Edoxaban Treatment Versus Vitamin K Antagonist (VKA) in Patients With Atrial Fibrillation (AF) Undergoing Catheter Ablation

Atrial Fibrillation Clinical Trial

— ELIMINATE-AF  

Official title:

A Prospective, Randomized, Open-Label, Blinded Endpoint Evaluation (PROBE) Parallel Group Study Comparing Edoxaban vs. VKA in Subjects Undergoing Catheter Ablation of Non-valvular Atrial Fibrillation (ELIMINATE-AF)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02942576
• Other study ID #: DSE-EDO-01-16-EU
• Secondary ID: 2016-003069-25
• Status: Completed
• Phase: Phase 3
• Start date: March 21, 2017
• Est. completion date: September 24, 2018

Study information

• Verified date: August 2019
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

There are insufficient data on the safety and efficacy of edoxaban therapy in subjects with AF following catheter ablation. This phase 3b study is designed to evaluate the safety and to explore the efficacy of an edoxaban-based antithrombotic regimen versus a VKA-based antithrombotic regimen in subjects with AF following catheter ablation. Bleeding is a central safety outcome in cardiovascular clinical trials, especially for antithrombotic strategies and invasive procedures.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 632
• Est. completion date: September 24, 2018
• Est. primary completion date: September 24, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female at least 18 years of age with documented history of paroxysmal (lasting =7 days), persistent (lasting >7 days but =12 months) or long-standing [long-lasting] persistent (>12 months) non-valvular AF. Duration of AF can be confirmed by any electrical tracing or a recording in the subject's medical records (e.g., medical chart, hospital discharge summary).

• Subject is eligible and is scheduled for either radio frequency (RF) or cryoballoon catheter ablation (both first and repeated procedure included).

• Signed informed consent form (ICF).

Exclusion Criteria:

• AF considered to be of a transient or reversible nature (such as in myocarditis, post-surgery, ionic disturbances, thyrotoxicosis, pneumonia, severe anemia etc.).

• Subject post stroke, or with a systemic thromboembolic event within the past 6 months prior to randomization.

• Subject has a thrombus in the left atrial appendage (LAA), left atrium (LA), left ventricle (LV), or aorta, or an intracardial mass.

• Subject had a myocardial infarction (MI) within the 2 months prior to randomization or coronary artery bypass graft (CABG) surgery within 3 months prior to the randomization.

• Subject has signs of bleeding, history of clinically-relevant bleeding according to International Society on Thrombosis and Hemostasis (ISTH), or conditions associated with high risk of bleeding

• Subjects with any contraindication for anticoagulant agents.

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Edoxaban
Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.
• VKA-Based Regimen
Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, United Kingdom (UK), Taiwan and Korea.
• VKA-Based Regimen
Dosed at INR levels. Standard of Care treatment in Germany, Belgium, and the Netherlands.
• VKA-Based Regimen
Dosed at INR levels. Standard of Care treatment in France.
• VKA-Based Regimen
Dosed at INR levels. Standard of Care treatment in Spain.

Locations

Country	Name	City	State
Belgium	ZNA Middelheim	Antwerpen
Belgium	Erasme Hospital	Brussels
Belgium	UZ Brussel	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Canada	University of Calgary	Calgary
Canada	Hamilton Health Sciences/McMaster University	Hamilton
Canada	Montreal Heart Institute	Montréal
Canada	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke
Czechia	FN Brno	Brno
Czechia	St. Anne's University Hospital Brno, International Clinical Research Center	Brno
Czechia	IKEM	Prague
Czechia	University Hospital Motol - Cardiology	Prague
Czechia	FN Kralovske Vinohrady	Praha
Czechia	VFN v Praze II. Interní klinika - Kardiologie a angiologie	Praha
Czechia	Masarykova nemocnice - Kardiologie Krajská zdravotní, a.s.	Ústí nad Labem
Germany	Universitäts Herzzentrum Freiburg-Bad Krozingen Klinik für Kardiologie und Angiologie II	Bad Krozingen
Germany	Charité Universitätsmedizin Berlin - CVK Medizinische Klinik m.S. Kardiologie	Berlin
Germany	Klinikum Bielefeld Klinik für Kardiologie/internist. Intensivmedizin	Bielefeld
Germany	Klinikum Coburg GmbH II.Med.Klinik	Coburg
Germany	Klinik für Innere Medizin I	Dortmund
Germany	University Clinic Duesseldorf Clinic for Cardiology, Pneumology and Angiology	Duesseldorf
Germany	Universitäres Herzzentrum Hamburg Kardiologie mit Schwerpunkt Elektrophysiologie	Hamburg
Germany	University Hospital of Heidelberg Clinic of Cardiology, Angiology and Pneumology	Heidelberg
Germany	Herzzentrum Leipzig - Universitätsklinik Abteilung für Rhythmologie	Leipzig
Germany	Univ. of Muenster.Cardiovascular Medicine	Muenster
Germany	Universitätsmedizin Rostock Zentrum für Innere Medizin I, Kardiologie	Rostock
Germany	Deutsches Herzk. Universitätsklinikum Tübingen Medizinische Klinik III. Kardiologie	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik I	Wuerzburg
Hungary	Magyar Honvédség Egészségügyi Központ Kardiológiai Osztály	Budapest
Hungary	Semmelweis Egyetem Városmajori Szív- és Érgyógyászati Klinika	Budapest
Hungary	Debreceni Egyetem Kardiológiai és Szívsebészeti Klinika	Debrecen
Hungary	Pecs University Clinical Center	Pécs
Hungary	Szegedi Tudományegyetem II. Belgyógyászati Klnika és Kardiológiai Központ	Szeged
Hungary	Zala Megyei Szent Rafael Kórház Kardiológia Osztály	Zalaegerszeg
Italy	Ospedale San Donato	Arezzo
Italy	Pineta Grande Hospital	Castel Volturno
Italy	Universita' degli Studi Catanzaro	Catanzaro
Italy	Arcispedale Sant'Anna	Cona
Italy	Azienda USL Toscana	Firenze
Italy	Ospedale della Misericordia	Grosseto
Italy	Ospedale dell'Angelo	Mestre
Italy	ASST Vimercate	Monza
Italy	Ospedale Santo Cuore	Negrar
Italy	Istituto di Cura cittè di Pavia	Pavia
Italy	Azienda Ospedaliera di Piacenza "Ospedale Guglielmo d Saliceto"	Piacenza
Italy	Policlinico Casilino	Roma
Italy	Largo Agostino Gemelli	Rome
Italy	Ospedale Ecclesiastico "Miulli"	Sant'Eramo
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul	Seoungbuk-gu
Korea, Republic of	Samsung Medical Center	Seoul	Gangnam-gu
Korea, Republic of	Seoul National University Hospital	Seoul	Jongno-gu
Korea, Republic of	Yonsei University Severance Hospital	Seoul	Seodaemun-Gu
Poland	University Hospital - Szpital Uniwersytecki	Kraków
Poland	Klinika Intensywnej Terapii Kardiologicznej	Lódz
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 4 Klinika Kardiologii	Lublin
Poland	Oddzial Kardiologii Szpital Grochowski im. dr R. Masztaka SPZOZ	Warszawa
Poland	Oddzial Kliniczny Kardiologii SUM Katedra Kardiologii	Zabrze
Spain	Hospital General Universitario	Alicante
Spain	Hospital Clinic Cardiologia	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario San Juan de Alicante	San Juan de Alicante
Taiwan	Chang Gung Memorial Hospital	Kaohsiung City
Taiwan	China Medical University Hospital	Taichung City
Taiwan	Taichung Veterans General Hospital (VGH-TC)	Taichung City
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital	Taoyuan City
United Kingdom	Blackpool Teaching Hospitals NHS	Blackpool
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Papworth Hospital NHS Trust	Cambridge
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	King's College Hospital	London
United Kingdom	Nottingham City Hospital	Nottingham

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

Countries where clinical trial is conducted

Belgium,  Canada,  Czechia,  Germany,  Hungary,  Italy,  Korea, Republic of,  Poland,  Spain,  Taiwan,  United Kingdom, 

References & Publications (8)

Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Natale A, Packer D, Skanes A, Ambrogi F, Biganzoli E. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol. 2010 Feb;3(1):32-8. doi: 10.1161/CIRCEP.109.859116. Epub 2009 Dec 7. — View Citation

Cappato R, Marchlinski FE, Hohnloser SH, Naccarelli GV, Xiang J, Wilber DJ, Ma CS, Hess S, Wells DS, Juang G, Vijgen J, Hügl BJ, Balasubramaniam R, De Chillou C, Davies DW, Fields LE, Natale A; VENTURE-AF Investigators. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J. 2015 Jul 21;36(28):1805-11. doi: 10.1093/eurheartj/ehv177. Epub 2015 May 14. — View Citation

Chen J, Todd DM, Hocini M, Larsen TB, Bongiorni MG, Blomström-Lundqvist C; Scientific Initiative Committee, European Heart Rhythm Association. Current periprocedural management of ablation for atrial fibrillation in Europe: results of the European Heart Rhythm Association survey. Europace. 2014 Mar;16(3):378-81. doi: 10.1093/europace/euu043. — View Citation

Crawford T, Oral H. Current status and outcomes of catheter ablation for atrial fibrillation. Heart Rhythm. 2009 Dec;6(12 Suppl):S12-7. doi: 10.1016/j.hrthm.2009.07.026. Epub 2009 Oct 23. Review. — View Citation

Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19. — View Citation

Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013 Oct 10;369(15):1406-15. doi: 10.1056/NEJMoa1306638. Epub 2013 Aug 31. Erratum in: N Engl J Med. 2014 Jan 23;370(4):390. — View Citation

Hussein AA, Martin DO, Saliba W, Patel D, Karim S, Batal O, Banna M, Williams-Andrews M, Sherman M, Kanj M, Bhargava M, Dresing T, Callahan T, Tchou P, Di Biase L, Beheiry S, Lindsay B, Natale A, Wazni O. Radiofrequency ablation of atrial fibrillation under therapeutic international normalized ratio: a safe and efficacious periprocedural anticoagulation strategy. Heart Rhythm. 2009 Oct;6(10):1425-9. doi: 10.1016/j.hrthm.2009.07.007. Epub 2009 Jul 10. — View Citation

Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace. 2016 Nov;18(11):1609-1678. Epub 2016 Aug 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Participants Undergoing Catheter Ablation (Adjudicated Data)	Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction >24 hours (h), duration of neurological dysfunction <24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death.; Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of >2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.	Day 1 to Day 90
Primary	Number of Participants Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)	Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of >2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.	Day 1 to Day 90
Secondary	Number of Participants Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)	An alternative definition characterized stroke (ischemic, hemorrhagic, or undetermined) as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that was not due to an identifiable nonvascular cause (ie, brain tumor or trauma), and that either lasted at least 24 hours or resulted in death within 24 hours of onset.; Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of >2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.	Day 1 to Day 90
Secondary	Number of Participants Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)	Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction >24 hours (h), duration of neurological dysfunction <24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death.; SEE was defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system, coronary, and pulmonary arterial circulation.; CV mortality was defined as cardiac or vascular death according to Academic Research Consortium.	Day 1 to Day 90