Uninterrupted Dabigatran Etexilate in Comparison to Uninterrupted Warfarin in Pulmonary Vein Ablation (RE-CIRCUIT)

Randomized Evaluation of Dabigatran Etexilate Compared to warfarIn in pulmonaRy Vein Ablation: Assessment of an Uninterrupted periproCedUral alntIcoagulation sTrategy (The RE-CIRCUIT Trial)

The primary objective of this trial is to assess the safety of an uninterrupted dabigatran etexilate periprocedural anticoagulant regimen compared to an uninterrupted warfarin regimen in Non-Valvular Atrial Fibrillation (NVAF) patients undergoing Atrial Fibrillation (AF) ablation in a PROBE (Prospective, randomized, open label, blinded end point) active controlled study.

Secondary objectives are to assess additional safety endpoints and efficacy in this clinical setting.

It is not intended to assess confirmatory hypothesis, this is an exploratory study.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Dabigatran Etexilate 150mg; Drug: Warfarin

• Study Type: Interventional
• Enrollment (Actual): 678
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium, 2820
    • Bonheiden - HOSP Imelda
  • Brussel, Belgium, 1090
    • Brussels - UNIV UZ Brussel
  • Gent, Belgium, 9000
    • UNIV UZ Gent
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire de Liège
  • Middelheim, Belgium, 2020
    • Antwerpen - HOSP ZNA Middelheim - Pneumo
  • Ukkel, Belgium, 1180
    • Brussels - HOSP Europe (Ste-Elisabeth)
• Canada
  • Quebec, Canada, G1V 4G5
    • IUCPQ (Laval University)
  • Alberta
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • British Columbia
    • Victoria, British Columbia, Canada, V8T 1Z4
      • Victoria Cardiac Arrhythmia Trials Inc.
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • Newmarket, Ontario, Canada, L3Y 2P9
      • Southlake Regional Health Centre
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • CHUS Fleurimont
• France
  • La Tronche, France, 38700
    • HOP Nord Michallon
  • Marseille, France, 13005
    • HOP Timone
  • Nantes, France, 44000
    • CLI Nouvelles Cliniques Nantaises,Cardio,Nantes Cedex 2
  • Paris, France, 75015
    • HOP Européen G. Pompidou
  • Paris cedex 13, France, 75013
    • HOP Salpêtrière, Cardio, Paris
  • Pessac, France, 33604
    • HOP Haut-Lévêque
  • Vandoeuvre les Nancy, France, 54511
    • HOP CHU Nancy Brabois, Cardiologie
• Germany
  • Berlin, Germany, 10967
    • Vivantes Netzwerk für Gesundheit GmbH
  • Göttingen, Germany, 37075
    • Universitätsmedizin Göttingen, Georg-August-Universität
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein, Campus Kiel
  • Köln, Germany, 50937
    • Universitätsklinikum Köln (AöR)
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Italy
  • Acquaviva Delle Fonti (BA), Italy, 70021
    • Ospedale generale regionale "Miulli"
  • Cuneo, Italy, 12100
    • A.S.O.S. Croce e Carle
  • Mestre-Venezia, Italy, 30174
    • Osp.dell'Angelo
  • Milano, Italy, 20132
    • Fondazione Centro San Raffaele del Monte Tabor
  • Milano, Italy, 20138
    • Centro Cardiologico Monzino-IRCCS
  • Roma, Italy, 00169
    • Policlinico Casilino U.O. Cardiologia
• Japan
  • Aichi, Anjo, Japan, 446-8602
    • Anjo-kosei Hospital
  • Aichi, Nagoya, Japan, 466-8650
    • Japanese Red Cross Nagoya Daini Hospital
  • Aichi, Nagoya, Japan, 466-8560
    • Nagoya University Hospital
  • Aichi, Nagoya, Japan, 464-8547
    • Nagoya City East Medical Center
  • Aomori, Hirosaki, Japan, 036-8563
    • Hirosaki University Hospital
  • Chiba, Matsudo, Japan, 271-0077
    • New Tokyo Heart Clinic
  • Kanagawa, Kamakura, Japan, 247-8533
    • Shonan Kamakura General Hospital
  • Osaka, Osaka, Japan, 530-0001
    • Sakurabashi Watanabe Hospital
  • Tokyo, Bunkyo-Ku, Japan, 113-8603
    • Nippon Medical School Hospital
  • Tokyo, Hachioji, Japan, 193-0998
    • Tokyo Medical University Hachioji Medical Center
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU Medisch Centrum
  • Amsterdam, Netherlands, 1091AC
    • Onze Lieve Vrouwe Gasthuis
  • Eindhoven, Netherlands, 5623 EJ
    • Catharina Ziekenhuis
  • Leeuwarden, Netherlands, 8934 AD
    • Medisch Centrum Leeuwarden
  • Nijmegen, Netherlands, 6525 GA
    • Radboud Universitair Medisch Centrum
• Russian Federation
  • Kemerovo, Russian Federation, 650002
    • Heart&Vessels Diseases,Cardiol&Cardiovas.SurgeryDep,Kamerovo
  • Moscow, Russian Federation, 117997
    • Instit.of Surgery na Vishnevskiy,Treatm.of comp.arrhythm.dep
  • Saint Petersburg, Russian Federation, 199 106
    • City Pokrovskiy Hospital, Cardiology Dept., Saint Petersburg
  • St. Petersburg, Russian Federation, 197341
    • North-Westrn Fed.med.res.cntr,Almazov Interven.arrhythmo.dep
  • Tyumen, Russian Federation, 625026
    • Tyumen Cardiology Center, Dept.of Cardiac Arrhythmia
  • Yaroslavl, Russian Federation, 150062
    • Yaroslavl Regional Clin. Hospital, Dept. Endocrinology
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Madrid, Spain, 28046
    • Hospital La Paz
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocío
  • Vigo (Pontevedra), Spain, 36312
    • Hospital Alvaro Cunqueiro
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Royal Bournemouth and Christchurch Hospital
  • Brighton, United Kingdom, BN2 5BE
    • Royal Sussex County Hospital
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital
  • Clydebank, United Kingdom, G81 4DY
    • Golden Jubilee National Hospital, Clydebank
  • Cottingham, United Kingdom, HU16 5JQ
    • Castle Hill Hopsital
  • Leeds, United Kingdom, LS1 3EX
    • Leeds General Infirmary
  • London, United Kingdom, EC1A 4NP
    • St Bartholomew's Hospital
  • Middlesbrough, United Kingdom, TS4 3BW
    • James Cook University Hospital
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cardiology, PA
  • California
    • Fremont, California, United States, 94538
      • Mission Cardiovascular Research Institute
    • Sacramento, California, United States, 95817
      • University of California
    • Sacramento, California, United States, 95819
      • Mercy Medical Group, a service of Dignity Health Medical Foundation
    • San Francisco, California, United States, 94143
      • University of California
  • Florida
    • Naples, Florida, United States, 34102
      • Southwest Florida Research, LLC
    • Tampa, Florida, United States, 33606
      • University Of South Florida
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Elkhart General Healthcare System
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Hospital and Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63136
      • St. Louis Heart and Vascular, P.C.
  • New York
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
    • Buffalo, New York, United States, 14203
      • University at Buffalo, The State University of New York
    • Staten Island, New York, United States, 10305
      • Staten Island University Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104-5068
      • University of Oklahoma
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • University of Tennessee Methodist Physicians
  • Texas
    • Dallas, Texas, United States, 75231
      • North Texas Heart Center
    • Houston, Texas, United States, 77030
      • St Luke's Health Baylor College of Medicine Med Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Medical Center

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:

• Male or female patients aged >= 18 years.
• Patients eligible for treatment with dabigatran etexilate 150 mg b.i.d. according to local label.
• Treatment naïve patients or patients on oral anticoagulant treatment with a Vitamin K Antagonist (VKA), dabigatran etexilate, rivaroxaban, apixaban or edoxaban.
• Patient with paroxysmal or persistent NVAF with a planned catheter ablation for AF unless it is performed an investigational ablation technique.
• AF must have been documented at least once either by ECG, Holter monitoring, loop recorder, telemetry, trans-telephonic monitoring, pacemaker or cardiac defibrillator read outs within 24 months prior to screening (Visit 1).
• The patient must be able to give informed consent in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and local legislation and/or regulations.

Exclusion criteria:

• Patients with permanent AF.
• Patients with AF felt to be secondary to an obvious reversible cause such as, but not limited to, an acute myocardial infarction, pulmonary embolism, recent surgery, pericarditis or thyrotoxicosis.
• Patients with Left Atrium (LA) size >= 60 mm
• Patients with contraindications to systemic anticoagulation with heparin, warfarin or dabigatran etexilate
• Patients with a known allergy to warfarin tablets and it excipients or to dabigatran etexilate or its excipients
• Mechanical or biological heart valve prosthesis
• Severe renal impairment (estimated Creatinine Clearance (CrCl) calculated by Cockcroft-Gault equation) <30mL/min at screening
• Stroke within 1 month prior to screening visit
• Major surgery per investigator judgement within the previous month prior to screening.
• Patient has received an organ transplant or is on a waiting list for an organ transplant
• History of intracranial haemorrhage, intraocular, spinal, retroperitoneal or non-traumatic intra-articular bleeding
• Gastrointestinal haemorrhage within one month prior to screening, unless, in the opinion of the investigator, the cause has been permanently eliminated (e.g. by surgery).
• Major bleeding episode (ISTH definition) one month prior to the screening visit.
• Haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, haemophilia A or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, history of prolonged bleeding after surgery/intervention)
• Anaemia (haemoglobin <10g/dL) or thrombocytopenia including heparin-induced thrombocytopenia (platelet count <100 x 10^9/L) at screening
• Recent malignancy or radiation therapy (<=6 months prior to screening) unless, in the opinion of the Investigator, the estimated life expectancy is greater than 36 months

• Active liver disease as indicated by at least one of the following:

  -- Prior and persistent alanine aminotransferase or Aspartate transaminase or alkaline phosphatase >3x upper limit of normal and/or -- Known active hepatitis C and/or -- Known active hepatitis B and/or -- Known active hepatitis A

• Need for continued treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John's Wort or any cytotoxic/myelosuppressive therapy.

• Pre-menopausal (last menstruation <=1 year prior to screening) who:

  • Are pregnant or breast-feeding or plan to become pregnant during study or
  • Are not surgically sterile or
  • Are of child bearing potential and not practising two acceptable method of birth control, or do not plan to continue practising an acceptable method of birth control throughout the trial
• Patients who have participated in another trial with an investigational drug or device within the past 30 days preceding the screening visit or are participating in another trial (patients participating in an observational study only will not be excluded)
• Patients not willing or able to comply with the protocol requirements or considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, who have a life expectancy less than the expected duration of the trial due to concomitant disease and/or subjects who are institutionalised due to official or court orders and/or vulnerable subjects who are dependent on the Sponsor or the Investigator or the site, or patients who have any condition which in the opinion of the Investigator, would not allow safe participation in the study (e.g. drug addiction, alcohol abuse).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dabigatran Etexilate 150mg; Patients receiving Dabigatran Etexilate 150mg twice daily dosing (BID)	Drug: Dabigatran Etexilate 150mg; Patients receiving Dabigatran Etexilate 150mg twice daily dosing (BID)
ACTIVE_COMPARATOR: Warfarin; Patients receiving Warfarin to keep International Normalized Ratio (INR) between 2.0 - 3.0	Drug: Warfarin; Patients receiving Warfarin to keep International Normalized Ratio (INR)between 2.0 - 3.0

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH)	Major bleeds were defined according to the ISTH definition of a major bleed, as follows; Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or; Bleeding associated with a reduction in haemoglobin of at least 2 g/dL (1.24 mmol/L), or leading to transfusion of 2 or more units of blood or packed cells. and/or; Fatal bleed These are based on adjudicated data (blinded evaluation) Point estimates for the incidence of ISTH MBEs and their 2-sided 95% confidence intervals (CI), based on the normal approximation of independent binomial distribution without stratification, are presented.	during and up to 2 months post-ablation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA)	Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction. Systemic embolism was defined as an acute vascular occlusion of the extremities or any organ (kidneys, mesenteric arteries, spleen, retina or grafts) and was to be documented by angiography, surgery, scintigraphy or autopsy. Transient ischemic attack was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. These are based on adjudicated data (blinded evaluation). Percentage of patients with composite of stroke, systemic embolism, or transient ischemic attack (TIA) is presented	during and up to 2 months post-ablation
Incidence of Minor Bleeding Events	Minor bleeds were clinical bleeds that did not fulfil the criteria for major bleeds. Percentage of patients with Minor bleeding events are presented. These are based on adjudicated data (blinded evaluation)	during and up to 2 months post-ablation
Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy	Percentage of patients with ISTH MBE, stroke, systemic embolism, or TIA (composite endpoint combining safety and efficacy) are presented. These are based on adjudicated data (blinded evaluation)	during and up to 2 months post-ablation

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Kimata A, Nogami A, Yamasaki H, Ohigashi T, Gosho M, Igarashi M, Sekiguchi Y, Ieda M, Calkins H, Aonuma K. Optimal interruption time of dabigatran oral administration to ablation (O-A time) in patients with atrial fibrillation: Integrated analysis of 2 randomized controlled clinical trials. J Cardiol. 2021 Jun;77(6):652-659. doi: 10.1016/j.jjcc.2020.12.010. Epub 2021 Jan 25.
• Hohnloser SH, Calkins H, Willems S, Verma A, Schilling R, Okumura K, Nordaby M, Kleine E, Biss B, Gerstenfeld EP; RE-CIRCUIT(R) investigators. Regional differences in patient characteristics and outcomes during uninterrupted anticoagulation with dabigatran versus warfarin in catheter ablation of atrial fibrillation: the RE-CIRCUIT study. J Interv Card Electrophysiol. 2019 Aug;55(2):145-152. doi: 10.1007/s10840-019-00518-x. Epub 2019 Feb 13.
• Calkins H, Willems S, Gerstenfeld EP, Verma A, Schilling R, Hohnloser SH, Okumura K, Serota H, Nordaby M, Guiver K, Biss B, Brouwer MA, Grimaldi M; RE-CIRCUIT Investigators. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med. 2017 Apr 27;376(17):1627-1636. doi: 10.1056/NEJMoa1701005. Epub 2017 Mar 19.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 28, 2015
• Primary Completion (ACTUAL): November 11, 2016
• Study Completion (ACTUAL): November 14, 2016

Study Registration Dates

• First Submitted: January 27, 2015
• First Submitted That Met QC Criteria: January 27, 2015
• First Posted (ESTIMATE): January 28, 2015

Study Record Updates

• Last Update Posted (ACTUAL): January 29, 2018
• Last Update Submitted That Met QC Criteria: January 4, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran; Warfarin
• Other Study ID Numbers: 1160.204; 2014-003890-40 (EUDRACT_NUMBER)