
Number of Patients With Clinically-Significant Bleeding
Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Clinically-Significant Bleeding | 14 Participants |
| Uninterrupted Apixaban | Number of Patients With Clinically-Significant Bleeding | 17 Participants |
Primary
Number of Patients With Thrombotic Events
Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Thrombotic Events | 0 Participants |
| Uninterrupted Apixaban | Number of Patients With Thrombotic Events | 0 Participants |
Secondary
Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events
Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events | 14 Participants |
| Uninterrupted Apixaban | Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events | 17 Participants |
Secondary
Number of Patients With Composite of Major Bleeding and Thrombotic Events
Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher. Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Composite of Major Bleeding and Thrombotic Events | 3 Participants |
| Uninterrupted Apixaban | Number of Patients With Composite of Major Bleeding and Thrombotic Events | 2 Participants |
Other Pre-specified
Number of Patients With Cardiovascular Death
Cardiovascular death is included in this measurement.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Cardiovascular Death | 0 Participants |
| Uninterrupted Apixaban | Number of Patients With Cardiovascular Death | 0 Participants |
Other Pre-specified
Number of Patients With Cardiovascular Death
Cardiovascular death is included in this measurement.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Cardiovascular Death | 0 Participants |
| Uninterrupted Apixaban | Number of Patients With Cardiovascular Death | 0 Participants |
Other Pre-specified
Number of Patients With Clinically-Significant Bleeding
Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Clinically-Significant Bleeding | 17 Participants |
| Uninterrupted Apixaban | Number of Patients With Clinically-Significant Bleeding | 17 Participants |
Other Pre-specified
Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events
Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. Clinically significant bleeding was defined as bleeding meeting Bleeding Academic Research Consortium (BARC) criteria type 2 or higher.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events | 14 Participants |
| Uninterrupted Apixaban | Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events | 17 Participants |
Other Pre-specified
Number of Patients With Composite of Major Bleeding and Thrombotic Events
Thrombotic events are defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events. Major bleeding is defined as bleeding meeting BARC criteria type 3 or higher.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Composite of Major Bleeding and Thrombotic Events | 3 Participants |
| Uninterrupted Apixaban | Number of Patients With Composite of Major Bleeding and Thrombotic Events | 2 Participants |
Other Pre-specified
Number of Patients With Death
Death is included in this measurement.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Death | 0 Participants |
| Uninterrupted Apixaban | Number of Patients With Death | 0 Participants |
Other Pre-specified
Number of Patients With Death
Death is included in this measurement.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Death | 0 Participants |
| Uninterrupted Apixaban | Number of Patients With Death | 0 Participants |
Other Pre-specified
Number of Patients With Major Bleeding
Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Major Bleeding | 3 Participants |
| Uninterrupted Apixaban | Number of Patients With Major Bleeding | 2 Participants |
Other Pre-specified
Number of Patients With Major Bleeding
Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Major Bleeding | 3 Participants |
| Uninterrupted Apixaban | Number of Patients With Major Bleeding | 2 Participants |
Other Pre-specified
Number of Patients With Thrombotic Events
Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With Thrombotic Events | 0 Participants |
| Uninterrupted Apixaban | Number of Patients With Thrombotic Events | 0 Participants |
Other Pre-specified
Number of Patients With TIAs or Non-Hemorrhagic Strokes
Number of Patients who had TIAs or non-hemorrhagic strokes.
Time frame: Enrollment to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With TIAs or Non-Hemorrhagic Strokes | 1 Participants |
| Uninterrupted Apixaban | Number of Patients With TIAs or Non-Hemorrhagic Strokes | 1 Participants |
Other Pre-specified
Number of Patients With TIAs or Non-Hemorrhagic Strokes
This measurement includes TIAs or non-hemorrhagic strokes.
Time frame: Randomization to 1 month post catheter ablation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Interrupted Apixaban | Number of Patients With TIAs or Non-Hemorrhagic Strokes | 1 Participants |
| Uninterrupted Apixaban | Number of Patients With TIAs or Non-Hemorrhagic Strokes | 1 Participants |