Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in AF (BRAIN-AF)

Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in AF (BRAIN-AF)

This is a prospective, multicenter, randomized, double-blinded clinical trial exploring the efficacy and safety of rivaroxaban as compared to standard of care in reducing stroke, transient ischemic attack (TIA) and neurocognitive decline, in subjects with non-valvular AF and with low risk of stroke.

Study Overview

• Status: Terminated
• Conditions: ATRIAL FIBRILLATION
• Intervention / Treatment: Other: standard of care; Drug: Rivaroxaban

Detailed Description

Subjects who qualify will be approached and those consenting will be enrolled to undergo a baseline evaluation. Subjects without a clinical diagnosis of dementia and with a Mini Mental State Examination score (MMSE) score ≥ 25 will undergo neurocognitive assessment (MoCA), psychosocial and QoL assessment before randomization.

Subjects will undergo regular visits (in-clinic, and/or by phone, or video conferencing) every 6 months during the treatment period. Subjects will take either rivaroxaban 15 mg or standard of care.

An independent clinical event committee will classify all endpoint events. An independent Data Safety Monitoring Committee (DSMC) was established to monitor the progress of the study and assure the safety of subjects enrolled in the trial.

• Study Type: Interventional
• Enrollment (Actual): 1238
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Isabelle Robert, M.Sc; Phone Number: 2037 514-461-1300; Email: Isabelle.Robert@mhicc.org

Study Locations

• Canada
  • Quebec, Canada
    • Institut universitaire de Cardiologie et de Pneumologie de Quebec
  • Quebec, Canada
    • CHU de Quebec-Universite Laval/Hotel Dieu de Quebec
  • Alberta
    • Calgary, Alberta, Canada
      • CardiAI Inc.
    • Calgary, Alberta, Canada
      • Libin Cardiovascular Institute of Alberta
    • Edmonton, Alberta, Canada
      • University of Alberta
  • British Columbia
    • Abbotsford, British Columbia, Canada, V5Z 1M9
      • Office of Dr. TunZan Maung, MD
    • North Vancouver, British Columbia, Canada
      • North Shore Heart Center
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital/UBC
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • St. Boniface Hospital
    • Winnipeg, Manitoba, Canada
      • Cardio 1
  • New Brunswick
    • Moncton, New Brunswick, Canada
      • Dr. Georges-L - Dumont University Hospital Center
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • QEll Health Sciences Center-Halifax Infirmary
  • Onatrio
    • London, Onatrio, Canada
      • Western University - London Health Sciences Centre
    • Newmarket, Onatrio, Canada
      • PACE (Partners in Advanced Cardiac Evaluation)
    • Oakville, Onatrio, Canada
      • Oakville Cardiovascular Research LP
  • Ontario
    • Cambridge, Ontario, Canada
      • Cambridge Cardiac Care Center
    • Cambridge, Ontario, Canada
      • Vizel Cardiac Research
    • Hamilton, Ontario, Canada
      • McMaster University
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences - General Site
    • Kitchener, Ontario, Canada
      • St. Mary's General Hospital
    • Kitchener, Ontario, Canada
      • Cardiology Clinic
    • Mississauga, Ontario, Canada
      • One Heart Care
    • Ottawa, Ontario, Canada
      • University of Ottawa Heart Institute
    • Toronto, Ontario, Canada
      • St. Michael's Hospital
  • Quebec
    • Brossard, Quebec, Canada
      • Viacar Recherche Clinique Inc.
    • Chicoutimi, Quebec, Canada
      • CIUSSS du Saguenay-Lac-Saint-Jean
    • Granby, Quebec, Canada
      • CIUSSS de l'Estrie-CHUS-Centre Haute-Yamaska (Hopital de Granby)
    • Greenfield Park, Quebec, Canada
      • CISSSMC-Hopital Charles-Lemoyne
    • Greenfield Park, Quebec, Canada
      • Viacar Recherche Clinique Inc.
    • Laval, Quebec, Canada
      • Hopital de la Cite-de-la-Sante
    • Levis, Quebec, Canada
      • Clinique Cardiologie de Levis
    • Montreal, Quebec, Canada
      • McGill University Health Center
    • Montreal, Quebec, Canada
      • CHUM
    • Montreal, Quebec, Canada
      • Montreal Heart Institute
    • Montreal, Quebec, Canada
      • Hopital Du Sacre Coeur de Montreal
    • Montreal, Quebec, Canada, H1T1C8
      • Montreal Heart Institute
    • Rimouski, Quebec, Canada
      • CISSS BSL-Hopital de Rimouski
    • Saint-Jerome, Quebec, Canada
      • CISSS des Laurentides-Unite de recherche clinique
    • Sherbrooke, Quebec, Canada
      • CIUSSS de l'Estrie-CHUS
    • Terrebonne, Quebec, Canada
      • CISSS de Lanaudiere-Hopital Pierre-Le Gardeur
    • Trois-Rivières, Quebec, Canada
      • CIUSSS MCQ CHAUR- Centre Hospitalier regional de Trois-Rivieres

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

For entry into the study, the following criteria must be met:

Inclusion Criteria:

• Age at consent ≥30 to ≤62 years;
• Non-valvular atrial fibrillation (paroxysmal, persistent or permanent) documented by any electrical tracing or any device (i.e. routine 12-lead electrocardiogram, Holter monitor [continuous ECG recording] rhythm strip, intracardiac electrogram, or pacemaker or implantable cardiac defibrillator interrogation of at least 30 s, transcutaneous monitoring or other) in the last 2 years;

• Low risk of stroke as defined by the absence of all of the following:

  i. Prior stroke or Transient Ischemic Attack, ii. Hypertension, iii. Diabetes mellitus, iv. Congestive heart failure (New York Heart Association class II or higher at the time of enrolment or a known left ventricular ejection fraction <35%);

• Signed informed consent

For entry into the study, none of the following criteria MUST be met

Exclusion Criteria:

• Known diagnosis of dementia;
• MMSE score <25;
• Valvular AF [mechanical heart valve, moderate to severe mitral stenosis (rheumatic or non rheumatic), or hypertrophic cardiomyopathy];
• Other indication for antiplatelet therapy or anticoagulation;
• History of GI bleeding;

• Conditions associated with an increased risk of bleeding described as follows:

  1. Major surgery within the previous month;
  2. Planned surgery or intervention within the next 3 months;
  3. History of intracranial, intraocular, spinal, retroperitoneal or a traumatic intra-articular bleeding;
  4. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days;
  5. Haemorrhagic disorder or bleeding diathesis;
  6. Fibrinolytic agents within 48 hours of study entry;
  7. Recent malignancy or radiation therapy (within 6 months from the time of enrolment) and not expected to survive 3 years;
• Reversible cause of AF (e.g. cardiac surgery, pulmonary embolism, untreated hyperthyroidism);
• Absence of recurrence of AF 3 months after AF ablation;
• Severe renal impairment (creatinine clearance 30 mL/min or less);
• Active infective endocarditis;
• Active liver disease (e.g. acute clinical hepatitis, chronic active hepatitis, cirrhosis), or Alanine Transaminase (ALT) >3 times the upper limit of normal;
• Women who are pregnant or of childbearing potential not using a medically acceptable form of contraception throughout the study;
• Women who are breastfeeding;
• Anemia or thrombocytopenia (according to the normal range values of the local laboratory);
• Participation in another study involving an investigational drug (under development) at the same time or within 30 days of randomization;
• Subjects considered unreliable, or having a life expectancy of less than 3 years or having any condition which, in the opinion of the investigator, would not allow safe participation in the study (e.g. drug addiction, alcohol abuse);
• History of allergic reaction to rivaroxaban.
• History of allergic reaction, in the absence of desensitization to acetylsalicylic acid in patients with vascular disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rivaroxaban; Rivaroxaban 15 mg, orally, once daily, preferably at the same time of the day throughout the study.	Drug: Rivaroxaban; 15 mg; Other Names: Xarelto
Active Comparator: standard of care	Other: standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of stroke, TIA and neurocognitive decline. Neurocognitive decline is defined by a decrease in the MoCA score greater than or equal to 2 at any follow-up visit from baseline.	From date of randomization until the date of first documented occurrence of any component of the composite, assessed up to the end of the study	estimated up to 84 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death (total and cardiovascular)	From date of randomization until the date of first documented death (total and cardiovascular), assessed up to the end of the study	estimated up to 84 months
Composite including stroke/transient ischemic attack (TIA) and systemic embolic events	From date of randomization until the date of first documented composite including stroke/transient ischemic attack (TIA) and systemic embolic events, assessed up to the end of the study	estimated up to 84 months
Neurocognitive decline	From date of randomization until the date of first documented neurocognitive decline, assessed up to the end of the study. First occurrence of decrease in MoCA score ≥2 at any follow up visit from baseline.	estimated up to 84 months
Hospitalization for cardiovascular (myocardial infarction, heart failure, AF, stroke or unstable angina or other cardiovascular events) or bleeding event	From date of randomization until the date of first documented hospitalization for cardiovascular (myocardial infarction, heart failure, AF, stroke, other cardiovascular events or bleeding event, assessed up to the end of the study. Hospitalization is defined as an admission to an inpatient unit or a visit to an emergency department that results in at least a 24 hour stay	estimated up to 84 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major clinical bleeding event	From date of randomization until the date of first documented major clinical bleeding event, assessed up to the end of the study. First occurrence of bleeding events consider as major or requiring hospitalization. Bleeding will be defined in accordance with the International Society on Thrombosis and Haemostasis (ISTH).	estimated up to 84 months

Collaborators and Investigators

• Sponsor: Montreal Heart Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); The Montreal Health Innovations Coordinating Center (MHICC); Bayer Healthcare Pharmaceuticals, Inc./Bayer Schering Pharma; Canadian Stroke Prevention Intervention Network; Montreal Heart Institute Foundation; Hewitt Foundation
• Investigators: Principal Investigator: Lena Rivard, MD, Montreal Heart Institute; Study Director: Sophie Tanguay, M.Sc., Montreal health Innovations Coordinating Centre

Publications and helpful links

General Publications

• Rivard L, Khairy P, Talajic M, Tardif JC, Nattel S, Bherer L, Black S, Healey J, Lanthier S, Andrade J, Massoud F, Nault I, Guertin MC, Dorian P, Kouz S, Essebag V, Ellenbogen KA, Wyse G, Racine N, Macle L, Mondesert B, Dyrda K, Tadros R, Guerra P, Thibault B, Cadrin-Tourigny J, Dubuc M, Roux JF, Mayrand H, Greiss I, Roy D. Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF): Methods and Design. Can J Cardiol. 2019 Aug;35(8):1069-1077. doi: 10.1016/j.cjca.2019.04.022. Epub 2019 May 7.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): December 1, 2023
• Study Completion (Actual): December 1, 2023

Study Registration Dates

• First Submitted: February 26, 2015
• First Submitted That Met QC Criteria: March 6, 2015
• First Posted (Estimated): March 12, 2015

Study Record Updates

• Last Update Posted (Estimated): December 14, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Stroke; Atrial Fibrillation; Rivaroxaban; Anticoagulation; Acetylsalicylic acid; Neurocognitive decline; Montreal Cognitive Assesssment (MoCA); Mini-Mental State Examination (MMSE)
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Stroke; Ischemic Stroke; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: BRAIN-001