Apixaban During Atrial Fibrillation Catheter Ablation: Comparison to Vitamin K Antagonist Therapy (AXAFA)

An Investigator-driven, Prospective, Parallel-group, Randomised, Open, Blinded Outcome Assessment (PROBE), Multi-centre Trial to Determine the Optimal Anticoagulation Therapy for Patients Untergoing Catheter Ablation of Atrial Fibrillation

Study objective is to demonstrate that anticoagulation with the direct factor Xa inhibitor apixaban is not less safe than Vitamin-K-antagonists (VKA) therapy in patients undergoing catheter ablation of non-valvular AF in the prevention of peri-procedural complications.

The AXAFA trial will compare peri-ablational treatment with apixaban to peri-ablational treatment wit VKA in a randomized trial of patients undergoing catheter ablation of atrial fibrillation (AF).

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Apixaban; Drug: Vitamin K antagonist

Detailed Description

AXAFA is an open-label trial designed to evaluate the safety and efficacy of two types of anticoagulant therapy, VKA therapy and therapy with the direct factor Xa inhibitor apixaban, in patients undergoing scheduled catheter ablation for AF. All patients will undergo the ablation procedure after pre-treatment with an anticoagulant (either apixaban in the "Xa group" or a vitamin K antagonist in the "VKA group").

Patients can undergo catheter ablation within the trial after at least 30 days of continuous effective anticoagulation. Ablation can be performed earlier when or timely after exclusion of atrial thrombi have been excluded by a clinically indicated by transthoracic echocardioggram (TEE). After TEE continuous effective anticoagulation must be ensured until the end of the trial.

In the MRI-substudy will be explored wether novel oral anticoagulants (NOAC) have the potential to reduce clinically silent brain lesions after catheter ablation of AF.

• Study Type: Interventional
• Enrollment (Actual): 676
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Different, Austria
    • 4 Sites
• Belgium
  • Different, Belgium
    • 5 Sites
• Denmark
  • Different, Denmark
    • 5 Sites
• Germany
  • Different, Germany
    • 13 Sites
• Italy
  • Different, Italy
    • 4 Sites
• Netherlands
  • Different, Netherlands
    • 6 Sites
• Spain
  • Different, Spain
    • 3 Sites
• United Kingdom
  • Different, United Kingdom
    • 4 Sites
• United States
  • New York
    • New York, New York, United States
      • Montefiore Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Hospital of the University of Pennsyvlania
  • Tennessee
    • Nashville, Tennessee, United States
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States
      • Texas Cardiac Arrhythmia Research
  • Virginia
    • Norfolk, Virginia, United States
      • Sentara Cariovascular Research Insititute

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:

I1. Non-valvular AF (ECG-documented) with a clinical indication for catheter ablation

I2. Clinical indication to undergo catheter ablation on continuous anticoagulant therapy

I3. Presence of at least one of the CHADS2 stroke risk factors

• Stroke or TIA
• age ≥ 75 years,
• hypertension, defined as chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mm Hg,
• diabetes mellitus,
• symptomatic heart failure (NYHA ≥ II).

I4. Age ≥ 18 years

I5. Provision of signed informed consent

Exclusion Criteria:

General exclusion criteria

E1. Any disease that limits life expectancy to less than 1 year

E2. Participation in another clinical trial, either within the past two months or still ongoing

E3. Previous participation in AXAFA

E4. Pregnant women or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception (oral contraception or intra-uterine device) or sterile women can be randomised.

E5. Breastfeeding women

E6. Drug abuse or clinically manifest alcohol abuse

E7. Any stroke within 14 days before randomisation

E8. Coadministration with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) or strong dual inducers of CYP3A4 and P-gp (Appendix VIII).

Exclusion criteria related to a cardiac condition

E9. Valvular AF (as defined by the focussed update of the ESC guidelines on AF, i.e. severe mitral valve stenosis, mechanical heart valve). Furthermore, patients who underwent mitral valve repair are not eligible for AXAFA.

E10. Any previous ablation or surgical therapy for AF

E11. Cardiac ablation therapy for any indication (catheter-based or surgical) within 3 months prior to randomisation

E12. Clinical need for "triple therapy" (combination therapy of clopidogrel, acetylsalicylic acid, and oral anticoagulation)

E13. Other contraindications for use of VKA or apixaban

E14. Documented atrial thrombi less than 3 months prior to randomisation.

Exclusion criteria based on laboratory abnormalities

E15. Severe chronic kidney disease with an estimated glomerular filtration rate (GFR) < 15 ml/min

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
Experimental: Apixaban; Xa group: factor Xa inhibitor Apixaban min. 30 days 5 mg twice daily (fix dose)	Drug: Apixaban; factor Xa inhibitor Apixaban min. 30 days 5 mg twice daily (fix dose) dose reduction Apixaban 2,5 mg twice daily in patients who fulfill tow of the following criteria at the time of randomisation: chronic kidney disease (serum creatine >= 1.5 mg/dl (133mM), <= 60 kg body weight or age >= 80 years.; Other Names: BMS-562247
Active Comparator: Vitamin K antagonist; VKA group: any Vitamin K antagonist (VKA), INR 2-3 , min. 30 days prescribed as in clinical routine	Drug: Vitamin K antagonist; any locally used VKA, INR 2-3, min. 30 days according to aplicable medical guidelines and local clinical routin; Other Names: warfarin; phenprocoumon; acecoumaril; fluindione

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
death and serious cardiovascular events	A composite of all-cause death, stroke (ischemic stroke, subarachnoid haemorrhage and haemorrhagic stroke), and major bleeding events, def.as BARC 2 or higher	appr. 4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
any bleeding event	number	appr. 4 months
major bleeding events acc. to the ISTH and TIMI definitions	number	appr. 4 months
strokes, other systemic embolic events and all-cause death	number	appr. 4 month
time from randomisation to ablation	number of days	appr. 4 months
nights spent in hospital after ablation	number	appr. 4 months
health-care related cost calculation		appr. 4 months
hospitalizations for cardiovascular reasons	number	appr. 4 months
Treatment duration prior to ablation and total time on oral anticoagulation	number of days	appr. 4 months
patients with clinically indicated TEE	number of patients	appr. 4 months
ACT during ablation	Active clotting measurements	during ablation
recurrent Atrial Fibrillation (AF)	time to recurrent AF	appr. 4 months
rhythm status at the end of follow-up	rythm status documented by 24 hour Holter ECG	end of follow-up
vascular access complications leading to prolongation of in-hospital stay or specific therapy	number of events	appr. 4 months
Quality-of-life changes	questionaire	baseline to 3 month follow-up
cognitive function change	questionaire	baseline to 3 month follow-up
clinically "silent" MRI-detected brain lesions	prevalence (MRI-substudy)	within 48 hours after ablation procedures
Impact of ablation-associated clinically overt strokes or MRI-detected bus clincally "silent" acute brain lesions on cognitive function after ablation	MRI-substudy	appr. 4 months

Collaborators and Investigators

• Sponsor: Atrial Fibrillation Network
• Collaborators: Bristol-Myers Squibb; Pfizer; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
• Investigators: Principal Investigator: Paulus Kirchhof, Professor, University of Birmingham Centre for Cardiovascular Scienes, UK and University Hospital Muenster, Germany

Publications and helpful links

General Publications

• Di Biase L, Callans D, Haeusler KG, Hindricks G, Al-Khalidi H, Mont L, Cosedis Nielsen J, Piccini JP, Schotten U, Kirchhof P. Rationale and design of AXAFA-AFNET 5: an investigator-initiated, randomized, open, blinded outcome assessment, multi-centre trial to comparing continuous apixaban to vitamin K antagonists in patients undergoing atrial fibrillation catheter ablation. Europace. 2017 Jan;19(1):132-138. doi: 10.1093/europace/euw368.
• Haeusler KG, Eichner FA, Heuschmann PU, Fiebach JB, Engelhorn T, Blank B, Callans D, Elvan A, Grimaldi M, Hansen J, Hindricks G, Al-Khalidi HR, Mont L, Nielsen JC, Piccini JP, Schotten U, Themistoclakis S, Vijgen J, Di Biase L, Kirchhof P. MRI-Detected Brain Lesions and Cognitive Function in Patients With Atrial Fibrillation Undergoing Left Atrial Catheter Ablation in the Randomized AXAFA-AFNET 5 Trial. Circulation. 2022 Mar 22;145(12):906-915. doi: 10.1161/CIRCULATIONAHA.121.056320. Epub 2022 Feb 9.
• Zink MD, Chua W, Zeemering S, di Biase L, Antoni BL, David C, Hindricks G, Haeusler KG, Al-Khalidi HR, Piccini JP, Mont L, Nielsen JC, Escobar LA, de Bono J, Van Gelder IC, de Potter T, Scherr D, Themistoclakis S, Todd D, Kirchhof P, Schotten U. Predictors of recurrence of atrial fibrillation within the first 3 months after ablation. Europace. 2020 Sep 1;22(9):1337-1344. doi: 10.1093/europace/euaa132.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): September 1, 2017

Study Registration Dates

• First Submitted: June 27, 2014
• First Submitted That Met QC Criteria: August 27, 2014
• First Posted (Estimate): August 28, 2014

Study Record Updates

• Last Update Posted (Actual): October 20, 2017
• Last Update Submitted That Met QC Criteria: October 19, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: anticoagulation; catheter ablation; Atrilal fibrillation; prevention of peri-procedural complication
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrin Modulating Agents; Protease Inhibitors; Micronutrients; Vitamins; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Apixaban; Phenprocoumon; Warfarin; Fluindione
• Other Study ID Numbers: AFNET 5 AXAFA; 2014-002442-45 (EudraCT Number)