Clinical trial NCT02348723: Uninterrupted Dabigatran Etexilate in Comparison to Uninterrupted Warfarin in Pulmonary Vein Ablation (RE-CIRCUIT)
Official title: Randomized Evaluation of Dabigatran Etexilate Compared to warfarIn in pulmonaRy Vein Ablation: Assessment of an Uninterrupted periproCedUral alntIcoagulation sTrategy (The RE-CIRCUIT Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atrial Fibrillation
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2015-01-28
Enrollment: 678
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 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.


Eligibility criteria: 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).

Primary outcomes:
measure: Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH)
timeFrame: during and up to 2 months post-ablation
Secondary outcomes:
measure: Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA)
timeFrame: during and up to 2 months post-ablation
measure: Incidence of Minor Bleeding Events
timeFrame: during and up to 2 months post-ablation
measure: Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy
timeFrame: during and up to 2 months post-ablation
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Cardiology, PA
state: Arkansas
city: Fremont
country: United States
facility: Mission Cardiovascular Research Institute
state: California
city: Sacramento
country: United States
facility: University of California
state: California
city: Sacramento
country: United States
facility: Mercy Medical Group, a service of Dignity Health Medical Foundation
state: California
city: San Francisco
country: United States
facility: University of California
state: California
city: Naples
country: United States
facility: Southwest Florida Research, LLC
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Elkhart
country: United States
facility: Elkhart General Healthcare System
state: Indiana
city: New Orleans
country: United States
facility: Tulane University Hospital and Clinic
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Saint Louis
country: United States
facility: St. Louis Heart and Vascular, P.C.
state: Missouri
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: Buffalo
country: United States
facility: University at Buffalo, The State University of New York
state: New York
city: Staten Island
country: United States
facility: Staten Island University Hospital
state: New York
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Memphis
country: United States
facility: University of Tennessee Methodist Physicians
state: Tennessee
city: Dallas
country: United States
facility: North Texas Heart Center
state: Texas
city: Houston
country: United States
facility: St Luke's Health Baylor College of Medicine Med Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Everett
country: United States
facility: Providence Regional Medical Center
state: Washington
city: Bonheiden
country: Belgium
facility: Bonheiden - HOSP Imelda
city: Brussel
country: Belgium
facility: Brussels - UNIV UZ Brussel
city: Gent
country: Belgium
facility: UNIV UZ Gent
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Middelheim
country: Belgium
facility: Antwerpen - HOSP ZNA Middelheim - Pneumo
city: Ukkel
country: Belgium
facility: Brussels - HOSP Europe (Ste-Elisabeth)
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Victoria
country: Canada
facility: Victoria Cardiac Arrhythmia Trials Inc.
state: British Columbia
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Centre
state: Ontario
city: Sherbrooke
country: Canada
facility: CHUS Fleurimont
state: Quebec
city: Quebec
country: Canada
facility: IUCPQ (Laval University)
city: La Tronche
country: France
facility: HOP Nord Michallon
city: Marseille
country: France
facility: HOP Timone
city: Nantes
country: France
facility: CLI Nouvelles Cliniques Nantaises,Cardio,Nantes Cedex 2
city: Paris cedex 13
country: France
facility: HOP Salpêtrière, Cardio, Paris
city: Paris
country: France
facility: HOP Européen G. Pompidou
city: Pessac
country: France
facility: HOP Haut-Lévêque
city: Vandoeuvre les Nancy
country: France
facility: HOP CHU Nancy Brabois, Cardiologie
city: Berlin
country: Germany
facility: Vivantes Netzwerk für Gesundheit GmbH
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen, Georg-August-Universität
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Kiel
city: Köln
country: Germany
facility: Universitätsklinikum Köln (AöR)
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Acquaviva Delle Fonti (BA)
country: Italy
facility: Ospedale Generale Regionale "Miulli"
city: Cuneo
country: Italy
facility: A.S.O.S. Croce e Carle
city: Mestre-Venezia
country: Italy
facility: Osp.dell'Angelo
city: Milano
country: Italy
facility: Fondazione Centro San Raffaele del Monte Tabor
city: Milano
country: Italy
facility: Centro Cardiologico Monzino-IRCCS
city: Roma
country: Italy
facility: Policlinico Casilino U.O. Cardiologia
city: Aichi, Anjo
country: Japan
facility: Anjo-kosei Hospital
city: Aichi, Nagoya
country: Japan
facility: Nagoya City East Medical Center
city: Aichi, Nagoya
country: Japan
facility: Nagoya University Hospital
city: Aichi, Nagoya
country: Japan
facility: Japanese Red Cross Nagoya Daini Hospital
city: Aomori, Hirosaki
country: Japan
facility: Hirosaki University Hospital
city: Chiba, Matsudo
country: Japan
facility: New Tokyo Heart Clinic
city: Kanagawa, Kamakura
country: Japan
facility: Shonan Kamakura General Hospital
city: Osaka, Osaka
country: Japan
facility: Sakurabashi Watanabe Hospital
city: Tokyo, Bunkyo-Ku
country: Japan
facility: Nippon Medical School Hospital
city: Tokyo, Hachioji
country: Japan
facility: Tokyo Medical University Hachioji Medical Center
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Nijmegen
country: Netherlands
facility: Radboud Universitair Medisch Centrum
city: Kemerovo
country: Russian Federation
facility: Heart&Vessels Diseases,Cardiol&Cardiovas.SurgeryDep,Kamerovo
city: Moscow
country: Russian Federation
facility: Instit.of Surgery na Vishnevskiy,Treatm.of comp.arrhythm.dep
city: Saint Petersburg
country: Russian Federation
facility: City Pokrovskiy Hospital, Cardiology Dept., Saint Petersburg
city: St. Petersburg
country: Russian Federation
facility: North-Westrn Fed.med.res.cntr,Almazov Interven.arrhythmo.dep
city: Tyumen
country: Russian Federation
facility: Tyumen Cardiology Center, Dept.of Cardiac Arrhythmia
city: Yaroslavl
country: Russian Federation
facility: Yaroslavl Regional Clin. Hospital, Dept. Endocrinology
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Hospital La Paz
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Vigo (Pontevedra)
country: Spain
facility: Hospital Álvaro Cunqueiro
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth and Christchurch Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital, Clydebank
city: Cottingham
country: United Kingdom
facility: Castle Hill Hopsital
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.