Apixaban Evaluation of Interrupted Or Uninterrupted Anticoagulation for Ablation of Atrial Fibrillation (AEIOU)

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).

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Interrupted apixaban; Drug: Uninterrupted apixaban

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.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Site 0020
  • California
    • Mission Viejo, California, United States, 92690
      • Site 0005
  • Connecticut
    • New Haven, Connecticut, United States, 06501
      • Site 0012
    • Trumbull, Connecticut, United States, 06611
      • Site 0011
  • Florida
    • Pensacola, Florida, United States, 32501
      • Site 0016
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Site 0014
  • Maine
    • Bangor, Maine, United States, 04401
      • Site 0018
    • Scarborough, Maine, United States, 04074
      • Site 0004
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Site 0008
    • Burlington, Massachusetts, United States, 01805
      • Site 0001
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Site 0006
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • Site 0021
  • New Mexico
    • Albuquerque, New Mexico, United States, 87101
      • Site 0019
  • Ohio
    • Toledo, Ohio, United States, 43615
      • Site 0002
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Site 0007
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19019
      • Site 0009
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Site 0010
  • Texas
    • Austin, Texas, United States, 78705
      • Site 0017
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Site 0003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: Interrupted Eliquis
Experimental: 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.	Drug: 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.; Other Names: Uninterrupted Eliquis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Randomization to 1 month post catheter ablation
Number of Patients With Thrombotic Events	Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events.	Randomization to 1 month post catheter ablation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Randomization to 1 month post catheter ablation
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.	Randomization to 1 month post catheter ablation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Enrollment to 1 month post catheter ablation
Number of Patients With Major Bleeding	Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher.	Randomization to 1 month post catheter ablation
Number of Patients With Major Bleeding	Major bleeding was defined as bleeding meeting BARC criteria type 3 or higher.	Enrollment to 1 month post catheter ablation
Number of Patients With Thrombotic Events	Thrombotic events were defined as a composite of non-hemorrhagic stroke and systemic thromboembolic events.	Enrollment to 1 month post catheter ablation
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.	Enrollment to 1 month post catheter ablation
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.	Enrollment to 1 month post catheter ablation
Number of Patients With TIAs or Non-Hemorrhagic Strokes	Number of Patients who had TIAs or non-hemorrhagic strokes.	Enrollment to 1 month post catheter ablation
Number of Patients With TIAs or Non-Hemorrhagic Strokes	This measurement includes TIAs or non-hemorrhagic strokes.	Randomization to 1 month post catheter ablation
Number of Patients With Death	Death is included in this measurement.	Enrollment to 1 month post catheter ablation
Number of Patients With Cardiovascular Death	Cardiovascular death is included in this measurement.	Enrollment to 1 month post catheter ablation
Number of Patients With Death	Death is included in this measurement.	Randomization to 1 month post catheter ablation
Number of Patients With Cardiovascular Death	Cardiovascular death is included in this measurement.	Randomization to 1 month post catheter ablation

Collaborators and Investigators

• Sponsor: Baim Institute for Clinical Research
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Matthew Reynolds, MD, MSc, Lahey Hospital & Medical Center; Principal Investigator: Christopher P Cannon, MD, Harvard Clinical Research Organization and Cardiovascular Division Brigham and Women's Hospital

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: November 9, 2015
• First Submitted That Met QC Criteria: November 16, 2015
• First Posted (Estimate): November 18, 2015

Study Record Updates

• Last Update Posted (Actual): March 17, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Atrial fibrillation; Non-valvular atrial fibrillation; Warfarin; Catheter ablation; Apixaban; Harvard Clinical Research Institute
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: CV185-373