Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in 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.

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.

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.