Clinical trial NCT02608099: Apixaban Evaluation of Interrupted Or Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation
Official title: Apixaban Evaluation of Interrupted Or Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atrial Fibrillation
Keywords: Atrial fibrillation
Non-valvular atrial fibrillation
Catheter ablation
Apixaban
Warfarin
Harvard Clinical Research Institute
Lead sponsor: Baim Institute for Clinical Research
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2015-11-18
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Patients With Clinically-Significant Bleeding
timeFrame: Randomization to 1 month post catheter ablation
measure: Number of Patients With Thrombotic Events
timeFrame: Randomization to 1 month post catheter ablation
Secondary outcomes:
measure: Number of Patients With Composite of Major Bleeding and Thrombotic Events
timeFrame: Randomization to 1 month post catheter ablation
measure: Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events
timeFrame: Randomization to 1 month post catheter ablation
Other outcomes:
measure: Number of Patients With Clinically-Significant Bleeding
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With Major Bleeding
timeFrame: Randomization to 1 month post catheter ablation
measure: Number of Patients With Major Bleeding
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With Thrombotic Events
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With Composite of Clinically Significant Bleeding and Thrombotic Events
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With Composite of Major Bleeding and Thrombotic Events
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With TIAs or Non-Hemorrhagic Strokes
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With TIAs or Non-Hemorrhagic Strokes
timeFrame: Randomization to 1 month post catheter ablation
measure: Number of Patients With Death
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With Cardiovascular Death
timeFrame: Enrollment to 1 month post catheter ablation
measure: Number of Patients With Death
timeFrame: Randomization to 1 month post catheter ablation
measure: Number of Patients With Cardiovascular Death
timeFrame: Randomization to 1 month post catheter ablation
Locations:
city: Huntsville
country: United States
facility: Site 0020
state: Alabama
city: Mission Viejo
country: United States
facility: Site 0005
state: California
city: New Haven
country: United States
facility: Site 0012
state: Connecticut
city: Trumbull
country: United States
facility: Site 0011
state: Connecticut
city: Pensacola
country: United States
facility: Site 0016
state: Florida
city: West Des Moines
country: United States
facility: Site 0014
state: Iowa
city: Bangor
country: United States
facility: Site 0018
state: Maine
city: Scarborough
country: United States
facility: Site 0004
state: Maine
city: Boston
country: United States
facility: Site 0008
state: Massachusetts
city: Burlington
country: United States
facility: Site 0001
state: Massachusetts
city: Kansas City
country: United States
facility: Site 0006
state: Missouri
city: Omaha
country: United States
facility: Site 0021
state: Nebraska
city: Albuquerque
country: United States
facility: Site 0019
state: New Mexico
city: Toledo
country: United States
facility: Site 0002
state: Ohio
city: Oklahoma City
country: United States
facility: Site 0007
state: Oklahoma
city: Philadelphia
country: United States
facility: Site 0009
state: Pennsylvania
city: Charleston
country: United States
facility: Site 0010
state: South Carolina
city: Austin
country: United States
facility: Site 0017
state: Texas
city: Richmond
country: United States
facility: Site 0003
state: Virginia
Study officials:
affiliation: Lahey Hospital & Medical Center
name: Matthew Reynolds, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard Clinical Research Organization and Cardiovascular Division Brigham and Women's Hospital
name: Christopher P Cannon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bawazeer GA, Alkofide HA, Alsharafi AA, Babakr NO, Altorkistani AM, Kashour TS, Miligkos M, AlFaleh KM, Al-Ansary LA. Interrupted versus uninterrupted anticoagulation therapy for catheter ablation in adults with arrhythmias. Cochrane Database Syst Rev. 2021 Oct 21;10(10):CD013504. doi: 10.1002/14651858.CD013504.pub2.
citation: Reynolds MR, Allison JS, Natale A, Weisberg IL, Ellenbogen KA, Richards M, Hsieh WH, Sutherland J, Cannon CP. A Prospective Randomized Trial of Apixaban Dosing During Atrial Fibrillation Ablation: The AEIOU Trial. JACC Clin Electrophysiol. 2018 May;4(5):580-588. doi: 10.1016/j.jacep.2017.11.005. Epub 2017 Dec 20.